Ample clinical evidence suggests a high incidence of cardiovascular events in Alzheimer’s disease(AD),although neither precise etiology nor effective treatment is available.This study was designed to evaluate cardiac...Ample clinical evidence suggests a high incidence of cardiovascular events in Alzheimer’s disease(AD),although neither precise etiology nor effective treatment is available.This study was designed to evaluate cardiac function in AD patients and APP/PS1 mutant mice,along with circulating levels of melatonin,mitochondrial aldehyde dehydrogenase(ALDH2)and autophagy.AD patients and APP/PS1 mice displayed cognitive and myocardial deficits,low levels of circulating melatonin,ALDH2 activity,and autophagy,ultrastructural,geometric(cardiac atrophy and interstitial fibrosis)and functional(reduced fractional shortening and cardiomyocyte contraction)anomalies,mitochondrial injury,cytosolic mtDNA buildup,apoptosis,and suppressed autophagy and mitophagy.APP/PS1 mutation downregulated cyclic GMP-AMP synthase(cGAS)and stimulator of interferon genes(STING)levels and TBK1 phosphorylation,while promoting Aβaccumulation.Treatment with melatonin overtly ameliorated unfavorable APP/PS1-induced changes in cardiac geometry and function,apoptosis,mitochondrial integrity,cytosolic mtDNA accumulation(using both immunocytochemistry and qPCR),mitophagy,and cGAS-STING-TBK1 signaling,although these benefits were absent in APP/PS1/ALDH2−/−mice.In vitro evidence indicated that melatonin attenuated APP/PS1-induced suppression of mitophagy and cardiomyocyte function,and the effect was negated by the nonselective melatonin receptor blocker luzindole,inhibitors or RNA interference of cGAS,STING,TBK1,and autophagy.Our data collectively established a correlation among cardiac dysfunction,low levels of melatonin,ALDH2 activity,and autophagy in AD patients,with compelling support in APP/PS1 mice,in which melatonin rescued myopathic changes by promoting cGAS-STING-TBK1 signaling and mitophagy via an ALDH2-dependent mechanism.展开更多
A major mitochondrial enzyme for protecting cells from acetaldehyde toxicity is aldehyde dehydrogenase 2(ALDH2).The correlation between ALDH2 dysfunction and tumorigenesis/growth/metastasis has been widely reported.Ei...A major mitochondrial enzyme for protecting cells from acetaldehyde toxicity is aldehyde dehydrogenase 2(ALDH2).The correlation between ALDH2 dysfunction and tumorigenesis/growth/metastasis has been widely reported.Either low or high ALDH2 expression contributes to tumor progression and varies among different tumor types.Furthermore,the ALDH2*2 polymorphism(rs671) is the most common single nucleotide polymorphism(SNP) in Asia.Epidemiological studies associate ALDH2*2 with tumorigenesis and progression.This study summarizes the essential functions and potential ALDH2 mechanisms in the occurrence,progression,and treatment of tumors in various types of cancer.Our study indicates that ALDH2 is a potential therapeutic target for cancer therapy.展开更多
Mitochondrial damage is a critical driver in myocardial ischemia-reperfusion(I/R)injury and can be alleviated via the mitochondrial transplantation.The efficiency of mitochondrial transplantation is determined by mito...Mitochondrial damage is a critical driver in myocardial ischemia-reperfusion(I/R)injury and can be alleviated via the mitochondrial transplantation.The efficiency of mitochondrial transplantation is determined by mitochondrial vitality.Because aldehyde dehydrogenase 2(ALDH2)has a key role in regulating mitochondrial homeostasis,we aimed to investigate its potential therapeutic effects on mitochondrial transplantation via the use of ALDH2 activator,Alda-1.Our present study demonstrated that time-dependent internalization of exogenous mitochondria by cardiomyocytes along with ATP production were significantly increased in response to mitochondrial transplantation.Furthermore,Alda-1 treatment remarkably promoted the oxygen consumption rate and baseline mechanical function of cardiomyocytes caused by mitochondrial transplantation.Mitochondrial transplantation inhibited cardiomyocyte apoptosis induced by the hypoxia-reoxygenation exposure,independent of Alda-1 treatment.However,promotion of the mechanical function of cardiomyocytes exposed to hypoxia-reoxygenation treatment was only observed after mitochondrial Alda-1 treatment and transplantation.By using a myocardial I/R mouse model,our results revealed that transplantation of Alda-1-treated mitochondria into mouse myocardial tissues limited the infarction size after I/R injury,which was at least in part due to increased mitochondrial potential-mediated fusion.In conclusion,ALDH2 activation in mitochondrial transplantation shows great potential for the treatment of myocardial I/R injury.展开更多
