AMPK-SIRT1 Signaling Research Articles

Coloprotective effects of chebulic myrobalan extract by regulation of AMPK-SIRT1 signaling: A pharmacological and histopathological evaluation

Ulcerative colitis is a chronic, refractory disease caused by dysregulation of mucosal immune responses to the indigenous bacterial flora as well as genetic and environmental variables. Recently, there has been increasing interest towards the use of herbal medicines for the treatment of ulcerative colitis and the potential benefits could lie in their high patient acceptability, effectiveness, safety, and relatively low cost. It has been reported that Chebulic myrobalan (Terminalia chebula) exhibits anti-oxidant, anti-inflammatory and immunomodulatory properties. The present study was designed to evaluate the protective potential of extract of dried fruit pulp of T. chebula against Dextran sulphate sodium (DSS)-induced ulcerative colitis in male BALB/c mice. Three cycles of DSS (3 % w/v in drinking water), each followed by a seven-day remission phase were used to induce ulcerative colitis in mice. Animals were treated with T. chebula (300 mg/kg and 600 mg/kg) starting from Ist remission period to the end of the study. Different biochemical assays, histological evaluation and molecular analysis were performed to evaluate the protective effects of T. chebula extract in DSS induced colitis. T. chebula modulates the expression of nuclear factor kappa B, adenosine monophosphate kinase, tumour necrosis factor-alpha, sirtuin 1 and interleukin-1β. Furthermore, it also accorded coloprotective effects against DNA damage, apoptosis, inflammation and nitrosative stress. Finally, it was found that the high dose of the T. chebula extract (600 mg/kg) was found to be more effective than a low dose (300 mg/kg) in restoring the ulcerative colitis induced colonic damage.

Mechanism Research of DHEA Treatment Improving Diminished Ovarian Reserve by Attenuating the AMPK-SIRT1 Signaling and Mitophagy.

This study aims to investigate the effect and mechanism of dehydroepiandrosterone (DHEA) on diminished ovarian reserve (DOR) by modulating the AMPK-SIRT1 signaling and mitophagy in rats. Three-month-old female Sprague-Dawley (SD) rats were randomized and injected intraperitoneally with sesame oil as the control or deoxyvinylcyclohexene (VCD) to induce DOR. The VCD-injected rats were randomized and injected subcutaneously with vehicle as the model group or with DHEA for 21days as the DHEA group. After being identified in proestrus, rat blood sampleswere collected to prepare serum samples, and their ovarian tissues were dissected. Compared with the controls, significantly lower serum estradiol (E2), anti-Müllerian hormone (AMH), and inhibin B (IHNB) and higher follicle-stimulating hormone (FSH) and luteinizing hormone (LH) levels were detected in the model group (DOR rats). The model group of rats displayed an increase in follicular atresia and a decrease in ovarian volume and the number of growing follicles and corpus luteum, accompanied by increased frequency of oocyte apoptosis and reduced levels of mitochondrial function. Furthermore, significantly higher levels of the AMPK-SIRT1 signaling and mitophagy were observed in the ovaries of rats in the model group. In contrast, treatment with DHEA significantly ameliorated the hormone disorder and morphological changes in the ovaries, reduced the frequency of apoptotic oocytes, and improved mitochondrial function in the ovaries of DOR rats. Mechanistically, DHEA treatment significantly attenuated the AMPK-SIRT1 signaling and mitophagy in the ovaries of DOR rats. DHEA treatment reduced the severity of DOR and enhanced ovarian reserve function by attenuating the AMPK-SIRT1 signaling and mitophagy in the ovaries of rats.

Role of AMPK in autophagy.

Adenosine monophosphate-activated protein kinase (AMPK) is a significant energy sensor in the maintenance of cellular energy homeostasis. Autophagy is a highly conserved catabolic process that involves an intracellular degradation system in which cytoplasmic components, such as protein aggregates, organelles, and other macromolecules, are directed to the lysosome through the self-degradative process to maintain cellular homeostasis. Given the triggered autophagy process in various situations including the nutrient deficit, AMPK is potentially linked with different stages of autophagy. Above all, AMPK increases ULK1 activity by directly phosphorylating Ser467, Ser555, Thr574, and Ser637at least four sites, which increases the recruitment of autophagy-relevant proteins (ATG proteins) to the membrane domains which affects autophagy at the initiation stage. Secondly, AMPK inhibits VPS34 complexes that do not contain pro-autophagic factors and are thus involved in isolation membrane forming processes, by direct phosphorylation of VPS34 on Thr163 and Ser165. After phosphorylation, AMPK can govern autophagosome formation through recruiting downstream autophagy-related proteins to the autophagosome formation site. Finally, the AMPK-SIRT1 signaling pathway can be activated by upregulating the transcription of autophagy-related genes, thereby enhancing autophagosome-lysosome fusion. This review provides an introduction to the role of AMPK in different stages of autophagy.

