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Posts Tagged ‘metabolic pathways’


A Reconstructed View of Personalized Medicine

Author: Larry H. Bernstein, MD, FCAP

 

There has always been Personalized Medicine if you consider the time a physician spends with a patient, which has dwindled. But the current recognition of personalized medicine refers to breakthrough advances in technological innovation in diagnostics and treatment that differentiates subclasses within diagnoses that are amenable to relapse eluding therapies.  There are just a few highlights to consider:

  1. We live in a world with other living beings that are adapting to a changing environmental stresses.
  2. Nutritional resources that have been available and made plentiful over generations are not abundant in some climates.
  3. Despite the huge impact that genomics has had on biological progress over the last century, there is a huge contribution not to be overlooked in epigenetics, metabolomics, and pathways analysis.

A Reconstructed View of Personalized Medicine

There has been much interest in ‘junk DNA’, non-coding areas of our DNA are far from being without function. DNA has two basic categories of nitrogenous bases: the purines (adenine [A] and guanine [G]), and the pyrimidines (cytosine [C], thymine [T], and  no uracil [U]),  while RNA contains only A, G, C, and U (no T).  The Watson-Crick proposal set the path of molecular biology for decades into the 21st century, culminating in the Human Genome Project.

There is no uncertainty about the importance of “Junk DNA”.  It is both an evolutionary remnant, and it has a role in cell regulation.  Further, the role of histones in their relationship the oligonucleotide sequences is not understood.  We now have a large output of research on noncoding RNA, including siRNA, miRNA, and others with roles other than transcription. This requires major revision of our model of cell regulatory processes.  The classic model is solely transcriptional.

  • DNA-> RNA-> Amino Acid in a protein.

Redrawn we have

  • DNA-> RNA-> DNA and
  • DNA->RNA-> protein-> DNA.

Neverthess, there were unrelated discoveries that took on huge importance.  For example, since the 1920s, the work of Warburg and Meyerhoff, followed by that of Krebs, Kaplan, Chance, and others built a solid foundation in the knowledge of enzymes, coenzymes, adenine and pyridine nucleotides, and metabolic pathways, not to mention the importance of Fe3+, Cu2+, Zn2+, and other metal cofactors.  Of huge importance was the work of Jacob, Monod and Changeux, and the effects of cooperativity in allosteric systems and of repulsion in tertiary structure of proteins related to hydrophobic and hydrophilic interactions, which involves the effect of one ligand on the binding or catalysis of another,  demonstrated by the end-product inhibition of the enzyme, L-threonine deaminase (Changeux 1961), L-isoleucine, which differs sterically from the reactant, L-threonine whereby the former could inhibit the enzyme without competing with the latter. The current view based on a variety of measurements (e.g., NMR, FRET, and single molecule studies) is a ‘‘dynamic’’ proposal by Cooper and Dryden (1984) that the distribution around the average structure changes in allostery affects the subsequent (binding) affinity at a distant site.

What else do we have to consider?  The measurement of free radicals has increased awareness of radical-induced impairment of the oxidative/antioxidative balance, essential for an understanding of disease progression.  Metal-mediated formation of free radicals causes various modifications to DNA bases, enhanced lipid peroxidation, and altered calcium and sulfhydryl homeostasis. Lipid peroxides, formed by the attack of radicals on polyunsaturated fatty acid residues of phospholipids, can further react with redox metals finally producing mutagenic and carcinogenic malondialdehyde, 4-hydroxynonenal and other exocyclic DNA adducts (etheno and/or propano adducts). The unifying factor in determining toxicity and carcinogenicity for all these metals is the generation of reactive oxygen and nitrogen species. Various studies have confirmed that metals activate signaling pathways and the carcinogenic effect of metals has been related to activation of mainly redox sensitive transcription factors, involving NF-kappaB, AP-1 and p53.

I have provided mechanisms explanatory for regulation of the cell that go beyond the classic model of metabolic pathways associated with the cytoplasm, mitochondria, endoplasmic reticulum, and lysosome, such as, the cell death pathways, expressed in apoptosis and repair.  Nevertheless, there is still a missing part of this discussion that considers the time and space interactions of the cell, cellular cytoskeleton and extracellular and intracellular substrate interactions in the immediate environment.

There is heterogeneity among cancer cells of expected identical type, which would be consistent with differences in phenotypic expression, aligned with epigenetics.  There is also heterogeneity in the immediate interstices between cancer cells.  Integration with genome-wide profiling data identified losses of specific genes on 4p14 and 5q13 that were enriched in grade 3 tumors with high microenvironmental diversity that also substratified patients into poor prognostic groups. In the case of breast cancer, there is interaction with estrogen , and we refer to an androgen-unresponsive prostate cancer.

Finally,  the interaction between enzyme and substrates may be conditionally unidirectional in defining the activity within the cell.  The activity of the cell is dynamically interacting and at high rates of activity.  In a study of the pyruvate kinase (PK) reaction the catalytic activity of the PK reaction was reversed to the thermodynamically unfavorable direction in a muscle preparation by a specific inhibitor. Experiments found that in there were differences in the active form of pyruvate kinase that were clearly related to the environmental condition of the assay – glycolitic or glyconeogenic. The conformational changes indicated by differential regulatory response were used to present a dynamic conformational model functioning at the active site of the enzyme. In the model, the interaction of the enzyme active site with its substrates is described concluding that induced increase in the vibrational energy levels of the active site decreases the energetic barrier for substrate induced changes at the site. Another example is the inhibition of H4 lactate dehydrogenase, but not the M4, by high concentrations of pyruvate. An investigation of the inhibition revealed that a covalent bond was formed between the nicotinamide ring of the NAD+ and the enol form of pyruvate.  The isoenzymes of isocitrate dehydrogenase, IDH1 and IDH2 mutations occur in gliomas and in acute myeloid leukemias with normal karyotype. IDH1 and IDH2 mutations are remarkably specific to codons that encode conserved functionally important arginines in the active site of each enzyme. In this case, there is steric hindrance by Asp279 where the isocitrate substrate normally forms hydrogen bonds with Ser94.

Personalized medicine has been largely viewed from a lens of genomics.  But genomics is only the reading frame.  The living activities of cell processes are dynamic and occur at rapid rates.  We have to keep in mind that personalized in reference to genotype is not complete without reconciliation of phenotype, which is the reference to expressed differences in outcomes.

