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Metformin revisited: Does this regulator of AMP-activated protein kinase secondarily affect bone metabolism and prevent diabetic osteopathy? 被引量:9
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作者 Antonio Desmond McCarthy Ana María Cortizo Claudia Sedlinsky 《World Journal of Diabetes》 SCIE CAS 2016年第6期122-133,共12页
Patients with long-term type 1 and type 2 diabetes mellitus(DM) can develop skeletal complications or "diabetic osteopathy". These include osteopenia, osteoporosis and an increased incidence of low-stress fr... Patients with long-term type 1 and type 2 diabetes mellitus(DM) can develop skeletal complications or "diabetic osteopathy". These include osteopenia, osteoporosis and an increased incidence of low-stress fractures. In this context, it is important to evaluate whether current anti-diabetic treatments can secondarily affect bone metabolism. Adenosine monophosphateactivated protein kinase(AMPK) modulates multiple metabolic pathways and acts as a sensor of the cellular energy status; recent evidence suggests a critical role for AMPK in bone homeostasis. In addition, AMPK activation is believed to mediate most clinical effects of the insulin-sensitizer metformin. Over the past decade, several research groups have investigated the effects of metformin on bone, providing a considerable body of pre-clinical(in vitro, ex vivo and in vivo) as well as clinical evidence for an anabolic action of metformin on bone. However, two caveats should be kept in mind when considering metformin treatment for a patient with type 2 DM at risk for diabetic osteopathy. In the first place, metformin should probably not be considered an antiosteoporotic drug; it is an insulin sensitizer with proven macrovascular benefits that can secondarily improve bone metabolism in the context of DM. Secondly, we are still awaiting the results of randomized placebo-controlled studies in humans that evaluate the effects of metformin on bone metabolism as a primary endpoint. 展开更多
关键词 Diabetes MELLITUS Osteoporosis Bone FRACTURES METFORMIN amp-activated KINASE
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T_3-induced liver AMP-activated protein kinase signaling:Redox dependency and upregulation of downstream targets 被引量:3
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作者 Luis A Videla Virginia Fernández +6 位作者 Pamela Cornejo Romina Vargas Paula Morales Juan Ceballo Alvaro Fischer Nicolás Escudero Oscar Escobar 《World Journal of Gastroenterology》 SCIE CAS 2014年第46期17416-17425,共10页
AIM: To investigate the redox dependency and promotion of downstream targets in thyroid hormone (T<sub>3</sub>)-induced AMP-activated protein kinase (AMPK) signaling as cellular energy sensor to limit meta... AIM: To investigate the redox dependency and promotion of downstream targets in thyroid hormone (T<sub>3</sub>)-induced AMP-activated protein kinase (AMPK) signaling as cellular energy sensor to limit metabolic stresses in the liver. 展开更多
关键词 LIVER Thyroid hormone N-ACETYLCYSTEINE amp-activated protein kinase Fatty acid oxidation
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Regulation of AMP-activated protein kinase by natural and synthetic activators 被引量:13
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作者 David Grahame Hardie 《Acta Pharmaceutica Sinica B》 SCIE CAS CSCD 2016年第1期1-19,共19页
The AMP-activated protein kinase(AMPK)is a sensor of cellular energy status that is almost universally expressed in eukaryotic cells.While it appears to have evolved in single-celled eukaryotes to regulate energy bala... The AMP-activated protein kinase(AMPK)is a sensor of cellular energy status that is almost universally expressed in eukaryotic cells.While it appears to have evolved in single-celled eukaryotes to regulate energy balance in a cell-autonomous manner,during the evolution of multicellular animals its role has become adapted so that it also regulates energy balance at the whole body level,by responding to hormones that act primarily on the hypothalamus.AMPK monitors energy balance at the cellular level by sensing the ratios of AMP/ATP and ADP/ATP,and recent structural analyses of the AMPK heterotrimer that have provided insight into the complex mechanisms for these effects will be discussed.Given the central importance of energy balance in diseases that are major causes of morbidity or death in humans,such as type 2 diabetes,cancer and inflammatory disorders,there has been a major drive to develop pharmacological activators of AMPK.Many such activators have been described,and the various mechanisms by which these activate AMPK will be discussed.A particularly large class of AMPK activators are natural products of plants derived from traditional herbal medicines.While the mechanism by which most of these activate AMPK has not yet been addressed,I will argue that many of them may be defensive compounds produced by plants to deter infection by pathogens or grazing by insects or herbivores,and that many of them will turn out to be inhibitors of mitochondrial function. 展开更多
