Background and Aims:Hepatic ischemia-reperfusion injury(IRI)is a common pathophysiological phenomenon in clinical practice,which usually occurs in liver transplantation,liver resection,severe trauma,and hemorrhagic sh...Background and Aims:Hepatic ischemia-reperfusion injury(IRI)is a common pathophysiological phenomenon in clinical practice,which usually occurs in liver transplantation,liver resection,severe trauma,and hemorrhagic shock.Proanthocyanidin(PC),exerted from various plants with antioxidant,antitumor,and antiaging activity,were administrated in our study to investigate the underlying mechanism of its protective function on IRI.Methods:Two doses of PC(50 mg/kg,100 mg/kg)were given to BALB/c mice by intragastric administration for 7 days before partial(70%)warm IR surgery.Serum and liver tissues were collected 2,8,and 24 h after reperfusion for relevant experiments.Results:The results of transaminase and hematoxylin and eosin staining indicated that PC pretreatment significantly alleviated IRI in mice.Serum total superoxide dismutase increased and malondialde-hyde decreased in PC pretreatment groups.Enzyme-linked immunosorbent assays,western blotting,quantitative real-time polymerase chain reaction,and immunohistochemistry showed that inflammation,apoptosis,and autophagy in PC preprocessing groups were significantly inhibited and were dose-dependent.The protein,mRNA expression,and immunohistochemical staining results of peroxisome proliferator-activated receptor alpha(PPARa)and peroxisome proliferator-activated receptor gamma coactivator 1-alpha(PGC1a)in the PC pretreatment groups were significantly upregulated compared with the IR group in a dose-dependent manner.Conclusions:PC pretreatment suppressed inflammation,apoptosis,and autophagy via the PPAR-α signaling pathway to protect against IRI of the liver in mice.展开更多
Dear Editor,The sirtuin family Nicotinamide adenine dinucleotide-dependent deacetylases have important roles in many biological processes(Milne and Denu,2008).SIRT1 is a mammalian homolog of yeast Sir2,which is the fo...Dear Editor,The sirtuin family Nicotinamide adenine dinucleotide-dependent deacetylases have important roles in many biological processes(Milne and Denu,2008).SIRT1 is a mammalian homolog of yeast Sir2,which is the founding member of the sirtuin family.Many SIRT1 substrates have been reported,including histones,p53,FOXOs,and PGC1α(Hsu et al.,2013).Stimulating the activity of SIRT1 has been shown to be an attractive therapeutic strategy for various physiological and pathological conditions such as aging,metabolic disorders,inflammation,and neurodegeneration(Guarente,2011).Several small molecules have been identified or developed as potential sirtuinactivating compounds(STACs).Most notably,resveratrol,a natural STAC,was shown to activate the SIRT1-catalyzed deacetylation of the Fluor de Lys(FDL)peptide,which is a p53 peptide fused to a 7-amino-4-methylcoumarin(AMC)fluorophore at the C-terminus(Table S1;Howitz et al.,2003).However,the activation of deacetylation of the p53 peptide is dependent on the presence of the AMC fluorophore(Borra et al.,2005;Wu et al.,2013).展开更多
Sirtuin 3(SIRT3),the main family member of mitochondrial deacetylase,targets the majority of substrates controlling mitochondrial biogenesis via lysine deacetylation and modulates important cellular functions such as ...Sirtuin 3(SIRT3),the main family member of mitochondrial deacetylase,targets the majority of substrates controlling mitochondrial biogenesis via lysine deacetylation and modulates important cellular functions such as energy metabolism,reactive oxygen species production and clearance,oxidative stress,and aging.Deletion of SIRT3 has a deleterious effect on mitochondrial biogenesis,thus leading to the defect in mitochondrial function and insufficient ATP production.Imbalance of mitochondrial dynamics leads to excessive mitochondrial biogenesis,dampening mitochondrial function.Mitochondrial dysfunction plays an important role in several diseases related to aging,such as cardiovascular disease,cancer and neurodegenerative diseases.Peroxisome proliferator-activated receptor gamma coactivator 1-alpha(PGC1α)launches mitochondrial biogenesis through activating nuclear respiratory factors.These factors act on genes,transcribing and translating mitochondrial DNA to generate new mitochondria.PGC1αbuilds a bridge between SIRT3 and mitochondrial biogenesis.This review described the involvement of SIRT3 and mitochondrial dynamics,particularly mitochondrial biogenesis in agingrelated diseases,and further illustrated the role of the signaling events between SIRT3 and mitochondrial biogenesis in the pathological process of aging-related diseases.展开更多
