Aldehyde dehydrogenase 2(ALDH2)is an important factor in inhibiting oxidative stress and has been shown to protect against renal ischemia/reperfusion injury.Therefore,we hypothesized that ALDH_2 could reduce spinal ...Aldehyde dehydrogenase 2(ALDH2)is an important factor in inhibiting oxidative stress and has been shown to protect against renal ischemia/reperfusion injury.Therefore,we hypothesized that ALDH_2 could reduce spinal cord ischemia/reperfusion injury.Spinal cord ischemia/reperfusion injury was induced in rats using the modified Zivin's method of clamping the abdominal aorta.After successful model establishment,the agonist group was administered a daily consumption of 2.5%alcohol.At 7 days post-surgery,the Basso,Beattie,and Bresnahan score significantly increased in the agonist group compared with the spinal cord ischemia/reperfusion injury group.ALDH_2expression also significantly increased and the number of apoptotic cells significantly decreased in the agonist group than in the spinal cord ischemia/reperfusion injury group.Correlation analysis revealed that ALDH_2 expression negatively correlated with the percentage of TUNEL-positive cells(r=-0.485,P〈0.01).In summary,increased ALDH_2 expression protected the rat spinal cord against ischemia/reperfusion injury by inhibiting apoptosis.展开更多
BACKGROUND:Disturbance of mitochondrial fi ssion and fusion(termed mitochondrial dynamics)is one of the leading causes of ischemia/reperfusion(I/R)-induced myocardial injury.Previous studies showed that mitochondrial ...BACKGROUND:Disturbance of mitochondrial fi ssion and fusion(termed mitochondrial dynamics)is one of the leading causes of ischemia/reperfusion(I/R)-induced myocardial injury.Previous studies showed that mitochondrial aldehyde dehydrogenase 2(ALDH2)conferred cardioprotective effect against myocardial I/R injury and suppressed I/R-induced excessive mitophagy in cardiomyocytes.However,whether ALDH2 participates in the regulation of mitochondrial dynamics during myocardial I/R injury remains unknown.METHODS:In the present study,we investigated the effect of ALDH2 on mitochondrial dynamics and the underlying mechanisms using the H9c2 cells exposed to hypoxia/reoxygenation(H/R)as an in vitro model of myocardial I/R injury.RESULTS:Cardiomyocyte apoptosis was significantly increased after oxygen-glucose deprivation and reoxygenation(OGD/R),and ALDH2 activation largely decreased the cardiomyocyte apoptosis.Additionally,we found that both ALDH2 activation and overexpression significantly inhibited the increased mitochondrial fission after OGD/R.Furthermore,we found that ALDH2 dominantly suppressed dynamin-related protein 1(Drp1)phosphorylation(Ser616)and adenosine monophosphate-activated protein kinase(AMPK)phosphorylation(Thr172)but not interfered with the expression levels of mitochondrial shaping proteins.CONCLUSIONS:We demonstrate the protective effect of ALDH2 against cardiomyocyte H/R injury with a novel mechanism on mitochondrial fission/fusion.展开更多
Chronic stress is strongly associated with the occurrence and development of depression and cardiovascular disease.Stress can induce altered mitochondrial function and activation of apoptosis in the cardio-cerebral sy...Chronic stress is strongly associated with the occurrence and development of depression and cardiovascular disease.Stress can induce altered mitochondrial function and activation of apoptosis in the cardio-cerebral system.However,it is unknown whether the protein kinase C ε(PKCε)-aldehyde dehydrogenase 2(ALDH2) pathway is altered under chronic stress,and this study sought to address this question.A rat model of depression was established using a chronic unpredictable mild stress(CUMS) protocol.After experiencing CUMS for 4 weeks,the sucrose preference test and the forced swim test verified depressive-like behaviors.Enzyme linked immunosorbent assays showed that ALDH2 activity was decreased in the rat hippocampus and prefrontal cortex,but was not altered in the myocardium.Western blot assays demonstrated reduced levels of ALDH2 and PKCε,but increased levels of 4-hydroxy-2-nonenal(4 HNE) adducts.Caspase-3 expression did not obviously alter,but active forms of caspase-3 were increased in the hippocampus and prefrontal cortex.In the myocardium,expression of ALDH2,PKCε and 4 HNE adducts did not remarkably alter;while caspase-3 expression was reduced and the active forms of caspase-3 were upregulated.Pearson's correlation test demonstrated that expression of 4 HNE adducts was positively correlated with levels of the active forms of caspase-3 in the hippocampus and prefrontal cortex,but not in the myocardium.In conclusion,chronic stress can damage the PKCε-ALDH2 signaling pathway in the hippocampus and prefrontal cortex,but not in the myocardium.Moreover,4 HNE is associated with active forms of caspase-3 in the hippocampus and prefrontal cortex.展开更多
Background:Nitroglycerin (NTG) is one of the few immediate treatments for acute angina.Aldehyde dehydrogenase 2 (ALDH2) is a key enzyme in the human body that facilitates the biological metabolism of NTG.The biol...Background:Nitroglycerin (NTG) is one of the few immediate treatments for acute angina.Aldehyde dehydrogenase 2 (ALDH2) is a key enzyme in the human body that facilitates the biological metabolism of NTG.The biological mechanism of NTG serves an important function in NTG efficacy.Some reports still contradict the results that the correlation between ALDH2 gene polymorphisms and NTG and its clinical efficacy is different.However,data on NTG measurement by pain relief are subjective.This study aimed to investigate the influence ofALDH2 gene polymorphism on intervention with sublingual NTG using noninvasive hemodynamic parameters of cardiac output (CO) and systemic vascular resistance (SVR) in Northern Chinese Han population.Methods:This study selected 559 patients from the Affiliated Hospital of Qingdao University.A total of 203 patients presented with coronary heart disease (CHD) and 356 had non-CHD (NCHD) cases.All patient ALDH2 genotypes (G504A) were detected and divided into two types:Wild (GG) and mutant (GA/AA).Among the CHD group,103 were wild-type cases,and 100 were mutant-type cases.Moreover,196 cases were wild-type,and 160 cases were mutant type among the NCHD volunteers.A noninvasive hemodynamic detector was used to monitor the CO and the SVR at the 0,5,and 15 minute time points after medication with 0.5 mg sublingual NTG.Two CO and SVR indicators were used for a comparative analysis of all case genotypes.Results:Both CO and SVR indicators significantly differed between the wild and mutant genotypes at various time points after intervention with sublingual NTG at 5 and 15 minutes in the NCHD (F =16.460,15.003,P =0.000,0.000) and CHD groups (F =194.482,60.582,P =0.000,0.000).All CO values in the wild-type case of both NCHD and CHD groups increased,whereas those in the mutant type decreased.The CO and △CO differences were statistically significant (P 〈 0.05; P 〈 0.05).The SVR and △SVR changed between the wild-and mutant-type cases at all-time points in both NCHD and CHD groups had statistically significant differences (P 〈 0.05; P 〈 0.05).Conclusion:ALDH2 (G504A) gene polymorphism is associated with changes in noninvasive hemodynamic parameters (i.e.CO and SVR) after intervention with sublingual NTG.This gene polymorphism may influence the effect of NTG intervention on Northern Chinese Han population.展开更多