关键词 amp-activated protein KINASE Energy balance AMP AMPK ACTIVATOR MITOCHONDRIAL function REGULATORY mechanism
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Cordycepin promotes browning of white adipose tissue through an AMP-activated protein kinase(AMPK)-dependent pathway 被引量:11
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作者 Guihong Qi Yue Zhou +5 位作者 Xiaopo Zhang Jiaqi Yu Xin Li Xiaoxue Cao Chongming Wu Peng Guo 《Acta Pharmaceutica Sinica B》 SCIE CSCD 2019年第1期135-143,共9页
Obesity is a worldwide epidemic. Promoting browning of white adipose tissue(WAT)contributes to increased energy expenditure and hence counteracts obesity. Here we show that cordycepin(Cpn), a natural derivative of ade... Obesity is a worldwide epidemic. Promoting browning of white adipose tissue(WAT)contributes to increased energy expenditure and hence counteracts obesity. Here we show that cordycepin(Cpn), a natural derivative of adenosine, increases energy expenditure, inhibits weight gain, improves metabolic profile and glucose tolerance, decreases WAT mass and adipocyte size, and enhances cold tolerance in normal and high-fat diet-fed mice. Cpn markedly increases the surface temperature around the inguinal WAT and turns the inguinal fat browner. Further investigations show that Cpn induces the development of brown-like adipocytes in inguinal and, to a less degree, epididymal WAT depots. Cpn also increases the expression of uncoupling protein 1(UCP1) and other thermogenic genes in WAT and3T3-L1 differentiated adipocytes, in which AMP-activated protein kinase(AMPK) plays an important role. Our results provide novel insights into the function of Cpn in regulating energy balance, and suggest a potential utility of Cpn in the treatment of obesity. 展开更多
关键词 CORDYCEPIN BROWNING of white adi POSE tissue(WAT) THERMOGENESIS amp-activated protein kinase(AMPK) Obesity
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AMP-activated kinase in human spermatozoa: identification, intracellular localization, and key function in the reRulation of sperm motility 被引量:7
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作者 Violeta Calle-Guisado Ana Hurtado de Llera +5 位作者 David Martin-Hidalgo Jose Mijares Maria C Gil Ignacio S Alvarez Maria J Bragado Luis J Garcia-Marin 《Asian Journal of Andrology》 SCIE CAS CSCD 2017年第6期707-714,共8页
AMP-activated kinase (AMPK), a protein that regulates energy balance and metabolism, has recently been identified in boar spermatozoa where regulates key functional sperm processes essential for fertilization. This ... AMP-activated kinase (AMPK), a protein that regulates energy balance and metabolism, has recently been identified in boar spermatozoa where regulates key functional sperm processes essential for fertilization. This work's aims are AMPK identification, intracellular localization, and their role in human spermatozoa function. Semen was obtained from healthy human donors. Sperm AMPK and phospho-Thr172-AMPK were analyzed by Western blotting and indirect immunofluorescence. High- and low-quality sperm populations were separated by a 40%-80% density gradient. Human spermatozoa motility was evaluated by an Integrated Semen Analysis System (ISAS) in the presence or absence of the AMPK inhibitor compound C (CC). AMPK is localized along the human spermatozoa, at the entire acrosome, midpiece and tail with variable intensity, whereas its active form, phospho-Thr172-AMPK, shows a prominent staining at the acrosome and sperm tail with a weaker staining in the midpiece and the postacrosomal region. Interestingly, spermatozoa bearing an excess residual cytoplasm show strong AMPK staining in this subcellular compartment. Both AMPK and phospho-Thr172-AMPK human spermatozoa contents exhibit important individual variations. Moreover, active AMPK is predominant in the high motility sperm population, where shows a stronger intensity compared with the low motility sperm population. Inhibition of AMPK activity in human spermatozoa by CC treatment leads to a significant reduction in any sperm motility parameter analyzed: percent of motile sperm, sperm velocities, progressivity, and other motility coefficients. This work identifies and points out AMPK as a new molecular mechanism involved in human spermatozoa motility. Further AMPK implications in the clinical efficiency of assisted reproduction and in other reproductive areas need to be studied. 展开更多
关键词 amp-activated kinase human spermatozoa IMMUNOLOCALIZATION sperm motility sperm quality
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A potential strategy for treating atherosclerosis: improving endothelial function via AMP-activated protein kinase 被引量:9
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作者 Feng Gao Jiemei Chen Haibo Zhu 《Science China(Life Sciences)》 SCIE CAS CSCD 2018年第9期1024-1029,共6页
