TXNIP aggravates cardiac fibrosis and dysfunction after myocardial infarction in mice by enhancing the TGFB1/Smad3 pathway and promoting NLRP3 inflammasome activation.

Myocardial infarction (MI) results in high mortality. The size of fibrotic scar tissue following MI is an independent predictor of MI outcomes. Thioredoxin-interacting protein (TXNIP) is involved in various fibrotic diseases. Its role in post-MI cardiac fibrosis, however, remains poorly understood. In the present study, we investigate the biological role of TXNIP in post-MI cardiac fibrosis and the underlying mechanism using mouse MI models of the wild-type (WT), Txnip-knockout ( Txnip-KO) type and Txnip-knock-in ( Txnip-KI) type. After MI, the animals present with significantly upregulated TXNIP levels, and their fibrotic areas are remarkably expanded with noticeably impaired cardiac function. These changes are further aggravated under Txnip-KI conditions but are ameliorated in Txnip-KO animals. MI also leads to increased protein levels of the fibrosis indices Collagen I, Collagen III, actin alpha 2 (ACTA2), and connective tissue growth factor (CTGF). The Txnip-KI group exhibits the highest levels of these proteins, while the lowest levels are observed in the Txnip-KO mice. Furthermore, Txnip-KI significantly upregulates the levels of transforming growth factor (TGF)B1, p-Smad3, NOD-, LRR- and pyrin domain-containing protein 3 (NLRP3), Cleaved Caspase-1, and interleukin (IL)1B after MI, but these effects are markedly offset by Txnip-KO. In addition, after MI, the Smad7 level significantly decreases, particularly in the Txnip-KI mice. TXNIP may aggravate the progression of post-MI fibrosis and cardiac dysfunction by activating the NLRP3 inflammasome, followed by IL1B generation and then the enhancement of the TGFB1/Smad3 pathway. As such, TXNIP might serve as a novel potential therapeutic target for the treatment of post-MI cardiac fibrosis.

Potent Intestinal Mucosal Barrier Enhancement of Nostoc commune Vaucher Polysaccharide Supplementation Ameliorates Acute Ulcerative Colitis in Mice Mediated by Gut Microbiota.

Ulcerative colitis (UC) is evolving into a global burden with a substantially increasing incidence in developing countries. It is characterized by inflammation confined to mucosa and is recognized as an intestinal barrier disease. The intestinal microbiota plays a crucial role in UC pathogenesis. N. commune has long been appreciated as a healthy food and supplement worldwide and polysaccharides account for 60%. Here, we examined the amelioration of N. commune polysaccharides against acute colitis in mice induced by DSS and assessed the mediating role of gut microbiota. An integrated analysis of microbiome, metabolomics, and transcriptomics fully elaborated it markedly enhanced intestinal mucosal barrier function, including: increasing the relative abundance of Akkermansia muciniphila, uncultured_bacterium_g__norank_f__Muribaculaceae, and unclassified_g__norank_f__norank_o__Clostridia_UCG-014; decreasing microbiota-derived phosphatidylcholines and thromboxane 2 levels mapped to arachidonic acid metabolism; improving mucin2 biosynthesis and secretion; enhancing ZO-1 and occludin expression; reducing neutrophil infiltration; regulating the level of colitis-related inflammatory cytokines; involving inflammation and immune function-associated signaling pathways. Further, the mediation effect of gut microbiota was evaluated by administering a cocktail of antibiotics. In conclusion, our results demonstrated that N. commune polysaccharides predominantly reinforced the gut microbiota-mediated intestinal mucosal barrier to confer protection against UC and exhibited dramatic prebiotic-like functions, providing an alternative or complementary treatment for UC.

Angiotensin II type 1a receptor knockout ameliorates high-fat diet-induced cardiac dysfunction by regulating glucose and lipid metabolism.

Obesity-related cardiovascular diseases are associated with overactivation of the renin-angiotensin system (RAS). However, the underlying mechanisms remain elusive. In this study, we investigate the role of angiotensin II (Ang II) in high-fat diet (HFD)-induced cardiac dysfunction by focusing on cardiac glucose and lipid metabolism and energy supply. Ang II plays a role in cardiovascular regulation mainly by stimulating angiotensin II type 1 receptor (AT1R), among which AT1aR is the most important subtype in regulating the function of the cardiovascular system. AT1aR gene knockout (AT1aR ‒/‒) rats and wild-type (WT) rats are randomly divided into four groups and fed with either a normal diet (ND) or a HFD for 12 weeks. The myocardial lipid content, Ang II level and cardiac function are then evaluated. The expressions of a number of genes involved in glucose and fatty acid oxidation and mitochondrial dynamics are measured by quantitative polymerase chain reaction and western blot analysis. Our results demonstrate that AT1aR knockout improves HFD-induced insulin resistance and dyslipidemia as well as lipid deposition and left ventricular dysfunction compared with WT rats fed a HFD. In addition, after feeding with HFD, AT1aR ‒/‒ rats not only show further improvement in glucose and fatty acid oxidation but also have a reverse effect on increased mitochondrial fission proteins. In conclusion, AT1aR deficiency ameliorates HFD-induced cardiac dysfunction by enhancing glucose and fatty acid oxidation, regulating mitochondrial dynamics-related protein changes, and further promoting cardiac energy supply.

Txnip deficiency promotes ß-cell proliferation in the HFD-induced obesity mouse model.

Elucidating the mechanisms of regulation of ß-cell proliferation is key to understanding the pathogenesis of diabetes mellitus. Txnip is a tumor suppressor that is upregulated in diabetes and plays an important role in the regulation of insulin sensitivity; however, its potential effect on pancreatic ß-cell proliferation remains unclear. Here, we evaluated the role of Txnip in pancreatic ß-cell compensatory proliferation by subjecting WT and Txnip knockout (KO) mice to a high-fat diet (HFD). Our results demonstrate that Txnip deficiency improves glucose tolerance and increases insulin sensitivity in HFD-induced obesity. The antidiabetogenic effect of Txnip deficiency was accompanied by increased ß-cell proliferation and enhanced ß-cell mass expansion. Furthermore, Txnip deficiency modulated the expression of a set of transcription factors with key roles in ß-cell proliferation and cell cycle regulation. Txnip KO in HFD mice also led to activated levels of p-PI3K, p-AKT, p-mTOR and p-GSK3ß, suggesting that Txnip may act via PI3K/AKT signaling to suppress ß-cell proliferation. Thus, our work provides a theoretical basis for Txnip as a new therapeutic target for the treatment of diabetes mellitus.