 

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IsomicroRNA

Larry H. Bernstein, MD, FCAP, Curator

LPBI

 

 

GEN Feb 15, 2016 (Vol. 36, No. 4)

MicroRNAs Rise from Trash to Treasure  

MicroRNAs Are More Plentiful and More Subtle In Action Than Was Once Suspected

Richard A. Stein, M.D., Ph.D.

 

One of the unexpected findings of the Human Genome Project was that over 98% of the human genome does not encode for proteins. Once dismissed as “junk” genomic material, non-protein-coding DNA is now appraised more highly.

Or to be more precise, at least some portions of non-protein-coding DNA are thought to serve important biological functions.

For example, some stretches of DNA give rise to a noncoding but still functional kind of RNA called microRNA. MicroRNAs have increasingly emerged in recent years as key regulators of biological processes and pathways.

During the years since their discovery, a key question in the biology of microRNAs has focused on the number of microRNAs encoded in the genome. Between 1993 and 2015, approximately 1,900 human genome loci were discovered to produce microRNAs and were added to miRBbase, the public database that catalogues and annotates microRNA molecules.

The cataloguing of microRNAs work has been pursued with extra urgency since 2004, the year the connection between microRNAs and human disease was first demonstrated. “When this connection was made, it launched a whole new field,” says Isidore Rigoutsos, Ph.D., professor of pathology, anatomy, and cell biology and director of the Computational Medicine Center at Thomas Jefferson University.

 

 

 

Another Set of MicroRNAs Emerge

“We wanted to know how many microRNA-producing loci really exist in humans,” recalls Dr. Rigoutsos. In a study published in 2015, Dr. Rigoutsos and colleagues analyzed datasets from 1,323 individuals that represented 13 different tissues and identified an additional 3,356 such genomic loci that produce (at least) 3,707 novel microRNs

“We basically tripled the number of locations in the human genome that are now known to encode microRNAs,” asserts Dr. Rigoutsos. Considering that each microRNA regulates up to hundreds of different mRNAs, and that each mRNA is regulated by tens of microRNAs, this finding adds a new layer of complexity to the regulatory dynamics of the human transcriptome.

The newly unveiled microRNAs and previously characterized microRNAs have distinct expression patterns. While 50–60% of the microRNAs previously deposited into the miRBase are expressed in multiple tissues, only about 10% of the newly discovered microRNAs are shared across multiple tissue types. Also, most of the newly found microRNAs show tissue-specific expression.

Using Argonaute CLIP-seq data, Dr. Rigoutsos and colleagues showed that similar percentages of the two sets of microRNAs were in complex with Argonaute proteins. “This shows that these novel microRNAs participate in RNA interference just as frequently as the miRBase microRNAs,” contends Dr. Rigoutsos.

In a comparative analysis between the human microRNA datasets and the chimpanzee, gorilla, orangutan, macaque, mouse, fruit fly, and mouse genomes, Dr. Rigoutsos and colleagues discovered that almost 95% of the newly unveiled microRNAs were primate-specific, and over 56% of them were found only in humans.

“We are seeing many human microRNAs that do not exist in the mouse,” states Dr. Rigoutsos. “This means that the mouse models engineered to capture human disease cannot recapitulate the interactions mediated by these microRNAs.

 

  • Interest in IsomiRs Grows

  • In the years since the biology of microRNAs started receiving increasing attention, the conventional view has been that one microRNA locus generates one microRNA. However, once deep sequencing became widely available, microRNA variants that showed differences at their 5′- or 3′-termini have been described.

    “It was initially presumed that these variants were likely the result of the enzyme Dicer not being sufficiently accurate when processing microRNA precursors,” notes Dr. Rigoutsos. Subsequent research revealed that microRNAs are more dynamic than previously thought, with each precursor being able to generate multiple mature microRNA species known as isomiRs.

    To gain insight into the biology of isomiRs, Dr. Rigoutsos and colleagues analyzed genomic datasets from 452 individuals participating in the 1000 Genomes Project. The datasets comprised five different populations and two races. In addition, each population was represented by an even number of men and women.

    This collection allowed the abundance of microRNA isoforms to be examined with respect to population, gender, and race. “We found that isomiRs have expression profiles that are population-, race-, and gender-dependent,” informs Dr. Rigoutsos.

    All the transcriptome data that this analysis was based on came from immortalized B cells. “These are cells that normally are not associated with gender differences, but molecularly we found, in these cells, differences between men and women of the same population and race,” explains Dr. Rigoutsos.

  • Expanding these observations to disease states, Dr. Rigoutsos and colleagues collected isomiR profiles from tissue affected by breast cancer, and compared them with isomiR profiles from control breast tissue. The investigators found that the isomiR profiles also depend on tissue state (healthy vs. diseased), on disease subtype, and on the patient’s race.

    For example, their analysis identified several miR-183-5p isoforms that were upregulated in white triple-negative breast cancer patients compared to control breast samples, but not in black/African-American triple-negative breast cancer patients. In an in vitro phase of this study, three isoforms of this microRNA species were overexpressed in human breast cancer cell lines.

    “We found very little overlap in the gene sets that were affected by each of these isoforms,” emphasizes Dr. Rigoutsos. Despite being generated simultaneously by the same locus, each of the three isoforms affected distinct groups of genes, thus exerting different effects on the transcriptome.

    “As the relative abundance of these isoforms changes ever so slightly from patient to patient, it will affect the corresponding gene groups slightly differently,” concludes Dr. Rigoutsos. “In the process, it creates a new molecular background in each patient.”

