Alzheimer’s Disease | Leaders in Pharmaceutical Business Intelligence Group, LLC, Doing Business As LPBI Group, Newton, MA

Archive for the ‘Alzheimer’s Disease’ Category

The Vibrant Philly Biotech Scene: Focus on Vaccines and Philimmune, LLC

Posted in Advanced Drug Manufacturing Technology, BioSimilars, Cancer and Current Therapeutics, Cancer Prevention: Research & Programs, Disease Biology, Small Molecules in Development of Therapeutic Drugs, Etiology, FDA, FDA Regulatory Affairs, Health Economics and Outcomes Research, Healthcare costs and reimbursement, Human Immune System in Health and in Disease, Immunodiagnostics, Infectious Disease & New Antibiotic Targets, Infectious Disease Immunodiagnostics, Innovation in Immunology Diagnostics, Innovations, Interviews with Scientific Leaders, Investment in Technological Breakthrough, Pharmaceutical Drug Discovery, Pharmaceutical R&D Investment, tagged @Biotech News, biotech startup, Biotechnology, breast cancer, Cancer - General, cervical cancer, Clinical trial, Conditions and Diseases, Drug development, Food and Drug Administration, health, immune activation, Infectious disease, medicine, Merck & Co Inc, philadelphia, Regulatory science, vaccines on December 10, 2014| Leave a Comment »

The Vibrant Philly Biotech Scene: Focus on Vaccines and Philimmune, LLC

Curator: Stephen J. Williams, Ph.D

Article ID #163: The Vibrant Philly Biotech Scene: Focus on Vaccines and Philimmune, LLC. Published on 12/10/2014

WordCloud Image Produced by Adam Tubman

I am intending to do a series of posts highlighting interviews with Philadelphia area biotech startup CEO’s and show how a vibrant biotech startup scene is evolving in the city as well as the Delaware Valley area. Philadelphia has been home to some of the nation’s oldest biotechs including Cephalon, Centocor, hundreds of spinouts from a multitude of universities as well as home of the first cloned animal (a frog), the first transgenic mouse, and Nobel laureates in the field of molecular biology and genetics. Although some recent disheartening news about the fall in rankings of Philadelphia as a biotech hub and recent remarks by CEO’s of former area companies has dominated the news, biotech incubators like the University City Science Center and Bucks County Biotechnology Center as well as a reinvigorated investment community (like PCCI and MABA) are bringing Philadelphia back. And although much work is needed to bring the Philadelphia area back to its former glory days (including political will at the state level) there are many bright spots such as the innovative young companies as outlined in these posts.

First up I got to talk with Florian Schodel, M.D., Ph.D., CEO of Philimmune, which provides expertise in medicine, clinical and regulatory development and analytical sciences to support successful development and registration of vaccines and biologics. Before founding Philimmune, Dr. Schodel was VP in Vaccines Clinical Research of Merck Research Laboratories and has led EU vaccine clinical trials and the clinical development of rotavirus, measles, mumps, hepatitis B, and rubella vaccines. In addition Dr. Schodel and Philimmune consult on several vaccine development efforts at numerous biotech companies including:

\His specialties and services include: vaccines and biologics development strategy, clinical development, clinical operations, strategic planning and alliances, international collaborations, analytical and assay development, project and portfolio integration and leadership.

Successful development of vaccines and biologics poses some unique challenges: including sterile manufacturing and substantial early capital investment before initiated clinical trials, assay development for clinical trial support, and unique trail design. Therefore vaccines and biologics development is a highly collaborative process between several disciplines.

The Philadelphia area has a rich history in vaccine development including the discovery and development of the rubella, cytomegaolovirus, a rabies, and the oral polio vaccine at the Wistar Institute. Dr. Schodel answered a few questions on the state of vaccine development and current efforts in the Philadelphia area, including recent efforts by companies such as GSK’s efforts and Inovio’s efforts developing an Ebola vaccine.

In his opinion, Dr. Schodel believes our biggest hurdle in vaccine development in a societal issue, not a preclinic development issue. Great advances have been made to speed the discovery process and enhance quality assurance of manufacture capabilities like

Making targets more immunogenic
Development strategies like “reverse vaccinology”

however there has not been a great history or support for developing vaccines for the plethora of infectious diseases seen in the developing world. As Dr. Schodel pointed out, there are relatively few players in the field, and tough to get those few players excited for investing in new targets.

However, some companies are rapidly expanding their vaccine portfolios including

GSK
Sanofi
Japanese companies are expanding their vaccine portfolios
Chinese companies are expanding their vaccine development efforts including for African-nation related diseases (see white paper on competition in China vaccine market)
Merck has supported hepatitis B vaccine distribution in China

Why haven’t 3^rd world countries developed their own vaccine programs?

Hard to find partners willing to invest and support development
Developing nations don’t have the money or infrastructure to support health programs
Doctors in these countries need to be educated on how to conduct trials, conduct vaccine programs like Gates Foundation does. For more information see Nature paper on obstacles to vaccine introduction in third world countries.

Lastly, Dr. Schodel touched on a growing area, cancer vaccine development. Recent advances in bladder cancer vaccine, cervical, and promising results in an early phase metastatic breast cancer vaccine trial and phase I oral cancer vaccine trial have reinvigorated this field of cancer vaccinology.

Historic Timeline of Vaccine Development

Graphic from http://en.pedaily.cn/Item.aspx?id=194125

Other posts on this site related to Biotech Startups in Philadelphia and some additional posts on infectious disease include:

RAbD Biotech Presents at 1st Pitch Life Sciences-Philadelphia

LytPhage Presents at 1st Pitch Life Sciences-Philadelphia

Hastke Inc. Presents at 1st Pitch Life Sciences-Philadelphia

1st Pitch Life Science- Philadelphia- What VCs Really Think of your Pitch

The History of Infectious Diseases and Epidemiology in the late 19th and 20th Century

Read Full Post »

Introduction to Impairments in Pathological States: Endocrine Disorders, Stress Hypermetabolism and Cancer

Posted in Alzheimer's Disease, Biochemical pathways, Biological Networks, Biomarkers & Medical Diagnostics, Bone Disease and Musculoskeletal Disease, Ca2+ triggered activation, Calcium Signaling, Cancer and Current Therapeutics, CANCER BIOLOGY & Innovations in Cancer Therapy, Cell Biology, Cerebrovascular and Neurodegenerative Diseases, Chemical Biology and its relations to Metabolic Disease, Clinical Diagnostics, Curation, Diabetes Mellitus, Disease Biology, Endocrine Diseases, Enzyme Induction, Frontiers in Cardiology and Cardiovascular Disorders, Gene Regulation, Gene Regulation and Evolution, Genome Biology, Hematology, Human Immune System in Health and in Disease, Innovations, Lipid metabolism, Metabolism, Metabolomics, Neurohumoral Transmission, Nutrition, Personalized and Precision Medicine & Genomic Research, Pharmaceutical Discovery, PKC, Proteins, Proteomics, RNA Biology, Signaling & Cell Circuits, Warburg effect, tagged Cancer - General, disease targets, inflammatory diseases, integrative therapeutics, Metabolism on November 8, 2014| Leave a Comment »

Introduction to Impairments in Pathological States: Endocrine Disorders, Stress Hypermetabolism and Cancer

Author and Curator: Larry H. Bernstein, MD, FCAP

This leads into a series of presentations and the metabolic imbalance central to findings of endocrine, metabolic, inflammatory, immune diseases and cancer. All of this has been a result of discoveries based on the methods of study of genomiocs, proteomics, transcriptomics, and metabolomics that have preceded this. In some cases there has been the use of knockout methods. The completion of the human genomic and other catalogues have been instrumental in the past few years. In all cases there has been a thorough guidance by a biological concept of mechanism based on gene expression, metabolic disturbance, signaling pathways, and up- or down- regulation of metabolic circuits. It is interesting to recall that a concept of metabolic circuits was not yet formulated at the time of the mid 20th century physiology, except perhaps with respect to the coagulation pathways, and to some extent, glycolysis, gluconeogenesis, the hexose monophosphate shunt, and mitochondrial respiration, which were linear strings of enzyme substrate reactions that intersected and that had flow restraints not then understood as to the complexity we now appreciate. We did know the importance of cytochrome c, the adenine and pyridine nucleotides, and the energy balance. Electron microscopy had opened the door to understanding the mechanism of contraction of skeletal muscle and myocardium, but it also opened the door to understanding kidney structure and function, explaining the “mesangium”. The first cardiac maker was discovered by Arthur Karmen in the serum alanine and aspartate aminotransferases, with a consequent differentiation between hepatic and myocardial damage. This was followed by lactic dehydrogenase and the H- and M-type isoenzymes in the 1960s, and in the next decade, by the MB-isoenzyme of creatine kinase. Troponins T and then I would not be introduced until the mid 1980s, and they have become a gold standard for the diagnosis of myocardial infarction.

In the 1980s we also saw the development of antiplatelet therapy that rapidly advanced interventional cardiology. But advances in surgical as well as medical intervention also proceeded as the understanding of the lipid metabolism was opened by the work of Brown and Goldstein, and UTSW Medical Campus, and major advances in treatment came at Baylor and UT Medical Center in Houston, and at the Cleveland Clinic. The next important advance came with the discovery of nitric oxide synthase role in endothelium and oxidative stress. The field of endocrinology saw advances as well for a solid period of 30 years in a comparable period for the adrenals, thyroid, and pituitary glands, and for the understanding of the male and female sex hormones, and discoveries in breast, ovarian, and prostate cancer. There were cancer markers, such as, CA125 and CA15-3, and PSA. This had more of an impact on timely surgical intervention, and if not that, post surgical followup. Despite a long time into the war on cancer, introduced by President Lynden Johnson, the fundamental knowledge needed was not sufficient. In the meantime, there were advances in the treatment of diabetes, with eventual introduction of the insulin pump for type I diabetes. The problem of Type 2 DM increased in prevalence, reaching into the childhood age group, with ascendent obesity. An epidemiological pattern of disease comorbidities was emergent. Our population has aged out, and with it we are seeing an increase in dementias, especially Alzheimer’s disease. But the knowledge of the brain has lagged far behind.

What follows is a series of chapters that address what has currently been advanced with repect to the alignment of our knowledge of the last decade and pharmacetical discovery. Pharmaceuticals were suitable for bacterial infections until the 1990s, when we saw the rise of resistance to penicillins and Vancomycin, and we had issues with gram negative enterobacter, salmonella, and E. coli strains. That has been and is a significant challenge. The elucidation of the gut microbiome in recent years will help to relieve this problem. The problem of the variety and different aggressive types of cancer has been another challenge. The door has been opened to better diagnostic tools with respsct to imaging and targeted biomarkers for localization. I am not dealing with imaging, which is not the subject here.

HLA targeting efficiency correlates with human T-cell response magnitude and with mortality from influenza A infection

From http://www.pnas.org – Sep 3, 2013 4:24 PM

Experimental and computational evidence suggests that HLAs preferentially bind

conserved regions of viral proteins, a concept we term “targeting efficiency,” and
that this preference may provide improved clearance of infection in several viral systems.

To test this hypothesis, T-cell responses to A/H1N1 (2009)

were measured from peripheral blood mononuclear cells
obtained from a household cohort study performed during the 2009–2010 influenza season.

We found that HLA targeting efficiency scores

significantly correlated with IFN-γ
enzyme-linked immunosorbent spot responses (P = 0.042, multiple regression).

A further population-based analysis found that

the carriage frequencies of the alleles with the lowest targeting efficiencies, A*24,
were associated with pH1N1 mortality (r = 0.37, P = 0.031) and
are common in certain indigenous populations in which
increased pH1N1 morbidity has been reported.

HLA efficiency scores and HLA use are associated with

CD8 T-cell magnitude in humans after influenza infection.

The computational tools used in this study may be useful predictors of

potential morbidity and identify immunologic differences of new variant influenza strains
more accurately than evolutionary sequence comparisons.

Population-based studies of the relative frequency of these alleles

in severe vs. mild influenza cases might advance clinical practices
for severe H1N1 infections among genetically susceptible populations.

A deeper look into cholesterol synthesis

By Swathi Parasuraman

The human body needs cholesterol to maintain membrane fluidity, and

it acts as a precursor molecule for several important biochemical pathways.

Its regulation requires strict control, as it can cause problems if it’s produced in excess. In 1964, Konrad Bloch received a Nobel Prize for his work elucidating the mechanisms of cholesterol synthesis. His work

eventually contributed to the discovery of statins, drugs used today to lower blood cholesterol levels.

The biosynthesis of cholesterol is a complex process with more than 20 steps. One of the first enzymes is

3-hydroxy-3-methylglutaryl-CoA reductase, also known as HMGCR, the main target of statins.

As links between intermediates in cholesterol synthesis and various diseases are being discovered continually, more information about the regulatory role of the post-HMGCR pathway is needed.

In a recent minireview in The Journal of Biological Chemistry, Laura Sharpe and Andrew Brown of the University of New South Wales describe

multiple ways various enzymes other than HMGCR
are implicated in the modulation of cholesterol synthesis.

One such enzyme is squalene monooxygenase, which, like HMGCR, can be destroyed

by the proteasome when cholesterol levels are high.

The minireview also explains how pathway intermediates

can have functions distinct from those of cholesterol.

For example, intermediate 7-dehydrocholesterol usually is converted to cholesterol by the enzyme DHCR7

but is also a vitamin D precursor.

To synthesize the enzymes necessary to make cholesterol,

SREBPs, short for sterol regulatory element binding proteins, have special functions.

Along with transcriptional cofactors, they activate gene expression

in response to low sterol levels and, conversely,
are suppressed when there is enough cholesterol around.

Additionally, SREBPs control production of

nicotinamide adenine dinucleotide phosphate, or NADPH,
which is the reducing agent required to carry out the different steps in the pathway.

Lipid carrier proteins also can facilitate cholesterol synthesis. One example is SPF, or supernatant protein factor,

which transfers substrate from an inactive to an active pool or
from one enzyme site to another.

Furthermore, translocation of several cholesterogenic enzymes

from the endoplasmic reticulum to other cell compartments can occur under various conditions,
thereby regulating levels and sites of intracellular cholesterol accumulation.

Immunology in the gut mucosa:

20 Feb 2013 by Kausik Datta, posted in Immunology, Science (Nature)

The human gut can be the scene for devastating conditions such as inflammatory bowel disease,

which arises through an improperly controlled immune response.

The gut is often the body’s first point of contact with microbes; every mouthful of food is accompanied by a cargo of micro-organisms that go on to encounter the mucosa, the innermost layer of the gut. Most microbes are destroyed by the harsh acidic environment in the stomach, but a hardy few make it through to the intestines.

The intestinal surface is covered with finger-like protrusions called villi,

whose primary function is the absorption of nutrients.

These structures and the underlying tissues

host the body’s largest population of immune cells.

Scattered along the intestinal mucosa are

dome-like structures called Peyer’s Patches.

These are enriched in lymphoid tissue, making them key sites for

coordinating immune responses to pathogens,
whilst promoting tolerance to harmless microbes and food.

The villi contain a network of blood vessels to transport nutrients from food to the rest of the body. Lymphatics

from both the Peyer’s Patches and the villi
drain into the mesenteric lymph nodes.

Within the villi is a network of loose connective tissue called the lamina propria, and

at the base of the villi are the crypts which host the stem cells that replenish the epithelium.

The epithelium together with its overlying mucus forms

a barrier against microbial invasion.

A mix of immune cells including T- and B-lymphocytes, macrophages, and dendritic cells are

embedded within the matrix of the Peyer’s Patches, .

A key function of the Peyer’s Patch is the sampling of antigens present in the gut. The Peyer’s Patch has a thin mucous layer and specialized phagocytic cells, called M-cells, which

transport material across the epithelial barrier via a process called transcytosis.

Dendritic cells extend dendrites between epithelial cells to sample antigens that are then

broken down and used for presenting to lymphocytes.

Sampling antigens in this way typically results in so-called tolerogenic activation, where

the immune system initiates an anti-inflammatory response.

With their cargo of antigens, these Dendritic Cells then

traffic to the T-cell zones of the Peyer’s Patch.

Upon encounter with specific T-cells, the Dendritic Cells

convert them into an immunomodulatory cell called regulatory T-cell or T-reg.

Defects in the function of these cells are associated with

inflammatory bowel disease in both animals and humans.

These T-regs migrate to lamina propria of the villi via the lymphatics. Here, the T-regs

secrete a molecule called Interleukin (IL)-10,
which exerts a suppressive action on immune cells within the lamina propria
and upon the epithelial layer itself.

IL10 is, therefore, critical in maintaining immune quiescence

and preventing unnecessary inflammation.

However, a breakdown in this process of immune homeostasis results in gut pathology and

when this occurs over a prolonged period and in an uncontrolled manner,
it can lead to inflammatory bowel disease.

Chemical, mechanical or pathogen-triggered barrier disruption

coupled with particular genetic susceptibilities may all combine to set off inflammation.

Epithelium coming into contact with bacteria

is activated, leading to bacterial influx.

Alarm molecules released by the epithelium

activates immune cells, and T-regs in the vicinity
scale down their IL10 secretion to enable an immune response to proceed.

Dendritic cells are also activated by this environment, and

start to release key inflammatory molecules,
such as IL6, IL12, and IL23.

Effector T-cells also appear on the scene and

these coordinate an escalation of the immune response
by secreting their own inflammatory molecules,
Tumor Necrosis Factor (TNF)-α, Interferon (IFN)-γ and IL17.

Soon after the effector T-cells are arrived, a voracious phagocyte called a neutrophil is recruited. Neutrophils are critical for the clearance of the bacteria. One weapon in the neutrophil armory is

the ability to undergo self-destruction.

This leaves behind a jumble of DNA saturated with enzymes, called the Neutrophil Extracellular Trap.

Although this can effectively destroy the bacterial invaders

and plug any breaches in the epithelial wall,
it also causes collateral damage to tissues.

Slowly the tide begins to turn and the bacterial invasion is repulsed. Any remaining neutrophils die off,

and are cleared by macrophages.

Epithelial integrity is restored by replacement of damaged cells with new ones from the intestinal crypts. Finally T-regs are recruited once again to calm the immune response.

Targeting the molecules involved in gut pathology is leading to

effective therapies for inflammatory bowel disease.

Notes:

T- and B-lymphocytes, Macrophages, and Dendritic Cells: These are all important immune effector cells. Macrophages and Dendritic cells are primary defence cells that can eat up (‘phagocytosis’) microbes and destroy them; they also can present parts of these microbes to lymphocytes. T-lymphocytes or T-cells help B-lymphocytes or B-cells recognize the antigen and form antibodies against it. Other types of T-cells can themselves kill microbes. All these cells also secrete various chemical substances, called cytokines and chemokines, which act as molecular messengers in recruiting various immune cells, coordinating and fine-tuning the immune response. Some of these cytokines are called Interleukins, shortened to IL.

Anti-inflammatory response: A type of immune response in which molecular messengers are used to scale down heavy-handed immune cell activity and switch off processes that recruit immune cells. This helps the body recognize and selectively tolerate beneficial substances such as commensalic microbes that live in the gut.

Neutrophils: These are highly versatile immune effector cells. Usually, they are one of the first cells recruited to the site of infection or tissue damage via message spread by molecular messengers. Neutrophils can themselves elaborate cytokines and chemokines, and have the ability to directly kill microbes.

Oxazoloisoindolinones with in vitro antitumor activity selectively activate a p53-pathway through potential inhibition of the p53-MDM2 interaction.

J Soares, et al. Eur J Pharm Sci 10/2014; http://dx.doi.org:/10.1016/j.ejps.2014.10.006

An appealing target for anticancer treatment is

the p53 tumor suppressor protein.

This protein is inactivated in half of human tumors

due to endogenous negative regulators such as MDM2.

Therefore, restoring the p53 activity through

the inhibition of its interaction with MDM2
is considered a valuable therapeutic strategy
against cancers with a wild-type p53 status.

We report the synthesis of nine enantiopure phenylalaninol-derived oxazolopyrrolidone lactams

and the evaluation of their biological effects as p53-MDM2 interaction inhibitors.

Using a yeast-based screening assay, two oxazoloisoindolinones,

were identified as potential p53-MDM2 inhibitors.

The molecular mechanism of oxazoloisoindolinone 3a validated

in human colon adenocarcinoma HCT116 cells with wild-type p53 (HCT116 p53(+/+)) and
in its isogenic derivative without p53 (HCT116 p53(-/-)).

we demonstrated that oxazoloisoindolinone 3a exhibited

a p53-dependent in vitro antitumor activity through
induction of G0/G1-phase cell cycle arrest and apoptosis.

The selective activation of a p53-apoptotic pathway by oxazoloisoindolinone 3a was further supported

by the occurrence of PARP cleavage only in p53-expressing HCT116 cells.

Oxazoloisoindolinone 3a led

to p53 protein stabilization
to the up-regulation of p53 transcriptional activity &
increased expression levels of several p53 target genes,
as p21, MDM2, BAX and PUMA,
in p53(+/+) but not in p53(-/-) HCT116 cells.

the ability of oxazoloisoindolinone 3a to block the p53-MDM2 interaction in HCT116 p53(+/+) cells was confirmed by co-immunoprecipitation.

molecular docking analysis of the interactions

between the compounds and MDM2 revealed that
oxazoloisoindolinone 3a binds to MDM2.

this work adds the oxazoloisoindolinone scaffold to the activators of a wild-type p53-pathway with promising antitumor activity.

it may open the way to the development of

a new class of p53-MDM2 interaction inhibitors.

TrypanoCyc: a community-led biochemical pathways database for Trypanosoma brucei.

Sanu Shameer, et al. Nucleic Acids Research10/2014;
http://dx.doi.org/10.1093/nar/gku944

The metabolic network of a cell represents the catabolic and anabolic reactions that interconvert small molecules (metabolites) through the activity of enzymes, transporters and non-catalyzed chemical reactions. Our understanding of individual metabolic networks is increasing as we learn more about the enzymes that are active in particular cells under particular conditions and as technologies advance to allow detailed measurements of the cellular metabolome.

Metabolic network databases are important in allowing us to

contextualise data sets emerging from transcriptomic, proteomic and metabolomic experiments.

Here we present a dynamic database, TrypanoCyc (http://www.metexplore.fr/trypanocyc/), which describes

the generic and condition-specific metabolic network of Trypanosoma brucei, a parasitic protozoan
responsible for human and animal African trypanosomiasis.

In addition to enabling navigation through the BioCyc-based TrypanoCyc interface, we have implemented a network

representation of the information through MetExplore,

yielding a novel environment in which to visualise the metabolism of this important parasite.

Read Full Post »

Summary of Signaling and Signaling Pathways

Posted in Academic Publishing, Alzheimer's Disease, Best evidence, Biochemical pathways, Bone Disease and Musculoskeletal Disease, Ca2+ triggered activation, Calcium Signaling, Calmodulin Kinase and Contraction, Cardiac muscle regeneration, Cardiomyopathy, Cardiovascular Research, Cerebrovascular and Neurodegenerative Diseases, Chemical Biology and its relations to Metabolic Disease, Curation, Cytoskeleton, Developmental biology, Dialectic, Discovery process, Disease Biology, Electrophysiology, Endocrine Diseases, Enzyme Induction, Epigenetics and Cardiovascular Risks, Experimental validation, Explanatory, Fatty acids, Frontiers in Cardiology and Cardiovascular Disorders, Gene Regulation, Genomic Expression, Human Immune System in Health and in Disease, Inferential analysis, Kinase, Lipid metabolism, Lipids, Mechanical Assist Devices: LVAD, Metabolism, Metabolomics, Mg++, MS, Mutant Gene Expression, Myocardial Metabolism, Neurohumoral Transmission, Neurological Diseases, Nitric Oxide in Health and Disease, Nutrition, Nutritional Supplements: Atherogenesis, Pharmaceutical Analytics, Pharmaceutical Discovery, Pharmaceutical R&D Investment, Pharmacodynamics and Pharmacokinetics, Phosphorylase, Phosphorylation, PKC, Population Health Management, Proteins, Proteomics, RNA Biology, Signaling, Signaling & Cell Circuits, Skeletal muscle regeneration, Small Molecules in Development of Therapeutic Drugs, Systemic Inflammatory Response Related Disorders, Transcriptomics, Translational Research, Translational Science, Ubiquitinylation, tagged Alzheimers Disease, a_b catenin, cell signaling, Cytoskeleton, Extracellular matrix, G-protein coupled receptors (GPCR), integrin, intracellular localization, myasthenia gravis, N-glycosylation, neuroendocrine signal, Neuroendocrine Transcriptome, nuclear receptor, Phosphorylation, protein signals, Receptor tyrosine kinases, second messenger, signaling, signaling cascades, transduction, Tyrosine Kinase, zinc on November 1, 2014| Leave a Comment »

Summary of Signaling and Signaling Pathways

Author and Curator: Larry H Bernstein, MD, FCAP

In the imtroduction to this series of discussions I pointed out JEDS Rosalino’s observation about the construction of a complex molecule of acetyl coenzyme A, and the amount of genetic coding that had to go into it. Furthermore, he observes – Millions of years later, or as soon as, the information of interaction leading to activity and regulation could be found in RNA, proteins like reverse transcriptase move this information to a more stable form (DNA). In this way it is easier to understand the use of CoA to make two carbon molecules more reactive.

acetylCoA

In the tutorial that follows we find support for the view that mechanisms and examples from the current literature, which give insight into the developments in cell metabolism, are achieving a separation from inconsistent views introduced by the classical model of molecular biology and genomics, toward a more functional cellular dynamics that is not dependent on the classic view. The classical view fits a rigid framework that is to genomics and metabolomics as Mendelian genetics if to multidimentional, multifactorial genetics. The inherent difficulty lies in two places:

Interactions between differently weighted determinants
A large part of the genome is concerned with regulatory function, not expression of the code

The goal of the tutorial was to achieve an understanding of how cell signaling occurs in a cell. Completion of the tutorial would provide

a basic understanding signal transduction and
the role of phosphorylation in signal transduction.

Regulation of the integrity of endothelial cell–cell contacts by phosphorylation of VE-cadherin

In addition – detailed knowledge of –

the role of Tyrosine kinases and
G protein-coupled receptors in cell signaling.

serine

threonine

protein kinase

We are constantly receiving and interpreting signals from our environment, which can come

in the form of light, heat, odors, touch or sound.

The cells of our bodies are also

constantly receiving signals from other cells.

These signals are important to

keep cells alive and functioning as well as
to stimulate important events such as
cell division and differentiation.

Signals are most often chemicals that can be found

in the extracellular fluid around cells.

These chemicals can come

from distant locations in the body (endocrine signaling by hormones), from
nearby cells (paracrine signaling) or can even
be secreted by the same cell (autocrine signaling).

Signaling molecules may trigger any number of cellular responses, including

changing the metabolism of the cell receiving the signal or
result in a change in gene expression (transcription) within the nucleus of the cell or both.

controlling the output of ribosomes.

To which I would now add..

result in either an inhibitory or a stimulatory effect

The three stages of cell signaling are:

Cell signaling can be divided into 3 stages:

Reception: A cell detects a signaling molecule from the outside of the cell.

Transduction: When the signaling molecule binds the receptor it changes the receptor protein in some way. This change initiates the process of transduction. Signal transduction is usually a pathway of several steps. Each relay molecule in the signal transduction pathway changes the next molecule in the pathway.

Response: Finally, the signal triggers a specific cellular response.

signal transduction

http://www.hartnell.edu/tutorials/biology/images/signaltransduction_simple.jpg

The initiation is depicted as follows:

Signal Transduction – ligand binds to surface receptor

Membrane receptors function by binding the signal molecule (ligand) and causing the production of a second signal (also known as a second messenger) that then causes a cellular response. These types of receptors transmit information from the extracellular environment to the inside of the cell.

by changing shape or
by joining with another protein
once a specific ligand binds to it.

Examples of membrane receptors include

G Protein-Coupled Receptors and

Understanding these receptors and identifying their ligands and the resulting signal transduction pathways represent a major conceptual advance.

Receptor Tyrosine Kinases.

intracellular signaling

http://www.hartnell.edu/tutorials/biology/images/membrane_receptor_tk.jpg

Intracellular receptors are found inside the cell, either in the cytopolasm or in the nucleus of the target cell (the cell receiving the signal).

Note that though change in gene expression is stated, the change in gene expression does not here imply a change in the genetic information – such as – mutation. That does not have to be the case in the normal homeostatic case.

This point is the differentiating case between what JEDS Roselino has referred as

a fast, adaptive reaction, that is the feature of protein molecules, and distinguishes this interaction from
a one-to-one transcription of the genetic code.

The rate of transcription can be controlled, or it can be blocked. This is in large part in response to the metabolites in the immediate interstitium.

This might only be

a change in the rate of a transcription or a suppression of expression through RNA.
Or through a conformational change in an enzyme

Swinging domains in HECT E3 enzymes

Since signaling systems need to be

responsive to small concentrations of chemical signals and act quickly,
cells often use a multi-step pathway that transmits the signal quickly,
while amplifying the signal to numerous molecules at each step.

