AMPK激活剂抗炎保护效应研究进展
|
摘要
腺苷酸活化蛋白激酶(AMP-activated protein kinase, AMPK)是细胞能量调节的关键激酶,近期研究表明AMPK也在炎症这一高耗能分子反应中发挥重要调控作用。目前常用的AMPK激活剂有5-氨基咪唑-4-甲酰胺核苷酸(5-aminoimidazole-4-carboxamide ribonucleotide, AICAR)和A-769662,此外二甲双胍及脂联素发挥生物活性也与激活AMPK密切相关。大量研究表明,这些激活剂可在急性肺损伤、哮喘、结肠s炎、肝炎、动脉粥样硬化等多种炎症相关性疾病动物模型中发挥有效的保护作用。因而,AMPK激活剂在炎症相关性疾病的防治中具有广阔的研发和应用前景。
AMP-activated protein kinase(AMPK) is a key enzyme in the regulation of cellular energy homeostasis. Recent studies demonstrated that AMPK also plays an important role in the modulation of inflammation, an energy-intensive molecular response. The commonly used AMPK activators include 5-aminoimidazole-4-carboxamide ribonucleotide(AICAR) and A-769662. In addition, the biological activities of metformin and adiponectin are closely related to activation of AMPK. Numerous studies have shown that these AMPK activators play an effectively protective role in animal models of acute lung injury, asthma, colitis, hepatitis, atherosclerosis and other inflammatory diseases. Therefore, AMPK activators may have promising potential for the prevention and treatment of inflammation related diseases.
AMP-activated protein kinase(AMPK) is a key enzyme in the regulation of cellular energy homeostasis. Recent studies demonstrated that AMPK also plays an important role in the modulation of inflammation, an energy-intensive molecular response. The commonly used AMPK activators include 5-aminoimidazole-4-carboxamide ribonucleotide(AICAR) and A-769662. In addition, the biological activities of metformin and adiponectin are closely related to activation of AMPK. Numerous studies have shown that these AMPK activators play an effectively protective role in animal models of acute lung injury, asthma, colitis, hepatitis, atherosclerosis and other inflammatory diseases. Therefore, AMPK activators may have promising potential for the prevention and treatment of inflammation related diseases.
引文
1 Hardie DG,Schaffer BE,Brunet A.AMPK:An energy-sensing pathway with multiple inputs and outputs.Trends Cell Biol 2016;26(3):190-201.
2 Kim J,Yang G,Kim Y,Kim J,Ha J.AMPK activators:mechanisms of action and physiological activities.Exp Mol Med 2016;48:e224.
3 Bridgeman SC,Ellison GC,Melton PE,Newsholme P,Mamotte CDS.Epigenetic effects of metformin:From molecular mechanisms to clinical implications.Diabetes Obes Metab 2018;20(7):1553-1562.
4 Sanz P,Rubio T,Garcia-Gimeno MA.AMPKbeta subunits:more than just a scaffold in the formation of AMPK complex.FEBS J 2013;280(16):3723-3733.
5 Steinberg GR,Kemp BE.AMPK in health and disease.Physiol Rev 2009;89(3):1025-1078.
6 Hardie DG.AMPK:positive and negative regulation,and its role in whole-body energy homeostasis.Curr Opin Cell Biol2015;33:1-7.
7 Jeon SM.Regulation and function of AMPK in physiology and diseases.Exp Mol Med 2016;48(7):e245.
8 Li P,Li X,Wu Y,Li M,Wang X.A novel AMPK activator hernandezine inhibits LPS-induced TNFalpha production.Oncotarget 2017;8(40):67218-67226.
9 Kumase F,Takeuchi K,Morizane Y,Suzuki J,Matsumoto H,Kataoka K,Al-Moujahed A,Maidana DE,Miller JW,Vavvas DG.AMPK-activated protein kinase suppresses Ccr2e x pression by inhibiting the NF-kappaB pathway in RAW264.7 macrophages.PLoS One 2016;11(1):e0147279.
