Translational research : the journal of laboratory and clinical medicine
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Review
Central and peripheral regulations mediated by short-chain fatty acids on energy homeostasis.
The human gut microbiota influences obesity, insulin resistance, and the subsequent development of type 2 diabetes (T2D). The gut microbiota digests and ferments nutrients resulting in the production of short-chain fatty acids (SCFAs), which generate various beneficial metabolic effects on energy and glucose homeostasis. However, their roles in the central nervous system (CNS)-mediated outputs on the metabolism have only been minimally studied. ⋯ These functions have been linked with AMPK signaling, GPCRs-dependent pathways, and inhibition of histone deacetylases (HDACs). However, the studies focusing on the central effects of SCFAs are still limited. The mechanisms by which central SCFAs regulate appetite, energy expenditure, and blood glucose during different physiological conditions warrant further investigation.
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Recently developed human intestinal epithelial 3D organoid cultures are a useful cell culture model to study intestinal transport physiology. From these, 2D monolayer cultures can be generated in which apical transporters are exposed to the medium, thereby better facilitating in vitro investigation of intestinal absorption processes. However, whether nutrient and electrolyte absorption can be physiologically regulated in human organoid-derived monolayers has not been determined. ⋯ An increase in cNO stimulated SGLT1, while NHE3 was inhibited. These results are similar to what is seen in vivo and in vitro in different animal intestinal models. Thus, human jejunal organoid-derived monolayers are an ideal in vitro model to better understand how intestinal nutrient absorption is regulated.
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Doxorubicin (Dox), as a widely used anthracycline antitumor drug, can cause severe cardiotoxicity. Cardiomyocyte death and inflammation are involved in the pathophysiology of Dox-induced cardiotoxicity (DIC). Gasdermin D (GSDMD) is known as a key executioner of pyroptosis, which is a pro-inflammatory programmed cell death. ⋯ Using molecular dynamics simulation and cell-free systems, we confirmed that Dox directly bound to GSDMD and facilitated GSDMD-N-mediated pyroptosis. Furthermore, GSDMD also mediated Dox-induced mitochondrial damage via Bnip3 and mitochondrial perforation in cardiomyocytes. These findings provide fresh insights into the mechanism of how Dox-engaged GSDMD orchestrates adverse cardiotoxicity and highlight the prospects of GSDMD as a potential target for DIC.
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Cardiac fibrosis is a process characterized by extracellular matrix accumulation leading to myocardial dysfunction. Angiotensin II (Ang II) has been shown to play an important role in the pathogenesis of cardiac fibrosis. However, the underlying mechanisms are not well established. ⋯ Bioinformatics analysis and further validation experiments revealed that RAP1 is a direct downstream target of miR-23a-3p, and overexpression of RAP1 reversed the profibrotic effect of miR-23a-3p. Taken together, these findings elucidated the role of eWAT in Ang II-induced myocardial fibrosis and indicated that adipocyte-derived exosomes mediate pathologic communication between dysfunctional adipose tissue and the heart by transporting miR-23a-3p into CFs, transforming fibroblasts into myofibroblasts and promoting excessive collagen deposition by targeting RAP1. Prevention of abnormal adipocyte exosome production, inhibition of miR-23a-3p biogenesis, and treatment with a miR-23a-3p antagonist are novel strategies for treating cardiac fibrosis.
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Currently, there are very few well-established treatments to stimulate corneal endothelial cell regeneration in vivo as a cure for corneal endothelial dysfunctions. The most frequently performed intervention for a damaged or dysfunctional corneal endothelium nowadays is corneal endothelial keratoplasty, also known as lamellar corneal transplantation surgery. Newer medical therapies are emerging and are targeting the regeneration of the corneal endothelium, helping the patients regain their vision without the need for donor tissue. ⋯ However, the literature offers little guidance and selective attention to the question of how to fully exploit these pathways. The purpose of this paper is to provide an overview of wound healing characteristics from a biochemical level in the lab to the regenerative features seen in the clinic. Studying the pathways involved in corneal wound healing together with their key effector proteins, can help explain the effect on the proliferation and migration capacity of the corneal endothelial cells.