Gingko biloba-inspired lactone prevents osteoarthritis by activating the AMPK-SIRT1 signaling pathway

BackgroundUncoupled extracellular matrix (ECM) causes cartilage degeneration and osteoarthritis (OA) by suppressing the synthesis and activating the degradation of ECM components. Gingko biloba is a natural Chinese herb with a variety of biological functions; however, the extent to which it can protect against OA and the mechanisms involved are unknown.MethodsIn our study, using bioinformatics tools, we were able to identify an important lactone, bilobalide (BB), from Gingko biloba. In vitro experiments were performed to evaluate the potential therapeutic effects of BB on ECM homeostasis. In vivo experiments were conducted to assess the protection of systemic administration of BB on cartilage degeneration. Molecular mechanisms underlying BB-regulated anti-arthritic role were further explored.ResultsIn interleukin-1β-incubated human chondrocytes, in vitro treatment with BB increased the expression of cartilage anabolic proteins, while inhibiting the activities of ECM degrading enzymes. In a mice model, systemic administration of BB, in vivo, prevented post-traumatic cartilage erosion and attenuated the formation of abnormal osteophytes in the subchondral bone. Mechanistically, the activation of the adenosine 5′-monophosphate-activated protein kinase (AMPK)-sirtuin 1 (SIRT1) signaling pathway was involved in the anti-arthritic effects of BB. In vitro, blocking BB’s chondroprotection with the AMPK-specific inhibitor Compound C abrogated it.ConclusionsThese results demonstrated that BB extracted from Gingko biloba regulates ECM balance to prevent OA by activating the AMPK-SIRT1 signaling pathway. This study proposed the monomer BB, a traditional Chinese medicine, as a de novo therapeutic insight for OA.Graphical Schematic representation of the experimental design. Based on the bioinformatic analysis, bilobalide (BB), a natural herb Gingko biloba-derived ingredient, was identified as a candidate for treating osteoarthritis. In vitro, BB treatment not only facilitates cartilage extracellular matrix synthesis but also inhibits proteolytic enzyme activities. In vivo intraperitoneal injection of BB improves cartilage degeneration and subchondral bone sclerosis. BB, in particular, had anti-arthritic effects by activating the AMPK-SIRT1 signaling pathway.

IBF-R, a botanical extract of Rhus verniciflua controls obesity in which AMPK-SIRT1 axis and ROS regulatory mechanism are involved in mice

Obesity is a major health concern worldwide and adds woes to the quality of life. Several natural herbs have been shown protective effects against obesity. Here, we investigated the protective effect of Rhus verniciflua extract (IBF-R) against obesity and the underlying mechanism in obese mice. IBF-R alleviated body weight, liver weight as well as adipose tissue weight without altering food intake. IBF-R extract reduced lipogenesis and adipogenesis in liver and epididymal white adipose tissue (eWAT). At the molecular level, AMPK-SIRT1 axis increased, and mTOR-SREBP1-ER stress axis decreased. In brown adipose tissue (BAT), IBF-R administration increased mitochondrial biogenesis and thermogenesis markers like PGC1α and UCP1 via AMPK-SIRT1 signaling and mTOR-SREBP1-ER stress-mitochondrial function axis. Moreover, IBF-R influenced the recovery of PGC1α deacetylation via SIRT1 activation. These observations suggest that IBF-R protects against obesity by playing multiple modulatory roles in liver steatosis, adipocyte metabolism, and BAT function mediated by AMPK-SIRT1 axis and ROS regulating pathways.

