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Archive for the ‘Signaling & Cell Circuits’ Category


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

 

Obesity is a global concern that is associated with many chronic complications such as type 2 diabetes, insulin resistance (IR), cardiovascular diseases, and cancer. Growing evidence has implicated the digestive system, including its microbiota, gut-derived incretin hormones, and gut-associated lymphoid tissue in obesity and IR. During high fat diet (HFD) feeding and obesity, a significant shift occurs in the microbial populations within the gut, known as dysbiosis, which interacts with the intestinal immune system. Similar to other metabolic organs, including visceral adipose tissue (VAT) and liver, altered immune homeostasis has also been observed in the small and large intestines during obesity.

 

A link between the gut microbiota and the intestinal immune system is the immune-derived molecule immunoglobulin A (IgA). IgA is a B cell antibody primarily produced in dimeric form by plasma cells residing in the gut lamina propria (LP). Given the importance of IgA on intestinal–gut microbe immunoregulation, which is directly influenced by dietary changes, scientists hypothesized that IgA may be a key player in the pathogenesis of obesity and IR. Here, in this study it was demonstrate that IgA levels are reduced during obesity and the loss of IgA in mice worsens IR and increases intestinal permeability, microbiota encroachment, and downstream inflammation in metabolic tissues, including inside the VAT.

 

IgA deficiency alters the obese gut microbiota and its metabolic phenotype can be recapitulated into microbiota-depleted mice upon fecal matter transplantation. In addition, the researchers also demonstrated that commonly used therapies for diabetes such as metformin and bariatric surgery can alter cellular and stool IgA levels, respectively. These findings suggested a critical function for IgA in regulating metabolic disease and support the emerging role for intestinal immunity as an important modulator of systemic glucose metabolism.

 

Overall, the researchers demonstrated a critical role for IgA in regulating intestinal homeostasis, metabolic inflammation, and obesity-related IR. These findings identify intestinal IgA+ immune cells as mucosal mediators of whole-body glucose regulation in diet-induced metabolic disease. This research further emphasized the importance of the intestinal adaptive immune system and its interactions with the gut microbiota and innate immune system within the larger network of organs involved in the manifestation of metabolic disease.

 

Future investigation is required to determine the impact of IgA deficiency during obesity in humans and the role of metabolic disease in human populations with selective IgA deficiency, especially since human IgA deficiency is associated with an altered gut microbiota that cannot be fully compensated with IgM. However, the research identified IgA as a critical immunological molecule in the intestine that impacts systemic glucose homeostasis, and treatments targeting IgA-producing immune populations and SIgA may have therapeutic potential for metabolic disease.

 

References:

 

https://www.nature.com/articles/s41467-019-11370-y?elqTrackId=dc86e0c60f574542b033227afd0fdc8e

 

https://www.jci.org/articles/view/88879

 

https://www.nature.com/articles/nm.2353

 

https://diabetes.diabetesjournals.org/content/57/6/1470

 

https://www.sciencedirect.com/science/article/pii/S1550413115001047?via%3Dihub

 

https://www.sciencedirect.com/science/article/pii/S1550413115002326?via%3Dihub

 

https://www.sciencedirect.com/science/article/pii/S1931312814004636?via%3Dihub

 

https://www.nature.com/articles/nature15766

 

https://www.sciencedirect.com/science/article/pii/S1550413116000371?via%3Dihub

 

https://www.nature.com/articles/nm.2001

 

https://www.sciencedirect.com/science/article/abs/pii/S1550413118305047?via%3Dihub

 

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An Intelligent DNA Nanorobot to Fight Cancer by Targeting HER2 Expression

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

 

HER2 is an important prognostic biomarker for 20–30% of breast cancers, which is the most common cancer in women. Overexpression of the HER2 receptor stimulates breast cells to proliferate and differentiate uncontrollably, thereby enhancing the malignancy of breast cancer and resulting in a poor prognosis for affected individuals. Current therapies to suppress the overexpression of HER2 in breast cancer mainly involve treatment with HER2-specific monoclonal antibodies. However, these monoclonal anti-HER2 antibodies have severe side effects in clinical trials, such as diarrhea, abnormal liver function, and drug resistance. Removing HER2 from the plasma membrane or inhibiting the gene expression of HER2 is a promising alternative that could limit the malignancy of HER2-positive cancer cells.

