Metformin promotes angiogenesis and functional recovery in aged mice after spinal cord injury by adenosine monophosphate-activated protein kinase/endothelial nitric oxide synthase pathway

Treatment with metformin can lead to the recovery of pleiotropic biological activities after spinal cord injury.However,its effect on spinal cord injury in aged mice remains unclear.Considering the essential role of angiogenesis during the regeneration process,we hypothesized that metformin activates the adenosine monophosphate-activated protein kinase/endothelial nitric oxide synthase pathway in endothelial cells,thereby promoting microvascular regeneration in aged mice after spinal cord injury.In this study,we established young and aged mouse models of contusive spinal cord injury using a modified Allen method.We found that aging hindered the recovery of neurological function and the formation of blood vessels in the spinal cord.Treatment with metformin promoted spinal cord microvascular endothelial cell migration and blood vessel formation in vitro.Furthermore,intraperitoneal injection of metformin in an in vivo model promoted endothelial cell proliferation and increased the density of new blood vessels in the spinal cord,thereby improving neurological function.The role of metformin was reversed by compound C,an adenosine monophosphate-activated protein kinase inhibitor,both in vivo and in vitro,suggesting that the adenosine monophosphate-activated protein kinase/endothelial nitric oxide synthase pathway likely regulates metformin-mediated angiogenesis after spinal cord injury.These findings suggest that metformin promotes vascular regeneration in the injured spinal cord by activating the adenosine monophosphate-activated protein kinase/endothelial nitric oxide synthase pathway,thereby improving the neurological function of aged mice after spinal cord injury.

Electroacupuncture preconditioning attenuates ischemic brain injury by activation of the adenosine monophosphate-activated protein kinase signaling pathway

Electroacupuncture has therapeutic effects on ischemic brain injury, but its mechanism is still poorly understood. In this study, mice were stimulated by electroacupuncture at the Baihui（GV20） acupoint for 30 minutes at 1 m A and 2/15 Hz for 5 consecutive days. A cerebral ischemia model was established by ligating the bilateral common carotid artery for 15 minutes. At 72 hours after injury, neuronal injury in the mouse hippocampus had lessened, and the number of terminal deoxynucleotide transferase-mediated d UTP nick-end labeling-positive cells reduced after electroacupuncture treatment. Moreover, expression of adenosine monophosphate-activated protein kinase α（AMPKα） and phosphorylated AMPKα was up-regulated. Intraperitoneal injection of the AMPK antagonist, compound C, suppressed this phenomenon. Our findings suggest that electroacupuncture preconditioning alleviates ischemic brain injury via AMPK activation.

AB015.Metabolic stress in glaucoma engages early activation of the energy biosensor adenosine monophosphate-activated protein kinase leading to neuronal dysfunction

Background:Metabolic stress has been proposed to contribute to neuronal damage in glaucoma,but the mechanism driving this response is not understood.The adenosine monophosphate-activated protein kinase(AMPK)is a master regulator of energy homeostasis that becomes active at the onset of energy stress.AMPK is a potent inhibitor of the mammalian target of rapamycin complex 1(mTORC1),which we showed is essential for the maintenance of retinal ganglion cell(RGC)dendrites,synapses,and survival.Here,we tested the hypothesis that AMPK is an early mediator of metabolic stress in glaucoma.Methods:Unilateral elevation of intraocular pressure was induced by injection of magnetic microbeads into the anterior chamber of mice expressing yellow fluorescent protein in RGCs.Inhibition of AMPK was achieved by administration of siRNA or compound C.RGC dendritic trees were 3D-reconstructed and analyzed with Imaris(Bitplane),and survival was assessed by counting Brn3a or RBPMS-labeled soma and axons in the optic nerve.RGC function was examined by quantification of anterograde axonal transport after intraocular administration of cholera toxinβ-subunit.Retinas from glaucoma patients were analyzed for expression of active AMPK.Results:Ocular hypertension triggered rapid upregulation of AMPK activity in RGCs concomitant with loss of mTORC1 function.AMPK inhibition with compound C or siRNA effectively restored mTORC1 activity and promoted an increase in total dendritic length,surface and complexity relative to control retinas.Attenuation of AMPK activity led to robust RGC soma and axon survival.For example,95%of RGCs(2,983±258 RGCs/mm2,mean±S.E.M.)survived with compound C compared to 77%in vehicle-treated eyes(2,430±233 RGCs/mm2)(ANOVA,P<0.001)at three weeks after glaucoma induction(n=8-10/group).Importantly,blockade of AMPK activity effectively restored anterograde axonal transport.Lastly,RGC-specific upregulation of AMPK activity was detected in human glaucomatous retinas relative to age-matched controls(n=10/group).Conclusions:Metabolic stress in glaucoma involves AMPK activation and mTORC1 inhibition promoting early RGC dendritic pathology,dysfunction and neurodegeneration.