Endothelial dysfunction is caused by many factors, such as dyslipidemia, endoplasmic reticulum(ER) stress, and inflammation.It has been demonstrated that endothelial dysfunction is the initial process of atheroscleros... Endothelial dysfunction is caused by many factors, such as dyslipidemia, endoplasmic reticulum(ER) stress, and inflammation.It has been demonstrated that endothelial dysfunction is the initial process of atherosclerosis. AMP-activated protein kinase(AMPK) is an important metabolic switch that plays a crucial role in lipid metabolism and inflammation. However, recent evidence indicates that AMPK could be a target for atherosclerosis by improving endothelial function. For instance, activation of AMPK inhibits the production of reactive oxygen species induced by mitochondrial dysfunction, ER stress, and NADPH oxidase. Moreover, activation of AMPK inhibits the production of pro-inflammatory factors induced by dyslipidemia and hyperglycemia and restrains production of perivascular adipose tissue-released adipokines. AMPK activation prevents endothelial dysfunction by increasing the bioavailability of nitric oxide. Therefore, we focused on the primary risk factors involved in endothelial dysfunction, and summarize the features of AMPK in the protection of endothelial function, by providing signaling pathways thought to be important in the pathological progress of risk factors. 展开更多
关键词 ATHEROSCLEROSIS amp-activated protein kinase cardiovascular diseases inflammation autophagy
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Mixture of five herbal extracts ameliorates pioglitazone-induced aggravation of hepatic steatosis via activating the adiponectin receptor 2/AMP-activated protein kinase signal pathway in diabetic KKAy mice 被引量:1
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作者 Wang Haiyan Li Linyi +5 位作者 Qin Lingling Wang Dongchao Jiang Yueying Wu Xinli Xu Tunhai Liu Tonghua 《Journal of Traditional Chinese Medicine》 SCIE CAS CSCD 2017年第5期588-598,共11页
OBJECTIVE: To assess the effect of a mixture of five herbal extracts(FT-5) on insulin resistance, glucose/lipid metabolism, hepatic steatosis, and to investigate whether the combination of FT-5 and pioglitazone would ... OBJECTIVE: To assess the effect of a mixture of five herbal extracts(FT-5) on insulin resistance, glucose/lipid metabolism, hepatic steatosis, and to investigate whether the combination of FT-5 and pioglitazone would provide a robust effect on diabetes treatment, while may minimize undesirable side-effects of pioglitazone in diabetic Ay gene(KKAy)mice.METHODS: Seven-week-old KKAy mice were randomly divided into five groups: control(CON)group, FT-5(2.0 g/kg) group, pioglitazone(20 mg/kg)(PIO) group, pioglitazone(20 mg/kg) + FT-5(2.0 g/kg)(P + F) group. Age-matched C57 BL/6 J micewere used as the control group. After seven weeks of continuous intragastric administration of medication, the glucose metabolism, insulin sensitivity and lipid metabolism of KKAy mice were evaluated by assessing the fasting blood glucose(FBG), oral glucose tolerance test(OGTT), fasting serum insulin(FINS), insulin tolerance test(ITT), homeostasis model of assessment-insulin resistance index(HOMA-IR), total cholesterol(TC), total triglycerides(TG), and free fatty acids(FFA) in plasma and liver.Plasma and hepatic adiponectin were measured via enzyme-linked immunosorbent assays. Genes related to adipogenesis and lipolysis in white adipose tissues(WAT) and liver were examined by real-time polymerase chain reaction. Lipid metabolism-related protein expression in the liver of KKAy mice were detected by Western blotting.RESULTS: PIO treatment remarkably improved insulin resistance. However, it also showed substantial side effects. FT-5 group exhibited no significant decrease in serum glucose. However, it reduced fasting plasma TG levels and improved hepatic steatosis of KKAy mice. P + F group showed improved insulin resistance and similar body weight gain, as compared with control group. The m RNA expression of genes related to fatty acid oxidation was markedly up-regulated in the liver of P + F group.Pioglitazone administration markedly decreased the phosphorylation levels of AMPK, as compared with all other groups. Besides, even though plasma adiponectin increased in PIO, FT-5, P + F group, adipo R2 gene expression significantly decreased in the liver of PIO group.CONCLUSION: FT-5 decreased plasma TG and alleviated aggravating hepatic steatosis induced by pioglitazone in KKAy mice. FT-5's mechanism might be associated with its ability to activate the Adipo R2/AMPK pathway. 展开更多
关键词 Pioglitazone Insulin resistance Hepatic steatosis amp-activated protein kinases FT-5 KKAy mice
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Gene expression profiles and phosphorylation patterns of AMP-activated protein kinase subunits in various mesenchymal cell types
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作者 Wang Yugang Fan Qiming Ma Rui Lin Wentao Tang Tingting 《Chinese Medical Journal》 SCIE CAS CSCD 2014年第13期2451-2457,共7页