    MicroRNAs Point to Therapeutic Strategies against Colorectal Cancer

  • “We are using microRNAs as modulators to overcome chemotherapy resistance in colorectal cancer,” says Jingfang Ju, Ph.D., associate professor of pathology and co-director of translational research at Stony Brook University School of Medicine. Resistance to chemotherapy is one of the major challenges in the clinical management of malignancies, including colorectal cancer. Chemotherapy is usually unable to eliminate cancer stem cells, which may become even more resistant over time, and several microRNAs have been implicated in this process.  “We reasoned that we could provide new modulatory approaches to target this small cell population and allow chemotherapy, radiotherapy, or immunotherapy to eliminate resistant populations or at least prolong long-term survival,”  Dr. Ju said.
  • http://www.genengnews.com/Media/images/Article/StonyBrookUniv_JingfangJu5310853233.jpg

    This image shows how miR-129 may function as a tumor suppressor in colorectal cancer. In this model, which has been proposed by researchers at Stony Brook University’s Translational Research Laboratory, miR-129 suppresses the protein expression of three critical targets—BCL2, TS, and E2F3. Downregulation of BCL2 activates the intrinsic apoptosis pathway by cleaving caspase-9 and caspase-3. Downregulation of TS and E2F3 inhibits cell proliferation by impacting the cell cycle. Consequently, miR-129 exerts a strong antitumor phenotype by induction of apoptosis and impairment of proliferation in tumor cells. [Mihriban Karaayvaz, Haiyan Zhai, Jingfang Ju]

     

    In a retrospective study in which colorectal patient samples were used, Dr. Ju and colleagues revealed that hsa-miR-140-5p expression progressively decreases from normal tissues to primary colorectal cancer tissue, and that it shows a further decrease in liver and lymph node metastases. The experimental overexpression of hsa-miR-140-5p inhibited colorectal cancer stem cell growth by disrupting autophagy, and in a mouse model of disease it abolished tumor formation and metastasis.

    In addition to hsa-miR-140-5p, Dr. Ju and colleagues recently identified hsa-miR-129 and found that it, too, has therapeutic potential. Specifically, they showed that hsa-miR-129 enhanced the sensitivity of colorectal cancer cells to 5-fluorouracil, pointing toward its ability to function as a tumor suppressor.

    One of the mechanisms implicated in this process was the ability of miR-192 to inhibit protein translation of several important targets. These include Bcl-2 (B-cell lymphoma 2), a key anti-apoptotic protein; E2F3, a major cell cycle regulator; and thymidylate synthase, an enzyme that is inhibited by 5-fluorouracil.

    The NIH recently awarded a $3 million grant to establish the Long Island Bioscience Hub (LIBH), which is part of the NIH’s Research Evaluation and Commercialization Hub (REACH) program and represents a partnership between the Center for Biotechnology, Stony Brook University, Cold Spring Harbor Laboratory, and Brookhaven National Laboratory. One of the technology development grants, as part of the first funding cycle of this initiative, will support a feasibility investigation of hsa-miR-129-based therapeutics in colon cancer, an effort led by Dr. Ju. “We are further exploring this novel mechanism,” states Dr. Ju. “We anticipate conducting pharmacokinetic studies and moving to a clinical trial in the future.”

    MicroRNA Insights Gleaned from Host-Virus Interactions

    http://www.genengnews.com/Media/images/Article/MtSinaiHosp_Benjamin_tenOever1664523413.jpg

    At Mount Sinai Hospital’s Icahn School of Medicine, researchers used a codon-optimized version of VP55 produced from an adenovirus-based vector to study the impact of microRNA deletion on the response to virus infection. This image shows RNA in situ hybridization of fibroblasts expressing VP55 (top left), and that of mock-treated fibroblasts (bottom right). Ribosomal RNA, DNA, and microRNAs (miR-26) are depicted by red, blue (DAPI), and green fluorophores, respectively.

    “We observed that when a poxvirus is artificially engineered to encode a microRNA, the microRNA is destroyed along with all the microRNAs from the host cell,” says Benjamin R. tenOever, Ph.D., professor of microbiology at the Icahn School of Medicine, Mount Sinai Hospital. Previously, Dr. tenOever’s group reported that a single vaccinia virus-encoded gene product, VP55, is sufficient to achieve this effect. The group also found that the protein adds nontemplate adenosines to the 3′-end of microRNAs associated with the RNA-induced silencing complex.

    biology,” asserts Dr. tenOever.

    In a recent study, Dr. tenOever and colleagues used a codon-optimized version of VP55 produced from an adenovirus-based vector to study the impact microRNA deletion would have on our normal response to virus infection. “We found that after administration of the vector and rapid ablation of microRNA expression, there is very little that happens over the first one to two days,” informs Dr. tenOever. During the first 24–48 hours after VP55 delivery, the elimination of cellular microRNAs impacted less than 0.35% of the over 11,000 genes expressed in the cell. After 9 days, however, almost 20% of the genes showed significant changes in expression.

    “MicroRNAs are very powerful and influential in controlling the biology of the cell but they do so over the long term,” declares Dr. tenOever. These findings are in agreement with knowledge that has accumulated over the years about microRNA biology, which established that microRNAs play a central role in determining how cells differentiate during development.

    “While microRNAs can act on hundreds of mRNAs, their action requires several days of fine-tuning to have long-term consequences,” adds Dr. tenOever. This finding suggests miRNAs are unable to significantly contribute to the acute response to virus infection.

    The one exception to this observation was that, even though very few genes were affected in the first 48 hours after VP55 delivery, several genes encoding chemokines were impacted. These included chemokines responsible for recruiting antigen-presenting cells, neutrophils, and other immune cells.

    An in vivo analysis of mouse lung tissue 48 hours after vector administration confirmed that several cytokines were specifically upregulated, resulting in immune cell infiltration following the degradation of all microRNAs. These results indicate that the acute viral infection is largely independent of microRNAs, and that microRNAs are primarily involved in the adaptive response to infection and other longer term processes.

    • MicroRNA Biomarkers Reveal Molecular Pathways of Kidney Damage

      “Our approach involves looking at microRNAs from the perspective of biomarkers as a readout for kidney damage,” says Vishal S. Vaidya, Ph.D., associate professor of medicine and environmental health at Brigham and Women’s Hospital, Harvard Medical School, and Harvard T.H. Chan School of Public Health. “At the same time, we are exploring their utility as therapeutics.”

      A large number of medications and occupational toxins cause kidney damage, but many tests to assess kidney function and damage are not sufficiently sensitive or specific, opening the need for novel diagnostic strategies. MicroRNAs, which are differentially expressed between healthy and diseased states, are promising as early biomarkers for impaired renal function.

      “MicroRNAs can also provide information about which pathways are active and which targets can be druggable,” points out Dr. Vaidya.

