2'-Fucosyllactose Ameliorates Oxidative Stress Damage in d-Galactose-Induced Aging Mice by Regulating Gut Microbiota and AMPK/SIRT1/FOXO1 Pathway.
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ABSTRACT:
SUBMITTER: Wang J
PROVIDER: S-EPMC8774504 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Terpenoids are a wide class of secondary metabolites with geroprotective properties that can alter the mechanism of aging and aging-related diseases. Camphorquinone (CQ) is a bicyclic monoterpenoid compound that can be efficiently synthesized through the continuous bromination and oxidation reaction of camphor. The purpose of this study is to investigate the effects of CQ on oxidative-stress-induced senescence and its underlying mechanisms. To generate oxidative stress in human bone marrow mesenchymal stem cells (hBM-MSCs) and mice, we used hydrogen peroxide (200 μM twice) and D-galactose (D-Gal) (150 mg/kg for 10 weeks), respectively. Our findings suggest that CQ potentially reduces senescence in hBM-MSCs and mouse heart tissue. In addition, we found that CQ boosted AMPK/SIRT1 activation and autophagy in both models. These results were subsequently verified in hBM-MSCs using compound C (an AMPK inhibitor) but AMPK inhibition by CC did not significantly reduce the SIRT1 and the autophagy markers. CQ treatment also reduced the gene expression of inflammation markers in D-Gal-induced aging mouse heart tissue. Furthermore, we determined that CQ fits all of the pharmacological parameters using the freely available SwissADME Web tool. Collectively, our findings demonstrate that CQ possesses antisenescence and cardioprotective properties, and that oxidative-stress-induced senescence could be suppressed by AMPK/SIRT1 and autophagy mechanisms.
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Project description:Forkhead transcription factor FoxO1 and the NAD(+)-dependent histone deacetylase SIRT1 are evolutionarily conserved regulators of the development of aging, oxidative stress resistance, insulin resistance, and metabolism in species ranging from invertebrates to mammals. SIRT1 deacetylates FoxO1 and enables activation of FoxO1 transcription in multiple systems. The functional consequences of the interactions between FoxO1 and SIRT1 remain incompletely understood. Here, we demonstrate that the 1.5-kb rat sirt1 promoter region contains a cluster of five putative FoxO1 core binding repeat motifs (5×IRS-1) and a forkhead-like consensus binding site (FKHD-L). Luciferase promoter assays demonstrate that FoxO1 directly activates SIRT1 promoter activity and that both the IRS-1 and FKHD-L enable FoxO1-dependent SIRT1 transcription. Electrophoretic mobility shift and chromatin immunoprecipitation assays show that FoxO1 binds to the IRS-1 and FKHD-L sites of the SIRT1 promoter. Consistently, FoxO1 overexpression increases SIRT1 expression, and FoxO1 depletion by siRNA reduces SIRT1 expression at both the messenger RNA and protein levels in vascular smooth muscle cells and HEK293 cells. Thus, endogenous FoxO1 is a positive transcriptional regulator of SIRT1. Conversely, SIRT1 promotes FoxO1-driven SIRT1 autotranscription through interacting with and deacetylating FoxO1. Moreover, resveratrol, a plant polyphenol activator of SIRT1, increases FoxO1-dependent SIRT1 transcription activity and thus induces its expression. These findings suggest that positive feedback mechanisms regulate FoxO1-dependent SIRT1 transcription and indicate a previously unappreciated function for FoxO1. This signaling network may coordinate multiple pathways acting upon immune, inflammatory, regenerative, and metabolic processes.
