ADH1B, the adipocyte-enriched alcohol dehydrogenase, plays an essential, cell-autonomous role in human adipogenesis.

Alcohol dehydrogenase 1B (ADH1B) is a primate-specific enzyme which, uniquely among the ADH class 1 family, is highly expressed both in adipose tissue and liver. Its expression in adipose tissue is reduced in obesity and increased by insulin stimulation. Interference with ADH1B expression has also been reported to impair adipocyte function. To better understand the role of ADH1B in adipocytes, we used CRISPR/Cas9 to delete ADH1B in human adipose stem cells (ASC). Cells lacking ADH1B failed to differentiate into mature adipocytes manifested by minimal triglyceride accumulation and a marked reduction in expression of established adipocyte markers. As ADH1B is capable of converting retinol to retinoic acid (RA), we conducted rescue experiments. Incubation of ADH1B-deficient preadipocytes with 9-cis-RA, but not with all-transretinol, significantly rescued their ability to accumulate lipids and express markers of adipocyte differentiation. A homozygous missense variant in ADH1B (p.Arg313Cys) was found in a patient with congenital lipodystrophy of unknown cause. This variant significantly impaired the protein's dimerization, enzymatic activity, and its ability to rescue differentiation in ADH1B-deficient ASC. The allele frequency of this variant in the Middle Eastern population suggests that it is unlikely to be a fully penetrant cause of severe lipodystrophy. In conclusion, ADH1B appears to play an unexpected, crucial and cell-autonomous role in human adipocyte differentiation by serving as a necessary source of endogenous retinoic acid.

Genome-wide identification and expression analysis of the ADH gene family under diverse stresses in tobacco (Nicotiana tabacum L.).

BACKGROUND: Alcohol dehydrogenases (ADHs) are the crucial enzymes that can convert ethanol into acetaldehyde. In tobacco, members of ADH gene family are involved in various stresses tolerance reactions, lipid metabolism and pathways related to plant development. It will be of great application significance to analyze the ADH gene family and expression profile under various stresses in tobacco. RESULTS: A total of 53 ADH genes were identified in tobacco (Nicotiana tabacum L.) genome and were grouped into 6 subfamilies based on phylogenetic analysis. Gene structure (exon/intron) and protein motifs were highly conserved among the NtADH genes, especially the members within the same subfamily. A total of 5 gene pairs of tandem duplication, and 3 gene pairs of segmental duplication were identified based on the analysis of gene duplication events. Cis-regulatory elements of the NtADH promoters participated in cell development, plant hormones, environmental stress, and light responsiveness. The analysis of expression profile showed that NtADH genes were widely expressed in topping stress and leaf senescence. However, the expression patterns of different members appeared to be diverse. The qRT-PCR analysis of 13 NtADH genes displayed their differential expression pattern in response to the bacterial pathogen Ralstonia solanacearum L. INFECTION: Metabolomics analysis revealed that NtADH genes were primarily associated with carbohydrate metabolism, and moreover, four NtADH genes (NtADH20/24/48/51) were notably involved in the pathway of alpha-linolenic acid metabolism which related to the up-regulation of 9-hydroxy-12-oxo-10(E), 15(Z)-octadecadienoic acid and 9-hydroxy-12-oxo-15(Z)-octadecenoic acid. CONCLUSION: The genome-wide identification, evolutionary analysis, expression profiling, and exploration of related metabolites and metabolic pathways associated with NtADH genes have yielded valuable insights into the roles of these genes in response to various stresses. Our results could provide a basis for functional analysis of NtADH gene family under stressful conditions.

Analysis of alcohol-metabolizing enzymes genetic variants and RAR/RXR expression in patients diagnosed with fetal alcohol syndrome: a case-control study.