      In a study that used microRNAs and proteins to provide a combined biomarker signature, Dr. Vaidya and colleagues examined two patient cohorts, one presenting with acetaminophen-induced kidney injury and the other one with cisplatin-induced kidney damage. “Protein biomarkers provide sensitivity, and microRNAs offer mechanistic insight,” explains Dr. Vaidya.

      This approach helped visualize metabolic pathways that are altered in the kidney during toxic injury. “The biggest challenge, from a therapeutic perspective, is that microRNAs regulate many mRNAs and, therefore, impact many proteins,” concludes Dr. Vaidya.

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Lipid Classification System

Curator: Larry H. Bernstein, MD, FCAP

Lipid Classification, Nomenclature and Structure Drawing

 

The LIPID MAPS consortium has developed a comprehensive classification, nomenclature, and chemical representation system for lipids, the details of which are described in the May 2009 issue of the Journal of Lipid Research:

Fahy E, Subramaniam S, Murphy R, Nishijima M, Raetz C, Shimizu T, Spener F, van Meer G, Wakelam M and Dennis E.A.,Update of the LIPID MAPS comprehensive classification system for lipids. J. Lipid Res. (2009) 50: S9-S14.PubMed ID:19098281.

Fahy E, Subramaniam S, Brown H, Glass C, Merrill JA, Murphy R, Raetz C, Russell D, Seyama Y, Shaw W, Shimizu T, Spener F, van Meer G, Vannieuwenhze M, White S, Witztum J and Dennis E.A.,A comprehensive classification system for lipids. J. Lipid Res. (2005) 46: 839-861.PubMed ID:15722563.

http://www.lipidmaps.org/resources/tutorials/lipid_cns.html

Lipid Classification System

The LIPID MAPS Lipid Classification System is comprised of eight lipid categories, each with its own sublassification hierarchy.

All lipids in the LIPID MAPS Structure Database (LMSD) have been classified using this system and have been assigned LIPID MAPS ID’s (LM_ID) which reflects their position in the classification hierarchy.

LMSD can be searched by lipid class, common name, systematic name or synonym, mass, InChIKey or LIPID MAPS ID with the “Quick Search” tool on the home page, or alternatively, by

LIPID MAPS ID, systematic or common name, mass, formula, category, main class, subclass data, or structure or sub-structure with one of the search interfaces in the LMSD database section.

Each LMSD record contains an image of the

  • molecular structure,
  • common and systematic names,
  • links to external databases,
  • Wikipedia pages (where available),
  • other annotations and links to structure viewing tools.

In addition to LMSD search interfaces, you can drill down through the classification hierarchy below to the LMSD record for an individual lipid.

 

Lipid Classes
Fatty Acyls [FA] Fatty Acids and Conjugates [FA01]Octadecanoids [FA02]Eicosanoids [FA03]

Docosanoids [FA04]

Fatty alcohols [FA05]

Fatty aldehydes [FA06]

Fatty esters [FA07]

Fatty amides [FA08]

Fatty nitriles [FA09]

Fatty ethers [FA10]

Hydrocarbons [FA11]

Oxygenated hydrocarbons [FA12]

Fatty acyl glycosides [FA13]

Other Fatty Acyls [FA00]

Glycerophospholipids [GP] Glycerophosphocholines [GP01]Glycerophosphoethanolamines [GP02]Glycerophosphoserines [GP03]

Glycerophosphoglycerols [GP04]

Glycerophosphoglycerophosphates [GP05]

Glycerophosphoinositols [GP06]

Glycerophosphoinositol monophosphates [GP07]

Glycerophosphoinositol bisphosphates [GP08]

Glycerophosphoinositol trisphosphates [GP09]

Glycerophosphates [GP10]

Glyceropyrophosphates [GP11]

Glycerophosphoglycerophosphoglycerols [GP12]

CDP-Glycerols [GP13]

Glycosylglycerophospholipids [GP14]

Glycerophosphoinositolglycans [GP15]

Glycerophosphonocholines [GP16]

Glycerophosphonoethanolamines [GP17]

Di-glycerol tetraether phospholipids (caldarchaeols) [GP18]

Glycerol-nonitol tetraether phospholipids [GP19]

Oxidized glycerophospholipids [GP20]

Other Glycerophospholipids [GP00]

Glycerolipids [GL] Monoradylglycerols [GL01]Diradylglycerols [GL02]Triradylglycerols [GL03]

Glycosylmonoradylglycerols [GL04]

Glycosyldiradylglycerols [GL05]

Other Glycerolipids [GL00]

Sphingolipids [SP] Sphingoidbases [SP01]Ceramides [SP02]Phosphosphingolipids [SP03]

Phosphonosphingolipids [SP04]

Neutral glycosphingolipids [SP05]

Acidic glycosphingolipids [SP06]

Basic glycosphingolipids [SP07]

Amphoteric glycosphingolipids [SP08]

Arsenosphingolipids [SP09]

Other Sphingolipids [SP00]

Sterol Lipids [ST] Sterols [ST01]Steroids [ST02]Secosteroids [ST03]

Bile acids and derivatives [ST04]

Steroid conjugates [ST05]

Other Sterol lipids [ST00]

Prenol Lipids [PR] Isoprenoids [PR01]Quinones andhydroquinones [PR02]Polyprenols [PR03]

Hopanoids [PR04]

Other Prenol lipids [PR00]

Saccharolipids [SL] Acylaminosugars [SL01]Acylaminosugarglycans [SL02]Acyltrehaloses [SL03]

Acyltrehalose glycans [SL04]

Other acyl sugars [SL05]

Other Saccharolipids [SL00]

Polyketides [PK] Linearpolyketides [PK01]Halogenatedacetogenins [PK02]Annonaceae acetogenins [PK03]

Macrolides and lactone polyketides [PK04]

Ansamycins and related polyketides [PK05]

Polyenes [PK06]

Linear tetracyclines [PK07]

Angucyclines [PK08]

Polyether polyketides [PK09]

Aflatoxins and related substances [PK10]

Cytochalasins [PK11]

Flavonoids [PK12]

Aromatic polyketides [PK13]

Non-ribosomal peptide/polyketide hybrids [PK14]

Other Polyketides [PK00]

 

 

LIPID MAPS Structure Database (LMSD)

 

The LIPID MAPS Structure Database (LMSD) is a relational database encompassing structures and annotations of biologically relevant lipids. As of May 3, 2013, LMSD contains over 37,500 unique lipid structures, making it the largest public lipid-only database in the world. Structures of lipids in the database come from several sources:

  • LIPID MAPS Consortium’s core laboratories and partners;
  • lipids identified by LIPID MAPS experiments;
  • biologically relevant lipids manually curated from LIPID BANK, LIPIDAT, Lipid Library, Cyberlipids, ChEBI and other public sources;
  • novel lipids submitted to peer-reviewed journals;
  • computationally generated structures for appropriate classes.