Background Recent studies on bone have shown an endocrine role of the skeleton,which could be impaired in various human diseases,including osteoporosis,obesity,and diabetes-associated bone diseases.As a sensor and reg... Background Recent studies on bone have shown an endocrine role of the skeleton,which could be impaired in various human diseases,including osteoporosis,obesity,and diabetes-associated bone diseases.As a sensor and regulator of energy metabolism,AMP-activated protein kinase (AMPK) may also play an important role in the regulation of bone metabolism.The current study aimed to establish the expression profiles and phosphorylation patterns of AMPK subunits in several mesenchymal cell types.Methods Reverse transcription-polymerase chain reaction (PCR) for relative quantification,real-time PCR for absolute quantification,and Western blotting were used to investigate the gene expression profiles and phosphorylation patterns of AMPK subunits in several mesenchymal cell types,including primary human mesenchymal stem cells (hMSCs) and hFOB,Saos-2,C3H/10T1/2,MC3T3-E1,3T3-L1,and C2C12 cells.Results AMPKα1 and AMPKβ1 mRNAs were abundantly expressed in all cell types.AMPKY1 mRNA was abundantly expressed in C3H/10T1/2,MC3T3-E1,3T3-L1,and C2C12 but not detected in human-derived cell types.AMPKY2 mRNA was mildly expressed in all cell types.AMPKα1 protein was highly expressed in all cell types and AMPKα2 protein was highly expressed only in hFOB and Saos-2 cells.AMPKβ1 protein was abundantly expressed in all cell types except for Saos-2,in which AMPKβ2 protein overwhelmed AMPKβ1 expression.AMPKy1 and AMPKY2 proteins were expressed in C3H/10T1/2,MC3T3-E1,3T3-L1,and C2C12 cells and only AMPKY2 protein was expressed in hMSCs,hFOB and Saos2 cells.AMPKα was phosphorylated at Thr172 and Ser485 and AMPKβ1 was phosphorylated at Ser108 and Ser182 in all cell types with a specific pattern in each cell type.Conclusion The combination of AMPK α,β,and Y subunits and phosphorylation of AMPKα (Thr172 and Ser485) and AMPKβ1 (Ser108 and Ser182) showed a specific pattern in each cell type. 展开更多
关键词 amp-activated protein kinase gene expression PHOSPHORYLATION mesenchymal stem cells
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Cardiovascular and nonalcoholic fatty liver disease:Sharing common ground through SIRT1 pathways
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作者 Kenneth Maiese 《World Journal of Cardiology》 2024年第11期632-643,共12页
As a non-communicable disease,cardiovascular disorders have become the lea-ding cause of death for men and women.Of additional concern is that cardio-vascular disease is linked to chronic comorbidity disorders that in... As a non-communicable disease,cardiovascular disorders have become the lea-ding cause of death for men and women.Of additional concern is that cardio-vascular disease is linked to chronic comorbidity disorders that include nonal-coholic fatty liver disease(NAFLD).NAFLD,also termed metabolic-dysfunction-associated steatotic liver disease,is the greatest cause of liver disease throughout the world,increasing in prevalence concurrently with diabetes mellitus(DM),and can progress to nonalcoholic steatohepatitis that leads to cirrhosis and liver fi-brosis.Individuals with metabolic disorders,such as DM,are more than two times likely to experience cardiac disease,stroke,and liver disease that includes NAFLD when compared individuals without metabolic disorders.Interestingly,cardiovascular disorders and NAFLD share a common underlying cellular me-chanism for disease pathology,namely the silent mating type information regu-lation 2 homolog 1(SIRT1;Saccharomyces cerevisiae).SIRT1,a histone deacetylase,is linked to metabolic pathways through nicotinamide adenine dinucleotide and can offer cellular protection though multiple avenues,including trophic factors such as erythropoietin,stem cells,and AMP-activated protein kinase.Translating SIRT1 pathways into clinical care for cardiovascular and hepatic disease can offer significant hope for patients,but further insights into the complexity of SIRT1 pathways are necessary for effective treatment regimens. 展开更多
关键词 amp-activated protein kinase Cardiovascular disease Diabetes mellitus ERYTHROPOIETIN Metabolic-dysfunction-associated steatotic liver disease NICOTINAMIDE Nicotinamide adenine dinucleotide Nonalcoholic fatty liver disease Silent mating type information regulation 2 homolog 1(Saccharomyces cerevisiae) Stem cells
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Targeting AMPKa1 Gene in PC3 Cells by Triphenylmethanol Derivatives
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作者 William Yaw Boadi Jamari Jemison +3 位作者 Kennedy Welbert Sanaa Dudley Tayalla Hizer Ryan Beni 《Natural Science》 2024年第7期111-120,共10页