Signal transduction pathways are shown (simplified):

Signal Transduction

Signal transduction occurs when an

extracellular signaling molecule activates a specific receptor located on the cell surface or inside the cell.
In turn, this receptor triggers a biochemical chain of events inside the cell, creating a response.
Depending on the cell, the response alters the cell’s metabolism, shape, gene expression, or ability to divide.
The signal can be amplified at any step. Thus, one signaling molecule can cause many responses.

In 1970, Martin Rodbell examined the effects of glucagon on a rat’s liver cell membrane receptor. He noted that guanosine triphosphate disassociated glucagon from this receptor and stimulated the G-protein, which strongly influenced the cell’s metabolism. Thus, he deduced that the G-protein is a transducer that accepts glucagon molecules and affects the cell. For this, he shared the 1994 Nobel Prize in Physiology or Medicine with Alfred G. Gilman.

Guanosine monophosphate structure

In 2007, a total of 48,377 scientific papers—including 11,211 e-review papers—were published on the subject. The term first appeared in a paper’s title in 1979. Widespread use of the term has been traced to a 1980 review article by Rodbell: Research papers focusing on signal transduction first appeared in large numbers in the late 1980s and early 1990s.

Signal transduction involves the binding of extracellular signaling molecules and ligands to cell-surface receptors that trigger events inside the cell. The combination of messenger with receptor causes a change in the conformation of the receptor, known as receptor activation.

This activation is always the initial step (the cause) leading to the cell’s ultimate responses (effect) to the messenger. Despite the myriad of these ultimate responses, they are all directly due to changes in particular cell proteins. Intracellular signaling cascades can be started through cell-substratum interactions; examples are the integrin that binds ligands in the extracellular matrix and steroids.

Integrin

Most steroid hormones have receptors within the cytoplasm and act by stimulating the binding of their receptors to the promoter region of steroid-responsive genes.

steroid hormone receptor

Various environmental stimuli exist that initiate signal transmission processes in multicellular organisms; examples include photons hitting cells in the retina of the eye, and odorants binding to odorant receptors in the nasal epithelium. Certain microbial molecules, such as viral nucleotides and protein antigens, can elicit an immune system response against invading pathogens mediated by signal transduction processes. This may occur independent of signal transduction stimulation by other molecules, as is the case for the toll-like receptor. It may occur with help from stimulatory molecules located at the cell surface of other cells, as with T-cell receptor signaling. Receptors can be roughly divided into two major classes: intracellular receptors and extracellular receptors.

Signal transduction cascades amplify the signal output

G protein-coupled receptors (GPCRs) are a family of integral transmembrane proteins that possess seven transmembrane domains and are linked to a heterotrimeric G protein. Many receptors are in this family, including adrenergic receptors and chemokine receptors.

Arrestin binding to active GPCR kinase (GRK)-phosphorylated GPCRs blocks G protein coupling

signal transduction pathways

Arrestin binding to active GPCR kinase (GRK)-phosphorylated GPCRs blocks G protein coupling

Signal transduction by a GPCR begins with an inactive G protein coupled to the receptor; it exists as a heterotrimer consisting of Gα, Gβ, and Gγ. Once the GPCR recognizes a ligand, the conformation of the receptor changes to activate the G protein, causing Gα to bind a molecule of GTP and dissociate from the other two G-protein subunits.

The dissociation exposes sites on the subunits that can interact with other molecules. The activated G protein subunits detach from the receptor and initiate signaling from many downstream effector proteins such as phospholipases and ion channels, the latter permitting the release of second messenger molecules.

Receptor tyrosine kinases (RTKs) are transmembrane proteins with an intracellular kinase domain and an extracellular domain that binds ligands; examples include growth factor receptors such as the insulin receptor.

insulin receptor and and insulin receptor signaling pathway (IRS)

To perform signal transduction, RTKs need to form dimers in the plasma membrane; the dimer is stabilized by ligands binding to the receptor.

RTKs

The interaction between the cytoplasmic domains stimulates the autophosphorylation of tyrosines within the domains of the RTKs, causing conformational changes.

Subsequent to this, the receptors’ kinase domains are activated, initiating phosphorylation signaling cascades of downstream cytoplasmic molecules that facilitate various cellular processes such as cell differentiation and metabolism.

Signal-Transduction-Pathway

As is the case with GPCRs, proteins that bind GTP play a major role in signal transduction from the activated RTK into the cell. In this case, the G proteins are

members of the Ras, Rho, and Raf families, referred to collectively as small G proteins.

They act as molecular switches usually

tethered to membranes by isoprenyl groups linked to their carboxyl ends.

Upon activation, they assign proteins to specific membrane subdomains where they participate in signaling. Activated RTKs in turn activate

small G proteins that activate guanine nucleotide exchange factors such as SOS1.

Once activated, these exchange factors can activate more small G proteins, thus

amplifying the receptor’s initial signal.

The mutation of certain RTK genes, as with that of GPCRs, can result in the expression of receptors that exist in a constitutively activate state; such mutated genes may act as oncogenes.

Integrin

Integrin

Integrin-mediated signal transduction

An overview of integrin-mediated signal transduction, adapted from Hehlgens et al. (2007).

Integrins are produced by a wide variety of cells; they play a role in

cell attachment to other cells and the extracellular matrix and
in the transduction of signals from extracellular matrix components such as fibronectin and collagen.

Ligand binding to the extracellular domain of integrins

changes the protein’s conformation,
clustering it at the cell membrane to
initiate signal transduction.

Integrins lack kinase activity; hence, integrin-mediated signal transduction is achieved through a variety of intracellular protein kinases and adaptor molecules, the main coordinator being integrin-linked kinase.

As shown in the picture, cooperative integrin-RTK signaling determines the

timing of cellular survival,
apoptosis,
proliferation, and
differentiation.

integrin-mediated signal transduction

Integrin signaling

ion channel

A ligand-gated ion channel, upon binding with a ligand, changes conformation

to open a channel in the cell membrane
through which ions relaying signals can pass.

An example of this mechanism is found in the receiving cell of a neural synapse. The influx of ions that occurs in response to the opening of these channels

induces action potentials, such as those that travel along nerves,
by depolarizing the membrane of post-synaptic cells,
resulting in the opening of voltage-gated ion channels.

RyR and Ca+ release from SR

An example of an ion allowed into the cell during a ligand-gated ion channel opening is Ca2+;

it acts as a second messenger
initiating signal transduction cascades and
altering the physiology of the responding cell.

This results in amplification of the synapse response between synaptic cells

by remodelling the dendritic spines involved in the synapse.

In eukaryotic cells, most intracellular proteins activated by a ligand/receptor interaction possess an enzymatic activity; examples include tyrosine kinase and phosphatases. Some of them create second messengers such as cyclic AMP and IP3,

cAMP

Inositol_1,4,5-trisphosphate.svg

the latter controlling the release of intracellular calcium stores into the cytoplasm.

Many adaptor proteins and enzymes activated as part of signal transduction possess specialized protein domains that bind to specific secondary messenger molecules. For example,

calcium ions bind to the EF hand domains of calmodulin,
allowing it to bind and activate calmodulin-dependent kinase.

calcium movement and RyR2 receptor

PIP3 and other phosphoinositides do the same thing to the Pleckstrin homology domains of proteins such as the kinase protein AKT.

Signals can be generated within organelles, such as chloroplasts and mitochondria, modulating the nuclear
gene expression in a process called retrograde signaling.

Recently, integrative genomics approaches, in which correlation analysis has been applied on transcript and metabolite profiling data of Arabidopsis thaliana, revealed the identification of metabolites which are putatively acting as mediators of nuclear gene expression.

http://fpls.com/unraveling_retrograde_signaling_pathways:_finding_candidate_signaling_molecules_via_metabolomics_and_systems_biology_driven_approaches

Systems Biology Approach Reveals Genome to Phenome Correlation in Type 2 Diabetes (plosone.org)
Gene Expression and Thiopurine Metabolite Profiling in Inflammatory Bowel Disease – Novel Clues to Drug Targets and Disease Mechanisms? (plosone.org)
Activation of the Jasmonic Acid Plant Defence Pathway Alters the Composition of Rhizosphere

Nutrients 2014, 6, 3245-3258; http://dx.doi.org:/10.3390/nu6083245

Omega-3 (ω-3) fatty acids are one of the two main families of long chain polyunsaturated fatty acids (PUFA). The main omega-3 fatty acids in the mammalian body are

α-linolenic acid (ALA), docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA).

Central nervous tissues of vertebrates are characterized by a high concentration of omega-3 fatty acids. Moreover, in the human brain,

DHA is considered as the main structural omega-3 fatty acid, which comprises about 40% of the PUFAs in total.

DHA deficiency may be the cause of many disorders such as depression, inability to concentrate, excessive mood swings, anxiety, cardiovascular disease, type 2 diabetes, dry skin and so on.

On the other hand,

zinc is the most abundant trace metal in the human brain.

There are many scientific studies linking zinc, especially

excess amounts of free zinc, to cellular death.

Neurodegenerative diseases, such as Alzheimer’s disease, are characterized by altered zinc metabolism. Both animal model studies and human cell culture studies have shown a possible link between

omega-3 fatty acids, zinc transporter levels and
free zinc availability at cellular levels.

Many other studies have also suggested a possible

omega-3 and zinc effect on neurodegeneration and cellular death.

Therefore, in this review, we will examine

the effect of omega-3 fatty acids on zinc transporters and
the importance of free zinc for human neuronal cells.

Moreover, we will evaluate the collective understanding of

mechanism(s) for the interaction of these elements in neuronal research and their
significance for the diagnosis and treatment of neurodegeneration.

Epidemiological studies have linked high intake of fish and shellfish as part of the daily diet to

reduction of the incidence and/or severity of Alzheimer’s disease (AD) and senile mental decline in

Omega-3 fatty acids are one of the two main families of a broader group of fatty acids referred to as polyunsaturated fatty acids (PUFAs). The other main family of PUFAs encompasses the omega-6 fatty acids. In general, PUFAs are essential in many biochemical events, especially in early post-natal development processes such as

cellular differentiation,
photoreceptor membrane biogenesis and
active synaptogenesis.

Despite the significance of these

two families, mammals cannot synthesize PUFA de novo, so they must be ingested from dietary sources. Though belonging to the same family, both

omega-3 and omega-6 fatty acids are metabolically and functionally distinct and have
opposing physiological effects. In the human body,
high concentrations of omega-6 fatty acids are known to increase the formation of prostaglandins and
thereby increase inflammatory processes [10].

the reverse process can be seen with increased omega-3 fatty acids in the body.

Many other factors, such as

thromboxane A2 (TXA2),
leukotriene
B4 (LTB4),
IL-1,
IL-6,
tumor necrosis factor (TNF) and
C-reactive protein,

which are implicated in various health conditions, have been shown to be increased with high omega-6 fatty acids but decreased with omega-3 fatty acids in the human body.

Dietary fatty acids have been identified as protective factors in coronary heart disease, and PUFA levels are known to play a critical role in

immune responses,
gene expression and
intercellular communications.

omega-3 fatty acids are known to be vital in

the prevention of fatal ventricular arrhythmias, and
are also known to reduce thrombus formation propensity by decreasing platelet aggregation, blood viscosity and fibrinogen levels

.Since omega-3 fatty acids are prevalent in the nervous system, it seems logical that a deficiency may result in neuronal problems, and this is indeed what has been identified and reported.

The main

In another study conducted with individuals of 65 years of age or older (n = 6158), it was found that

only high fish consumption, but
not dietary omega-3 acid intake,
had a protective effect on cognitive decline

In 2005, based on a meta-analysis of the available epidemiology and preclinical studies, clinical trials were conducted to assess the effects of omega-3 fatty acids on cognitive protection. Four of the trials completed have shown

a protective effect of omega-3 fatty acids only among those with mild cognitive impairment conditions.

A trial of subjects with mild memory complaints demonstrated

an improvement with 900 mg of DHA.

We review key findings on

the effect of the omega-3 fatty acid DHA on zinc transporters and the
importance of free zinc to human neuronal cells.

DHA is the most abundant fatty acid in neural membranes, imparting appropriate

fluidity and other properties,

and is thus considered as the most important fatty acid in neuronal studies. DHA is well conserved throughout the mammalian species despite their dietary differences. It is mainly concentrated

in membrane phospholipids at synapses and
in retinal photoreceptors and
also in the testis and sperm.

In adult rats’ brain, DHA comprises approximately

17% of the total fatty acid weight, and
in the retina it is as high as 33%.

DHA is believed to have played a major role in the evolution of the modern human –

in particular the well-developed brain.

Premature babies fed on DHA-rich formula show improvements in vocabulary and motor performance.

Analysis of human cadaver brains have shown that

people with AD have less DHA in their frontal lobe
and hippocampus compared with unaffected individuals

Furthermore, studies in mice have increased support for the

protective role of omega-3 fatty acids.

Mice administrated with a dietary intake of DHA showed

an increase in DHA levels in the hippocampus.

Errors in memory were decreased in these mice and they demonstrated

reduced peroxide and free radical levels,
suggesting a role in antioxidant defense.

Another study conducted with a Tg2576 mouse model of AD demonstrated that dietary

DHA supplementation had a protective effect against reduction in
drebrin (actin associated protein), elevated oxidation, and to some extent, apoptosis via
decreased caspase activity.

Zinc

Zinc is a trace element, which is indispensable for life, and it is the second most abundant trace element in the body. It is known to be related to

growth,
development,
differentiation,
immune response,
receptor activity,
DNA synthesis,
gene expression,
neuro-transmission,
enzymatic catalysis,
hormonal storage and release,
tissue repair,
memory,
the visual process

and many other cellular functions. Moreover, the indispensability of zinc to the body can be discussed in many other aspects, as

a component of over 300 different enzymes
an integral component of a metallothioneins
a gene regulatory protein.

Approximately 3% of all proteins contain

zinc binding motifs .

The broad biological functionality of zinc is thought to be due to its stable chemical and physical properties. Zinc is considered to have three different functions in enzymes;

catalytic,
coactive and

Indeed, it is the only metal found in all six different subclasses

of enzymes. The essential nature of zinc to the human body can be clearly displayed by studying the wide range of pathological effects of zinc deficiency. Anorexia, embryonic and post-natal growth retardation, alopecia, skin lesions, difficulties in wound healing, increased hemorrhage tendency and severe reproductive abnormalities, emotional instability, irritability and depression are just some of the detrimental effects of zinc deficiency.

Proper development and function of the central nervous system (CNS) is highly dependent on zinc levels. In the mammalian organs, zinc is mainly concentrated in the brain at around 150 μm. However, free zinc in the mammalian brain is calculated to be around 10 to 20 nm and the rest exists in either protein-, enzyme- or nucleotide bound form. The brain and zinc relationship is thought to be mediated

through glutamate receptors, and
it inhibits excitatory and inhibitory receptors.

Vesicular localization of zinc in pre-synaptic terminals is a characteristic feature of brain-localized zinc, and

its release is dependent on neural activity.

Retardation of the growth and development of CNS tissues have been linked to low zinc levels. Peripheral neuropathy, spina bifida, hydrocephalus, anencephalus, epilepsy and Pick’s disease have been linked to zinc deficiency. However, the body cannot tolerate excessive amounts of zinc.

The relationship between zinc and neurodegeneration, specifically AD, has been interpreted in several ways. One study has proposed that β-amyloid has a greater propensity to

form insoluble amyloid in the presence of
high physiological levels of zinc.

Insoluble amyloid is thought to

aggregate to form plaques,

which is a main pathological feature of AD. Further studies have shown that

chelation of zinc ions can deform and disaggregate plaques.

In AD, the most prominent injuries are found in

hippocampal pyramidal neurons, acetylcholine-containing neurons in the basal forebrain, and in
somatostatin-containing neurons in the forebrain.

All of these neurons are known to favor

rapid and direct entry of zinc in high concentration
leaving neurons frequently exposed to high dosages of zinc.

This is thought to promote neuronal cell damage through oxidative stress and mitochondrial dysfunction. Excessive levels of zinc are also capable of

inhibiting Ca2+ and Na+ voltage gated channels
and up-regulating the cellular levels of reactive oxygen species (ROS).

High levels of zinc are found in Alzheimer’s brains indicating a possible zinc related neurodegeneration. A study conducted with mouse neuronal cells has shown that even a 24-h exposure to high levels of zinc (40 μm) is sufficient to degenerate cells.

If the human diet is deficient in zinc, the body

efficiently conserves zinc at the tissue level by compensating other cellular mechanisms

to delay the dietary deficiency effects of zinc. These include reduction of cellular growth rate and zinc excretion levels, and

redistribution of available zinc to more zinc dependent cells or organs.

A novel method of measuring metallothionein (MT) levels was introduced as a biomarker for the

assessment of the zinc status of individuals and populations.

In humans, erythrocyte metallothionein (E-MT) levels may be considered as an indicator of zinc depletion and repletion, as E-MT levels are sensitive to dietary zinc intake. It should be noted here that MT plays an important role in zinc homeostasis by acting

as a target for zinc ion binding and thus
assisting in the trafficking of zinc ions through the cell,
which may be similar to that of zinc transporters

Zinc Transporters

Deficient or excess amounts of zinc in the body can be catastrophic to the integrity of cellular biochemical and biological systems. The gastrointestinal system controls the absorption, excretion and the distribution of zinc, although the hydrophilic and high-charge molecular characteristics of zinc are not favorable for passive diffusion across the cell membranes. Zinc movement is known to occur

via intermembrane proteins and zinc transporter (ZnT) proteins

These transporters are mainly categorized under two metal transporter families; Zip (ZRT, IRT like proteins) and CDF/ZnT (Cation Diffusion Facilitator), also known as SLC (Solute Linked Carrier) gene families: Zip (SLC-39) and ZnT (SLC-30). More than 20 zinc transporters have been identified and characterized over the last two decades (14 Zips and 8 ZnTs).

Members of the SLC39 family have been identified as the putative facilitators of zinc influx into the cytosol, either from the extracellular environment or from intracellular compartments (Figure 1).

The identification of this transporter family was a result of gene sequencing of known Zip1 protein transporters in plants, yeast and human cells. In contrast to the SLC39 family, the SLC30 family facilitates the opposite process, namely zinc efflux from the cytosol to the extracellular environment or into luminal compartments such as secretory granules, endosomes and synaptic vesicles; thus decreasing intracellular zinc availability (Figure 1). ZnT3 is the most important in the brain where

it is responsible for the transport of zinc into the synaptic vesicles of
glutamatergic neurons in the hippocampus and neocortex,

Figure 1: Subcellular localization and direction of transport of the zinc transporter families, ZnT and ZIP. Arrows show the direction of zinc mobilization for the ZnT (green) and ZIP (red) proteins. A net gain in cytosolic zinc is achieved by the transportation of zinc from the extracellular region and organelles such as the endoplasmic reticulum (ER) and Golgi apparatus by the ZIP transporters. Cytosolic zinc is mobilized into early secretory compartments such as the ER and Golgi apparatus by the ZnT transporters. Figures were produced using Servier Medical Art, http://www.servier.com/. http://www.hindawi.com/journals/jnme/2012/173712.fig.001.jpg

Figure 2: Early zinc signaling (EZS) and late zinc signaling (LZS). EZS involves transcription-independent mechanisms where an extracellular stimulus directly induces an increase in zinc levels within several minutes by releasing zinc from intracellular stores (e.g., endoplasmic reticulum). LSZ is induced several hours after an external stimulus and is dependent on transcriptional changes in zinc transporter expression. Components of this figure were produced using Servier Medical Art, http://www.servier.com/ and adapted from Fukada et al. [30].

omega-3 fatty acids in the mammalian body are

α-linolenic acid (ALA),
docosahexenoic acid (DHA) and
eicosapentaenoic acid (EPA).

In general, seafood is rich in omega-3 fatty acids, more specifically DHA and EPA (Table 1). Thus far, there are nine separate epidemiological studies that suggest a possible link between

increased fish consumption and reduced risk of AD
and eight out of ten studies have reported a link between higher blood omega-3 levels

DHA and Zinc Homeostasis

Many studies have identified possible associations between DHA levels, zinc homeostasis, neuroprotection and neurodegeneration. Dietary DHA deficiency resulted in

increased zinc levels in the hippocampus and
elevated expression of the putative zinc transporter, ZnT3, in the rat brain.

Altered zinc metabolism in neuronal cells has been linked to neurodegenerative conditions such as AD. A study conducted with transgenic mice has shown a significant link between ZnT3 transporter levels and cerebral amyloid plaque pathology. When the ZnT3 transporter was silenced in transgenic mice expressing cerebral amyloid plaque pathology,

a significant reduction in plaque load
and the presence of insoluble amyloid were observed.

In addition to the decrease in plaque load, ZnT3 silenced mice also exhibited a significant

reduction in free zinc availability in the hippocampus
and cerebral cortex.

Collectively, the findings from this study are very interesting and indicate a clear connection between

zinc availability and amyloid plaque formation,

thus indicating a possible link to AD.

DHA supplementation has also been reported to limit the following:

amyloid presence,
synaptic marker loss,
hyper-phosphorylation of Tau,
oxidative damage and
cognitive deficits in transgenic mouse model of AD.

In addition, studies by Stoltenberg, Flinn and colleagues report on the modulation of zinc and the effect in transgenic mouse models of AD. Given that all of these are classic pathological features of AD, and considering the limiting nature of DHA in these processes, it can be argued that DHA is a key candidate in preventing or even curing this debilitating disease.

In order to better understand the possible links and pathways of zinc and DHA with neurodegeneration, we designed a study that incorporates all three of these aspects, to study their effects at the cellular level. In this study, we were able to demonstrate a possible link between omega-3 fatty acid (DHA) concentration, zinc availability and zinc transporter expression levels in cultured human neuronal cells.

When treated with DHA over 48 h, ZnT3 levels were markedly reduced in the human neuroblastoma M17 cell line. Moreover, in the same study, we were able to propose a possible

neuroprotective mechanism of DHA,

which we believe is exerted through

a reduction in cellular zinc levels (through altering zinc transporter expression levels)
that in turn inhibits apoptosis.

DHA supplemented M17 cells also showed a marked depletion of zinc uptake (up to 30%), and

free zinc levels in the cytosol were significantly low compared to the control

This reduction in free zinc availability was specific to DHA; cells treated with EPA had no significant change in free zinc levels (unpublished data). Moreover, DHA-repleted cells had

low levels of active caspase-3 and
high Bcl-2 levels compared to the control treatment.

These findings are consistent with previous published data and further strengthen the possible

correlation between zinc, DHA and neurodegeneration.

On the other hand, recent studies using ZnT3 knockout (ZnT3KO) mice have shown the importance of

ZnT3 in memory and AD pathology.

For example, Sindreu and colleagues have used ZnT3KO mice to establish the important role of

ZnT3 in zinc homeostasis that modulates presynaptic MAPK signaling
required for hippocampus-dependent memory

Results from these studies indicate a possible zinc-transporter-expression-level-dependent mechanism for DHA neuroprotection.

Read Full Post »

Complex Models of Signaling: Therapeutic Implications

Posted in Academic Publishing, Alzheimer's Disease, Best evidence, Biological Networks, Gene Regulation and Evolution, Biomarkers & Medical Diagnostics, Bone Disease and Musculoskeletal Disease, Cancer and Current Therapeutics, Cell Biology, Signaling & Cell Circuits, Cerebrovascular and Neurodegenerative Diseases, Chemical Biology and its relations to Metabolic Disease, Curation, Cytoskeleton, Developmental biology, Disease Biology, Small Molecules in Development of Therapeutic Drugs, Drug Toxicity, Electrophysiology, Epigenetics and Cardiovascular Risks, Etiology, Experimental validation, Explanatory, Fatty acids, Frontiers in Cardiology and Cardiovascular Disorders, Gene Regulation, Human Immune System in Health and in Disease, Inferential analysis, Innovation in Immunology Diagnostics, Innovations in Neurophysiology & Neuropsychology, Kinase, Lipid metabolism, Liver & Digestive Diseases Research, Metabolism, Metabolomics, MS, Myocardial Ischemia, Neurodegenerative Diseases, Neurohumoral Transmission, Nitric Oxide in Health and Disease, Nutrition, Nutritional Supplements: Atherogenesis, lipid metabolism, Personalized and Precision Medicine & Genomic Research, Pharmaceutical Analytics, Pharmaceutical Discovery, Pharmacologic toxicities, Phosphorylation, Population Health Management, Proteins, Proteomics, Regenerative Biology and Medicine, Signaling, Signaling & Cell Circuits, Small Molecules in Development of Therapeutic Drugs, Translational Effectiveness, Translational Research, Translational Science, Ubiquitinylation, tagged Alzheimers Disease, Amyloid, B-type natriuretic peptide, cell differentiation, cell signaling, DHA, Extracellular matrix, Heart Failure, intracellular localization, multiple schlerosis, neuritogenesis, Omega-3 fatty acid, plasticity, prion protein, zinc on October 31, 2014| Leave a Comment »

Complex Models of Signaling: Therapeutic Implications

Curator: Larry H. Bernstein, MD, FCAP

Updated 6/24/2019

Fishy Business: Effect of Omega-3 Fatty Acids on Zinc Transporters and Free Zinc Availability in Human Neuronal Cells

Damitha De Mel and Cenk Suphioglu *

NeuroAllergy Research Laboratory (NARL), School of Life and Environmental Sciences, Faculty of Science, Engineering and Built Environment, Waurn Ponds, Victoria, Australia.

Nutrients 2014, 6, 3245-3258; http://dx.doi.org:/10.3390/nu6083245

Omega-3 (ω-3) fatty acids are one of the two main families of long chain polyunsaturated fatty acids (PUFA). The main omega-3 fatty acids in the mammalian body are

α-linolenic acid (ALA), docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA).

Central nervous tissues of vertebrates are characterized by a high concentration of omega-3 fatty acids. Moreover, in the human brain,

DHA is considered as the main structural omega-3 fatty acid, which comprises about 40% of the PUFAs in total.

DHA deficiency may be the cause of many disorders such as depression, inability to concentrate, excessive mood swings, anxiety, cardiovascular disease, type 2 diabetes, dry skin and so on.

On the other hand,

zinc is the most abundant trace metal in the human brain.

There are many scientific studies linking zinc, especially

excess amounts of free zinc, to cellular death.

Neurodegenerative diseases, such as Alzheimer’s disease, are characterized by altered zinc metabolism. Both animal model studies and human cell culture studies have shown a possible link between

omega-3 fatty acids, zinc transporter levels and
free zinc availability at cellular levels.

Many other studies have also suggested a possible

omega-3 and zinc effect on neurodegeneration and cellular death.

Therefore, in this review, we will examine

the effect of omega-3 fatty acids on zinc transporters and
the importance of free zinc for human neuronal cells.

Moreover, we will evaluate the collective understanding of

mechanism(s) for the interaction of these elements in neuronal research and their
significance for the diagnosis and treatment of neurodegeneration.

Epidemiological studies have linked high intake of fish and shellfish as part of the daily diet to

reduction of the incidence and/or severity of Alzheimer’s disease (AD) and senile mental decline in

cellular differentiation,
photoreceptor membrane biogenesis and
active synaptogenesis.

Despite the significance of these

two families, mammals cannot synthesize PUFA de novo, so they must be ingested from dietary sources. Though belonging to the same family, both

omega-3 and omega-6 fatty acids are metabolically and functionally distinct and have
opposing physiological effects. In the human body,
high concentrations of omega-6 fatty acids are known to increase the formation of prostaglandins and
thereby increase inflammatory processes [10].

the reverse process can be seen with increased omega-3 fatty acids in the body.

Many other factors, such as

thromboxane A2 (TXA2),
leukotriene
B4 (LTB4),
IL-1,
IL-6,
tumor necrosis factor (TNF) and
C-reactive protein,

which are implicated in various health conditions, have been shown to be increased with high omega-6 fatty acids but decreased with omega-3 fatty acids in the human body.

Dietary fatty acids have been identified as protective factors in coronary heart disease, and PUFA levels are known to play a critical role in

immune responses,
gene expression and
intercellular communications.

omega-3 fatty acids are known to be vital in

the prevention of fatal ventricular arrhythmias, and
are also known to reduce thrombus formation propensity by decreasing platelet aggregation, blood viscosity and fibrinogen levels

.Since omega-3 fatty acids are prevalent in the nervous system, it seems logical that a deficiency may result in neuronal problems, and this is indeed what has been identified and reported.

The main omega-3 fatty acids in the mammalian body are

α-linolenic acid (ALA),
docosahexenoic acid (DHA) and
eicosapentaenoic acid (EPA).

In general, seafood is rich in omega-3 fatty acids, more specifically DHA and EPA (Table 1). Thus far, there are nine separate epidemiological studies that suggest a possible link between

increased fish consumption and reduced risk of AD
and eight out of ten studies have reported a link between higher blood omega-3 levels

Table 1. Total percentage of omega-3 fatty acids in common foods and supplements.