Tenofovir disoproxil fumarate(TDF),is a product of tenofovir and has been recommended for long-term use by guidelines1 because of its favorable efficacy in the treatment of human immunodeficiency virus(HIV)and hepatit...Tenofovir disoproxil fumarate(TDF),is a product of tenofovir and has been recommended for long-term use by guidelines1 because of its favorable efficacy in the treatment of human immunodeficiency virus(HIV)and hepatitis B virus(HBV)infection.Hence,a better understanding of the safety profiles of long-term TDF use is extremely important.Lactic acidosis,as a rare but fatal adverse event of TDF,were reported both in HIV-infected patients,2-4 and in CHB patients.5-7 Hyperlactatemia occurred in 15.6%HIV-infected patients using TDF in a Cameroon cohort study8 and was 3%in another South Africa cohort study.9 Therefore,TDF increases the risk of abnormal serum lactate,but the mechanism is unclear.展开更多
基金supported by the Natural Science Foundation of Shanghai(19ZR1439900)Changzhou Science and Technology Bureau(CJ20200086).
文摘Background and Aims:Hepatic ischemia-reperfusion injury(IRI)is a common pathophysiological phenomenon in clinical practice,which usually occurs in liver transplantation,liver resection,severe trauma,and hemorrhagic shock.Proanthocyanidin(PC),exerted from various plants with antioxidant,antitumor,and antiaging activity,were administrated in our study to investigate the underlying mechanism of its protective function on IRI.Methods:Two doses of PC(50 mg/kg,100 mg/kg)were given to BALB/c mice by intragastric administration for 7 days before partial(70%)warm IR surgery.Serum and liver tissues were collected 2,8,and 24 h after reperfusion for relevant experiments.Results:The results of transaminase and hematoxylin and eosin staining indicated that PC pretreatment significantly alleviated IRI in mice.Serum total superoxide dismutase increased and malondialde-hyde decreased in PC pretreatment groups.Enzyme-linked immunosorbent assays,western blotting,quantitative real-time polymerase chain reaction,and immunohistochemistry showed that inflammation,apoptosis,and autophagy in PC preprocessing groups were significantly inhibited and were dose-dependent.The protein,mRNA expression,and immunohistochemical staining results of peroxisome proliferator-activated receptor alpha(PPARa)and peroxisome proliferator-activated receptor gamma coactivator 1-alpha(PGC1a)in the PC pretreatment groups were significantly upregulated compared with the IR group in a dose-dependent manner.Conclusions:PC pretreatment suppressed inflammation,apoptosis,and autophagy via the PPAR-α signaling pathway to protect against IRI of the liver in mice.
基金the Chinese Ministry of Science and Technology,Natural Science Foundation of China(Grant Nos.2018YFA0107004,2019YFA0508900,91853204,31870737,32170549 and 22103040)the National Postdoctoral Program for Innovative Talents(BX20180149)Haihe Laboratory of Cell Ecosystem Innovation Fund(HH22KYZX0021)and the State Key Laboratory of Medicinal Chemical Biology.
文摘Dear Editor,The sirtuin family Nicotinamide adenine dinucleotide-dependent deacetylases have important roles in many biological processes(Milne and Denu,2008).SIRT1 is a mammalian homolog of yeast Sir2,which is the founding member of the sirtuin family.Many SIRT1 substrates have been reported,including histones,p53,FOXOs,and PGC1α(Hsu et al.,2013).Stimulating the activity of SIRT1 has been shown to be an attractive therapeutic strategy for various physiological and pathological conditions such as aging,metabolic disorders,inflammation,and neurodegeneration(Guarente,2011).Several small molecules have been identified or developed as potential sirtuinactivating compounds(STACs).Most notably,resveratrol,a natural STAC,was shown to activate the SIRT1-catalyzed deacetylation of the Fluor de Lys(FDL)peptide,which is a p53 peptide fused to a 7-amino-4-methylcoumarin(AMC)fluorophore at the C-terminus(Table S1;Howitz et al.,2003).However,the activation of deacetylation of the p53 peptide is dependent on the presence of the AMC fluorophore(Borra et al.,2005;Wu et al.,2013).
