Particularly, epithelial NFAT5 was found to orchestrate the mucosal microenvironment by regulating mucus production and antimicrobial peptides. […]
Therapeutically, enhancing the NFAT5–HSP70 axis might reinforce intestinal barrier integrity and reduce IBD severity, although careful evaluation of such interventions is necessary. […]
NFAT5 may regulate a broad network of other heat shock proteins, trefoil factors, tight-junction proteins, and Wnt pathway modulators that collectively promote epithelial integrity and maintain the stem cell niche. […]
Since NFAT5 can be activated by gut osmolarity, which changes with diet or inflammation (18), it is plausible that dietary factors (e.g., high salt or fiber content) modulate NFAT5 expression in the gut and thereby influence disease outcomes. In short, future mechanistic studies should aim to delineate the NFAT5-centered regulatory network that preserves epithelial homeostasis, potentially uncovering additional targets or strategies to strengthen this natural protective mechanism in the intestine. […]
In summary, this study identifies NFAT5 as a previously unrecognized intrinsic protector of IECs, crucial for both injury regeneration and the maintenance of a protective microbiome under stress. NFAT5 deficiency unveils a two-pronged mechanism of colitis susceptibility: an epithelial-intrinsic vulnerability to injury and an extrinsic shift in the microbiota toward a colitogenic profile. This contrasts with traditional T cell–mediated colitis and expands our understanding of how epithelial stress adaptation factors contribute to inflammatory diseases. Our findings also have potential clinical ramifications. Given that NFAT5 expression is diminished in patients with active IBD, approaches aimed at enhancing epithelial NFAT5 activity or its downstream pathways may reinforce gut barrier integrity, improving healing in an inflammatory setting.
In this study, we aimed to understand the mechanism by which NFAT5 interferes with infection of Coxsackievirus B3 (CVB3), a major cause of viral myocarditis. Our initial results demonstrated that although the mRNA level of NFAT5 remained constant during CVB3 infection, NFAT5 protein level decreased because the protein was cleaved. […] Such cleavage led to the inactivation of NFAT5, and the 70-kDa N-terminal cleavage product (p70-NFAT5) exerted a dominant negative effect on the full-length NFAT5 protein. We further showed that elevated expression of NFAT5 to counteract viral protease cleavage, especially overexpression of a non-cleavable mutant of NFAT5, significantly inhibited CVB3 replication. Ectopic expression of NFAT5 resulted in elevated expression of inducible nitric oxide synthase (iNOS), a factor reported to inhibit CVB3 replication. The necessity of iNOS for the anti-CVB3 effect of NFAT5 was supported by the observation that inhibition of iNOS blocked the anti-CVB3 effect of NFAT5. In a murine model of viral myocarditis, we observed that treatment with hypertonic saline or mannitol solution upregulated NFAT5 and iNOS expression, inhibited CVB3 replication and reduced tissue damage in the heart. Taken together, our data demonstrate that the anti-CVB3 activity of NFAT5 is impaired during CVB3 infection due to 2A-mediated cleavage of NFAT5. Thus induction of NFAT5 by hypertonic agents may be a promising strategy for the development of anti-CVB3 therapeutics.
The persistence of coxsackieviral B RNA is of great interest because of its implication in the pathogenesis of several chronic human diseases. However, a few studies have dealt with the persistence of these viruses at the intestinal level. The aim of this study is to test the capacity of the six CV-B serotypes to establish persistent infection in human intestinal Caco-2 cell line. Ten CV-B isolates, including CV-B3 prototype strain (Nancy) and a recombinant isolate (B3-B4), were tested. Six CV-B isolates were found to establish persistent infections in Caco-2 cell line.
Persistent infection of human intestinal Caco-2 cell line by Coxsackieviruses B
Coxsackieviruses have been implicated as possible co-factors in the etiology of the selenium (Se)-responsive cardiomyopathy known as Keshan disease. Here we report that a cloned and sequenced amyocarditic coxsackievirus B3 (CVB3/0), which causes no pathology in the hearts of Se-adequate mice, induces extensive cardiac pathology in Se-deficient mice.
Benign human enterovirus becomes virulent in selenium-deficient mice
The analysis confirms that inflammatory bowel disease patients, especially those with Crohn's disease, have significantly lower levels of selenium compared to controls, suggesting that that selenium supplementation may serve as a valuable adjunct to the therapeutic regimen for managing inflammatory bowel disease, particularly in patients identified with selenium insufficiency.
Selenium deficiency in inflammatory bowel disease: A comprehensive meta-analysis
The analysis of UK Biobank data revealed a significant correlation between low dietary Se levels and an increased incidence of IBS. In the experimental study, a low Se diet induced IBS symptoms, evidenced by elevated abdominal withdrawal reflex scores, colon inflammation, and severe pathological damage to the colon. […]
Combined colonic fecal metabolomics and colon transcriptome analysis indicated that Se deficiency might trigger IBS through disruptions in pathways related to "bile excretion", "steroid hormone biosynthesis", "arachidonic acid metabolism", and "drug metabolism-cytochrome P450".
After acute infections, enteroviruses can persist in patients resulting in manifestation of ME/CFS. Chronic enterovirus infection in an immunocompetent host may be an example of a stalemate between attenuated, intracellular viruses and an ineffective immune response.
The well-known symptoms of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) are chronic pain, cognitive dysfunction, post-exertional malaise and severe fatigue. Another class of symptoms commonly reported in the context of ME/CFS are gastrointestinal (GI) problems. These may occur due to comorbidities such as Crohn’s disease or irritable bowel syndrome (IBS), or as a symptom of ME/CFS itself due to an interruption of the complex interplay between the gut microbiota (GM) and the host GI tract.
Furthermore, FXR increased the expression and nuclear translocation of hypertonicity-induced tonicity-responsive enhance-binding protein (TonEBP), the expressions of its downstream target gene sodium myo-inositol transporter (SMIT), and heat shock protein 70 (HSP70). The present study demonstrates that the NF-κB/FXR/TonEBP pathway protects RMICs against hypertonic stress.
The NF-κB/FXR/TonEBP pathway protects renal medullary interstitial cells against hypertonic stress
In addition, organic selenium decreased the bile acid (BA) concentrations in gut contents, downregulated the expression of hepatic CYP7A1, and upregulated the expression of hepatic Farnesoid X‐activated receptor (FXR).
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