Food/Supplement	EPA	DHA	ALA	Total %
Fish
SalmonSardine Anchovy Halibut Herring Mackerel Tuna Fresh Bluefin	XX X X X X X X	XX X X X X X X		>50%>50% >50% >50% >50% >50% >50% >50%
Oils/Supplements
Fish oil capsulesCod liver oils Salmon oil Sardine oil	XX X X	XX X X		>50%>50% >50% >50%
Black currant oilCanola oil Mustard seed oils Soybean oil Walnut oil Wheat germ oil			XX X X X X	10%–50%10%–50% 10%–50% 10%–50% 10%–50% 10%–50%
Seeds and other foods
Flaxseeds/LinseedsSpinach Wheat germ Human milk Peanut butter Soybeans Olive oil Walnuts			XX X X X X X X	>50%>50% 10%–50% 10%–50% <10% <10% <10% <10%

Table adopted from Maclean C.H. et al. [18].

In another study conducted with individuals of 65 years of age or older (n = 6158), it was found that

only high fish consumption, but
not dietary omega-3 acid intake,
had a protective effect on cognitive decline

a protective effect of omega-3 fatty acids only among those with mild cognitive impairment conditions.

A trial of subjects with mild memory complaints demonstrated

an improvement with 900 mg of DHA.

We review key findings on

the effect of the omega-3 fatty acid DHA on zinc transporters and the
importance of free zinc to human neuronal cells.

DHA is the most abundant fatty acid in neural membranes, imparting appropriate

fluidity and other properties,

and is thus considered as the most important fatty acid in neuronal studies. DHA is well conserved throughout the mammalian species despite their dietary differences. It is mainly concentrated

in membrane phospholipids at synapses and
in retinal photoreceptors and
also in the testis and sperm.

In adult rats’ brain, DHA comprises approximately

17% of the total fatty acid weight, and
in the retina it is as high as 33%.

DHA is believed to have played a major role in the evolution of the modern human –

in particular the well-developed brain.

Premature babies fed on DHA-rich formula show improvements in vocabulary and motor performance.

Analysis of human cadaver brains have shown that

people with AD have less DHA in their frontal lobe
and hippocampus compared with unaffected individuals

Furthermore, studies in mice have increased support for the

protective role of omega-3 fatty acids.

Mice administrated with a dietary intake of DHA showed

an increase in DHA levels in the hippocampus.

Errors in memory were decreased in these mice and they demonstrated

reduced peroxide and free radical levels,
suggesting a role in antioxidant defense.

Another study conducted with a Tg2576 mouse model of AD demonstrated that dietary

DHA supplementation had a protective effect against reduction in
drebrin (actin associated protein), elevated oxidation, and to some extent, apoptosis via
decreased caspase activity.

Zinc

Zinc is a trace element, which is indispensable for life, and it is the second most abundant trace element in the body. It is known to be related to

growth,
development,
differentiation,
immune response,
receptor activity,
DNA synthesis,
gene expression,
neuro-transmission,
enzymatic catalysis,
hormonal storage and release,
tissue repair,
memory,
the visual process

and many other cellular functions. Moreover, the indispensability of zinc to the body can be discussed in many other aspects, as

a component of over 300 different enzymes
an integral component of a metallothioneins
a gene regulatory protein.

Approximately 3% of all proteins contain

zinc binding motifs .

The broad biological functionality of zinc is thought to be due to its stable chemical and physical properties. Zinc is considered to have three different functions in enzymes;

catalytic,
coactive and

Indeed, it is the only metal found in all six different subclasses

through glutamate receptors, and
it inhibits excitatory and inhibitory receptors.

Vesicular localization of zinc in pre-synaptic terminals is a characteristic feature of brain-localized zinc, and

its release is dependent on neural activity.

The relationship between zinc and neurodegeneration, specifically AD, has been interpreted in several ways. One study has proposed that β-amyloid has a greater propensity to

form insoluble amyloid in the presence of
high physiological levels of zinc.

Insoluble amyloid is thought to

aggregate to form plaques,

which is a main pathological feature of AD. Further studies have shown that

chelation of zinc ions can deform and disaggregate plaques.

In AD, the most prominent injuries are found in

hippocampal pyramidal neurons, acetylcholine-containing neurons in the basal forebrain, and in
somatostatin-containing neurons in the forebrain.

All of these neurons are known to favor

rapid and direct entry of zinc in high concentration
leaving neurons frequently exposed to high dosages of zinc.

This is thought to promote neuronal cell damage through oxidative stress and mitochondrial dysfunction. Excessive levels of zinc are also capable of

inhibiting Ca2+ and Na+ voltage gated channels
and up-regulating the cellular levels of reactive oxygen species (ROS).

If the human diet is deficient in zinc, the body

efficiently conserves zinc at the tissue level by compensating other cellular mechanisms

to delay the dietary deficiency effects of zinc. These include reduction of cellular growth rate and zinc excretion levels, and

redistribution of available zinc to more zinc dependent cells or organs.

A novel method of measuring metallothionein (MT) levels was introduced as a biomarker for the

assessment of the zinc status of individuals and populations.

as a target for zinc ion binding and thus
assisting in the trafficking of zinc ions through the cell,
which may be similar to that of zinc transporters

Zinc Transporters

via intermembrane proteins and zinc transporter (ZnT) proteins

Members of the SLC39 family have been identified as the putative facilitators of zinc influx into the cytosol, either from the extracellular environment or from intracellular compartments (Figure 1).

it is responsible for the transport of zinc into the synaptic vesicles of
glutamatergic neurons in the hippocampus and neocortex,

Figure 1. Putative cellular localization of some of the different human zinc transporters (i.e., Zip1- Zip4 and ZnT1- ZnT7). Arrows indicate the direction of zinc passage by the appropriate putative zinc transporters in a generalized human cell. Although there are fourteen Zips and eight ZnTs known so far, only the main zinc transporters are illustrated in this figure for clarity and brevity.

zinc transporters

Early zinc signaling (EZS) and late zinc signaling (LZS)

http://www.hindawi.com/journals/jnme/2012/floats/173712/thumbnails/173712.fig.002_th.jpg

DHA and Zinc Homeostasis

Many studies have identified possible associations between DHA levels, zinc homeostasis, neuroprotection and neurodegeneration. Dietary DHA deficiency resulted in

increased zinc levels in the hippocampus and
elevated expression of the putative zinc transporter, ZnT3, in the rat brain.

a significant reduction in plaque load
and the presence of insoluble amyloid were observed.

In addition to the decrease in plaque load, ZnT3 silenced mice also exhibited a significant

reduction in free zinc availability in the hippocampus
and cerebral cortex.

Collectively, the findings from this study are very interesting and indicate a clear connection between

zinc availability and amyloid plaque formation,

thus indicating a possible link to AD.

DHA supplementation has also been reported to limit the following:

amyloid presence,
synaptic marker loss,
hyper-phosphorylation of Tau,
oxidative damage and
cognitive deficits in transgenic mouse model of AD.

When treated with DHA over 48 h, ZnT3 levels were markedly reduced in the human neuroblastoma M17 cell line. Moreover, in the same study, we were able to propose a possible

neuroprotective mechanism of DHA,

which we believe is exerted through

a reduction in cellular zinc levels (through altering zinc transporter expression levels)
that in turn inhibits apoptosis.

DHA supplemented M17 cells also showed a marked depletion of zinc uptake (up to 30%), and

free zinc levels in the cytosol were significantly low compared to the control

This reduction in free zinc availability was specific to DHA; cells treated with EPA had no significant change in free zinc levels (unpublished data). Moreover, DHA-repleted cells had

low levels of active caspase-3 and
high Bcl-2 levels compared to the control treatment.

These findings are consistent with previous published data and further strengthen the possible

correlation between zinc, DHA and neurodegeneration.

On the other hand, recent studies using ZnT3 knockout (ZnT3KO) mice have shown the importance of

ZnT3 in memory and AD pathology.

For example, Sindreu and colleagues have used ZnT3KO mice to establish the important role of

ZnT3 in zinc homeostasis that modulates presynaptic MAPK signaling
required for hippocampus-dependent memory

Results from these studies indicate a possible zinc-transporter-expression-level-dependent mechanism for DHA neuroprotection.

Collectively from these studies, the following possible mechanism can be proposed (Figure 2).

possible benefits of DHA in neuroprotection through reduction of ZnT3 transporter

Figure 2. Proposed neuroprotection mechanism of docosahexaenoic acid (DHA) in reference to synaptic zinc. Schematic diagram showing possible benefits of DHA in neuroprotection through reduction of ZnT3 transporter expression levels in human neuronal cells, which results in a reduction of zinc flux and thus lowering zinc concentrations in neuronal synaptic vesicles, and therefore contributing to a lower incidence of neurodegenerative diseases (ND), such as Alzheimer’s disease (AD).

More recent data from our research group have also shown a link between the expression levels of histone H3 and H4 proteins in human neuronal cells in relation to DHA and zinc. Following DHA treatment, both H3 and H4 levels were up-regulated. In contrast, zinc treatment resulted in a down-regulation of histone levels. Both zinc and DHA have shown opposing effects on histone post-translational modifications, indicating a possible distinctive epigenetic pattern. Upon treatment with zinc, M17 cells displayed an increase in histone deacetylase (HDACs) and a reduction in histone acetylation. Conversely, with DHA treatment, HDAC levels were significantly reduced and the acetylation of histones was up-regulated. These findings also support a possible interaction between DHA and zinc availability.

Conclusions

It is possible to safely claim that there is more than one potential pathway by which DHA and zinc interact at a cellular level, at least in cultured human neuronal cells. Significance and importance of both DHA and zinc in neuronal survival is attested by the presence of these multiple mechanisms.
Most of these reported studies were conducted using human neuroblastoma cells, or similar cell types, due to the lack of live mature human neuronal cells. Thus, the results may differ from results achieved under actual human physiological conditions due to the structural and functional differences between these cells and mature human neurons. Therefore, an alternative approach that can mimic the human neuronal cells more effectively would be advantageous.

Sphingosine-1-phosphate signaling as a therapeutic target

E Giannoudaki, DJ Swan, JA Kirby, S Ali

Applied Immunobiology and Transplantation Research Group, Institute of Cellular Medicine, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, UK

Cell Health and Cytoskeleton 2012; 4: 63–72

S1P is a 379Da member of the lysophospholipid family. It is the direct metabolite of sphingosine through the action of two sphingosine kinases, SphK1 and SphK2. The main metabolic pathway starts with the hydrolysis of sphingomyelin, a membrane sphingolipid, into ceramide by the enzyme sphingomyelinase and the subsequent production of sphingosine by ceramidase (Figure 1). Ceramide can also be produced de novo in the endoplasmic reticulum (ER) from serine and palmitoyl coenzyme A through multiple intermediates. S1P production is regulated by various S1P-specific and general lipid phosphatases, as well as S1P lyase, which irreversibly degrades S1P into phosphoethanolamine and hexadecanal. The balance between intracellular S1P and its metabolite ceramide can determine cellular fate. Ceramide promotes apoptosis, while S1P suppresses cell death and promotes cell survival. This creates an S1P ceramide “rheostat” inside the cells. S1P lyase expression in tissue is higher than it is in erythrocytes and platelets, the main “suppliers” of S1P in blood. This causes a tissue–blood gradient of S1P, which is important in many S1P-mediated responses, like the lymphocyte egress from lymphoid organs.

S1P signaling overview

S1P is produced inside cells; however, it can also be found extracellularly, in a variety of different tissues. It is abundant in the blood, at concentrations of 0.4–1.5 μM, where it is mainly secreted by erythrocytes and platelets. Blood S1P can be found separately, but mainly it exists in complexes with high-density lipoprotein (HDL) (∼60%). Many of the cardioprotective effects of HDL are hypothesized to involve S1P. Before 1996, S1P was thought to act mainly intracellularly as a second messenger. However, the identification of several GPCRs that bind S1P led to the initiation of many studies on

extracellular S1P signaling through those receptors.

There are five receptors that have been identified currently. These can be coupled with different G-proteins. Assuming that each receptor coupling with a G protein has a slightly different function, one can recognize the complexity of S1P receptor signaling.

S1P as a second messenger

S1P is involved in many cellular processes through its GPCR signaling; studies demonstrate that S1P also acts at an intracellular level. Intracellular S1P plays a role in maintaining the balance of cell survival signal toward apoptotic signals, creating a

cell “rheostat” between S1P and its precursor ceramide.

Important evidence that S1P can act intracellularly as a second messenger came from yeast (Saccharomyces cerevisiae) and plant (Arabidopsis thaliana) cells. Yeast cells do not express any S1P receptors, although they can be affected by S1P during heat-shock responses. Similarly, Arabidopsis has only one GPCR-like protein, termed “GCR1,” which does not bind S1P, although S1P regulates stomata closure during drought.

Sphingosine-1-phosphate

In mammals, the sphingosine kinases have been found to localize in different cell compartments, being responsible for the accumulation of S1P in those compartments to give intracellular signals. In mitochondria, for instance,

S1P was recently found to interact with prohibitin 2,

a conserved protein that maintains mitochondria assembly and function. According to the same study,

SphK2 is the major producer of S1P in mitochondria and the knockout of its gene can cause

disruption of mitochondrial respiration and cytochrome c oxidase function.

SphK2 is also present in the nucleus of many cells and has been implicated to cause cell cycle arrest, and it causes S1P accumulation in the nucleus. It seems that nuclear S1P is affiliated with the histone deacetylases HDAC1 and HDAC2,

inhibiting their activity, thus having an indirect effect in epigenetic regulation of gene expression.

In the ER, SphK2 has been identified to translocate during stress, and promote apoptosis. It seems that S1P has specific targets in the ER that cause apoptosis, probably through calcium mobilization signals.

Sphingosine 1-phosphate (S1P) is a small bioactive lipid molecule that is involved in several processes both intracellularly and extracellularly. It acts intracellularly

to promote the survival and growth of the cell,

through its interaction with molecules in different compartments of the cell.

It can also exist at high concentrations extracellularly, in the blood plasma and lymph. This causes an S1P gradient important for cell migration. S1P signals through five G protein-coupled receptors, S1PR1–S1PR5, whose expression varies in different types of cells and tissue. S1P signaling can be involved in physiological and pathophysiological conditions of the cardiovascular, nervous, and immune systems and diseases such as ischemia/reperfusion injury, autoimmunity, and cancer. In this review, we discuss how it can be used to discover novel therapeutic targets.

The involvement of S1P signaling in disease

In a mouse model of myocardial ischemia-reperfusion injury (IRI), S1P and its carrier, HDL, can help protect myocardial tissue and decrease the infarct size. It seems they reduce cardiomyocyte apoptosis and neutrophil recruitment to the ischemic tissue and may decrease leukocyte adhesion to the endothelium. This effect appears to be S1PR3 mediated, since in S1PR3 knockout mice it is alleviated.

Ischemia activates SphK1, which is then translocated to the plasma membrane. This leads to an increase of intracellular S1P, helping to promote cardiomyocyte survival against apoptosis, induced by ceramide. SphK1 knockout mice cannot be preconditioned against IRI, whereas SphK1 gene induction in the heart protects it from IRI. Interestingly, a recent study shows SphK2 may also play a role, since its knockout reduces the cardioprotective effects of preconditioning. Further, administration of S1P or sphingosine during reperfusion results in better recovery and attenuation of damage to cardiomyocytes. As with preconditioning, SphK1 deficiency also affects post-conditioning of mouse hearts after ischemia reperfusion (IR).

S1P does not only protect the heart from IRI. During intestinal IR, multiple organs can be damaged, including the lungs. S1P treatment of mice during intestinal IR seems to have a protective effect on lung injury, probably due to suppression of iNOS-induced nitric oxide generation. In renal IRI, SphK1 seems to be important, since its deficiency increased the damage in kidney tissue, whereas the lentiviral overexpression of the SphK1 gene protected from injury. Another study suggests that, after IRI, apoptotic renal cells release S1P, which recruits macrophages through S1PR3 activation and might contribute to kidney regeneration and restoration of renal epithelium. However, SphK2 is negatively implicated in hepatic IRI, its inhibition helping protect hepatocytes and restoring mitochondrial function.

Further studies are implicating S1P signaling or sphingosine kinases in several kinds of cancer as well as autoimmune diseases.

Figure 2 FTY720-P causes retention of T cells in the lymph nodes.

Notes: C57BL/6 mice were injected with BALB/c splenocytes in the footpad to create an allogenic response then treated with FTY720-P or vehicle every day on days 2 to 5. On day 6, the popliteal lymph nodes were removed. Popliteal node-derived cells were mixed with BALB/c splenocytes in interferon gamma (IFN-γ) cultured enzyme-linked immunosorbent spot reactions. Bars represent the mean number of IFN-γ spot-forming cells per 1000 popliteal node-derived cells, from six mice treated with vehicle and seven with FTY720-P. **P , 0.01. (not shown)

Fingolimod (INN, trade name Gilenya, Novartis) is an immunomodulating drug, approved for treating multiple sclerosis. It has reduced the rate of relapses in relapsing-remitting multiple sclerosis by over half. Fingolimod is a sphingosine-1-phosphate receptor modulator, which sequesters lymphocytes in lymph nodes, preventing them from contributing to an autoimmune reaction.

Fingolimod3Dan

http://upload.wikimedia.org/wikipedia/commons/thumb/4/48/Fingolimod3Dan.gif/200px-Fingolimod3Dan.gif

The S1P antagonist FTY720 has been approved by the US Food and Drug Administration to be used as a drug against multiple sclerosis (MS). FTY720 is in fact a prodrug, since it is phosphorylated in vivo by SphK2 into FTY720-P, an S1P structural analog, which can activate S1PR1, 3, 4, and 5. FTY720-P binding to S1PR1 causes internalization of the receptor, as does S1P – but instead of recycling it back to the cell surface, it promotes its ubiquitination and degradation at the proteasome. This has a direct effect on lymphocyte trafficking through the lymph nodes, since it relies on S1PR1 signaling and S1P gradient (Figure 2). In MS, it stops migrating lymphocytes into the brain, but it may also have direct effects on the CNS through neuroprotection. FTY720 can pass the blood–brain barrier and it could be phosphorylated by local sphingosine kinases to act through S1PR1 and S1PR3 receptors that are mainly expressed in the CNS. In MS lesions, astrocytes upregulate those two receptors and it has been shown that FTY720-P treatment in vitro inhibits astrocyte production of inflammatory cytokines. A recent study confirms the importance of S1PR3 signaling on activated astrocytes, as well as SphK1, that are upregulated and promote the secretion of the potentially neuroprotective cytokine CXCL-1.

There are several studies implicating the intracellular S1P ceramide rheostat to cancer cell survival or apoptosis and resistance to chemotherapy or irradiation in vitro. Studies with SphK1 inhibition in pancreatic, prostate cancers, and leukemia, show increased ceramide/S1P ratio and induction of apoptosis. However, S1P receptor signaling plays conflicting roles in cancer cell migration and metastasis.

Modulation of S1P signaling: therapeutic potential

S1P signaling can be involved in many pathophysiological conditions. This means that we could look for therapeutic targets in all the molecules taking part in S1P signaling and production, most importantly the S1P receptors and the sphingosine kinases. S1P agonists and antagonists could also be used to modulate S1P signaling during pathological conditions.

S1P can have direct effects on the cardiovascular system. During IRI, intracellular S1P can protect the cardiomyocytes and promote their survival. Pre- or post-conditioning of the heart with S1P could be used as a treatment, but upregulation of sphingosine kinases could also increase intracellular S1P bioavailability. S1P could also have effects on endothelial cells and neutrophil trafficking. Vascular endothelial cells mainly express S1PR1 and S1PR3; only a few types express S1PR2. S1PR1 and S1PR3 activation on these cells has been shown to enhance their chemotactic migration, probably through direct phosphorylation of S1PR1 by Akt, in a phosphatidylinositol 3-kinase and Rac1-dependent signaling pathway. Moreover, it stimulates endothelial cell proliferation through an ERK pathway. S1PR2 activation, however, inhibits endothelial cell migration, morphogenesis, and angiogenesis, most likely through Rho-dependent inhibition of Rac signaling pathway, as Inoki et al showed in mouse cells with the use of S1PR1 and S1PR3 specific antagonists.

Regarding permeability of the vascular endothelium and endothelial barrier integrity, S1P receptors can have different effects. S1PR1 activation enhances endothelial barrier integrity by stimulation of cellular adhesion and upregulation of adhesion molecules. However, S1PR2 and S1PR3 have been shown to have barrier-disrupting effects in vitro, and vascular permeability increasing effects in vivo. All the effects S1P can have on vascular endothelium and smooth muscle cells suggest that activation of S1PR2, not S1PR1 and S1PR3, signaling, perhaps with the use of S1PR2 specific agonists, could be used therapeutically to inhibit angiogenesis and disrupt vasculature, suppressing tumor growth and progression.

An important aspect of S1P signaling that is being already therapeutically targeted, but could be further investigated, is immune cell trafficking. Attempts have already been made to regulate lymphocyte cell migration with the use of the drug FTY720, whose phosphorylated form can inhibit the cells S1PR1-dependent egress from the lymph nodes, causing lymphopenia. FTY720 is used as an immunosuppressant for MS but is also being investigated for other autoimmune conditions and for transplantation. Unfortunately, Phase II and III clinical trials for the prevention of kidney graft rejection have not shown an advantage over standard therapies. Moreover, FTY720 can have some adverse cardiac effects, such as bradycardia. However, there are other S1PR1 antagonists that could be considered instead, including KRP-203, AUY954, and SEW2871. KRP-203 in particular has been shown to prolong rat skin and heart allograft survival and attenuate chronic rejection without causing bradycardia, especially when combined with other immunomodulators.

There are studies that argue S1P pretreatment has a negative effect on neutrophil chemotaxis toward the chemokine CXCL-8 (interleukin-8) or the potent chemoattractant formyl-methionyl-leucyl-phenylalanine. S1P pretreatment might also inhibit trans-endothelial migration of neutrophils, without affecting their adhesion to the endothelium. S1P effects on neutrophil migration toward CXCL-8 might be the result of S1PRs cross-linking with the CXCL-8 receptors in neutrophils, CXCR-1 and CXCR-2. Indeed, there is evidence suggesting S1PR4 and S1PR3 form heterodimers with CXCR-1 in neutrophils. Another indication that S1P plays a role in neutrophil trafficking is a recent paper on S1P lyase deficiency, a deficiency that impairs neutrophil migration from blood to tissue in knockout mice.

S1P lyase and S1PRs in neutrophils may be new therapeutic targets against IRI and inflammatory conditions in general. Consistent with these results, another study has shown that inhibition of S1P lyase can have a protective effect on the heart after IRI and this effect is alleviated when pretreated with an S1PR1 and S1PR3 antagonist. Inhibition was achieved with a US Food and Drug Administration-approved food additive, 2-acetyl-4-tetrahydroxybutylimidazole, providing a possible new drug perspective. Another S1P lyase inhibitor, LX2931, a synthetic analog of 2-acetyl-4-tetrahydroxybutylimidazole, has been shown to cause peripheral lymphopenia when administered in mice, providing a potential treatment for autoimmune diseases and prevention of graft rejection in transplantation. This molecule is currently under Phase II clinical trials in rheumatoid arthritis patients.

S1P signaling research has the potential to discover novel therapeutic targets. S1P signaling is involved in many physiological and pathological processes. However, the complexity of S1P signaling makes it necessary to consider every possible pathway, either through its GPCRs, or intracellularly, with S1P as a second messenger. Where the activation of one S1P receptor may lead to the desired outcome, the simultaneous activation of another S1P receptor may lead to the opposite outcome. Thus, if we are to target a specific signaling pathway, we might need specific agonists for S1P receptors to activate one S1P receptor pathway, while, at the same time, we might need to inhibit another through S1P receptor antagonists.

Evidence of sphingolipid signaling in cancer

Biologically active lipids are important cellular signaling molecules and play a role in cell communication and cancer cell proliferation, and cancer stem cell biology. A recent study in ovarian cancer cell lines shows that exogenous sphingosine 1 phosphate (SIP1) or overexpression of the sphingosine kinase (SPHK1) increases ovarian cancer cell proliferation, invasion and contributes to cancer stem cell like phenotype. The diabetes drug metformin was shown to be an inhibitor of SPHK1 and reduce ovarian cancer tumor growth.

2019 Apr;17(4):870-881. doi: 10.1158/1541-7786.MCR-18-0409. Epub 2019 Jan 17.

SPHK1 Is a Novel Target of Metformin in Ovarian Cancer.

Hart PC^#¹, Chiyoda T^#^1,², Liu X³, Weigert M¹, Curtis M¹, Chiang CY¹, Loth R¹, Lastra R⁴, McGregor SM^4,⁵, Locasale JW³, Lengyel E¹, Romero IL⁶.

Author information

Abstract

The role of phospholipid signaling in ovarian cancer is poorly understood. Sphingosine-1-phosphate (S1P) is a bioactive metabolite of sphingosine that has been associated with tumor progression through enhanced cell proliferation and motility. Similarly, sphingosine kinases (SPHK), which catalyze the formation of S1P and thus regulate the sphingolipid rheostat, have been reported to promote tumor growth in a variety of cancers. The findings reported here show that exogenous S1P or overexpression of SPHK1 increased proliferation, migration, invasion, and stem-like phenotypes in ovarian cancer cell lines. Likewise, overexpression of SPHK1 markedly enhanced tumor growth in a xenograft model of ovarian cancer, which was associated with elevation of key markers of proliferation and stemness. The diabetes drug, metformin, has been shown to have anticancer effects. Here, we found that ovarian cancer patients taking metformin had significantly reduced serum S1P levels, a finding that was recapitulated when ovarian cancer cells were treated with metformin and analyzed by lipidomics. These findings suggested that in cancer the sphingolipid rheostat may be a novel metabolic target of metformin. In support of this, metformin blocked hypoxia-induced SPHK1, which was associated with inhibited nuclear translocation and transcriptional activity of hypoxia-inducible factors (HIF1α and HIF2α). Further, ovarian cancer cells with high SPHK1 were found to be highly sensitive to the cytotoxic effects of metformin, whereas ovarian cancer cells with low SPHK1 were resistant. Together, the findings reported here show that hypoxia-induced SPHK1 expression and downstream S1P signaling promote ovarian cancer progression and that tumors with high expression of SPHK1 or S1P levels might have increased sensitivity to the cytotoxic effects of metformin. IMPLICATIONS: Metformin targets sphingolipid metabolism through inhibiting SPHK1, thereby impeding ovarian cancer cell migration, proliferation, and self-renewal.

Nrf2:INrf2(Keap1) Signaling in Oxidative Stress

James W. Kaspar, Suresh K. Niture, and Anil K. Jaiswal*

Department of Pharmacology, University of Maryland School of Medicine, Baltimore, MD

Free Radic Biol Med. 2009 Nov 1; 47(9): 1304–1309. http://dx.doi.org:/10.1016/j.freeradbiomed.2009.07.035

Nrf2:INrf2(Keap1) are cellular sensors of chemical and radiation induced oxidative and electrophilic stress. Nrf2 is a nuclear transcription factor that

controls the expression and coordinated induction of a battery of defensive genes encoding detoxifying enzymes and antioxidant proteins.

This is a mechanism of critical importance for cellular protection and cell survival. Nrf2 is retained in the cytoplasm by an inhibitor INrf2. INrf2 functions as an adapter for

Cul3/Rbx1 mediated degradation of Nrf2.
In response to oxidative/electrophilic stress,
Nrf2 is switched on and then off by distinct

early and delayed mechanisms.

Oxidative/electrophilic modification of INrf2cysteine151 and/or PKC phosphorylation of Nrf2serine40 results in the escape or release of Nrf2 from INrf2. Nrf2 is stabilized and translocates to the nucleus, forms heterodimers with unknown proteins, and binds antioxidant response element (ARE) that leads to coordinated activation of gene expression. It takes less than fifteen minutes from the time of exposure

to switch on nuclear import of Nrf2.

This is followed by activation of a delayed mechanism that controls

switching off of Nrf2 activation of gene expression.

GSK3β phosphorylates Fyn at unknown threonine residue(s) leading to

nuclear localization of Fyn.

Fyn phosphorylates Nrf2tyrosine568 resulting in

nuclear export of Nrf2,
binding with INrf2 and
degradation of Nrf2.

The switching on and off of Nrf2 protects cells against free radical damage, prevents apoptosis and promotes cell survival.

NPRA-mediated suppression of AngII-induced ROS production contributes to the antiproliferative effects of B-type natriuretic peptide in VSMC

Pan Gao, De-Hui Qian, Wei Li, Lan Huang
Mol Cell Biochem (2009) 324:165–172

http://dx.doi.org/10.1007/s11010-008-9995-y

Excessive proliferation of vascular smooth cells (VSMCs) plays a critical role in the pathogenesis of diverse vascular disorders, and inhibition of VSMCs proliferation has been proved to be beneficial to these diseases.

In this study, we investigated the antiproliferative effect of

B-type natriuretic peptide (BNP), a natriuretic peptide with potent antioxidant capacity,

on rat aortic VSMCs, and the possible mechanisms involved. The results indicate that

BNP potently inhibited Angiotensin II (AngII)-induced VSMCs proliferation,

as evaluated by [3H]-thymidine incorporation assay. Consistently, BNP significantly decreased

AngII-induced intracellular reactive oxygen species (ROS)
and NAD(P)H oxidase activity.