10 Almabrouk TAM,White AD,Ugusman AB,Skiba DS,Katwan OJ,Alganga H,Guzik TJ,Touyz RM,Salt IP,Kennedy S.High fat diet attenuates the anticontractile activity of aortic PVAT via a mechanism involving AMPK and reduced adiponectin secretion.Front Physiol 2018;9:51.
11 Trevino-Saldana N,Garcia-Rivas G.Regulation of sirtuinmediated protein deacetylation by cardioprotective phytochemicals.Oxid Med Cell Longev 2017;2017:1750306.
12 Xie J,Zhang X,Zhang L.Negative regulation of inflammation by SIRT1.Pharmacol Res 2013;67(1):60-67.
13 Canto C,Gerhart-Hines Z,Feige JN,Lagouge M,Noriega L,Milne JC,Elliott PJ,Puigserver P,Auwerx J.AMPK regulates energy expenditure by modulating NAD+metabolism and SIRT1 activity.Nature 2009;458(7241):1056-1060.
14 Velagapudi R,El-Bakoush A,Lepiarz I,Ogunrinade F,Olajide OA.AMPK and SIRT1 activation contribute to inhibition of neuroinflammation by thymoquinone in BV2microglia.Mol Cell Biochem 2017;435(1-2):149-162.
15 Mendes KL,Lelis DF,Santos SHS.Nuclear sirtuins and inflammatory signaling pathways.Cytokine Growth Factor Rev 2017;38:98-105.
16 Song YN(宋亚男),Yuan D,Zhang CC,Wang LP,He YM,Wang T,Zhou ZY.Effect of saponins extracted from Panax japonicus on inhibiting cardiomyocyte apoptosis by AMPK/Sirt1/NF-kappaB signaling pathway in aging rats.Chin JChin Mater Med(中国中药杂志)2017;42(23):4656-4660(in Chinese with English abstract).
17 Zhang J,Zhang Y,Xiao F,Liu Y,Wang J,Gao H,Rong S,Yao Y,Li J,Xu G.The peroxisome proliferator-activated receptor gamma agonist pioglitazone prevents NF-kappaBactivation in cisplatin nephrotoxicity through the reduction of p65 acetylation via the AMPK-SIRT1/p300 pathway.Biochem Pharmacol 2016;101:100-111.
18 Rabinovitch RC,Samborska B,Faubert B,Ma EH,Gravel SP,Andrzejewski S,Raissi TC,Pause A,St-Pierre J,Jones RG.AMPK Maintains cellular metabolic homeostasis through regulation of mitochondrial reactive oxygen species.Cell Rep 2017;21(1):1-9.
19 Li J,Wang Y,Wang Y,Wen X,Ma XN,Chen W,Huang F,Kou J,Qi LW,Liu B,Liu K.Pharmacological activation of AMPK prevents Drp1-mediated mitochondrial fission and alleviates endoplasmic reticulum stress-associated endothelial dysfunction.J Mol Cell Cardiol 2015;86:62-74.
20 She C,Zhu LQ,Zhen YF,Wang XD,Dong QR.Activation of AMPK protects against hydrogen peroxide-induced osteoblast apoptosis through autophagy induction and NADPHmaintenance:new implications for osteonecrosis treatment?Cell Signal 2014;26(1):1-8.
21 Guha M,Mackman N.The phosphatidylinositol 3-kinase-Akt pathway limits lipopolysaccharide activation of signaling pathways and expression of inflammatory mediators in human monocytic cells.J Biol Chem 2002;277(35):32124-32132.
22 Grimes CA,Jope RS.CREB DNA binding activity is inhibited by glycogen synthase kinase-3 beta and facilitated by lithium.J Neurochem 2001;78(6):1219-1232.
23 Platzer C,Fritsch E,Elsner T,Lehmann MH,Volk HD,Prosch S.Cyclic adenosine monophosphate-responsive elements are involved in the transcriptional activation of the human IL-10 gene in monocytic cells.Eur J Immunol 1999;29(10):3098-3104.