 

DNA origami is an emerging field of DNA-based nanotechnology and intelligent DNA nanorobots show great promise in working as a drug delivery system in healthcare. Different DNA-based nanorobots have been developed as affordable and facile therapeutic drugs. In particular, many studies reported that a tetrahedral framework nucleic acid (tFNA) could serve as a promising DNA nanocarrier for many antitumor drugs, owing to its high biocompatibility and biosecurity. For example, tFNA was reported to effectively deliver paclitaxel or doxorubicin to cancer cells for reversing drug resistance, small interfering RNAs (siRNAs) have been modified into tFNA for targeted drug delivery. Moreover, the production and storage of tFNA are not complicated, and they can be quickly degraded in lysosomes by cells. Since both free HApt and tFNA can be diverted into lysosomes, so,  combining the HApt and tFNA as a novel DNA nanorobot (namely, HApt-tFNA) can be an effective strategy to improve its delivery and therapeutic efficacy in treating HER2-positive breast cancer.

 

Researchers reported that a DNA framework-based intelligent DNA nanorobot for selective lysosomal degradation of tumor-specific proteins on cancer cells. An anti-HER2 aptamer (HApt) was site-specifically anchored on a tetrahedral framework nucleic acid (tFNA). This DNA nanorobot (HApt-tFNA) could target HER2-positive breast cancer cells and specifically induce the lysosomal degradation of the membrane protein HER2. An injection of the DNA nanorobot into a mouse model revealed that the presence of tFNA enhanced the stability and prolonged the blood circulation time of HApt, and HApt-tFNA could therefore drive HER2 into lysosomal degradation with a higher efficiency. The formation of the HER2-HApt-tFNA complexes resulted in the HER2-mediated endocytosis and digestion in lysosomes, which effectively reduced the amount of HER2 on the cell surfaces. An increased HER2 digestion through HApt-tFNA further induced cell apoptosis and arrested cell growth. Hence, this novel DNA nanorobot sheds new light on targeted protein degradation for precision breast cancer therapy.

 

It was previously reported that tFNA was degraded by lysosomes and could enhance cell autophagy. Results indicated that free Cy5-HApt and Cy5-HApt-tFNA could enter the lysosomes; thus, tFNA can be regarded as an efficient nanocarrier to transmit HApt into the target organelle. The DNA nanorobot composed of HApt and tFNA showed a higher stability and a more effective performance than free HApt against HER2-positive breast cancer cells. The PI3K/AKT pathway was inhibited when membrane-bound HER2 decreased in SK-BR-3 cells under the action of HApt-tFNA. The research findings suggest that tFNA can enhance the anticancer effects of HApt on SK-BR-3 cells; while HApt-tFNA can bind to HER2 specifically, the compounded HER2-HApt-tFNA complexes can then be transferred and degraded in lysosomes. After these processes, the accumulation of HER2 in the plasma membrane would decrease, which could also influence the downstream PI3K/AKT signaling pathway that is associated with cell growth and death.

 

However, some limitations need to be noted when interpreting the findings: (i) the cytotoxicity of the nanorobot on HER2-positive cancer cells was weak, and the anticancer effects between conventional monoclonal antibodies and HApt-tFNA was not compared; (ii) the differences in delivery efficiency between tFNA and other nanocarriers need to be confirmed; and (iii) the confirmation of anticancer effects of HApt-tFNA on tumors within animals remains challenging. Despite these limitations, the present study provided novel evidence of the biological effects of tFNA when combined with HApt. Although the stability and the anticancer effects of HApt-tFNA may require further improvement before clinical application, this study initiates a promising step toward the development of nanomedicines with novel and intelligent DNA nanorobots for tumor treatment.