8-Br-cGMP, a cGMP analog,

mimicked these effects.

To confirm its mechanism, siRNA of natriuretic peptide receptor-A(NRPA) strategy technology was used

to block cGMP production in VSMCs, and
siNPRA attenuated the inhibitory effects of BNP in VSMCs.

Taken together, these results indicate that

BNP was capable of inhibiting VSMCs proliferation by
NPRA/cGMP pathway,

which might be associated with

the suppression of ROS production.

These results might be related, at least partly, to the anti-oxidant property of BNP.

Cellular prion protein is required for neuritogenesis: fine-tuning of multiple signaling pathways involved in focal adhesions and actin cytoskeleton dynamics

A Alleaume-Butaux, C Dakowski, M Pietri, S Mouillet-Richard, Jean-Marie Launay, O Kellermann, B Schneider

1INSERM, UMR-S 747, 2Paris Descartes University, Sorbonne Paris, 3Public Hospital of Paris, Department of Biochemistry, Paris, France; 4Pharma Research Department, Hoffmann La Roche Ltd, Basel, Switzerland

Cell Health and Cytoskeleton 2013; 5: 1–12

Neuritogenesis is a complex morphological phenomena accompanying neuronal differentiation. Neuritogenesis relies on the initial breakage of the rather spherical symmetry of neuroblasts and the formation of buds emerging from the postmitotic neuronal soma. Buds then evolve into neurites, which later convert into an axon or dendrites. At the distal tip of neurites, the growth cone integrates extracellular signals and guides the neurite to its target. The acquisition of neuronal polarity depends on deep modifications of the neuroblast cytoskeleton characterized by the remodeling and activation of focal adhesions (FAs) and localized destabilization of the actin network in the neuronal sphere.Actin instability in unpolarized neurons allows neurite sprouting, ie, the protrusion of microtubules, and subsequent neurite outgrowth. Once the neurite is formed, actin microfilaments recover their stability and exert a sheathed action on neurites, a dynamic process necessary for the maintenance and integrity of neurites.

A combination of extrinsic and intrinsic cues pilots the architectural and functional changes in FAs and the actin network along neuritogenesis. This process includes neurotrophic factors (nerve growth factor, brain derived neurotrophic factor, neurotrophin, ciliary neurotrophic factor, glial derived neurotrophic factor) and their receptors, protein components of the extracellular matrix (ECM) (laminin, vitronectin, fibronectin), plasma membrane integrins and neural cell adhesion molecules (NCAM), and intracellular molecular protagonists such as small G proteins (RhoA, Rac, Cdc42) and their downstream targets.

Neuritogenesis is a dynamic phenomenon associated with neuronal differentiation that allows a rather spherical neuronal stem cell to develop dendrites and axon, a prerequisite for the integration and transmission of signals. The acquisition of neuronal polarity occurs in three steps:

(1) neurite sprouting, which consists of the formation of buds emerging from the postmitotic neuronal soma;

(2) neurite outgrowth, which represents the conversion of buds into neurites, their elongation and evolution into axon or dendrites; and

(3) the stability and plasticity of neuronal polarity.

In neuronal stem cells, remodeling and activation of focal adhesions (FAs) associated with deep modifications of the actin cytoskeleton is a prerequisite for neurite sprouting and subsequent neurite outgrowth. A multiple set of growth factors and interactors located in the extracellular matrix and the plasma membrane orchestrate neuritogenesis

by acting on intracellular signaling effectors,
notably small G proteins such as RhoA, Rac, and Cdc42,
which are involved in actin turnover and the dynamics of FAs.

The cellular prion protein (PrPC), a glycosylphosphatidylinositol

(GPI)-anchored membrane protein

mainly known for its role in a group of fatal

neurodegenerative diseases,

has emerged as a central player in neuritogenesis.

Here, we review the contribution of PrPC to neuronal polarization and detail the current knowledge on the

signaling pathways fine-tuned by PrPC
to promote neurite sprouting, outgrowth, and maintenance.

We emphasize that PrPC-dependent neurite sprouting is a process in which PrPC

governs the dynamics of FAs and the actin cytoskeleton
via β1 integrin signaling.

The presence of PrPC is necessary to render neuronal stem cells

competent to respond to neuronal inducers and
to develop neurites.

In differentiating neurons, PrPC exerts

a facilitator role towards neurite elongation.

This function relies on the interaction of PrPC with a set of diverse partners such as

elements of the extracellular matrix,
plasma membrane receptors,
adhesion molecules, and
soluble factors that control actin cytoskeleton turnover through Rho-GTPase signaling.

Once neurons have reached their terminal stage of differentiation and acquired their polarized morphology, PrPC also

takes part in the maintenance of neurites.

By acting on tissue nonspecific alkaline phosphatase, or

matrix metalloproteinase type 9,

PrPC stabilizes interactions between

neurites and the extracellular matrix.

Keywords: prion, neuronal differentiation

Read Full Post »

Diabetes Mellitus

Posted in Academic Publishing, Alzheimer's Disease, Cerebrovascular and Neurodegenerative Diseases, Chemical Biology and its relations to Metabolic Disease, Chemical Genetics, Curation, Diabetes Mellitus, Disease Biology, Epigenetics and Cardiovascular Risks, Etiology, Gene Regulation, Innovations, Lipid metabolism, Metabolism, Metabolomics, Nephrology, Neurological Diseases, Nitric Oxide in Health and Disease, Nutrition, Nutrition and Phytochemistry, Nutritional Supplements: Atherogenesis, Origins of Cardiovascular Disease, Plant extract, tagged amylin, Amyloid, Beta cell, Diabetes Mellitus, glomerulosclerosis, Insulin resistance, Insulin Sensitivity, islet cells of pancreas, pharmacotherapy, proinsulin on October 24, 2014| Leave a Comment »

Diabetes Mellitus

Author & Curator: Larry H. Bernstein, MD, FCAP

Diabetes mellitus (DM) is a group of metabolic diseases defined by high blood glucose levels, which, depending on the fasting blood glucose, may be pre-diabetes or overt diabetes (110 mg/dl. 124 mg/dl). This blood glucose level reflects a disorder of control of glucose metabolism, which is mediated through the pituitary growth hormone acting on the liver, which produces insulin growth factor 1 (IGF1). Diabetes is due to either the pancreas not producing enough insulin, or the cells of the body not responding properly to the insulin produced. That said, there is much to be understood about the long term systemic effects of this disorder, a multisystem disease. The presence of pre-diabetes glucose levels is sufficient to proactively take measures to reduce the circulating glucose.

Globally, as of 2013, an estimated 382 million people have diabetes worldwide, with type 2 diabetes making up about 90% of the cases. This is equal to 8.3% of the adults population, with equal rates in both women and men. Worldwide in 2012 and 2013 diabetes resulted in 1.5 to 5.1 million deaths per year, making it the 8th leading cause of death. Diabetes overall at least doubles the risk of death. The number of people with diabetes is expected to rise to 592 million by 2035. The economic costs of diabetes globally was estimated in 2013 at $548 billion and in the United States in 2012 $245 billion.

The observation of symptoms of frequent urination, increased thirst, and increased hunger is symptomatic of overt DM, and is seen with diabetic ketoacidosis, with very high hyperglycemia and glucosuria, particularly in Type 1 DM. Untreated, diabetes leads to serious complications. Acute complications include diabetic ketoacidosis. Serious long-term complications include heart disease, stroke, kidney failure, foot ulcers and damage to the eyes.

There are three main types of diabetes mellitus:

Type 1 DM results from the body’s failure to produce enough insulin. This form was previously referred to as “insulin-dependent diabetes mellitus” (IDDM) or “juvenile diabetes”. The cause is unknown.
Type 2 DM begins with insulin resistance, a condition in which cells fail to respond to insulin properly. As the disease progresses a lack of insulin may also develop. This form was previously referred to as “non insulin-dependent diabetes mellitus” (NIDDM) or “adult-onset diabetes”. The primary cause is excessive body weight and not enough exercise.
Gestational diabetes, the third, occurs when pregnant women without a previous history of diabetes develop a high blood glucose level.

Type 1 DM, which presents suddenly in children or young adults, is possibly an as yet unidentified post-translational or epigenetic form, unrelated to Type 2, which is becoming more common in children. It results in the destruction of islet beta cells that then have no capacity to produce insulin. A family history of the disease would be a signal to raise a child with great care to not stress the pancreas. Even though I raised the possibility of an epigenetic factor, it is important to keep in mind that the regulation of glucose is responsive to a number of stresses, even in a healthy person. These are:

Corticosteroids
Glucagon
Growth hormone
Catecholamines
Proinflammatory cytokines
Anxiety disorder
Eating disorder

Gestational diabetes is perhaps Type 2 diabetes in a pregnant woman initiated by the condition of pregnancy. Whether these women were not diabetic, with a glucose level between 100-110 prior to pregnancy, is an open question. However, the pregnant state is accompanied by large effects by hormone levels.

Type 2 diabetes has been increasing worldwide, not only in western nations. However, in non-western countries that have large populations of underserved, there is still a major problem with protein energy malnutrition (PEM). Globally, as of 2013, an estimated 382 million people have diabetes worldwide, with type 2 diabetes making up about 90% of the cases. This is equal to 8.3% of the adults population, with equal rates in both women and men. Worldwide in 2012 and 2013 diabetes resulted in 1.5 to 5.1 million deaths per year, making it the 8th leading cause of death. Diabetes overall at least doubles the risk of death. The number of people with diabetes is expected to rise to 592 million by 2035. The economic costs of diabetes globally was estimated in 2013 at $548 billion and in the United States in 2012 $245 billion.

The major long-term complications relate to damage to blood vessels. Diabetes doubles the risk of cardiovascular disease and about 75% of deaths in diabetics are due to coronary artery disease. Other “macrovascular” diseases are stroke, and peripheral vascular disease. The primary microvascular complications of diabetes include damage to the eyes, kidneys, and nerves. Damage to the eyes, known as diabetic retinopathy, is caused by damage to the blood vessels in the retina of the eye, and can result in gradual vision loss and potentially blindness. Damage to the kidneys, known as diabetic nephropathy, can lead to tissue scarring, urine protein loss, and eventually chronic kidney disease, sometimes requiring dialysis or kidney transplant. Damage to the nerves of the body, known as diabetic neuropathy, is the most common complication of diabetes.

Prevention and treatment involves a healthy diet, physical exercise, not using tobacco and being a normal body weight. Blood pressure control and proper foot care are also important for people with the disease. Type 1 diabetes must be managed with insulin injections. Type 2 diabetes may be treated with medications with or without insulin. Insulin and some oral medications can cause low blood sugar. Weight loss surgery in those with obesity is an effective measure in those with type 2 DM. Gestational diabetes usually resolves after the birth of the baby.

A number of articles in http://pharmaceuticalintelligence,com (this journal) have presented the relationship of DM to heart and vascular disease. The complexity of the disease is not to be underestimated, and there havr been serious controversies with adverse consequences over the use of the class of drugs that includes rosiglitazone and piaglitazone, which has opened serious issues about how clinical trials are conducted, and how the data obtained in studies may be compromised.

Pharmaceutical Insights

Management of Diabetes Mellitus: Could Simultaneous Targeting of Hyperglycemia and Oxidative Stress Be a Better Panacea?

Omotayo O. Erejuwa
Int. J. Mol. Sci. 2012, 13, 2965-2972; http://www.mdpi.com/journal/ijms http://dx.doi.org:/10.3390/ijms13032965

The primary aim of the current management of diabetes mellitus is to achieve and/or maintain a glycated hemoglobin level of ≤6.5%. However, recent evidence indicates that intensive treatment of hyperglycemia is characterized by increased weight gain, severe hypoglycemia and higher mortality. Besides, evidence suggests that it is difficult to achieve and/or maintain optimal glycemic control in many diabetic patients; and that the benefits of intensively-treated hyperglycemia are restricted to microvascular complications only. Evidence also indicates that multiple drugs are required to achieve optimal glycemic target in many diabetic patients. In fact, in many diabetic patients in whom optimal glycemic goal is achieved, glycemic control deteriorates even with optimal drug therapy. It does suggest that with the current hypoglycemic or antidiabetic drugs, it is difficult to achieve and/or maintain tight glycemic control in diabetic patients. In many developing countries, the vast majority of diabetic patients have limited or lack access to quality healthcare providers and good therapeutic monitoring.

While increased weight gain could be due to some component drugs (such as sulphonylureas or insulin) of the intensive therapy regimens, hypoglycemia could be drug-induced or comorbidity-induced. Considering the evidence that associates hypoglycemia with increased mortality, higher incidence of mortality in intensive therapy group could be due to hypoglycemia or too low levels of glycosylated hemoglobin. However, it is difficult to contend that increased mortality was entirely due to hypoglycemia. The possibility of drug-induced or drug-associated toxicities could not be ruled out. For instance, rosiglitazone, which has been prohibited and withdrawn from the market in Europe, was one of the hypoglycemic drugs used to achieve intensive therapy of hyperglycemia in Action to Control Cardiovascular Risk in Diabetes (ACCORD). If these findings are anything to go by, does it not suggest that targeting hyperglycemia as the only therapeutic goal in the management of diabetes mellitus could be detrimental to diabetic patients? In addition, the current hypoglycemic drugs are characterized by limitations and adverse effects. Together with the limitations of intensive glycemic treatment (only beneficial in reducing the risk of microvascular complications, but not macrovascular disease complications), does it not imply that targeting hyperglycemia alone is not only deleterious but also limited and ineffective?

The latest figures predict that the global incidence of diabetes mellitus, which was estimated to be 366 million in 2011, will rise to 522 million by 2030. In view of these frightening statistics on the prevalence of diabetes mellitus and on the lack of adequate healthcare, together with the associated diabetic complications, morbidity and mortality, does it not suggest that there is an urgent need for a better therapeutic management of this disorder? Taken together, with these findings and statistics, it can be contended that it is high time alternative and/or complementary therapies to the currently available hypoglycemic agents (which target primarily hyperglycemia only) were sought.

All these may contribute to the unabated increase in global prevalence of diabetes mellitus and its complications In view of these adverse effects and limitations of intensive treatment of hyperglycemia in preventing diabetic complications, which is linked to oxidative stress,

this commentary proposes a hypothesis that “simultaneous targeting of hyperglycemia and oxidative stress” could be more effective than “intensive treatment of hyperglycemia” in the management of diabetes mellitus.

Oxidative stress is defined as

an “imbalance between oxidants and antioxidants in favor of the oxidants, potentially leading to damage”.

It is implicated in the pathogenesis and complications of diabetes mellitus. The role of oxidative stress is more definite in the pathogenesis of type 2 diabetes mellitus than in type 1 diabetes mellitus. In regard to diabetic complications, there is compelling evidence in support of the role of oxidative stress in both types of diabetes mellitus. Evidence suggests that elevated reactive oxygen species (ROS), which causes factor of increased ROS production, causes tissue damage or diabetic complications have been identified. These include:

hyperglycemia-enhanced polyol pathway;
hyperglycemia-enhanced formation of advanced glycation endproducts (AGEs);
hyperglycemia-activated protein kinase C (PKC) pathway;
hyperglycemia-enhanced hexosamine pathway; and
hyperglycemia-activated Poly-ADP ribose polymerase (PARP) pathway.

These pathways are activated or enhanced by hyperglycemia-driven mitochondrial superoxide overproduction.

Even though oxidative stress plays an important role in its pathogenesis and complications,

unlike other diseases characterized by oxidative stress, diabetes mellitus is unique.

Its cure (restoration of euglycemia, e.g., via pancreas transplants) does not prevent oxidative stress and diabetic complications. This is very important because hyperglycemia exacerbates oxidative stress which is linked to diabetic complications. Theoretically, restoration of euglycemia should prevent oxidative stress and diabetic complications. However, this is not the case. At present, it remains unclear why restoration of euglycemia does not automatically prevent oxidative stress and diabetic complications. The development of diabetes-related complications (both microvascular and macrovascular) may occur in diabetic patients after normoglycemia has been restored. It is a phenomenon whereby previous hyperglycemic milieu is remembered in many target organs such as heart, eyes, kidneys and nerves. This phenomenon is also documented in diabetic animals. Compelling evidence implicates the role of oxidative stress as an important mechanism by which glycemic memory causes tissue damage and diabetic complications. In view of higher incidence of diabetic complications (of which oxidative stress plays an important role) in conventionally-treated diabetic patients, targeting oxidative stress in these patients might be beneficial. In other words, it is possible that the combination of a conventional therapy of hyperglycemia and antioxidant therapy might be more effective and beneficial than intensive therapy of hyperglycemia alone, which is the gold standard at the moment.

Loss of ACE 2 Exaggerates High-Calorie Diet-Induced Insulin Resistance by Reduction of GLUT4 in Mice

M Takeda, K Yamamoto, Y Takemura, H Takeshita, K Hongyo, et al. Diabetes 61:1–11, 2012

ACE type 2 (ACE2) functions as

a negative regulator of the renin angiotensin system
by cleaving angiotensin II (AII) into angiotensin 1–7 (A1–7).

This study assessed the role of

endogenous ACE2 in maintaining insulin sensitivity.

Twelve-week-old male ACE2 knockout (ACE2KO) mice had normal insulin sensitivities when fed a standard diet. AII infusion or a high-fat high-sucrose (HFHS) diet impaired glucose tolerance and insulin sensitivity more severely

in ACE2KO mice than in their wild-type (WT) littermates.

The strain difference in glucose tolerance

was not eliminated by an AII receptor type 1 (AT1) blocker
but was eradicated by A1–7 or an AT1 blocker combined with the A1–7 inhibitor (A779).

The expression of GLUT4 and a transcriptional factor, myocyte enhancer factor (MEF) 2A,

was dramatically reduced in the skeletal muscles of the standard diet–fed ACE2KO mice.

The expression of GLUT4 and MEF2A was increased

by A1–7 in ACE2KO mice and
decreased by A779 in WT mice.

A1–7 enhanced upregulation of MEF2A and GLUT4 during differentiation of myoblast cells. In conclusion,

ACE2 protects against high calorie diet-induced insulin resistance in mice.

This mechanism may involve the transcriptional regulation of GLUT4 via an A1–7-dependent pathway.
Modulation of the action of insulin by angiotensin-(1–7)
FP. Dominici, V Burghi, MC. Munoz, JF. Giani

Clinical Science (2014) 126, 613–630 http://dx.doi.org:/10.1042/CS20130333

The prevalence of Type 2 diabetes mellitus is predicted to increase dramatically over the coming years and the clinical implications and healthcare costs from this disease are overwhelming. In many cases, this pathological condition is linked to a cluster of metabolic disorders, such as

obesity,
systemic hypertension and
dyslipidaemia,

defined as the metabolic syndrome.

Insulin resistance has been proposed as the key mediator of all of these features and contributes to the associated high cardiovascular morbidity and mortality. Although the molecular mechanisms behind insulin resistance are not completely understood, a negative cross-talk between

AngII (angiotensin II) and the insulin signalling pathway

has been the focus of great interest in the last decade. Indeed,

substantial evidence has shown that

anti-hypertensive drugs that block the RAS (renin–angiotensin system) may also act to prevent diabetes.

Despite its long history, new components within the RAS continue to be discovered.

Among them, Ang-(1–7) [angiotensin-(1–7)] has gained special attention as a counter-regulatory hormone

opposing many of the AngII-related deleterious effects.

Specifically, we and others have demonstrated that Ang-(1–7) improves the action of insulin and opposes the negative effect that AngII exerts at this level. In the present review, we provide evidence showing that

insulin and Ang-(1–7) share a common intracellular signalling pathway.

We also address the molecular mechanisms behind the beneficial effects of Ang-(1–7) on

AngII-mediated insulin resistance.

Finally, we discuss potential therapeutic approaches leading to modulation of the

ACE2 (angiotensin-converting enzyme 2)/Ang-(1–7)/Mas receptor axis

as a very attractive strategy in the therapy of the metabolic syndrome and diabetes-associated diseases.

Increased Skeletal Muscle Capillarization After Aerobic Exercise Training and Weight Loss Improves Insulin Sensitivity in Adults With IGT

Prior, JB. Blumenthal, LI. Katzel, AP. Goldberg, AS. Ryan. Diabetes Care 2014;37:1469–1475
http://dx.doi.org:/10.2337/dc13-2358

Transcapillary transport of insulin is one determinant of glucose uptake by skeletal muscle; thus,

a reduction in capillary density (CD) may worsen insulin sensitivity.

Skeletal muscle CD is lower in older adults with impaired glucose tolerance (IGT) compared with those with normal glucose tolerance and

may be modifiable through aerobic exercise training and weight loss (AEX+WL).

Insulin sensitivity (M) and 120-min postprandial glucose (G120) correlated with CD at baseline (r = 0.58 and r = 20.60, respectively, P < 0.05).

AEX+WL increased maximal oxygen consumption (VO2max) 18%(P = 0.02) and reduced weight and fat mass 8% (P < 0.02).

Regression analyses showed that the AEX+WL-induced increase in CD

independently predicted the increase in M (r = 0.74, P < 0.01)
as well as the decrease in G120 (r = 20.55, P < 0.05).

AEX+WL increases skeletal muscle CD in older adults with IGT. This represents one mechanism by which AEX+WL improves insulin sensitivity in older adults with IGT.

Glycaemic durability with dipeptidyl peptidase-4 inhibitors in type 2 diabetes: a systematic review and meta-analysis of long-term randomised controlled trials.

K Esposito, P Chiodini, MI Maiorino, G Bellastella, A Capuano, D Giugliano. BMJ Open 2014;4:e005442.
http://dx.doi.org:/10.1136/bmjopen-2014-005442

A systematic review and meta-analysis of longterm randomised trials of DPP-4 inhibitors (sitagliptin, vildagliptin, saxagliptin, linagliptin and alogliptin). on haemoglobin A1c (HbA1c) was conducted. The difference between final and intermediate HbA1c assessment was the primary outcome. All trials were of 76 weeks duration at least. The difference in HbA1c changes between final and intermediate points averaged 0.22% (95% CI 0.15% to 0.29%), with high heterogeneity (I2=91%, p<0.0001). Estimates
of differences were not affected by the analysis of six extension trials (0.24%, 0.02 to 0.46), or five trials in which a DPP-4 inhibitor was added to metformin (0.24%, 0.16 to 0.32).

The effect of DPP-4 inhibitors on HbA1c in type 2 diabetes significantly declines during the second year of treatment.

Overcoming Diabetes Mellitus & Borderline Diabetes
By Max Stanley Chartrand, Ph.D. (Behavioral Medicine)

The over-arching biomarker that has more to do with the ability to restore normal metabolic processes is in achieving a cellular pH 7.45 (via the Kreb’s Cycle). To say the least, getting one’s cellular pH to 7.45 and A1C score below 6.0 can be a daunting task!

SIRCLE®: Naturally Achieved Targets

 Cellular pH 7.35-7.45

 Oxygen 99-100% @55-65 bpm

 Resting Blood Pressure: 110-135/ 65-80

mmHg (differs male vs female)

 Fasting blood sugar consistently <70-99

mg/dL or 3.5-5.5 mmol/L

 HgA1C score: .04-5.8

 HDL: 40-60 mg/dL; LDL: 100 -140 mg/dL;

triglycerides: <85 mg/dL

 C-Reactive Protein (CRP) Score <.5

 Galectin-3 Assay <17.8 ng/mL

Antidiabetic Activity of Hydroalcoholic Extracts of Nardostachys jatamansi in Alloxan-induced Diabetic Rats

M.A. Aleem, B.S. Asad, T Mohammed, R.A. Khan, M.F. Ahmed, A. Anjum, M. Ibrahim. Brit J Med & Medical Res 4(28): 4665-4673, 2014. http://www.sciencedomain.org/review-history.php?iid=579&id=12&aid=5024

The antidiabetic study was carried out to estimate the anti hyperglycemic potential of Nardostachys Jatamansi rhizome’s hydroalcoholic extracts in alloxan induced diabetic rats over a period of two weeks. The hydroalcoholic extract HAE1 at a dose (500mg/kg) exhibited significantly greater antihyperglycemic activity than extract HAE2 at a dose (500mg/kg) in diabetic rats. The hydroalcoholic extracts showed improvement in different parameters associated with diabetes, like body weight, lipid
profile and biochemical parameters. Extracts also showed improvement in

regeneration of β-cells of pancreas in diabetic rats.

Histopathological studies support the healing of pancreas by hydro alcoholic extracts (HAE1& HAE2) of Nardostachys Jatamansi, as a probable mechanism of their antidiabetic activity.

Antidiabetic and Antihyperlipidemic Effect of Parmelia Perlata. Ach. in Alloxan Induced Diabetic Rats.
Jothi G and Brindha P
Internat J of Pharmacy and Pharmaceut Sciences 2014; 6(suppl 1)

The aqueous extract of the selected plant was administered at dose levels of 200mg and 400mg/kg body weight for 60 days. After the experimental period the blood and tissue samples were collected and subjected to various biochemical and enzymic parameters. There were profound alteration in

fasting blood glucose,
serum insulin,
glycosylated hemoglobin (HbA1C) and
liver glycogen levels in alloxanized rats.

Glucose-6-phosphatase,
glucokinase, and
fructose 1-6 bisphosphatase activity

were also altered in diabetic rats.

Administration of plant extract significantly (P<0.05)

reduced the fasting blood glucose and HbA1C level and increased the level of plasma insulin.

The activities of glucose metabolizing enzymes were also resumed to normal. There was a profound improvement in serum lipid profiles by

reducing serum triglyceride, cholesterol, LDL, VLDL, free fatty acids, phospholipids and increasing the HDL level in a dose dependent manner.

The effects of leaf extract were compared with standard drug glibenclamide (600μg/Kg bw). The results indicate that Parmelia perlata. Ach., Linn. could be a good natural source for developing an antidiabetic drug that can effectively maintained the blood glucose levels and lipid profile to near normal values.

Pathophysiological Insights
Diabetic glomerulosclerosis

Reviewers: Nikhil Sangle, M.D.
Revised: 21 February 2014,
Copyright: (c) 2003-2012, PathologyOutlines.com, Inc.

General

==================================================

Diffuse capillary basement membrane thickening, diffuse and nodular glomerulosclerosis
Causes glomerular disease, arteriolar sclerosis, pyelonephritis, papillary necrosis; similar between type I and II patients
Accounts for 30% of long term dialysis patients in US; causes 20% of deaths in patients with diabetes < age 40
Changes may be related to nephronectin, which functions in the assembly of extracellular matrix (Nephrol Dial Transplant 2012;27:1889)

Clinical features

==================================================

Proteinuria occurs in 50%, usually 12-22 years after onset of diabetes
End stage renal disease occurs in 30% of type I patients
Early increased GFR and microalbuminemia (30-300 mg/day) are predictive of future diabetic nephropathy
Renal disease reduced by tight diabetic control; may recur with renal allografts; ACE inhibitors may reduce progression

Micro description

==================================================

Basement membrane thickening and increased mesangial matrix in ALL patients
Diffuse glomerulosclerosis: increase in mesangial matrix associated with PAS+ basement membrane thickening, eventually obliterates mesangial cells
Nodular glomerulosclerosis: also called intercapillary glomerulosclerosis or Kimmelstiel-Wilson disease; ovoid, spherical, laminated hyaline masses in peripheral of glomerulus, PAS+, eventually obliterates glomerular tuft; specific for diabetes and membranoproliferative glomerulonephritis, light-chain disease and amyloidosis (Hum Pathol 1993;24:77 (pathogenesis of Kimmelstiel-Wilson nodule))
Profound hyalinization of afferent arterioles (insudative lesion-intramural): specific for diabetes in afferent arterioles, but non-specific if in periphery of glomerular loop, Bowman’s capsule or mesangium; insudative material composed of proteins, lipids and mucopolysaccharides
Organizing fibroepithelial crescents: associated with aggressive clinical course
Diffuse thickening of tubular basement membrane, tubular atrophy and interstitial fibrosis
Isolated thickened glomerular basement membrane and proteinuria may be an early predictor of diabetic disease (Mod Pathol 2004;17:1506)

Nodular glomerulosclerosis, Kidney

Glomeruli:

Acellular, homogeneous, eosinophilic, globular nodules in the mesangial orintercapillary region of a glomerular tuft with capillary displaced to the periphery.
Diffuse intercapillary glomerulosclerosis: increasing eosinophilic mesangial matrix materials.
Capsular drop: eosinophilic small nodules on Bowman’s capsule.
Fibrin cap: eosinophilic, waxy, fatty structure within the lumen of one or more capillary loops of glomerular tufts.

nodular glomeruloschlerosis

http://www.kidneypathology.com/Imagenes/Diabetes/Imagen.Hial.jul.w.jpg

Islet amyloid polypeptide, islet amyloid, and diabetes mellitus.

Westermark P1, Andersson A, Westermark GT.
Physiol Rev. 2011 Jul;91(3):795-826.
http://dx.doi.org:/10.1152/physrev.00042.2009.

Islet amyloid polypeptide (IAPP), or amylin, was named for its tendency to

aggregate into insoluble amyloid fibrils, features typical of islets of most individuals with type 2 diabetes.