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Project description:Excessive fat accumulation has been considered as a major contributing factor for muscle mitochondrial dysfunction and its associated metabolic complications. The purpose of present study is to investigate a role of vitamin D in muscle fat accumulation and mitochondrial changes. In differentiated C2C12 muscle cells, palmitic acid (PA) was pretreated, followed by incubation with 1,25-dihyroxyvitamin D (1,25(OH)2D) for 24 h. PA led to a significant increment of triglyceride (TG) levels with increased lipid peroxidation and cellular damage, which were reversed by 1,25(OH)2D. The supplementation of 1,25(OH)2D significantly enhanced PA-decreased mtDNA levels as well as mRNA levels involved in mitochondrial biogenesis such as nuclear respiratory factor 1 (NRF1), peroxisome proliferative activated receptor gamma coactivator-1? (PGC-1?), and mitochondrial transcription factor A (Tfam) in C2C12 myotubes. Additionally, 1,25(OH)2D significantly increased ATP levels and gene expression related to mitochondrial function such as carnitine palmitoyltransferase 1 (CPT1), peroxisome proliferator-activated receptor ? (PPAR?), very long-chain acyl-CoA dehydrogenase (VLCAD), long-chain acyl-CoA dehydrogenase (LCAD), medium-chain acyl-CoA dehydrogenase (MCAD), uncoupling protein 2 (UCP2), and UCP3 and the vitamin D pathway including 25-dihydroxyvitamin D3 24-hydroxylase (CYP24) and 25-hydroxyvitamin D3 1-alpha-hydroxylase (CYP27) in PA-treated C2C12 myotubes. In addition to significant increment of sirtuin 1 (SIRT1) mRNA expression, increased activation of adenosine monophosphate-activated protein kinase (AMPK) and SIRT1 was found in 1,25(OH)2D-treated C2C12 muscle cells. Thus, we suggest that the observed protective effect of vitamin D on muscle fat accumulation and mitochondrial dysfunction in a positive manner via modulating AMPK/SIRT1 activation.
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Project description:Diabetic nephropathy (DN) is a common complication of diabetes and an important cause of end-stage renal disease. Increasing evidence suggests that microRNAs (miRNAs) regulate the development of DN. In a preliminary study, high levels of miR-150-5p were detected in the serum and urine of patients with DN. Consequently, we investigated the effect and mechanism of action of miR-150-5p in DN in vitro and in vivo. Our results showed that inhibition of miR-150-5p reversed high glucose-induced podocyte injury and Streptozocin (STZ)-induced diabetic nephropathy in mice. Further analysis revealed that miR-150-5p targeted the 3' untranslated region (UTR) of sirtuin 1 (SIRT1), consequently decreasing SIRT1 levels in podocytes. Importantly, we found that the silencing of miR-150-5p promoted the interaction between SIRT1 and p53, causing the suppression of p53 acetylation in podocytes and kidney tissue. This resulted in the stimulation of AMP-activated protein kinase (AMPK)-dependent autophagy. In conclusion, our study demonstrated that the silencing of miR-150-5p played a reno-protective role in DN mice through targeting SIRT1.
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Project description:Necrotizing enterocolitis (NEC) is a severe gastrointestinal disease affecting premature infants. Mounting evidence supports the therapeutic effect of melatonin on NEC, although the underlying mechanisms remain unclear. Methods: NEC was induced in 10-day-old C57BL/6 pups via hypoxia and gavage feeding of formula containing enteric bacteria, and then, mice received melatonin, melatonin + recombinant IL-17, melatonin + anti-CD25 monoclonal antibody, melatonin + Ex-527, or melatonin + Compound C treatment. Control mice were left with their dams to breastfeed and vehicle-treated NEC pups were used as controls for treatment. Ileal tissues were collected from mice and analyzed by histopathology, immunoblotting, and flow cytometry. FITC-labeled dextran was administered to all surviving pups to evaluate gut barrier function by fluorometry. We used molecular biology and cell culture approaches to study the related mechanisms in CD4+ T cells from umbilical cord blood. Results: We demonstrated that melatonin treatment ameliorates disease in an NEC mouse model in a manner dependent on improved intestinal Th17/Treg balance. We also showed that melatonin blocks the differentiation of pathogenic Th17 cells and augments the generation of protective Treg cells in vitro. We further demonstrated that the Th17/Treg balance is influenced by melatonin through activation of AMPK in the intestine, in turn promoting SIRT1 activation and stabilization. Conclusions: These results demonstrate that melatonin-induced activation of AMPK/SIRT1 signaling regulates the balance between Th17 and Treg cells and that therapeutic strategies targeting the Th17/Treg balance via the AMPK/SIRT1 pathway might be beneficial for the treatment of NEC.