 

References:

 

https://pubs.acs.org/doi/10.1021/acs.nanolett.9b01320

 

https://www.ncbi.nlm.nih.gov/pubmed/27939064

 

https://www.ncbi.nlm.nih.gov/pubmed/11694782

 

https://www.ncbi.nlm.nih.gov/pubmed/27082923

 

https://www.ncbi.nlm.nih.gov/pubmed/25365825

 

https://www.ncbi.nlm.nih.gov/pubmed/26840503

 

https://www.ncbi.nlm.nih.gov/pubmed/29802035

 

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

 

Leigh syndrome is one of the hundreds of so-called mitochondrial diseases, which are caused by defects in the mitochondria that produce 90 percent of the body’s energy. These disorders are rare; about 1,000 to 4,000 babies in the United States are born with one every year. But they are devastating and can result in grave impairment of nearly any bodily system. They are largely untreatable, uniformly incurable and very difficult to screen.

 

Leigh syndrome is a terrible disease. It emerges shortly after birth and claims one major organ after another. Movement becomes difficult, and then impossible. A tracheotomy and feeding tube are often necessary by toddlerhood, and as the disease progresses, lungs frequently have to be suctioned manually. Most children with the condition die by the age of 5 or 6.

 

Scientists have devised a procedure called mitochondrial replacement therapy (M.R.T.) that involves transplanting the nucleus of an affected egg (mitochondrial diseases are passed down from the mother’s side) into an unaffected one whose nucleus has been removed. The procedure is sometimes called “three-parent in vitro fertilization”. Mitochondria contain a minuscule amount of DNA, any resulting embryo would have mitochondrial DNA from the donor egg and nuclear DNA from each of its parents.

 

After decades of careful study in cell and animal research M.R.T. is now finally being tested in human clinical trials by doctors in Britain (no births confirmed yet officially). In the United States, however, this procedure is effectively illegal. M.R.T. does not involve altering any genetic code. Defective mitochondria are swapped out for healthy ones.

 

Mitochondrial DNA governs only a handful of basic cellular functions. It is separate from nuclear DNA, which helps determine individual traits like physical appearance, intelligence and personality. That means M.R.T. cannot be used to produce the genetically enhanced “designer babies” and thus should be allowed in humans. But, there is no way to know how safe or effective M.R.T. is until doctors and scientists test it in humans.

 

References:

 

 

https://pharmaceuticalintelligence.com/2016/10/07/the-three-parent-technique-to-avoid-mitochondrial-disease-in-embryo/

 

 

 

 

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

 

Protein kinase C (PKC) isozymes function as tumor suppressors in increasing contexts. These enzymes are crucial for a number of cellular activities, including cell survival, proliferation and migration — functions that must be carefully controlled if cells get out of control and form a tumor. In contrast to oncogenic kinases, whose function is acutely regulated by transient phosphorylation, PKC is constitutively phosphorylated following biosynthesis to yield a stable, autoinhibited enzyme that is reversibly activated by second messengers. Researchers at University of California San Diego School of Medicine found that another enzyme, called PHLPP1, acts as a “proofreader” to keep careful tabs on PKC.

 

The researchers discovered that in pancreatic cancer high PHLPP1 levels lead to low PKC levels, which is associated with poor patient survival. They reported that the phosphatase PHLPP1 opposes PKC phosphorylation during maturation, leading to the degradation of aberrantly active species that do not become autoinhibited. They discovered that any time an over-active PKC is inadvertently produced, the PHLPP1 “proofreader” tags it for destruction. That means the amount of PHLPP1 in patient’s cells determines his amount of PKC and it turns out those enzyme levels are especially important in pancreatic cancer.

 

This team of researchers reversed a 30-year paradigm when they reported evidence that PKC actually suppresses, rather than promotes, tumors. For decades before this revelation, many researchers had attempted to develop drugs that inhibit PKC as a means to treat cancer. Their study implied that anti-cancer drugs would actually need to do the opposite — boost PKC activity. This study sets the stage for clinicians to one day use a pancreatic cancer patient’s PHLPP1/PKC levels as a predictor for prognosis, and for researchers to develop new therapeutic drugs that inhibit PHLPP1 and boost PKC as a means to treat the disease.