This pathological characteristic is most probably of

great importance for the development of the β-cell failure in this disease,
but the molecule also has regulatory properties in normal physiology.

In addition, it possibly contributes to the diabetic condition. This review deals with both these facets of IAPP.

Islet amyloid polypeptide (IAPP, or amylin) is one of the major secretory products of β-cells of the pancreatic islets of Langerhans. It is

a regulatory peptide with putative function
both locally in the islets, where it inhibits insulin and glucagon secretion, and at distant targets.

It has binding sites in the brain, possibly contributing also to satiety regulation and inhibits gastric emptying. Effects on several other organs have also been described.

IAPP was discovered through its ability to

aggregate into pancreatic islet amyloid deposits,

which are seen particularly in association with type 2 diabetes in humans and with diabetes in a few other mammalian species, especially monkeys and cats.

Aggregated IAPP has cytotoxic properties and is believed to be

of critical importance for the loss of β-cells in type 2 diabetes

and also in pancreatic islets transplanted into individuals with type 1 diabetes. This review deals both with physiological aspects of IAPP and with the

pathophysiological role of aggregated forms of IAPP,
including mechanisms whereby human IAPP forms toxic aggregates and amyloid fibrils.

Islet amyloid, initially named “islet hyalinization,” was described in 1901 by two researchers independently and for a long time was considered an enigma. It was found to occur in association with diabetes mellitus, particularly in elderly individuals, but its possible pathogenetic importance was often denied. The similarity of the hyaline substance to amyloid was noted at an early date, and some researchers reported staining reactions typical of amyloid. It had been shown in 1959 that

amyloid of several types has a characteristic ultrastructure,
and islet deposits were found to share this appearance.

When biochemical analyses of amyloid fibrils from systemic primary and secondary amyloidoses showed that

these consisted of distinctive proteins,
it was suspected that the islet deposits might also be a polymerized protein.

The chemical composition of islet amyloid did not attract much attention even after the characteristics of other amyloid fibrils had been elucidated. The finding that the amyloid in C cell-derived medullary thyroid carcinoma is of polypeptide hormonal origin was an important indication that amyloid in other endocrine tissues also comes from the local secretory products, and it was believed that

insulin, or proinsulin, or split products thereof constitute the islet amyloid fibrils.

Immunological trials to characterize the amyloid yielded equivocal results. Only when concentrated formic acid was used on amyloid,

extracted from an amyloid-rich insulinoma, was it possible to purify the major fibril protein
and characterize it by NH2-terminal amino acid sequence analysis,

which very unexpectedly revealed a novel peptide,

not resembling any part of proinsulin
but with partial identity to the neuropeptide calcitonin gene-related peptide (CGRP).

Further characterization of the peptide purified from an insulinoma and from islet amyloid of human and feline origin proved it to be a 37-amino acid (aa) residue peptide. The peptide was initially named “insulinoma amyloid peptide” , later diabetes-associated peptide (DAP), and finally islet amyloid polypeptide (IAPP), or “amylin”.

IAPP is a 37-aa residue long peptide, but by the application of molecular biological methods it was quickly shown that IAPP is expressed initially as

part of an 89-aa residue preproprotein containing a 22-aa signal peptide and
two short flanking peptides, the latter cleaved off at double basic aa residues similar to proinsulin.

IAPP is expressed by one single-copy gene on the short arm of chromosome 12,

in contrast to insulin and the other members of the calcitonin family, including
CGRP,
adrenomedullin, and
calcitonin,

all of which are encoded by genes on the evolutionary related chromosome 11.

The preproIAPP gene contains three exons, of which

the last two encode the full prepromolecule.

The signal peptide is cleaved

off in the endoplasmic reticulum (ER), and
conversion of proIAPP to IAPP takes place in the secretory vesicles.

ProIAPP and proinsulin are both processed by the two endoproteases

prohormone convertase 2 (PC2) and
prohormone convertase 1/3 (PC1/3) and
by carboxypeptidase E (CPE) (Figure 1).

amylin

A: the amino acid sequence of human pro-islet amyloid polypeptide (proIAPP) with the cleavage site for PC2 at the NH2 terminus and the cleavage site for PC1/3 at the COOH terminus, indicated by arrows. The KR residues (blue) that remain at the COOH terminus after PC1/3 processing are removed by carboxypeptidase E. This event exposes the glycine residue that is used for COOH-terminal amidation.
Below is a cartoon of IAPP in blue with the intramolecular S-S bond between residues 2–7 and the amidated COOH terminus.

B: the amino acid sequence of human proinsulin with the basic residues at the B-chain/C-peptide junction and the A-chain/C-peptide/junction indicated in blue and the processing sites indicated by arrows. PC1/3 does almost exclusively process proinsulin at the B-chain/C-peptide junction while PC2 preferentially processes proinsulin at the A-chain/C-peptide junction. The basic residues (RR) (position 31, 32) that remain at the COOH terminus of the B-chain is removed by the carboxypeptidase CPE. Below is a cartoon of insulin A-chain and B-chain in red with intermolecular SS bonds between cystein residues 7 in the A and B chains, between cystein residues at position 19 in the B-chain and 20 in the A-chain and the intermolecular SS bond between cystein residues at position 6 and 11 of the A-chain.

http://physrev.physiology.org/content/physrev/91/3/795/F1.large.jpg

IAPP and insulin genes contain similar promoter elements,
and the transcription factor PDX1 regulates the effects of glucose on both genes.
Glucose stimulated β-cells respond with a parallel expression pattern of IAPP and insulin in the rat.

However, this parallel secretion of IAPP and insulin is altered in experimental diabetes models in rodents. Perfused rat pancreas secreted relatively

more IAPP than insulin when exposed to dexamethasone, whereas
high doses of streptozotocin or alloxan reduced insulin secretion more than that of IAPP.

Oleat and palmitate increased the expression of IAPP but not of insulin in MIN6 cells. In mice fed a diet high in fat for 6 mo, plasma IAPP increased 4.5 times more than insulin compared with mice fed standard food containing 4% fat.

In human recipients who had become insulin-independent by intrahepatically transplanted islets, there was disproportionately

more IAPP than normal secreted during hyperglycemia.

These examples show that the strictly parallel expression of IAPP and insulin may be disturbed under certain conditions.

The crystalline structure of insulin in granules is well characterized.

Hexameric insulin, together with zinc, constitutes the core of the mature granules, while
IAPP, together with a large number of additional components, including the C peptide, is found in the halo region.

The highly fibrillogenic human IAPP has to be protected in some way from aggregation, which otherwise would take place spontaneously. The fact that very fibril-prone proteins can be kept in solution at high concentrations is known from studies of arthropod silk. The composition of the β-cell granule is extremely complex, and it has many components in addition to insulin and C peptide, in micromolar concentrations.

It is probable that IAPP is protected from aggregation by interaction with other components. Plausible candidates are

proinsulin, insulin, or their processing intermediates.

Insulin has been found to be

a strong inhibitor of IAPP fibril formation.

This finding has been verified in a number of subsequent studies, which have also shown the potency of the inhibition. The inhibition seems to depend

solely on the B-chain,
which binds specifically to a short segment of IAPP.

An insulin-to-IAPP ratio of between 1:5 and 1:100 had a strong inhibitory effect. The molar ratio between IAPP and insulin in the granule as a whole is ∼1–2:50.

Type 2 Diabetes, APOE Gene, and the Risk for Dementia and Related Pathologies. The Honolulu-Asia Aging Study

Rita Peila, Beatriz L. Rodriguez and Lenore J. Launer
Diabetes Apr 2002; 51(4): 1256-1262
http://dx.doi.org:/10.2337/diabetes.51.4.1256

Type 2 diabetes may be a risk factor for dementia, but the associated pathological mechanisms remains unclear. We evaluated the association of diabetes

alone or combined with the apolipoprotein E (APOE) gene
with incident dementia and neuropathological outcomes

in a population-based cohort of 2,574 Japanese-American men enrolled in the Honolulu-Asia Aging Study, including 216 subjects who underwent autopsy. Type 2 diabetes was ascertained by interview and direct glucose testing. Dementia was assessed in 1991 and 1994 by clinical examination and magnetic resonance imaging and was diagnosed according to international guidelines. Logistic regression was used to assess the RR of developing dementia, and log-linear regression was used to estimate the incident rate ratio (IRR) of neuropathological outcomes.

Diabetes was associated with

total dementia (RR 1.5 [95% CI 1.01–2.2]),
Alzheimer’s disease (AD; 1.8 [1.1–2.9]), and
vascular dementia (VsD; 2.3 [1.1–5.0]).

Individuals with both type 2 diabetes and the APOE ε4 allele

had an RR of 5.5 (CI 2.2–13.7) for AD compared with those with neither risk factor.

Participants with type 2 diabetes and the ε4 allele had

a higher number of hippocampal neuritic plaques (IRR 3.0 [CI 1.2–7.3]) and
neurofibrillary tangles in the cortex (IRR 3.5 [1.6–7.5]) and hippocampus (IRR 2.5 [1.5–3.7]), and
they had a higher risk of cerebral amyloid angiopathy (RR 6.6, 1.5–29.6).

Type 2 diabetes is a risk factor for AD and VsD. The association between diabetes and AD is particularly strong among carriers of the APOE ε4 allele. The neuropathological data are consistent with the clinical results.

Role of insulin signaling impairment, adiponectin and dyslipidemia in peripheral and central neuropathy in mice

Anderson, MR. King, L Delbruck, CG. Jolivalt
Dis. Model. Mech. June 2014; 7(6): 625-633
http://dx.doi.org:/10.1242/dmm.015750

One of the tissues or organs affected by diabetes is the nervous system,

predominantly the peripheral system (peripheral polyneuropathy and/or painful peripheral neuropathy)
but also the central system with impaired learning, memory and mental flexibility.

The aim of this study was to test the hypothesis that the pre-diabetic or diabetic condition caused by a high-fat diet (HFD) can damage both the peripheral and central nervous systems. Groups of C57BL6 and Swiss Webster mice were fed a diet containing 60% fat for 8 months and compared to control and streptozotocin (STZ)-induced diabetic groups that were fed a standard diet containing 10% fat. Aspects of peripheral nerve function (conduction velocity, thermal sensitivity) and central nervous system function (learning ability, memory) were measured at assorted times during the study. Both strains of mice on HFD developed impaired glucose tolerance, indicative of insulin resistance, but

only the C57BL6 mice showed statistically significant hyperglycemia.

STZ-diabetic C57BL6 mice

developed learning deficits in the Barnes maze after 8 weeks of diabetes, whereas
neither C57BL6 nor Swiss Webster mice fed a HFD showed signs of defects at that time point.

By 6 months on HFD, Swiss Webster mice developed

learning and memory deficits in the Barnes maze test,
whereas their peripheral nervous system remained normal.

In contrast, C57BL6 mice fed the HFD developed peripheral nerve dysfunction,

as indicated by nerve conduction slowing and thermal hyperalgesia,
but showed normal learning and memory functions.

Our data indicate that STZ-induced diabetes or a HFD can damage

both peripheral and central nervous systems,
but learning deficits develop more rapidly in insulin-deficient than in insulin-resistant conditions
and only in Swiss Webster mice.

In addition to insulin impairment, dyslipidemia or adiponectinemia might determine the neuropathy phenotype.

Neuroinflammation and neurologic deficits in diabetes linked to brain accumulation of amylin

S Srodulski, S Sharma, AB Bachstetter, JM Brelsfoard, et al.
Molecular Neurodegeneration 2014; 9(30):
http://dx.doi.org:/10.1186/1750-1326-9-30

Background: We recently found that brain tissue from patients with type-2 diabetes (T2D) and cognitive impairment

contains deposits of amylin, an amyloidogenic hormone synthesized and co-secreted with insulin by pancreatic β-cells.

Amylin deposition is promoted by

chronic hypersecretion of amylin (hyperamylinemia), which is common in humans with obesity or pre-diabetic insulin resistance.

Human amylin oligomerizes quickly when oversecreted, which is toxic,

induces inflammation in pancreatic islets and
contributes to the development of T2D.

Here, we tested the hypothesis that accumulation of oligomerized amylin affects brain function.

Methods: In contrast to amylin from humans,

rodent amylin is neither amyloidogenic nor cytotoxic.

We exploited this fact by comparing

rats overexpressing human amylin in the pancreas (HIP rats) with their littermate rats

which express only wild-type (WT) non-amyloidogenic rodent amylin. Cage activity, rotarod and novel object recognition tests were performed on animals nine months of age or older. Amylin deposition in the brain was documented by immunohistochemistry, and western blot. We also measured neuroinflammation by immunohistochemistry, quantitative real-time PCR and cytokine protein levels.

Results: Compared to WT rats, HIP rats show

i) reduced exploratory drive,
ii) impaired recognition memory and
iii) no ability to improve the performance on the rotarod.

The development of neurological deficits is

associated with amylin accumulation in the brain.

The level of oligomerized amylin in supernatant fractions and pellets from brain homogenates

is almost double in HIP rats compared with WT littermates (P < 0.05).

Large amylin deposits (>50 μm diameter) were also occasionally seen in HIP rat brains. Accumulation of oligomerized amylin

alters the brain structure at the molecular level.

Immunohistochemistry analysis with an ED1 antibody indicates possible activated microglia/macrophages which

are clustering in areas positive for amylin infiltration.

Multiple inflammatory markers are expressed in HIP rat brains as opposed to WT rats, confirming that

amylin deposition in the brain induces a neuroinflammatory response.

Conclusions:

Hyperamylinemia promotes accumulation of oligomerized amylin in the brain
leading to neurological deficits through an oligomerized amylin-mediated inflammatory response.

Additional studies are needed to determine

whether brain amylin accumulation may predispose to diabetic brain injury and cognitive decline.

Keywords: Diabetes, Alzheimer’s Disease, Amylin, Pre-diabetes, Insulin Resistance, Inflammation, Behavior

Read Full Post »

Metabolomics is about Metabolic Systems Integration

Posted in Alzheimer's Disease, Best evidence, Bio Instrumentation in Experimental Life Sciences Research, CANCER BIOLOGY & Innovations in Cancer Therapy, Cardiovascular Research, Cerebrovascular and Neurodegenerative Diseases, Chemical Biology and its relations to Metabolic Disease, Computational Biology/Systems and Bioinformatics, tagged antiniotics by design, drug targets, enzyme alignments, metabolic sequences, Metabolomics, nitric oxide synthase (NOS) isozymes, transcription on October 13, 2014| Leave a Comment »

Metabolomics is about Metabolic Systems Integration

Author and Curator: Larry H Bernstein, MD, FCAP

This is an exploration of biological thoughts in the series on metabolomics, putting enzymatic reactions, proteins and protein conformation, and subanatomic structure into a more complete perspective in order to realize normal and dysfunctional states

of eukaryoticcells and organ systems and prokaryotic organisms. There are structures and functions that have evolved in evolution that have concordance, even
if we find variation on themes. Moreover, these have to be understood in a systems oriented view to have any clarity, which is currently an ongoing proposal.
It is perhaps relevant to quote Radoslav Bosov on his observation:

“After finishing her portion of the work on DNA, Franklin led pioneering work on the tobacco mosaic virus and the polio virus. She died in 1958 at the age of 37 of ovarian cancer.” My job is to illuminate what is cancer, but serving structural identity issues.

DNA is not DNA, as RNA is not RNA as proteins are not Proteins, there is only time – interference of particles/strings/waves within ever emerging discrete relative spaces where energy transforms from one absolute form into another!

He adds the following: “A 2005 study showed methionine restriction without energy restriction extends mouse lifespan.” BUT balancing energy is not as same as balancing matter due quantum electrodynamics interference and transfromability – http://en.wikipedia.org/wiki/Methionine

I have made the following calculations!

1 – methyl groups = i Ln (1 – Lactate )/Ln (Oxygen) – K (O) =

i Ln (1/(Sqrt (1 – Acetate^2)) /Ln(Oxygen) – K(O) = i Ln (Glyoxylate)/Ln (Oxygen) – K(O)

where K(O) – mechanical electro magnetics pressure, with increase of T, increase of S (entropy), and 1-S = negative entropy

But don’t try to realize the path of derivation, it would get you in dark matter issues – water!

The problem seems to be:

Methionine is necessary to provide S for acetyl CoA
Insufficiency of this amino acid has consequences, which leads to increased homocysteine
This imbalance is also associated with a decrease in lewan body mass
Of course, the reality is that geographic location, proximity to volcanic ash, and temperate zone have relevance, as does food source, and they are relevant variables

JEDS Rosalino has referred to the important conclusion in Erwin Schroedinger’s “What is Life?”, and Schroedinger’s cat. It is impossible to come up with a predictive equation to explain life.
It had to come from a founder of “Quantum Mechanics” because, unlike economics, physics is a science based on experimental validation. In entering biology from Physics to make it more rigorous, as was the case for Max Delbruck, who was preceded by the Cori’s, Beadle and Tatum, Herschey, Luria, Dubecco, Kornberg and Ochoa, Lipmann, Watson and Crick, a discipline called “Molecular Biology and Biochemistry” emerged that would open the secrets of life. Beadle and Tatum gave us “one gene – one enzyme”, a formulation that led in medical teaching from William Osler’s edict to “Inherited Metabolic Disorders” – gene related disruption of the chemical reactions taking place in the body to convert or use energy. Physiological chemistry taught:

Breaking down the carbohydrates, proteins, and fats in food to release energy.
Transforming excess nitrogen into waste products excreted in urine.
Breaking down or converting chemicals into other substances and transporting them inside cells.

Metabolism is an organized but chaotic chemical assembly line. Raw materials, half-finished products, and waste materials are constantly being used, produced, transported, and excreted. The “workers” on the assembly line are enzymes and other proteins that make chemical reactions happen. – http://www.webmd.com/a-to-z-guides/inherited-metabolic-disorder-types-and-treatments

The original cause of most genetic metabolic disorders is a gene mutation that occurred many, many generations ago. Each inherited metabolic disorder is quite rare in the general population, affecting about 1 in 1,000 to 2,500 newborns. But the developments now refocused an emphasis on HOW – a gene mutation occurs that is passed on through generations. This had to be derived initially from methods developed in prokaryotes in order to relieve the complexity. However, complexity came from evolutionary events over a long time span.

Part I. Transcription regulation

The timing is right

R Magnus N Friis & Michael C Schultz
Affiliations Corresponding author

Nature Structural & Molecular Biology 07 Oct 2014; 21: 846–847
http://dx.doi.org:/10.1038/nsmb.2898

Yeast cells display synchronized oscillation between

phases of high and low oxygen consumption
accompanied by a program of cyclical gene expression.

A study monitoring

mRNA levels,
histone modifications and
chromatin occupancy of histone modifiers

during the yeast metabolic cycle (YMC) at high temporal resolution reveals both

‘just-in-time’ supply of YMC gene products and
new patterns of chromatin reconfiguration

associated with transcriptional regulation.

Figure 1: The yeast metabolic cycle.

The YMC is divided into metabolic phases that correspond to periods of high and low oxygen concentration in the culture medium. The program of gene (mRNA) expression during the YMC is composed of successive reductive-charging (RC),…
http://www.nature.com/nsmb/journal/v21/n10/carousel/nsmb.2898-F1.jpg

Figure 2: Modes of transcriptional regulation during the YMC.

Modes of transcriptional regulation during the YMC

(a) Previous work on cycling cells in batch culture revealed that H3K4me3 is typically limited to the promoter region of active genes (MET16 shown here ^{9, 10}). (b) During the YMC, however, the OX gene RMT2 is marked by H3K4me3 regardles…

http://www.nature.com/nsmb/journal/v21/n10/carousel/nsmb.2898-F2.jpg

High-temporal-resolution view of transcription and chromatin states across distinct metabolic states in budding yeast

Z Kuang, L Cai, X Zhang, H Ji, BP Tu & JD Boeke
Affiliations Contributions Corresponding authors

Nature Structural & Molecular Biology 31 Aug,2014; 21: 854–863
http://dx.doi.org:/10.1038/nsmb.2881

Under continuous, glucose-limited conditions, budding yeast exhibit

robust metabolic cycles
associated with major oscillations of gene expression.

We examine the correlated

genome-wide transcription and chromatin states
across the yeast metabolic cycle
at unprecedented temporal resolution,
revealing a ‘just-in-time supply chain’

by which components from specific cellular processes such as ribosome biogenesis become available in a highly coordinated manner. We identify

distinct chromatin and splicing patterns
associated with different gene categories and
determine the relative timing of chromatin modifications
relative to maximal transcription.

There is unexpected variation in the chromatin modification and expression relationship, with

histone acetylation peaks occurring with
varying timing and ‘sharpness’ relative to RNA expression
both within and between cycle phases.

Chromatin-modifier occupancy reveals subtly distinct spatial and temporal patterns compared to those of the modifications themselves.

Figure 1: High-temporal-resolution analysis of gene expression reveals meticulous temporal compartmentalization in yeast.

High-temporal-resolution analysis of gene expression

Oscillation of oxygen (dO2) in the YMC. The 16 time points of one cycle for RNA-seq are labeled. Metabolic phases are color coded throughout figures: magenta, OX phase; green, RB phase; blue, RC phase. (b–d) Subtly distinct tempor…

http://www.nature.com/nsmb/journal/v21/n10/carousel/nsmb.2881-F1.jpg

Figure 2: RNA-seq analysis at introns reveals transient accumulation of pre-mRNAs during OX phase.

RNA-seq analysis at introns reveals transient accumulation of pre-mRNAs

Relative RNA signals at intron-containing genes. Each track represents relative RNA levels at one of 16 time points, ordered sequentially from top to bottom. Signals are displayed as a percentage of the maximum value of the 16 time…
http://www.nature.com/nsmb/journal/v21/n10/carousel/nsmb.2881-F2.jpg

Figure 3: Dynamic chromatin states across the YMC.

Dynamic chromatin states across the YMC

(a)Oscillation of oxygen in one YMC. Cycling cells were collected at 16 intentionally uneven time points over one cycle for ChIP-seq. (b,c) Temporal relationship between RNA level and histone modifications at the RMT2 locus. (b) RNA…

http://www.nature.com/nsmb/journal/v21/n10/carousel/nsmb.2881-F3.jpg

Part 2. Structure of metabolic channeling

Enzyme clustering accelerates processing of intermediates through metabolic channeling

Michele Castellana, Maxwell Z Wilson, Yifan Xu, Preeti Joshi, Ileana M Cristea, Joshua D Rabinowitz, Zemer Gitai & Ned S Wingreen
Affiliations Contributions Corresponding authors

Nature Biotechnology (2014)32, 1011–1018
http://dx.doi.org:/10.1038/nbt.3018

We present a quantitative model to demonstrate that

coclustering multiple enzymes into compact agglomerates
accelerates the processing of intermediates,
yielding the same efficiency benefits as direct channeling,

a well-known mechanism in which enzymes are funneled between enzyme active sites through a physical tunnel. The model predicts

the separation and size of coclusters that maximize metabolic efficiency,
and this prediction is in agreement with previously reported spacings between coclusters in mammalian cells.

For direct validation, we study a metabolic branch point in Escherichia coli and experimentally confirm the model prediction that enzyme agglomerates can

accelerate the processing of a shared intermediate by one branch, and thus
regulate steady-state flux division.

Our studies establish a quantitative framework to understand coclustering-mediated metabolic channeling

Figure 1: Different types of intermediate channeling in a two-step metabolic pathway, where a substrate is processed by enzyme E1 and turned into intermediate, which is then processed by enzyme E2 and turned into product.

two-step metabolic pathway

Direct channeling. The intermediate is funneled from enzyme E1 to enzyme E2 by means of a protein tunnel that connects the active sites of E1 and E2, thus preventing the intermediate from diffusing away. (b) Proximity channeling. http://www.nature.com/nbt/journal/v32/n10/carousel/nbt.3018-F1.jpg

Figure 2: Two-step metabolic pathway with an unstable intermediate.

Two-step metabolic pathway with an unstable intermediate

(a) The two-step metabolic pathway. Substrate S0 is processed by enzyme E1 and turned into intermediate S1, which is then processed by enzyme E2 and turned into product P. (b) Enzyme configurations in the two-step metabolic pathway. Le…
http://www.nature.com/nbt/journal/v32/n10/carousel/nbt.3018-F2.jpg

Part 3. Antibiotics directed at specific DNA sequences

Sequence-specific antimicrobials using efficiently delivered RNA-guided nucleases

Robert J Citorik, Mark Mimee & Timothy K Lu
Affiliations Contributions Corresponding author

Nature Biotechnology 21 Sep 2014;
http://dx.doi.org:/10.1038/nbt.3011

Current antibiotics tend to be broad spectrum, leading to

indiscriminate killing of commensal bacteria and
accelerated evolution of drug resistance.

Here, we use CRISPR-Cas technology to create antimicrobials

whose spectrum of activity is chosen by design.

RNA-guided nucleases (RGNs) targeting specific DNA sequences are delivered efficiently to microbial populations using bacteriophage or bacteria carrying plasmids transmissible by conjugation. The DNA targets of RGNs can be

undesirable genes or polymorphisms,
including antibiotic resistance and virulence determinants in

carbapenem-resistant Enterobacteriaceae and
enterohemorrhagic Escherichia coli.

Delivery of RGNs significantly improves survival in a Galleria mellonella infection model. We also show that

RGNs enable modulation of complex bacterial populations
by selective knockdown of targeted strains
based on genetic signatures.

RGNs constitute a class of highly discriminatory, customizable antimicrobials that enact

selective pressure at the DNA level to

reduce the prevalence of undesired genes,
minimize off-target effects and
enable programmable remodeling of microbiota.

Figure 1: RGN constructs delivered by bacteriophage particles (ΦRGN) exhibit efficient and specific antimicrobial effects against strains harboring plasmid or chromosomal target sequences

RGN constructs delivered by bacteriophage particles

(a) Bacteriophage-delivered RGN constructs differentially affect host cell physiology in a sequence-dependent manner. If the target sequence is: (i) absent, the RGN exerts no effect; (ii) chromosomal, RGN activity is cytotoxic; (iii) e…

http://www.nature.com/nbt/journal/vaop/ncurrent/carousel/nbt.3011-F1.jpg

Figure 3: ΦRGN particles elicit sequence-specific toxicity against enterohemorrhagic E. coli in vitroand in vivo.

ΦRGN particles elicit sequence-specific toxicity against enterohemorrhagic E. coli in vitro and in vivo.

(a) E. coli EMG2 wild-type (WT) cells or ATCC 43888 F′ (EHEC) cells were treated with SM buffer, ΦRGNndm-1 orΦRGNeae at a multiplicity of infection (MOI) ~100 and plated onto LB agar to enumerate total cell number or LB+kanamycin (Km)… http://www.nature.com/nbt/journal/vaop/ncurrent/carousel/nbt.3011-F3.jpg

Part 4. Structure and Isoform functions

Structures of human constitutive nitric oxide synthases.

H Li, J Jamal, C Plaza, SH Pineda, G Chreifi, Q Jing, MA Cinelli, RB Silverman, TLPoulos, [more]
Acta Crystallographica Section D Biological Crystallography (Impact Factor: 12.67). 10/2014; 70(Pt 10):2667-74.
http://dx.doi.org:/10.1107/S1399004714017064

Mammals produce three isoforms of nitric oxide synthase (NOS):

neuronal NOS (nNOS),
inducible NOS (iNOS) and
endothelial NOS (eNOS).

The overproduction of NO by nNOS is associated with a number of neurodegenerative disorders; therefore, a desirable therapeutic goal is

the design of drugs that target nNOS
but not the other isoforms.

Crystallography, coupled with computational approaches and medicinal chemistry, has played a critical role in developing highly

selective nNOS inhibitors that
exhibit exceptional neuroprotective properties.

For historic reasons, crystallography has focused on rat nNOS and bovine eNOS because these were available in high quality; thus, their structures have been used in

structure-activity-relationship studies.

Although these constitutive NOSs share more than 90% sequence identity across mammalian species for each NOS isoform,

inhibitor-binding studies revealed that subtle differences near the heme active site
in the same NOS isoform across species still impact enzyme-inhibitor interactions.

Therefore, structures of the human constitutive NOSs are indispensible. Here, the first structure of human neuronal NOS at 2.03 Å resolution is reported and a different crystal form of human endothelial NOS is reported at 1.73 Å resolution.

“We are learning more about less and less” – PJ Russell. 1973.

Part 5. Global Metabolomics

Global Metabolomics Market (Technique, Application, Indication and Geography) – Size, Application Analysis, Regional Outlook, Competitive Strategies and Forecasts, 2014 – 2020

Metabolomics is

the study of chemical processes which involve metabolites.

Metabolites are small molecules present in the blood, tissues and urine. Metabolomics pertains to the study of the

unique chemical fingerprints left behind by cellular processes.

These metabolite fingerprints could be used to learn about the health of an organism. It is an upcoming technology in the field of analytical biochemistry. Metabolomics has become an experimental technique that can be applied in medicine, biology and environmental science. The incorporation of computers has enabled

the creation of computational metabolomics that has application in life sciences.

Metabolics finds application in other areas as well; for instance, it is used to identify the quality, taste and nutritional value of food in the food science field.