Metformin attenuates motility,contraction,and fibrogenic response of hepatic stellate cells in vivo and in vitro by activating AMP-activated protein kinase

AIM To investigate the effect of metformin on activated hepatic stellate cells(HSCs) and the possible signaling pathways involved. METHODS A fibrotic mouse model was generated by intraperitoneal injection of carbon tetrachloride(CCl_4) and subsequent treatment with or without metformin. The level of fibrosis was detected by hematoxylin-eosin staining, Sirius Red staining, and immunohistochemistry. The HSC cell line LX-2 was used for in vitro studies. The effect of metformin on cell proliferation(CCK8 assay),motility(scratch test and Transwell assay), contraction(collagen gel contraction assay), extracellular matrix(ECM) secretion(Western blot), and angiogenesis(ELISA and tube formation assay) was investigated. We also analyzed the possible signaling pathways involved by Western blot analysis.RESULTS Mice developed marked liver fibrosis after intraperitoneal injection with CCl_4 for 6 wk. Metformin decreased the activation of HSCs, reduced the deposition of ECM, and inhibited angiogenesis in CCl_4-treated mice. Platelet-derived growth factor(PDGF) promoted the fibrogenic response of HSCs in vitro, while metformin inhibited the activation, proliferation, migration, and contraction of HSCs, and reduced the secretion of ECM. Metformin decreased the expression of vascular endothelial growth factor(VEGF) in HSCs through inhibition of hypoxia inducible factor(HIF)-1α in both PDGF-BB treatment and hypoxic conditions, and it down-regulated VEGF secretion by HSCs and inhibited HSC-based angiogenesis in hypoxic conditions in vitro. The inhibitory effects of metformin on activated HSCs were mediated by inhibiting the Akt/mammalian target of rapamycin(m TOR) and extracellular signal-regulated kinase(ERK) pathways via the activation of adenosine monophosphate-activated protein kinase(AMPK).CONCLUSION Metformin attenuates the fibrogenic response of HSCs in vivo and in vitro, and may therefore be useful for the treatment of chronic liver diseases.

Beneficial effects of metformin on primary cardiomyocytes via activation of adenosine monophosphate-activated protein kinase

Background Metformin has become a cornerstone in the treatment of patients with type-2 diabetes. Accumulated evidence suggests that metformin supports direct cardiovascular effects. The present study aimed to investigate if metformin has beneficial effects on primary cardiomyocytes damaged by H2O2, and reveal the potential mechanism of action of metformin. Methods Cardiomyocytes were incubated in the presence of 100μmol/L H2O2 for 12 hours. Cardiomyocytes were pretreated with metformin at different concentrations and time and with aminoimidazole carboxamide ribonucleotide （AICAR） （500μmol/L）, an adenosine monophophate （AMP）-activated protein kinase （AMPK） agonist for 60 minutes before the addition of H2O2. Other cells were preincubated with compound C （an AMPK antagonist, 20μmol/L） for 4 hours. The viability and apoptosis of cells were analyzed. AMPK, endothelial nitric oxide synthase （eNOS）, and transforming growth factor （TGF）-β1 were analyzed using immunblotting. Results Metformin had antagonistic effects on the influences of H2O2 on cell viability and attenuated oxidative stress-induced apoptosis. Metformin also increased phosphorylation of AMPK and eNOS, and reduced the expression of TGF-β1, basic fibroblast growth factor （bFGF）, and tumor necrosis factor （TNF）-α. Conclusions Metformin has beneficial effects on cardiomyocytes, and this effect involves activation of the AMPK-eNOS pathway. Metformin may be potentially beneficial for the treatment of heart disease.

