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Lipopolysaccharide (LPS) derived from Porphyromonas gingivalis ( P . g .), which causes periodontal disease, contributes to the development of non-alcoholic steatohepatitis (NASH). We investigated the role of Nrf2, an antioxidative stress sensor, in macrophages in the development of NASH induced by LPS from P . g . We generated macrophage-specific Nrf2 gene rescue mice ( Nrf2 -mRes), which express Nrf2 only in macrophages, using the cre/loxp system. Wild-type (WT) mice, whole body Nrf2 -knockout ( Nrf2 -KO) mice, and Nrf2 -mRes mice were fed a high-fat diet for 18 weeks, and LPS from P . g . was administered intraperitoneally for the last 6 weeks. Nrf2 -KO mice developed severe steatohepatitis with liver inflammation and fibrosis compared with WT mice, and steatohepatitis was ameliorated in Nrf2 -mRes mice. The mRNA expressions of Toll-like receptor ( Tlr ) -2 , which activates inflammatory signaling pathways after LPS binding, and α-smooth muscle actin ( αSma ), which promotes hepatic fibrosis, were reduced in Nrf2 -mRes mice compared with Nrf2 -KO mice. The protein levels of LPS-binding protein in livers were increased in Nrf2 -KO mice compared with WT mice; however, the levels were reduced in Nrf2 -mRes mice despite similar numbers of F4/80 positive cells, which reflect macrophage/Kupffer cell infiltration into the livers. Nrf2 in macrophages ameliorates NASH through the increased hepatic clearance of LPS.

Background While decreased protein intake is associated with muscle mass loss, it is unclear whether a decrease in carbohydrate intake adversely affects muscle atrophy independently of protein intake. Herein, we examined whether a low‐carbohydrate (low‐CHO) diet exacerbates denervation‐induced muscle atrophy under conditions of identical protein intake. Methods On day one of the experiment, male Wistar rats underwent unilateral denervation. The contralateral leg was used as the control. After denervation, rats were divided into two dietary groups: high‐carbohydrate (high‐CHO) and low‐CHO. Each group was fed a high‐CHO (70% carbohydrate) or low‐CHO (20% carbohydrate) diet over 7 days. Total protein and energy intakes in both groups were matched by pair feeding. Rats were provided with deuterium oxide (D2O) tracer over the last 3 days of dietary intervention to quantify myofibrillar (muscle) protein synthesis (MPS). Results Denervation reduced wet weight of the gastrocnemius muscle compared to the contralateral control (p < 0.05). Reductions in gastrocnemius muscle weight were greater in the low‐CHO group (−34%) than the high‐CHO group (−28%) (p < 0.05). Although denervation decreased MPS compared to the contralateral control (p < 0.05), no dietary effect on MPS was observed. Denervation resulted in increased mRNA and protein expression of Atrogin‐1, a ubiquitin E3 ligase, compared to that in the contralateral control (p < 0.05). Increases in Atrogin‐1 gene and protein expression due to denervation were greater in the low‐CHO group than in the high‐CHO group (p < 0.05). Conclusions We conclude that a low‐CHO diet may exacerbate denervation‐induced atrophy in fast‐twitch‐dominant muscles compared to a high‐CHO diet, even when the same protein intake is maintained. Although blunted MPS contributed to muscle atrophy due to denervation, exacerbation of muscle atrophy by the low‐CHO diet was not accompanied by explanatory changes in MPS. The effect of the low‐CHO diet might be related to promotion of muscle‐specific ubiquitin E3 ligase gene expression.

Oxidative stress (OS) contributes to nonalcoholic steatohepatitis (NASH) and hepatocarcinogenesis. We investigated whether antioxidative self-assembling nanoparticles (SMAPoTN) could reduce the development of NASH and hepatocellular carcinoma (HCC) in p62/Sqstm1 and Nrf2 double knockout (DKO) mice and studied protective mechanisms. We measured disease development in male DKO mice fed a normal chow (NASH model) or a 60% high-fat diet (HFD; HCC model) with or without SMAPoTN administration for 26 weeks. SMAPoTN inhibited liver fibrosis in both groups and prevented HCC development (0% vs. 33%, p < 0.05) in the HFD group. SMAPoTN reduced OS, inflammatory cytokine signaling, and liver fibrosis. RNA-sequencing revealed that SMAPoTN decreased endoplasmic reticulum stress signaling genes in both groups, HCC driver genes, and cancer pathway genes, especially PI3K-AKT in the HFD groups. In the SMAPoTN treatment HFD group, serum lipopolysaccharide levels and liver lipopolysaccharide-binding protein expression were significantly lower compared with those in the nontreatment group. SMAPoTN improved the α-diversity of gut microbiota, and changed the microbiota composition. Oral SMAPoTN administration attenuated NASH development and suppressed hepatocarcinogenesis in DKO mice by improving endoplasmic reticulum stress in the liver and intestinal microbiota. SMAPoTN may be a new therapeutic option for NASH subjects and those with a high HCC risk.