Background: Aldehyde dehydrogenase 2 (ALDH2) is involved in the pathophysiological processes of cardiovascular diseases. Recent studies showed that mutant ALDH2 could increase oxidative stress and is a susceptible ...Background: Aldehyde dehydrogenase 2 (ALDH2) is involved in the pathophysiological processes of cardiovascular diseases. Recent studies showed that mutant ALDH2 could increase oxidative stress and is a susceptible factor for hypertension. In addition, wild-type ALDH2 could improve the endothelial functions, therefore reducing the risk of developing atherosclerosis. The aim of the present study was to explore the frequency of the Glu504Lys polymorphism of the ALDH2 gene and its relation to carotid intima-media thickness (CIMT) in a group of patients with essential hypertension (EH) and to investigate the association between the Glu504Lys polymorphism and CIMT in Chinese Han patients with EH. Methods: In this study, 410 Chinese Han patients with EH who received physical examinations at the People's Hospital of Sichuan Province (China) were selected. DNA microarray chip was used for the genotyping of the Glu504Lys polymorphism of the ALDH2 gene. The differences in CIMT among patients with different Glu504Lys ALDH2 genotypes were analyzed. Results: The mean CIMT of the patients carrying AA/AG and GG genotypes was 1.02 ± 0.31 mm and 0.78 ±0.28 mm, respectively. One-way ANOVA showed that the CIMT of the patients carrying the AA/AG genotype was significantly higher than in the ones carrying the GG genotype (P 〈 0.001). Multivariate logistic regression showed that the Glu504Lys AA/AG genotype of the ALDH2 gene was one of the major factors influencing the CIMT in patients with EH (odds ratio = 3.73 l, 95% confidence interval = 1.589-8.124, P = 0.001). Conclusions: The Glu504Lys polymorphism of the ALDH2 gene is associated with the CIMT of Chinese Han patients with EH in Sichuan, China.展开更多
AIM:To demonstrate the possible associations between genetic polymorphisms of aldehyde dehydrogenase-2(ALDH2) and esophageal squamous cell dysplasia(ESCD).METHODS:All participants came from an area of high incidence o...AIM:To demonstrate the possible associations between genetic polymorphisms of aldehyde dehydrogenase-2(ALDH2) and esophageal squamous cell dysplasia(ESCD).METHODS:All participants came from an area of high incidence of esophageal cancer and underwent an endoscopic staining examination;biopsies were taken from a non-staining area of the mucosa and diagnosed by histopathology.Based on the examinations,the subjects were divided into the control group with normal esophageal squamous epithelial cells and the ESCD group.ALDH2 genotypes of 396 cases were determined including 184 ESCD cases and 212 controls.The odds ratio(OR) and 95% confidence intervals(95% CI) were calculated by binary logistic regression models.RESULTS:The distribution of ALDH2 genotypes showed significant differences between the two groups.The adjustment factors were gender and age in the logistic regression models.Compared with 2*2/2*2 genotype,2*1/2*1 genotype was found to be a risk factor for ESCD,and the OR(95% CI) was 4.50(2.21-9.19).There were significant correlations between ALDH2 genotypes and alcohol drinking/smoking/history of esophageal cancer.CONCLUSION:The ALDH2 polymorphism is significantly associated with ESCD.展开更多
11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) and type 2 (11β-HSD2) are expressed in rat testis, where they regulate the local concentrations of glucocorticoids. Here, we investigated the expression and lo...11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) and type 2 (11β-HSD2) are expressed in rat testis, where they regulate the local concentrations of glucocorticoids. Here, we investigated the expression and localization of 11β-HSD in rat testis during postnatal development, and the regulation of these genes by luteinizing hormone (LH) and androgens, mRNA and protein levels were analyzed by quantitative real-time-polymerase chain reaction and western blotting, respectively, in testes collected from rats at postnatal day (PND) 7, 14, 21, 35, and 90, and from rats treated with LH, 7α.methyl-19-nortestosterone (MENT) and testosterone at PND 21 and PND 90. Immunohistochemical staining was used to identify the localization of the 11β-HSD in rat testis at PND 7, 14, and 90. We found that 11β-HSD1 expression was restricted to the interstitial areas, and that its levels increased during rat testis development. In contrast, whereas 11β-HSD2 was expressed in both the interstitial areas and seminiferous tubules at PND 7, it was present only in the interstitial areas at PND 90, and its levels declined during testicular development. Moreover, 11β-HSD1 mRNA was induced by LH in both the PND 21 and 90 testes and by MENT at PND 21, whereas 11β-HSD2 mRNA was induced by testosterone and MENT in the PND 21 testis and by LH in the PND 90 testis. In conclusion, our study indicates that the 11β-HSD1 and 11β-HSD2 genes have distinct patterns of spatiotemporal expression and hormonal regulation during postnatal development of the rat testis.展开更多
Methylenetetrahydrofolate dehydrogenase 2 (MTHFD2) is a mitochondrial enzyme that plays an important role in purinecarbon metabolism and thymidine biosynthesis. It has attracted broad interest as a novel therapeutic t...Methylenetetrahydrofolate dehydrogenase 2 (MTHFD2) is a mitochondrial enzyme that plays an important role in purinecarbon metabolism and thymidine biosynthesis. It has attracted broad interest as a novel therapeutic target for cancer. However, a major problem of current MTHFD2 inhibitors is their lack of selectivity and reactivity with its closest isoform, MTHFD1. Recently, the first selective MTHFD2 inhibitor, DS44960156, has been reported and it exhibits a more than 18-fold selectivity for MTHFD2 over MTHFD1. However, mechanism of DS44960156 selective binding to MTHFD2 over MTHFD1 is unknown. In this study, molecular docking, molecular dynamics (MD) simulations, molecular mechanics generalized born/surface area (MM_GBSA) binding free energy calculations, and analysis of the decomposition of binding free energies were used to investigate the selective binding mechanism of DS44960156 to the folate-binding site of MTHFD2 over MTHFD1. The results revealed that contributions from residues Gln100/Gln132, Val55/Asn87, and Gly237/Gly310 in the binding pocket of MTHFD1/MTHFD2 are the key factors responsible for the binding selectivity. These findings explain the selectivity of DS44960156 to MTHFD2 over MTHFD1, and may provide guidance for the future study and design of novel MTHFD2 inhibitors.展开更多
Primary cultures of rat cortical neurons were treated with H2O2 in an in vitro model of free radical neurotoxicity. Flavonoids extracted from the stems and leaves of Scutellaria baicalensis Georgi, known as SSF, at co...Primary cultures of rat cortical neurons were treated with H2O2 in an in vitro model of free radical neurotoxicity. Flavonoids extracted from the stems and leaves of Scutellaria baicalensis Georgi, known as SSF, at concentrations of 18.98, 37.36 and 75.92 μg/mL, protected neurons against H2O2 injury in a dose-dependent manner. SSF increased cell survival, reduced lactate dehydrogenase release and inhibited malondialdehyde production. SSF also inhibited reductions in superoxide dismutase, glutathione peroxidase and Na+-K+-ATPase activities. These results in-dicate that SSF can protect rat cortical neurons against H2O2-induced oxidative injury.展开更多
