Celastrol alleviated acute kidney injury by inhibition of ferroptosis through Nrf2/GPX4 pathway.

Ferroptosis is an important pathological process in acute kidney injury (AKI) which could lead to chronic kidney disease (CKD) and end-stage renal disease (ESRD). As an active ingredient of Chinese medicine Tripterygium wilfordii, celastrol has been reported to alleviate inflammation and preclinical studies have confirmed its anticancer effect. In the present study, we investigated the renal protective effects of celastrol against cisplatin induced AKI. Mice were administrated cisplatin by intraperitoneal injection and we found that celastrol reduced serum levels of BUN and creatinine, inhibited renal dysfunction, inflammation and oxidative stress. In addition, renal iron accumulation and ferroptosis were significantly reduced by celastrol treatment. Further mechanistic analyses suggested that Nrf2 is essential for celastrol upregulated GPX4 to alleviate ferroptosis and reduction of LDH release, intracellular iron accumulation and lipid peroxidation. These findings expand the potential uses of celastrol for treatment of various kinds of AKI associated with ferroptosis.

rFGF4 alleviates lipopolysaccharide-induced acute lung injury by inhibiting the TLR4/NF-κB signaling pathway.

Acute lung injury (ALI) is a serious and common clinical disease. Despite significant progress in ALI treatment, the morbidity and mortality rates remain high. However, no effective drug has been discovered for ALI. FGF4, a member of the FGF family, plays an important role in the regulation of various physiological and pathological processes. Therefore, in the present study, we aimed to study the protective effects of FGF4 against LPS-induced lung injury in vivo and in vitro. We found that rFGF4 treatment improved the lung W/D weight ratio, the survival rate, immune cell infiltration and protein concentrations in mice with LPS-induced ALI. Histological analysis revealed that rFGF4 significantly attenuated lung tissue injury and cell apoptosis. Furthermore, rFGF4 inhibited the activation of the TLR4/NF-κB signaling pathway and the production of pro-inflammatory mediators in LPS-injured lung tissues, murine alveolar macrophages (MH-S) and murine pulmonary epithelial (MLE-12) cells. The results of cell experiments further verified that rFGF4 inhibited the production of inflammatory mediators in MH-S cells and MLE-12 cells by regulating the TLR4/NF-κB signaling pathway. These results revealed that rFGF4 protected lung tissues and inhibited inflammatory mediators in mice with LPS-induced ALI by inhibiting the TLR4/NF-κB signaling pathway in MH-S and MLE-12 cells.

Fishing trip cost modeling using generalized linear model and machine learning methods - A case study with longline fisheries in the Pacific and an application in Regulatory Impact Analysis.

Fishing trip cost is an important element in evaluating economic performance of fisheries, assessing economic effects from fisheries management alternatives, and serving as input for ecosystem and bioeconomic modeling. However, many fisheries have limited trip-level data due to low observer coverage. This article introduces a generalized linear model (GLM) utilizing machine learning (ML) techniques to develop a modeling approach to estimate the functional forms and predict the fishing trip costs of unsampled trips. GLM with Lasso regularization and ML cross-validation of model are done simultaneously for predictor selection and evaluation of the predictive power of a model. This modeling approach is applied to estimate the trip-level fishing costs using the empirical sampled trip costs and the associated trip-level fishing operational data and vessel characteristics in the Hawaii and American Samoa longline fisheries. Using this approach to build models is particularly important when there is no strong theoretical guideline on predictor selection. Also, the modeling approach addresses the issue of skewed trip cost data and provides predictive power measurement, compared with the previous modeling efforts in trip cost estimation for the Hawaii longline fishery. As a result, fishing trip costs for all trips in the fishery can be estimated. Lastly, this study applies the estimated trip cost model to conduct an empirical analysis to evaluate the impacts on trip costs due to spatial regulations in the Hawaii longline fishery. The results show that closing the Western and Central Pacific Ocean (WCPO) could induce an average 14% increase in fishing trip costs, while the trip cost impacts of the Eastern Pacific Ocean (EPO) closures could be lower.

PPARγ Mediates the Anti-Epithelial-Mesenchymal Transition Effects of FGF1ΔHBS in Chronic Kidney Diseases via Inhibition of TGF-ß1/SMAD3 Signaling.

Podocytes are essential components of the glomerular basement membrane. Epithelial-mesenchymal-transition (EMT) in podocytes results in proteinuria. Fibroblast growth factor 1 (FGF1) protects renal function against diabetic nephropathy (DN). In the present study, we showed that treatment with an FGF1 variant with decreased mitogenic potency (FGF1ΔHBS) inhibited podocyte EMT, depletion, renal fibrosis, and preserved renal function in two nephropathy models. Mechanistic studies revealed that the inhibitory effects of FGF1ΔHBS podocyte EMT were mediated by decreased expression of transforming growth factor ß1 via upregulation of PPARγ. FGF1ΔHBS enhanced the interaction between PPARγ and SMAD3 and suppressed SMAD3 nuclei translocation. We found that the anti-EMT activities of FGF1ΔHBS were independent of glucose-lowering effects. These findings expand the potential uses of FGF1ΔHBS in the treatment of diseases associated with EMT.