Understanding the mechanisms underlying alcohol metabolism and its regulation, including the effect of polymorphisms in alcohol-metabolizing enzymes, is crucial for research on Fetal Alcohol Spectrum Disorders. The aim of this study was to identify specific single nucleotide polymorphisms in key alcohol-metabolizing enzymes in a cohort of 71 children, including children with fetal alcohol syndrome, children prenatally exposed to ethanol but without fetal alcohol spectrum disorder, and controls. We hypothesized that certain genetic variants related to alcohol metabolism may be fixed in these populations, giving them a particular alcohol metabolism profile. In addition, the difference in certain isoforms of these enzymes determines their affinity for alcohol, which also affects the metabolism of retinoic acid, which is key to the proper development of the central nervous system. Our results showed that children prenatally exposed to ethanol without fetal alcohol spectrum disorder traits had a higher frequency of the ADH1B*3 and ADH1C*1 alleles, which are associated with increased alcohol metabolism and therefore a protective factor against circulating alcohol in the fetus after maternal drinking, compared to FAS children who had an allele with a lower affinity for alcohol. This study also revealed the presence of an ADH4 variant in the FAS population that binds weakly to the teratogen, allowing increased circulation of the toxic agent and direct induction of developmental abnormalities in the fetus. However, both groups showed dysregulation in the expression of genes related to the retinoic acid pathway, such as retinoic acid receptor and retinoid X receptor, which are involved in the development, regeneration, and maintenance of the nervous system. These findings highlight the importance of understanding the interplay between alcohol metabolism, the retinoic acid pathway and genetic factors in the development of fetal alcohol syndrome.

Effectiveness of genetic feedback on alcohol metabolism to reduce alcohol consumption in young adults: an open-label randomized controlled trial.

BACKGROUND: It is unclear whether brief interventions using the combined classification of alcohol-metabolizing enzymes aldehyde dehydrogenase 2 (ALDH2) and alcohol dehydrogenase 1B (ADH1B) together with behavioral changes in alcohol use can reduce excessive alcohol consumption. This study aimed to examine the effects of a brief intervention based on the screening of ALDH2 and ADH1B gene polymorphisms on alcohol consumption in Japanese young adults. METHODS: In this open-label randomized controlled trial, we enrolled adults aged 20-30 years who had excessive drinking behavior (average amount of alcohol consumed: men, ≥ 4 drinks/per day and women, ≥ 2 drinks/per day; 1 drink = 10 g of pure alcohol equivalent). Participants were randomized into intervention or control group using a simple random number table. The intervention group underwent saliva-based genotyping of alcohol-metabolizing enzymes (ALDH2 and ADH1B), which were classified into five types. A 30-min in-person or online educational counseling was conducted approximately 1 month later based on genotyping test results and their own drinking records. The control group received traditional alcohol education. Average daily alcohol consumption was calculated based on the drinking diary, which was recorded at baseline and at 3 and 6 months of follow-up. The primary endpoint was average daily alcohol consumption, and the secondary endpoints were the alcohol-use disorder identification test for consumption (AUDIT-C) score and behavioral modification stages assessed using a transtheoretical model. RESULTS: Participants were allocated to the intervention (n = 100) and control (n = 96) groups using simple randomization. Overall, 28 (29.2%) participants in the control group and 21 (21.0%) in the intervention group did not complete the follow-up. Average alcohol consumption decreased significantly from baseline to 3 and 6 months in the intervention group but not in the control group. The reduction from baseline alcohol consumption values and AUDIT-C score at 3 months were greater in the intervention group than in the control group (p < 0.001). In addition, the behavioral modification stages were significantly changed by the intervention (p < 0.001). CONCLUSIONS: Genetic testing for alcohol-metabolizing enzymes and health guidance on type-specific excessive drinking may be useful for reducing sustained average alcohol consumption associated with behavioral modification. TRIAL REGISTRATION: R000050379, UMIN000044148, Registered on June 1, 2021.

Roles of alcohol dehydrogenase 1 in the biological activities of Candida albicans.

Candida albicans stands as the foremost prevalent human commensal pathogen and a significant contributor to nosocomial fungal infections. In the metabolism of C. albicans, alcohol dehydrogenase 1 (Adh1) is one of the important enzymes that converts acetaldehyde produced by pyruvate decarboxylation into ethanol at the end of glycolysis. Leveraging the foundational processes of alcoholic fermentation, Adh1 plays an active role in multiple biological phenomena, including biofilm formation, interactions between different species, the development of drug resistance, and the potential initiation of gastrointestinal cancer. Additionally, Adh1 within C. albicans has demonstrated associations with regulating the cell cycle, stress responses, and various intracellular states. Furthermore, Adh1 is extracellularly localized on the cell wall surface, where it plays roles in processes such as tissue invasion and host immune responses. Drawing from an analysis of ADH1 gene structure, expression patterns, and fundamental functions, this review elucidates the intricate connections between Adh1 and various biological processes within C. albicans, underscoring its potential implications for the prevention, diagnosis, and treatment of candidiasis.