Metformin inhibits nuclear factor-κB activation and inflammatory cytokines expression induced by high glucose via adenosine monophosphate-activated protein kinase activation in rat glomerular mesangial cells in vitro

Background The renoprotective mechanisms of adenosine monophosphate （AMP）-activated protein kinase （AMPK） agonist-metformin have not been stated clearly.We hypothesized that metformin may ameliorate inflammation via AMPK interaction with critical inflammatory cytokines The aim of this study was to observe the effects of metformin on expression of nuclear factor-κB （NF-κB）,monocyte chemoattractant protein-1 （MCP-1）,intercellular adhesion molecule-1 （ICAM-1） and transforming growth factor-beta 1 （TGF-β1） induced by high glucose （HG） in cultured rat glomerular mesangial cells （MCs）.Methods MCs were cultured in the medium with normal concentration glucose （group NG,5.6 mmol/L）,high concentration glucose （group HG,25 mmol/L） and different concentrations of metformin （group M1,M2,M3）.After 48-hour exposure,the supernatants and MCs were collected.The expression of NF-κB,MCP-1,ICAM-1,and TGF-β1 mRNA was analyzed by real time polymerase chain reaction.Westem blotting was used to detect the expression of AMPK,phospho-Thr-172 AMPK （p-AMPK）,NF-κB p65,MCP-1,ICAM-1,and TGF-β1 protein.Results After stimulated by HG,the expression of NF-κB,MCP-1,ICAM-1,TGF-β1 mRNA and protein of MCs in group HG increased significantly compared with group NG （P ＜0.05）.Both genes and protein expression of NF-κB,MCP-1,ICAM-1,TGF-β1 of MCs induced by high glucose were markedly reduced after metformin treatment in a dose-dependent manner （P ＜0.05）.The expression of p-AMPK increased with the rising of metformin concentration,presenting the opposite trend,while the level of total-AMPK protein was unchanged with exposure to HG or metformin.Conlusion Metformin can suppress the expression of NF-κB,MCP-1,ICAM-1 and TGF-β1 of glomerular MCs induced by high glucose via AMPK activation,which may partlv contribute to its reno-protection.

Adenosine Monophosphate-Activated Protein Kinase,Oxidative Stress,and Diabetic Endothelial Dysfunction

Endothelial dysfunction characterized by impaired endothelium-dependent vaso-relaxation is one of the earliest detectable pathological events in smoking,diabetes,and many cardiovascular diseases including hypertension,atherosclerosis.Overwhelming data from human and animals demonstrate that the endothelial dysfunction associated with diabetes is due to the local formation of oxidants and free radicals.However,the mechanisms by which diabetes instigates oxidative stress,and those by which oxidative stress perpetuates endothelial dysfunction are the subjects of intensive research in the last 3 decades.The studies from us and others have demonstrated that adenosine monophosphate-activated protein kinase(AMPK),a well-characterized energy sensor and modulator,serves as a highly efficient sensor as AMPK can be activated by very low levels of reactive oxygen species(ROS)and reactive nitrogen species(RNS)generated by physiological,pharmacological,and pathologic stimuli(redox sensor).Interestingly,oxidants-activated AMPK feedback lowers the levels of ROS by either suppressing ROS/RNS from reduced nicotinamide adenine dinucleotide phosphate(NADPH)oxidase and mitochondria or by increasing the levels of antioxidant enzymes(redox modulator).Further,our studies demonstrate that AMPK’s functions as a redox sensor and modulator are vital to maintain endothelial cell function under physiological conditions.Finally,we discover that under chronic oxidative stress or large influx of ROS,AMPK is particularly susceptible to inhibition by ROS.We conclude that oxidative inactivation of AMPK in diabetes perpetuates oxidative stress and accelerates atherosclerosis in diabetes.