 

The ratio — high PHLPP1/low PKC — correlated with poor prognoses: no pancreatic patient with low PKC in the database survived longer than five-and-a-half years. On the flip side, 50 percent of the patients with low PHLPP1/high PKC survived longer than that. While still in the earliest stages, the researchers hope that this information might one day aid pancreatic diagnostics and treatment. The researchers are next planning to screen chemical compounds to find those that inhibit PHLPP1 and restore PKC levels in low-PKC-pancreatic cancer cells in the lab. These might form the basis of a new therapeutic drug for pancreatic cancer.

 

References:

 

https://health.ucsd.edu/news/releases/Pages/2019-03-20-two-enzymes-linked-to-pancreatic-cancer-survival.aspx?elqTrackId=b6864b278958402787f61dd7b7624666

 

https://www.ncbi.nlm.nih.gov/pubmed/30904392

 

https://www.ncbi.nlm.nih.gov/pubmed/29513138

 

https://www.ncbi.nlm.nih.gov/pubmed/18511290

 

https://www.ncbi.nlm.nih.gov/pubmed/28476658

 

https://www.ncbi.nlm.nih.gov/pubmed/28283201

 

https://www.ncbi.nlm.nih.gov/pubmed/24231509

 

https://www.ncbi.nlm.nih.gov/pubmed/28112438

 

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Immunoediting can be a constant defense in the cancer landscape


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

 

There are many considerations in the cancer immunoediting landscape of defense and regulation in the cancer hallmark biology. The cancer hallmark biology in concert with key controls of the HLA compatibility affinity mechanisms are pivotal in architecting a unique patient-centric therapeutic application. Selection of random immune products including neoantigens, antigens, antibodies and other vital immune elements creates a high level of uncertainty and risk of undesirable immune reactions. Immunoediting is a constant process. The human innate and adaptive forces can either trigger favorable or unfavorable immunoediting features. Cancer is a multi-disease entity. There are multi-factorial initiators in a certain disease process. Namely, environmental exposures, viral and / or microbiome exposure disequilibrium, direct harm to DNA, poor immune adaptability, inherent risk and an individual’s own vibration rhythm in life.

 

When a human single cell is crippled (Deranged DNA) with mixed up molecular behavior that is the initiator of the problem. A once normal cell now transitioned into full threatening molecular time bomb. In the modeling and creation of a tumor it all begins with the singular molecular crisis and crippling of a normal human cell. At this point it is either chop suey (mixed bit responses) or a productive defensive and regulation response and posture of the immune system. Mixed bits of normal DNA, cancer-laden DNA, circulating tumor DNA, circulating normal cells, circulating tumor cells, circulating immune defense cells, circulating immune inflammatory cells forming a moiety of normal and a moiety of mess. The challenge is to scavenge the mess and amplify the normal.

 

Immunoediting is a primary push-button feature that is definitely required to be hit when it comes to initiating immune defenses against cancer and an adaptation in favor of regression. As mentioned before that the tumor microenvironment is a “mixed bit” moiety, which includes elements of the immune system that can defend against circulating cancer cells and tumor growth. Personalized (Precision-Based) cancer vaccines must become the primary form of treatment in this case. Current treatment regimens in conventional therapy destroy immune defenses and regulation and create more serious complications observed in tumor progression, metastasis and survival. Commonly resistance to chemotherapeutic agents is observed. These personalized treatments will be developed in concert with cancer hallmark analytics and immunocentrics affinity and selection mapping. This mapping will demonstrate molecular pathway interface and HLA compatibility and adaptation with patientcentricity.

