Research Round-up

From the Fall 2019 edition of Vanderbilt Medicine Magazine

Blueprint for rebuilding the heart

Cell fate reprogramming — converting one cell type into another — is a potential strategy for generating cardiac cells to treat heart diseases.

Although previous studies have shown that the expression of cardiogenic transcription factors directly reprograms fibroblasts (connective tissue cells) into induced cardiomyocyte-like cells (iCMs), there remains the obstacle of a low conversion rate from fibroblast to iCM.

To determine whether the low efficiency of cardiac reprogramming results from the incomplete expression of the whole “set” of four core cardiogenic transcription factors (GHMT), Young-Jae Nam, MD, PhD, and colleagues forced cells to co-express various combinations of cardiogenic transcription factors.

In the journal Scientific Reports, they reported that expression of specific combinations of two or three factors is sufficient to generate sarcomeric (structural) proteins that enable muscle contraction and relaxation. However, all four factors are integral to the contractility and organization of sarcomeric structures.

These findings provide a blueprint for devising more efficient cardiac reprogramming and regeneration strategies.

 

Mouth microbes and colorectal cancer

Chronic inflammation and periodontal disease caused by certain microbial species in the mouth — part of the oral microbiome — have been suggested to play a role in colorectal cancer development.

Yaohua Yang, PhD, Jirong Long, PhD, and colleagues investigated the association of the oral microbiome with colorectal cancer risk among participants in the Southern Community Cohort Study. They analyzed microbial species in mouth rinse samples collected at enrollment (before colorectal cancer diagnosis) and compared the oral microbiome of 231 people who were later diagnosed with colorectal cancer and 462 matched controls.

The researchers reported in the International Journal of Cancer that two oral pathogens, Treponema denticola and Prevotella intermedia, were associated with increased risk of colorectal cancer. In addition, 11 common and 16 rare bacterial species were associated with risk of colorectal cancer.

The research suggests that the oral microbiome may play a role in colorectal cancer development and supports further studies to explore using the oral microbiome for early detection or prevention of colorectal cancer.

 

Steroid binding to metabolic enzyme

The human cytochrome P450 enzymes are responsible for metabolizing a variety of substances — from lipids (fats) and steroid hormones to drugs and toxic chemicals.

One such enzyme, P450 17A1, generates androstenedione and dehydroepiandrosterone (DHEA), involved in the production of sex hormones. How the enzyme binds to its substrates has remained a mystery until now.

Using kinetics and modeling techniques, F. Peter (Fred) Guengerich, PhD, Tadashi Inagami Ph.D. Professor of Biochemistry, and colleagues Clayton Wilkey, Sarah Glass and Michael Reddish, PhD, determined that the dominant mode of binding is via conformational selection rather than induced fit.

Their findings, reported as an Editors’ Pick in the Journal of Biological Chemistry, show that P450 enzymes exist in different conformational states and then bind drugs or chemicals presented to them.

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