All the lipid structures in LMSD adhere to the structure drawing rules proposed by the LIPID MAPS consortium. A number of structure viewing options are offered: gif image (default), Chemdraw (requires Chemdraw ActiveX/Plugin), MarvinView (Java applet) and JMol (Java applet).

All lipids in the LMSD have been classified using the LIPID MAPS Lipid Classification System. Each lipid structure has been assigned a LIPID MAPS ID (LM_ID) which reflects its position in the classification hierarchy. In addition to a classification-based retrieval of lipids, users can search LMSD using either text-based or structure-based search options.

 

The text-based search implementation supports data retrieval by any combination of these data fields: LIPID MAPS ID, systematic or common name, mass, formula, category, main class, and subclass data fields. The structure-based search, in conjunction with optional data fields, provides the capability to perform a substructure search or exact match for the structure drawn by the user. Search results, in addition to structure and annotations, also include relevant links to external databases.

Statistics

(as of 10/8/14)

Number of lipids per category

Fatty acyls          5869

Glycerolipids       7541

Glycerophospholipids       8002

Sphingolipids      4338

Sterol lipids         2715

Prenol lipids        1259

Sacccharolipids  1293

Polyketides         6742

TOTAL  37,759 structures

References

Sud M, Fahy E, Cotter D, Brown A, Dennis EA, Glass CK, Merrill AH Jr, Murphy RC, Raetz CR, Russell DW, Subramaniam S. LMSD: LIPID MAPS structure database Nucleic Acids Research 35: p. D527-32. PMID:17098933 [http://dx.doi.org:/10.1093/nar/gkl838]     PMID: 17098933

Fahy E, Sud M, Cotter D & Subramaniam S. LIPID MAPS online tools for lipid research Nucleic Acids Research (2007) 35: p. W606-12.PMID:17584797 [http://dx.doi.org:/10.1093/nar/gkm324] PMID: 17584797

 

Proteome Database (LMPD)

– over 2,400 lipid-associated proteins from human and mouse

Pathways

– manually curated lipid metabolism and signaling pathways

MS analysis tools

– tools for searching various lipid classes by precursor or product ion

Structure Drawing Tools

– draw and save lipid structures using online menus

 

References

Time-varying causal inference from phosphoproteomic measurements in macrophage cells.

IEEE Trans Biomed Circuits Syst. 2014 Feb;8(1):74-86.
http://dx.doi.org:/10.1109/TBCAS.2013.2880235.

 

 

research highlights icon Modeling of eicosanoid fluxes reveals functional coupling between cyclooxygenases and terminal synthases.

Biophys J. 2014 Feb 18;106(4):966-75.
http://dx.doi.org:/10.1016/j.bpj.2014.01.015.

 

Lipid Classification

Starting from a lipid category, the user can navigate through the hierarchy by clicking on the “[+]” icon next to a main class name.

This will expand that item to reveal its sub classes.

Clicking on hyperlinks to the right of main classes, sub classes or level 4 classes will display a tabular listing of all lipids corresponding to that particular subset in the LMSD database.

Finally, clicking on the LM_ID hyperlink displays the LMSD record for an individual lipid, which contains

  • an image of the molecular structure,
  • common and systematic names,
  • links to external databases,
  • Wikipedia pages (where available),
  • other annotations and links to structure viewing tools.

LIPID MAPS classification hierarchy

Category (Example: Prenol lipids [LMPR])

Main class (Example: Isoprenoids [LMPR01])

Sub class (where applicable) (Example: C15 Isoprenoids (sesquiterpenes) [LMPR0103])

Level 4 class (where applicable) (Example: Bisabolane sesquiterpenoids [LMPR010306])

Pathways

We have carefully constructed these lipid pathways based on LIPID MAPS experimental data and data from the literature. LIPID MAPS experimental data obtained from our lipid time course experiments and microarray experiments on macrophagese were mapped to corresponding lipids and genes, respectively.

Pathway maps created using VANTED

VANTED is a tool for the visualization and analysis of networks with related experimental data. For more information on VANTED, please refer to: Björn H. Junker, Christian Klukas and Falk Schreiber (2006): VANTED: A system for advanced data analysis and visualization in the context of biological networks. BMC Bioinformatics, 7:109 (http://www.biomedcentral.com/1471-2105/7/109)

References

Fahy E, Subramaniam S, Murphy R, Nishijima M, Raetz C, Shimizu T, Spener F, van Meer G, Wakelam M and Dennis E.A.,Update of the LIPID MAPS comprehensive classification system for lipids. J. Lipid Res. (2009) 50: S9-S14.PubMed ID:19098281.

Fahy E, Subramaniam S, Brown H, Glass C, Merrill JA, Murphy R, Raetz C, Russell D, Seyama Y, Shaw W, Shimizu T, Spener F, van Meer G, Vannieuwenhze M, White S, Witztum J and Dennis E.A.,A comprehensive classification system for lipids. J. Lipid Res. (2005) 46: 839-861.PubMed ID:15722563.

Introduction to lipids

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Introduction to Metabolic Pathways

Author: Larry H. Bernstein, MD, FCAP

 

Humans, mammals, plants and animals, and eukaryotes and prokaryotes all share a common denominator in their manner of existence.  It makes no difference whether they inhabit the land, or the sea, or another living host. They exist by virtue of their metabolic adaptation by way of taking in nutrients as fuel, and converting the nutrients to waste in the expenditure of carrying out the functions of motility, breakdown and utilization of fuel, and replication of their functional mass.

There are essentially two major sources of fuel, mainly, carbohydrate and fat.  A third source, amino acids which requires protein breakdown, is utilized to a limited extent as needed from conversion of gluconeogenic amino acids for entry into the carbohydrate pathway. Amino acids follow specific metabolic pathways related to protein synthesis and cell renewal tied to genomic expression.

