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Objective To investigate the effect of pterostilbene (PTE) on exercise intolerance induced by sleep restriction (SR) in mice and explore the underlying mechanism. Methods Thirty male C57BL/6J mice were randomized into control group, SR group and SR with PTE treatment (SR+PTE) group. The mice in the latter 2 groups were kept awake using a sleep deprivation apparatus with their daily sleep time limited to 4 h for 5 consecutive days. In SR+PTE group, the mice received PTE treatment by gavage at a daily dose of 100 mg/kg (administered at 08:00 am). After the 5-day treatment, body weight changes of the mice were recorded, and a weight-loaded forced swimming test was performed; blood samples were collected for detecting serum levels of biochemical indicators of exercise fatigue. HE staining was used to observe the pathological changes of the skeletal muscle tissue. The mitochondrial DNA (mtDNA) content and the expressions of AMPK, SIRT1 and mitochondrial biogenesis-related genes were determined by real-time PCR and Western blotting. Results Compared with those in the control group, the mice in both SR and SR+PTE groups showed significant weight loss after the treatment (P < 0.05), and the decrease was more obvious in SR group (P < 0.05). Compared with those in SR group, the mice in SR+PTE group had significantly prolonged exhaustive swimming time and significantly lowered serum levels of LDH and CK (P < 0.05). No significant differences were found in skeletal muscle pathologies among the groups. The mtDNA content and expression levels of mitochondrial biosynthesis-related genes including PGC1α, NRF1, ERRα and TFAM were significantly higher in SR+PTE group than in SR group (P < 0.05). Western blotting showed that the expression levels of p-AMPK and SIRT1 were significantly higher in SR+PTE group than in SR group (P < 0.05), while that of AMPK were comparable between the 2 groups. Conclusion PTE can improve exercise intolerance in mice exposed to SR possibly by activating AMPK/SIRT1 signaling pathway to enhance mitochondrial biogenesis.

Diabetic kidney disease is associated with the dysbiosis of the gut microbiota and its metabolites. db/db mice were fed chow diet with or without 0.4% resveratrol for 12 weeks, after which the gut microbiota, faecal short-chain fatty acids (SCFAs), and renal fibrosis were analysed. Resveratrol ameliorated the progression of diabetic kidney disease and alleviated tubulointerstitial fibrosis. Further studies showed that gut microbiota dysbiosis was modulated by resveratrol, characterised by the expansion of SCFAs-producing bacteria Faecalibaculum and Lactobacillus, which increased the concentrations of SCFAs (especially acetic acid) in the faeces. Moreover, microbiota transplantation experiments found that alteration of the gut microbiota contributed to the prevention of diabetic kidney disease. Acetate treatment ameliorated proteinuria, glomerulosclerosis and tubulointerstitial fibrosis in db/db mice. Overall, resveratrol improved the progression of diabetic kidney disease by suppressing tubulointerstitial fibrosis, which may be involved, at least in part, in the regulation of the gut microbiota-SCFAs axis. [ABSTRACT FROM AUTHOR]

Metabolic endotoxemia originating from dysbiotic gut microbiota has been identified as a primary mediator for triggering the chronic low-grade inflammation (CLGI) responsible for the development of obesity. Capsaicin (CAP) is the major pungent bioactivator in chili peppers and has potent anti-obesity functions, yet the mechanisms linking this effect to gut microbiota remain obscure. Here we show that mice fed a high-fat diet (HFD) supplemented with CAP exhibit lower levels of metabolic endotoxemia and CLGI associated with lower body weight gain. High-resolution responses of the microbiota were examined by 16S rRNA sequencing, short-chain fatty acid (SCFA) measurements, and phylogenetic reconstruction of unobserved states (PICRUSt) analysis. The results showed, among others, that dietary CAP induced increased levels of butyrate-producing Ruminococcaceae and Lachnospiraceae, while it caused lower levels of members of the lipopolysaccharide (LPS)-producing family S24_7. Predicted function analysis (PICRUSt) showed depletion of genes involved in bacterial LPS synthesis in response to CAP. We further identified that inhibition of cannabinoid receptor type 1 (CB1) by CAP also contributes to prevention of HFD-induced gut barrier dysfunction. Importantly, fecal microbiota transplantation experiments conducted in germfree mice demonstrated that dietary CAP-induced protection against HFD-induced obesity is transferrable. Moreover, microbiota depletion by a cocktail of antibiotics was sufficient to block the CAP-induced protective phenotype against obesity, further suggesting the role of microbiota in this context. Together, our findings uncover an interaction between dietary CAP and gut microbiota as a novel mechanism for the anti-obesity effect of CAP acting through prevention of microbial dysbiosis, gut barrier dysfunction, and chronic low-grade inflammation.

Objectives: The aim of this study was to investigate the mechanism of itaconate's potential effect in diabetic kidney disease., Methods: Renal immune responsive gene 1 (IRG1) levels were measured in db/db mice and streptozotocin (STZ) + high-fat diet (HFD)-induced diabetic mice. Irg1 knockout mice were generated. db/db mice were treated with 4-octyl itaconate (4-OI, 50 mg/kg), a derivative of itaconate, for 4 weeks. Renal function and morphological changes were investigated. Ultrastructural alterations were determined by transmission electron microscopy., Results: Renal IRG1 levels were reduced in two diabetic models. STZ+HFD-treated Irg1 knockout mice exhibited aggravated renal tubular injury and worsened renal function. Treatment with 4-OI lowered urinary albumin-to-creatinine ratio and blood urea nitrogen levels, and restored renal histological changes in db/db mice. It improved mitochondrial damage, increased expressions of peroxisome-proliferator-activated receptor γ coactivator-1α (PGC-1α) and mitochondrial transcription factor A (TFAM) in the renal cortex of db/db mice. These were confirmed in vitro ; 4-OI improved high glucose-induced abnormal mitochondrial morphology and TFAM expression in HK-2 cells, effects that were inhibited by PGC-1α silencing. Moreover, 4-OI reduced the number of apoptotic cells in the renal cortex of db/db mice. Further study showed that 4-OI increased renal Nrf2 expression and decreased oxidative stress levels in db/db mice. In HK-2 cells, 4-OI decreased high glucose-induced mitochondrial ROS production, which was reversed by Nrf2 silencing. Nrf2 depletion also inhibited 4-OI-mediated regulation of PGC-1α, TFAM, and mitochondrial apoptotic protein expressions., Conclusions: 4-OI attenuates renal tubular injury in db/db mice by activating Nrf2 and promoting PGC-1α-mediated mitochondrial biogenesis.