2B4: potential immune target for sepsis survival

Emory immunologists have identified a potential target for treatments aimed at reducing mortality in sepsis, an often deadly reaction to Read more

EHR data superior for studying sepsis

Analysis of EHR data says sepsis rates and mortality have been holding steady, contrary to what is suggested by after-the-fact Read more

New pediatric digestive/liver disease gene identified by international team

A multinational team of researchers describes a newly identified cause of congenital diarrhea and liver disease in Read more

insulin

How metabolic syndrome interacts with stress – mouse model

Emory researchers recently published a paper in Brain, Behavior and Immunity on the interaction between psychological stress and diet-induced metabolic syndrome in a mouse model.

“The metabolic vulnerability and inflammation associated with conditions present in metabolic syndrome may share common risk factors with mood disorders. In particular, an increased inflammatory state is recognized to be one of the main mechanisms promoting depression,” writes lead author Betty Rodrigues, a postdoc in Malu Tansey’s lab in the Department of Physiology.

This model may be useful for identification of possible biomarkers and therapeutic targets to treat metabolic syndrome and mood disorders. As a follow-up, Tansey reports that her team is investigating the protective effects of an anti-inflammatory agent on both the brain and the liver using the same model.

Metabolic syndrome and stress have a complex interplay throughout the body, the researchers found. For example, psychological stress by itself does not affect insulin or cholesterol levels, but it does augment them when combined with a high-fat, high-fructose diet. In contrast, stress promotes adaptive anti-inflammatory markers in the hippocampus (part of the brain), but those changes are wiped out by a high-fat, high-fructose diet.

The findings show synergistic effects by diet and stress on gut permeability promoted by inflammation, and the biliverdin pathway. Biliverdin, a product of heme breakdown, is responsible for a greenish color sometimes seen in bruises.

“Stress and high-fat high-fructose diet promoted disturbances in biliverdin, a metabolite associated with insulin resistance,” Rodrigues writes. “To the best of our knowledge, our results reveal for the first time evidence for the synergistic effect of diet and chronic psychological stress affecting the biliverdin pathway.”

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Posted on by Quinn Eastman in Heart, Immunology, Neuro Leave a comment

Islet transplants from fish?

The shortage of human organ donors has led scientists to investigate animals as a potential source for transplantable organs or tissues. Pigs are often mentioned because of their size: similar to ours.

Recently, prospects for xenotransplantation brightened when Harvard geneticist George Church demonstrated the removal of dozens of endogenous retroviruses from the pig genome, in a tour de force of the CRISPR/Cas9 gene editing technique.

Emory researchers Susan Safley and Collin Weber have been exploring the possibility of using different animals for xenotransplantation: fish, specifically tilapia.

Why fish? This review details several advantages tilapia may offer in the field of islet transplant, but first – a reminder about islets.

Islets are the clusters of cells in the pancreas that produce insulin. Several clinical trials, including this one led by Emory’s Nicole Turgeon, have shown that islets isolated from deceased human donors can restore normal blood sugar regulation in patients with type 1 diabetes. Still, obstacles remain such as the shortage of human islets, and the loss of insulin independence over time, even with the use of drugs that hold off immune rejection.

For islet transplant, here are some of the proposed advantages presented by tilapia:

*tilapia have large, distinct islet organs called Brockmann bodies that are easy to isolate

*tilapia grow quickly and cost less to raise than pigs

*tilapia islets are resistant to hypoxia, thought to contribute to graft loss

*tilapia do not express alpha (1,3) gal, a carbohydrate structure present on mammalian cells that causes hyperacute rejection Read more

Posted on by Quinn Eastman in Immunology Leave a comment

Hunting for potential diabetes drugs

Pathologist Keqiang Ye and his colleagues have been prolific in finding small molecules able to mimic the action of the brain growth factor BDNF. Aiming to export that success to similar molecules (that is, other receptor tyrosine kinases), they have been searching for potential drugs able to substitute for insulin.