Determination of Factors Associated with Upstage in Atypical Ductal Hyperplasia to Identify Low-Risk Patients Where Active Surveillance May be an Alternative.

BACKGROUND: Excision is routinely recommended for atypical ductal hyperplasia (ADH) found on core biopsy given cancer upstage rates of near 20%. Identifying a cohort at low-risk for upstage may avoid low-value surgery. Objectives were to elucidate factors predictive of upstage in ADH, specifically near-complete core sampling, to potentially define a group at low upstage risk. PATIENTS AND METHODS: This retrospective, cross-sectional, multi-institutional study from 2015 to 2019 of 221 ADH lesions in 216 patients who underwent excision or active observation (≥ 12 months imaging surveillance, mean follow-up 32.6 months) evaluated clinical, radiologic, pathologic, and procedural factors for association with upstage. Radiologists prospectively examined imaging for lesional size and sampling proportion. RESULTS: Upstage occurred in 37 (16.7%) lesions, 25 (67.6%) to ductal carcinoma in situ (DCIS) and 12 (32.4%) to invasive cancer. Factors independently predictive of upstage were lesion size ≥ 10 mm (OR 5.47, 95% CI 2.03-14.77, p < 0.001), pathologic suspicion for DCIS (OR 12.29, 95% CI 3.24-46.56, p < 0.001), and calcification distribution pattern (OR 8.08, 95% CI 2.04-32.00, p = 0.003, "regional"; OR 19.28, 95% CI 3.47-106.97, p < 0.001, "linear"). Near-complete sampling was not correlated with upstage (p = 0.64). All three significant predictors were absent in 65 (29.4%) cases, with a 1.5% upstage rate. CONCLUSIONS: The upstage rate among 221 ADH lesions was 16.7%, highest in lesions ≥ 10 mm, with pathologic suspicion of DCIS, and linear/regional calcifications on mammography. Conversely, 30% of the cohort exhibited all low-risk factors, with an upstage rate < 2%, suggesting that active surveillance may be permissible in lieu of surgery.

ADH4-a potential prognostic marker for hepatocellular carcinoma with possible immune-related implications.

OBJECTIVE: This study aims to explore ADH4 expression in hepatocellular carcinoma (HCC), its prognostic impact, and its immune correlation to provide novel insights into HCC prognostication and treatment. METHODS: HCC prognostic marker genes were rigorously selected using GEO database, Lasso regression, GEPIA, Kaplan-Meier and pROC analyses. The expression of interested markers (ADH4, DNASE1L3, RDH16, LCAT, HGFAC) in HCC and adjacent tissues was assessed by Immunohistochemistry (IHC). We observed that ADH4 exhibited low expression levels in liver cancer tissues and high expression levels in normal liver tissues. However, the remaining four genes did not manifest any statistically significant differences between hepatocellular carcinoma (HCC) tissue and adjacent non-cancerous tissue. Consequently, ADH4 became the primary focus of our research. ADH4 expression was validated by signed-rank tests and unpaired Wilcoxon rank sum tests across pan-cancer and HCC datasets. Clinical significance and associations with clinicopathological variables were determined using Kaplan-Meier, logistic regression and Cox analyses on TCGA data. The ADH4-related immune responses were explored by Spearman correlation analysis using TIMER2 data. CD68, CD4, and CD19 protein levels were confirmed by IHC in HCC and non-cancerous tissues. RESULTS: ADH4 showed significant downregulation in various cancers, particularly in HCC. Moreover, low ADH4 expression was associated with clinicopathological variables and served as an independent prognostic marker for HCC patients. Additionally, ADH4 affects a variety of biochemical functions and may influence cancer development, prognosis, and treatment by binding to immune cells. Furthermore, at the immune level, the low expression pattern of ADH4 is TME-specific, indicating that ADH4 has the potential to be used as a target for cancer immunotherapy. CONCLUSION: This study highlights the diagnostic, prognostic and immunomodulatory roles of ADH4 in HCC. ADH4 could serve as a valuable biomarker for HCC diagnosis and prognosis, as well as a potential target for immunotherapeutic interventions.