Objective:To investigate the changes of serum carcinoembryonic antigen (CEA), carbohydrate antigen 125 (CA125), lactate dehydrogenase (LDH) andβ2-microglobulin (β2-MG) in patients with malignant lymphoma.Methods: A ...Objective:To investigate the changes of serum carcinoembryonic antigen (CEA), carbohydrate antigen 125 (CA125), lactate dehydrogenase (LDH) andβ2-microglobulin (β2-MG) in patients with malignant lymphoma.Methods: A total of 71 patients with malignant lymphoma treated in our hospital from April 2015 to April 2017 were selected. All patients were treated with first-line chemotherapy CHOP, with 28 d as the 1 cycle and continuous chemotherapy for 4 cycles. CEA andβ2-MG were detected by fluorescence immunoassay, CA125 by enzyme-linked immunosorbent assay and LHD by rate method. The changes of serum CEA, CA125, LDH andβ2-MG levels were compared in patients with different stages, different curative effects and 1-year survival and death.Results: The levels of serum CEA, CA125, LDH andβ2-MG in stage III-IV were higher than those in stage I-II. The levels of serum CEA, CA125, LDH andβ2-MG in the ineffective patients were significantly higher than those in the effective patients. The levels of serum CEA, CA125, LDH andβ2-MG in the death group were higher than those in the survival group.Conclusion: The serum levels of CEA, CA125, LDH andβ2-MG in patients with malignant lymphoma increase with the increase of clinical stages and poor prognosis, which can be used as an effective indicator for the condition, treatment and prognosis of patients with malignant lymphoma.展开更多
Background Endogenous aldehyde damages DNA and potentiates an ageing phenotype. The aldehyde dehydrogenase 2(ALDH2) rs671 polymorphism has a prevalence of 30%–50% in Asian populations. In this study, we aimed to anal...Background Endogenous aldehyde damages DNA and potentiates an ageing phenotype. The aldehyde dehydrogenase 2(ALDH2) rs671 polymorphism has a prevalence of 30%–50% in Asian populations. In this study, we aimed to analyze risk factors contributing to the development of heart failure with preserved ejection fraction(HFpEF) along with the genetic exposure in Chinese patients hospitalized with cardiovascular diseases(CVD). Methods From July 2017 to October 2018, a total of 770 consecutive Chinese patients with normal left ventricular ejection fractions(LVEF) and established CVD(hypertension, coronary heart diseases, or diabetes) were enrolled in this prospective cross-sectional study. HFpEF was defined by the presence of at least one of symptom(dyspnoea and fatigue) or sign(rales and ankle swelling) related to heart failure;N-terminal pro-B-Type natriuretic peptide(NT pro-BNP ≥ 280 pg/mL);LVEF ≥ 50%;and at least one criterion related to elevated ventricular filling pressure or diastolic dysfunction(left atrial diameter > 40 mm, E/E’ ≥ 13, E’/A’ < 1 or concurrent atrial fibrillation). Logistic regression was performed to yield adjusted odds ratios(ORs) for HFp EF incidence associated with traditional and/or genetic exposures. Results Finally, among 770 patients with CVD, 92(11.9%) patients were classified into the HFpEF group according to the diagnostic criteria. The mean age of the participants was 67 ± 12 years, and 278(36.1%) patients were females. A total of 303(39.4%) patients were ALDH2*2 variant carriers. In the univariate analysis, eight exposures were found to be associated with HFpEF: atrial fibrillation, ALDH2*2 variants, hypertension, age, anaemia, smoking, alcohol consumption and sex. Multivariable logistic regression showed that 4 ‘A’ variables(atrial fibrillation, ALDH2*2 variants, age and anaemia) were significantly associated with an increased risk of HFpEF. Atrial fibrillation was associated with a 3.8-fold increased HFpEF risk(95% CI: 2.21–6.61, P < 0.001), and the other three exposures associated with increased HFpEF risk were the ALDH2*2 variant(OR = 2.41, 95% CI: 1.49–3.87, P < 0.001), age(OR = 2.14, 95% CI: 1.27–3.60, P = 0.004), and anaemia(OR = 1.79, 95% CI: 1.05–3.03, P = 0.032). These four variables predicted HFpEF incidence in Chinese CVD patients(C-statistic = 0.745, 95% CI: 0.691–0.800, P < 0.001). Conclusions 4 A traits(atrial fibrillation, ALDH2*2 variants, age and anaemia) were associated with an increased risk of HFpEF in Chinese CVD patients. Our results provide potential clues to the aetiology, pathophysiology and therapeutic targets of HFpEF.展开更多
Background:Excessive alcohol intake with hepatitis B virus(HBV)infection accelerates chronic liver disease progression and patients with HBV infection are more susceptible to alcohol-induced liver disease.Hepatitis B ...Background:Excessive alcohol intake with hepatitis B virus(HBV)infection accelerates chronic liver disease progression and patients with HBV infection are more susceptible to alcohol-induced liver disease.Hepatitis B virus X protein(HBx)plays a crucial role in disease pathogenesis,while its specific role in alcoholic liver disease(ALD)progression has not yet been elucidated.Here,we studied the role of HBx on the development of ALD.Methods:HBx-transgenic(HBx-Tg)mice and their wild-type littermates were exposed to chronic plus binge alcohol feeding.Primary hepatocytes,cell lines,and human samples were used to investigate the interaction between HBx and acetaldehyde dehydrogenase 2(ALDH2).Lipid profiles in mouse livers and cells were assessed by using liquid chromatography–mass spectrometry.Results:We identified that HBx significantly aggravated alcohol-induced steatohepatitis,oxidative stress,and lipid peroxidation in mice.In addition,HBx induced worse lipid profiles with high lysophospholipids generation in alcoholic steatohepatitis,as shown by using lipidomic analysis.Importantly,serum and liver acetaldehyde were markedly higher in alcoholfed HBx-Tg mice.Acetaldehyde induced lysophospholipids generation through oxidative stress in hepatocytes.Mechanistically,HBx directly bound to mitochondrial ALDH2 to induce its ubiquitin–proteasome degradation,resulting in acetaldehyde accumulation.More importantly,we also identified that patients with HBV infection reduced ALDH2 protein levels in the liver.Conclusions:Our study demonstrated that HBx-induced ubiquitin-dependent degradation of mitochondrial ALDH2 aggravates alcoholic steatohepatitis.展开更多