24 Sid B,Glorieux C,Valenzuela M,Rommelaere G,Najimi M,Dejeans N,Renard P,Verrax J,Calderon PB.AICAR induces Nrf2 activation by an AMPK-independent mechanism in hepatocarcinoma cells.Biochem Pharmacol 2014;91(2):168-180.
25 Scott JW,van Denderen BJ,Jorgensen SB,Honeyman JE,Steinberg GR,Oakhill JS,Iseli TJ,Koay A,Gooley PR,Stapleton D,Kemp BE.Thienopyridone drugs are selective activators of AMP-activated protein kinase beta1-containing complexes.Chem Biol 2008;15(11):1220-1230.
26 Guigas B,Sakamoto K,Taleux N,Reyna SM,Musi N,Viollet B,Hue L.Beyond AICA riboside:in search of new specific AMP-activated protein kinase activators.IUBMBLife 2009;61(1):18-26.
27 Ducommun S,Ford RJ,Bultot L,Deak M,Bertrand L,Kemp BE,Steinberg GR,Sakamoto K.Enhanced activation of cellular AMPK by dual-small molecule treatment:AICARand A769662.Am J Physiol Endocrinol Metab 2014;306(6):E688-E696.
28 Steinberg GR.Cellular energy sensing and metabolismimplications for treating diabetes:The 2017 outstanding scientific achievement award lecture.Diabetes 2018;67(2):169-179.
29 Troncone M,Cargnelli SM,Villani LA,Isfahanian N,Broadfield LA,Zychla L,Wright J,Pond G,Steinberg GR,Tsakiridis T.Targeting metabolism and AMP-activated kinase with metformin to sensitize non-small cell lung cancer(NSCLC)to cytotoxic therapy:translational biology and rationale for current clinical trials.Oncotarget 2017;8(34):57733-57754.
30 Kim Y,Lim JH,Kim MY,Kim EN,Yoon HE,Shin SJ,Choi BS,Kim YS,Chang YS,Park CW.The adiponectin receptor agonist adiporon ameliorates diabetic nephropathy in a model of type 2 diabetes.J Am Soc Nephrol 2018;29(4):1108-1127.
31 Lovren F,Pan Y,Quan A,Szmitko PE,Singh KK,Shukla PC,Gupta M,Chan L,Al-Omran M,Teoh H,Verma S.Adiponectin primes human monocytes into alternative antiinflammatory M2 macrophages.Am J Physiol Heart Circ Physiol 2010;299(3):H656-H663.
32 Choi SR,Lim JH,Kim MY,Kim EN,Kim Y,Choi BS,Kim YS,Kim HW,Lim KM,Kim MJ,Park CW.Adiponectin receptor agonist AdipoRon decreased ceramide,and lipotoxicity,and ameliorated diabetic nephropathy.Metabolism 2018;85:348-360.
33 Mulchandani N,Yang WL,Khan MM,Zhang F,Marambaud P,Nicastro J,Coppa GF,Wang P.Stimulation of brain AMP-activated protein kinase attenuates inflammation and acute lung injury in sepsis.Mol Med 2015;21:637-644.
34 Wang G,Song Y,Feng W,Liu L,Zhu Y,Xie X,Pan Y,Ke R,Li S,Li F,Yang L,Li M.Activation of AMPK attenuates LPS-induced acute lung injury by upregulation of PGC1alpha and SOD1.Exp Ther Med 2016;12(3):1551-1555.
35 Zhang X,Shang F,Hui L,Zang K,Sun G.The alleviative effects of metformin for lipopolysaccharide-induced acute lung injury rat model and its underlying mechanism.Saudi Pharm J 2017;25(4):666-670.
36 Piao C,Park JH,Lee M.Anti-inflammatory therapeutic effect of adiponectin gene delivery using a polymeric carrier in an acute lung injury model.Pharm Res 2017;34(7):1517-1526.
37 Park CS,Bang BR,Kwon HS,Moon KA,Kim TB,Lee KY,Moon HB,Cho YS.Metformin reduces airway inflammation and remodeling via activation of AMP-activated protein kinase.Biochem Pharmacol 2012;84(12):1660-1670.