Le Carbone prevents liver damage in non-alcoholic steatohepatitis-hepatocellular carcinoma mouse model via AMPKα-SIRT1 signaling pathway activation

Le Carbone (LC), a fiber-enriched activated charcoal dietary supplement, claimed to be effective against inflammation associated with colitis, trimethylaminuria, and sclerosis. The study aimed to investigate the underlying mechanisms of LC to protect liver damage and its progression in non-alcoholic steatohepatitis-hepatocellular carcinoma (NASH-HCC) mice. To induce this model, C57BL/6J male baby mice were injected with a low-dose of streptozotocin and fed with a high-fat diet (HFD) 32 during 4 weeks–16 weeks of age. The LC suspension was administered orally at a dose of 5 mg/mouse/day started at the age of 6 weeks and continued until 16 weeks of age along with HFD32 feeding. At the end of the experiment, serum and liver tissues were collected for the biochemical, histological, and molecular analysis. We found that LC suspension improved the histopathological changes, serum aminotransferases in NASH mice. The hepatic expression of metabolic proteins, p-AMPKα and sirtuin 1, and proteins responsible for β-oxidation of fatty acids, peroxisome proliferator-activated receptor (PPAR) γ coactivator-α, PPARα were significantly repressed in NASH mice. LC treatment markedly restored these expressions. LC treatment significantly reduced the hepatic proteins expressions of PPARγ, tissue inhibitor of metalloproteinases 4, p47phox, p-JNK, p-ERK1/2, glypican-3, and prothrombin in NASH mice. Our findings demonstrate that LC prevents the liver damage and progression of NASH, possibly by enhancing the AMPK-SIRT1 signaling pathway.

Mogroside IIIE Alleviates High Glucose-Induced Inflammation, Oxidative Stress and Apoptosis of Podocytes by the Activation of AMPK/SIRT1 Signaling Pathway.

BackgroundDiabetic nephropathy (DN) is the leading cause of impaired renal function. The purpose of this study was to investigate the effects of Mogroside IIIE (MG IIIE), a cucurbitane-type compound isolated from Siraitia grosvenorii, in high glucose (HG)-induced podocytes and the possible mechanisms.MethodsMPC-5 cells were cultured under normal glucose or HG conditions. After treatment with MG IIIE, cell viability was examined using a cell counting kit-8 assay. The contents of inflammatory factors and oxidative stress-related markers were determined using the corresponding kits. Additionally, apoptosis of MPC-5 cells was determined using flow cytometry assay and the levels of apoptosis-associated proteins were evaluated by Western blot analysis. Moreover, the expression of proteins in AMPK/SIRT1 signaling was tested and the compound C, an AMPK inhibitor, was used to study whether the effects of MG IIIE on HG-induced MPC-5 cells were mediated by activation of the AMPK/SIRT1 signaling pathway.ResultsMG IIIE elevated the cell viability of HG-induced MPC-5 cells, reduced the concentrations of inflammatory cytokines and decreased the levels of oxidative stress-related markers. What’s more, the apoptosis of podocytes induced by HG was inhibited after MG IIIE intervention, accompanied by the upregulated expression of Bcl-2 and downregulated expression of Bax, cleaved caspase-3 and cleaved caspase-9. It was also found that MG IIIE could activate the AMPK/SIRT1 signaling, but compound C inhibited this pathway and reversed the inhibitory effects of MG IIIE on inflammation, oxidative stress and apoptosis in HG-stimulated podocytes.ConclusionMG IIIE can alleviate HG-induced inflammation and oxidative stress of podocytes by the activation of AMPK-SIRT1 signaling.

Mst1 promotes mitochondrial dysfunction and apoptosis in oxidative stress-induced rheumatoid arthritis synoviocytes.

In this study, we investigated the role of macrophage stimulating 1 (Mst1) and the AMPK-Sirt1 signaling pathway in the oxidative stress-induced mitochondrial dysfunction and apoptosis seen in rheumatoid arthritis-related fibroblast-like synoviocytes (RA-FLSs). Mst1 mRNA and protein expression was significantly higher in hydrogen peroxide (H2O2)-treated RA-FLSs than untreated controls. H2O2 treatment induced the mitochondrial apoptotic pathway by activating caspase3/9 and Bax in the RA-FLSs. Moreover, H2O2 treatment significantly reduced mitochondrial membrane potential and mitochondrial state-3 and state-4 respiration, but increased reactive oxygen species (ROS). Mst1 silencing significantly reduced oxidative stress-induced mitochondrial dysfunction and apoptosis in RA-FLSs. Sirt1 expression was significantly reduced in the H2O2-treated RA-FLSs, but was higher in the H2O2-treated Mst1-silenced RA-FLSs. Pretreatment with selisistat (Sirt1-specific inhibitor) or compound C (AMPK antagonist) significantly reduced the viability and mitochondrial function in H2O2-treated Mst1-silenced RA-FLSs by inhibiting Sirt1 function or Sirt1 expression, respectively. These findings demonstrate that oxidative stress-related upregulation and activation of Mst1 promotes mitochondrial dysfunction and apoptosis in RA-FLSs by inhibiting the AMPK-Sirt1 signaling pathway. This suggests the Mst1-AMPK-Sirt1 axis is a potential target for RA therapy.