Epidemiological studies indicate that treatment with metformin, an AMP-activated protein kinase (AMPK) activator, reduces the incidence of cancers. Activation of AMPK has also been reported to oppose tumor progression... Epidemiological studies indicate that treatment with metformin, an AMP-activated protein kinase (AMPK) activator, reduces the incidence of cancers. Activation of AMPK has also been reported to oppose tumor progression in diverse types of cancers and offers promising cancer therapy. Furthermore, AMPK is a primary regulator of energy metabolism and has also been implicated in cell cycle progression, angiogenesis, cell transformation, migration, and cancer. We have recently synthesized novel flavonoids, namely, triphenylmethanol derivatives (TPMs), but the effectiveness of the TPMs on the activity of AMPK remains unclear. We hypothesized that the novel TPMs would inhibit cancer cell proliferation through the activation of AMPK isoforms in cells. The effects of TPMs on prostate cells (PC-3) were investigated. Cells were exposed to TPMs for either 12 or 24 hr. at the respective doses of 0, 25, 50 100, and 200 µM based on the cell viability studies by the (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide, a tetrazole) (MTT) assay. The results indicate that cells exposed to the respective doses of TPMs increased both phospho- and total-AMPKα1 in a dose- and time-dependent manner. The effects of the increases for the phospho- and total-AMPKα in cells were greater for the 24-hr than the 12-hr. incubation. Further studies are currently going on to elucidate the specificities of the said insults in increasing the phospho- and total-AMPKα activities and for the other respective isoforms. 展开更多
关键词 PRODRUGS amp-activated Protein Kinase POLYPHENOLS Prostate Cancer Triphenylmethanol
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Bexarotene improves motor function after spinal cord injury in mice 被引量:2
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作者 Xingyu Wang Zhihao Shen +7 位作者 Haojie Zhang Hao-Jie Zhang Feida Li Letian Yu Hua Chen Kailiang Zhou Hui Xu Sunren Sheng 《Neural Regeneration Research》 SCIE CAS CSCD 2023年第12期2733-2742,共10页
Spinal cord injury is a challenge in orthopedics because it causes irreversible damage to the central nervous system.Therefore,early treatment to prevent lesion expansion is crucial for the management of patients with... Spinal cord injury is a challenge in orthopedics because it causes irreversible damage to the central nervous system.Therefore,early treatment to prevent lesion expansion is crucial for the management of patients with spinal cord injury.Bexarotene,a type of retinoid,exerts therapeutic effects on patients with cutaneous T-cell lymphoma and Parkinson's disease.Bexarotene has been proven to promote autophagy,but it has not been used in the treatment of spinal cord injury.To investigate the effects of bexarotene on spinal cord injury,we established a mouse model of T11–T12 spinal cord contusion and performed daily intraperitoneal injection of bexarotene for 5 consecutive days.We found that bexarotene effectively reduced the deposition of collagen and the number of pathological neurons in the injured spinal cord,increased the number of synapses of nerve cells,reduced oxidative stress,inhibited pyroptosis,promoted the recovery of motor function,and reduced death.Inhibition of autophagy with 3-methyladenine reversed the effects of bexarotene on spinal cord injury.Bexarotene enhanced the nuclear translocation of transcription factor E3,which further activated AMP-activated protein kinase-S-phase kinase-associated protein 2-coactivator-associated arginine methyltransferase 1 and AMP-activated protein kinase-mammalian target of rapamycin signaling pathways.Intravenous injection of transcription factor E3 sh RNA or intraperitoneal injection of compound C,an AMP-activated protein kinase blocker,inhibited the effects of bexarotene.These findings suggest that bexarotene regulates nuclear translocation of transcription factor E3 through the AMP-activated protein kinase-Sphase kinase-associated protein 2-coactivator-associated arginine methyltransferase 1 and AMP-activated protein kinase-mammalian target of rapamycin signal pathways,promotes autophagy,decreases reactive oxygen species level,inhibits pyroptosis,and improves motor function after spinal cord injury. 展开更多
关键词 3-methyladenine amp-activated protein kinase autophagy BEXAROTENE MITOPHAGY oxidative stress PYROPTOSIS reactive oxygen species spinal cord injury transcription factor E3
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腺苷酸活化蛋白激酶(AMPK)活性对动物宰后糖酵解的影响 被引量:3
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作者 张铭灏 朱立贤 +4 位作者 张一敏 沈瑾 张明月 罗欣 梁荣蓉 《食品与发酵工业》 CAS CSCD 北大核心 2016年第12期234-239,共6页
动物宰后其骨骼肌的能量代谢是影响宰后肉品品质的重要因素之一。在动物宰后的糖酵解中,腺苷酸蛋白活化激酶(AMP-activated proteinkinase,AMPK)可以通过对糖酵解关键限速酶活性的控制进而对宰后的糖酵解和肉的品质产生影响。文中综述了... 动物宰后其骨骼肌的能量代谢是影响宰后肉品品质的重要因素之一。在动物宰后的糖酵解中,腺苷酸蛋白活化激酶(AMP-activated proteinkinase,AMPK)可以通过对糖酵解关键限速酶活性的控制进而对宰后的糖酵解和肉的品质产生影响。文中综述了AMPK结构、其活性变化及活性调控对宰后糖酵解进程的影响,并对通过AMPK活性的人工调控来改善肉质提出了展望。 展开更多
关键词 腺苷酸活化蛋白激酶(amp-activated protein kinase AMPK) 宰后糖酵解 活性调控
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LB100 ameliorates nonalcoholic fatty liver disease via the AMPK/Sirt1 pathway 被引量:9