38 Liu L,Pan Y,Song Y,Su X,Ke R,Yang L,Gao L,Li M.Activation of AMPK alpha2 inhibits airway smooth muscle cells proliferation.Eur J Pharmacol 2016;791:235-243.
39 Bianco A,Nigro E,Monaco ML,Matera MG,Scudiero O,Mazzarella G,Daniele A.The burden of obesity in asthma and COPD:Role of adiponectin.Pulm Pharmacol Ther2017;43:20-25.
40 Sun X,Yang Q,Rogers CJ,Du M,Zhu MJ.AMPK improves gut epithelial differentiation and barrier function via regulating Cdx2 expression.Cell Death Differ 2017;24(5):819-831.
41 Deng J,Zeng L,Lai X,Li J,Liu L,Lin Q,Chen Y.Metformin protects against intestinal barrier dysfunction via AMPKalpha1-dependent inhibition of JNK signalling activation.J Cell Mol Med 2018;22(1):546-557.
42 Obeid S,Wankell M,Charrez B,Sternberg J,Kreuter R,Esmaili S,Ramezani-Moghadam M,Devine C,Read S,Bhathal P,Lopata A,Ahlensteil G,Qiao L,George J,Hebbard L.Adiponectin confers protection from acute colitis and restricts a B cell immune response.J Biol Chem 2017;292(16):6569-6582.
43 Peralta C,Bartrons R,Serafin A,Blazquez C,Guzman M,Prats N,Xaus C,Cutillas B,Gelpi E,Rosello-Catafau J.Adenosine monophosphate-activated protein kinase mediates the protective effects of ischemic preconditioning on hepatic ischemia-reperfusion injury in the rat.Hepatology 2001;34(6):1164-1173.
44 Yang C,Gong X,Ai Q,Ge P,Lin L,Zhang L.5-Aminoimidazole-4-carboxamide-1-beta-d-ribofuranoside alleviated carbon tetrachloride-induced acute hepatitis in mice.Int Immunopharmacol 2015;25(2):393-399.
45 Tsai WL,Chang TH,Sun WC,Chan HH,Wu CC,Hsu PI,Cheng JS,Yu ML.Metformin activates type I interferon signaling against HCV via activation of adenosine monophosphate-activated protein kinase.Oncotarget 2017;8(54):91928-91937.
46 Carvalho RF,Atta AM,de Oliveira IS,Santos TPS,Santos JPA,Schinoni MI,de Sousa-Atta MLB.Adiponectin levels and insulin resistance among patients with chronic hepatitis C.Acta Trop 2018;178:258-263.
47 Ramachandran S,Vinitha A,Kartha CC.Cyclophilin Aenhances macrophage differentiation and lipid uptake in high glucose conditions:a cellular mechanism for accelerated macro vascular disease in diabetes mellitus.Cardiovasc Diabetol 2016;15(1):152.
48 Ramachandran S,Anandan V,Kutty VR,Mullasari A,Pillai MR,Kartha CC.Metformin attenuates effects of cyclophilin A on macrophages,reduces lipid uptake and secretion of cytokines by repressing decreased AMPK activity.Clin Sci(Lond)2018;132(6):719-738.
49 Karnewar S,Neeli PK,Panuganti D,Kotagiri S,Mallappa S,Jain N,Jerald MK,Kotamraju S.Metformin regulates mitochondrial biogenesis and senescence through AMPK mediated H3K79 methylation:Relevance in age-associated vascular dysfunction.Biochim Biophys Acta 2018;1864(4 Pt A):1115-1128.
50 Ma A,Wang J,Yang L,An Y,Zhu H.AMPK activation enhances the anti-atherogenic effects of high density lipoproteins in apoE(-/-)mice.J Lipid Res 2017;58(8):1536-1547.
51 Sargolzaei J,Chamani E,Kazemi T,Fallah S,Soori H.The role of adiponectin and adipolin as anti-inflammatory adipokines in the formation of macrophage foam cells and their association with cardiovascular diseases.Clin Biochem2018;54:1-10.