Hepatoprotective Effect of Citrus aurantium L. Against APAP-induced Liver Injury by Regulating Liver Lipid Metabolism and Apoptosis.

Acetaminophen (APAP) refers to a medication used to manage pain and fever symptoms, but it always causes liver injury when overdosed. Zhishi, dried young fruit of Citrus aurantium L., is a famous Citrus herbal medicine in Asian countries which is rich in dietary phenolic substances. In this study, the mechanism of Zhishi protected against APAP-induced liver injury was studied more deeply by metabolomic strategy and pharmacological study. The metabolomics results demonstrated that Zhishi can prevent the APAP-induced liver injury model by regulating liver metabolic disorders in glycerophospholipid metabolism, fatty acid biosynthesis and glycerolipid metabolism. Moreover, it is confirmed that Zhishi blocked apoptosis of APAP-induced BRL-3A cell by simultaneously regulating p53 up-regulated apoptosis regulator (PUMA), AMPK-SIRT1 and JNK1 signaling pathways. Our findings indicated that Zhishi exhibited a hepaprotective effect against APAP-induced liver necrosis by inhibiting the PUMA and reversing disorder of liver lipid metabolism which could assist in improving the clinical outcomes of chemical-induced liver injury.

Integrated Network and Experimental Pharmacology for Deciphering the Medicinal Substances and Multiple Mechanisms of Duhuo Jisheng Decoction in Osteoarthritis Therapy.

Osteoarthritis (OA) is currently the most common joint disorder worldwide. In last decades, herbal remedies have achieved a significant advancement in the treatment of OA. Duhuo Jisheng Decoction (DHJS), an herbal formula consisting of 15 medicinal herbs, has a long-time practice in OA therapy in China. However, its therapeutic mechanisms have not been comprehensively elucidated. In the present work, integrated network and experimental pharmacology were performed for investigating the therapeutic substances and mechanisms of DHJS. Based on network analysis, the contribution of each herb to OA therapy was evaluated. Furthermore, a series of potential targets and signaling pathways were enriched, which could be involved in the therapeutic effects and mechanisms of DHJS. Further experimental results indicated that DHJS attenuated TNFα, IL-6, MMP-1, MMP-9, MMP-13, and ADAMTs-5 expression, inhibited NF-κB and p38 MAPK signaling pathway, activated AMPK-SIRT1 signaling pathway, and suppressed chondrocyte apoptosis, which synergistically contributed to OA therapy. Our work demonstrated that DHJS could be very promising for OA therapy through synergistically acting on multitargets and multipathways.

Acanthoic acid modulates lipogenesis in nonalcoholic fatty liver disease via FXR/LXRs-dependent manner

Acanthoic acid (AA) is a pimaradiene diterpene isolated from Acanthopanax koreanum Nakai (Araliaceae), with anti-inflammatory and hepatic-protective effects. The present study intended to reveal the effect and mechanism of AA on nonalcoholic fatty liver disease (NAFLD) associated with lipid accumulation by activating Farnesoid X receptor (FXR) and liver X receptors (LXRs) signaling. C57BL/6 mice were received a modified Lieber-DeCarli diet with 71% high-fat (L-D) and treated with AA (20 and 40 mg/kg) or equal volume of saline for 12 weeks. The regulation of AA on lipid accumulation was also detected in pro-steatotic stimulated AML12 cells with palmitic acid (PA). When L-D diet-fed mice were treated with AA, loss in body weight, liver index, and liver lipid droplet were observed along with reduced triglyceride (TG) and serum transaminase. Furthermore, AA decreased sterol regulatory element binding protein 1 (SREBP-1) and target genes expression, regulated PPARα and PPARγ expressions, ameliorated hepatic fibrosis markers, enhanced hepatic FXR and LXR, and regulated AMPK-LKB1 and SIRT1 signaling pathway. Moreover, AA attenuated lipid accumulation via FXR and LXR activation in steatotic AML-12 cells, which was confirmed by guggulsterones (FXR antagonist) or GW3965 (LXR agonist). Activation of FXR and LXR signaling caused by AA might increase AMPK-SIRT1 signaling and then contribute to modulating lipid accumulation and fatty acid synthesis, which suggested that activated FXR-LXR axis by AA represented an effective strategy for relieving NAFLD.