Targeted metabolomics reveals the aberrant energy status in diabetic peripheral neuropathy and the neuroprotective mechanism of traditional Chinese medicine JinMaiTong

Diabetic peripheral neuropathy (DPN) is a common and devastating complication of diabetes, for which effective therapies are currently lacking. Disturbed energy status plays a crucial role in DPN pathogenesis. However, the integrated profile of energy metabolism, especially the central carbohydrate metabolism, remains unclear in DPN. Here, we developed a metabolomics approach by targeting 56 metabolites using high-performance ion chromatography-tandem mass spectrometry (HPIC-MS/MS) to illustrate the integrative characteristics of central carbohydrate metabolism in patients with DPN and streptozotocin-induced DPN rats. Furthermore, JinMaiTong (JMT), a traditional Chinese medicine (TCM) formula, was found to be effective for DPN, improving the peripheral neurological function and alleviating the neuropathology of DPN rats even after demyelination and axonal degeneration. JMT ameliorated DPN by regulating the aberrant energy balance and mitochondrial functions, including excessive glycolysis restoration, tricarboxylic acid cycle improvement, and increased adenosine triphosphate (ATP) generation. Bioenergetic profile was aberrant in cultured rat Schwann cells under high-glucose conditions, which was remarkably corrected by JMT treatment. In-vivo and in-vitro studies revealed that these effects of JMT were mainly attributed to the activation of adenosine monophosphate (AMP)-activated protein kinase (AMPK) and downstream peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α). Our results expand the therapeutic framework for DPN and suggest the integrative modulation of energy metabolism using TCMs, such as JMT, as an effective strategy for its treatment.

The potential of herbal drugs to treat heart failure:The roles of Sirt1/AMPK

Heart failure(HF)is a highly morbid syndrome that seriously affects the physical and mental health of patients and generates an enormous socio-economic burden.In addition to cardiac myocyte oxidative stress and apoptosis,which are considered mechanisms for the development of HF,alterations in cardiac energy metabolism and pathological autophagy also contribute to cardiac abnormalities and ultimately HF.Silent information regulator 1(Sirt1)and adenosine monophosphate-activated protein kinase(AMPK)are nicotinamide adenine dinucleotide(NAD+)-dependent deacetylases and phosphorylated kinases,respectively.They play similar roles in regulating some pathological processes of the heart through regulating targets such as peroxisome proliferator-activated receptorγcoactivator 1α(PGC-1α),protein 38 mitogen-activated protein kinase(p38 MAPK),peroxisome proliferator-activated receptors(PPARs),and mammalian target of rapamycin(mTOR).We summarized the synergistic effects of Sirt1 and AMPK in the heart,and listed the traditional Chinese medicine(TCM)that exhibit cardioprotective properties by modulating the Sirt1/AMPK pathway,to provide a basis for the development of Sirt1/AMPK activators or inhibitors for the treatment of HF and other cardiovascular diseases(CVDs).

Fusobacterium nucleatum-induced imbalance in microbiome-derived butyric acid levels promotes the occurrence and development of colorectal cancer