Carbohydrates are a major fuel utilized by way of either of two pathways.  They are a source of readily available fuel that is accessible either from breakdown of disaccharides or from hepatic glycogenolysis by way of the Cori cycle.  Fat derived energy is a high energy source that is metabolized by one carbon transfers using the oxidation of fatty acids in mitochondria. In the case of fats, the advantage of high energy is conferred by chain length.

Carbohydrate metabolism has either of two routes of utilization.  This introduces an innovation by way of the mitochondrion or its equivalent, for the process of respiration, or aerobic metabolism through the tricarboxylic acid, or Krebs cycle.  In the presence of low oxygen supply, carbohydrate is metabolized anaerobically, the six carbon glucose being split into two three carbon intermediates, which are finally converted from pyruvate to lactate.  In the presence of oxygen, the lactate is channeled back into respiration, or mitochondrial oxidation, referred to as oxidative phosphorylation. The actual mechanism of this process was of considerable debate for some years until it was resolved that the mechanism involve hydrogen transfers along the “electron transport chain” on the inner membrane of the mitochondrion, and it was tied to the formation of ATP from ADP linked to the so called “active acetate” in Acetyl-Coenzyme A, discovered by Fritz Lipmann (and Nathan O. Kaplan) at Massachusetts General Hospital.  Kaplan then joined with Sidney Colowick at the McCollum Pratt Institute at Johns Hopkins, where they shared tn the seminal discovery of the “pyridine nucleotide transhydrogenases” with Elizabeth Neufeld,  who later established her reputation in the mucopolysaccharidoses (MPS) with L-iduronidase and lysosomal storage disease.

This chapter covers primarily the metabolic pathways for glucose, anaerobic and by mitochondrial oxidation, the electron transport chain, fatty acid oxidation, galactose assimilation, and the hexose monophosphate shunt, essential for the generation of NADPH. The is to be more elaboration on lipids and coverage of transcription, involving amino acids and RNA in other chapters.

The subchapters are as follows:

1.1      Carbohydrate Metabolism

1.2      Studies of Respiration Lead to Acetyl CoA

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

1.4      The Multi-step Transfer of Phosphate Bond and Hydrogen Exchange Energy

Complex I or NADH-Q oxidoreductase

Complex I or NADH-Q oxidoreductase

Fatty acid oxidation and ETC

Fatty acid oxidation and ETC

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Preface to Metabolomics as a Discipline in Medicine

Author: Larry H. Bernstein, MD, FCAP

 

The family of ‘omics fields has rapidly outpaced its siblings over the decade since
the completion of the Human Genome Project.  It has derived much benefit from
the development of Proteomics, which has recently completed a first draft of the
human proteome.  Since genomics, transcriptomics, and proteomics, have matured
considerably, it has become apparent that the search for a driver or drivers of cellular signaling and metabolic pathways could not depend on a full clarity of the genome. There have been unresolved issues, that are not solely comprehended from assumptions about mutations.

The most common diseases affecting mankind are derangements in metabolic
pathways, develop at specific ages periods, and often in adulthood or in the
geriatric period, and are at the intersection of signaling pathways.  Moreover,
the organs involved and systemic features are heavily influenced by physical
activity, and by the air we breathe and the water we drink.

The emergence of the new science is also driven by a large body of work
on protein structure, mechanisms of enzyme action, the modulation of gene
expression, the pH dependent effects on protein binding and conformation.
Beyond what has just been said, a significant portion of DNA has been
designated as “dark matter”. It turns out to have enormous importance in
gene regulation, even though it is not transcriptional, effected in a
modulatory way by “noncoding RNAs.  Metabolomics is the comprehensive
analysis of small molecule metabolites. These might be substrates of
sequenced enzyme reactions, or they might be “inhibiting” RNAs just
mentioned.  In either case, they occur in the substructures of the cell
called organelles, the cytoplasm, and in the cytoskeleton.

The reactions are orchestrated, and they can be modified with respect to
the flow of metabolites based on pH, temperature, membrane structural
modifications, and modulators.  Since most metabolites are generated by
enzymatic proteins that result from gene expression, and metabolites give
organisms their biochemical characteristics, the metabolome links
genotype with phenotype.

Metabolomics is still developing, and the continued development has
relied on two major events. The first is chromatographic separation and
mass  spectroscopy (MS), MS/MS, as well as advances in fluorescence
ultrasensitive optical photonic methods, and the second, as crucial,
is the developments in computational biology. The continuation of
this trend brings expectations of an impact on pharmaceutical and
on neutraceutical developments, which will have an impact on medical
practice. What has lagged behind, and may continue to contribute to the
lag is the failure to develop a suitable electronic medical record to
assist the physician in decisions confronted with so much as yet,
hidden data, the ready availability of which could guide more effective
diagnosis and management of the patient. Put all of this together, and
we can meet series challenges as the research community
interprets and integrates the complex data they are acquiring.

.

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Selected References to Signaling and Metabolic Pathways in PharmaceuticalIntelligence.com

Curator: Larry H. Bernstein, MD, FCAP

 

This is an added selection of articles in Leaders in Pharmaceutical Intelligence after the third portion of the discussion in a series of articles that began with signaling and signaling pathways. There are fine features on the functioning of enzymes and proteins, on sequential changes in a chain reaction, and on conformational changes that we shall return to.  These are critical to developing a more complete understanding of life processes.  I have indicated that many of the protein-protein interactions or protein-membrane interactions and associated regulatory features have been referred to previously, but the focus of the discussion or points made were different.

  1. Signaling and signaling pathways
  2. Signaling transduction tutorial.
  3. Carbohydrate metabolism3.1  Selected References to Signaling and Metabolic Pathways in Leaders in Pharmaceutical Intelligence
  4. Lipid metabolism
  5. Protein synthesis and degradation
  6. Subcellular structure
  7. Impairments in pathological states: endocrine disorders; stress hypermetabolism; cancer.