Risk stratification of synchronous gastric cancers including alcohol-related genetic polymorphisms.

BACKGROUND AND AIM: We previously identified that ever-smoking and severe gastric atrophy in pepsinogen are risk factors for synchronous gastric cancers (SGCs). This study aimed to determine the association of alcohol drinking status or alcohol-related genetic polymorphism with SGCs and also stratify their risk. METHODS: This multi-center prospective cohort study included patients who underwent endoscopic submucosal dissection for the initial early gastric cancers at 22 institutions in Japan. We evaluated the association of alcohol drinking status or alcohol dehydrogenase 1B (ADH1B) and acetaldehyde dehydrogenase 2 (ALDH2) genotypes with SGCs. We then stratified the risk of SGCs by combining prespecified two factors and risk factors identified in this study. RESULTS: Among 802 patients, 130 had SGCs. Both the ADH1B Arg and ALDH2 Lys alleles demonstrated a significant association with SGCs on multivariate analysis (odds ratio, 1.77), although alcohol drinking status showed no association. The rates of SGCs in 0-3 risk factors in the combined evaluation of three risk factors (ever-smoking, severe gastric atrophy in pepsinogen, and both the ADH1B Arg and ALDH2 Lys alleles) were 7.6%, 15.0%, 22.0%, and 32.1%, respectively. The risk significantly increased from 0 to 3 risk factors on multivariate analysis (P for trend <0.001). CONCLUSIONS: Both the ADH1B Arg and ALDH2 Lys alleles were at high risk for SGCs. The risk stratification by these three factors may be a less invasive and promising tool for predicting their risk.

Tolvaptan and urea in paediatric hyponatraemia.

BACKGROUND: The syndrome of inappropriate antidiuretic hormone (SIADH) is usually treated with fluid restriction. This can be challenging in patients with obligate fluid intake for nutrition or medication. Pharmaceutical treatment with tolvaptan and urea is available but minimal paediatric data are available. We review the efficacy and safety of tolvaptan and urea in paediatric patients with SIADH. METHODS: Retrospective review of paediatric inpatients with clinical diagnosis of SIADH. Patients were identified from pharmacy records based on tolvaptan and urea prescriptions. Relevant information was extracted from patient electronic records. The main outcome measures included the number of days to sodium normalisation, the daily change in plasma sodium concentration, and the maximum increase of plasma sodium concentration in 24 h. Reported side effects were captured. RESULTS: Thirteen patients received tolvaptan and six urea. Five patients had both agents (tolvaptan converted to urea). Tolvaptan led to plasma sodium normalisation in 10/13 (77%) within 6 days (median 2.5 days, range [1, 6]), with a median change of sodium concentration of 7 mmol/L (- 1, 14) within the first 24 h of treatment. Three patients experienced a change in plasma sodium > 10 mmol/l/day but had no apparent side effects. Urea led to sodium normalisation in 5/6 (83%) patients. The median number of days to normalisation with urea was 2 (1, 10) with a median change of plasma sodium concentration of 2 mmol/L (- 1, 6) within the first 24 h. All patients tolerated tolvaptan and/or urea without unexpected side effects. CONCLUSIONS: Tolvaptan and urea appear to be safe and effective when fluid restriction is challenging in paediatric SIADH. A higher resolution version of the Graphical abstract is available as Supplementary information.

Elevated ADH5 expression suggested better prognosis in kidney renal clear cell carcinoma (KIRC) and related to immunity through single-cell and bulk RNA-sequencing.