BACKGROUND Schizophrenia afflicts 1%of the world population.Clinical studies suggest that schizophrenia patients may have an imbalance of mitochondrial energy metabolism via inhibition of mitochondrial complex I activ...BACKGROUND Schizophrenia afflicts 1%of the world population.Clinical studies suggest that schizophrenia patients may have an imbalance of mitochondrial energy metabolism via inhibition of mitochondrial complex I activity.Moreover,recent studies have shown that ERVWE1 is also a risk factor for schizophrenia.Nevertheless,there is no available literature concerning the relationship between complex I deficits and ERVWE1 in schizophrenia.Identifying risk factors and blood-based biomarkers for schizophrenia may provide new guidelines for early interventions and prevention programs.AIM To address novel potential risk factors and the underlying mechanisms of mitochondrial complex I deficiency caused by ERVWE1 in schizophrenia.METHODS Quantitative polymerase chain reaction(qPCR)and enzyme-linked immunosorbent assay were used to detect differentially expressed risk factors in blood samples.Clinical statistical analyses were performed by median analyses and Mann-Whitney U analyses.Spearman’s rank correlation was applied to examine the correlation between different risk factors in blood samples.qPCR,western blot analysis,and luciferase assay were performed to confirm the relationship among ERVWE1,cytoplasmic polyadenylation element-binding protein 1(CPEB1),NADH dehydrogenase ubiquinone flavoprotein 2(NDUFV2),and NDUFV2 pseudogene(NDUFV2P1).The complex I enzyme activity microplate assay was carried out to evaluate the complex I activity induced by ERVWE1.RESULTS Herein,we reported decreasing levels of CPEB1 and NDUFV2 in schizophrenia patients.Further studies showed that ERVWE1 was negatively correlated with CPEB1 and NDUFV2 in schizophrenia.Moreover,NDUFV2P1 was increased and demonstrated a significant positive correlation with ERVWE1 and a negative correlation with NDUFV2 in schizophrenia.In vitro experiments disclosed that ERVWE1 suppressed NDUFV2 expression and promoter activity by increasing NDUFV2P1 level.The luciferase assay revealed that ERVWE1 could enhance the promoter activity of NDUFV2P1.Additionally,ERVWE1 downregulated the expression of CPEB1 by suppressing the promoter activity,and the 400 base pair sequence at the 3′terminus of the promoter was the minimum sequence required.Advanced studies showed that CPEB1 participated in regulating the NDUFV2P1/NDUFV2 axis mediated by ERVWE1.Finally,we found that ERVWE1 inhibited complex I activity in SH-SY5Y cells via the CPEB1/NDUFV2P1/NDUFV2 signaling pathway.CONCLUSION In conclusion,CPEB1 and NDUFV2 might be novel potential blood-based biomarkers and pathogenic factors in schizophrenia.Our findings also reveal a novel mechanism of ERVWE1 in the etiology of schizophrenia.展开更多
Acute myeloid leukaemia(AML) is the most common form of acute leukaemia in adults,with increasing incidence with age and a generally poor prognosis.Almost 20% of AML patients express mutant isocitrate dehydrogenase 2(...Acute myeloid leukaemia(AML) is the most common form of acute leukaemia in adults,with increasing incidence with age and a generally poor prognosis.Almost 20% of AML patients express mutant isocitrate dehydrogenase 2(mIDH2),which leads to the accumulation of the carcinogenic metabolite 2-hydroxyglutarate(2-HG),resulting in poor prognosis.Thus,global institutions have been working to develop mIDH2 inhibitors.SH1573 is a novel mIDH2 inhibitor that we independently designed and synthesised.We have conducted a comprehensive study on its pharmacodynamics,pharmacokinetics and safety.First,SH1573 exhibited a strong selective inhibition of mIDH2 R140 Q protein,which could effectively reduce the production of 2-HG in cell lines,serum and tumors of an animal model.It could also promote the differentiation of mutant AML cell lines and granulocytes in PDX models.Then,it was confirmed that SH1573 possessed characteristics of high bioavailability,good metabolic stability and wide tissue distribution.Finally,toxicological data showed that SH1573 had no effects on the respiratory system,cardiovascular system and nervous system,and was genetically safe.This research successfully promoted the approval of SH1573 for clinical trials(CTR20200247).All experiments demonstrated that,as a potential drug against mIDH2 R140 Q acute myeloid leukaemia,SH1573 was effective and safe.展开更多
Aldehyde dehydrogenase 2(ALDH2)is a key enzyme of alcohol metabolism and it is involved in the cellular mechanism of alcohol liver disease.ALDH2 gene mutations exist in about 8%of the world’s population,with the inci...Aldehyde dehydrogenase 2(ALDH2)is a key enzyme of alcohol metabolism and it is involved in the cellular mechanism of alcohol liver disease.ALDH2 gene mutations exist in about 8%of the world’s population,with the incidence reaching 45%in East Asia.The mutations will result in impairment of enzyme activity and accumulation of acetaldehyde,facilitating the progression of other liver diseases,including non-alcoholic fatty liver diseases,viral hepatitis and hepatocellular carcinoma,through adduct formation and inflammatory responses.In this review,we seek to summarize recent research progress on the correlation between ALDH2 gene polymorphism and multiple liver diseases,with an attempt to provide clues for better understanding of the disease mechanism and for strategy making.展开更多
Gene polymorphism of acetaldehyde dehydrogenase 2(ALDH2),a key enzyme for alcohol metabolism in humans,can affect catalytic activity.The ALDH2 Glu504Lys mutant allele has a high-frequency distribution in East Asian po...Gene polymorphism of acetaldehyde dehydrogenase 2(ALDH2),a key enzyme for alcohol metabolism in humans,can affect catalytic activity.The ALDH2 Glu504Lys mutant allele has a high-frequency distribution in East Asian populations and has been demonstrated to be associated with an increased risk of cardiovascular disease,stroke,and tumors.Available evidence suggests that the evolution of the ALDH2 gene has been influenced by multiple factors.Random mutations pro-duce Glu504Lys,and genetic drift alters the frequency of this allele;additionally,environmental factors such as hepatitis B virus infection and high-elevation hypoxia affect its frequency through selective effects,ultimately resulting in a high frequency of this allele in East Asian populations.Here,the origin,selection,and spread of the ALDH2 Glu504Lys allele are discussed,and an outlook for further research is proposed to realize a precision medical strategy based on the genetic and environmental variations in ALDH2.展开更多
Endometriosis is a common benign gynecological disorder with an enigmatic etiology and pathogenesis.It affects approximately 10%women of reproductive age.Although its etiology and pathogenesis remain poorly understood...Endometriosis is a common benign gynecological disorder with an enigmatic etiology and pathogenesis.It affects approximately 10%women of reproductive age.Although its etiology and pathogenesis remain poorly understood,it is characterized by the elevated local production of estrogen in the endometriotic tissues.In this paper,we review the mechanisms of estrogen biosynthesis and its regulation in endometriosis.展开更多
基金supported by the Natural Science Research Fund Project of Shanghai Ninth People's HospitalShanghai Jiao Tong University School of Medicine of China,No.syz2014-014
文摘Aldehyde dehydrogenase 2(ALDH2)is an important factor in inhibiting oxidative stress and has been shown to protect against renal ischemia/reperfusion injury.Therefore,we hypothesized that ALDH_2 could reduce spinal cord ischemia/reperfusion injury.Spinal cord ischemia/reperfusion injury was induced in rats using the modified Zivin's method of clamping the abdominal aorta.After successful model establishment,the agonist group was administered a daily consumption of 2.5%alcohol.At 7 days post-surgery,the Basso,Beattie,and Bresnahan score significantly increased in the agonist group compared with the spinal cord ischemia/reperfusion injury group.ALDH_2expression also significantly increased and the number of apoptotic cells significantly decreased in the agonist group than in the spinal cord ischemia/reperfusion injury group.Correlation analysis revealed that ALDH_2 expression negatively correlated with the percentage of TUNEL-positive cells(r=-0.485,P〈0.01).In summary,increased ALDH_2 expression protected the rat spinal cord against ischemia/reperfusion injury by inhibiting apoptosis.
