Aldehyde dehydrogenase 2 overexpression inhibits neuronal apoptosis after spinal cord ischemia/reperfusion injury

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.

Association of genetic polymorphisms of aldehyde dehydrogenase-2 with esophageal squamous cell dysplasia

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.

Aldehyde dehydrogenase 2 preserves mitochondrial morphology and attenuates hypoxia/reoxygenationinduced cardiomyocyte injury

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.

Chronic stress causes protein kinase C epsilon-aldehyde dehydrogenase 2 signaling pathway perturbation in the rat hippocampus and prefrontal cortex,but not in the myocardium

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.

Transcriptional Regulation of Expression of the Maize Aldehyde Dehydrogenase 7 Gene (ZmALDH7B6) in Response to Abiotic Stresses

Aldehyde dehydrogenases（ALDHs） represent a large protein family, which includes several members that catalyze the oxidation of an aldehyde to its corresponding carboxylic acid in plants. Genes encoding members of the ALDH7 subfamily have been suggested to play important roles in various stress adaptations in plants. In this study, quantitative RT-PCR analysis revealed that a maize ALDH7 subfamily member（ZmALDH7B6） was constitutively expressed in various organs, including roots, leaves, immature ears, tassels, and developing seeds. The abundance of ZmALDH7B6 mRNA transcripts in maize roots was increased by ammonium, NaCl, and mannitol treatments. To further analyze tissue-specific and stress-induced expression patterns, the 1.5-kb 5′-flanking ZmALDH7B6 promoter region was fused to the β-glucuronidase（GUS） reporter gene and introduced into maize plants. In roots of independent transgenic lines, there was significant induction of GUS activity in response to ammonium supply, confirming ammonium-dependent expression of ZmALDH7B6 at the transcript level. Histochemical staining showed that GUS activity driven by the ZmALDH7B6 promoter was mainly localized in the vascular tissues of maize roots. These results suggested that ZmALDH7B6 is induced by multiple environmental stresses in maize roots, and may play a role in detoxifying aldehydes, particularly in vascular tissue.

Functional Characterization of an Aldehyde Dehydrogenase Homologue in Rice

The aldehyde dehydrogenase （ALDH） superfamily of NAD（P）-dependent enzymes, in general, oxidize a wide range of endogenous and exogenous aliphatic and aromatic aldehydes to their corresponding carboxylic acids and play an essential role in detoxification of reactive oxygen species （ROS） accumulated under the stressed conditions. In order to identify genes required for the stresses responses in the grass crop Oryza sativa, a homologue of ALDH gene （OsALDH22） was isolated and characterized. OsALDH22 is conserved in eukaryotes, shares high homology with the orthologs from aldehyde dehydrogenase subfamily ALDH22. The OsALDH22 encodes a protein of 597 amino acids that in plants exhibit high identity with the orthologs from Zea mays, Sorghum bicolor, Hordeum vulgare and Arabidopsis thaliana, respectively, and the conserved amino acid characteristics for ALDHs are present, including the possible NAD~ binding site （F-V-G-S- P-G-V-G）, the catalytic site （V-T-L-E-L-G-G-K） and the Cys active site. Semi-quantitative PCR and real-time PCR analysis indicates that OsALDH22 is expressed differentially in different tissues. Various elevated levels of OsALDH22 expression have been detected when the seedlings exposed to abiotic stresses including dehydration, high salinity and abscisic acid （ABA）. Transgenic rice plants overexpressing OsALDH22 show elevated stresses tolerance. On the contrary, down- 0 regulation of OsALDH22 in the RNA interference （RNAi） repression transgenic lines manifests declined stresses tolerance.

The effect of inactivation of aldehyde dehydrogenase on pheromone production by a gut bacterium of an invasive bark beetle,Dendroctonus valens