BACKGROUND: Despite the rapid advances in modern medical technology, kidney renal clear cell carcinoma (KIRC) remains a challenging clinical problem in urology. Researchers urgently search for useful markers to break through the therapeutic conundrum due to its high lethality. Therefore, the study explores the value of ADH5 on overall survival (OS) and the immunology of KIRC. METHODS: The gene expression matrix and clinical information on ADH5 in the TCGA database were validated using external databases and qRT-PCR. To confirm the correlation between ADH5 and KIRC prognosis, univariate/multivariate Cox regression analysis was used. We also explored the signaling pathways associated with ADH5 in KIRC and investigated its association with immunity. RESULTS: The mRNA and protein levels showed an apparent downregulation of ADH5 in KIRC. Correlation analysis revealed that ADH5 was directly related to histological grade, clinical stage, and TMN stage (p < 0.05). Univariate and multivariate Cox regression analysis identified ADH5 as an independent factor affecting the prognosis of KIRC. Enrichment analysis looked into five ADH5-related signaling pathways. The results showed no correlation between ADH5 and TMB, TNB, and MSI. From an immunological perspective, ADH5 was found to be associated with the tumor microenvironment, immune cell infiltration, and immune checkpoints. Lower ADH5 expression was associated with greater responsiveness to immunotherapy. Single-cell sequencing revealed that ADH5 is highly expressed in immune cells. CONCLUSION: ADH5 could be a promising prognostic biomarker and a potential therapeutic target for KIRC. Besides, it was found that KIRC patients with low ADH5 expression were more sensitive to immunotherapy.

A Versatile Aldehyde: Ferredoxin Oxidoreductase from the Organic Acid Reducing Thermoanaerobacter sp. Strain X514.

Aldehyde:ferredoxin oxidoreductases (AORs) have been isolated and biochemically-characterized from a handful of anaerobic or facultative aerobic archaea and bacteria. They catalyze the ferredoxin (Fd)-dependent oxidation of aldehydes to acids. Recently, the involvement of AOR in the reduction of organic acids to alcohols with electrons derived from sugar or synthesis gas was demonstrated, with alcohol dehydrogenases (ADHs) carrying out the reduction of the aldehyde to the alcohol (AOR-ADH pathway). Here, we describe the biochemical characterization of an AOR of the thermophilic fermentative bacterium Thermoanaerobacter sp. strain X514 (AORX514). The putative aor gene (Teth514_1380) including a 6x-His-tag was introduced into the genome of the genetically-accessible, related species Thermoanaerobacter kivui. The protein was purified to apparent homogeneity, and indeed revealed AOR activity, as measured by acetaldehyde-dependent ferredoxin reduction. AORX514 was active over a wide temperature (10 to 95 °C) and pH (5.5 to 11.5) range, utilized a wide variety of aldehydes (short and branched-chained, aliphatic, aromatic) and resembles archaeal sensu stricto AORs, as the protein is active in a homodimeric form. The successful, recombinant production of AORX514 in a related, well-characterized and likewise strict anaerobe paves the road towards structure-function analyses of this enzyme and possibly similar oxygen-sensitive or W/Mo-dependent proteins in the future.

Identification of Corn Peptides with Alcohol Dehydrogenase Activating Activity Absorbed by Caco-2 Cell Monolayers.

Alcohol dehydrogenase (ADH) plays a pivotal role in constraining alcohol metabolism. Assessing the ADH-activating activity in vitro can provide insight into the capacity to accelerate ethanol metabolism in vivo. In this study, ADH-activating peptides were prepared from corn protein meal (CGM) using enzymatic hydrolysis, and these peptides were subsequently identified following simulated gastrointestinal digestion and their absorption through the Caco-2 cell monolayer membrane. The current investigation revealed that corn protein hydrolysate hydrolyzed using alcalase exhibited the highest ADH activation capability, maintaining an ADH activation rate of 52.93 ± 2.07% following simulated gastrointestinal digestion in vitro. After absorption through the Caco-2 cell monolayer membrane, ADH-activating peptides were identified. Among them, SSNCQPF, TGCPVLQ, and QPQQPW were validated to possess strong ADH activation activity, with EC50 values of 1.35 ± 0.22 mM, 2.26 ± 0.16 mM, and 2.73 ± 0.13 mM, respectively. Molecular Docking revealed that the activation of ADH occurred via the formation of a stable complex between the peptide and the active center of ADH by hydrogen bonds and hydrophobic interactions. The results of this study also suggest that corn protein hydrolysate could be a novel functional dietary element that helps protects the liver from damage caused by alcohol and aids in alcohol metabolism.