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Project description:ObjectiveCelastrol was recently identified as a potential novel treatment for obesity. However, the effect of Celastrol on nonalcoholic fatty liver disease (NAFLD) remains elusive. The aim of this study is to evaluate the role of Celastrol in NAFLD.MethodsFunctional studies were performed using wild-type C57BL/6J (WT) mice and liver specific Sirt1-deficient (LKO) mice. The molecular mechanism was explored in primary mouse liver and primary hepatocytes.ResultsWhen WT mice receiving a high-fat diet (HFD) were treated with Celastrol, reductions in body weight, subcutaneous and visceral fat content, and liver lipid droplet formation were observed, along with reduced hepatic intracellular triglyceride and serum triglyceride, free fatty acid, and ALT concentrations. Furthermore, Celastrol decreased hepatic sterol regulatory element binding protein 1c (Srebp-1c) expression, enhanced the phosphorylation of hepatic AMP-activated protein kinase ? (AMPK?), and increased the expression of hepatic serine-threonine liver kinase B1 (LKB1). Additionally, Celastrol treatment improved glucose tolerance and insulin sensitivity in WT mice fed the HFD. Celastrol administration also improved the anti-inflammatory and anti-oxidative status by inhibiting nuclear factor kappa B (NF?B) activity and the mRNA levels of proinflammatory cytokines and increasing mitochondrial DNA copy number and anti-oxidative stress genes expression in WT mice liver, in vivo and in vitro. Moreover, Celastrol induced hepatic Sirt1 expression in WT mice, in vivo and in vitro. These Celastrol-mediated protective effects in WT mice fed a HFD were abolished in LKO mice fed a HFD. It was more interesting that Celastrol aggravated HFD-induced liver damage in LKO mice fed a HFD by inhibiting the phosphorylation of AMPK? and boosting the translocation of NF?B into the nucleus, thereby resulting in the increase of Srebp-1c expression and the mRNA levels of liver proinflammatory cytokines.ConclusionsCelastrol ameliorates NAFLD by decreasing lipid synthesis and improving the anti-oxidative and anti-inflammatory status. And Sirt1 has an important role in Celastrol-ameliorating liver metabolic damage caused by HFD.
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Project description:Obesity is characterized by increased fat mass, as adipose tissue serves as a storage site for excess energy from food consumption. In obesity, altered lipid metabolism of adipose tissue, characterized by fatty acid uptake, de novo lipogenesis, and lipolysis, are induced. In this study, we examined the effect of zerumbone, a major sesquiterpene from wild ginger, on high-fat diet (HF)-induced obesity and dysregulated lipid metabolism in the white adipose tissues (WAT) of C57BL/6N mice. Dietary supplementation with zerumbone ameliorated HF-induced obesity and improved impaired lipid metabolism in WAT. Zerumbone additionally induced AMPK activation and phosphorylation of acetyl-CoA carboxylase, and effectively decreased adipogenic differentiation, in a concentration-dependent manner in the 3T3-L1 cells. Dysregulated microRNAs in obese WAT and adipocytes were examined, and zerumbone treatment was found to effectively reverse the robust upregulation of microRNA-146b. An increase in the levels of SIRT1, the direct target of microRNA-146b, was observed in zerumbone-treated differentiated adipocytes. This increase was additionally observed in WAT of zerumbone-supplemented mice. The antiadipogenic effect of zerumbone was found to be abolished in SIRT1-silenced 3T3-L1 cells. The increase in SIRT1 levels induced by zerumbone led to deacetylation of FOXO1 and PGC1? in WAT and differentiated 3T3-L1 cells. These findings indicate that zerumbone ameliorated diet-induced obesity and inhibited adipogenesis, and that the underlying mechanisms involved AMPK and the microRNA-146b/SIRT1 pathway. Zerumbone may represent a potential therapeutic candidate for the prevention and treatment of metabolic diseases, particularly obesity.
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Project description:Liuweidihuang Pill (LP) is a traditional Chinese herbal formula that is often used in clinical practice to treat kidney deficiency syndrome. The present study investigated the antiaging effects of LP in a D-galactose- (D-Gal-) induced subacute aging rat model. The study also attempted to explore whether anti-inflammatory mechanisms that underpin the antiaging effects are mediated by the AMPK/SIRT1/NF-?B signaling pathway. Rats were subcutaneously injected with D-Gal at a dosage of 100?mg/kg/d for 8 weeks. Upon successful induction of aging in the rats, the animal was administered LP at 0.9?g/kg/d by gavage for 4 weeks. Proteins of the testis were subsequently examined by western blot analysis, and associated locations in the testicular tissue were determined by immunohistochemistry. We observed that LP exerted antiaging effects in aging rats following the activation of AMPK/SIRT1. It was also observed that LP inhibited the expression of NF-?B, thereby further attenuating inflammation of the testis. Therefore, LP can alleviate inflammation of the testis via the AMPK/SIRT1/NF-?B pathway in aging rats.
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