52 Zhang M,Zhu H,Ding Y,Liu Z,Cai Z,Zou MH.AMP-activated protein kinase alpha1 promotes atherogenesis by increasing monocyte-to-macrophage differentiation.J Biol Chem 2017;292(19):7888-7903.
53 Paiva MA,Goncalves LM,Providencia LA,Davidson SM,Yellon DM,Mocanu MM.Transitory activation of AMPK at reperfusion protects the ischaemic-reperfused rat myocardium against infarction.Cardiovasc Drugs Ther 2010;24(1):25-32.
54 Declèves AE,Sharma K,Satriano J.Beneficial effects of AMP-activated protein kinase agonists in kidney ischemiareperfusion:autophagy and cellular stress markers.Nephron Exp Nephrol 2014;128:98-110.
55 Xu N,Zhang Y,Doycheva DM,Ding Y,Zhang Y,Tang J,Guo H,Zhang JH.Adiponectin attenuates neuronal apoptosis induced by hypoxia-ischemia via the activation of AdipoR1/APPL1/LKB1/AMPK pathway in neonatal rats.Neuropharmacology 2018;133:415-428.
2 Kim J,Yang G,Kim Y,Kim J,Ha J.AMPK activators:mechanisms of action and physiological activities.Exp Mol Med 2016;48:e224.
3 Bridgeman SC,Ellison GC,Melton PE,Newsholme P,Mamotte CDS.Epigenetic effects of metformin:From molecular mechanisms to clinical implications.Diabetes Obes Metab 2018;20(7):1553-1562.
4 Sanz P,Rubio T,Garcia-Gimeno MA.AMPKbeta subunits:more than just a scaffold in the formation of AMPK complex.FEBS J 2013;280(16):3723-3733.
5 Steinberg GR,Kemp BE.AMPK in health and disease.Physiol Rev 2009;89(3):1025-1078.
6 Hardie DG.AMPK:positive and negative regulation,and its role in whole-body energy homeostasis.Curr Opin Cell Biol2015;33:1-7.
7 Jeon SM.Regulation and function of AMPK in physiology and diseases.Exp Mol Med 2016;48(7):e245.
8 Li P,Li X,Wu Y,Li M,Wang X.A novel AMPK activator hernandezine inhibits LPS-induced TNFalpha production.Oncotarget 2017;8(40):67218-67226.
9 Kumase F,Takeuchi K,Morizane Y,Suzuki J,Matsumoto H,Kataoka K,Al-Moujahed A,Maidana DE,Miller JW,Vavvas DG.AMPK-activated protein kinase suppresses Ccr2e x pression by inhibiting the NF-kappaB pathway in RAW264.7 macrophages.PLoS One 2016;11(1):e0147279.
10 Almabrouk TAM,White AD,Ugusman AB,Skiba DS,Katwan OJ,Alganga H,Guzik TJ,Touyz RM,Salt IP,Kennedy S.High fat diet attenuates the anticontractile activity of aortic PVAT via a mechanism involving AMPK and reduced adiponectin secretion.Front Physiol 2018;9:51.
11 Trevino-Saldana N,Garcia-Rivas G.Regulation of sirtuinmediated protein deacetylation by cardioprotective phytochemicals.Oxid Med Cell Longev 2017;2017:1750306.
12 Xie J,Zhang X,Zhang L.Negative regulation of inflammation by SIRT1.Pharmacol Res 2013;67(1):60-67.
13 Canto C,Gerhart-Hines Z,Feige JN,Lagouge M,Noriega L,Milne JC,Elliott PJ,Puigserver P,Auwerx J.AMPK regulates energy expenditure by modulating NAD+metabolism and SIRT1 activity.Nature 2009;458(7241):1056-1060.
14 Velagapudi R,El-Bakoush A,Lepiarz I,Ogunrinade F,Olajide OA.AMPK and SIRT1 activation contribute to inhibition of neuroinflammation by thymoquinone in BV2microglia.Mol Cell Biochem 2017;435(1-2):149-162.