BACKGROUND Colorectal cancer(CRC)ranks among the most prevalent malignant tumors globally.Recent reports suggest that Fusobacterium nucleatum(F.nucleatum)contributes to the initiation,progression,and prognosis of CRC.Butyrate,a short-chain fatty acid derived from the bacterial fermentation of soluble dietary fiber,is known to inhibit various cancers.This study is designed to explore whether F.nucleatum influences the onset and progression of CRC by impacting the intestinal metabolite butyric acid.AIM To investigate the mechanism by which F.nucleatum affects CRC occurrence and development.METHODS Alterations in the gut microbiota of BALB/c mice were observed following the oral administration of F.nucleatum.Additionally,DLD-1 and HCT116 cell lines were exposed to sodium butyrate(NaB)and F.nucleatum in vitro to examine the effects on proliferative proteins and mitochondrial function.RESULTS Our research indicates that the prevalence of F.nucleatum in fecal samples from CRC patients is significantly greater than in healthy counterparts,while the prevalence of butyrate-producing bacteria is notably lower.In mice colonized with F.nucleatum,the population of butyrate-producing bacteria decreased,resulting in altered levels of butyric acid,a key intestinal metabolite of butyrate.Exposure to NaB can impair mitochondrial morphology and diminish mitochondrial membrane potential in DLD-1 and HCT116 CRC cells.Consequently,this leads to modulated production of adenosine triphosphate and reactive oxygen species,thereby inhibiting cancer cell prolif-eration.Additionally,NaB triggers the adenosine monophosphate-activated protein kinase(AMPK)signaling pathway,blocks the cell cycle in HCT116 and DLD-1 cells,and curtails the proliferation of CRC cells.The combined presence of F.nucleatum and NaB attenuated the effects of the latter.By employing small interfering RNA to suppress AMPK,it was demonstrated that AMPK is essential for NaB’s inhibition of CRC cell proliferation.CONCLUSION F.nucleatum can promote cancer progression through its inhibitory effect on butyric acid,via the AMPK signaling pathway.

Effects of Ginsenoside Rb1 on Skeletal Muscle Insulin Resistance and Adenosine Monophosphate?activated Protein Kinase Signaling Pathway in Obese Mice

Objectives: The objective of the study is to observe the effects of ginsenoside Rb1 on indexes of body weight, body composition, blood lipid, skeletal muscle endurance, and insulin sensitivity in obese mice, probe into its pharmacological action, and further explore its effects on adenosine monophosphate-activated protein kinase(AMPK) signaling pathway in skeletal muscle. Materials and Methods: Eight-week-old C57 BL/6 J mice were fed with high-fat diet for 12 weeks to establish obese mouse model. The model-establishment obese mice were randomly divided into three groups including model control group, metformin group, and ginsenoside Rb1 group. In the normal control group, normal diet was administered. The intervention period was 8 weeks. Body weight and food intake of the mice were measured regularly every week. The treadmill test was performed at weeks 3 and 7, and the oral glucose tolerance test was carried out at weeks 4 and 8. Body composition of the mice was detected by applying NMR Animal Body Composition Analyzer at week 8. Four parameters of blood lipids and free fatty acid(FFA)levels were detected. The m RNA expression of AMPKα and proliferator-activated receptor gamma coactivator-1α(PGC-1α) in skeletal muscle was examined by real-time fluorescence quantitative polymerase chain reaction, and the influence of ginsenoside Rb1 on protein expression of AMPKα, p-AMPKα, and PGC-1α was observed by western blotting. Results: The body weight(since the 5 th week of drug administration)and food intake of the mice in the ginsenoside Rb1 group were significantly lower than those in the model control group(P < 0.05) in a time-dependent manner. Ginsenoside Rb1 could significantly reduce the levels of triglyceride and low-density lipoprotein cholesterol, while increase the high-density lipoprotein cholesterol level(P < 0.05). In addition, ginsenoside Rb1 could reduce the serum FFA level(P < 0.05).After the administration of ginsenoside Rb1 for 8 weeks, the body fat mass of obese mice decreased and the lean mass increased(P < 0.05).The skeletal muscle endurance and the oral glucose tolerance of the obese mice improved using ginsenoside Rb1. At the molecular level,ginsenoside Rb1 could up-regulate the mRNA and protein expression of AMPKα in skeletal muscle, and increase the content of p-AMPK protein significantly(P < 0.01). At the same time, the mRNA and protein level of PGC-1α was also un-regulated, correspondingly(P < 0.01).Conclusion: Ginsenoside Rb1 exerts effects on reducing body weight, decreasing blood lipid levels, enhancing the skeletal muscle endurance,and increasing the insulin sensitivity in obese mice by activating the related proteins in AMPK signaling pathway in skeletal muscle.