Objective Excessive exercise increases the production of reactive oxygen species in skeletal muscles. Sulforaphane activates nuclear factor erythroid 2‐related factor 2 (Nrf2) and induces a protective effect against oxidative stress. In a recent report, sulforaphane intake suppressed exercise‐induced oxidative stress and muscle damage in mice. However, the effect of sulforaphane intake on delayed onset muscle soreness after eccentric exercise in humans is unknown. We evaluated the effect of sulforaphane supplement intake in humans regarding the delayed onset muscle soreness (DOMS) after eccentric exercise. Research Methods & Procedures To determine the duration of sulforaphane supplementation, continuous blood sampling was performed and NQO1 mRNA expression levels were analyzed. Sixteen young men were randomly divided into sulforaphane and control groups. The sulforaphane group received sulforaphane supplements. Each group performed six set of five eccentric exercise with the nondominant arm in elbow flexion with 70% maximum voluntary contraction. We assessed muscle soreness in the biceps using the visual analog scale, range of motion (ROM), muscle damage markers, and oxidative stress marker (malondialdehyde; MDA). Results Sulforaphane supplement intake for 2 weeks increased NQO1 mRNA expression in peripheral blood mononuclear cells (PBMCs). Muscle soreness on palpation and ROM were significantly lower 2 days after exercise in the sulforaphane group compared with the control group. Serum MDA showed significantly lower levels 2 days after exercise in the sulforaphane group compared with the control group. Conclusion Our findings suggest that sulforaphane intake from 2 weeks before to 4 days after the exercise increased NQO1, a target gene of Nrf2, and suppressed DOMS after 2 days of eccentric exercise. Sulforaphane supplement intake for 2 weeks enhances antioxidant capacity, and suppression exercise induced oxidative stress. Muscle soreness on palpation and ROM were significantly lower 2 days after exercise in the sulforaphane group compared with the control group. This result should contribute to the improvement of performance in athletes and may also increase the exercise orientation of generally healthy people.

Exercise ameliorates nonalcoholic fatty liver disease (NAFLD) by inducing phenotypic changes in Kupffer cells (KCs). p62/Sqstm1‐knockout (p62‐KO) mice develop NAFLD alongside hyperphagia‐induced obesity. We evaluated (1) the effects of long‐term exercise on the foreign‐body phagocytic capacity of KCs, their surface marker expression, and the production of steroid hormones in p62‐KO mice; and (2) whether long‐term exercise prevented the development of non‐alcoholic steatohepatitis (NASH) in p62‐KO mice fed a high‐fat diet (HFD). In experiment 1, 30‐week‐old male p62‐KO mice were allocated to resting (p62‐KO‐Rest) or exercise (p62‐KO‐Ex) groups, and the latter performed long‐term exercise over 4 weeks. Then, the phenotype of their KCs was compared to that of p62‐KO‐Rest and wild‐type (WT) mice. In experiment 2, 5‐week‐old male p62‐KO mice that were fed a HFD performed long‐term exercise over 12 weeks. In experiment 1, the phagocytic capacity of KCs and the proportion of CD68‐positive cells were lower in the p62‐KO‐Rest group than in the WT group, but they increased with long‐term exercise. The percentage of CD11b‐positive KCs was higher in the p62‐KO‐Rest group than in the WT group, but lower in the p62‐KO‐Ex group. The circulating dehydroepiandrosterone (DHEA) concentration was higher in p62‐KO‐Ex mice than in p62‐KO‐Rest mice. In experiment 2, the body mass and composition of the p62‐KO‐Rest and p62‐KO‐Ex groups were similar, but the hepatomegaly, hepatic inflammation, and fibrosis were less marked in p62‐KO‐Ex mice. The DHEA concentration was higher in p62‐KO‐Ex mice than in WT or p62‐KO‐Rest mice. Thus, long‐term exercise restores the impaired phagocytic capacity of KCs in NAFLD obese mice, potentially through greater DHEA production, and prevents the development of NASH by ameliorating hepatic inflammation and fibrogenesis. These results suggest a molecular mechanism for the beneficial effect of exercise in the management of patients with NAFLD. Long‐term running exercise by a high fat diet‐fed hyperphagic obese mice (p62‐KO mice) prevented the development of hepatic inflammation and fibrosis in non‐alcoholic steatohepatitis, via the restoration of foreign‐body phagocytic capacity and induction of phenotypic changes in the Kupffer cells.

We present a new catalog of \\(9318\\) Ly\\(\\alpha\\) emitter (LAE) candidates at \\(z = 2.2\\), \\(3.3\\), \\(4.9\\), \\(5.7\\), \\(6.6\\), and \\(7.0\\) that are photometrically selected by the SILVERRUSH program with a machine learning technique from large area (up to \\(25.0\\) deg\\(^2\\)) imaging data with six narrowband filters taken by the Subaru Strategic Program with Hyper Suprime-Cam (HSC SSP) and a Subaru intensive program, Cosmic HydrOgen Reionization Unveiled with Subaru (CHORUS). We construct a convolutional neural network that distinguishes between real LAEs and contaminants with a completeness of \\(94\\)% and a contamination rate of \\(1\\)%, enabling us to efficiently remove contaminants from the photometrically selected LAE candidates. We confirm that our LAE catalogs include \\(177\\) LAEs that have been spectroscopically identified in our SILVERRUSH programs and previous studies, ensuring the validity of our machine learning selection. In addition, we find that the object-matching rates between our LAE catalogs and our previous results are \\(\\simeq 80\\)-\\(100\\)% at bright NB magnitudes of \\(\\lesssim 24\\) mag. We also confirm that the surface number densities of our LAE candidates are consistent with previous results. Our LAE catalogs will be made public on our project webpage.