15 Mendes KL,Lelis DF,Santos SHS.Nuclear sirtuins and inflammatory signaling pathways.Cytokine Growth Factor Rev 2017;38:98-105.
16 Song YN(宋亚男),Yuan D,Zhang CC,Wang LP,He YM,Wang T,Zhou ZY.Effect of saponins extracted from Panax japonicus on inhibiting cardiomyocyte apoptosis by AMPK/Sirt1/NF-kappaB signaling pathway in aging rats.Chin JChin Mater Med(中国中药杂志)2017;42(23):4656-4660(in Chinese with English abstract).
17 Zhang J,Zhang Y,Xiao F,Liu Y,Wang J,Gao H,Rong S,Yao Y,Li J,Xu G.The peroxisome proliferator-activated receptor gamma agonist pioglitazone prevents NF-kappaBactivation in cisplatin nephrotoxicity through the reduction of p65 acetylation via the AMPK-SIRT1/p300 pathway.Biochem Pharmacol 2016;101:100-111.
18 Rabinovitch RC,Samborska B,Faubert B,Ma EH,Gravel SP,Andrzejewski S,Raissi TC,Pause A,St-Pierre J,Jones RG.AMPK Maintains cellular metabolic homeostasis through regulation of mitochondrial reactive oxygen species.Cell Rep 2017;21(1):1-9.
19 Li J,Wang Y,Wang Y,Wen X,Ma XN,Chen W,Huang F,Kou J,Qi LW,Liu B,Liu K.Pharmacological activation of AMPK prevents Drp1-mediated mitochondrial fission and alleviates endoplasmic reticulum stress-associated endothelial dysfunction.J Mol Cell Cardiol 2015;86:62-74.
20 She C,Zhu LQ,Zhen YF,Wang XD,Dong QR.Activation of AMPK protects against hydrogen peroxide-induced osteoblast apoptosis through autophagy induction and NADPHmaintenance:new implications for osteonecrosis treatment?Cell Signal 2014;26(1):1-8.
21 Guha M,Mackman N.The phosphatidylinositol 3-kinase-Akt pathway limits lipopolysaccharide activation of signaling pathways and expression of inflammatory mediators in human monocytic cells.J Biol Chem 2002;277(35):32124-32132.
22 Grimes CA,Jope RS.CREB DNA binding activity is inhibited by glycogen synthase kinase-3 beta and facilitated by lithium.J Neurochem 2001;78(6):1219-1232.
23 Platzer C,Fritsch E,Elsner T,Lehmann MH,Volk HD,Prosch S.Cyclic adenosine monophosphate-responsive elements are involved in the transcriptional activation of the human IL-10 gene in monocytic cells.Eur J Immunol 1999;29(10):3098-3104.
24 Sid B,Glorieux C,Valenzuela M,Rommelaere G,Najimi M,Dejeans N,Renard P,Verrax J,Calderon PB.AICAR induces Nrf2 activation by an AMPK-independent mechanism in hepatocarcinoma cells.Biochem Pharmacol 2014;91(2):168-180.
25 Scott JW,van Denderen BJ,Jorgensen SB,Honeyman JE,Steinberg GR,Oakhill JS,Iseli TJ,Koay A,Gooley PR,Stapleton D,Kemp BE.Thienopyridone drugs are selective activators of AMP-activated protein kinase beta1-containing complexes.Chem Biol 2008;15(11):1220-1230.
26 Guigas B,Sakamoto K,Taleux N,Reyna SM,Musi N,Viollet B,Hue L.Beyond AICA riboside:in search of new specific AMP-activated protein kinase activators.IUBMBLife 2009;61(1):18-26.
27 Ducommun S,Ford RJ,Bultot L,Deak M,Bertrand L,Kemp BE,Steinberg GR,Sakamoto K.Enhanced activation of cellular AMPK by dual-small molecule treatment:AICARand A769662.Am J Physiol Endocrinol Metab 2014;306(6):E688-E696.