Semiochemical-based management strategies are important for controlling bark beetles,such as invasive Red Turpentine Beetle(Denroctonus valens),the causal agent for mass mortality of pine trees(Pinus spp.)in China.It has been previously shown that the pheromone verbenone regulates the attack density of this beetle in a dose-dependent manner and that the gut bacteria of D.valens are involved in verbenone production.However,molecular functional verification of the role of gut bacteria in the pheromone production of D.valens is still lacking.To better understand the molecular function of gut bacterial verbenone production,we chose a facultative anaerobic gut bacterium(Enterobacter xiangfangensis)of D.valens based on its strong ability to convert cis-verbenol to verbenone,as shown in our previous study,and investigated its transcriptomics in the presence or absence of cis-verbenol under anaerobic conditions(simulating the anoxic environment in the beetle's gut).Based on this transcriptome analysis,aldehyde dehydrogenase(ALDH1)was identified as a putative key gene responsible for verbenone production and was knocked-down by homologous recombination to obtain a mutant E.xiangfangensis strain.Our results show that these mutants had significantly decreased the ability to convert the monoterpene precursor to verbenone compared with the wild-type bacteria,indicating that ALDH1 is primarily responsible for verbenone conversion for this bacterium species.These findings provide further mechanistic evidence of bacterially mediated pheromone production by D.valens,add new perspective for functional studies of gut bacteria in general,and may aid the development of new gene silencing-based pest management strategies.

Effect of Aldehyde Dehydrogenase 2 Gene Polymorphism on Hemodynamics After Nitroglycerin Intervention in Northern Chinese Han Population

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.

Association between Carotid Intima-media Thickness and Aldehyde Dehydrogenase 2 Glu504Lys Polymorphism in Chinese Han with Essential Hypertension

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.

Interferon-gamma inhibits aldehyde dehydrogenase^(bright)cancer stem cells in the 4T1 mouse model of breast cancer

Background:Despite improvements in disease diagnosis,treatment,and prognosis,breast cancer is still a leading cause of cancer death for women.Compelling evidence suggests that targeting cancer stem cells(CSCs)have a crucial impact on overcoming the current shortcomings of chemotherapy and radiotherapy.In the present study,we aimed to study the effects of T cells and a critical anti-tumor cytokine,interferon-gamma(IFN-γ),on breast cancer stem cells.Methods:BALB/c mice and BALB/c nude mice were subcutaneously injected with 4T1 tumor cells.Tumor growth and pulmonary metastasis were assessed.ALDEFLOUR™assays were performed to identify aldehyde dehydrogenase^(bright)(ALDH^(br))tumor cells.ALDH^(br)cells as well as T cells from tumor-bearing BALB/c mice were analyzed using flow cytometry.The effects of CD8^(+)T cells on ALDH^(br)tumor cells were assessed in vitro and in vivo.The expression profiles of ALDH^(br)and ALDH^(dim)4T1 tumor cells were determined.The levels of plasma IFN-γwere measured by enzyme-linked immunosorbent assay,and their associations with the percentages of ALDH^(br)tumor cells were evaluated.The effects of IFN-γon ALDH expression and the malignancy of 4T1 tumor cells were analyzed in vitro.Results:There were fewer metastatic nodules in tumor-bearing BALB/c mice than those in tumor-bearing BALB/c nude mice(25.40 vs.54.67,P<0.050).CD8^(+)T cells decreased the percentages of ALDH^(br)4T1 tumor cells in vitro(control vs.effector to target ratio of 1:1,10.15%vs.5.76%,P<0.050)and in vivo(control vs.CD8^(+)T cell depletion,10.15%vs.21.75%,P<0.001).The functions of upregulated genes in ALDH^(br)4T1 tumor cells were enriched in the pathway of response to IFN-γ.The levels of plasma IFN-γdecreased gradually in tumor-bearing BALB/c mice,while the percentages of ALDH^(br)tumor cells in primary tumors increased.IFN-γat a concentration of 26.68 ng/mL decreased the percentages of ALDH^(br)4T1 tumor cells(22.88%vs.9.88%,P<0.050)and the protein levels of aldehyde dehydrogenase 1 family member A1 in 4T1 tumor cells(0.86 vs.0.49,P<0.050)and inhibited the abilities of sphere formation(sphere diameter<200μm,159.50 vs.72.0;≥200μm,127.0 vs.59.0;both P<0.050)and invasion(89.67 vs.67.67,P<0.001)of 4T1 tumor cells.Conclusion:CD8^(+)T cells and IFN-γdecreased CSC numbers in a 4T1 mouse model of breast cancer.The application of IFN-γmay be a potential strategy for reducing CSCs in breast cancer.