基金the National Key R&D Program of China(2017YFC0908700,2017YFC0908703)National Natural Science Foundation of China(81772036,81671952,81873950,81873953,81570401,81571934)+4 种基金National S&T Fundamental Resources Investigation Project(2018FY100600,2018FY100602)Taishan Pandeng Scholar Program of Shandong Province(tspd20181220)Taishan Young Scholar Program of Shandong Province(tsqn20161065,tsqn201812129)Key R&D Program of Shandong Province(2018GSF118003)the Fundamental Research Funds of Shandong University(2018JC011).
文摘BACKGROUND:Disturbance of mitochondrial fi ssion and fusion(termed mitochondrial dynamics)is one of the leading causes of ischemia/reperfusion(I/R)-induced myocardial injury.Previous studies showed that mitochondrial aldehyde dehydrogenase 2(ALDH2)conferred cardioprotective effect against myocardial I/R injury and suppressed I/R-induced excessive mitophagy in cardiomyocytes.However,whether ALDH2 participates in the regulation of mitochondrial dynamics during myocardial I/R injury remains unknown.METHODS:In the present study,we investigated the effect of ALDH2 on mitochondrial dynamics and the underlying mechanisms using the H9c2 cells exposed to hypoxia/reoxygenation(H/R)as an in vitro model of myocardial I/R injury.RESULTS:Cardiomyocyte apoptosis was significantly increased after oxygen-glucose deprivation and reoxygenation(OGD/R),and ALDH2 activation largely decreased the cardiomyocyte apoptosis.Additionally,we found that both ALDH2 activation and overexpression significantly inhibited the increased mitochondrial fission after OGD/R.Furthermore,we found that ALDH2 dominantly suppressed dynamin-related protein 1(Drp1)phosphorylation(Ser616)and adenosine monophosphate-activated protein kinase(AMPK)phosphorylation(Thr172)but not interfered with the expression levels of mitochondrial shaping proteins.CONCLUSIONS:We demonstrate the protective effect of ALDH2 against cardiomyocyte H/R injury with a novel mechanism on mitochondrial fission/fusion.
基金supported by the Medical Research Fund of Guangdong Province of China,No.B2014449a grant from the Science and Technology Project of Zhongshan City of China,No.2014A1FC137
文摘Chronic stress is strongly associated with the occurrence and development of depression and cardiovascular disease.Stress can induce altered mitochondrial function and activation of apoptosis in the cardio-cerebral system.However,it is unknown whether the protein kinase C ε(PKCε)-aldehyde dehydrogenase 2(ALDH2) pathway is altered under chronic stress,and this study sought to address this question.A rat model of depression was established using a chronic unpredictable mild stress(CUMS) protocol.After experiencing CUMS for 4 weeks,the sucrose preference test and the forced swim test verified depressive-like behaviors.Enzyme linked immunosorbent assays showed that ALDH2 activity was decreased in the rat hippocampus and prefrontal cortex,but was not altered in the myocardium.Western blot assays demonstrated reduced levels of ALDH2 and PKCε,but increased levels of 4-hydroxy-2-nonenal(4 HNE) adducts.Caspase-3 expression did not obviously alter,but active forms of caspase-3 were increased in the hippocampus and prefrontal cortex.In the myocardium,expression of ALDH2,PKCε and 4 HNE adducts did not remarkably alter;while caspase-3 expression was reduced and the active forms of caspase-3 were upregulated.Pearson's correlation test demonstrated that expression of 4 HNE adducts was positively correlated with levels of the active forms of caspase-3 in the hippocampus and prefrontal cortex,but not in the myocardium.In conclusion,chronic stress can damage the PKCε-ALDH2 signaling pathway in the hippocampus and prefrontal cortex,but not in the myocardium.Moreover,4 HNE is associated with active forms of caspase-3 in the hippocampus and prefrontal cortex.
文摘Background:Nitroglycerin (NTG) is one of the few immediate treatments for acute angina.Aldehyde dehydrogenase 2 (ALDH2) is a key enzyme in the human body that facilitates the biological metabolism of NTG.The biological mechanism of NTG serves an important function in NTG efficacy.Some reports still contradict the results that the correlation between ALDH2 gene polymorphisms and NTG and its clinical efficacy is different.However,data on NTG measurement by pain relief are subjective.This study aimed to investigate the influence ofALDH2 gene polymorphism on intervention with sublingual NTG using noninvasive hemodynamic parameters of cardiac output (CO) and systemic vascular resistance (SVR) in Northern Chinese Han population.Methods:This study selected 559 patients from the Affiliated Hospital of Qingdao University.A total of 203 patients presented with coronary heart disease (CHD) and 356 had non-CHD (NCHD) cases.All patient ALDH2 genotypes (G504A) were detected and divided into two types:Wild (GG) and mutant (GA/AA).Among the CHD group,103 were wild-type cases,and 100 were mutant-type cases.Moreover,196 cases were wild-type,and 160 cases were mutant type among the NCHD volunteers.A noninvasive hemodynamic detector was used to monitor the CO and the SVR at the 0,5,and 15 minute time points after medication with 0.5 mg sublingual NTG.Two CO and SVR indicators were used for a comparative analysis of all case genotypes.Results:Both CO and SVR indicators significantly differed between the wild and mutant genotypes at various time points after intervention with sublingual NTG at 5 and 15 minutes in the NCHD (F =16.460,15.003,P =0.000,0.000) and CHD groups (F =194.482,60.582,P =0.000,0.000).All CO values in the wild-type case of both NCHD and CHD groups increased,whereas those in the mutant type decreased.The CO and △CO differences were statistically significant (P 〈 0.05; P 〈 0.05).The SVR and △SVR changed between the wild-and mutant-type cases at all-time points in both NCHD and CHD groups had statistically significant differences (P 〈 0.05; P 〈 0.05).Conclusion:ALDH2 (G504A) gene polymorphism is associated with changes in noninvasive hemodynamic parameters (i.e.CO and SVR) after intervention with sublingual NTG.This gene polymorphism may influence the effect of NTG intervention on Northern Chinese Han population.