文摘Sirtuin 3(SIRT3),the main family member of mitochondrial deacetylase,targets the majority of substrates controlling mitochondrial biogenesis via lysine deacetylation and modulates important cellular functions such as energy metabolism,reactive oxygen species production and clearance,oxidative stress,and aging.Deletion of SIRT3 has a deleterious effect on mitochondrial biogenesis,thus leading to the defect in mitochondrial function and insufficient ATP production.Imbalance of mitochondrial dynamics leads to excessive mitochondrial biogenesis,dampening mitochondrial function.Mitochondrial dysfunction plays an important role in several diseases related to aging,such as cardiovascular disease,cancer and neurodegenerative diseases.Peroxisome proliferator-activated receptor gamma coactivator 1-alpha(PGC1α)launches mitochondrial biogenesis through activating nuclear respiratory factors.These factors act on genes,transcribing and translating mitochondrial DNA to generate new mitochondria.PGC1αbuilds a bridge between SIRT3 and mitochondrial biogenesis.This review described the involvement of SIRT3 and mitochondrial dynamics,particularly mitochondrial biogenesis in agingrelated diseases,and further illustrated the role of the signaling events between SIRT3 and mitochondrial biogenesis in the pathological process of aging-related diseases.
基金This work was supported in part by grants from the National Science and Technology Major Project of China(2017ZX10202203008,2017ZX10202203007)the National Natural Science Foundation of China(81772171)+1 种基金the Chongqing Talents Project(cstc2021ycjh-bgzxm0150)Remarkable Innovation–Clinical Research Project,the Second Affiliated Hospital of Chongqing Medical University。
文摘Tenofovir disoproxil fumarate(TDF),is a product of tenofovir and has been recommended for long-term use by guidelines1 because of its favorable efficacy in the treatment of human immunodeficiency virus(HIV)and hepatitis B virus(HBV)infection.Hence,a better understanding of the safety profiles of long-term TDF use is extremely important.Lactic acidosis,as a rare but fatal adverse event of TDF,were reported both in HIV-infected patients,2-4 and in CHB patients.5-7 Hyperlactatemia occurred in 15.6%HIV-infected patients using TDF in a Cameroon cohort study8 and was 3%in another South Africa cohort study.9 Therefore,TDF increases the risk of abnormal serum lactate,but the mechanism is unclear.
文摘目的 探讨AMPK激动剂二甲双胍对脂多糖(LPS)诱导的小鼠急性肺损伤的保护作用及可能的机制。方法 6-8周雄性BALB/c小鼠15只随机分为3组:对照组(气管内滴注无菌PBS 60 μl),LPS模型组(LPS组,气管内滴注1 mg/ml LPS 60 μl,作用24 h),二甲双胍治疗组(Met+LPS组,于滴注LPS前30 min腹腔注射二甲双胍250 mg/kg,再气管内滴注LPS作用24 h)。观察小鼠肺组织病理学改变,肺泡灌洗液中细胞总数及中性粒性细胞数变化,测定肺组织内髓过氧化物酶(MPO)活性。Western blot法检测肺组织中AMPK、P-AMPK(Thr172)及PGC1α表达的变化。结果 与对照组比较,LPS模型组小鼠组织病理学显示,肺泡壁结构明显破坏,炎性细胞浸润及组织出血增加,肺泡灌洗液中细胞总数及中性粒细胞比例明显增高( P <0.01),肺组织内MPO活性显著升高( P <0.01),PGC1α表达减少( P <0.01),P-AMPK(Thr172)水平下降。与LPS模型组比较,二甲双胍治疗组小鼠肺泡壁破坏减轻,炎性细胞浸润及组织出血减轻,髓过氧化物酶活性下降( P <0.01),P-AMPK水平( P <0.01)及PGC1α( P <0.05)的表达明显增加。结论 本研究提示AMPK激动剂二甲双胍对LPS诱导急性肺损伤具有一定保护作用,这种保护作用可能与PGC1α上调有关。