The metabolomics market is segmented based on its application in different fields such as

biomarkers discovery,
drug discovery,
toxicology testing,
nutrigenomics,
clinical studies etc.

The drug discovery segment holds the dominant share in the metabolomics market due to its crucial role in

drug target identification & validation and
optimization & prioritization of diagnostic approaches for oncology research.

The metabolomics market is expected to grow at a rapid rate due to the rise in the number of

pre clinical & clinical trials,
advancements in toxicological studies and
growing awareness about nutritional products.

The stellar growth of data analysis software & solutions in metabolomics and its use in the biomarker screening of diseases would fuel the growth of the metabolomics market. The metabolomics market is also segmented based on techniques into

gas chromatography,
high performance liquid chromatography (HPLC),
ultra performance liquid chromatography, and
capillary electrophoresis.

HPLC holds the dominant share in the metabolomics market.

KEY BENEFITS

In-depth analysis of various regions would enable a clear understanding of current and future trends so that companies can make region specific plans

Comprehensive analysis of the factors that drive and restrict the growth of the metabolomics market

Key regulatory guidelines in various regions which impact the metabolomics market

Quantitative analysis of the current market

Deep dive analysis of various regions

Value chain analysis enables a clear understanding of the roles of the stakeholders involved in the supply chain of the metabolomics market

Market Segmentation

The metabolomics market is segmented based on techniques, applications, indication and geography

Techniques

Separation Method

Gas Chromatography
Capillary Electrophoresis
High Performance Liquid Chromatography
Ultra Performance Liquid Chromatography

Detection Methods

Nuclear Magnetic Resonance
Mass Spectrometry
Surface Base Mass Analysis

Application

Biomarkers Discovery
Drug Discovery
Toxicology Testing
Nutrigenomics
Clinical & Preclinical Studies

Indications

Oncology
Neurology
Cardiology
Others

Read Full Post »

The Use of Light Waves to Visualize and Stimulate the Human Brain

Posted in Alzheimer's Disease on September 9, 2014| Leave a Comment »

The Use of Light Waves to Visualize and Stimulate the Human Brain

Reporter: Aviva Lev-Ari, PhD, RN

A new way to understand the human brain: Interview

By Viviana Gradinaru

Sep 2 2014

Video footage from your research shows a mouse with a fiberoptic cable connected to its brain. When you shine a blue light down the cable, the mouse runs around in circles. When you switch off the light, the mouse stops. What’s happening?

FULL ARTICLE

http://forumblog.org/2014/09/interview-shining-light-brains-work/

Read Full Post »

Plant-based Nutrition, Neutraceuticals and Alternative Medicine: Article Compilation the Journal PharmaceuticalIntelligence.com

Posted in Advanced Drug Manufacturing Technology, CANCER BIOLOGY & Innovations in Cancer Therapy, Diabetes Mellitus, Human Immune System in Health and in Disease, Infectious Disease & New Antibiotic Targets, Lipid metabolism, Nutrition, Nutrition and Phytochemistry, Nutritional Supplements: Atherogenesis, Pharmacotherapy and Cell Activity, Population Health Management, Proteomics, Systemic Inflammatory Response Related Disorders, Translational Effectiveness, Translational Science, tagged Biotechnology and Pharmaceuticals, Cancer research, Cardiovascular disease, Cardiovascular Disorders, Chemotherapy, Diabetes mellitus type 2, FDA, Nutrition on September 1, 2014| Leave a Comment »

Plant-based Nutrition, Neutraceuticals and Alternative Medicine: Article Compilation the Journal PharmaceuticalIntelligence.com

Curator: Larry H. Bernstein, MD, FCAP

Green tea polyphenols alleviate early BBB damage
http://pharmaceuticalintelligence.com/2013/07/31/green-tea-polyphenols-alleviate-early-bbb-damage-during/
What do you know about Plants and Neutraceuticals?

Author and Curator, Larry H. Bernstein, MD, FCAP

http://pharmaceuticalintelligence.com/2014/07/30/what-do-you-know-about-plants-and-neutraceuticals/

The Final Considerations of the Role of Platelets and Platelet Endothelial Reactions in Atherosclerosis and Novel Treatments

Author and Curator: Larry H Bernstein, MD, FCAP

http://pharmaceuticalintelligence.com/2013/10/15/the-final-considerations-of-the-role-of-platelets-and-platelet-endothelial-reactions-in-atherosclerosis-and-novel-treatments/

Endothelial Function and Cardiovascular Disease

Author and Curator: Larry H Bernstein, MD, FCAP

http://pharmaceuticalintelligence.com/2012/10/25/endothelial-function-and-cardiovascular-disease/

NO Nutritional remedies for hypertension and atherosclerosis. It’s 12 am: do you know where your electrons are?

Author and Reporter: Meg Baker, Ph.D., Registered Patent Agent

http://pharmaceuticalintelligence.com/2012/10/07/no-nutritional-remedies-for-hypertension-and-atherosclerosis-its-12-am-do-you-know-where-your-electrons-are/

Cocoa and Heart Health

Reporter: Larry H Bernstein, MD, FCAP

http://pharmaceuticalintelligence.com/2013/11/17/cocoa-and-heart-health/

Metabolomics: its applications in food and nutrition research

Reporter and Curator: Dr. Sudipta Saha, Ph.D.

http://pharmaceuticalintelligence.com/2013/05/12/metabolomics-its-applications-in-food-and-nutrition-research/

Japanese knotweed extract (Polygonum cuspidatum) Resveratrol 98%

Reporter: Larry H Bernstein, MD, FCAP Stanford Lee, Shanghai Natural Bio-engineering Co., Ltd
Key products: resveratrol, curcumin,artemisinin,artemether,artesunate,dihydroartemisinin,Lumefantrine,etc
https://www.linkedin.com/today/post/article/20140805055958-283555965-japanese-knotweed-extract-polygonum-cuspidatum-resveratrol-98?/

http://pharmaceuticalintelligence.com/2014/08/20/japanese-knotweed-extract-polygonum-cuspidatum-resveratrol-98/

Antimicrobial resistance
Reporter: Larry H Bernstein, MD, FCAP
http://pharmaceuticalintelligence.com/2014/08/18/antimicrobial-resistance/
Macrocycles in new drug discovery
Reporter: Larry H Bernstein, MD, FCAP Jamie Mallinson, Ian Collins
Future Medicinal Chemistry, Jul 2012, Vol. 4, No. 11, Pages 1409-1438.

Natural product macrocycles and their synthetic derivatives

http://pharmaceuticalintelligence.com/2014/08/16/macrocycles-in-new-drug-discovery/

Lipid Metabolism

ALA and LA, LCPUFAs (EPA, DHA, and AA), eicosanoids, delta-3-desaturase, prostaglandins, leukotrienes

Ginseng fights fatigue in cancer patients, Mayo Clinic-led study finds http://pharmaceuticalintelligence.com/2014/08/15/lipid-metabolism/

Ginseng fights fatigue in cancer patients, Mayo Clinic-led study finds

Reporter: Larry H Bernstein, MD, FCAP

http://pharmaceuticalintelligence.com/2014/08/10/ginseng-fights-fatigue-in-cancer-patients-mayo-clinic-led-study-finds/

Scientists develop new cancer-killing compound from salad plant / 1,200 times more specific in killing certain kinds of cancer cells than currently available drugs
Reporter: Larry H Bernstein, MD, FCAP
http://pharmaceuticalintelligence.com/2014/07/17/scientists-develop-new-cancer-killing-compound-from-salad-plant-1200-times-more-specific-in-killing-certain-kinds-of-cancer-cells-than-currently-available-drugs/
Protein heals wounds, boosts immunity and protects from cancer – Lactoferrin
Reporter: Larry H Bernstein, MD, FCAP
http://pharmaceuticalintelligence.com/2014/07/17/protein-heals-wounds-boosts-immunity-and-protects-from-cancer-lactoferrin/
Inula helenium ( elecampane ) 100% Effective against MRSA in vitro, 200 Strains
Reporter: Larry H Bernstein, MD, FCAP
http://pharmaceuticalintelligence.com/2014/07/15/inula-helenium-elecampane-100-effective-against-mrsa-in-vitro-200-strains/
Thymoquinone, an extract of nigella sativa seed oil, blocked pancreatic cancer cell growth and killed the cells by enhancing the process of programmed cell death.
Reporter: Larry H Bernstein, MD, FCAP
http://pharmaceuticalintelligence.com/2014/07/15/thymoquinone-an-extract-of-nigella-sativa-seed-oil-blocked-pancreatic-cancer-cell-growth-and-killed-the-cells-by-enhancing-the-process-of-programmed-cell-death/
Cinnamon is lethal weapon against E. coli O157:H7
Reporter: Larry H Bernstein, MD, FCAP
http://pharmaceuticalintelligence.com/2014/07/15/cinnamon-is-lethal-weapon-against-e-coli-o157h7/
Garlic compound fights source of food-borne illness better than antibiotics (100 times more effective than two popular antibiotics )

Reporter: Larry H Bernstein, MD, FCAP

http://pharmaceuticalintelligence.com/2014/07/15/garlic-compound-fights-source-of-food-borne-illness-better-than-antibiotics-100-times-more-effective-than-two-popular-antibiotics/

Reference Genes in the Human Gut Microbiome: The BGI Catalogue

Reporter: Aviva Lev-Ari, PhD, RN

http://pharmaceuticalintelligence.com/2014/07/14/reference-genes-in-the-human-gut-microbiome-the-bgi-catalogue/

Study suggests consuming whey protein before meals could help improve blood glucose control in people with diabetes
Reporter: Larry H Bernstein, MD, FCAP
http://pharmaceuticalintelligence.com/2014/07/12/study-suggests-consuming-whey-protein-before-meals-could-help-improve-blood-glucose-control-in-people-with-diabetes/
Omega-3 fatty acids, depleting the source, and protein insufficiency in renal disease
Larry H. Bernstein, MD, FCAP, Curator
http://pharmaceuticalintelligence.com/2014/07/06/omega-3-fatty-acids-depleting-the-source-and-protein-insufficiency-in-renal-disease/
Health benefit of anthocyanins from apples and berries noted for men
Larry H. Bernstein, MD, FCAP, Curator
http://pharmaceuticalintelligence.com/2014/07/06/health-benefit-of-anthocyanins-from-apples-and-berries-noted-for-men/
Carrots Cut Men’s Prostate Cancer Risk by 50%
Larry H. Bernstein, MD, FCAP, Reporter
http://pharmaceuticalintelligence.com/2014/07/03/carrots-cut-mens-prostate-cancer-risk-by-50/
A Recipe To Make Cannabis Oil For A Chemotherapy Alternative
Larry H. Bernstein, MD, FCAP, Reporter
http://pharmaceuticalintelligence.com/2014/07/02/a-recipe-to-make-cannabis-oil-for-a-chemotherapy-alternative/
Plant flavonoid found to reduce inflammatory response in the brain: luteolin
Larry H. Bernstein, MD, FCAP, Reporter
http://pharmaceuticalintelligence.com/2014/06/29/plant-flavonoid-found-to-reduce-inflammatory-response-in-the-brain-luteolin/
Omega-3 fatty acids protect eyes against retinopathy, study finds
Larry H. Bernstein, MD, FCAP, Reporter
http://pharmaceuticalintelligence.com/2014/06/28/omega-3-fatty-acids-protect-eyes-against-retinopathy-study-finds/
Scientists identify new pathogenic and protective microbes associated with severe diarrhea
Larry H. Bernstein, MD, FCAP, Reporter
http://pharmaceuticalintelligence.com/2014/06/28/scientists-identify-new-pathogenic-and-protective-microbes-associated-with-severe-diarrhea/
2,000-year-old herb regulates autoimmunity and inflammation / Chang Shan, from a type of hydrangea that grows in Tibet and Nepal
Larry H. Bernstein, MD, FCAP, Reporter
http://pharmaceuticalintelligence.com/2014/06/27/2000-year-old-herb-regulates-autoimmunity-and-inflammation-chang-shan-from-a-type-of-hydrangea-that-grows-in-tibet-and-nepal/
Turmeric-based drug effective on Alzheimer flies
Larry H. Bernstein, MD, FCAP, Reporter
http://pharmaceuticalintelligence.com/2014/06/27/turmeric-based-drug-effective-on-alzheimer-flies/
Plant flavonoid luteolin blocks cell signaling pathways in colon cancer cells
Larry H. Bernstein, MD, FCAP, Reporter
http://pharmaceuticalintelligence.com/2014/06/26/plant-flavonoid-luteolin-blocks-cell-signaling-pathways-in-colon-cancer-cells/
Study Finds Shu Gan Liang Xue Herbal Formula Has Breast Cancer Anti Tumor Effect
Larry H. Bernstein, MD, FCAP, Reporter
http://pharmaceuticalintelligence.com/2014/06/25/study-finds-shu-gan-liang-xue-herbal-formula-has-breast-cancer-anti-tumor-effect/
HMPC Q&A Documents on Herbal Medicinal Products published
Larry H. Bernstein, MD, FCAP, Reporter
http://pharmaceuticalintelligence.com/2014/06/25/hmpc-qa-documents-on-herbal-medicinal-products-published/
Garden Cress Extract Kills 97% of Breast Cancer Cells in Vitro
Larry H. Bernstein, MD, FCAP, Reporter
http://pharmaceuticalintelligence.com/2014/06/21/garden-cress-extract-kills-97-of-breast-cancer-cells-in-vitro/
Moringa Oleifera Kills 97% of Pancreatic Cancer Cells in Vitro
Larry H. Bernstein, MD, FCAP, Reporter
http://pharmaceuticalintelligence.com/2014/06/21/moringa-oleifera-kills-97-of-pancreatic-cancer-cells-in-vitro/

16. The Discovery and Properties of Avemar – Fermented Wheat Germ Extract: Carcinogenesis Suppressor
Larry H. Bernstein, MD, FCAP, Author and Curator
http://pharmaceuticalintelligence.com/2014/06/09/the-discovery-and-properties-of-avemar-fermented-wheat-germ-extract-carcinogenesis-suppressor-2/

Read Full Post »

Proteomics, Metabolomics, Signaling Pathways, and Cell Regulation: a Compilation of Articles in the Journal http://pharmaceuticalintelligence.com

Posted in Biological Networks, Biomarkers & Medical Diagnostics, Biomedical Measurement Science, Calcium Signaling, CANCER BIOLOGY & Innovations in Cancer Therapy, Cardiovascular Research, Cell Biology, Chemical Biology and its relations to Metabolic Disease, Chemical Genetics, Coagulation Therapy and Internal Bleeding, Diabetes Mellitus, Disease Biology, FDA Regulatory Affairs, Frontiers in Cardiology and Cardiovascular Disorders, Gene Regulation and Evolution, Genetics & Pharmaceutical, Genome Biology, Genomic Expression, Genomic Testing: Methodology for Diagnosis, Infectious Disease & New Antibiotic Targets, Innovation in Immunology Diagnostics, Lipid metabolism, Liver & Digestive Diseases Research, Metabolomics, Molecular Genetics & Pharmaceutical, Myocardial adenine nucleotide metabolism, Myocardial Ischemia, Myocardial Metabolism, Nitric Oxide in Health and Disease, Nutritional Supplements: Atherogenesis, Pharmacotherapy and Cell Activity, Pharmacotherapy of Cardiovascular Disease, Population Health Management, Proteomics, Signaling, Signaling & Cell Circuits, Small Molecules in Development of Therapeutic Drugs, Systemic Inflammatory Response Related Disorders, Translational Research, Translational Science, tagged Alzheimers Disease, Apoptosis, Aviva Lev-Ari, bibliorgaphy, Biochemistry and Molecular Biology, biomarkers, breast cancer, Cancer research, Cardiovascular disease, Chemotherapy, compilation, Conditions and Diseases, curations, Diabetes mellitus type 2, DNA, Endothelium, gene, gene expression, Genome-wide association study, Human Genome Project, immune system, Leaders in Pharmaceutical Intelligence, Messenger RNA, Metabolism, Metabolomics, metastasis, MicroRNA, mitochondria, National Human Genome Research Institute, National Institutes of Health, Nitric oxide synthase, NO, Personalized medicine, Proceedings of the National Academy of Sciences of the United States of America, Proteomics, RNA, Signal transduction, Single-nucleotide polymorphism, Stanford University, Stem cell, Warburg Effect on September 1, 2014| Leave a Comment »

Compilation of References by Leaders in Pharmaceutical Business Intelligence in the Journal http://pharmaceuticalintelligence.com about
Proteomics, Metabolomics, Signaling Pathways, and Cell Regulation

Curator: Larry H Bernstein, MD, FCAP

Proteomics

The Human Proteome Map Completed

Reporter and Curator: Larry H. Bernstein, MD, FCAP

http://pharmaceuticalintelligence.com/2014/08/28/the-human-proteome-map-completed/

Proteomics – The Pathway to Understanding and Decision-making in Medicine

Author and Curator, Larry H Bernstein, MD, FCAP

http://pharmaceuticalintelligence.com/2014/06/24/proteomics-the-pathway-to-
understanding-and-decision-making-in-medicine/

3. Advances in Separations Technology for the “OMICs” and Clarification of Therapeutic Targets

Author and Curator, Larry H Bernstein, MD, FCAP

http://pharmaceuticalintelligence.com/2012/10/22/advances-in-separations-technology-for-the-omics-and-clarification- of-therapeutic-targets/

Expanding the Genetic Alphabet and Linking the Genome to the Metabolome

Author and Curator, Larry H Bernstein, MD, FCAP

http://pharmaceuticalintelligence.com/2012/09/24/expanding-the-genetic-alphabet-and-linking-the-genome-to-the- metabolome/

5. Genomics, Proteomics and standards

Larry H Bernstein, MD, FCAP, Author and Curator

http://pharmaceuticalintelligence.com/2014/07/06/genomics-proteomics-and-standards/

6. Proteins and cellular adaptation to stress

Larry H Bernstein, MD, FCAP, Author and Curator

http://pharmaceuticalintelligence.com/2014/07/08/proteins-and-cellular-adaptation-to-stress/

Metabolomics

Extracellular evaluation of intracellular flux in yeast cells

Larry H. Bernstein, MD, FCAP, Reviewer and Curator

http://pharmaceuticalintelligence.com/2014/08/25/extracellular-evaluation-of-intracellular-flux-in-yeast-cells/

Metabolomic analysis of two leukemia cell lines. I.

Larry H. Bernstein, MD, FCAP, Reviewer and Curator

http://pharmaceuticalintelligence.com/2014/08/23/metabolomic-analysis-of-two-leukemia-cell-lines-_i/

Metabolomic analysis of two leukemia cell lines. II.

Larry H. Bernstein, MD, FCAP, Reviewer and Curator

http://pharmaceuticalintelligence.com/2014/08/24/metabolomic-analysis-of-two-leukemia-cell-lines-ii/

Metabolomics, Metabonomics and Functional Nutrition: the next step in nutritional metabolism and biotherapeutics

Reviewer and Curator, Larry H. Bernstein, MD, FCAP

http://pharmaceuticalintelligence.com/2014/08/22/metabolomics-metabonomics-and-functional-nutrition-the-next-step- in-nutritional-metabolism-and-biotherapeutics/

Buffering of genetic modules involved in tricarboxylic acid cycle metabolism provides homeomeostatic regulation

Larry H. Bernstein, MD, FCAP, Reviewer and curator

http://pharmaceuticalintelligence.com/2014/08/27/buffering-of-genetic-modules-involved-in-tricarboxylic-acid-cycle- metabolism-provides-homeomeostatic-regulation/

Metabolic Pathways

Pentose Shunt, Electron Transfer, Galactose, more Lipids in brief

Reviewer and Curator: Larry H. Bernstein, MD, FCAP

http://pharmaceuticalintelligence.com/2014/08/21/pentose-shunt-electron-transfer-galactose-more-lipids-in-brief/

Mitochondria: More than just the “powerhouse of the cell”

Ritu Saxena, PhD

http://pharmaceuticalintelligence.com/2012/07/09/mitochondria-more-than-just-the-powerhouse-of-the-cell/

Mitochondrial fission and fusion: potential therapeutic targets?

Ritu saxena

http://pharmaceuticalintelligence.com/2012/10/31/mitochondrial-fission-and-fusion-potential-therapeutic-target/

4. Mitochondrial mutation analysis might be “1-step” away

Ritu Saxena

http://pharmaceuticalintelligence.com/2012/08/14/mitochondrial-mutation-analysis-might-be-1-step-away/

Selected References to Signaling and Metabolic Pathways in PharmaceuticalIntelligence.com

Curator: Larry H. Bernstein, MD, FCAP

http://pharmaceuticalintelligence.com/2014/08/14/selected-references-to-signaling-and-metabolic-pathways-in- leaders-in-pharmaceutical-intelligence/

Metabolic drivers in aggressive brain tumors

Prabodh Kandal, PhD

http://pharmaceuticalintelligence.com/2012/11/11/metabolic-drivers-in-aggressive-brain-tumors/

Metabolite Identification Combining Genetic and Metabolic Information: Genetic association links unknown metabolites to functionally related genes

Writer and Curator, Aviva Lev-Ari, PhD, RD

http://pharmaceuticalintelligence.com/2012/10/22/metabolite-identification-combining-genetic-and-metabolic- information-genetic-association-links-unknown-metabolites-to-functionally-related-genes/

Mitochondria: Origin from oxygen free environment, role in aerobic glycolysis, metabolic adaptation

Larry H Bernstein, MD, FCAP, author and curator

http://pharmaceuticalintelligence.com/2012/09/26/mitochondria-origin-from-oxygen-free-environment-role-in-aerobic- glycolysis-metabolic-adaptation/

Therapeutic Targets for Diabetes and Related Metabolic Disorders

Reporter, Aviva Lev-Ari, PhD, RD

http://pharmaceuticalintelligence.com/2012/08/20/therapeutic-targets-for-diabetes-and-related-metabolic-disorders/

10. Buffering of genetic modules involved in tricarboxylic acid cycle metabolism provides homeomeostatic regulation

Larry H. Bernstein, MD, FCAP, Reviewer and curator

http://pharmaceuticalintelligence.com/2014/08/27/buffering-of-genetic-modules-involved-in-tricarboxylic-acid-cycle- metabolism-provides-homeomeostatic-regulation/

11. The multi-step transfer of phosphate bond and hydrogen exchange energy

Larry H. Bernstein, MD, FCAP, Curator:

http://pharmaceuticalintelligence.com/2014/08/19/the-multi-step-transfer-of-phosphate-bond-and-hydrogen- exchange-energy/

12. Studies of Respiration Lead to Acetyl CoA

http://pharmaceuticalintelligence.com/2014/08/18/studies-of-respiration-lead-to-acetyl-coa/

13. Lipid Metabolism

Author and Curator: Larry H. Bernstein, MD, FCAP

http://pharmaceuticalintelligence.com/2014/08/15/lipid-metabolism/

14. Carbohydrate Metabolism

Author and Curator: Larry H. Bernstein, MD, FCAP

http://pharmaceuticalintelligence.com/2014/08/13/carbohydrate-metabolism/

15. Update on mitochondrial function, respiration, and associated disorders

Larry H. Bernstein, MD, FCAP, Author and Curator

http://pharmaceuticalintelligence.com/2014/07/08/update-on-mitochondrial-function-respiration-and-associated- disorders/

16. Prologue to Cancer – e-book Volume One – Where are we in this journey?

Author and Curator: Larry H. Bernstein, MD, FCAP

http://pharmaceuticalintelligence.com/2014/04/13/prologue-to-cancer-ebook-4-where-are-we-in-this-journey/

17. Introduction – The Evolution of Cancer Therapy and Cancer Research: How We Got Here?

Author and Curator: Larry H. Bernstein, MD, FCAP

http://pharmaceuticalintelligence.com/2014/04/04/introduction-the-evolution-of-cancer-therapy-and-cancer-research- how-we-got-here/

18. Inhibition of the Cardiomyocyte-Specific Kinase TNNI3K

Author and Curator: Larry H. Bernstein, MD, FCAP

http://pharmaceuticalintelligence.com/2013/11/01/inhibition-of-the-cardiomyocyte-specific-kinase-tnni3k/

19. The Binding of Oligonucleotides in DNA and 3-D Lattice Structures

Author and Curator: Larry H. Bernstein, MD, FCAP

http://pharmaceuticalintelligence.com/2013/05/15/the-binding-of-oligonucleotides-in-dna-and-3-d-lattice-structures/

20. Mitochondrial Metabolism and Cardiac Function

Author and Curator: Larry H. Bernstein, MD, FCAP

http://pharmaceuticalintelligence.com/2013/04/14/mitochondrial-metabolism-and-cardiac-function/

21. How Methionine Imbalance with Sulfur-Insufficiency Leads to Hyperhomocysteinemia

Curator: Larry H. Bernstein, MD, FCAP

http://pharmaceuticalintelligence.com/2013/04/04/sulfur-deficiency-leads_to_hyperhomocysteinemia/

22. AMPK Is a Negative Regulator of the Warburg Effect and Suppresses Tumor Growth In Vivo

Author and Curator: Stephen J. Williams, PhD

http://pharmaceuticalintelligence.com/2013/03/12/ampk-is-a-negative-regulator-of-the-warburg-effect-and-suppresses- tumor-growth-in-vivo/

23. A Second Look at the Transthyretin Nutrition Inflammatory Conundrum

Author and Curator: Larry H. Bernstein, MD, FCAP

http://pharmaceuticalintelligence.com/2012/12/03/a-second-look-at-the-transthyretin-nutrition-inflammatory- conundrum/

24. Mitochondrial Damage and Repair under Oxidative Stress

Author and Curator: Larry H. Bernstein, MD, FCAP

http://pharmaceuticalintelligence.com/2012/10/28/mitochondrial-damage-and-repair-under-oxidative-stress/

25. Nitric Oxide and Immune Responses: Part 2

Author and Curator: Aviral Vatsa, PhD, MBBS

http://pharmaceuticalintelligence.com/2012/10/28/nitric-oxide-and-immune-responses-part-2/

26. Overview of Posttranslational Modification (PTM)

Writer and Curator: Larry H. Bernstein, MD, FCAP

http://pharmaceuticalintelligence.com/2014/07/29/overview-of-posttranslational-modification-ptm/

27. Malnutrition in India, high newborn death rate and stunting of children age under five years

Writer and Curator: Larry H. Bernstein, MD, FCAP

http://pharmaceuticalintelligence.com/2014/07/15/malnutrition-in-india-high-newborn-death-rate-and-stunting-of- children-age-under-five-years/

28. Update on mitochondrial function, respiration, and associated disorders

Writer and Curator: Larry H. Bernstein, MD, FCAP

http://pharmaceuticalintelligence.com/2014/07/08/update-on-mitochondrial-function-respiration-and-associated- disorders/

29. Omega-3 fatty acids, depleting the source, and protein insufficiency in renal disease

Larry H. Bernstein, MD, FCAP, Curator

http://pharmaceuticalintelligence.com/2014/07/06/omega-3-fatty-acids-depleting-the-source-and-protein-insufficiency- in-renal-disease/

30. Introduction to e-Series A: Cardiovascular Diseases, Volume Four Part 2: Regenerative Medicine

Larry H. Bernstein, MD, FCAP, writer, and Aviva Lev- Ari, PhD, RN

http://pharmaceuticalintelligence.com/2014/04/27/larryhbernintroduction_to_cardiovascular_diseases- translational_medicine-part_2/

31. Epilogue: Envisioning New Insights in Cancer Translational Biology
Series C: e-Books on Cancer & Oncology

Author & Curator: Larry H. Bernstein, MD, FCAP, Series C Content Consultant

http://pharmaceuticalintelligence.com/2014/03/29/epilogue-envisioning-new-insights/

32. Ca2+-Stimulated Exocytosis: The Role of Calmodulin and Protein Kinase C in Ca2+ Regulation of Hormone and Neurotransmitter

Writer and Curator: Larry H Bernstein, MD, FCAP and
Curator and Content Editor: Aviva Lev-Ari, PhD, RN

http://pharmaceuticalintelligence.com/2013/12/23/calmodulin-and-protein-kinase-c-drive-the-ca2-regulation-of- hormone-and-neurotransmitter-release-that-triggers-ca2-stimulated-exocy

33. Cardiac Contractility & Myocardial Performance: Therapeutic Implications of Ryanopathy (Calcium Release- related Contractile Dysfunction) and Catecholamine Responses

Author, and Content Consultant to e-SERIES A: Cardiovascular Diseases: Justin Pearlman, MD, PhD, FACC
Author and Curator: Larry H Bernstein, MD, FCAP
and Article Curator: Aviva Lev-Ari, PhD, RN

http://pharmaceuticalintelligence.com/2013/08/28/cardiac-contractility-myocardium-performance-ventricular-arrhythmias- and-non-ischemic-heart-failure-therapeutic-implications-for-cardiomyocyte-ryanopathy-calcium-release-related- contractile/

34. Role of Calcium, the Actin Skeleton, and Lipid Structures in Signaling and Cell Motility

Author and Curator: Larry H Bernstein, MD, FCAP Author: Stephen Williams, PhD, and Curator: Aviva Lev-Ari, PhD, RN

http://pharmaceuticalintelligence.com/2013/08/26/role-of-calcium-the-actin-skeleton-and-lipid-structures-in-signaling-and-cell-motility/