References:

 

https://www.linkedin.com/pulse/immunoediting-cancer-landscape-john-catanzaro/

 

https://www.cell.com/cell/fulltext/S0092-8674(16)31609-9

 

https://www.researchgate.net/publication/309432057_Circulating_tumor_cell_clusters_What_we_know_and_what_we_expect_Review

 

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4190561/

 

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5840207/

 

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5593672/

 

https://www.frontiersin.org/articles/10.3389/fimmu.2018.00414/full

 

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5593672/

 

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4190561/

 

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4388310/

 

https://www.linkedin.com/pulse/cancer-hallmark-analytics-omics-data-pathway-studio-review-catanzaro/

 

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Benefits of Fiber in Diet

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

 

UPDATED on 1/15/2019

This is How Much Daily Fiber to Eat for Better Health – More appears better in meta-analysis — as in more than 30 g/day

by Ashley Lyles, Staff Writer, MedPage Today

In the systematic review, observational data showed a 15% to 30% decline in cardiovascular-related death, all-cause mortality, and incidence of stroke, coronary heart disease, type 2 diabetes, and colorectal cancer among people who consumed the most dietary fiber compared to those consuming the lowest amounts.

Whole grain intake yielded similar findings.

Risk reduction associated with a range of critical outcomes was greatest when daily intake of dietary fibre was between 25 g and 29 g. Dose-response curves suggested that higher intakes of dietary fibre could confer even greater benefit to protect against cardiovascular diseases, type 2 diabetes, and colorectal and breast cancer.

https://www.thelancet.com/pdfs/journals/lancet/PIIS0140-6736(18)31809-9.pdf

Eating more dietary fiber was linked with lower risk of disease and death, a meta-analysis showed.

According to observational studies, risk was reduced most for a range of critical outcomes from all-cause mortality to stroke when daily fiber consumption was between 25 grams and 29 grams, reported Jim Mann, PhD, of University of Otago in Dunedin, New Zealand, and colleagues in The Lancet.

By upping daily intake to 30 grams or more, people had even greater prevention of certain conditions: colorectal and breast cancer, type 2 diabetes, and cardiovascular diseases, according to dose-response curves the authors created.

Quantitative guidelines relating to dietary fiber have not been available, the researchers said. With the GRADE method, they determined that there was moderate and low-to-moderate certainty of evidence for the benefits of dietary fiber consumption and whole grain consumption, respectively.

Included in the systematic review were 58 clinical trials and 185 prospective studies for a total of 4,635 adult participants with 135 million person-years of information (one trial in children was included, but analyzed separately from adults). Trials and prospective studies assessing weight loss, supplement use, and participants with a chronic disease were excluded.

 

Food is digested by bathing in enzymes that break down its molecules. Those molecular fragments then pass through the gut wall and are absorbed in our intestines. But our bodies make a limited range of enzymes, so that we cannot break down many of the tough compounds in plants. The term “dietary fiber” refers to those indigestible molecules. These dietary fibers are indigestible only to us. The gut is coated with a layer of mucus, on which sits a carpet of hundreds of species of bacteria, part of the human microbiome. Some of these microbes carry the enzymes needed to break down various kinds of dietary fibers.

 

Scientists at the University of Gothenburg in Sweden are running experiments that are yielding some important new clues about fiber’s role in human health. Their research indicates that fiber doesn’t deliver many of its benefits directly to our bodies. Instead, the fiber we eat feeds billions of bacteria in our guts. Keeping them happy means our intestines and immune systems remain in good working order. The scientists have recently reported that the microbes are involved in the benefits obtained from the fruits-and-vegetables diet. Research proved that low fiber diet decreases the gut bacteria population by tenfold.

 

Along with changes to the microbiome there were also rapid changes observed in the experimental mice. Their intestines got smaller, and its mucus layer thinner. As a result, bacteria wound up much closer to the intestinal wall, and that encroachment triggered an immune reaction. After a few days on the low-fiber diet, mouse intestines developed chronic inflammation. After a few weeks, they started putting on fat and developing higher blood sugar levels. Inflammation can help fight infections, but if it becomes chronic, it can harm our bodies. Among other things, chronic inflammation may interfere with how the body uses the calories in food, storing more of it as fat rather than burning it for energy.