文摘Background: Aldehyde dehydrogenase 2 (ALDH2) is involved in the pathophysiological processes of cardiovascular diseases. Recent studies showed that mutant ALDH2 could increase oxidative stress and is a susceptible factor for hypertension. In addition, wild-type ALDH2 could improve the endothelial functions, therefore reducing the risk of developing atherosclerosis. The aim of the present study was to explore the frequency of the Glu504Lys polymorphism of the ALDH2 gene and its relation to carotid intima-media thickness (CIMT) in a group of patients with essential hypertension (EH) and to investigate the association between the Glu504Lys polymorphism and CIMT in Chinese Han patients with EH. Methods: In this study, 410 Chinese Han patients with EH who received physical examinations at the People's Hospital of Sichuan Province (China) were selected. DNA microarray chip was used for the genotyping of the Glu504Lys polymorphism of the ALDH2 gene. The differences in CIMT among patients with different Glu504Lys ALDH2 genotypes were analyzed. Results: The mean CIMT of the patients carrying AA/AG and GG genotypes was 1.02 ± 0.31 mm and 0.78 ±0.28 mm, respectively. One-way ANOVA showed that the CIMT of the patients carrying the AA/AG genotype was significantly higher than in the ones carrying the GG genotype (P 〈 0.001). Multivariate logistic regression showed that the Glu504Lys AA/AG genotype of the ALDH2 gene was one of the major factors influencing the CIMT in patients with EH (odds ratio = 3.73 l, 95% confidence interval = 1.589-8.124, P = 0.001). Conclusions: The Glu504Lys polymorphism of the ALDH2 gene is associated with the CIMT of Chinese Han patients with EH in Sichuan, China.
基金Supported by The Project of National Natural Science Foundation of China,No.30571601the 2004 Key Special Project of Scientific and Technological Development in Shandong Province,China,No.2004GG1108039the 2007 Special Foundation for Postdoctoral Innovation Subject in Shandong Province of China,No.200702034
文摘AIM:To demonstrate the possible associations between genetic polymorphisms of aldehyde dehydrogenase-2(ALDH2) and esophageal squamous cell dysplasia(ESCD).METHODS:All participants came from an area of high incidence of esophageal cancer and underwent an endoscopic staining examination;biopsies were taken from a non-staining area of the mucosa and diagnosed by histopathology.Based on the examinations,the subjects were divided into the control group with normal esophageal squamous epithelial cells and the ESCD group.ALDH2 genotypes of 396 cases were determined including 184 ESCD cases and 212 controls.The odds ratio(OR) and 95% confidence intervals(95% CI) were calculated by binary logistic regression models.RESULTS:The distribution of ALDH2 genotypes showed significant differences between the two groups.The adjustment factors were gender and age in the logistic regression models.Compared with 2*2/2*2 genotype,2*1/2*1 genotype was found to be a risk factor for ESCD,and the OR(95% CI) was 4.50(2.21-9.19).There were significant correlations between ALDH2 genotypes and alcohol drinking/smoking/history of esophageal cancer.CONCLUSION:The ALDH2 polymorphism is significantly associated with ESCD.
文摘11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) and type 2 (11β-HSD2) are expressed in rat testis, where they regulate the local concentrations of glucocorticoids. Here, we investigated the expression and localization of 11β-HSD in rat testis during postnatal development, and the regulation of these genes by luteinizing hormone (LH) and androgens, mRNA and protein levels were analyzed by quantitative real-time-polymerase chain reaction and western blotting, respectively, in testes collected from rats at postnatal day (PND) 7, 14, 21, 35, and 90, and from rats treated with LH, 7α.methyl-19-nortestosterone (MENT) and testosterone at PND 21 and PND 90. Immunohistochemical staining was used to identify the localization of the 11β-HSD in rat testis at PND 7, 14, and 90. We found that 11β-HSD1 expression was restricted to the interstitial areas, and that its levels increased during rat testis development. In contrast, whereas 11β-HSD2 was expressed in both the interstitial areas and seminiferous tubules at PND 7, it was present only in the interstitial areas at PND 90, and its levels declined during testicular development. Moreover, 11β-HSD1 mRNA was induced by LH in both the PND 21 and 90 testes and by MENT at PND 21, whereas 11β-HSD2 mRNA was induced by testosterone and MENT in the PND 21 testis and by LH in the PND 90 testis. In conclusion, our study indicates that the 11β-HSD1 and 11β-HSD2 genes have distinct patterns of spatiotemporal expression and hormonal regulation during postnatal development of the rat testis.
文摘Methylenetetrahydrofolate dehydrogenase 2 (MTHFD2) is a mitochondrial enzyme that plays an important role in purinecarbon metabolism and thymidine biosynthesis. It has attracted broad interest as a novel therapeutic target for cancer. However, a major problem of current MTHFD2 inhibitors is their lack of selectivity and reactivity with its closest isoform, MTHFD1. Recently, the first selective MTHFD2 inhibitor, DS44960156, has been reported and it exhibits a more than 18-fold selectivity for MTHFD2 over MTHFD1. However, mechanism of DS44960156 selective binding to MTHFD2 over MTHFD1 is unknown. In this study, molecular docking, molecular dynamics (MD) simulations, molecular mechanics generalized born/surface area (MM_GBSA) binding free energy calculations, and analysis of the decomposition of binding free energies were used to investigate the selective binding mechanism of DS44960156 to the folate-binding site of MTHFD2 over MTHFD1. The results revealed that contributions from residues Gln100/Gln132, Val55/Asn87, and Gly237/Gly310 in the binding pocket of MTHFD1/MTHFD2 are the key factors responsible for the binding selectivity. These findings explain the selectivity of DS44960156 to MTHFD2 over MTHFD1, and may provide guidance for the future study and design of novel MTHFD2 inhibitors.