35. Identification of Biomarkers that are Related to the Actin Cytoskeleton

Larry H Bernstein, MD, FCAP, Author and Curator

http://pharmaceuticalintelligence.com/2012/12/10/identification-of-biomarkers-that-are-related-to-the-actin- cytoskeleton/

36. Advanced Topics in Sepsis and the Cardiovascular System at its End Stage

Author: Larry H Bernstein, MD, FCAP

http://pharmaceuticalintelligence.com/2013/08/18/advanced-topics-in-Sepsis-and-the-Cardiovascular-System-at-its- End-Stage/

37. The Delicate Connection: IDO (Indolamine 2, 3 dehydrogenase) and Cancer Immunology

Demet Sag, PhD, Author and Curator

http://pharmaceuticalintelligence.com/2013/08/04/the-delicate-connection-ido-indolamine-2-3-dehydrogenase-and- immunology/

38. IDO for Commitment of a Life Time: The Origins and Mechanisms of IDO, indolamine 2, 3-dioxygenase

Demet Sag, PhD, Author and Curator

http://pharmaceuticalintelligence.com/2013/08/04/ido-for-commitment-of-a-life-time-the-origins-and-mechanisms-of- ido-indolamine-2-3-dioxygenase/

39. Confined Indolamine 2, 3 dioxygenase (IDO) Controls the Homeostasis of Immune Responses for Good and Bad

Curator: Demet Sag, PhD, CRA, GCP

http://pharmaceuticalintelligence.com/2013/07/31/confined-indolamine-2-3-dehydrogenase-controls-the-hemostasis- of-immune-responses-for-good-and-bad/

40. Signaling Pathway that Makes Young Neurons Connect was discovered @ Scripps Research Institute

Reporter: Aviva Lev-Ari, PhD, RN

http://pharmaceuticalintelligence.com/2013/06/26/signaling-pathway-that-makes-young-neurons-connect-was- discovered-scripps-research-institute/

41. Naked Mole Rats Cancer-Free

Writer and Curator: Larry H. Bernstein, MD, FCAP

http://pharmaceuticalintelligence.com/2013/06/20/naked-mole-rats-cancer-free/

42. Late Onset of Alzheimer’s Disease and One-carbon Metabolism

Reporter and Curator: Dr. Sudipta Saha, Ph.D.

http://pharmaceuticalintelligence.com/2013/05/06/alzheimers-disease-and-one-carbon-metabolism/

43. Problems of vegetarianism

Reporter and Curator: Dr. Sudipta Saha, Ph.D.

http://pharmaceuticalintelligence.com/2013/04/22/problems-of-vegetarianism/

44. Amyloidosis with Cardiomyopathy

Writer and Curator: Larry H. Bernstein, MD, FCAP

http://pharmaceuticalintelligence.com/2013/03/31/amyloidosis-with-cardiomyopathy/

45. Liver endoplasmic reticulum stress and hepatosteatosis

Larry H Bernstein, MD, FACP

http://pharmaceuticalintelligence.com/2013/03/10/liver-endoplasmic-reticulum-stress-and-hepatosteatosis/

46. The Molecular Biology of Renal Disorders: Nitric Oxide – Part III

Curator and Author: Larry H Bernstein, MD, FACP

http://pharmaceuticalintelligence.com/2012/11/26/the-molecular-biology-of-renal-disorders/

47. Nitric Oxide Function in Coagulation – Part II

Curator and Author: Larry H. Bernstein, MD, FCAP

http://pharmaceuticalintelligence.com/2012/11/26/nitric-oxide-function-in-coagulation/

48. Nitric Oxide, Platelets, Endothelium and Hemostasis

Curator and Author: Larry H Bernstein, MD, FACP

http://pharmaceuticalintelligence.com/2012/11/08/nitric-oxide-platelets-endothelium-and-hemostasis/

49. Interaction of Nitric Oxide and Prostacyclin in Vascular Endothelium

Curator and Author: Larry H Bernstein, MD, FACP

http://pharmaceuticalintelligence.com/2012/09/14/interaction-of-nitric-oxide-and-prostacyclin-in-vascular-endothelium/

50. Nitric Oxide and Immune Responses: Part 1

Curator and Author: Aviral Vatsa PhD, MBBS

http://pharmaceuticalintelligence.com/2012/10/18/nitric-oxide-and-immune-responses-part-1/

51. Nitric Oxide and Immune Responses: Part 2

Curator and Author: Aviral Vatsa PhD, MBBS

http://pharmaceuticalintelligence.com/2012/10/28/nitric-oxide-and-immune-responses-part-2/

52. Mitochondrial Damage and Repair under Oxidative Stress

Curator and Author: Larry H Bernstein, MD, FACP

http://pharmaceuticalintelligence.com/2012/10/28/mitochondrial-damage-and-repair-under-oxidative-stress/

53. Is the Warburg Effect the cause or the effect of cancer: A 21st Century View?

Curator and Author: Larry H Bernstein, MD, FACP

http://pharmaceuticalintelligence.com/2012/10/17/is-the-warburg-effect-the-cause-or-the-effect-of-cancer-a-21st- century-view/

54. Ubiquinin-Proteosome pathway, autophagy, the mitochondrion, proteolysis and cell apoptosis

Curator and Author: Larry H Bernstein, MD, FACP

http://pharmaceuticalintelligence.com/2012/10/30/ubiquinin-proteosome-pathway-autophagy-the-mitochondrion- proteolysis-and-cell-apoptosis/

55. Ubiquitin-Proteosome pathway, Autophagy, the Mitochondrion, Proteolysis and Cell Apoptosis: Part III

Curator and Author: Larry H Bernstein, MD, FACP

http://pharmaceuticalintelligence.com/2013/02/14/ubiquinin-proteosome-pathway-autophagy-the-mitochondrion- proteolysis-and-cell-apoptosis-reconsidered/

56. Nitric Oxide and iNOS have Key Roles in Kidney Diseases – Part II

Curator and Author: Larry H Bernstein, MD, FACP

http://pharmaceuticalintelligence.com/2012/11/26/nitric-oxide-and-inos-have-key-roles-in-kidney-diseases/

57. New Insights on Nitric Oxide donors – Part IV

Curator and Author: Larry H Bernstein, MD, FACP

http://pharmaceuticalintelligence.com/2012/11/26/new-insights-on-no-donors/

58. Crucial role of Nitric Oxide in Cancer

Curator and Author: Ritu Saxena, Ph.D.

http://pharmaceuticalintelligence.com/2012/10/16/crucial-role-of-nitric-oxide-in-cancer/

59. Nitric Oxide has a ubiquitous role in the regulation of glycolysis -with a concomitant influence on mitochondrial function

Curator and Author: Larry H Bernstein, MD, FACP

http://pharmaceuticalintelligence.com/2012/09/16/nitric-oxide-has-a-ubiquitous-role-in-the-regulation-of-glycolysis-with- a-concomitant-influence-on-mitochondrial-function/

60. Targeting Mitochondrial-bound Hexokinase for Cancer Therapy

Curator and Author: Ziv Raviv, PhD, RN 04/06/2013

http://pharmaceuticalintelligence.com/2013/04/06/targeting-mitochondrial-bound-hexokinase-for-cancer-therapy/

61. Biochemistry of the Coagulation Cascade and Platelet Aggregation – Part I

Curator and Author: Larry H Bernstein, MD, FACP

http://pharmaceuticalintelligence.com/2012/11/26/biochemistry-of-the-coagulation-cascade-and-platelet-aggregation/

Genomics, Transcriptomics, and Epigenetics

What is the meaning of so many RNAs?

Writer and Curator: Larry H. Bernstein, MD, FCAP

http://pharmaceuticalintelligence.com/2014/08/06/what-is-the-meaning-of-so-many-rnas/

RNA and the transcription the genetic code

Larry H. Bernstein, MD, FCAP, Writer and Curator

http://pharmaceuticalintelligence.com/2014/08/02/rna-and-the-transcription-of-the-genetic-code/

A Primer on DNA and DNA Replication

Writer and Curator: Larry H. Bernstein, MD, FCAP

http://pharmaceuticalintelligence.com/2014/07/29/a_primer_on_dna_and_dna_replication/

4. Synthesizing Synthetic Biology: PLOS Collections

Reporter: Aviva Lev-Ari

http://pharmaceuticalintelligence.com/2012/08/17/synthesizing-synthetic-biology-plos-collections/

5. Pathology Emergence in the 21st Century

Author and Curator: Larry Bernstein, MD, FCAP

http://pharmaceuticalintelligence.com/2014/08/03/pathology-emergence-in-the-21st-century/

6. RNA and the transcription the genetic code

Writer and Curator, Larry H. Bernstein, MD, FCAP

http://pharmaceuticalintelligence.com/2014/08/02/rna-and-the-transcription-of-the-genetic-code/

7. A Great University engaged in Drug Discovery: University of Pittsburgh

Larry H. Bernstein, MD, FCAP, Reporter and Curator

http://pharmaceuticalintelligence.com/2014/07/15/a-great-university-engaged-in-drug-discovery/

8. microRNA called miRNA-142 involved in the process by which the immature cells in the bone marrow give rise to all the types of blood cells, including immune cells and the oxygen-bearing red blood cells

Aviva Lev-Ari, PhD, RN, Author and Curator

http://pharmaceuticalintelligence.com/2014/07/24/microrna-called-mir-142-involved-in-the-process-by-which-the- immature-cells-in-the-bone-marrow-give-rise-to-all-the-types-of-blood-cells-including-immune-cells-and-the-oxygen- bearing-red-blood-cells/

9. Genes, proteomes, and their interaction

Larry H. Bernstein, MD, FCAP, Writer and Curator

http://pharmaceuticalintelligence.com/2014/07/28/genes-proteomes-and-their-interaction/

10. Regulation of somatic stem cell Function

Larry H. Bernstein, MD, FCAP, Writer and Curator Aviva Lev-Ari, PhD, RN, Curator

http://pharmaceuticalintelligence.com/2014/07/29/regulation-of-somatic-stem-cell-function/

11. Scientists discover that pluripotency factor NANOG is also active in adult organisms

Larry H. Bernstein, MD, FCAP, Reporter

http://pharmaceuticalintelligence.com/2014/07/10/scientists-discover-that-pluripotency-factor-nanog-is-also-active-in- adult-organisms/

12. Bzzz! Are fruitflies like us?

Larry H Bernstein, MD, FCAP, Author and Curator

http://pharmaceuticalintelligence.com/2014/07/07/bzzz-are-fruitflies-like-us/

13. Long Non-coding RNAs Can Encode Proteins After All

Larry H Bernstein, MD, FCAP, Reporter

http://pharmaceuticalintelligence.com/2014/06/29/long-non-coding-rnas-can-encode-proteins-after-all/

14. Michael Snyder @Stanford University sequenced the lymphoblastoid transcriptomes and developed an
allele-specific full-length transcriptome

Aviva Lev-Ari, PhD, RN, Author and Curator

http://pharmaceuticalintelligence.com/014/06/23/michael-snyder-stanford-university-sequenced-the-lymphoblastoid- transcriptomes-and-developed-an-allele-specific-full-length-transcriptome/

15. Commentary on Biomarkers for Genetics and Genomics of Cardiovascular Disease: Views by Larry H Bernstein, MD, FCAP

Author: Larry H Bernstein, MD, FCAP

http://pharmaceuticalintelligence.com/2014/07/16/commentary-on-biomarkers-for-genetics-and-genomics-of- cardiovascular-disease-views-by-larry-h-bernstein-md-fcap/

16. Observations on Finding the Genetic Links in Common Disease: Whole Genomic Sequencing Studies

Author an curator: Larry H Bernstein, MD, FCAP

http://pharmaceuticalintelligence.com/2013/05/18/observations-on-finding-the-genetic-links/

17. Silencing Cancers with Synthetic siRNAs

Larry H. Bernstein, MD, FCAP, Reviewer and Curator

http://pharmaceuticalintelligence.com/2013/12/09/silencing-cancers-with-synthetic-sirnas/

18. Cardiometabolic Syndrome and the Genetics of Hypertension: The Neuroendocrine Transcriptome Control Points

Reporter: Aviva Lev-Ari, PhD, RN

http://pharmaceuticalintelligence.com/2013/12/12/cardiometabolic-syndrome-and-the-genetics-of-hypertension-the-neuroendocrine-transcriptome-control-points/

19. Developments in the Genomics and Proteomics of Type 2 Diabetes Mellitus and Treatment Targets

Larry H. Bernstein, MD, FCAP, Reviewer and Curator

http://pharmaceuticalintelligence.com/2013/12/08/developments-in-the-genomics-and-proteomics-of-type-2-diabetes- mellitus-and-treatment-targets/

20. Loss of normal growth regulation

Larry H Bernstein, MD, FCAP, Curator

http://pharmaceuticalintelligence.com/2014/07/06/loss-of-normal-growth-regulation/

21. CT Angiography & TrueVision™ Metabolomics (Genomic Phenotyping) for new Therapeutic Targets to Atherosclerosis

Reporter: Aviva Lev-Ari, PhD, RN

http://pharmaceuticalintelligence.com/2013/11/15/ct-angiography-truevision-metabolomics-genomic-phenotyping-for- new-therapeutic-targets-to-atherosclerosis/

22. CRACKING THE CODE OF HUMAN LIFE: The Birth of BioInformatics & Computational Genomics

Genomics Curator, Larry H Bernstein, MD, FCAP

http://pharmaceuticalintelligence.com/2014/08/30/cracking-the-code-of-human-life-the-birth-of-bioinformatics- computational-genomics/

23. Big Data in Genomic Medicine

Author and Curator, Larry H Bernstein, MD, FCAP

http://pharmaceuticalintelligence.com/2012/12/17/big-data-in-genomic-medicine/

24. From Genomics of Microorganisms to Translational Medicine

Author and Curator: Demet Sag, PhD

http://pharmaceuticalintelligence.com/2014/03/20/without-the-past-no-future-but-learn-and-move-genomics-of- microorganisms-to-translational-medicine/

25. Summary of Genomics and Medicine: Role in Cardiovascular Diseases

Author and Curator, Larry H Bernstein, MD, FCAP

http://pharmaceuticalintelligence.com/2014/01/06/summary-of-genomics-and-medicine-role-in-cardiovascular-diseases/

26. Genomic Promise for Neurodegenerative Diseases, Dementias, Autism Spectrum, Schizophrenia, and Serious Depression

Author and Curator, Larry H Bernstein, MD, FCAP

http://pharmaceuticalintelligence.com/2013/02/19/genomic-promise-for-neurodegenerative-diseases-dementias-autism- spectrum-schizophrenia-and-serious-depression/

27. BRCA1 a tumour suppressor in breast and ovarian cancer – functions in transcription, ubiquitination and DNA repair

Sudipta Saha, PhD

http://pharmaceuticalintelligence.com/2012/12/04/brca1-a-tumour-suppressor-in-breast-and-ovarian-cancer-functions- in-transcription-ubiquitination-and-dna-repair/

28. Personalized medicine gearing up to tackle cancer

Ritu Saxena, PhD

http://pharmaceuticalintelligence.com/2013/01/07/personalized-medicine-gearing-up-to-tackle-cancer/

29. Differentiation Therapy – Epigenetics Tackles Solid Tumors

Stephen J Williams, PhD

http://pharmaceuticalintelligence.com/2013/01/03/differentiation-therapy-epigenetics-tackles-solid-tumors/

30. Mechanism involved in Breast Cancer Cell Growth: Function in Early Detection & Treatment

Aviva Lev-Ari, PhD, RN

http://pharmaceuticalintelligence.com/2013/01/17/mechanism-involved-in-breast-cancer-cell-growth-function-in-early- detection-treatment/

31. The Molecular pathology of Breast Cancer Progression

Tilde Barliya, PhD

http://pharmaceuticalintelligence.com/2013/01/10/the-molecular-pathology-of-breast-cancer-progression

32. Gastric Cancer: Whole-genome reconstruction and mutational signatures

Aviva Lev-Ari, PhD, RN

http://pharmaceuticalintelligence.com/2012/12/24/gastric-cancer-whole-genome-reconstruction-and-mutational- signatures-2/

33. Paradigm Shift in Human Genomics – Predictive Biomarkers and Personalized Medicine – Part 1 (pharmaceuticalintelligence.com)

Aviva Lev-Ari, PhD, RN

http://pharmaceuticalntelligence.com/2013/01/13/paradigm-shift-in-human-genomics-predictive-biomarkers-and-personalized-medicine-part-1/

34. LEADERS in Genome Sequencing of Genetic Mutations for Therapeutic Drug Selection in Cancer Personalized Treatment: Part 2

A Lev-Ari, PhD, RN

http://pharmaceuticalintelligence.com/2013/01/13/leaders-in-genome-sequencing-of-genetic-mutations-for-therapeutic- drug-selection-in-cancer-personalized-treatment-part-2/

35. Personalized Medicine: An Institute Profile – Coriell Institute for Medical Research: Part 3

Aviva Lev-Ari, PhD, RN

http://pharmaceuticalintelligence.com/2013/01/13/personalized-medicine-an-institute-profile-coriell-institute-for-medical- research-part-3/

36. Harnessing Personalized Medicine for Cancer Management, Prospects of Prevention and Cure: Opinions of Cancer Scientific Leaders @http://pharmaceuticalintelligence.com

Aviva Lev-Ari, PhD, RN

http://pharmaceuticalintelligence.com/2013/01/13/7000/Harnessing_Personalized_Medicine_for_ Cancer_Management- Prospects_of_Prevention_and_Cure/

37. GSK for Personalized Medicine using Cancer Drugs needs Alacris systems biology model to determine the in silico
effect of the inhibitor in its “virtual clinical trial”

Aviva Lev-Ari, PhD, RN

http://pharmaceuticalintelligence.com/2012/11/14/gsk-for-personalized-medicine-using-cancer-drugs-needs-alacris- systems-biology-model-to-determine-the-in-silico-effect-of-the-inhibitor-in-its-virtual-clinical-trial/

38. Personalized medicine-based cure for cancer might not be far away

Ritu Saxena, PhD

http://pharmaceuticalintelligence.com/2012/11/20/personalized-medicine-based-cure-for-cancer-might-not-be-far-away/

39. Human Variome Project: encyclopedic catalog of sequence variants indexed to the human genome sequence

Aviva Lev-Ari, PhD, RN

http://pharmaceuticalintelligence.com/2012/11/24/human-variome-project-encyclopedic-catalog-of-sequence-variants- indexed-to-the-human-genome-sequence/

40. Inspiration From Dr. Maureen Cronin’s Achievements in Applying Genomic Sequencing to Cancer Diagnostics

Aviva Lev-Ari, PhD, RN

http://pharmaceuticalintelligence.com/2013/01/10/inspiration-from-dr-maureen-cronins-achievements-in-applying- genomic-sequencing-to-cancer-diagnostics/

41. The “Cancer establishments” examined by James Watson, co-discoverer of DNA w/Crick, 4/1953

Aviva Lev-Ari, PhD, RN

http://pharmaceuticalintelligence.com/2013/01/09/the-cancer-establishments-examined-by-james-watson-co-discover- of-dna-wcrick-41953/

42. What can we expect of tumor therapeutic response?

Author and curator: Larry H Bernstein, MD, FACP

http://pharmaceuticalintelligence.com/2012/12/05/what-can-we-expect-of-tumor-therapeutic-response/

43. Directions for genomics in personalized medicine

Author and Curator: Larry H. Bernstein, MD, FCAP

http://pharmaceuticalintelligence.com/2013/01/27/directions-for-genomics-in-personalized-medicine/

44. How mobile elements in “Junk” DNA promote cancer. Part 1: Transposon-mediated tumorigenesis.

Stephen J Williams, PhD

http://pharmaceuticalintelligence.com/2012/10/31/how-mobile-elements-in-junk-dna-prote-cancer-part1-transposon- mediated-tumorigenesis/

45. mRNA interference with cancer expression

Author and Curator, Larry H. Bernstein, MD, FCAP

http://pharmaceuticalintelligence.com/2012/10/26/mrna-interference-with-cancer-expression/

46. Expanding the Genetic Alphabet and linking the genome to the metabolome

Aviva Lev-Ari, PhD, RD

http://pharmaceuticalintelligence.com/2012/09/24/expanding-the-genetic-alphabet-and-linking-the-genome-to-the- metabolome/

47. Breast Cancer, drug resistance, and biopharmaceutical targets

Author and Curator: Larry H Bernstein, MD, FCAP

http://pharmaceuticalintelligence.com/2012/09/18/breast-cancer-drug-resistance-and-biopharmaceutical-targets/

48. Breast Cancer: Genomic profiling to predict Survival: Combination of Histopathology and Gene Expression Analysis

Aviva Lev-Ari, PhD, RD

http://pharmaceuticalintelligence.com/2012/12/24/breast-cancer-genomic-profiling-to-predict-survival-combination-of- histopathology-and-gene-expression-analysis

49. Gastric Cancer: Whole-genome reconstruction and mutational signatures

Aviva Lev-Ari, PhD, RD

http://pharmaceuticalintelligence.com/2012/12/24/gastric-cancer-whole-genome-reconstruction-and-mutational- signatures-2/

50. Genomic Analysis: FLUIDIGM Technology in the Life Science and Agricultural Biotechnology

Aviva Lev-Ari, PhD, RD

http://pharmaceuticalintelligence.com/2012/08/22/genomic-analysis-fluidigm-technology-in-the-life-science-and- agricultural-biotechnology/

51. 2013 Genomics: The Era Beyond the Sequencing Human Genome: Francis Collins, Craig Venter, Eric Lander, et al.

Aviva Lev-Ari, PhD, RD

http://pharmaceuticalintelligence.com/2013_Genomics

52. Paradigm Shift in Human Genomics – Predictive Biomarkers and Personalized Medicine – Part 1

Aviva Lev-Ari, PhD, RD

http://pharmaceuticalintelligence.com/Paradigm Shift in Human Genomics_/

Signaling Pathways

Proteins and cellular adaptation to stress

Larry H Bernstein, MD, FCAP, Curator

http://pharmaceuticalintelligence.com/2014/07/08/proteins-and-cellular-adaptation-to-stress/

A Synthesis of the Beauty and Complexity of How We View Cancer:
Cancer Volume One – Summary

Author and Curator: Larry H. Bernstein, MD, FCAP

http://pharmaceuticalintelligence.com/2014/03/26/a-synthesis-of-the-beauty-and-complexity-of-how-we-view-cancer/

Recurrent somatic mutations in chromatin-remodeling and ubiquitin ligase complex genes in
serous endometrial tumors

Sudipta Saha, PhD

http://pharmaceuticalintelligence.com/2012/11/19/recurrent-somatic-mutations-in-chromatin-remodeling-ad-ubiquitin- ligase-complex-genes-in-serous-endometrial-tumors/

4. Prostate Cancer Cells: Histone Deacetylase Inhibitors Induce Epithelial-to-Mesenchymal Transition

Stephen J Williams, PhD

http://pharmaceuticalintelligence.com/2012/11/30/histone-deacetylase-inhibitors-induce-epithelial-to-mesenchymal- transition-in-prostate-cancer-cells/

5. Ubiquinin-Proteosome pathway, autophagy, the mitochondrion, proteolysis and cell apoptosis

Author and Curator: Larry H Bernstein, MD, FCAP

http://pharmaceuticalintelligence.com/2012/10/30/ubiquinin-proteosome-pathway-autophagy-the-mitochondrion- proteolysis-and-cell-apoptosis/

6. Signaling and Signaling Pathways

Larry H. Bernstein, MD, FCAP, Reporter and Curator

http://pharmaceuticalintelligence.com/2014/08/12/signaling-and-signaling-pathways/

7. Leptin signaling in mediating the cardiac hypertrophy associated with obesity

Larry H. Bernstein, MD, FCAP, Reporter and Curator

http://pharmaceuticalintelligence.com/2013/11/03/leptin-signaling-in-mediating-the-cardiac-hypertrophy-associated- with-obesity/

Sensors and Signaling in Oxidative Stress

Larry H. Bernstein, MD, FCAP, Reporter and Curator

http://pharmaceuticalintelligence.com/2013/11/01/sensors-and-signaling-in-oxidative-stress/

The Final Considerations of the Role of Platelets and Platelet Endothelial Reactions in Atherosclerosis and Novel
Treatments

Larry H. Bernstein, MD, FCAP, Reporter and Curator

http://pharmaceuticalintelligence.com/2013/10/15/the-final-considerations-of-the-role-of-platelets-and-platelet- endothelial-reactions-in-atherosclerosis-and-novel-treatments

10. Platelets in Translational Research – Part 1

Larry H. Bernstein, MD, FCAP, Reporter and Curator

http://pharmaceuticalintelligence.com/2013/10/07/platelets-in-translational-research-1/

11. Disruption of Calcium Homeostasis: Cardiomyocytes and Vascular Smooth Muscle Cells: The Cardiac and
Cardiovascular Calcium Signaling Mechanism

Author and Curator: Larry H Bernstein, MD, FCAP, Author, and Content Consultant to e-SERIES A:
Cardiovascular Diseases: Justin Pearlman, MD, PhD, FACC and Curator: Aviva Lev-Ari, PhD, RN

http://pharmaceuticalintelligence.com/2013/09/12/disruption-of-calcium-homeostasis-cardiomyocytes-and-vascular- smooth-muscle-cells-the-cardiac-and-cardiovascular-calcium-signaling-mechanism/

12. The Centrality of Ca(2+) Signaling and Cytoskeleton Involving Calmodulin Kinases and
Ryanodine Receptors in Cardiac Failure, Arterial Smooth Muscle, Post-ischemic Arrhythmia,
Similarities and Differences, and Pharmaceutical Targets

Author and Curator: Larry H Bernstein, MD, FCAP, Author, and Content Consultant to
e-SERIES A: Cardiovascular Diseases: Justin Pearlman, MD, PhD, FACC and
Curator: Aviva Lev-Ari, PhD, RN

http://pharmaceuticalintelligence.com/2013/09/08/the-centrality-of-ca2-signaling-and-cytoskeleton-involving-calmodulin- kinases-and-ryanodine-receptors-in-cardiac-failure-arterial-smooth-muscle-post-ischemic-arrhythmia-similarities-and- differen/

13. Nitric Oxide Signalling Pathways

Aviral Vatsa, PhD, MBBS

http://pharmaceuticalintelligence.com/2012/08/22/nitric-oxide-signalling-pathways/

14. Immune activation, immunity, antibacterial activity

Larry H. Bernstein, MD, FCAP, Curator

http://pharmaceuticalintelligence.com/2014/07/06/immune-activation-immunity-antibacterial-activity/

15. Regulation of somatic stem cell Function

Larry H. Bernstein, MD, FCAP, Writer and Curator Aviva Lev-Ari, PhD, RN, Curator

http://pharmaceuticalintelligence.com/2014/07/29/regulation-of-somatic-stem-cell-function/

16. Scientists discover that pluripotency factor NANOG is also active in adult organisms

Larry H. Bernstein, MD, FCAP, Reporter

http://pharmaceuticalintelligence.com/2014/07/10/scientists-discover-that-pluripotency-factor-nanog-is-also-active-in-adult-organisms/

Read Full Post »

Compilation of References in Leaders in Pharmaceutical Intelligence about proteomics, metabolomics, signaling pathways, and cell regulation