Sevoflurane pretreatment inhibits the myocardial apoptosis caused by hypoxia reoxygenation through AMPK pathway:An experimental study

Objective:To study whether sevoflurane pretreatment inhibits the myocardial apoptosis caused by hypoxia reoxygenation through AMPK pathway.Methods:H9c2 myocardial cell lines were cultured and divided into control group(C group),hypoxia reoxygenation group(H/R group),sevoflurane pretreatment+hypoxia reoxygenation group(SP group) and sevoflurane combined with Compound C pretreatment+hypoxia reoxygenation group(ComC group),and the cell proliferation activity and apoptosis rate,myocardial enzyme levels in culture medium as well as the expression of apoptosis genes and p-AMPK in cells were determined.Results:p-AMPK expression in cells of H/R group was significantly lower than that of C group,SP group was significantly higher than that of H/R group;cell proliferation activity value and Bcl-2 expression in cells of H/R group were significantly lower than those of C group,SP group were significantly higher than those of H/R group,Com C group were significantly lower than those of SP group;apoptosis rate,LDH,CK and AST levels as well as the Bax and Caspase-3 expression in cells of H/R group were significantly higher than those of C group,SP group were significantly lower than those of H/R group,ComC group were significantly higher than those of SP group.Conclusions:Sevoflurane pretreatment can activate AMPK signaling pathway to inhibit the myocardial apoptosis caused by hypoxia reoxygenation.

AMPK-associated signaling to bridge the gap between fuel metabolism and hepatocyte viability

The adenosine monophosphate-activated protein kinase (AMPK) and p70 ribosomal S6 kinase-1 pathway may serve as a key signaling flow that regulates energy metabolism; thus, this pathway becomes an attractive target for the treatment of liver diseases that result from metabolic derangements. In addition, AMPK emerges as a kinase that controls the redox-state and mitochondrial function, whose activity may be modulated by antioxidants. A close link exists between fuel metabolism and mitochondrial biogenesis. The relationship between fuel metabolism and cell survival strongly implies the existence of a shared signaling network, by which hepatocytes respond to challenges of external stimuli. The AMPK pathway may belong to this network. A series of drugs and therapeutic candidates enable hepatocytes to protect mitochondria from radical stress and increase cell viability, which may be associated with the activation of AMPK, liver kinase B1, and other molecules or components. Consequently, the components downstream of AMPK may contribute to stabilizing mitochondrial membrane potential for hepatocyte survival. In this review, we discuss the role of the AMPK pathway in hepatic energy metabolism and hepatocyte viability. This information may help identify ways to prevent and/or treat hepatic diseases caused by the metabolic syndrome. Moreover, clinical drugs and experimental therapeutic candidates that directly or indirectly modulate the AMPK pathway in distinct manners are discussed here with particular emphasis on their effects on fuel metabolism and mitochondrial function.

Polyethylene glycol rinse solution:An effective way to prevent ischemia-reperfusion injury

AIM: To test whether a new rinse solution containing polyethylene glycol 35 (PEG-35) could prevent ischemia-reperfusion injury (IRI) in liver grafts.

Gypenoside ameliorates insulin resistance and hyperglycemia via the AMPK-mediated signaling pathways in the liver of type 2 diabetes mellitus mice

Gynostemma pentaphyllum,also called"Southern Ginseng"in China,is a traditional Asian folk medicinal plant.Gypenosides(Gps)are the biologically active constituents of G.pentaphyllum,which have been reported with hypoglycemic activity.However,the underlying mechanisms are unclear.The effects of two Gps(Gp-Ⅰand Gp-Ⅱ)on type 2 diabetic mellitus(T2DM)mice,induced by high-fat and high-sugar diet and streptozotocin,were evaluated to explore the mechanism of their hypoglycemic actions.Gps reduced fasting blood glucose and serum lipids,as well as significantly improved T2DM mice glucose tolerance and insulin resistance(IR).After Gps treatment,the severity of liver injury was reduced and liver glycogen content increased.In addition,Gps promoted the phosphorylation of adenosine monophosphate-activated protein kinase(AMPK),and downregulated the key proteins phosphoenolpyruvate carboxy kinase and glucose-6 phosphatase,in the AMPK signaling pathway.Thus,our study suggests that Gps mediate hepatic gluconeogenesis and improve IR via activating AMPK signaling pathway in T2DM mice.