Hyponatremia With Anticonvulsant Medications: A Narrative Review.

Hyponatremia is an adverse effect of many antiseizure medications (ASMs). It occurs with interference with the normal balance of electrolytes within the body. Various risk factors associated with the development of hyponatremia in patients taking these medications include age, gender, dosage, and combinations with other drugs. ASMs such as carbamazepine (CBZ), oxcarbazepine (OXC), and valproic acid have a higher risk of hyponatremia. Hyponatremia induced by an antiseizure medication can occur through various mechanisms depending on the drug's specific mechanism of action. Hyponatremia can be a potentially fatal side effect. Patients taking these medications need to be monitored closely for the signs and symptoms of hyponatremia. Acute hyponatremia, defined as developing in <48 hours, is more likely to show symptoms than chronic hyponatremia. Signs of acute hyponatremia include delirium, seizures, decerebrate posturing, and cerebral edema with uncal herniation. Chronic hyponatremia, defined as developing in >48 hours, can cause lethargy, dizziness, weakness, headache, nausea, and confusion. Hyponatremia is associated with longer hospital stays and increased mortality. Treatment varies based on the degree of severity of hyponatremia. Choosing a treatment option should include consideration of the drug causing the electrolyte disturbance, the patient's risk factor profile, and the severity of symptoms as they present in the individual patient. Healthcare providers should be aware of hyponatremia as a potential side effect of ASMs, the signs and symptoms of hyponatremia, the different treatment options available, and the potential complications associated with rapid correction of hyponatremia.

Syndrome of inappropriate antidiuretic hormone secretion as an adverse reaction of ciprofloxacin: a case report and literature review.

Antidiuretic hormone (ADH) is secreted by the posterior pituitary gland. Unsuppressed release of ADH leads to hyponatremia. This condition is referred to as syndrome of inappropriate antidiuretic hormone secretion (SIADH). Hereby, a case report is presented on ciprofloxacin-induced SIADH. A 67-year-old male patient was examined in the emergency room with symptoms of lethargy, headache, lack of attention, and a generally depressed mood lasting for three days. One week prior, empirical antimicrobial therapy involving ciprofloxacin for prostatitis was initiated. Laboratory analysis showed no relevant abnormalities except for hyponatremia (Na = 129 mmol/L). Chronic hyponatremia, thyroid dysfunction, and adrenal dysfunction were ruled out. Serum osmolality was 263 mOsmol/kg, urine osmolality was 206 mOsmol/kg, and urine sodium was 39 mmol/L. Given that all criteria for SIADH were met, ciprofloxacin was discontinued, and fluid restriction was advised. Four days later, the patient's serum sodium concentrations nearly normalized (Na = 135 mmol/L), and all symptoms resolved. The Naranjo Scale yielded a score of 8, supporting the likelihood of a probable adverse reaction to ciprofloxacin. This case is presented to raise awareness among clinicians about the potential of ciprofloxacin to cause even mild hyponatremia.

Alcohol consumption and risk of psoriasis: Results from observational and genetic analyses in more than 100,000 individuals from the Danish general population.

Background: Psoriasis is associated with high alcohol consumption, but the causality of this relationship is unclear. Objective: We aimed to use a Mendelian randomization approach to investigate the causal effects of alcohol on incident psoriasis. Methods: We included 102,655 adults from the prospective Copenhagen studies. All participants filled out a questionnaire on alcohol consumption, were physically examined, and had blood drawn for biochemical and genetic analyses. We created a genetic instrument based on the number of fast-metabolizing alleles in alcohol dehydrogenase 1B and alcohol dehydrogenase 1C, known to be associated with alcohol consumption, to test whether alcohol consumption was causally associated with psoriasis. Results: Observationally, we found an increased risk of incident psoriasis among individuals with high alcohol consumption compared to those with low alcohol consumption with a hazard ratio of 1.30 (95% confidence interval 1.05-1.60) in the fully adjusted model. Using genetic data to predict alcohol consumption to avoid confounding and reverse causation, we found no association between number of fast-metabolizing alleles and risk of psoriasis. Limitations: Alcohol consumption was self-reported and psoriasis was defined using the International Classification of Diseases 10th revision and 8th revision codes. Conclusion: Alcohol consumption is observationally but not causally associated with incident psoriasis.