Posted in Academic Publishing, Alzheimer's Disease, Amino acids, Anaerobic Glycolysis, Atherogenic Processes & Pathology, Best evidence, Biochemical pathways, Biological Networks, Gene Regulation and Evolution, Biomarkers & Medical Diagnostics, Ca2+ triggered activation, Ca2+ triggered activation, Cachexia, Calcium Signaling, Calmodulin, Calmodulin Kinase and Contraction, CANCER BIOLOGY & Innovations in Cancer Therapy, Cardiomyopathy, Cardiovascular Research, Cell Biology, Signaling & Cell Circuits, Cerebrovascular and Neurodegenerative Diseases, Chemical Biology and its relations to Metabolic Disease, Chemical Genetics, Coagulation Therapy and Internal Bleeding, Computational Biology/Systems and Bioinformatics, Curation, Cytoskeleton, Dehydrogenase, Diabetes Mellitus, Discovery process, Epigenetics and Cardiovascular Risks, Evolutionary cognition, Experimental validation, Explanatory, Fatty acids, Gene Regulation, Genome Biology, Genomic Expression, Hematology, Hexokinase, Historical relevance, Human Immune System in Health and in Disease, Inferential analysis, Inosine nucleotides, Kinase, Leloir pathway, Lipid metabolism, Lipids, Metabolism, Metabolomics, Myocardial Ischemia, Myocardial Metabolism, Na-K transport, Nephrology, Neurohumoral Transmission, Nitric Oxide in Health and Disease, Nutrition, Nutritional Supplements: Atherogenesis, Oxidative phosphorylation, Pentose monophosphate shunt, Personalized and Precision Medicine & Genomic Research, Pharmaceutical Drug Discovery, Phosphorylase, Phosphorylation, PKC, Proteins, Proteomics, Pyridine nucleotide transhydrogenase, Pyridine nucleotides, Regenerative Biology and Medicine, RNA Biology, RNA Biology, Cancer and Therapeutics, S-nitrosylation, Sensors & Analytics, Signaling, Signaling & Cell Circuits, Synaptic vesicle, Systemic Inflammatory Response Related Disorders, Technology Advance Assessment of, Theoretic convergence, Transcriptomics, Translational Research, Translational Science, Ubiquitinylation, Warburg effect, tagged 6-phosphogluconate, adaptive compensatory glycolysis, Adaptive immune system, adenine nucleotides, Adenosine, anabolism, anaerobic and aerobic gycolysis, anion, Aptamer affinity chromatography, Aptamer-based multiplexed technology, ATP, Bibliography, Calcium, cancers, carbohydrates, catabolism, cation, Coagulation, Cytoskeleton, drug targets, Endothelial Cell Coagulation Activation, ETC, Gene Regulation, genetics, genomics, hysrogen transfer, inner membrane, inosine nucleotide, ion chromatography, Leaders in Pharmaceutical Intelligence, Lipids, magnesium, metabolic regulation, Metabolism, Metabolomics, mitochondia, mitochondrial dynamics, mitochondrial function, Monounsaturated fat, NADH, NADPH, nitric oxide, NOS, omega 3 FA, omega 6 FA, omega-6/omega-3, platelet endothelial interaction, platelet signaling, PLI references, Polyunsaturated fatty acid, post-translation modifications, protein separation methods, Pyridine nucleotides, saturated fatty acids, separation methods, signaling cascades, signaling pathways, SIRS, Sodium, systemic inflammatory disorders, systemic inflammatory response, Transcriptomics on August 31, 2014| Leave a Comment »

Compilation of References in Leaders in Pharmaceutical Intelligence about
proteomics, metabolomics, signaling pathways, and cell regulation

Curator: Larry H. Bernstein, MD, FCAP

Proteomics

The Human Proteome Map Completed
Reporter and Curator: Larry H. Bernstein, MD, FCAP
http://pharmaceuticalintelligence.com/2014/08/28/the-human-proteome-map-completed/

Proteomics – The Pathway to Understanding and Decision-making in Medicine
Author and Curator, Larry H Bernstein, MD, FCAP
http://pharmaceuticalintelligence.com/2014/06/24/proteomics-the-pathway-to-understanding-and-decision-making-in-medicine/

Advances in Separations Technology for the “OMICs” and Clarification of Therapeutic Targets
Author and Curator, Larry H Bernstein, MD, FCAP
http://pharmaceuticalintelligence.com/2012/10/22/advances-in-separations-technology-for-the-omics-and-clarification-of-therapeutic-targets/

Expanding the Genetic Alphabet and Linking the Genome to the Metabolome
Author and Curator, Larry H Bernstein, MD, FCAP
http://pharmaceuticalintelligence.com/2012/09/24/expanding-the-genetic-alphabet-and-linking-the-genome-to-the-metabolome/

Synthesizing Synthetic Biology: PLOS Collections
Reporter: Aviva Lev-Ari
http://pharmaceuticalintelligence.com/2012/08/17/synthesizing-synthetic-biology-plos-collections/

Metabolomics

Extracellular evaluation of intracellular flux in yeast cells
Larry H. Bernstein, MD, FCAP, Reviewer and Curator
http://pharmaceuticalintelligence.com/2014/08/25/extracellular-evaluation-of-intracellular-flux-in-yeast-cells/
Metabolomic analysis of two leukemia cell lines. I.
Larry H. Bernstein, MD, FCAP, Reviewer and Curator
http://pha rmaceuticalintelligence.com/2014/08/23/metabolomic-analysis-of-two-leukemia-cell-lines-_i/
Metabolomic analysis of two leukemia cell lines. II.
Larry H. Bernstein, MD, FCAP, Reviewer and Curator
http://pharmaceuticalintelligence.com/2014/08/24/metabolomic-analysis-of-two-leukemia-cell-lines-ii/
Metabolomics, Metabonomics and Functional Nutrition: the next step in nutritional metabolism and biotherapeutics
Reviewer and Curator, Larry H. Bernstein, MD, FCAP
http://pharmaceuticalintelligence.com/2014/08/22/metabolomics-metabonomics-and-functional-nutrition-the-next-step-in-nutritional-metabolism-and-biotherapeutics/
Buffering of genetic modules involved in tricarboxylic acid cycle metabolism provides homeomeostatic regulation
Larry H. Bernstein, MD, FCAP, Reviewer and curator
http://pharmaceuticalintelligence.com/2014/08/27/buffering-of-genetic-modules-involved-in-tricarboxylic-acid-cycle-metabolism-provides-homeomeostatic-regulation/

Metabolic Pathways

Pentose Shunt, Electron Transfer, Galactose, more Lipids in brief
Reviewer and Curator: Larry H. Bernstein, MD, FCAP
http://pharmaceuticalintelligence.com/2014/08/21/pentose-shunt-electron-transfer-galactose-more-lipids-in-brief/
Mitochondria: More than just the “powerhouse of the cell”
Reviewer and Curator: Ritu Saxena
http://pharmaceuticalintelligence.com/2012/07/09/mitochondria-more-than-just-the-powerhouse-of-the-cell/
Mitochondrial fission and fusion: potential therapeutic targets?
Reviewer and Curator: Ritu saxena
http://pharmaceuticalintelligence.com/2012/10/31/mitochondrial-fission-and-fusion-potential-therapeutic-target/
Mitochondrial mutation analysis might be “1-step” away
Reviewer and Curator: Ritu Saxena
http://pharmaceuticalintelligence.com/2012/08/14/mitochondrial-mutation-analysis-might-be-1-step-away/
Selected References to Signaling and Metabolic Pathways in PharmaceuticalIntelligence.com
Curator: Larry H. Bernstein, MD, FCAP
http://pharmaceuticalintelligence.com/2014/08/14/selected-references-to-signaling-and-metabolic-pathways-in-leaders-in-pharmaceutical-intelligence/
Metabolic drivers in aggressive brain tumors
Prabodh Kandal, PhD
http://pharmaceuticalintelligence.com/2012/11/11/metabolic-drivers-in-aggressive-brain-tumors/
Metabolite Identification Combining Genetic and Metabolic Information: Genetic association links unknown metabolites to functionally related genes
Author and Curator: Aviva Lev-Ari, PhD, RD
http://pharmaceuticalintelligence.com/2012/10/22/metabolite-identification-combining-genetic-and-metabolic-information-genetic-association-links-unknown-metabolites-to-functionally-related-genes/
Mitochondria: Origin from oxygen free environment, role in aerobic glycolysis, metabolic adaptation
Author and curator:Larry H Bernstein, MD, FCAP
http://pharmaceuticalintelligence.com/2012/09/26/mitochondria-origin-from-oxygen-free-environment-role-in-aerobic-glycolysis-metabolic-adaptation/
Therapeutic Targets for Diabetes and Related Metabolic Disorders
Reporter, Aviva Lev-Ari, PhD, RD
http://pharmaceuticalintelligence.com/2012/08/20/therapeutic-targets-for-diabetes-and-related-metabolic-disorders/
Buffering of genetic modules involved in tricarboxylic acid cycle metabolism provides homeomeostatic regulation
Larry H. Bernstein, MD, FCAP, Reviewer and curator
http://pharmaceuticalintelligence.com/2014/08/27/buffering-of-genetic-modules-involved-in-tricarboxylic-acid-cycle-metabolism-provides-homeomeostatic-regulation/
The multi-step transfer of phosphate bond and hydrogen exchange energy
Curator:Larry H. Bernstein, MD, FCAP,
http://pharmaceuticalintelligence.com/2014/08/19/the-multi-step-transfer-of-phosphate-bond-and-hydrogen-exchange-energy/
Studies of Respiration Lead to Acetyl CoA
Author and Curator: Larry H. Bernstein, MD, FCAP
http://pharmaceuticalintelligence.com/2014/08/18/studies-of-respiration-lead-to-acetyl-coa/
Lipid Metabolism
Author and Curator: Larry H. Bernstein, MD, FCAP
http://pharmaceuticalintelligence.com/2014/08/15/lipid-metabolism/
Carbohydrate Metabolism
Author and Curator: Larry H. Bernstein, MD, FCAP
http://pharmaceuticalintelligence.com/2014/08/13/carbohydrate-metabolism/
Prologue to Cancer – e-book Volume One – Where are we in this journey?
Author and Curator: Larry H. Bernstein, MD, FCAP
http://pharmaceuticalintelligence.com/2014/04/13/prologue-to-cancer-ebook-4-where-are-we-in-this-journey/
Introduction – The Evolution of Cancer Therapy and Cancer Research: How We Got Here?
Author and Curator: Larry H. Bernstein, MD, FCAP
http://pharmaceuticalintelligence.com/2014/04/04/introduction-the-evolution-of-cancer-therapy-and-cancer-research-how-we-got-here/
Inhibition of the Cardiomyocyte-Specific Kinase TNNI3K
Author and Curator: Larry H. Bernstein, MD, FCAP
http://pharmaceuticalintelligence.com/2013/11/01/inhibition-of-the-cardiomyocyte-specific-kinase-tnni3k/
The Binding of Oligonucleotides in DNA and 3-D Lattice Structures
Author and Curator: Larry H. Bernstein, MD, FCAP
http://pharmaceuticalintelligence.com/2013/05/15/the-binding-of-oligonucleotides-in-dna-and-3-d-lattice-structures/
Mitochondrial Metabolism and Cardiac Function
Author and Curator: Larry H. Bernstein, MD, FCAP
http://pharmaceuticalintelligence.com/2013/04/14/mitochondrial-metabolism-and-cardiac-function/
How Methionine Imbalance with Sulfur-Insufficiency Leads to Hyperhomocysteinemia
Curator: Larry H. Bernstein, MD, FCAP
http://pharmaceuticalintelligence.com/2013/04/04/sulfur-deficiency-leads_to_hyperhomocysteinemia/
AMPK Is a Negative Regulator of the Warburg Effect and Suppresses Tumor Growth In Vivo
Author and Curator: SJ. Williams
http://pharmaceuticalintelligence.com/2013/03/12/ampk-is-a-negative-regulator-of-the-warburg-effect-and-suppresses-tumor-growth-in-vivo/
A Second Look at the Transthyretin Nutrition Inflammatory Conundrum
Author and Curator: Larry H. Bernstein, MD, FCAP
http://pharmaceuticalintelligence.com/2012/12/03/a-second-look-at-the-transthyretin-nutrition-inflammatory-conundrum/
Overview of Posttranslational Modification (PTM)
Writer and Curator: Larry H. Bernstein, MD, FCAP
http://pharmaceuticalintelligence.com/2014/07/29/overview-of-posttranslational-modification-ptm/
Malnutrition in India, high newborn death rate and stunting of children age under five years
Writer and Curator: Larry H. Bernstein, MD, FCAP
http://pharmaceuticalintelligence.com/2014/07/15/malnutrition-in-india-high-newborn-death-rate-and-stunting-of-children-age-under-five-years/
Update on mitochondrial function, respiration, and associated disorders
Writer and Curator: Larry H. Bernstein, MD, FCAP
http://pharmaceuticalintelligence.com/2014/07/08/update-on-mitochondrial-function-respiration-and-associated-disorders/
Omega-3 fatty acids, depleting the source, and protein insufficiency in renal disease
Larry H. Bernstein, MD, FCAP, Curator
http://pharmaceuticalintelligence.com/2014/07/06/omega-3-fatty-acids-depleting-the-source-and-protein-insufficiency-in-renal-disease/
Late Onset of Alzheimer’s Disease and One-carbon Metabolism
Reporter and Curator: Dr. Sudipta Saha, Ph.D.
http://pharmaceuticalintelligence.com/2013/05/06/alzheimers-disease-and-one-carbon-metabolism/
Problems of vegetarianism
Reporter and Curator: Dr. Sudipta Saha, Ph.D.
http://pharmaceuticalintelligence.com/2013/04/22/problems-of-vegetarianism/

Signaling Pathways

Introduction to e-Series A: Cardiovascular Diseases, Volume Four Part 2: Regenerative Medicine
Larry H. Bernstein, MD, FCAP, writer, and Aviva Lev- Ari, PhD, RN http://pharmaceuticalintelligence.com/2014/04/27/larryhbernintroduction_to_cardiovascular_diseases-translational_medicine-part_2/
Epilogue: Envisioning New Insights in Cancer Translational Biology
Series C: e-Books on Cancer & Oncology
Author & Curator: Larry H. Bernstein, MD, FCAP, Series C Content Consultant
http://pharmaceuticalintelligence.com/2014/03/29/epilogue-envisioning-new-insights/
Ca2+-Stimulated Exocytosis: The Role of Calmodulin and Protein Kinase C in Ca2+ Regulation of Hormone and Neurotransmitter Writer and Curator: Larry H Bernstein, MD, FCAP and Curator and Content Editor: Aviva Lev-Ari, PhD, RN
http://pharmaceuticalintelligence.com/2013/12/23/calmodulin-and-protein-kinase-c-drive-the-ca2-regulation-of-hormone-and-neurotransmitter-release-that-triggers-ca2-stimulated-exocy
Cardiac Contractility & Myocardial Performance: Therapeutic Implications of Ryanopathy (Calcium Release-related Contractile Dysfunction) and Catecholamine Responses
Author, and Content Consultant to e-SERIES A: Cardiovascular Diseases: Justin Pearlman, MD, PhD, FACC
Author and Curator: Larry H Bernstein, MD, FCAP and Article Curator: Aviva Lev-Ari, PhD, RN
http://pharmaceuticalintelligence.com/2013/08/28/cardiac-contractility-myocardium-performance-ventricular-arrhythmias-and-non-ischemic-heart-failure-therapeutic-implications-for-cardiomyocyte-ryanopathy-calcium-release-related-contractile/
Role of Calcium, the Actin Skeleton, and Lipid Structures in Signaling and Cell Motility
Author and Curator: Larry H Bernstein, MD, FCAP Author: Stephen Williams, PhD, and Curator: Aviva Lev-Ari, PhD, RN
http://pharmaceuticalintelligence.com/2013/08/26/role-of-calcium-the-actin-skeleton-and-lipid-structures-in-signaling-and-cell-motility/
Identification of Biomarkers that are Related to the Actin Cytoskeleton
Larry H Bernstein, MD, FCAP, Author and Curator
http://pharmaceuticalintelligence.com/2012/12/10/identification-of-biomarkers-that-are-related-to-the-actin-cytoskeleton/
Advanced Topics in Sepsis and the Cardiovascular System at its End Stage
Author and Curator: Larry H Bernstein, MD, FCAP
http://pharmaceuticalintelligence.com/2013/08/18/advanced-topics-in-Sepsis-and-the-Cardiovascular-System-at-its-End-Stage/
The Delicate Connection: IDO (Indolamine 2, 3 dehydrogenase) and Cancer Immunology
Demet Sag, PhD, Author and Curator
http://pharmaceuticalintelligence.com/2013/08/04/the-delicate-connection-ido-indolamine-2-3-dehydrogenase-and-immunology/
IDO for Commitment of a Life Time: The Origins and Mechanisms of IDO, indolamine 2, 3-dioxygenase
Demet Sag, PhD, Author and Curator
http://pharmaceuticalintelligence.com/2013/08/04/ido-for-commitment-of-a-life-time-the-origins-and-mechanisms-of-ido-indolamine-2-3-dioxygenase/
Confined Indolamine 2, 3 dioxygenase (IDO) Controls the Homeostasis of Immune Responses for Good and Bad
Author and Curator: Demet Sag, PhD, CRA, GCP
http://pharmaceuticalintelligence.com/2013/07/31/confined-indolamine-2-3-dehydrogenase-controls-the-hemostasis-of-immune-responses-for-good-and-bad/
Signaling Pathway that Makes Young Neurons Connect was discovered @ Scripps Research Institute
Reporter: Aviva Lev-Ari, PhD, RN
http://pharmaceuticalintelligence.com/2013/06/26/signaling-pathway-that-makes-young-neurons-connect-was-discovered-scripps-research-institute/
Naked Mole Rats Cancer-Free
Writer and Curator: Larry H. Bernstein, MD, FCAP
http://pharmaceuticalintelligence.com/2013/06/20/naked-mole-rats-cancer-free/
Amyloidosis with Cardiomyopathy
Writer and Curator: Larry H. Bernstein, MD, FCAP
http://pharmaceuticalintelligence.com/2013/03/31/amyloidosis-with-cardiomyopathy/
Liver endoplasmic reticulum stress and hepatosteatosis
Larry H Bernstein, MD, FACP
http://pharmaceuticalintelligence.com/2013/03/10/liver-endoplasmic-reticulum-stress-and-hepatosteatosis/
The Molecular Biology of Renal Disorders: Nitric Oxide – Part III
Curator and Author: Larry H Bernstein, MD, FACP
http://pharmaceuticalintelligence.com/2012/11/26/the-molecular-biology-of-renal-disorders/
Nitric Oxide Function in Coagulation – Part II
Curator and Author: Larry H. Bernstein, MD, FCAP
http://pharmaceuticalintelligence.com/2012/11/26/nitric-oxide-function-in-coagulation/
Nitric Oxide, Platelets, Endothelium and Hemostasis
Curator and Author: Larry H Bernstein, MD, FACP
http://pharmaceuticalintelligence.com/2012/11/08/nitric-oxide-platelets-endothelium-and-hemostasis/
Interaction of Nitric Oxide and Prostacyclin in Vascular Endothelium
Curator and Author: Larry H Bernstein, MD, FACP
http://pharmaceuticalintelligence.com/2012/09/14/interaction-of-nitric-oxide-and-prostacyclin-in-vascular-endothelium/
Nitric Oxide and Immune Responses: Part 1
Curator and Author: Aviral Vatsa PhD, MBBS
http://pharmaceuticalintelligence.com/2012/10/18/nitric-oxide-and-immune-responses-part-1/
Nitric Oxide and Immune Responses: Part 2
Curator and Author: Aviral Vatsa PhD, MBBS
http://pharmaceuticalintelligence.com/2012/10/28/nitric-oxide-and-immune-responses-part-2/
Nitric Oxide and iNOS have Key Roles in Kidney Diseases – Part II
Curator and Author: Larry H Bernstein, MD, FACP
http://pharmaceuticalintelligence.com/2012/11/26/nitric-oxide-and-inos-have-key-roles-in-kidney-diseases/
New Insights on Nitric Oxide donors – Part IV
Curator and Author: Larry H Bernstein, MD, FACP
http://pharmaceuticalintelligence.com/2012/11/26/new-insights-on-no-donors/
Crucial role of Nitric Oxide in Cancer
Curator and Author: Ritu Saxena, Ph.D.
http://pharmaceuticalintelligence.com/2012/10/16/crucial-role-of-nitric-oxide-in-cancer/
Nitric Oxide has a ubiquitous role in the regulation of glycolysis -with a concomitant influence on mitochondrial function
Curator and Author: Larry H Bernstein, MD, FACP
http://pharmaceuticalintelligence.com/2012/09/16/nitric-oxide-has-a-ubiquitous-role-in-the-regulation-of-glycolysis-with-a-concomitant-influence-on-mitochondrial-function/
Nitric Oxide and Immune Responses: Part 2
Author and Curator: Aviral Vatsa, PhD, MBBS
http://pharmaceuticalintelligence.com/2012/10/28/nitric-oxide-and-immune-responses-part-2/
Mitochondrial Damage and Repair under Oxidative Stress
Author and Curator: Larry H. Bernstein, MD, FCAP
http://pharmaceuticalintelligence.com/2012/10/28/mitochondrial-damage-and-repair-under-oxidative-stress/
Is the Warburg Effect the cause or the effect of cancer: A 21st Century View?
Curator and Author: Larry H Bernstein, MD, FACP
http://pharmaceuticalintelligence.com/2012/10/17/is-the-warburg-effect-the-cause-or-the-effect-of-cancer-a-21st-century-view/
Targeting Mitochondrial-bound Hexokinase for Cancer Therapy
Curator and Author: Ziv Raviv, PhD, RN 04/06/2013
http://pharmaceuticalintelligence.com/2013/04/06/targeting-mitochondrial-bound-hexokinase-for-cancer-therapy/
Ubiquinin-Proteosome pathway, autophagy, the mitochondrion, proteolysis and cell apoptosis
Curator and Author: Larry H Bernstein, MD, FACP
http://pharmaceuticalintelligence.com/2012/10/30/ubiquinin-proteosome-pathway-autophagy-the-mitochondrion-proteolysis-and-cell-apoptosis/
Ubiquitin-Proteosome pathway, Autophagy, the Mitochondrion, Proteolysis and Cell Apoptosis: Part III
Curator and Author: Larry H Bernstein, MD, FACP
http://pharmaceuticalintelligence.com/2013/02/14/ubiquinin-proteosome-pathway-autophagy-the-mitochondrion-proteolysis-and-cell-apoptosis-reconsidered/
Biochemistry of the Coagulation Cascade and Platelet Aggregation – Part I
Curator and Author: Larry H Bernstein, MD, FACP
http://pharmaceuticalintelligence.com/2012/11/26/biochemistry-of-the-coagulation-cascade-and-platelet-aggregation/

Genomics, Transcriptomics, and Epigenetics

What is the meaning of so many RNAs?
Writer and Curator: Larry H. Bernstein, MD, FCAP
http://pharmaceuticalintelligence.com/2014/08/06/what-is-the-meaning-of-so-many-rnas/
RNA and the transcription the genetic code
Larry H. Bernstein, MD, FCAP, Writer and Curator
http://pharmaceuticalintelligence.com/2014/08/02/rna-and-the-transcription-of-the-genetic-code/
A Primer on DNA and DNA Replication
Writer and Curator: Larry H. Bernstein, MD, FCAP
http://pharmaceuticalintelligence.com/2014/07/29/a_primer_on_dna_and_dna_replication/
Pathology Emergence in the 21st Century
Author and Curator: Larry Bernstein, MD, FCAP
http://pharmaceuticalintelligence.com/2014/08/03/pathology-emergence-in-the-21st-century/
RNA and the transcription the genetic code
Writer and Curator, Larry H. Bernstein, MD, FCAP
http://pharmaceuticalintelligence.com/2014/08/02/rna-and-the-transcription-of-the-genetic-code/
Commentary on Biomarkers for Genetics and Genomics of Cardiovascular Disease: Views by Larry H Bernstein, MD, FCAP
Author: Larry H Bernstein, MD, FCAP
http://pharmaceuticalintelligence.com/2014/07/16/commentary-on-biomarkers-for-genetics-and-genomics-of-cardiovascular-disease-views-by-larry-h-bernstein-md-fcap/
Observations on Finding the Genetic Links in Common Disease: Whole Genomic Sequencing Studies
Author an Curator: Larry H Bernstein, MD, FCAP
http://pharmaceuticalintelligence.com/2013/05/18/observations-on-finding-the-genetic-links/
Silencing Cancers with Synthetic siRNAs
Larry H. Bernstein, MD, FCAP, Reviewer and Curator
http://pharmaceuticalintelligence.com/2013/12/09/silencing-cancers-with-synthetic-sirnas/
Cardiometabolic Syndrome and the Genetics of Hypertension: The Neuroendocrine Transcriptome Control Points
Reporter: Aviva Lev-Ari, PhD, RN
http://pharmaceuticalintelligence.com/2013/12/12/cardiometabolic-syndrome-and-the-genetics-of-hypertension-the-neuroendocrine-transcriptome-control-points/
Developments in the Genomics and Proteomics of Type 2 Diabetes Mellitus and Treatment Targets
Larry H. Bernstein, MD, FCAP, Reviewer and Curator
http://pharmaceuticalintelligence.com/2013/12/08/developments-in-the-genomics-and-proteomics-of-type-2-diabetes-mellitus-and-treatment-targets/
CT Angiography & TrueVision™ Metabolomics (Genomic Phenotyping) for new Therapeutic Targets to Atherosclerosis
Reporter: Aviva Lev-Ari, PhD, RN
http://pharmaceuticalintelligence.com/2013/11/15/ct-angiography-truevision-metabolomics-genomic-phenotyping-for-new-therapeutic-targets-to-atherosclerosis/
CRACKING THE CODE OF HUMAN LIFE: The Birth of BioInformatics & Computational Genomics
Genomics Curator, Larry H Bernstein, MD, FCAP
http://pharmaceuticalintelligence.com/2014/08/30/cracking-the-code-of-human-life-the-birth-of-bioinformatics-computational-genomics/
Big Data in Genomic Medicine
Author and Curator, Larry H Bernstein, MD, FCAP
http://pharmaceuticalintelligence.com/2012/12/17/big-data-in-genomic-medicine/
From Genomics of Microorganisms to Translational Medicine
Author and Curator: Demet Sag, PhD
http://pharmaceuticalintelligence.com/2014/03/20/without-the-past-no-future-but-learn-and-move-genomics-of-microorganisms-to-translational-medicine/
Summary of Genomics and Medicine: Role in Cardiovascular Diseases
Author and Curator, Larry H Bernstein, MD, FCAP
http://pharmaceuticalintelligence.com/2014/01/06/summary-of-genomics-and-medicine-role-in-cardiovascular-diseases/

Read Full Post »

« Newer Posts - Older Posts »

Leaders in Pharmaceutical Business Intelligence Group, LLC, Doing Business As LPBI Group, Newton, MA

Archive for the ‘Alzheimer’s Disease’ Category

The Vibrant Philly Biotech Scene: Focus on Vaccines and Philimmune, LLC

The Vibrant Philly Biotech Scene: Focus on Vaccines and Philimmune, LLC

Historic Timeline of Vaccine Development

RAbD Biotech Presents at 1st Pitch Life Sciences-Philadelphia

LytPhage Presents at 1st Pitch Life Sciences-Philadelphia

Hastke Inc. Presents at 1st Pitch Life Sciences-Philadelphia

1st Pitch Life Science- Philadelphia- What VCs Really Think of your Pitch

The History of Infectious Diseases and Epidemiology in the late 19th and 20th Century

Like this:

Introduction to Impairments in Pathological States: Endocrine Disorders, Stress Hypermetabolism and Cancer

Introduction to Impairments in Pathological States: Endocrine Disorders, Stress Hypermetabolism and Cancer

Like this:

Complex Models of Signaling: Therapeutic Implications

Complex Models of Signaling: Therapeutic Implications

Evidence of sphingolipid signaling in cancer

SPHK1 Is a Novel Target of Metformin in Ovarian Cancer.

Author information

Abstract

Like this:

Diabetes Mellitus

Diabetes Mellitus

Like this:

Metabolomics is about Metabolic Systems Integration

Metabolomics is about Metabolic Systems Integration

Like this:

The Use of Light Waves to Visualize and Stimulate the Human Brain

The Use of Light Waves to Visualize and Stimulate the Human Brain

A new way to understand the human brain: Interview

Like this:

Follow Blog via Email

Recent Posts

Archives

Categories

Meta

Archive for the ‘Alzheimer’s Disease’ Category

The Vibrant Philly Biotech Scene: Focus on Vaccines and Philimmune, LLC

Historic Timeline of Vaccine Development

Share this:

Like this:

Introduction to Impairments in Pathological States: Endocrine Disorders, Stress Hypermetabolism and Cancer

Share this:

Like this:

Summary of Signaling and Signaling Pathways

Share this:

Like this:

Complex Models of Signaling: Therapeutic Implications

Evidence of sphingolipid signaling in cancer

SPHK1 Is a Novel Target of Metformin in Ovarian Cancer.

Abstract

Share this:

Like this:

Diabetes Mellitus

Share this:

Like this:

Metabolomics is about Metabolic Systems Integration

Share this:

Like this:

The Use of Light Waves to Visualize and Stimulate the Human Brain

Share this:

Like this:

Plant-based Nutrition, Neutraceuticals and Alternative Medicine: Article Compilation the Journal PharmaceuticalIntelligence.com

Share this:

Like this:

12. The Centrality of Ca(2+) Signaling and Cytoskeleton Involving Calmodulin Kinases and Ryanodine Receptors in Cardiac Failure, Arterial Smooth Muscle, Post-ischemic Arrhythmia, Similarities and Differences, and Pharmaceutical Targets

Author and Curator: Larry H Bernstein, MD, FCAP, Author, and Content Consultant to e-SERIES A: Cardiovascular Diseases: Justin Pearlman, MD, PhD, FACC and Curator: Aviva Lev-Ari, PhD, RN

Share this:

Like this:

Share this:

Like this:

Follow Blog via Email

Recent Posts

Archives

Categories

Meta

12. The Centrality of Ca(2+) Signaling and Cytoskeleton Involving Calmodulin Kinases and
Ryanodine Receptors in Cardiac Failure, Arterial Smooth Muscle, Post-ischemic Arrhythmia,
Similarities and Differences, and Pharmaceutical Targets

Author and Curator: Larry H Bernstein, MD, FCAP, Author, and Content Consultant to
e-SERIES A: Cardiovascular Diseases: Justin Pearlman, MD, PhD, FACC and
Curator: Aviva Lev-Ari, PhD, RN