28 Steinberg GR.Cellular energy sensing and metabolismimplications for treating diabetes:The 2017 outstanding scientific achievement award lecture.Diabetes 2018;67(2):169-179.
29 Troncone M,Cargnelli SM,Villani LA,Isfahanian N,Broadfield LA,Zychla L,Wright J,Pond G,Steinberg GR,Tsakiridis T.Targeting metabolism and AMP-activated kinase with metformin to sensitize non-small cell lung cancer(NSCLC)to cytotoxic therapy:translational biology and rationale for current clinical trials.Oncotarget 2017;8(34):57733-57754.
30 Kim Y,Lim JH,Kim MY,Kim EN,Yoon HE,Shin SJ,Choi BS,Kim YS,Chang YS,Park CW.The adiponectin receptor agonist adiporon ameliorates diabetic nephropathy in a model of type 2 diabetes.J Am Soc Nephrol 2018;29(4):1108-1127.
31 Lovren F,Pan Y,Quan A,Szmitko PE,Singh KK,Shukla PC,Gupta M,Chan L,Al-Omran M,Teoh H,Verma S.Adiponectin primes human monocytes into alternative antiinflammatory M2 macrophages.Am J Physiol Heart Circ Physiol 2010;299(3):H656-H663.
32 Choi SR,Lim JH,Kim MY,Kim EN,Kim Y,Choi BS,Kim YS,Kim HW,Lim KM,Kim MJ,Park CW.Adiponectin receptor agonist AdipoRon decreased ceramide,and lipotoxicity,and ameliorated diabetic nephropathy.Metabolism 2018;85:348-360.
33 Mulchandani N,Yang WL,Khan MM,Zhang F,Marambaud P,Nicastro J,Coppa GF,Wang P.Stimulation of brain AMP-activated protein kinase attenuates inflammation and acute lung injury in sepsis.Mol Med 2015;21:637-644.
34 Wang G,Song Y,Feng W,Liu L,Zhu Y,Xie X,Pan Y,Ke R,Li S,Li F,Yang L,Li M.Activation of AMPK attenuates LPS-induced acute lung injury by upregulation of PGC1alpha and SOD1.Exp Ther Med 2016;12(3):1551-1555.
35 Zhang X,Shang F,Hui L,Zang K,Sun G.The alleviative effects of metformin for lipopolysaccharide-induced acute lung injury rat model and its underlying mechanism.Saudi Pharm J 2017;25(4):666-670.
36 Piao C,Park JH,Lee M.Anti-inflammatory therapeutic effect of adiponectin gene delivery using a polymeric carrier in an acute lung injury model.Pharm Res 2017;34(7):1517-1526.
37 Park CS,Bang BR,Kwon HS,Moon KA,Kim TB,Lee KY,Moon HB,Cho YS.Metformin reduces airway inflammation and remodeling via activation of AMP-activated protein kinase.Biochem Pharmacol 2012;84(12):1660-1670.
38 Liu L,Pan Y,Song Y,Su X,Ke R,Yang L,Gao L,Li M.Activation of AMPK alpha2 inhibits airway smooth muscle cells proliferation.Eur J Pharmacol 2016;791:235-243.
39 Bianco A,Nigro E,Monaco ML,Matera MG,Scudiero O,Mazzarella G,Daniele A.The burden of obesity in asthma and COPD:Role of adiponectin.Pulm Pharmacol Ther2017;43:20-25.
40 Sun X,Yang Q,Rogers CJ,Du M,Zhu MJ.AMPK improves gut epithelial differentiation and barrier function via regulating Cdx2 expression.Cell Death Differ 2017;24(5):819-831.
41 Deng J,Zeng L,Lai X,Li J,Liu L,Lin Q,Chen Y.Metformin protects against intestinal barrier dysfunction via AMPKalpha1-dependent inhibition of JNK signalling activation.J Cell Mol Med 2018;22(1):546-557.
