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Prostate cancer (PCa) is the most common cancer in men in the United States. About 10 – 20% of PCa progress to castration-resistant PCa (CRPC), which is accompanied by metastasis and therapeutic resistance. Aldehyde dehydrogenase (ALDH) is famous as a marker of cancer stem-like cells in different cancer types, including PCa. Generally, ALDHs catalyze aldehyde oxidation into less toxic carboxylic acids and give cancers a survival advantage by reducing oxidative stress caused by aldehyde accumulation. In PCa, the expression of ALDHs is associated with a higher tumor stage and more lymph node metastasis. Functionally, increased ALDH activity makes PCa cells gain more capabilities in self-renewal and metastasis and reduces the sensitivity to castration and radiotherapy. Therefore, it is promising to target ALDH or ALDHhigh cells to eradicate PCa. However, challenges remain in moving the ALDH inhibitors to PCa therapy, potentially due to the toxicity of pan-ALDH inhibitors, the redundancy of ALDH isoforms, and the lack of explicit understanding of the metabolic signaling transduction details. For targeting PCa stem-like cells (PCSCs), different regulators have been revealed in ALDHhigh cells to control cell proliferation and tumorigenicity. ALDH rewires essential signaling transduction in PCa cells. It has been shown that ALDHs produce retinoic acid (RA), bind with androgen, and modulate diverse signaling. This review summarizes and discusses the pathways directly modulated by ALDHs, the crucial regulators that control the activities of ALDHhigh PCSCs, and the recent progress of ALDH targeted therapies in PCa. These efforts will provide insight into improving ALDH-targeted treatment. [ABSTRACT FROM AUTHOR]

Background: Ischemic stroke has no approved treatments to enhance recovery. ALD-401 is an enriched population of aldehyde dehydrogenase-bright stem cells, capable of reducing neurological deficits in animal models. The primary objective of this trial was to determine the safety of internal carotid artery, intra-arterially delivered autologous bone marrow-derived ALD-401 in patients with disabling middle cerebral artery stroke in comparison with sham harvest with sham infusion. Secondary objectives were to determine feasibility and efficacy.Methods: This was a prospective phase 2, industry-funded, randomized, sham-controlled, parallel-group, multicenter study with blinded assessments. One hundred subjects were planned, aged 30 to 83 years, with confirmed first-time middle cerebral artery ischemic stroke with modified Rankin scale ≥3. Study patients were randomly assigned 3:2 to bone marrow harvest at 11 to 17 days after stroke followed 2 days later by intracarotid infusion of ALD-401 versus sham harvest and then sham infusion in the same timeframe. The primary study outcome was safety based on the incidence of a 4-point National Institutes of Health Stroke Scale worsening and the proportion of serious adverse events. Efficacy was based on modified Rankin scale change at 90 days. Other secondary outcomes were the proportions of patients experiencing adverse events, disability by Barthel Index, quality of life using EQ-5D, rehabilitation utilization, disability at 1 year, and MRI evidence of complications.Results: There were no infusional or allergic reactions and no difference in treatment emergent adverse events. Four patients had small areas of asymptomatic restricted diffusion on MRI in the treatment group. There was no significant difference between the ALD-401 and placebo groups on the modified Rankin scale for the intent-to-treat population at day 90 (mean difference, 0.3; 95% CI, -0.3 to 0.8; P=0.330). There were no significant differences between the groups on any of the secondary efficacy measures.Conclusions: Intracarotid infusion of ALD-401 does not lead to clinical adverse events in patients with subacute ischemic stroke, although there was a higher incidence of small lesions on MRI in the treatment group. There was no difference in the primary efficacy end point between the groups. The study provides a framework for the design and conduct of future intra-arterial cell therapy trials in stroke.Clinical Trial Registration: URL: https://www.clinicaltrials.gov . Unique identifier: NCT01273337. [ABSTRACT FROM AUTHOR]