A phenome-wide association and Mendelian randomisation study of alcohol use variants in a diverse cohort comprising over 3 million individuals.

BACKGROUND: Alcohol consumption is associated with numerous negative social and health outcomes. These associations may be direct consequences of drinking, or they may reflect common genetic factors that influence both alcohol consumption and other outcomes. METHODS: We performed exploratory phenome-wide association studies (PheWAS) of three of the best studied protective single nucleotide polymorphisms (SNPs) in genes encoding ethanol metabolising enzymes (ADH1B: rs1229984-T, rs2066702-A; ADH1C: rs698-T) using up to 1109 health outcomes across 28 phenotypic categories (e.g., substance-use, mental health, sleep, immune, cardiovascular, metabolic) from a diverse 23andMe cohort, including European (N ≤ 2,619,939), Latin American (N ≤ 446,646) and African American (N ≤ 146,776) populations to uncover new and perhaps unexpected associations. These SNPs have been consistently implicated by both candidate gene studies and genome-wide association studies of alcohol-related behaviours but have not been investigated in detail for other relevant phenotypes in a hypothesis-free approach in such a large cohort of multiple ancestries. To provide insight into potential causal effects of alcohol consumption on the outcomes significant in the PheWAS, we performed univariable two-sample and one-sample Mendelian randomisation (MR) analyses. FINDINGS: The minor allele rs1229984-T, which is protective against alcohol behaviours, showed the highest number of PheWAS associations across the three cohorts (N = 232, European; N = 29, Latin American; N = 7, African American). rs1229984-T influenced multiple domains of health. We replicated associations with alcohol-related behaviours, mental and sleep conditions, and cardio-metabolic health. We also found associations with understudied traits related to neurological (migraines, epilepsy), immune (allergies), musculoskeletal (fibromyalgia), and reproductive health (preeclampsia). MR analyses identified evidence of causal effects of alcohol consumption on liability for 35 of these outcomes in the European cohort. INTERPRETATION: Our work demonstrates that polymorphisms in genes encoding alcohol metabolising enzymes affect multiple domains of health beyond alcohol-related behaviours. Understanding the underlying mechanisms of these effects could have implications for treatments and preventative medicine. FUNDING: MVJ, NCK, SBB, SSR and AAP were supported by T32IR5226 and 28IR-0070. SSR was also supported by NIDA DP1DA054394. NCK and RBC were also supported by R25MH081482. ASH was supported by funds from NIAAA K01AA030083. JLMO was supported by VA 1IK2CX002095. JLMO and JJMM were also supported by NIDA R21DA050160. JJMM was also supported by the Kavli Postdoctoral Award for Academic Diversity. EGA was supported by K01MH121659 from the NIMH/NIH, the Caroline Wiess Law Fund for Research in Molecular Medicine and the ARCO Foundation Young Teacher-Investigator Fund at Baylor College of Medicine. MSA was supported by the Instituto de Salud Carlos III and co-funded by the European Union Found: Fondo Social Europeo Plus (FSE+) (P19/01224, PI22/00464 and CP22/00128).

Melatonin derivative 6a protects Caenorhabditis elegans from formaldehyde neurotoxicity via ADH5.

Formaldehyde (FA) is a carcinogen that is not only widespread in the environment, but is also produced endogenously by metabolic processes. In organisms, FA is converted to formic acid in a glutathione (GSH)-dependent manner by alcohol dehydrogenase 5 (ADH5). The abnormal accumulation of FA in the body can cause a variety of diseases, especially cognitive impairment leading to Alzheimer's disease (AD). In this study, melatonin derivative 6a (MD6a) markedly improved the survival and chemotactic performance of wild-type Caenorhabditis elegans exposed to high concentrations of FA. MD6a lowered FA levels in the nematodes by enhancing the release of covalently-bound GSH from S-hydroxymethyl-GSH in an adh-5-dependent manner. In addition, MD6a protected against mitochondrial dysfunction and cognitive impairment in beta-amyloid protein (Aß) transgenic nematodes by lowering endogenous FA levels and reducing Aß aggregation in an adh-5-dependent manner. Our findings suggest that MD6a detoxifies FA via ADH5 and protects against Aß toxicity by reducing endogenous FA levels in the C. elegans AD models. Thus, ADH5 might be a potential therapeutic target for FA toxicity and AD.