Selected References to Signaling and Metabolic Pathwayspublished in this Open Access Online Scientific Journal, include the following:

Update on mitochondrial function, respiration, and associated disorders

Curator and writer: Larry H. Benstein, MD, FCAP

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

A Synthesis of the Beauty and Complexity of How We View Cancer


Cancer Volume One – Summary

A Synthesis of the Beauty and Complexity of How We View Cancer

Author: Larry H. Bernstein, MD, FCAP

https://pharmaceuticalintelligence.com/2014/03/26/a-synthesis-of-the-beauty-and-complexity-of-how-we-view-cancer/

Introduction – The Evolution of Cancer Therapy and Cancer Research: How We Got Here?

Author and Curator: Larry H Bernstein, MD, FCAP

https://pharmaceuticalintelligence.com/2014/04/04/introduction-the-evolution-of-cancer-therapy-and-cancer-research-how-we-got-here/

 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

https://pharmaceuticalintelligence.com/2013/09/08/the-centrality-of-ca2-signaling-and-cytoskeleton-involving-calmodulin-kinases-and-ryanodine-receptors-in-cardiac-failure

Renal Distal Tubular Ca2+ Exchange Mechanism in Health and Disease

Author and Curator: Larry H. Bernstein, MD, FCAP
Curator:  Stephen J. Williams, PhD
and Curator: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2013/09/02/renal-distal-tubular-ca2-exchange-mechanism-in-health-and-disease/

Mitochondrial Metabolism and Cardiac Function

Curator: Larry H Bernstein, MD, FACP

https://pharmaceuticalintelligence.com/2013/04/14/mitochondrial-metabolism-and-cardiac-function/

Mitochondrial Dysfunction and Cardiac Disorders

Curator: Larry H Bernstein, MD, FACP

https://pharmaceuticalintelligence.com/2013/04/14/mitochondrial-metabolism-and-cardiac-function/

Reversal of Cardiac mitochondrial dysfunction

Curator: Larry H Bernstein, MD, FACP

https://pharmaceuticalintelligence.com/2013/04/14/reversal-of-cardiac-mitochondrial-dysfunction/

Advanced Topics in Sepsis and the Cardiovascular System  at its End Stage

Author: Larry H Bernstein, MD, FCAP

https://pharmaceuticalintelligence.com/2013/08/18/advanced-topics-in-Sepsis-and-the-Cardiovascular-System-at-its-End-Stage/

Ubiquinin-Proteosome pathway, autophagy, the mitochondrion, proteolysis and cell apoptosis

Curator: Larry H Bernstein, MD, FACP

https://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: Larry H Bernstein, MD, FCAP

https://pharmaceuticalintelligence.com/2013/02/14/ubiquinin-proteosome-pathway-autophagy-the-mitochondrion-proteolysis-and-cell-apoptosis-reconsidered/

 

Nitric Oxide, Platelets, Endothelium and Hemostasis (Coagulation Part II)

Curator: Larry H. Bernstein, MD, FCAP 

https://pharmaceuticalintelligence.com/2012/11/08/nitric-oxide-platelets-endothelium-and-hemostasis/


Mitochondrial Damage and Repair under Oxidative Stress

Curator: Larry H Bernstein, MD, FCAP

https://pharmaceuticalintelligence.com/2012/10/28/mitochondrial-damage-and-repair-under-oxidative-stress/

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

Reporter and Curator: Larry H Bernstein, MD, FACP

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

 

Nitric Oxide has a Ubiquitous Role in the Regulation of Glycolysis – with a Concomitant Influence on Mitochondrial Function

Reporter, Editor, and Topic Co-Leader: Larry H. Bernstein, MD, FCAP

https://pharmaceuticalintelligence.com/2012/09/16/nitric-oxide-has-a-ubiquitous-role-in-the-regulation-of-glycolysis-with-a-concomitant-influence-on-mitochondrial-function/


Mitochondria and Cancer: An overview of mechanisms

Author and Curator: Ritu Saxena, Ph.D.

https://pharmaceuticalintelligence.com/2012/09/01/mitochondria-and-cancer-an-overview/

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

Author and Curator: Ritu Saxena, Ph.D.

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

Overview of Posttranslational Modification (PTM)

Curator: Larry H. Bernstein, MD, FCAP

https://pharmaceuticalintelligence.com/2014/07/29/overview-of-posttranslational-modification-ptm/


Ubiquitin Pathway Involved in Neurodegenerative Diseases

Author and curator: Larry H Bernstein, MD,  FCAP

https://pharmaceuticalintelligence.com/2013/02/15/ubiquitin-pathway-involved-in-neurodegenerative-diseases/

Is the Warburg Effect the Cause or the Effect of Cancer: A 21st Century View?

Author: Larry H. Bernstein, MD, FCAP 

https://pharmaceuticalintelligence.com/2012/10/17/is-the-warburg-effect-the-cause-or-the-effect-of-cancer-a-21st-century-view/

New Insights on Nitric Oxide donors – Part IV

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

https://pharmaceuticalintelligence.com/2012/11/26/new-insights-on-no-donors/

Perspectives on Nitric Oxide in Disease Mechanisms [Kindle Edition]

Margaret Baker PhD (Author), Tilda Barliya PhD (Author), Anamika Sarkar PhD (Author), Ritu Saxena PhD (Author), Stephen J. Williams PhD (Author), Larry Bernstein MD FCAP (Editor), Aviva Lev-Ari PhD RN (Editor), Aviral Vatsa PhD (Editor)

https://pharmaceuticalintelligence.com/biomed-e-books/series-a-e-books-on-cardiovascular-diseases/perspectives-on-nitric-oxide-in-disease-mechanisms-v2/

 

Summary

Nitric oxide and its role in vascular biology

Signal transmission by a gas that is produced by one cell, penetrates through membranes and regulates the function of another cell represents an entirely new principle for signaling in biological systems.   All compounds that inhibit endothelium-derived relaxation-factor (EDRF) have one property in common, redox activity, which accounts for their inhibitory action on EDRF. One exception is hemoglobin, which inactivates EDRF by binding to it. Furchgott, Ignarro and Murad received the Nobel Prize in Physiology and Medicine for discovery of EDRF in 1998 and demonstrating that it might be nitric oxide (NO) based on a study of the transient relaxations of endothelium-denuded rings of rabbit aorta.  These investigators working independently demonstrated that NO is indeed produced by mammalian cells and that NO has specific biological roles in the human body. These studies highlighted the role of NO in cardiovascular, nervous and immune systems. In cardiovascular system NO was shown to cause relaxation of vascular smooth muscle cells causing vasodilatation, in nervous system NO acts as a signaling molecule and in immune system it is used against pathogens by the phagocytosis cells. These pioneering studies opened the path of investigation of role of NO in biology.