Native Americans as a group have the highest rates of alcohol-related deaths of all ethnicities in the United States; however, it remains unclear how and why a greater proportion of individuals in some Native American communities develop alcohol-related problems and alcohol use disorders (AUDs). One potential factor that can influence responses to alcohol are variations in alcohol-metabolizing enzymes. Researchers have analyzed the frequencies of variants in the alcohol-metabolizing enzymes alcohol dehydrogenase (ADH) and aldehyde dehydrogenase (ALDH) in some Native American populations. So far the studies have yielded no evidence that an ALDH2 variant, which has shown protective effects in other populations, is found in either American Indians or Alaska Natives. A variant of the ALDH1 enzyme that is encoded by the ALDH1A1*2 allele, however, was found in a small proportion of a group of Southwest California Indians and had a protective effect against alcoholism in that population. Furthermore, a variant of the ADH1B enzyme that is encoded by the ADH1B*3 allele was found in a similar proportion of Southwest California Indians and also was associated with a protective effect. However, these findings do not explain the high prevalence of alcoholism in the tribes investigated. [ABSTRACT FROM AUTHOR]

Background: A standard measure defines binge drinking as the consumption of 5 or more drinks in a row for men (4 or more drinks for women) on at least 1 occasion during the past 2 weeks. A revised operational definition of binge drinking was developed by the National Institute on Alcohol Abuse and Alcoholism in 2004 and incorporated the duration of the drinking episode in addition to the quantity of alcohol consumed. This study compares the standard and new binge measures for overall and subgroup prevalence rates; associations with gender, race/ethnicity, and age of drinking onset; and associations with negative drinking consequences. Methods: A probability sample of 4,580 randomly selected college students (50.3% female, M age=19.9, SD=2.0) at a large Midwestern university in the United States completed a Web-based survey of alcohol and other drug use. Participants reported on past 2-week binge drinking using the standard measure and past-year binge drinking using the new measure. Results: The longer past-year time frame of the new measure yielded a higher prevalence estimate of binge drinking (63.6%) compared with the 2-week standard measure (53.2%). Approximately 9.9% of those who were classified as binge drinkers using the 2-week standard measure were classified as non–binge drinkers using the new measure specification of a 2-hour duration for the drinking episode. The past-year new binge measure was positively associated with negative drinking consequences even when the 2-week measure was statistically controlled. Conclusions: Using a longer time frame and incorporating the duration of the drinking episode, the new measure of binge drinking appears to capture an important element of risky alcohol involvement in college students that is not fully assessed by the standard measure. [ABSTRACT FROM AUTHOR]

Studies of Asian adults have found that alcohol use and alcohol dependence are related to variation in the aldehyde dehydrogenase (ALDH2) gene. To investigate the association of ALDH2 with the development of drug involvement, the authors analyzed retrospective information about the onset and regular use of alcohol and other substances as reported by 180 Asian American college students. Possession of an ALDH2*2 allele was not related to initiation of alcohol use or having ever been intoxicated, but individuals with ALDH2*2 alleles were less likely to be regular drinkers, were less likely to have engaged in a binge-drinking episode, reported a lower number of maximum drinks consumed in a 24-hr period, and were less likely to have used tobacco regularly than those without this genetic variant. These findings suggest that ALDH2 is associated with the development of not only alcohol-related behavior but other substance use behavior as well. [ABSTRACT FROM AUTHOR]

Investigates the aldehyde oxidoreductase activity in Desulfovibrio alaskensis NCIMB 13491, a strain isolated from a soured oil reservoir in Purdu Bay, Alaska. Oxidation of aldehydes to carboxylic acid form; Reduction of protein with excess dithionite; Crystal structures of homologous enzymes.

Examines the validity of Self-Rating of the Effects of Alcohol (SRE) form in Asian Americans with Aldehyde Dehydrogenase (ALDH2) polymorphisms in the United States. Individual differences in response to alcohol; SRE scores of participants; Relationship between SRE scores and participants with ALDH2; Risk factors of alcoholism.

The article presents a study which explores the characteristic of Disulfiram (DSF) and Dithiocarbamates (DTCs) and their role on melanoma cancer. It mentions that DSF has been approved by the U.S. Food and Drug Administration (FDA) to use for alcohol aversion therapy due to its ability to fight against aldehyde dehydrogenase production as well as exemplifies selective toxicity for melanoma cancer cells in vitro. It also notes that the toxicity of the DSF is dependent on the presence of metal ions such as DTCs. With this, laboratory experiment was undertaken encompassing four different procedures classified by synthesis procedure for synthesizing DTC. The result of the study shows that the procedure which uses metathesis process yields 80% of DTC complexes.