Objective: This study aimed to determine if gastric cardia adenocarcinoma(GCA) risk was associated with the lys(A or *2) allele at the rs671(glu504lys) polymorphism within the aldehyde dehydrogenase 2(ALDH2) gene in a...Objective: This study aimed to determine if gastric cardia adenocarcinoma(GCA) risk was associated with the lys(A or *2) allele at the rs671(glu504lys) polymorphism within the aldehyde dehydrogenase 2(ALDH2) gene in a Chinese Han population. We also aimed to investigate ALDH2 genotypic distributions between subjects from high- and low-incidence areas for both GCA and esophageal squamous cell carcinoma(ESCC).Methods: We designed a case-control study including 2,686 patients with GCA and 3,675 control subjects from high- and lowincidence areas for both GCA and ESCC in China. Taq Man allele discrimination assay was used to genotype the rs671 polymorphism. χ~2 test and binary logistic regression analysis were used to estimate the odds ratios for the development of GCA,and multivariate ordinal logistic regression was used to analyze ALDH2 genotypic distributions among different groups.Results: Compared with ALDH2*1/*1 homozygotes, ALDH2*1/*2 and ALDH2*2/*2 carriers did not increase the risk for GCA in the Chinese Han population(P>0.05). Interestingly, the ratio of homozygous or heterozygous ALDH2 *2 carriers in highincidence areas for both GCA and ESCC was lower than that in low-incidence areas(P<0.001).Conclusions: Genotypes of rs671 at ALDH2 may not increase GCA susceptibility in Chinese Han populations. In addition, the ALDH2 genotypic distribution differs between Chinese Han populations from high- and low-incidence areas for both GCA and ESCC. Our findings may shed light on the possible genetic mechanism for the dramatic geographic differences of GCA occurrence in China.展开更多
基金supported in part by grants from the National Key R&D Program of China(2017YFA0506000)National Natural Science Foundation of China(91749128)the Shannxi Province Key Science and Natural Project(2019JQ-704).
文摘Ample clinical evidence suggests a high incidence of cardiovascular events in Alzheimer’s disease(AD),although neither precise etiology nor effective treatment is available.This study was designed to evaluate cardiac function in AD patients and APP/PS1 mutant mice,along with circulating levels of melatonin,mitochondrial aldehyde dehydrogenase(ALDH2)and autophagy.AD patients and APP/PS1 mice displayed cognitive and myocardial deficits,low levels of circulating melatonin,ALDH2 activity,and autophagy,ultrastructural,geometric(cardiac atrophy and interstitial fibrosis)and functional(reduced fractional shortening and cardiomyocyte contraction)anomalies,mitochondrial injury,cytosolic mtDNA buildup,apoptosis,and suppressed autophagy and mitophagy.APP/PS1 mutation downregulated cyclic GMP-AMP synthase(cGAS)and stimulator of interferon genes(STING)levels and TBK1 phosphorylation,while promoting Aβaccumulation.Treatment with melatonin overtly ameliorated unfavorable APP/PS1-induced changes in cardiac geometry and function,apoptosis,mitochondrial integrity,cytosolic mtDNA accumulation(using both immunocytochemistry and qPCR),mitophagy,and cGAS-STING-TBK1 signaling,although these benefits were absent in APP/PS1/ALDH2−/−mice.In vitro evidence indicated that melatonin attenuated APP/PS1-induced suppression of mitophagy and cardiomyocyte function,and the effect was negated by the nonselective melatonin receptor blocker luzindole,inhibitors or RNA interference of cGAS,STING,TBK1,and autophagy.Our data collectively established a correlation among cardiac dysfunction,low levels of melatonin,ALDH2 activity,and autophagy in AD patients,with compelling support in APP/PS1 mice,in which melatonin rescued myopathic changes by promoting cGAS-STING-TBK1 signaling and mitophagy via an ALDH2-dependent mechanism.