NO modulates vascular tone, fibrinolysis, blood pressure and proliferation of vascular smooth muscles. In cardiovascular system disruption of NO pathways or alterations in NO production can result in preponderance to hypertension, hypercholesterolemia, diabetes mellitus, atherosclerosis and thrombosis. The three enzyme isoforms of NO synthase family are responsible for generating NO in different tissues under various circumstances.

Reduction in NO production is implicated as one of the initial factors in initiating endothelial dysfunction. This reduction could be due to

  • reduction in eNOS production
  • reduction in eNOS enzymatic activity
  • reduced bioavailability of NO

Nitric oxide is one of the smallest molecules involved in physiological functions in the body. It is seeks formation of chemical bonds with its targets.  Nitric oxide can exert its effects principally by two ways:

  • Direct
  • Indirect

Direct actions, as the name suggests, result from direct chemical interaction of NO with its targets e.g. with metal complexes, radical species. These actions occur at relatively low NO concentrations (<200 nM)

Indirect actions result from the effects of reactive nitrogen species (RNS) such as NO2 and N2O3. These reactive species are formed by the interaction of NO with superoxide or molecular oxygen. RNS are generally formed at relatively high NO concentrations (>400 nM)

Although it can be tempting for scientists to believe that RNS will always have deleterious effects and NO will have anabolic effects, this is not entirely true as certain RNS mediated actions mediate important signalling steps e.g. thiol oxidation and nitrosation of proteins mediate cell proliferation and survival, and apoptosis respectively.

  • Cells subjected to NO concentration between 10-30 nM were associated with cGMP dependent phosphorylation of ERK
  • Cells subjected to NO concentration between 30-60 nM were associated with Akt phosphorylation
  • Concentration nearing 100 nM resulted in stabilisation of hypoxia inducible factor-1
  • At nearly 400 nM NO, p53 can be modulated
  • >1μM NO, it nhibits mitochondrial respiration

 

Nitric oxide signaling, oxidative stress,  mitochondria, cell damage

Recent data suggests that other NO containing compounds such as S- or N-nitrosoproteins and iron-nitrosyl complexes can be reduced back to produce NO. These NO containing compounds can serve as storage and can reach distant tissues via blood circulation, remote from their place of origin. Hence NO can have both paracrine and ‘endocrine’ effects.

Intracellularly the oxidants present in the cytosol determine the amount of bioacitivity that NO performs. NO can travel roughly 100 microns from NOS enzymes where it is produced.

NO itself in low concentrations have protective action on mitochondrial signaling of cell death.

The aerobic cell was an advance in evolutionary development, but despite the energetic advantage of using oxygen, the associated toxicity of oxygen abundance required adaptive changes.

Oxidation-reduction reactions that are necessary for catabolic and synthetic reactions, can cumulatively damage the organism associated with cancer, cardiovascular disease, neurodegerative disease, and inflammatory overload.  The normal balance between production of pro-oxidant species and destruction by the antioxidant defenses is upset in favor of overproduction of the toxic species, which leads to oxidative stress and disease.

We reviewed the complex interactions and underlying regulatory balances/imbalances between the mechanism of vasorelaxation and vasoconstriction of vascular endothelium by way of nitric oxide (NO), prostacyclin, in response to oxidative stress and intimal injury.

Nitric oxide has a ubiquitous role in the regulation of glycolysis with a concomitant influence on mitochondrial function. The influence on mitochondrial function that is active in endothelium, platelets, vascular smooth muscle and neural cells and the resulting balance has a role in chronic inflammation, asthma, hypertension, sepsis and cancer.

Potential cytotoxic mediators of endothelial cell (EC) apoptosis include increased formation of reactive oxygen and nitrogen species (ROSRNS) during the atherosclerotic process. Nitric oxide (NO) has a biphasic action on oxidative cell killing with low concentrations protecting against cell death, whereas higher concentrations are cytotoxic.

ROS induces mitochondrial DNA damage in ECs, and this damage is accompanied by a decrease in mitochondrial RNA (mtRNA) transcripts, mitochondrial protein synthesis, and cellular ATP levels.

NO and circulatory diseases

Blood vessels arise from endothelial precursors that are thin, flat cells lining the inside of blood vessels forming a monolayer throughout the circulatory system. ECs are defined by specific cell surface markers that characterize their phenotype.

Scientists at the University of Helsinki, Finland, wanted to find out if there exists a rare vascular endothelial stem cell (VESC) population that is capable of producing very high numbers of endothelial daughter cells, and can lead to neovascular growth in adults.

VESCs discovered that reside at the blood vessel wall endothelium are a small population of CD117+ ECs capable of self-renewal.  These cells are capable of undergoing clonal expansion unlike the surrounding ECs that bear limited proliferating potential. A single VESC cell isolated from the endothelial population was able to generate functional blood vessels.

Among many important roles of Nitric oxide (NO), one of the key actions is to act as a vasodilator and maintain cardiovascular health. Induction of NO is regulated by signals in tissue as well as endothelium.

Chen et. al. (Med. Biol. Eng. Comp., 2011) developed a 3-D model consisting of two branched arterioles and nine capillaries surrounding the vessels. Their model not only takes into account of the 3-D volume, but also branching effects on blood flow.

The model indicates that wall shear stress changes depending upon the distribution of RBC in the microcirculations of blood vessels, lead to differential production of NO along the vascular network.

Endothelial dysfunction, the hallmark of which is reduced activity of endothelial cell derived nitric oxide (NO), is a key factor in developing atherosclerosis and cardiovascular disease. Vascular endothelial cells play a pivotal role in modulation of leukocyte and platelet adherence, thrombogenicity, anticoagulation, and vessel wall contraction and relaxation, so that endothelial dysfunction has become almost a synonym for vascular disease. A single layer of endothelial cells is the only constituent of capillaries, which differ from other vessels, which contain smooth muscle cells and adventitia. Capillaries directly mediate nutritional supply as well as gas exchange within all organs. The failure of the microcirculation leads to tissue apoptosis/necrosis.

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