Spironolactone and colitis: Increased mortality in rodents and in humans

Background: Crohn's disease causes intestinal inflammation leading to intestinal fibrosis. Spironolactone is an antifibrotic medication commonly used in heart failure to reduce mortality. We examined whether spironolactone is antifibrotic in the context of intestinal inflammation. Methods: In vitro, spironolactone repressed fibrogenesis in transforming growth factor beta (TGF‐β)‐stimulated human colonic myofibroblasts. However, spironolactone therapy significantly increased mortality in two rodent models of inflammation‐induced intestinal fibrosis, suggesting spironolactone could be harmful during intestinal inflammation. Since inflammatory bowel disease (IBD) patients rarely receive spironolactone therapy, we examined whether spironolactone use was associated with mortality in a common cause of inflammatory colitis, Clostridium difficile infection (CDI). Results: Spironolactone use during CDI infection was associated with increased mortality in a retrospective cohort of 4008 inpatients (15.9% vs. 9.1%, n = 390 deaths, P < 0.0001). In patients without liver disease, the adjusted odds ratio (OR) for inpatient mortality associated with 80 mg spironolactone was 1.99 (95% confidence interval [CI]: 1.51–2.63) In contrast to the main effect of spironolactone mortality, multivariate modeling revealed a protective interaction between liver disease and spironolactone dose. The adjusted OR for mortality after CDI was 1.96 (95% CI: 1.50–2.55) for patients without liver disease on spironolactone vs. 1.28 (95% CI: 0.82–2.00) for patients with liver disease on spironolactone when compared to a reference group without liver disease or spironolactone use. Conclusions: We propose that discontinuation of spironolactone in patients without liver disease during CDI could reduce hospital mortality by 2‐fold, potentially reducing mortality from CDI by 35,000 patients annually across Europe and the U.S. (Inflamm Bowel Dis 2011;)Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/92045/1/21929_ftp.pd

Dual-role of beta borophene nanosheets as highly effective antibacterial and antifungal agent

Antimicrobial resistance toward antibiotics has been a serious clinical problem to current bacterial infections therapy. In this context, current research and development have been focused on developing new perspectives on two-dimensional (2D) materials based antimicrobial agents. With the rapid development of 2D borophene, it has been regarded as a promising agent for sensor, energy, and biomedical applications. Herein, we have reported the fabrication of the multifunctional antibacterial and antifungal agent, beta-rhombohedral crystalline structured borophene nanosheets, which were prepared using a top-down synthesis approach. The antibacterial and antifungal activities of beta borophene nanosheets were investigated to determine using different pathogenic microorganisms such as Staphylococcus aureus (NCTC 10788/Lot 0350520029), Pseudomonas aureginosa (ATCC 9027/Lot 3270513), Escherichia coli (ATCC 8739/Lot 4835151), Candida albicans (NCPF 3179/Lot040920020), and Aspergillus brasilliensis (NCPF 2275/Lot 020620065) using the total aerobic mesophilic microorganism (lSO 21149) and mold-yeast (lSO 16212) guidelines. According to the experimental results, we showed that the borophene nanosheets had an effectively inhibitory activity against several medically serious bacterial and fungal pathogenic microorganisms

CLINICAL SIGNIFICANCE OF GENETIC IN PATIENTS WITH C3 GLOMERULOPATHIES

WOS: 00046979710034

A multi-faceted approach to unravel coding and non-coding gene fusions and target chimeric proteins in ataxia

Ataxia represents a heterogeneous group of neurodegenerative disorders characterized by a loss of balance and coordination, often resulting from mutations in genes vital for cerebellar function and maintenance. Recent advances in genomics have identified gene fusion events as critical contributors to various cancers and neurodegenerative diseases. However, their role in ataxia pathogenesis remains largely unexplored. Our study Hdelved into this possibility by analyzing RNA sequencing data from 1443 diverse samples, including cell and mouse models, patient samples, and healthy controls. We identified 7067 novel gene fusions, potentially pivotal in disease onset. These fusions, notably in-frame, could produce chimeric proteins, disrupt gene regulation, or introduce new functions. We observed conservation of specific amino acids at fusion breakpoints and identified potential aggregate formations in fusion proteins, known to contribute to ataxia. Through AI-based protein structure prediction, we identified topological changes in three high-confidence fusion proteins—TEN1-ACOX1, PEX14-NMNAT1, and ITPR1-GRID2—which could potentially alter their functions. Subsequent virtual drug screening identified several molecules and peptides with high-affinity binding to fusion sites. Molecular dynamics simulations confirmed the stability of these protein-ligand complexes at fusion breakpoints. Additionally, we explored the role of non-coding RNA fusions as miRNA sponges. One such fusion, RP11-547P4-FLJ33910, showed strong interaction with hsa-miR-504-5p, potentially acting as its sponge. This interaction correlated with the upregulation of hsa-miR-504-5p target genes, some previously linked to ataxia. In conclusion, our study unveils new aspects of gene fusions in ataxia, suggesting their significant role in pathogenesis and opening avenues for targeted therapeutic interventions. Communicated by Ramaswamy H. Sarma</p

CLINICAL SIGNIFICANCE OF GENETIC VARIANTS IN PATIENTS WITH C3 GLOMERULOPATHIES

WOS: 00046979710237