基金funded by grants from the National Natural Science Foundation of China (81673463)the National Key Research and Development Program (No. 2018ZX09711002-003-011, China)+1 种基金the Guangdong Provincial Special Fund for Marine Economic Development Project (GDNRC [2020]042, China)Leading Talent Project of Guangzhou Development Zone (CY2018-002, China)。
文摘A major mitochondrial enzyme for protecting cells from acetaldehyde toxicity is aldehyde dehydrogenase 2(ALDH2).The correlation between ALDH2 dysfunction and tumorigenesis/growth/metastasis has been widely reported.Either low or high ALDH2 expression contributes to tumor progression and varies among different tumor types.Furthermore,the ALDH2*2 polymorphism(rs671) is the most common single nucleotide polymorphism(SNP) in Asia.Epidemiological studies associate ALDH2*2 with tumorigenesis and progression.This study summarizes the essential functions and potential ALDH2 mechanisms in the occurrence,progression,and treatment of tumors in various types of cancer.Our study indicates that ALDH2 is a potential therapeutic target for cancer therapy.
基金This work was supported by grants from the National Science Fund for Distinguished Young Scholars(817200010)the Foundation for Innovative Research Groups of the National Natural Science Foundation of China(81521001)+1 种基金the National Natural Science Foundation of China(81900353)the China Postdoctoral Science Foundation(2019M651377).
文摘Mitochondrial damage is a critical driver in myocardial ischemia-reperfusion(I/R)injury and can be alleviated via the mitochondrial transplantation.The efficiency of mitochondrial transplantation is determined by mitochondrial vitality.Because aldehyde dehydrogenase 2(ALDH2)has a key role in regulating mitochondrial homeostasis,we aimed to investigate its potential therapeutic effects on mitochondrial transplantation via the use of ALDH2 activator,Alda-1.Our present study demonstrated that time-dependent internalization of exogenous mitochondria by cardiomyocytes along with ATP production were significantly increased in response to mitochondrial transplantation.Furthermore,Alda-1 treatment remarkably promoted the oxygen consumption rate and baseline mechanical function of cardiomyocytes caused by mitochondrial transplantation.Mitochondrial transplantation inhibited cardiomyocyte apoptosis induced by the hypoxia-reoxygenation exposure,independent of Alda-1 treatment.However,promotion of the mechanical function of cardiomyocytes exposed to hypoxia-reoxygenation treatment was only observed after mitochondrial Alda-1 treatment and transplantation.By using a myocardial I/R mouse model,our results revealed that transplantation of Alda-1-treated mitochondria into mouse myocardial tissues limited the infarction size after I/R injury,which was at least in part due to increased mitochondrial potential-mediated fusion.In conclusion,ALDH2 activation in mitochondrial transplantation shows great potential for the treatment of myocardial I/R injury.
基金supported by grants from the National Natural Science Foundation of China(Grant No.81472323)Top Talent Support Project of Zhengzhou University(Grant No.ZDGD 13001)Innovation Scientists and Technicians Troop Construction Projects of Henan Province(Grant No.3047)
文摘Objective: This study aimed to determine if gastric cardia adenocarcinoma(GCA) risk was associated with the lys(A or *2) allele at the rs671(glu504lys) polymorphism within the aldehyde dehydrogenase 2(ALDH2) gene in a Chinese Han population. We also aimed to investigate ALDH2 genotypic distributions between subjects from high- and low-incidence areas for both GCA and esophageal squamous cell carcinoma(ESCC).Methods: We designed a case-control study including 2,686 patients with GCA and 3,675 control subjects from high- and lowincidence areas for both GCA and ESCC in China. Taq Man allele discrimination assay was used to genotype the rs671 polymorphism. χ~2 test and binary logistic regression analysis were used to estimate the odds ratios for the development of GCA,and multivariate ordinal logistic regression was used to analyze ALDH2 genotypic distributions among different groups.Results: Compared with ALDH2*1/*1 homozygotes, ALDH2*1/*2 and ALDH2*2/*2 carriers did not increase the risk for GCA in the Chinese Han population(P>0.05). Interestingly, the ratio of homozygous or heterozygous ALDH2 *2 carriers in highincidence areas for both GCA and ESCC was lower than that in low-incidence areas(P<0.001).Conclusions: Genotypes of rs671 at ALDH2 may not increase GCA susceptibility in Chinese Han populations. In addition, the ALDH2 genotypic distribution differs between Chinese Han populations from high- and low-incidence areas for both GCA and ESCC. Our findings may shed light on the possible genetic mechanism for the dramatic geographic differences of GCA occurrence in China.