AMPK Subunit Expression Regulates Intramuscular Fat Content and Muscle Fiber Type in Chickens

The objective of this study was to assess the role of AMPK in intramuscular fat(IMF) and fiber type in chicken muscle. The chickens were slaughtered and their muscles were collected at the ages of 4, 8, and 16 weeks so as to determine the IMF contents, as well as the expression levels of AMPK subunits, regulators of adipogenesis. In addition, the myosin heavy chains(My HCs) in thigh muscle tissues were also measured. The results showed that the IMF contents in 16-week old chickens were higher than those in 4 and 8-week-old chickens(P<0.05).The expression levels of fatty acid synthase(FAS) and fatty aicd translocase CD36(FAT/CD36) m RNA were increased significantly in samples collected at the ages of4 and 16 weeks(P<0.05). The expression levels of My HC IIa and IIb differed significantly among all the developmental stages(P <0.05). The AMPKα2, AMPKγ1,and AMPKγ3 m RNA levels were dramatically decreased with the increase of age(P <0.05). To examine the role of AMPK in adipogenesis regulation, the SV cells were cultured in an adipogenesis medium and treated with AICAR and Compound C respectively, the specific activator and inhibit of AMPK. The Compound C induced dramatically a greater expression of C/EBPβ, SREBP1 and PPARγ(P <0.05). In conclusion, the expression of AMPKα2, AMPKγ1, and AMPKγ3 m RNA is significantly correlated with the adipogenesis in skeletal muscle of chickens.

Too hard to die:Exercise training mediates specific and immediate SARS-CoV-2 protection

Several mechanisms may explain how exercise training mechanistically confers protection against coronavirus disease 2019(COVID-19).Here we propose two new perspectives through which cardiorespiratory fitness may protect against severe acute respiratory syndrome coronavirus-2(SARS-CoV-2).Physical exercise-activated adenosine monophosphate(AMP)-activated protein kinase(AMPK)signaling induces endothelial nitric oxide(NO)synthase(eNOS),increases NO bio-availability,and inhibits palmitoylation,leading to specific and immediate SARS-CoV-2 protection.AMPK signaling also induces angiotensin 1-7 release and enhances eNOS activation thus further mediating cardio-and renoprotection.Irisin,a myokine released from skeletal muscles during aerobic exercise,also participates in the AMPK/Akt-eNOS/NO pathway,protects mitochondrial functions in endothelial cells,and antagonizes renin angiotensin system proinflammatory action leading to reductions in genes associated with severe COVID-19 outcomes.Collectively,all the above findings point to the fact that increased AMPK and irisin activity through exercise training greatly benefits molecular processes that mediate specific,immediate,and delayed SARS-CoV-2 protection.Maintaining regular physical activity levels is a safe and affordable lifestyle strategy against the current and future pandemics and may also mitigate against obesity and cardiometabolic disease syndemics.Move more because a moving target is harder to kill.

Electroacupuncture activates AMPKα1 to improve learning and memory in the APP/PS1 mouse model of early Alzheimer’s disease by regulating hippocampal mitochondrial dynamics