Aldehyde Dehydrogenase 1 making molecular inroads into the differential vulnerability of nigrostriatal dopaminergic neuron subtypes in Parkinson’s disease

A preferential dysfunction/loss of dopaminergic(DA)neurons in the substantia nigra pars compacta(SNpc)accounts for the main motor symptoms of Parkinson’s disease(PD),the most common degenerative movement disorder.However,the neuronal loss is not stochastic,but rather displays regionally selectivity,indicating the existence of different DA subpopulations in the SNpc.To identify the underlying molecular determinants is thereby instrumental in understanding the pathophysiological mechanisms of PD-related neuron dysfunction/loss and offering new therapeutic targets.Recently,we have demonstrated that aldehyde dehydrogenase 1(ALDH1A1)is one such molecular determinant that defines and protects an SNpc DA neuron subpopulation preferentially affected in PD.In this review,we provide further analysis and discussion on the roles of ALDH1A1 in the function and survival of SNpc DA neurons in both rodent and human brains.We also explore the feasibility of ALDH1A1 as a potential biomarker and therapeutic target for PD.

Expression and regulation of aldehyde dehydrogenases in prostate cancer

The functional role of aldehyde dehydrogenases(ALDHs)in prostate cancer remains an area of some controversy.Many studies have used high ALDH functional activity to isolate putative cancer stem cells with tumour-initiating and propagating properties,while evidence is also emerging about the involvement of specific isoforms in migration,invasiveness and metastasis.Identification of specific ALDH isoforms,which contribute to both drug resistance and aggressiveness of the disease remains a challenge within the complex heterogeneity of prostate cancer.The purpose of this perspective is to dissect functional roles for ALDH in the tumour microenvironment and to evaluate the potential of the ALDH gene family as biomarkers and/or targets for therapeutic intervention.

Structural Insight into the Substrate Gating Mechanism by Staphylococcus aureus Aldehyde Dehydrogenase

Staphylococcus aureus produces staphyloxanthin,a C30 carotenoid with golden color,as an antioxidant to promote bacterial resistance to reactive oxygen species.The biosynthesis pathway of staphyloxanthin involves a series of catalytic enzymes.Aldehyde dehydrogenase(AldH)is a dehydrogenase recently identified to convert 4,4’-diaponeurosporenaldehyde into 4,4’-diaponeurosporenoic acid during staphyloxanthin biosynthesis.Here,we present the crystallographic structures of apo-and holo-forms of S.aureus AldH.The dimeric enzyme contains a unique C-terminal helix,which resembles a“gatekeeper”helix found in human membrane-bound fatty aldehyde dehydrogenase(FALDH).Particularly,the helix adopts“open”and“closed”conformations in apo-and holo-AldH,respectively,to control the access of the substrate tunnel.Mutagenesis in combination with in vitro and in vivo activity assays identifies several residues essential for S.aureus AldH substrate recognition and enzyme catalytic turnover.Our results provide insights into substrate recognition of S.aureus AldH toward polyunsaturated long-chain aldehydes at atomic resolution.

Association of alcohol dehydrogenase and aldehyde dehydrogenase 2 genetic polymorphisms with serum lipid profile: meta-analysis of mendelian randomisation studies

Background Alcohol dehydrogenase （ADH） and aldehyde dehydrogenase 2 （ALDH2） are the key en- zymes for alcohol metabolism. Several genetic studies have investigated the association between ADH and ALDH2 genetic polymorphisms and serum lipid profile （SLP）, however, the results were inconsistent. Methods Fourteen articles involving 27,917 participants were included in this meta-analysis. Weighted mean difference （WMD） and 95% confidence intervals （CIs） were presented using random effects model. Publication bias was evaluated by funnel plot and Begg＇s test. In addition, to further explore the heterogeneity, subgroup analysis were performed. Results Overall, there was no association between ADH genetic polymorphisms and SLP with no regard for drinking status. However, compared with ALDH2 wild homozygous genotype, ALDH2 mutant genotypes were associated with significant decrease in serum high density lipoprotein cholesterol （HDL- C） （WMD -1.80 mg/dL, 95% CI -1.88 to -1.72, P 〈 0.001） and total cholesterol （TC） levels （WMD -1.]0 mg/dL, 95% CI -1.59 to -0.62, P 〈 0.001）, and significant increase in serum low density lipoprotein choles- terol （LDL-C） level （WMD 0.30 mg/dL, 95% CI 0.18 to 0.43, P 〈 0.001）. Although there was no significant difference in serum triglyceride level in the overall population, subgroup analysis revealed that compared with ALDH2 ＊ 1 wild homozygote, ALDH2 ＊ 2 allele displayed a significant difference in serum triglyceride level between the female and male （female： WMD 1.69 mg/dl, 95% CI 1.08 to 2.30, P 〈 0.001; male： WMD -6.42 mg/dL, 95% CI -12.15 to -0.68, P = 0.028）. Conclusion ADH genetic polymorphism has no association with SLP, regardless of sex category and drinking status. ALDH2 genetic polymorphism has slight association with HDL-C, LDL-C and TC levels and sex-specific association with serum triglyceride level. Whether or not the association between ADH2 genetic polymorphisms and SLP is resulted from alcohol con-sumption needs further investigation.

