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Introduction: Kidney fibrosis is the main pathologic change in diabetic nephropathy (DN), which is the major cause of end-stage renal disease. Current therapeutic strategies slow down but cannot reverse the progression of renal dysfunction in DN. Plant-derived bioactive peptides in foodstuffs are widely used in many fields because of their potential pharmaceutical and nutraceutical benefits. However, this type of peptide has not yet been studied in renal fibrosis of DN. Previous studies have indicated that the peptide YWDHNNPQIR (named RAP), a natural peptide derived from rapeseed protein, has an antioxidative stress effect. The oxidative stress is believed to be associated with DN. The aim of this study was to evaluate the pharmacologic effects of RAP against renal fibrosis of DN and high glucose (HG)-induced mesangial dysfunction., Materials and Methods: Diabetes was induced by streptozotocin and high-fat diet in C57BL/6 mice and these mice were treated by subcutaneous injection of different doses of RAP (0.1 mg/kg and 0.5 mg/kg, every other day) or PBS for 12 weeks. Later, functional and histopathologic analyses were performed. Parallel experiments verifying the molecular mechanism by which RAP alleviates DN were carried out in HG-induced mesangial cells (MCs)., Results: RAP improved the renal function indices, including 24-h albuminuria, triglyceride, serum creatinine, and blood urea nitrogen levels, but did not lower blood glucose levels in DN mice. RAP also simultaneously attenuated extracellular matrix accumulation in DN mice and HG-induced MCs. Furthermore, RAP reduced HG-induced cell proliferation, but it showed no toxicity in MCs. Additionally, RAP inhibited the mitogen-activated protein kinase (MAPK) and nuclear factor κB (NF-κB) signaling pathways., Conclusion: RAP can attenuate fibrosis in vivo and in vitro by antagonizing the MAPK and NF-κB pathways., Competing Interests: Disclosure The authors report no conflicts of interest in this work.

The antimicrobial peptide APKGVQGPNG (named YD), a natural peptide originating from Bacillus amyloliquefaciens CBSYD1, exhibited excellent antibacterial and antioxidant properties in vitro. These characteristics are closely related to inflammatory responses which is the central trigger for liver fibrosis. However, the therapeutic effects of YD against hepatic fibrosis and the underlying mechanisms are rarely studied. In this study, we show that YD improved liver function and inhibited the progression of liver fibrosis by measuring the serum transaminase activity and the expression of α -smooth muscle actin and collagen I in carbon tetrachloride-induced mice. Then we found that YD inhibited the level of miR-155, which plays an important role in inflammation and liver fibrosis. Bioinformatics analysis and luciferase reporter assay indicate that Casp12 is a new target of miR-155. We demonstrate that YD significantly decreases the contents of inflammatory cytokines and suppresses the NF- κ B signaling pathway. Further studies show that transfection of the miR-155 mimic in RAW264.7 cells partially reversed the YD-mediated CASP12 upregulation, the downregulated levels of inflammatory cytokines, and the inactivation of the NF- κ B pathways. Collectively, our study indicates that YD reduces inflammation through the miR-155– Casp12 –NF- κ B axis during liver fibrosis and provides a promising therapeutic candidate for hepatic fibrosis. The antimicrobial peptide YD is beneficial for alleviating liver fibrosis. The inhibitory role of YD in inflammatory responses is mediated by the miR-155– Casp12 –NF- κ B axis. Image 1 [ABSTRACT FROM AUTHOR]

A Correction to this paper has been published: https://doi.org/10.1038/s41467-021-22414-7 [ABSTRACT FROM AUTHOR]

Chronic nonalcoholic steatohepatitis (NASH) is a metabolic disorder that often leads to liver fibrosis, a condition with limited therapy options. Adiponectin is an adipocytokine that regulates glucose and lipid metabolism via binding to its receptors AdipoR1 and AdipoR2, and AdipoRs signaling is reported to enhance fatty acid oxidation and glucose uptake. Here, we synthesize and report an adiponectin-based agonist JT003, which potently improves insulin resistance in high fat diet induced NASH mice and suppresses hepatic stellate cells (HSCs) activation in CCl4 induced liver fibrosis. Mechanistic studies indicate that JT003 simultaneously stimulates AdipoR1- and AdipoR2- mediated signaling pathways as well as the PI3K-Akt pathway. Moreover, JT003 treatment significantly improves ER-mitochondrial axis function, which contributes to the reduced HSCs activation. Thus, the AdipoR1/AdipoR2 dual agonist improves both NASH and fibrosis in mice models, which provides the pharmacological and biological foundation for developing AdipoRs-based therapeutic agents on liver fibrosis. Nonalcoholic steatohepatitis (NASH) and associated liver fibrosis have limited therapy options. Here the authors report a novel adiponectin-based dual agonist for adiponectin receptors 1 and 2 with a longer half-life, and show that it ameliorates NASH and liver fibrosis in mouse models. [ABSTRACT FROM AUTHOR]

The rapeseed protein derived peptide DHNNPQIR (named as RAP-8) has been previously reported to possess antioxidant activity and alleviate liver fibrosis. The purpose of the present study was to investigate the potential crucial pathways involved in ameliorating liver fibrosis of RAP-8. Next-generation sequencing of messenger RNA (RNA-Seq) analysis of the fibrotic and RAP-8 treated mice was performed. Western blot, qPCR and flow cytometry detection analysis were conducted to measure cell cycle and oxidative stress in LX-2 cells and liver samples. 588 overlapped differentially expressed genes were obtained from a batch of genes RAP-8 altered. Gene Ontology enrichment analysis revealed that changes in the most significant modules were mainly enriched in cell division, nuclear division and mitotic cell cycle process, while alterations in Kyoto Encyclopedia of Genes and Genomes were mainly enriched in cell cycle. Thereafter, according to the co-expression network analysis, the regulations of three core genes (Cenpp, Cyp2c55, Serpinh1) were verified that might be targets for treating liver fibrosis. Furthermore, through experimental verification, we demonstrated that RAP-8 induced cell cycle arrest and prevents oxidation stress. As a promising therapeutic candidate for hepatic fibrosis treating, RAP-8 exhibited anti-fibrotic effects via exerting cell cycle arrest and inhibiting oxidative stress. [ABSTRACT FROM AUTHOR]