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作者 Xue-Yang Chen Chang-Zhou Cai +5 位作者 Meng-Li Yu Ze-Min Feng Yu-Wei Zhang Pei-Hao Liu Hang Zeng Chao-Hui Yu 《World Journal of Gastroenterology》 SCIE CAS 2019年第45期6607-6618,共12页
BACKGROUND It is well known that nonalcoholic fatty liver disease(NAFLD)is associated with insulin resistance(IR).LB100,a serine/threonine protein phosphatase 2A(PP2A)inhibitor,is closely related to IR.However,there i... BACKGROUND It is well known that nonalcoholic fatty liver disease(NAFLD)is associated with insulin resistance(IR).LB100,a serine/threonine protein phosphatase 2A(PP2A)inhibitor,is closely related to IR.However,there is little data regarding its direct influence on NAFLD.AIM To elucidate the effect and underlying mechanism of LB100 in NAFLD.METHODS After 10 wk of high fat diet(HFD)feeding,male C57BL/6 mice were injected intraperitoneally with vehicle or LB100 for an additional 6 wk(three times a week).The L02 cell line was treated with LB100 and free fatty acids(FFAs)for 24 h.Hematoxylin and eosin and oil red O staining were performed for histological examination.Western blot analysis was used to detect the protein expression of Sirtuin 1(Sirt1),total and phosphorylated AMP-activated protein kinaseα(AMPKα),and the proteins involved in lipogenesis and fatty acid oxidation.The mRNA levels were determined by qPCR.Pharmacological inhibition of AMPK was performed to further examine the exact mechanism of LB100 in NAFLD.RESULTS LB100 significantly ameliorated HFD-induced obesity,hepatic lipid accumulation and hepatic injury in mice.In addition,LB100 significantly downregulated the protein levels of acetyl-CoA carboxylase,sterol regulatory element-binding protein 1 and its lipogenesis target genes,including stearoyl-CoA desaturase-1 and fatty acid synthase,and upregulated the levels of proteins involved in fatty acidβ-oxidation,such as peroxisome proliferator-activated receptorα(PPARα),peroxisome proliferator-activated receptor gamma coactivator-1α(PGC-1α),carnitine palmitoyltransferase 1α,acyl-CoA oxidase 1 and uncoupling protein 2,as well as the upstream mediators Sirt1 and AMPKαin the livers of HFD-fed mice.In vitro,LB100 alleviated FFA-induced lipid accumulation in L02 cells through the AMPK/Sirt1 signaling pathway.Further studies showed that the curative effect of LB100 on lipid accumulation was abolished by inhibiting AMPKαin L02 cells.CONCLUSION PP2A inhibition by LB100 significantly ameliorates hepatic steatosis by regulating hepatic lipogenesis and fatty acid oxidation via the AMPK/Sirt1 pathway.LB100 may be a potential therapeutic agent for NAFLD. 展开更多
关键词 LB100 NONALCOHOLIC fatty liver disease Serine/threonine-protein PHOSPHATASE 2A Lipid metabolism amp-activated PROTEIN kinaseα SIRTUIN 1
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Green tea polyphenols ameliorate non-alcoholic fatty liver disease through upregulating AMPK activation in high fat fed Zucker fatty rats 被引量:12
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作者 Yi Tan Jane Kim +7 位作者 Jing Cheng Madeleine Ong Wei-Guo Lao Xing-Liang Jin Yi-Guang Lin Linda Xiao Xue-Qiong Zhu Xian-Qin Qu 《World Journal of Gastroenterology》 SCIE CAS 2017年第21期3805-3814,共10页
AIM To investigate protective effects and molecular mechanisms of green tea polyphenols(GTP) on nonalcoholic fatty liver disease(NAFLD) in Zucker fatty(ZF) rats.METHODS Male ZF rats were fed a high-fat diet(HFD) for 2... AIM To investigate protective effects and molecular mechanisms of green tea polyphenols(GTP) on nonalcoholic fatty liver disease(NAFLD) in Zucker fatty(ZF) rats.METHODS Male ZF rats were fed a high-fat diet(HFD) for 2 wk then treated with GTP(200 mg/kg) or saline(5 m L/kg) for 8 wk, with Zucker lean rat as their control. At the end of experiment, serum and liver tissue were collected for measurement of metabolic parameters, alanine aminotransferase(ALT) and aspartate aminotransferase(AST), inflammatory cytokines and hepatic triglyceride and liver histology. Immunoblotting was used to detect phosphorylation of AMP-activated protein kinase(AMPK) acetyl-Co A carboxylase(ACC), and sterol regulatory element-binding protein 1c(SREBP1c). RESULTS Genetically obese ZF rats on a HFD presented with metabolic features of hepatic pathological changes comparable to human with NAFLD. GTP intervention decreased weight gain(10.1%, P = 0.052) and significantly lowered visceral fat(31.0%, P < 0.01). Compared with ZF-controls, GTP treatment significantly reduced fasting serum insulin, glucose and lipids levels. Reduction in serum ALT and AST levels(both P < 0.01) were observed in GTP-treated ZF rats. GTP treatment also attenuated the elevated TNFα and IL-6 in the circulation. The increased hepatic TG accumulation and cytoplasmic lipid droplet were attenuated by GTP treatment, associated with significantly increased expression of AMPK-Thr172(P < 0.05) and phosphorylated ACC and SREBP1c(both P < 0.05), indicating diminished hepatic lipogenesis and triglycerides out flux from liver in GTP treated rats. CONCLUSION The protective effects of GTP against HFD-induced NAFLD in genetically obese ZF rats are positively correlated to reduction in hepatic lipogenesis through upregulating the AMPK pathway. 展开更多