Background: Prostate cancer (PCa) remains the second leading cause of deaths due to cancer in the United States in men. The aim of this study was to perform an integrative epigenetic analysis of prostate adenocarcinoma to explore the epigenetic abnormalities involved in the development and progression of prostate adenocarcinoma. The key DNA methylation-driven genes were also identified.Methods: Methylation and RNA-seq data were downloaded for The Cancer Genome Atlas (TCGA). Methylation and gene expression data from TCGA were incorporated and analyzed using MethylMix package. Methylation data from the Gene Expression Omnibus (GEO) were assessed by R package limma to obtain differentially methylated genes. Pathway analysis was performed on genes identified by MethylMix criteria using ConsensusPathDB. Gene Ontology (GO) term enrichment analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis were also applied for the identification of pathways in which DNA methylation-driven genes significantly enriched. The protein-protein interaction (PPI) network and module analysis in Cytoscape software were used to find the hub genes. Two methylation profile (GSE112047 and GSE76938) datasets were utilized to validate screened hub genes. Immunohistochemistry of these hub genes were evaluated by the Human Protein Atlas.Results: A total of 553 samples in TCGA database, 32 samples in GSE112047 and 136 samples in GSE76938 were included in this study. There were a total of 266 differentially methylated genes were identified by MethylMix. Plus, a total of 369 differentially methylated genes and 594 differentially methylated genes were identified by the R package limma in GSE112047 and GSE76938, respectively. GO term enrichment analysis suggested that DNA methylation-driven genes significantly enriched in oxidation-reduction process, extracellular exosome, electron carrier activity, response to reactive oxygen species, and aldehyde dehydrogenase [NAD(P)+] activity. KEGG pathway analysis found DNA methylation-driven genes significantly enriched in five pathways including drug metabolism-cytochrome P450, phenylalanine metabolism, histidine metabolism, glutathione metabolism, and tyrosine metabolism. The validated hub genes were MAOB and RTP4.Conclusions: Methylated hub genes, including MAOB and RTP4, can be regarded as novel biomarkers for accurate PCa diagnosis and treatment. Further studies are needed to draw more attention to the roles of these hub genes in the occurrence and development of PCa. [ABSTRACT FROM AUTHOR]

Alcohol misuse is the 4th leading cause of preventable mortality in the United States and contributes to over 3 million deaths worldwide each year. The use of alcohol in a pathologic fashion, alcohol use disorder, affects all populations, and the prevalence of this disorder has remained stable over the last several decades. The risk of developing alcohol use disorder has a substantial genetic component, with approximately 50% heritability. Some genetic risk variants are known, most notably variation in genes that are involved in the metabolism of alcohol – alcohol dehydrogenase (ADH) and aldehyde dehydrogenase (ALHD) genes. Our goal is to integrate 'omic data from multiple resources to accelerate discovery of relevant genetic contributions to disease. By leveraging complementary data sources, we can narrow the search space and boost power. This successful approach is illustrated through our study of alcohol use disorder. As our first step, we mapped cis-methylation quantitative trait loci (cis-meQTL) and cis-expression quantitative trait loci (cis-eQTL) that correlate with DNA methylation and RNA expression in the alcohol metabolizing genes (ADH gene family and ALDH2) in pre-frontal cortex samples from 240 decedents using the Lieber Institute for Brain Development (LIBD) biobank. We found novel cis-meQTL SNPs for ADH1C (smallest P = 2.6×10-11) that associate with alcohol use disorder (smallest P = 2.3×10-5, surpassing Bonferroni correction) in our newly assembled alcohol use disorder GWAS meta-analysis. These novel SNPs are not in linkage disequilibrium with prior GWAS-identified SNPs, and this novel approach demonstrates the power for discovery that focuses on regulatory SNPs to narrow the search space for association testing. Integrative omics approach can be extended genome wide by focusing on genes highly expressed in the brain. By leveraging multi-omics data (genome-wide DNAm, RNAexp, and SNP genotypes) from multiple sources, we can focus on genetic variation at the intersection of these datasets that can accelerate the discovery of new genes for diseases and their susceptibility variants beyond the strategy of increasing sample sizes for meta-analysis. This proposed approach focuses on neurobiologically meaningful genes and variants and will expand our understanding of the etiology of alcohol use disorder and the neuropathology underlying this disease. [ABSTRACT FROM AUTHOR]