The Never-Ending Story of Hyponatremia: A Current Problem to Overcome.

Hyponatremia is a common complication in patients undergoing neurosurgery. If undiagnosed, it has a negative prognostic impact. The two dominant causes of refractory hyponatremia include syndrome of inappropriate ADH secretion (SIADH) and cerebral salt wasting syndrome (CSWS). Discrimination between the two types of disease is not always obvious. We present a case of undiagnosed chronic hyponatremia caused by CSWS after neurosurgery, which not only resulted in a longer hospital stay but also slowed the patient's postoperative recovery. Meticulous clinical evaluation and the performance of appropriate laboratory tests are therefore essential not only for decisive treatment, but also for the establishment of comprehensive diagnostic algorithms that allow timely diagnosis and decisive therapy. LEARNING POINTS: The syndrome of inappropriate secretion of antidiuretic hormone (SIADH) and cerebral salt-wasting syndrome (CSWS) are in general associated to refractory hyponatremia especially in patients with neurologic disorders.Extracellular fluid (ECF) assessment is the key to distinguish between SIADH and CSWS.Nevertheless, measurement of the ECF volume is not sufficient to determine the correct etiology and more established diagnostic algorithms are required.

Exploring patterns of alcohol use and alcohol use disorder among Asian Americans with a finer lens.

BACKGROUND: National survey data suggest Asian Americans (AA) are less likely to consume alcohol and develop AUD than Americans in other groups. However, it is common for AA to be born outside of the US and carry gene variants that alter alcohol metabolism, both of which can lead to lower levels of alcohol involvement. The current study examined differences in alcohol use and AUD between AA and other groups before and after controlling for birth location and gene variants. DESIGN: Past year alcohol measures were examined from adults 18+ (N=22,848) in the 2012-2013 National Epidemiologic Survey on Alcohol and Related Conditions III before and after controlling for birth location (inside or outside of the US) and gene variants (ALDH2*2 and ADH1B*2/ADH1B*3). Gender gaps in alcohol measures also were assessed. RESULTS: Before adjustments, AA were less likely than White Americans to drink in the previous year (OR=0.50, 95% CI 0.41-0.62), binge (OR=0.68, 95% CI 0.52-0.88), engage in frequent heavy drinking (OR=0.55, 95% CI 0.42-0.73), and reach criteria for AUD (OR=0.71, 95% CI 0.53-0.94). After controlling for birth location and gene variants, AA remained less likely to drink in the past year (OR=0.54, 95% CI 0.41-0.70) but all other differences disappeared. Gender gaps were only observed for AA born outside of the US, highlighting the importance of experience rather than racial category per se. CONCLUSIONS: Findings indicate that heterogeneity among AA leads to spurious generalizations regarding alcohol use and AUD and challenge the model minority myth.

Case report: Secondary failure to tolvaptan in a patient with SCLC and paraneoplastic SIADH.

The syndrome of inappropriate antidiuretic hormone secretion (SIADH) is frequent in lung cancer patients. Here, we report a case with persistent hyponatremia, which suggested malignant SIADH and facilitated an early diagnosis of small cell lung cancer (SCLC). A combined radio-chemotherapy led to a partial remission and resolution of SIADH. An early relapse was indicated by reoccurring severe hyponatremia and increased copeptin levels, which were used as surrogate markers for the antidiuretic hormone (ADH). As palliative immunochemotherapy, together with fluid restriction and solute substitution, were unable to control hyponatremia, treatment with the ADH V2-receptor antagonist tolvaptan was initiated. Over time, the dose of tolvaptan needed to be increased, paralleled by a well-documented exponential increase of copeptin levels. In summary and conclusion, this is a rare case of a secondary failure to tolvaptan with unique documentary evidence of increasing copeptin levels. This observation supports the hypothesis that exceedingly high ADH levels may lead to competitive displacement of tolvaptan from the V2 receptor.