Limonin inhibits the stemness of cancer stem-like cells derived from colorectal carcinoma cells potentially via blocking STAT3 signaling

BACKGROUND Limonin is one of the most abundant active ingredients of Tetradium ruticarpum.It exerts antitumor effects on several kinds of cancer cells.However,whether limonin exerts antitumor effects on colorectal cancer(CRC)cells and cancer stem-like cells(CSCs),a subpopulation responsible for a poor prognosis,is unclear.AIM To evaluate the effects of limonin on CSCs derived from CRC cells.METHODS CSCs were collected by culturing CRC cells in serum-free medium.The cytotoxicity of limonin against CSCs and parental cells(PCs)was determined by cholecystokinin octapeptide-8 assay.The effects of limonin on stemness were detected by measuring stemness hallmarks and sphere formation ability.RESULTS As expected,limonin exerted inhibitory effects on CRC cell behaviors,including cell proliferation,migration,invasion,colony formation and tumor formation in soft agar.A relatively low concentration of limonin decreased the expression stemness hallmarks,including Nanog andβ-catenin,the proportion of aldehyde dehydrogenase 1-positive CSCs,and the sphere formation rate,indicating that limonin inhibits stemness without presenting cytotoxicity.Additionally,limonin treatment inhibited invasion and tumor formation in soft agar and in nude mice.Moreover,limonin treatment significantly inhibited the phosphorylation of STAT3 at Y705 but not S727 and did not affect total STAT3 expression.Inhibition of Nanog andβ-catenin expression and sphere formation by limonin was obviously reversed by pretreatment with 2μmol/L colievlin.CONCLUSION Taken together,these results indicate that limonin is a promising compound that targets CSCs and could be used to combat CRC recurrence and metastasis.

Comparative Effects of Salt Stress and Extreme pH Stress Combined on Glycinebetaine Accumulation,Photosynthetic Abilities and Growth Characters of Two Rice Genotypes

Glycinebetaine （Glybet） accumulation, photosynthetic efficiency and growth performance in indica rice cultivated under salt stress and extreme pH stress were investigated. Betaine aldehyde dehydrogenase （BADH） activity and Glybet accumulation in the seedlings of salt-tolerant and salt-sensitive rice varieties grown under saline and acidic conditions peaked after treatment for 72 h and 96 h, respectively, and were higher than those grown under neutral pH and alkaline salt stress. A positive correlation was found between BADH activity and Glybet content in both salt-tolerant （P=0.71） and salt-sensitive （P=0.86） genotypes. The chlorophyll a, chlorophyll b, total chlorophyll and total carotenoids contents in the stressed seedlings significantly decreased under both acidic and alkaline stresses, especially in the salt-sensitive genotype. Similarly, the maximum quantum yield of PSII （Fv/Fm）, photon yield of PSII （ФPSII）, non-photochemical quenching （NPQ） and net photosynthetic rate （Pn） in the stressed seedlings were inhibited, leading to overall growth reduction. The positive correlations between chlorophyll a content and Fv/Fm, total chlorophyll content and ФPSII, and Pn as well as Pn and leaf area in both salt-tolerant and salt-sensitive genotypes were found. Saline acidic and saline alkaline soils may play a key role affecting vegetative growth prior to the reproductive stage in rice plants.

Risks of incident heart failure with preserved ejection fraction in Chinese patients hospitalized for cardiovascular diseases

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.

Deterioration in Hemodynamics Reaction, Baroreflex Sensitivity, Sympathetic Nerve Activity and Redox State of Thoracic Aorta in the Experimental Model of Nitrate Tolerance and Its Pharmacological Correction

