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Colistin (polymyxin E) is an antibiotic that is effective against multidrug-resistant gram-negative bacteria. However, the high incidence of nephrotoxicity caused by colistin limits its clinical use. To identify compounds that might ameliorate colistin-induced nephrotoxicity, we obtained 1707 compounds from the Korea Chemical Bank and used a high-content screening (HCS) imaging-based assay. In this way, we found that bimatoprost (one of prostaglandin F2α analogue) ameliorated colistin-induced nephrotoxicity. To further assess the effects of bimatoprost on colistin-induced nephrotoxicity, we used in vitro and in vivo models. In cultured human proximal tubular cells (HK-2), colistin induced dose-dependent cytotoxicity. The number of terminal deoxynucleotidyl transferase dUTP nick-end labeling (TUNEL)-positive cells, indicative of apoptosis, was higher in colistin-treated cells, but this effect of colistin was ameliorated by cotreatment with bimatoprost. The generation of reactive oxygen species, assessed using 2,7-dichlorodihydrofluorescein diacetate, was less marked in cells treated with both colistin and bimatoprost than in those treated with colistin alone. Female C57BL/6 mice (n = 10 per group) that were intraperitoneally injected with colistin (10 mg/kg/12 hr) for 14 days showed high blood urea nitrogen and serum creatinine concentrations that were reduced by the coadministration of bimatoprost (0.5 mg/kg/12 hr). In addition, kidney injury molecule-1 (KIM1) and Neutrophil gelatinase-associated lipocalin (NGAL) expression also reduced by bimatoprost administration. Further investigation in tubuloid and kidney organoids also showed that bimatoprost attenuated the nephrotoxicity by colistin, showing dose-dependent reducing effect of KIM1 expression. In this study, we have identified bimatoprost, prostaglandin F2α analogue as a drug that ameliorates colistin-induced nephrotoxicity. [Display omitted] • Colistin treats multidrug-resistant bacterial infections, but its nephrotoxicity risk limits use. • High-Content Screening reveals Bimatoprost as a potential protector against colistin's nephrotoxicity. • Bimatoprost might be a protective drug for nephrotoxicity, its systemic use needs more study. [ABSTRACT FROM AUTHOR]

Objective Severe fever with thrombocytopenia syndrome (SFTS) is an emerging infectious disease with high mortality. T cell deficiency has recently been described, but the changes in T cell functionality during acute SFTS virus (SFTSV) infection and the mechanisms leading to T lymphocyte death remain largely unknown. This study was conducted to evaluate T cell functionality and the expression of apoptotic/proliferation and activation/inhibition markers during acute SFTSV infection. Methods Twenty-eight surviving SFTS patients were sequentially sampled during their entire hospital stay. SFTSV RNA copies were investigated using real-time RT-PCR. The expression levels of apoptotic markers (annexin V and CD95) and proliferation and activation markers (Ki-67, HLA-DR, and CD25) and the expression levels of programmed cell death-1 (PD-1), interferon gamma (IFN-γ), and granzyme B in T cells were evaluated by flow cytometry for the SFTS patients. Results In parallel with T cell depletion, higher annexin V and CD95 expression was observed in SFTS patients. Additionally, the expression levels of Ki-67, HLA-DR, CD25, and PD-1 and the levels of IFN-γ and granzyme B in T lymphocytes were markedly increased in the SFTS patients. Conclusions T cell proliferation, activation, and functional enhancement were apparent despite the observation of T cell apoptosis, suggesting that these processes are involved in the complex protective response to SFTSV infection. [ABSTRACT FROM AUTHOR]

Background: Cardiac fibrosis (CF) is associated with increased ventricular stiffness and diastolic dysfunction and is an independent predictor of long-term clinical outcomes of patients with heart failure (HF). We previously showed that the matricellular CCN5 protein is cardioprotective via its ability to inhibit CF and preserve cardiac contractility.Objectives: This study examined the role of CCN5 in human heart failure and tested whether CCN5 can reverse established CF in an experimental model of HF induced by pressure overload.Methods: Human hearts were obtained from patients with end-stage heart failure. Extensive CF was induced by applying transverse aortic constriction for 8 weeks, which was followed by adeno-associated virus-mediated transfer of CCN5 to the heart. Eight weeks following gene transfer, cellular and molecular effects were examined.Results: Expression of CCN5 was significantly decreased in failing hearts from patients with end-stage heart failure compared to nonfailing hearts. Trichrome staining and myofibroblast content measurements revealed that the established CF had been reversed by CCN5 gene transfer. Anti-CF effects of CCN5 were associated with inhibition of the transforming growth factor beta signaling pathway. CCN5 significantly inhibited endothelial-mesenchymal transition and fibroblast-to-myofibroblast transdifferentiation, which are 2 critical processes for CF progression, both in vivo and in vitro. In addition, CCN5 induced apoptosis in myofibroblasts, but not in cardiomyocytes or fibroblasts, both in vivo and in vitro. CCN5 provoked the intrinsic apoptotic pathway specifically in myofibroblasts, which may have been due the ability of CCN5 to inhibit the activity of NFκB, an antiapoptotic molecule.Conclusions: CCN5 can reverse established CF by inhibiting the generation of and enhancing apoptosis of myofibroblasts in the myocardium. CCN5 may provide a novel platform for the development of targeted anti-CF therapies. [ABSTRACT FROM AUTHOR]