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Source: Thailand Medical News  Jul 24, 2019  4 years, 2 months, 1 week, 1 day ago

Researchers Discover Epigenetic Enzyme That Can Aid in Diabetic Non-Healing Wounds

Researchers Discover Epigenetic Enzyme That Can Aid in Diabetic Non-Healing Wounds
Source: Thailand Medical News  Jul 24, 2019  4 years, 2 months, 1 week, 1 day ago
Type 2 Diabetic patients are normally at risk of non-healing wounds should they ever get cut or scrape on their foot. Small wounds like these can be life-threatening and around 35 % of all Type 2 Diabetic patients will end up in such a dire situation which normally leads to amputation.

Statistically, this is a major problem as a patient who has had a amputation due to Type 2 Diabetic non-healing wound, have only a fifty percent survival rate at three years, which is actually worst than most cancers.

Researchers from the University Of Michigan, lead by Dr Andrew Kimball and Dr Frank Davis, have discovered for the first time, an enzyme that seem critical for normal healing. They also discovered that this enzyme known as Setdb2 , is missing in diabetics with Type 2 disease. This discovery could revolutionize treatment approaches for Diabetic Type 2 patients and prevent cases of non-healing wounds and also amputations

The normal healing process for wounds starts with the immune system and cells called macrophages. During normal healing, an injury triggers the body’s immune system to release monocytes in the blood which travel to the site of damaged tissue and become macrophages. At first, these macrophages create an inflammatory response to engulf and eliminate any bacteria or other pathogens. These same macrophages then change into a non-inflammatory repair mode to generate new tissue and promote healing. With diabetes, this conversion never takes place and inflammation persists.

The research team  suspected that something environmental triggers epigenetic changes that prevents the macrophages from completing their job. Type 2 diabetes typically develops over 20 to 30 years, and while genetics  play a role, it was speculated that behaviors such as smoking or a long-term unhealthy diet were causing permanent epigenetic changes in the cells. Epigenetics refers to changes in gene expression that do not come from changes from the underlying DNA sequence.

Using animal models  and human tissues, the team  discovered for the first time that an epigenetic enzyme called Setdb2 regulates the conversion of macrophages from an inflammatory type to a repair type. In diabetic animal models, Setdb2 did not increase at the critical time and their wounds remained inflamed.

The researchers also found that Setdb2 appears to be a player in the metabolism of uric acid, known to be elevated in people with diabetes. People with high blood concentrations of uric acid can develop gout, which can cause painful inflamed joints.
The research  team found that in normal healing, Setdb2 turns off xanthine oxidase, the enzyme that produces uric acid. In doing so, Setdb2 turns off inflammation.

To further investigate whether blocking uric acid could help wound healing, the team administered allopurinol, a common drug used to treat gout and kidney stones, locally to wound sites in their diabetic animal  models.

Associate Professor Dr Katherine Gallagher, Departments of Surgery and Microbiology/Immunology at University Of Michigan and team member commented in an exclusive interview with Thailand Medical News, "The drug seemed to improve healing and our data looks very promising for using this as a local therapy. Applying allopurinol directly to the wounds could help avoid some of the toxic systemic side effects associated with the drug”

The team hopes to eventually bring their findings to clinical trials, look for other inflammatory genes that may be targets, and explore ways of increasing Setdb2 for cell-based therapy.

Reference: Immunity (2019). DOI: 10.1016/j.immuni.2019.06.015


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