Continuous treatment with organic nitrates causes nitrate tolerance and provides evidence for a relationship between mitochondrial complex 1 activity and mitochondrial aldehyde dehydrogenase-2 (ALDH-2) with disturbances of the hemodynamics reaction during nitroglycerin (NTG) tolerance (NTGT). The purpose of this study was the evaluation of efficacy of original oxidized form NAD-containing drug, NADCIN®, on hemodynamic reactions, baroreflex sensitivity (BRS) and reflex control of splanchnic sympathetic nerve activity (SSNA), level of redox-potential, activity of ALDH-2 and superoxide anion generation in aortic tissue in rat model of NTGT. Five groups (7 - 9 each) of male Wistar rats, including control, acute i.v. NTG (150 mcg/kg) administration, NTG tolerance NTGT treatment with NADCIN® 8 mg/kg and methylene blue (MB, 2.5 mg/kg) were used. NTGT in rats was accompanied with the greatly attenuation of hemodynamics reaction, BRS, the decreasing of the ability to reflex control of SSNA without pronounce overexpression of endothelin-1 in vessels (aorta). In NTGT rats i.v. NTG along induced less hypotensive reactions and alterations in heart period vs single NTG treated group, more expressively decreased BRS (-34%) and reflex control of SSNA (-18%). NADCIN® significantly inhibits tolerance-inducing properties of the prolonged nitroglycerin infusion (max decrease of blood pressure response to nitroglycerin injection, % of normal controls: NTGT 51.2%, NADCIN® 91.6%, MB 55.8%). NADCIN® in NTGT rats after NTG i.v. administration increased reduced BRS (+37.8%, p < 0,05), reflex control of SSNA (+29.4%, p < 0.05) and reversed the decreasing of NAD/NADH ratio, ALDH-2 activity and decreasing in superoxide generation in thoracic aortic tissue. Thus, course treatment with NADCIN® of NTGT rats restores hemodynamics changes, BRS and SSNA throughout the increasing of redox-potential NAD/NADH and cessates the NTGT developing.

Disulfiram:A novel repurposed drug for cancer therapy

Cancer is a major global health issue.Effective therapeutic strategies can prolong patients’survival and reduce the costs of treatment.Drug repurposing,which identifies new therapeutic uses for approved drugs,is a promising approach with the advantages of reducing research costs,shortening development time,and increasing efficiency and safety.Disulfiram(DSF),a Food and Drug Administration(FDA)-approved drug used to treat chronic alcoholism,has a great potential as an anticancer drug by targeting diverse human malignancies.Several studies show the antitumor effects of DSF,particularly the combination of DSF and copper(DSF/Cu),on a wide range of cancers such as glioblastoma(GBM),breast cancer,liver cancer,pancreatic cancer,and melanoma.In this review,we summarize the antitumor mechanisms of DSF/Cu,including induction of intracellular reactive oxygen species(ROS)and various cell death signaling pathways,and inhibition of proteasome activity,as well as inhibition of nuclear factor-kappa B(NF-κB)signaling.Furthermore,we highlight the ability of DSF/Cu to target cancer stem cells(CSCs),which provides a new approach to prevent tumor recurrence and metastasis.Strikingly,DSF/Cu inhibits several molecular targets associated with drug resistance,and therefore it is becoming a novel option to increase the sensitivity of chemo-resistant and radio-resistant patients.Studies of DSF/Cu may shed light on its improved application to clinical tumor treatment.

Physiological and Growth Responses of Tomato Progenies Harboring the Betaine Alhyde Dehydrogenase Gene to Salt Stress

The responses of five transgenic tomato （Lycopersicon esculentum Mill） lines containing the betaine aldehyde dehydrogenase （BADH） gene to salt stress were evaluated. Proline, betaine （N, N, N-trimethylglycine, hereafter betalne）, chlorophyll and ion contents, BADH activity, electrolyte leakage （EL）, and some growth parameters of the plants under 1.0% and 1.5% NaCl treatments were examined. The transgenic tomatoes had enhanced BADH activity and betaine content, compared to the wild type under stress conditions. Salt stress reduced chlorophyll contents to s higher extent in the wild type than in the transgenic plants. The wild type exhibited significantly higher proline content than the transgenic plants at 0.9% and 1.3% NaCh Cell membrane of the wild type was severely damaged as determined by higher EL under salinity stress. K^＋ and Ca^2＋ contents of all tested lines decreased under salt stress, but the transgenic plants showed a significantly higher accumulation of K^＋ and Ca^2＋ than the wild type. In contrast, the wild type had significantly higher CI- and Na^2＋ contents than the transgenic plants under salt stress. Although yield reduction among various lines varied, the wild type had the highest yield reduction. Fruit quality of the transgenic plants was better in comparison with the wild type as shown by a low ratio of blossom end rot fruits. The results show that the transgenic plants have improved salt tolerance over the wild type.