AMPKα1 overexpression improves postoperative cognitive dysfunction in aged rats through AMPK-Sirt1 and autophagy signaling.

Postoperative cognitive dysfunction (POCD) is a common complication in elderly patients who undergo surgery involving anesthesia. Its underlying mechanisms remain unclear. Autophagy plays an important role in the damage and repair of the nervous system and is associated with the development of POCD. Using a rat model, adenosine monophosphate-activated protein kinase α1 (AMPKα1), an important autophagy regulator, was found to be significantly downregulated in rats with POCD that was induced by sevoflurane anesthesia or by appendectomy. Overexpression of AMPKα1-ameliorated POCD, as indicated by decreased escape latencies and increased target quadrant swimming times, swimming distances, and platform crossing times during Morris water maze tests. AMPKα1 overexpression activated autophagy signals by increasing the expression of light chain 3 II (LC3-II) and Beclin1 and decreasing the expression of p62 in the hippocampus of rats with POCD. Moreover, blocking autophagy by 3-methyladenine partly attenuated AMPKα1-mediated POCD improvement. Furthermore, overexpression of AMPKα1 could upregulate the expression of p-AMPK and Sirt1 in the hippocampus of rats with POCD. Intriguingly, inhibiting AMPK signals via Compound C effectively attenuated AMPKα1-mediated POCD improvement, concomitant with the downregulation of p-AMPK, Sirt1, LC3-II, and Beclin1 and the upregulation of p62. We thus concluded that overexpression of AMPKα1 can improve POCD via the AMPK-Sirt1 and autophagy signaling pathway.

Mechanical stretch induces antioxidant responses and osteogenic differentiation in human mesenchymal stem cells through activation of the AMPK-SIRT1 signaling pathway

Mesenchymal stem cells (MSCs) are promising cell sources for regenerative medicine. Growing evidence has indicated that mechanical stimuli are crucial for their lineage-specific differentiation. However, the effect of mechanical loading on redox balance and the intracellular antioxidant system in MSCs was unknown. In this study, human bone marrow-derived MSCs (BM-MSCs) were subjected to cyclic stretch at the magnitude of 2.5%, 5%, and 10%. Cell proliferation, intracellular reactive oxygen species (ROS), expression of antioxidant enzymes, and osteogenic differentiation were evaluated. RNA was extracted and subjected to DNA microarray analysis. Sirtinol and compound C were used to investigate the underlying mechanisms involved silent information regulator type 1 (SIRT1) and AMP-activated protein kinase (AMPK). Our results showed that mechanical stretch at appropriate magnitudes increased cell proliferation, up-regulated extracellular matrix organization, and down-regulated matrix disassembly. After 3 days of stretch, intracellular ROS in BM-MSCs were decreased but the levels of antioxidant enzymes, especially superoxide dismutase 1 (SOD1), were up-regulated. Osteogenesis was improved by 5% stretch rather than 10% stretch, as evidenced by increased matrix mineralization and osteogenic marker gene expression. The expression of SIRT1 and phosphorylation of AMPK were enhanced by mechanical stretch; however, inhibition of SIRT1 or AMPK abrogated the stretch-induced antioxidant effect on BM-MSCs and inhibited the stretch-mediated osteogenic differentiation. Our findings reveal that mechanical stretch induced antioxidant responses, attenuated intracellular ROS, and improved osteogenesis of BM-MSCs. The stretch-induced antioxidant effect was through activation of the AMPK-SIRT1 signaling pathway. Our findings demonstrated that appropriate mechanical stimulation can improve MSC antioxidant functions and benefit bone regeneration.

Luteolin decreases atherosclerosis in LDL receptor-deficient mice via a mechanism including decreasing AMPK-SIRT1 signaling in macrophages.

