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The prevalence of nonalcoholic fatty liver disease (NAFLD) has been rapidly increasing worldwide. A choline-deficient, L-amino acid-defined, high-fat diet (CDAHFD) has been used to create a mouse model of nonalcoholic steatohepatitis (NASH). There are some reports on the effects on mice of being fed a CDAHFD for long periods of 1 to 3 months. However, the effect of this diet over a short period is unknown. Therefore, we examined the effect of 1-week CDAHFD feeding on the mouse liver. Feeding a CDAHFD diet for only 1-week induced lipid droplet deposition in the liver with increasing activity of liver-derived enzymes in the plasma. On the other hand, it did not induce fibrosis or cirrhosis. Additionally, it was demonstrated that CDAHFD significantly impaired mitochondrial respiration with severe oxidative stress to the liver, which is associated with a decreasing mitochondrial DNA copy number and complex proteins. In the gene expression analysis of the liver, inflammatory and oxidative stress markers were significantly increased by CDAHFD. These results demonstrated that 1 week of feeding CDAHFD to mice induces steatohepatitis with mitochondrial dysfunction and severe oxidative stress, without fibrosis, which can partially mimic the early stage of NASH in humans.

Aims: Renalase expression is regulated by Nuclear Factor (NF)-κB and hypoxia inducible factor (HIF)-1α, and antioxidative stress function in renal cells were reported. However, dynamics of renalase and localizes in intestine were remain unknown. We evaluated the effects of oxidative stress on renalase expression and localization using model of fasting induced oxidative stress and Caco-2 cell, and examined the its physiological effects., Main Methods: 24 male mice were divided into three groups: Control (Con), 72 h fasting (Fast), and 24 h refeeding after fasting (Refeed). Jejunum and ileum were collected respectively. The structure of jejunum and ileum were observed by hematoxylin and eosin (HE) stain. The expression levels of carbonylated protein, renalase, NF-κB p65 and HIF-1α were measured by immunoblotting. Localization of renalase was observed by immunofluorescent. in vitro assay was performed using Caco-2 cell. Renalase was overexpressed using adenovirus. After that, Caco-2 cell was treated with 2 mM H 2 O 2 for 30 min or 24 h., Key Findings: Renalase was increased in Fast and it was localized in crypt. HIF-1α did not increase, but NF-κB p65 increased in Fast. Renalase overexpression protects the Caco-2 cells against H 2 O 2 induced oxidative stress., Significance: Renalase was localized in crypt and increased in Fast. This increase suggested protect response to oxidative stress because undifferenced cells were localized in crypt and need to be protected. Actually, renalase protected Caco-2 cells against H 2 O 2 induced oxidative stress. Small intestinal renalase expression was regulated by NF-κB p65 and was considered to be a defense mechanism against oxidative stress., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Ulcerative colitis (UC) develops as a result of complex interactions between various cell types in the mucosal microenvironment. In this study, we aim to elucidate the pathogenesis of ulcerative colitis at the single-cell level and unveil its clinical significance. Using single-cell RNA sequencing and high-dimensional weighted gene co-expression network analysis, we identify a subpopulation of plasma cells (PCs) with significantly increased infiltration in UC colonic mucosa, characterized by pronounced oxidative stress. Combining 10 machine learning approaches, we find that the PC oxidative stress genes accurately distinguish diseased mucosa from normal mucosa (independent external testing AUC=0.991, sensitivity=0.986, specificity=0.909). Using MCPcounter and non-negative matrix factorization, we identify the association between PC oxidative stress genes and immune cell infiltration as well as patient heterogeneity. Spatial transcriptome data is used to verify the infiltration of oxidatively stressed PCs in colitis. Finally, we develop a gene-immune convolutional neural network deep learning model to diagnose UC mucosa in different cohorts (independent external testing AUC=0.984, sensitivity=95.9%, specificity=100%). Our work sheds light on the key pathogenic cell subpopulations in UC and is essential for the development of future clinical disease diagnostic tools.