 

In a way fiber benefits human health is by giving, indirectly, another source of food. When bacteria finished harvesting the energy in the dietary fiber, they cast off the fragments as waste. That waste — in the form of short-chain fatty acids — is absorbed by intestinal cells, which use it as fuel. But the gut’s microbes do more than just make energy. They also send messages. Intestinal cells rely on chemical signals from the bacteria to work properly. The cells respond to the signals by multiplying and making a healthy supply of mucus. They also release bacteria-killing molecules. By generating these responses, gut bacteria help to maintain a peaceful coexistence with the immune system. They rest on the gut’s mucus layer at a safe distance from the intestinal wall. Any bacteria that wind up too close get wiped out by antimicrobial poisons.

 

A diet of fiber-rich foods, such as fruits and vegetables, reduces the risk of developing diabetes, heart disease and arthritis. Eating more fiber seems to lower people’s mortality rate, whatever be the cause. Researchers hope that they will learn more about how fiber influences the microbiome to use it as a way to treat disorders. Lowering inflammation with fiber may also help in the treatment of immune disorders such as inflammatory bowel disease. Fiber may also help reverse obesity. They found that fiber supplements helped obese people to lose weight. It’s possible that each type of fiber feeds a particular set of bacteria, which send their own important signals to our bodies.

 

References:

 

https://www.nytimes.com/2018/01/01/science/food-fiber-microbiome-inflammation.html

 

 

https://www.ncbi.nlm.nih.gov/pubmed/29276171

 

https://www.ncbi.nlm.nih.gov/pubmed/29276170

 

https://www.ncbi.nlm.nih.gov/pubmed/29486139

 

https://www.mayoclinic.org/healthy-lifestyle/nutrition-and-healthy-eating/in-depth/fiber/art-20043983

 

https://nutritiouslife.com/eat-empowered/high-fiber-diet/

 

http://www.eatingwell.com/article/287742/10-amazing-health-benefits-of-eating-more-fiber/

 

http://www.cookinglight.com/eating-smart/nutrition-101/what-is-a-high-fiber-diet

 

https://www.helpguide.org/articles/healthy-eating/high-fiber-foods.htm

 

https://www.gicare.com/diets/high-fiber-diet/

 

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Energy dysfunction detected in skin cells a possible additional explanation of the Alzheimer’s disease’s hallmark Dementia

Reporter: Aviva Lev-Ari, PhD, RN

A team at Harvard-affiliated McLean Hospital tested the cells of late-onset Alzheimer’s patients and found malfunctions in their energy production, including problems with the health of their mitochondria, the cellular power plants that provide most of their energy.

The brain, because it is the body’s most energy-hungry organ, demanding as much as 20 times the energy of other tissues. Such a malfunction, he said, could damage or kill nerve cells and help explain the cognitive decline associated with the disease.

McLean researchers detect dysfunction in cells’ energy production in late-onset patients

“Although people hope with a lot of these conditions we study — normal or abnormal — that there are going to be simple answers … it’s never simple, it’s always all kinds of factors interacting to determine whether you get lucky or not, whether you get sick or not,” Cohen said.

The next step, Cohen said, will be to do a similar study on the neurons and other brain cells of Alzheimer’s patients, to see whether the energy dysfunction detected in skin cells is replicated there. Even if medical understanding of the disease remains imperfect, Cohen said the ultimate hope is to find an intervention that interrupts Alzheimer’s most devastating effects.

“You don’t have to fix everything to keep somebody from getting sick,” Cohen said. “The reason somebody gets sick is you’re unlucky five different ways and it all combines to tip you over the edge. Maybe you only need to fix one of them and you don’t tip over the edge anymore.”

SOURCE

https://news.harvard.edu/gazette/story/2017/11/new-clues-to-alzheimers-disease/

Other related articles on Mitochondria’s functions published in this Open Access Online Scientific Journal include the following:

Search all +5,200 Journal articles for “Mitochondria”

https://pharmaceuticalintelligence.com/?s=Mitochondria

Proteomics, Metabolomics, Signaling Pathways, and Cell Regulation – Articles of Note, LPBI Group’s Scientists @ http://pharmaceuticalintelligence.com

https://www.linkedin.com/pulse/proteomics-metabolomics-signaling-pathways-cell-lev-ari-phd-rn/

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