Lipid metabolism dysfunction and inflammatory infiltration into arterial walls are associated with the initiation and progression of atherosclerosis. Luteolin has been reported to possess anti-inflammatory actions and protect against tumor necrosis factor-α (TNF-α)-induced vascular inflammation, monocyte adhesion to endothelial cells and the formation of lipid-laden macrophages in vitro. However, the role of luteolin in atherosclerosis and the associated vascular inflammatory remains to be elucidated. The aim of the present study was to investigate the effects of luteolin on plaque development, lipid accumulation and macrophage inflammation low-density lipoprotein receptor-deficient (LDLR-/-) mice with atherosclerosis, as well as the underlying mechanisms in ox-induced THP-1-derived macrophages. Firstly, 9-week-old male C57BL/6 mice were fed a standard chow diet, western diet or western diet supplemented with 100 mg/kg luteolin for 14 weeks. The results of histological staining revealed that 100 mg/kg dietary luteolin ameliorated western diet-induced atherosclerotic plaque development and lipid accumulation in the abdominal aorta. Furthermore, total cholesterol, triglyceride and LDL-cholesterol levels were decreased in the plasma of western diet + luteolin mice compared with those fed with a western diet alone. Quantitative polymerase chain reaction analysis revealed that dietary luteolin inhibited the expression of cluster of differentiation 68, macrophage chemoattractant protein 2 and inflammatory cytokines, including interleukin-6 (IL-6) and TNF-α. Mechanistically, luteolin decreased the total cholesterol level as well as macrophage chemokine and inflammatory cytokine expression in THP-1-derived macrophages via AMP-activated protein kinase (AMPK)-Sirtuin (SIRT)1 signaling following induction with oxidized low-density lipoprotein. The results of the present study suggest that luteolin prevents plaque development and lipid accumulation in the abdominal aorta by decreasing macrophage inflammation during atherosclerosis, which is mediated by mechanisms including AMPK-SIRT1 signaling.

Caloric Restriction Increases the Resistance of Aged Heart to Myocardial Ischemia/Reperfusion Injury

Ischemic tolerance of heart decreases with age. Caloric restriction (CR) is the most reliable intervention to extend lifespan and prevent age-related disorders. We have revealed that both AMPK and SIRT1 signaling pathways are involved in the impairments occurred in aged hearts. We hypothesize that cardiac AMPK-SIRT1 signaling cascade mediates the increased tolerance of aged heart to ischemic insults by caloric restriction. Aged (18-20 months) mice were divided into 2 groups: al libitum (AL) food intake group and caloric restriction (diet 70% of standard food intake for 6 weeks) (CR) group. Each group was divided into sham operations and ischemia/reperfusion (I/R) semi-groups. I/R groups were subjected to ligation of left anterior descending coronary artery for 30 min of ischemia and 24 hours of reperfusion. The body fat composition was significantly decreased in CR group vs. AL group, moreover, the maximum of oxygen consumption was significantly improved in CR group vs. AL group. Importantly, there is a significantly smaller myocardial infarction size induced by ischemia (30 min) and reperfusion (24 hours) in CR group than that in AL group. The immunoblotting results demonstrated that the impaired ischemic AMPK activation in AL group was augmented in CR group, and the AMPK downstream acetyl CoA carboxylase (ACC) phosphorylation and PGC-1alpha phosphorylation were also augmented in CR vs. AL group in response to ischemic insults. Intriguingly, the expression levels of a longevity protein, SIRT1, were upregulated in the heart of CR group vs. the corresponding AL group. Furthermore, the inducible cardiomyocyte SIRT1 deficiency mice (icSIRT1 KO) did not show any recused impaired ischemic AMPK activation in the CR group vs. icSIRT1 KO AL group. Thus, caloric restriction is a non-pharmacological approach to increase the tolerance of aged heart to ischemic insults. The AMPK-SIRT1 signaling cascade plays a critical role in the cardiac CR benefits in the elderly. Disclosure Z. Guo: None. T. Rousselle: None. J. Li: None.