基金the State Administration of Traditional Chinese Medicine, People’s Republic of China, No.02-03-ZP18Hebei Provincial Education Department,No. 20015Hebei Provincial Hundred Outstanding Innovated Talents, First Batch
文摘Primary cultures of rat cortical neurons were treated with H2O2 in an in vitro model of free radical neurotoxicity. Flavonoids extracted from the stems and leaves of Scutellaria baicalensis Georgi, known as SSF, at concentrations of 18.98, 37.36 and 75.92 μg/mL, protected neurons against H2O2 injury in a dose-dependent manner. SSF increased cell survival, reduced lactate dehydrogenase release and inhibited malondialdehyde production. SSF also inhibited reductions in superoxide dismutase, glutathione peroxidase and Na+-K+-ATPase activities. These results in-dicate that SSF can protect rat cortical neurons against H2O2-induced oxidative injury.
文摘Objective:To investigate the changes of serum carcinoembryonic antigen (CEA), carbohydrate antigen 125 (CA125), lactate dehydrogenase (LDH) andβ2-microglobulin (β2-MG) in patients with malignant lymphoma.Methods: A total of 71 patients with malignant lymphoma treated in our hospital from April 2015 to April 2017 were selected. All patients were treated with first-line chemotherapy CHOP, with 28 d as the 1 cycle and continuous chemotherapy for 4 cycles. CEA andβ2-MG were detected by fluorescence immunoassay, CA125 by enzyme-linked immunosorbent assay and LHD by rate method. The changes of serum CEA, CA125, LDH andβ2-MG levels were compared in patients with different stages, different curative effects and 1-year survival and death.Results: The levels of serum CEA, CA125, LDH andβ2-MG in stage III-IV were higher than those in stage I-II. The levels of serum CEA, CA125, LDH andβ2-MG in the ineffective patients were significantly higher than those in the effective patients. The levels of serum CEA, CA125, LDH andβ2-MG in the death group were higher than those in the survival group.Conclusion: The serum levels of CEA, CA125, LDH andβ2-MG in patients with malignant lymphoma increase with the increase of clinical stages and poor prognosis, which can be used as an effective indicator for the condition, treatment and prognosis of patients with malignant lymphoma.
基金supported by the he National Natural Science Foundation of China (No. 81770441, No. 81700398, No. 81970309)Nanjing Municipal Healthcare Grant YKK16127
文摘Background Endogenous aldehyde damages DNA and potentiates an ageing phenotype. The aldehyde dehydrogenase 2(ALDH2) rs671 polymorphism has a prevalence of 30%–50% in Asian populations. In this study, we aimed to analyze risk factors contributing to the development of heart failure with preserved ejection fraction(HFpEF) along with the genetic exposure in Chinese patients hospitalized with cardiovascular diseases(CVD). Methods From July 2017 to October 2018, a total of 770 consecutive Chinese patients with normal left ventricular ejection fractions(LVEF) and established CVD(hypertension, coronary heart diseases, or diabetes) were enrolled in this prospective cross-sectional study. HFpEF was defined by the presence of at least one of symptom(dyspnoea and fatigue) or sign(rales and ankle swelling) related to heart failure;N-terminal pro-B-Type natriuretic peptide(NT pro-BNP ≥ 280 pg/mL);LVEF ≥ 50%;and at least one criterion related to elevated ventricular filling pressure or diastolic dysfunction(left atrial diameter > 40 mm, E/E’ ≥ 13, E’/A’ < 1 or concurrent atrial fibrillation). Logistic regression was performed to yield adjusted odds ratios(ORs) for HFp EF incidence associated with traditional and/or genetic exposures. Results Finally, among 770 patients with CVD, 92(11.9%) patients were classified into the HFpEF group according to the diagnostic criteria. The mean age of the participants was 67 ± 12 years, and 278(36.1%) patients were females. A total of 303(39.4%) patients were ALDH2*2 variant carriers. In the univariate analysis, eight exposures were found to be associated with HFpEF: atrial fibrillation, ALDH2*2 variants, hypertension, age, anaemia, smoking, alcohol consumption and sex. Multivariable logistic regression showed that 4 ‘A’ variables(atrial fibrillation, ALDH2*2 variants, age and anaemia) were significantly associated with an increased risk of HFpEF. Atrial fibrillation was associated with a 3.8-fold increased HFpEF risk(95% CI: 2.21–6.61, P < 0.001), and the other three exposures associated with increased HFpEF risk were the ALDH2*2 variant(OR = 2.41, 95% CI: 1.49–3.87, P < 0.001), age(OR = 2.14, 95% CI: 1.27–3.60, P = 0.004), and anaemia(OR = 1.79, 95% CI: 1.05–3.03, P = 0.032). These four variables predicted HFpEF incidence in Chinese CVD patients(C-statistic = 0.745, 95% CI: 0.691–0.800, P < 0.001). Conclusions 4 A traits(atrial fibrillation, ALDH2*2 variants, age and anaemia) were associated with an increased risk of HFpEF in Chinese CVD patients. Our results provide potential clues to the aetiology, pathophysiology and therapeutic targets of HFpEF.
基金supported by grants from the National Natural Science Foundation of China[82170604,82070574,82122009]the Natural Science Foundation Team Project of Guangdong Province[2018B03031200].
文摘Background:Excessive alcohol intake with hepatitis B virus(HBV)infection accelerates chronic liver disease progression and patients with HBV infection are more susceptible to alcohol-induced liver disease.Hepatitis B virus X protein(HBx)plays a crucial role in disease pathogenesis,while its specific role in alcoholic liver disease(ALD)progression has not yet been elucidated.Here,we studied the role of HBx on the development of ALD.Methods:HBx-transgenic(HBx-Tg)mice and their wild-type littermates were exposed to chronic plus binge alcohol feeding.Primary hepatocytes,cell lines,and human samples were used to investigate the interaction between HBx and acetaldehyde dehydrogenase 2(ALDH2).Lipid profiles in mouse livers and cells were assessed by using liquid chromatography–mass spectrometry.Results:We identified that HBx significantly aggravated alcohol-induced steatohepatitis,oxidative stress,and lipid peroxidation in mice.In addition,HBx induced worse lipid profiles with high lysophospholipids generation in alcoholic steatohepatitis,as shown by using lipidomic analysis.Importantly,serum and liver acetaldehyde were markedly higher in alcoholfed HBx-Tg mice.Acetaldehyde induced lysophospholipids generation through oxidative stress in hepatocytes.Mechanistically,HBx directly bound to mitochondrial ALDH2 to induce its ubiquitin–proteasome degradation,resulting in acetaldehyde accumulation.More importantly,we also identified that patients with HBV infection reduced ALDH2 protein levels in the liver.Conclusions:Our study demonstrated that HBx-induced ubiquitin-dependent degradation of mitochondrial ALDH2 aggravates alcoholic steatohepatitis.