42 Obeid S,Wankell M,Charrez B,Sternberg J,Kreuter R,Esmaili S,Ramezani-Moghadam M,Devine C,Read S,Bhathal P,Lopata A,Ahlensteil G,Qiao L,George J,Hebbard L.Adiponectin confers protection from acute colitis and restricts a B cell immune response.J Biol Chem 2017;292(16):6569-6582.
43 Peralta C,Bartrons R,Serafin A,Blazquez C,Guzman M,Prats N,Xaus C,Cutillas B,Gelpi E,Rosello-Catafau J.Adenosine monophosphate-activated protein kinase mediates the protective effects of ischemic preconditioning on hepatic ischemia-reperfusion injury in the rat.Hepatology 2001;34(6):1164-1173.
44 Yang C,Gong X,Ai Q,Ge P,Lin L,Zhang L.5-Aminoimidazole-4-carboxamide-1-beta-d-ribofuranoside alleviated carbon tetrachloride-induced acute hepatitis in mice.Int Immunopharmacol 2015;25(2):393-399.
45 Tsai WL,Chang TH,Sun WC,Chan HH,Wu CC,Hsu PI,Cheng JS,Yu ML.Metformin activates type I interferon signaling against HCV via activation of adenosine monophosphate-activated protein kinase.Oncotarget 2017;8(54):91928-91937.
46 Carvalho RF,Atta AM,de Oliveira IS,Santos TPS,Santos JPA,Schinoni MI,de Sousa-Atta MLB.Adiponectin levels and insulin resistance among patients with chronic hepatitis C.Acta Trop 2018;178:258-263.
47 Ramachandran S,Vinitha A,Kartha CC.Cyclophilin Aenhances macrophage differentiation and lipid uptake in high glucose conditions:a cellular mechanism for accelerated macro vascular disease in diabetes mellitus.Cardiovasc Diabetol 2016;15(1):152.
48 Ramachandran S,Anandan V,Kutty VR,Mullasari A,Pillai MR,Kartha CC.Metformin attenuates effects of cyclophilin A on macrophages,reduces lipid uptake and secretion of cytokines by repressing decreased AMPK activity.Clin Sci(Lond)2018;132(6):719-738.
49 Karnewar S,Neeli PK,Panuganti D,Kotagiri S,Mallappa S,Jain N,Jerald MK,Kotamraju S.Metformin regulates mitochondrial biogenesis and senescence through AMPK mediated H3K79 methylation:Relevance in age-associated vascular dysfunction.Biochim Biophys Acta 2018;1864(4 Pt A):1115-1128.
50 Ma A,Wang J,Yang L,An Y,Zhu H.AMPK activation enhances the anti-atherogenic effects of high density lipoproteins in apoE(-/-)mice.J Lipid Res 2017;58(8):1536-1547.
51 Sargolzaei J,Chamani E,Kazemi T,Fallah S,Soori H.The role of adiponectin and adipolin as anti-inflammatory adipokines in the formation of macrophage foam cells and their association with cardiovascular diseases.Clin Biochem2018;54:1-10.
52 Zhang M,Zhu H,Ding Y,Liu Z,Cai Z,Zou MH.AMP-activated protein kinase alpha1 promotes atherogenesis by increasing monocyte-to-macrophage differentiation.J Biol Chem 2017;292(19):7888-7903.
53 Paiva MA,Goncalves LM,Providencia LA,Davidson SM,Yellon DM,Mocanu MM.Transitory activation of AMPK at reperfusion protects the ischaemic-reperfused rat myocardium against infarction.Cardiovasc Drugs Ther 2010;24(1):25-32.
54 Declèves AE,Sharma K,Satriano J.Beneficial effects of AMP-activated protein kinase agonists in kidney ischemiareperfusion:autophagy and cellular stress markers.Nephron Exp Nephrol 2014;128:98-110.
55 Xu N,Zhang Y,Doycheva DM,Ding Y,Zhang Y,Tang J,Guo H,Zhang JH.Adiponectin attenuates neuronal apoptosis induced by hypoxia-ischemia via the activation of AdipoR1/APPL1/LKB1/AMPK pathway in neonatal rats.Neuropharmacology 2018;133:415-428.