关键词 Non-alcoholic fatty liver disease Green tea polyphenols Hepatic lipogenesis Inflammatory cytokines amp-activated protein kinase
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Fat cell-secreted adiponectin mediates physical exercise-induced hippocampal neurogenesis: an alternative anti-depressive treatment? 被引量:8
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作者 Suk Yu Yau Ang Li +1 位作者 Aimin Xu Kwok-fai So 《Neural Regeneration Research》 SCIE CAS CSCD 2015年第1期7-9,共3页
Psychological depression is drawing accumulating attention nowadays, due to the skyrocketing incidence worldwide and the enormous burdens it incurs. Physical exercise has been long recog- nized for its therapeutic eff... Psychological depression is drawing accumulating attention nowadays, due to the skyrocketing incidence worldwide and the enormous burdens it incurs. Physical exercise has been long recog- nized for its therapeutic effects on depressive disorders, although knowledge of the underlying mechanisms remains limited. Suppressed hippocampal neurogenesis in adult brains has been regarded, at least partly, contributive to depression, whereas physical exercise that restores neuro- genesis accordingly exerts the anti-depressive action. Several recent publications have suggested the potential role of adiponectin, a protein hormone secreted by peripheral mature adipocytes, in mediating physical exercise-triggered enhancement of hippocampal neurogenesis and alleviation of depression. Here, we briefly review these novel findings and discuss the possibility of counter- acting depression by modulating adiponectin signaling in the hippocampus with interventions including physical exercise and administration of pharmacological agents. 展开更多
关键词 HIPPOCAMPUS adult neurogenesis physical exercise voluntary wheel running depression neural progenitor cell ADIPOCYTE ADIPONECTIN adiponectin receptor amp-activated protein kinase
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MK-0626,a selective DPP-4 inhibitor,attenuates hepatic steatosis in ob/ob mice 被引量:4
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作者 Tatsuya Ohyama Ken Sato +6 位作者 Yuichi Yamazaki Hiroaki Hashizume Norio Horiguchi Satoru Kakizaki Masatomo Mori Motoyasu Kusano Masanobu Yamada 《World Journal of Gastroenterology》 SCIE CAS 2014年第43期16227-16235,共9页
AIM: To investigate the mechanism and in vivo effects of MK-0626, a dipeptidyl peptidase-4 inhibitor, on hepatic steatosis using ob/ob mice.
关键词 Dipeptidyl peptidase-4 inhibitor Hepatic steatosis ob/ob mice amp-activated protein kinase Microsomal triglyceride transfer protein ADIPONECTIN
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Neuroprotective effects of statins against amyloid β-induced neurotoxicity 被引量:4
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作者 Hsin-Hua Li Chih-Li Lin Chien-Ning Huang 《Neural Regeneration Research》 SCIE CAS CSCD 2018年第2期198-206,共9页
A growing body of evidence suggests that disruption of the homeostasis of lipid metabolism affects the pathogenesis of Alzheimer's disease (AD). In particular, dysregulation of cholesterol homeostasis in the brain ... A growing body of evidence suggests that disruption of the homeostasis of lipid metabolism affects the pathogenesis of Alzheimer's disease (AD). In particular, dysregulation of cholesterol homeostasis in the brain has been reported to considerably increase the risk of developing AD. Thus, dysregulation of lipid homeostasis may increase the amyloid β (Aβ) levels by affecting amyloid precursor protein (APP) cleavage, which is the most important risk factor involved in the pathogenesis of AD. Previous research demonstrated that Aβ can trigger neuronal insulin resistance, which plays an important role in response to Aβ-induced neurotoxicity in AD. Epidemiological studies also suggested that statin use is associated with a decreased incidence of AD. Therefore, statins are believed to be a good candidate for conferring neuropro- tective effects against AD. Statins may play a beneficial role in reducing A^-induced neurotoxicity. Their effect involves a putative mechanism beyond its cholesterol-lowering effects in preventing A[3-induced neurotoxicity. However, the underlying molecular mechanisms of the protective effect of statins have not been clearly determined in Aβ-induced neurotoxicity. Given that statins may provide benefits beyond the inhibition of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, these drugs may also improve the brain. Thus, statins may have beneficial effects on impaired insulin signaling by activating AMP-activated protein kinase (AMPK) in neuronal cells. They play a potential therapeutic role in targeting Aβ-mediated neurotoxicity. 展开更多
关键词 STATINS neuroprotective effects amyloid E-induced neurotoxicity insulin signaling amp-activated protein kinase