Objective Studies have shown that electroacupuncture(EA)can alleviate cognitive impairments from Alzheimer’s disease(AD)by regulating the expression of adenosine monophosphate-activated protein kinase(AMPK),but the specific mechanism involved remains to be elucidated.Therefore,this study explores the potential mechanism by which EA improves cognitive function from the perspective of mitochondrial dynamics.Methods The four-month-old transgenic mice with amyloid precursor protein(APP)/presenilin 1(PS1)and AMPKα1-subunit conditional knockout(AMPKα1-cKO)were used for experiments.To evaluate the effects of EA treatment on cognitive function,the T-maze and Morris water maze were used.In addition,chemical exchange saturation transfer,thioflavin staining,transmission electron microscopy,mitochondrial membrane potential,and Western blotting were used to examine the potential mechanisms underlying the effects of EA on APP/PS1 mice.Results Both APP/PS1 mice and AMPKα1-cKO mice exhibited dysfunction in mitochondrial dynamics accompanied by learning and memory impairment.Inactivation of the AMPK/peroxisome proliferator-activated receptor-γcoactivator-1α(PGC-1α)pathway increased pathological amyloid-β(Aβ)deposition and aggravated the dysfunction in mitochondrial dynamics.In addition,EA rescued learning and memory deficits in APP/PS1 mice by activating the AMPK/PGC-1αpathway,specifically by reducing pathological Aβdeposition,normalizing energy metabolism,protecting the structure and function of mitochondria,increasing the levels of mitochondrial fusion proteins,and downregulating the expression of fission proteins.However,the therapeutic effect of EA on cognition in APP/PS1 mice was hindered by AMPKα1 knockout.Conclusion The regulation of hippocampal mitochondrial dynamics and reduction in Aβdeposition via the AMPK/PGC-1αpathway are critical for the ability of EA to ameliorate cognitive impairment in APP/PS1 mice.

Mechanisms of insulin resistance in obesity

Obesity increases the risk for type 2 diabetes through induction of insulin resistance.Treatment of type 2 diabetes has been limited by little translational knowledge of insulin resistance although there have been several well-documented hypotheses for insulin resistance.In those hypotheses,inflammation,mitochondrial dysfunction,hyperinsulinemia and lipotoxicity have been the major concepts and have received a lot of attention.Oxidative stress,endoplasmic reticulum(ER)stress,genetic background,aging,fatty liver,hypoxia and lipodystrophy are active subjects in the study of these concepts.However,none of those concepts or views has led to an effective therapy for type 2 diabetes.The reason is that there has been no consensus for a unifying mechanism of insulin resistance.In this review article,literature is critically analyzed and reinterpreted for a new energy-based concept of insulin resistance,in which insulin resistance is a result of energy surplus in cells.The energy surplus signal is mediated by ATP and sensed by adenosine monophosphate-activated protein kinase(AMPK)signaling pathway.Decreasing ATP level by suppression of production or stimulation of utilization is a promising approach in the treatment of insulin resistance.In support,many of existing insulin sensitizing medicines inhibit ATP production in mitochondria.The effective therapies such as weight loss,exercise,and caloric restriction all reduce ATP in insulin sensitive cells.This new concept provides a unifying cellular and molecular mechanism of insulin resistance in obesity,which may apply to insulin resistance in aging and lipodystrophy.

Role of AMPK in atherosclerosis via autophagy regulation

Atherosclerosis is characterized by the accumulation of lipids and deposition of fibrous elements in the vascular wall, which is the primary cause of cardiovascular diseases. Adenosine monophosphate-activated protein kinase(AMPK) is a metabolic sensor of energy metabolism that regulates multiple physiological processes, including lipid and glucose metabolism and the normalization of energy imbalances. Overwhelming evidence indicates that AMPK activation markedly attenuates atherosclerosis development. Autophagy inhibits cell apoptosis and inflammation and promotes cholesterol efflux and efferocytosis. Physiological autophagy is essential for maintaining normal cardiovascular function. Increasing evidence demonstrates that autophagy occurs in developing atherosclerotic plaques. Emerging evidence indicates that AMPK regulates autophagy via a downstream signaling pathway. The complex relationship between AMPK and autophagy has attracted the attention of many researchers because of this close relationship to atherosclerosis development. This review demonstrates the role of AMPK and autophagy in atherosclerosis. An improved understanding of this interrelationship will create novel preventive and therapeutic strategies for atherosclerosis.