Progression of nonalcoholic steatohepatitis (NASH) is attributed to several factors, including inflammation and oxidative stress. In recent years, renalase has been reported to suppress oxidative stress, apoptosis and inflammation. A number of studies have suggested that renalase may be associated with protecting the liver from injury. The present study aimed to clarify the effects of renalase knockout (KO) in mice with NASH that were induced with a choline-deficient high-fat diet (CDAHFD) supplemented with 0.1% methionine. Wild type (WT) and KO mice (6-week-old) were fed a normal diet (ND) or CDAHFD for 6 weeks, followed by analysis of the blood liver function markers and liver tissues. CDAHFD intake was revealed to increase blood hepatic function markers, lipid accumulation and oxidative stress compared with ND, but no significant differences were observed between the WT and KO mice. However, in the KO-CDAHFD group, the Adgre1 and Tgfb1 mRNA levels were significantly higher, and α-SMA expression was significantly lower compared with the WT-CDAHFD group. Furthermore, the Gclc mRNA and phosphorylated protein kinase B (Akt) levels were significantly lower in the KO-ND group compared with the WT-ND group. The results of the current study indicated that as NASH progressed in the absence of renalase, oxidative stress, macrophage infiltration and TGF-β expression were enhanced, while α-SMA expression in NASH may be partly suppressed due to the decreased phosphorylation of Akt level. [ABSTRACT FROM AUTHOR]

Abstract Aims Renalase expression in the kidneys and liver is regulated by nuclear factor (NF)-κB, Sp1, and hypoxia-inducible factor (HIF)-1α. The dynamics of renalase expression in acute exercise, and its mechanism and physiological effects are unclear. We evaluated the effect of different exercise intensities on renalase expression and examined its mechanism and physiological effects. Main methods 21 male Wistar rats ran for 30 min on a treadmill after resting for 15 min. The sedentary group rested on the treadmill while the exercise group ran for 30 min at 10 or 30 m/min. Skeletal muscles, the kidney, heart, liver, and blood samples were collected after exercise. The expression of renalase and phosphate IkB-α and Akt was measured by western blotting, while HIF-1α, Sp1, MuRF-1, and MAFbx were measured in the skeletal muscle by real-time RT-PCR. Key findings Renalase expression in skeletal muscles increased after acute exercise, while its expression in the kidneys, heart, and liver decreased. NF-κB regulated renalase expression in the plantaris muscle and that of HIF-1α in the soleus muscle. Phosphate Akt in the plantaris muscle significantly increased in the 30 m/min group compared with that in the sedentary group. MuRF-1 in the plantaris did not change between these groups. Significance Renalase expression in skeletal muscles increased after acute exercise but decreased in other tissues. This increase may be a response to exercise-induced oxidative stress. Furthermore, NF-κB in the plantaris muscle may mainly regulate renalase expression, and support a relationship with the cell protective effects of renalase. [ABSTRACT FROM AUTHOR]

While molecular oxygen is essential for aerobic organisms, its utilization is inseparably connected with generation of oxidative insults. To cope with the detrimental aspects, cells evolved antioxidative defense systems, and insufficient management of the oxidative insults underlies the pathogenesis of a wide range of diseases. A battery of genes for this antioxidative defense are regulated by the transcription factors nuclear factor-erythroid 2-like 1 and 2 (NRF1 and NRF2). While the regulatory steps for the activation of NRFs have been investigated with particular emphasis on nuclear translocation and proteosomal degradation, unknown redundancy may exist considering the indispensable nature of these defense systems. Here we unraveled that C-terminal binding protein 2 (CtBP2), a transcriptional cofactor with redox-sensing capability, is an obligate partner of NRFs. CtBP2 forms transcriptional complexes with NRF1 and NRF2 that is required to promote the expression of antioxidant genes in response to oxidative insults. Our findings illustrate a basis for understanding the transcriptional regulation of antioxidative defense systems that may be exploited therapeutically. • A transcriptional co-factor CtBP2 forms novel complexes with NRF1 and NRF2. • CtBP2 promotes the antioxidant defense programs through these complexes. • The binding activity of CtBP2 is regulated by cellular redox state, confering metabolite-sensing capabilities to NRF1 and NRF2. [ABSTRACT FROM AUTHOR]