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Activation of AMPK/MnSOD signaling mediates anti-apoptotic effect of hepatitis B virus in hepatoma cells 被引量:3
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作者 Lei Li Hong-Hai Hong +3 位作者 Shi-Ping Chen Cai-Qi Ma Han-Yan Liu Ya-Chao Yao 《World Journal of Gastroenterology》 SCIE CAS 2016年第17期4345-4353,共9页
AIM: To investigate the anti-apoptotic capability of the hepatitis B virus(HBV) in the HepG2 hepatoma cell line and the underlying mechanisms.METHODS: Cell viability and apoptosis were measured by MTT assay and flow c... AIM: To investigate the anti-apoptotic capability of the hepatitis B virus(HBV) in the HepG2 hepatoma cell line and the underlying mechanisms.METHODS: Cell viability and apoptosis were measured by MTT assay and flow cytometry, respectively. Targeted knockdown of manganese superoxide dismutase(Mn SOD), AMP-activated protein kinase(AMPK) and hepatitis B virus X protein(HBx) genes as well as AMPK agonist AICAR and antagonist compound C were employed to determine the correlations of expression of these genes.RESULTS: HBV markedly protected the hepatoma cells from growth suppression and cell death in the condition of serum deprivation. A decrease of superoxide anion production accompanied with an increase of Mn SOD expression and activity was found in Hep G2.215 cells. Moreover, AMPK activation contributed to the up-regulation of Mn SOD. HBx protein was identified to induce the expression of AMPK and Mn SOD. CONCLUSION: Our results suggest that HBV suppresses mitochondrial superoxide level and exerts an antiapoptotic effect by activating AMPK/Mn SOD signaling pathway, which may provide a novel pharmacological strategy to prevent HCC. 展开更多
关键词 Hepatitis B virus Reactive oxygen species Apoptosis Manganese superoxide dismutase amp-activated protein kinase
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Hypothermic machine perfusion with metformin-University of Wisconsin solution for ex vivo preservation of standard and marginal liver grafts in a rat model 被引量:3
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作者 Yi-Chao Chai Guo-Xin Dang +6 位作者 Hai-Qi He Jian-Hua Shi Hong-Ke Zhang Rui-Tao Zhang Bo Wang Liang-Shuo Hu Yi Lv 《World Journal of Gastroenterology》 SCIE CAS 2017年第40期7221-7231,共11页
AIM To compare the effect of University of Wisconsin(UW) solution with or without metformin, an AMP-activated protein kinase(AMPK) activator, for preserving standard and marginal liver grafts of young and aged rats ex... AIM To compare the effect of University of Wisconsin(UW) solution with or without metformin, an AMP-activated protein kinase(AMPK) activator, for preserving standard and marginal liver grafts of young and aged rats ex vivo by hypothermic machine perfusion(HMP).METHODS Eighteen young(4 mo old) and 18 aged(17 mo old)healthy male SD rats were selected and randomly divided into three groups: control group, UW solution perfusion group(UWP), and UW solution with metformin perfusion group(MUWP). Aspartate aminotransferase(AST), alanine aminotransferase(ALT), lactate dehydrogenase(LDH), interleukin-18(IL-18), and tumor necrosis factor-alpha(TNF-α) in the perfused liquid were tested. The expression levels of AMPK and endothelial nitric oxide synthase(e NOS) in liver sinusoidal endothelial cells were also examined.Additionally, microscopic evaluation of the harvested perfused liver tissue samples was done. RESULTS AST, ALT, LDH, IL-18 and TNF-α levels in the young and aged liver-perfused liquid were, respectively,significantly lower in the MUWP group than in the UWP group(P < 0.05), but no significant differences were found between the young and aged MUWP groups.Metformin increased the expression of AMPK and e NOS protein levels, and promoted the extracellular release of nitric oxide through activation of the AMPK-e NOS mediated pathway. Histological examination revealed that in the MUWP group, the extent of liver cells and tissue damage was significantly reduced compared with the UWP group.CONCLUSION The addition of metformin to the UW preservative solution for ex vivo HMP can reduce rat liver injury during cold ischemia, with significant protective effects on livers, especially of aged rats. 展开更多
关键词 METFORMIN amp-activated protein kinase Cold ischemia injury Hypothermic machine perfusion Liver Grafts
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Risk of gastric cancer is associated with PRKAA1 gene polymorphisms in Koreans 被引量:3
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作者 Yong-Dae Kim Dong-Hyuk Yim +10 位作者 Sang-Yong Eom Sun In Moon Hyo-Yung Yun Young-Jin Song Sei-Jin Youn Taisun Hyun Joo-Seung Park Byung Sik Kim Jong-Young Lee Hee Kwan Won Heon Kim 《World Journal of Gastroenterology》 SCIE CAS 2014年第26期8592-8598,共7页
AIM: To evaluate the association between genetic polymorphisms of the gene encoding AMP-activated protein kinase (PRKAA1) and the risk of gastric cancer.
关键词 amp-activated protein kinase Gastric cancer PRKAA1 Single nucleotide polymorphism Case-control study
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