Nobiletin protects against insulin resistance and disorders of lipid metabolism by reprogramming of circadian clock in hepatocytes

ScopeCircadian clock plays a principal role in orchestrating our daily physiology and metabolism, and their perturbation can evoke metabolic diseases such as fatty liver and insulin resistance. Nobiletin (NOB) has been demonstrated to possess antitumor and neuroprotective activities. The objective of the current study is to determine potential effects of NOB on modulating the core clock gene Bmal1 regarding ameliorating glucolipid metabolic disorders. ResultsOur results revealed that NOB partially reverse the relatively shallow daily oscillations of circadian clock genes and reset phase-shifting circadian rhythms in primary hepatocytes under metabolic disorders conditions. Importantly, NOB was found to be effective at amplifying glucose uptake via stimulating IRS-1/AKT signaling pathway, as well as blunting palmitate-induced lipogenesis in HepG2 cells via modulating AMPK-Sirt1 signaling pathway and key enzymes of de novo lipogenesis in a Bmal1-dependent manner. NOB attenuated palmitate-stimulated excessive secretions of ROS, restored the depletions of mitochondrial membrane potential, which is similar to the recovery in expressions of mitochondrial respiration complex I-IV. ConclusionThis study is the first to provide compelling evidences that NOB prevent cellular glucolipid metabolic imbalance and mitochondrial function in a Bmal1-dependent manner. Overall, NOB may serve as a nutritional preventive strategy in recovering metabolic disorders relevant to circadian clock.

Upregulation of SIRT1 by Kartogenin Enhances Antioxidant Functions and Promotes Osteogenesis in Human Mesenchymal Stem Cells.

Osteoarthritis is a chronic degenerative joint disease involving both articular cartilage and subchondral bone. Kartogenin (KGN) was recently identified to improve in vivo cartilage repair; however, its effect on bone formation is unknown. The aim of this study was to investigate the effect of KGN on antioxidant properties and osteogenic differentiation of bone marrow-derived mesenchymal stem cells (BM-MSCs). Human BM-MSCs were treated with KGN at concentrations ranging from 10−8 M to 10−6 M. Our results indicated that KGN improved cell proliferation and attenuated intracellular reactive oxygen species. The levels of antioxidant enzymes and osteogenic differentiation of BM-MSCs were enhanced by KGN in a dose-dependent manner. Furthermore, KGN-treated BM-MSCs showed upregulation of silent information regulator type 1 (SIRT1) and increased phosphorylation of adenosine 5′-monophosphate-activated protein kinase (AMPK), indicating that KGN activated the AMPK-SIRT1 signaling pathway in BM-MSCs. Inhibition of SIRT1 by nicotinamide reversed the antioxidant effect of KGN on BM-MSCs and suppressed osteogenic differentiation. In conclusion, our results demonstrated that KGN improved intracellular antioxidant properties and promoted osteogenic differentiation of BM-MSCs by activating the AMPK-SIRT1 signaling pathway. Thus, KGN may have the potential for not only articular cartilage repair but also the clinical application of MSCs in bone tissue engineering.

PPARα agonist, fenofibrate, ameliorates age-related renal injury

The kidney ages quickly compared with other organs. Expression of senescence markers reflects changes in the energy metabolism in the kidney. Two important issues in aging are mitochondrial dysfunction and oxidative stress. Peroxisome proliferator-activated receptor α (PPARα) is a member of the ligand-activated nuclear receptor superfamily. PPARα plays a major role as a transcription factor that regulates the expression of genes involved in various processes. In this study, 18-month-old male C57BL/6 mice were divided into two groups, the control group (n=7) and the fenofibrate-treated group (n=7) was fed the normal chow plus fenofibrate for 6months. The PPARα agonist, fenofibrate, improved renal function, proteinuria, histological change (glomerulosclerosis and tubular interstitial fibrosis), inflammation, and apoptosis in aging mice. This protective effect against age-related renal injury occurred through the activation of AMPK and SIRT1 signaling. The activation of AMPK and SIRT1 allowed for the concurrent deacetylation and phosphorylation of their target molecules and decreased the kidney's susceptibility to age-related changes. Activation of the AMPK-FOXO3a and AMPK-PGC-1α signaling pathways ameliorated oxidative stress and mitochondrial dysfunction. Our results suggest that activation of PPARα and AMPK-SIRT1 signaling may have protective effects against age-related renal injury. Pharmacological targeting of PPARα and AMPK-SIRT1 signaling molecules may prevent or attenuate age-related pathological changes in the kidney.

Highlights from the Literature

Highlights from the Literature

Metformin, metabolic stress, and mitochondria. Focus on “A novel inverse relationship between metformin-triggered AMPK-SIRT1 signaling and p53 protein abundance in high glucose-exposed HepG2 cells”

the p53 protein, best known as a tumor suppressor, participates in responses to cellular stresses, including DNA damage and hypoxia, but also determines metabolic substrate disposition. In cancer, p53 represses glycolysis while promoting mitochondrial oxidative phosphorylation via effects on gene