基金Supported by the National Natural Science Foundation of China,No.81971943,No.81772196,No.31470264,No.81271820,No.30870789,and No.30300117the Stanley Foundation of United States,No.06R-1366(for Zhu F)the Medical Science Advancement Program(Basic Medical Sciences)of Wuhan University,No.TFJC 2018002.
文摘BACKGROUND Schizophrenia afflicts 1%of the world population.Clinical studies suggest that schizophrenia patients may have an imbalance of mitochondrial energy metabolism via inhibition of mitochondrial complex I activity.Moreover,recent studies have shown that ERVWE1 is also a risk factor for schizophrenia.Nevertheless,there is no available literature concerning the relationship between complex I deficits and ERVWE1 in schizophrenia.Identifying risk factors and blood-based biomarkers for schizophrenia may provide new guidelines for early interventions and prevention programs.AIM To address novel potential risk factors and the underlying mechanisms of mitochondrial complex I deficiency caused by ERVWE1 in schizophrenia.METHODS Quantitative polymerase chain reaction(qPCR)and enzyme-linked immunosorbent assay were used to detect differentially expressed risk factors in blood samples.Clinical statistical analyses were performed by median analyses and Mann-Whitney U analyses.Spearman’s rank correlation was applied to examine the correlation between different risk factors in blood samples.qPCR,western blot analysis,and luciferase assay were performed to confirm the relationship among ERVWE1,cytoplasmic polyadenylation element-binding protein 1(CPEB1),NADH dehydrogenase ubiquinone flavoprotein 2(NDUFV2),and NDUFV2 pseudogene(NDUFV2P1).The complex I enzyme activity microplate assay was carried out to evaluate the complex I activity induced by ERVWE1.RESULTS Herein,we reported decreasing levels of CPEB1 and NDUFV2 in schizophrenia patients.Further studies showed that ERVWE1 was negatively correlated with CPEB1 and NDUFV2 in schizophrenia.Moreover,NDUFV2P1 was increased and demonstrated a significant positive correlation with ERVWE1 and a negative correlation with NDUFV2 in schizophrenia.In vitro experiments disclosed that ERVWE1 suppressed NDUFV2 expression and promoter activity by increasing NDUFV2P1 level.The luciferase assay revealed that ERVWE1 could enhance the promoter activity of NDUFV2P1.Additionally,ERVWE1 downregulated the expression of CPEB1 by suppressing the promoter activity,and the 400 base pair sequence at the 3′terminus of the promoter was the minimum sequence required.Advanced studies showed that CPEB1 participated in regulating the NDUFV2P1/NDUFV2 axis mediated by ERVWE1.Finally,we found that ERVWE1 inhibited complex I activity in SH-SY5Y cells via the CPEB1/NDUFV2P1/NDUFV2 signaling pathway.CONCLUSION In conclusion,CPEB1 and NDUFV2 might be novel potential blood-based biomarkers and pathogenic factors in schizophrenia.Our findings also reveal a novel mechanism of ERVWE1 in the etiology of schizophrenia.
基金supported by National Key Research and Development Program of China(No.2017YFA0205200)National Natural Science Foundation of China(Nos.81773766 and 81903845)+1 种基金the Natural Science Foundation of Jiangsu Province(BK20161458,China)the“Double First-Class”University project(No.CPU2018GY38,China)。
文摘Acute myeloid leukaemia(AML) is the most common form of acute leukaemia in adults,with increasing incidence with age and a generally poor prognosis.Almost 20% of AML patients express mutant isocitrate dehydrogenase 2(mIDH2),which leads to the accumulation of the carcinogenic metabolite 2-hydroxyglutarate(2-HG),resulting in poor prognosis.Thus,global institutions have been working to develop mIDH2 inhibitors.SH1573 is a novel mIDH2 inhibitor that we independently designed and synthesised.We have conducted a comprehensive study on its pharmacodynamics,pharmacokinetics and safety.First,SH1573 exhibited a strong selective inhibition of mIDH2 R140 Q protein,which could effectively reduce the production of 2-HG in cell lines,serum and tumors of an animal model.It could also promote the differentiation of mutant AML cell lines and granulocytes in PDX models.Then,it was confirmed that SH1573 possessed characteristics of high bioavailability,good metabolic stability and wide tissue distribution.Finally,toxicological data showed that SH1573 had no effects on the respiratory system,cardiovascular system and nervous system,and was genetically safe.This research successfully promoted the approval of SH1573 for clinical trials(CTR20200247).All experiments demonstrated that,as a potential drug against mIDH2 R140 Q acute myeloid leukaemia,SH1573 was effective and safe.
基金supported by the National Natural Science Foundation of China(NSFC),Grant numbers 81600467 and 81670527.
文摘Aldehyde dehydrogenase 2(ALDH2)is a key enzyme of alcohol metabolism and it is involved in the cellular mechanism of alcohol liver disease.ALDH2 gene mutations exist in about 8%of the world’s population,with the incidence reaching 45%in East Asia.The mutations will result in impairment of enzyme activity and accumulation of acetaldehyde,facilitating the progression of other liver diseases,including non-alcoholic fatty liver diseases,viral hepatitis and hepatocellular carcinoma,through adduct formation and inflammatory responses.In this review,we seek to summarize recent research progress on the correlation between ALDH2 gene polymorphism and multiple liver diseases,with an attempt to provide clues for better understanding of the disease mechanism and for strategy making.
基金supported by National Science Fund for Distinguished Young Scholars(81725002).
文摘Gene polymorphism of acetaldehyde dehydrogenase 2(ALDH2),a key enzyme for alcohol metabolism in humans,can affect catalytic activity.The ALDH2 Glu504Lys mutant allele has a high-frequency distribution in East Asian populations and has been demonstrated to be associated with an increased risk of cardiovascular disease,stroke,and tumors.Available evidence suggests that the evolution of the ALDH2 gene has been influenced by multiple factors.Random mutations pro-duce Glu504Lys,and genetic drift alters the frequency of this allele;additionally,environmental factors such as hepatitis B virus infection and high-elevation hypoxia affect its frequency through selective effects,ultimately resulting in a high frequency of this allele in East Asian populations.Here,the origin,selection,and spread of the ALDH2 Glu504Lys allele are discussed,and an outlook for further research is proposed to realize a precision medical strategy based on the genetic and environmental variations in ALDH2.
基金supported in part by grants 81471434(SWG),81530040(SWG),81370695(XSL),and 81671436(XSL)the National Natural Science Foundation of China.
文摘Endometriosis is a common benign gynecological disorder with an enigmatic etiology and pathogenesis.It affects approximately 10%women of reproductive age.Although its etiology and pathogenesis remain poorly understood,it is characterized by the elevated local production of estrogen in the endometriotic tissues.In this paper,we review the mechanisms of estrogen biosynthesis and its regulation in endometriosis.