Diabetes drugs Januvia (sitagliptin) and Lantus (insulin analog) are top 20 drugs, both in terms of dollars and monthly prescriptions, and the inconvenience of insulin injection is well known, so the business potential is clear.

A paper published in the journal Diabetes in April describes Ye’s team’s identification of a compound called chaetochromin A, which was originally isolated by Japanese researchers studying toxins found in moldy rice. Chaetochromin A can drive down blood sugar in normal, type 1 diabetes and type 2 diabetes mouse models, the authors show.

See here for another compound identified in Ye’s lab with similar properties.

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Posted on by Quinn Eastman in Uncategorized Leave a comment

Drug discovery: shifting from brain growth factors to insulin

Earlier this year, the FDA put limitations on some anti-diabetic drugs because of their cardiovascular risks. The prevalence of diabetes in the United States continues to increase and is now above 8 percent of the population, so the need for effective therapies remains strong.

Keqiang Ye, PhD

Pathologist Keqiang Ye and colleagues have a paper in the Journal of Biological Chemistry describing their identification of a compound that mimics the action of insulin. This could be the starting point for developing new anti-diabetes drugs.

The new research is an extension of the Ye laboratory’s work on TrkA and TrkB, which are important for the response of neurons to growth factors. Ye and Sung-Wuk Jang, a remarkably productive postdoc who is now an assistant professor at Korea University, developed an assay that allowed them to screen drug libraries for compounds that directly activate TrkA and TrkB. This led them to find a family of growth-factor-mimicking compounds that could treat conditions such as Parkinson’s disease, depression and stroke.

Since TrkA/B and the insulin receptor are basically the same kind of molecule — receptor tyrosine kinases– and use some of the same cellular circuitry, Ye and Jang’s assay could also be used with the insulin receptor. Kunyan He and Chi-Bun Chan are the first two authors on the new paper. They report that the compound DDN can make cells more sensitive to insulin and improve their ability to take up glucose. They show that DDN (5,8-diacetyloxy-2,3-dichloro-1,4- naphthoquinone) can lower blood sugar, both in standard laboratory mice and in obese mice that serve as a model for type II diabetes.

Ye reports that he and his colleagues are working with medicinal chemists to identify related compounds that may have improved efficacy and potency.

“I hope in the near future we may have something that could replace insulin for treating diabetes orally,” he says.

Posted on by Quinn Eastman in Uncategorized Leave a comment

Pig stem cells: hope for Type 1 diabetes treatment

University of Georgia researchers recently reported on their work to create pigs with induced pluripotent stem cells. This type of cell, first developed about five years ago, has the ability to turn into any other kind of cell in the body.

An Emory transplant team, working with the UGA group, hopes to use this technology to develop pig islet cells as an alternative to human islets to treat patients with Type 1 diabetes. Type 1 diabetes usually occurs early in life and affects more than one million Americans who are unable to manufacture their own insulin because their pancreatic islets do not function.

Emory islet transplant team

The Emory Transplant Center has conducted clinical trials since 2003 transplanting human pancreatic islet cells into patients with Type I diabetes. Some of these patients have been able to give up insulin injections, either temporarily or permanently. Other sources of islets are needed for transplant though because of the large number of potential patients and because each transplant typically requires islets from several pancreases.

To create pigs using pluripotent stem cells, the UGA team injected new genes into pig bone marrow cells to reprogram the cells into functioning like embryonic stem cells. The resulting pluripotent cells were inserted into blastocysts (developing embryos), and the embryos were implanted into surrogate mothers. The resulting pigs had cells from the stem cell lines as well as the embryo donor in multiple tissue types.

The pluripotent stem cell process could allow researchers to make genetic changes to dampen or potentially eliminate the rejection of the pig islets by the human immune system.

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Posted on by Holly Korschun in Uncategorized Leave a comment