Excessive Alcohol Intake Research Articles

The steatotic liver disease burden paradox: unravelling the key role of alcohol.

The classification of steatotic liver disease (SLD) has evolved, incorporating all conditions characterized by hepatic lipid accumulation. SLD represents a continuum of disorders that are shaped by the dynamic factors of alcohol intake and cardiometabolic risk factors. This updated classification has profound implications for both the management and research of SLD, especially with the new distinct category of patients with both metabolic and alcohol-related liver disease. In this Perspective, we highlight the pivotal role of alcohol within the SLD framework. We introduce the 'SLD burden paradox': a concept illustrating the disparity in which metabolic dysfunction-associated steatotic liver disease is more prevalent, yet individuals with SLD and excessive alcohol intake (such as in metabolic and alcohol-related liver disease and in alcohol-related liver disease) account for greater global liver-related morbidity and mortality. We explore strategies to mitigate the effect of SLD on morbidity and mortality, emphasizing the importance of early detection and reducing stigma associated with alcohol intake. Our discussion extends to methods for assessing and monitoring alcohol intake together with the critical role of managing cardiometabolic risk factors in patients across the SLD spectrum. Conclusively, we advocate for a coordinated care framework that adopts a person-centric approach when managing SLD, aiming to improve outcomes and patient care.

Proanthocyanidins alleviate acute alcohol liver injury by inhibiting pyroptosis via inhibiting the ROS-MLKL-CTSB-NLRP3 pathway

BackgroundAlcoholic Liver Disease (ALD) is a hepatic disorder resulting from prolonged or excessive alcohol intake. The predominant manifestation of ALD is fatty liver, which progresses to alcoholic hepatitis as the disease worsens. Pyroptosis is a novel type of programmed cell death that is intricately linked to the inflammatory cascade, presenting a promising avenue for therapeutic intervention in the management of ALD. Oligomeric proanthocyanidins (OPCs) are polyphenols extracted from grape seeds that have anti-inflammatory and antioxidant properties. However, whether OPCs can treat ALD by suppressing pyroptosis is not completely clarified. PurposeTo explore the role of OPCs in ALD to inhibit pyroptosis and its mechanism. MethodsIn vitro, HepG2 cells were employed to evaluate the beneficial impact of OPCs on alcohol-induced pyroptosis. MTT colorimetric method, enzyme-linked immunosorbent assay (ELISA), western blot (WB), immunofluorescence, acridine orange (AO) staining, and reactive oxygen species (ROS) assay were performed. In vivo, C57BL mice were used and gavaged with alcohol and OPCs. Hematoxylin-eosin staining (HE) staining, alanine aminotransferase (ALT), aspartate aminotransferase (AST) level assay, and WB were performed. ResultsThe findings revealed that OPCs could reduce the alcohol-induced increase in pyroptosis-related proteins, such as pyrin domain-containing 3 protein (NLRP3), cleaved-caspase 1, gasdermin D (GSDMD-N), Interleukin-18 (IL-18), IL-1β (IL-1β). In in vitro mechanistic experiments, We discovered that OPCs ameliorate alcohol-induced pyroptosis by decreasing cathepsin B (CTSB) leakage-mediated NLRP3 activation. More significantly, we discovered that alcohol phosphorylates mixed lineage kinase domain-like protein (MLKL), enabling P-MLKL to translocate to the lysosomal membrane and induce lysosomal membrane permeabilization (LMP). OPCs might counteract the effects of alcohol by reducing the leakage of CTSB and inhibiting the phosphorylation of MLKL through the scavenging of ROS. Conclusions: These results suggested that OPCs might counteract ALD by inhibiting pyroptosis through the ROS-MLKL-CTSB-NLRP3 pathway. Our study offered fresh insight into the ways in which naturally occurring chemicals shield ALD against harm.

Green Radish Polysaccharide Prevents Alcoholic Liver Injury by Interfering with Intestinal Bacteria and Short-Chain Fatty Acids in Mice.

This study aimed to ascertain the potential benefits of green radish polysaccharide (GRP) in treating alcoholic liver disease (ALD) in mice and explore its mechanism of action. Using biochemical analysis, high-throughput sequencing of gut microbiota, and gas chromatography-mass spectrometry to measure short-chain fatty acids (SCFAs) in feces, we found that GRP intervention significantly improved lipid metabolism and hepatic function in mice subjected to excessive alcohol intake. The GRP intervention reduced malondialdehyde levels by 66% and increased total superoxide dismutase levels by 22%, thereby mitigating alcohol-induced oxidative stress. Furthermore, GRP intervention in mice with alcohol consumption resulted in a reduction in tumor necrosis factor, interleukin 6, and lipopolysaccharide levels by 12%, 9%, and 25%, respectively, effectively attenuating alcoholic liver inflammation. 16S rRNA amplicon sequencing demonstrated that excessive alcohol consumption markedly altered the gut microbiota composition in mice. The GRP treatment resulted in a significant reduction in the number of beneficial bacteria (Lactobacillus and Lachnospiraceae_NK4A136_group) and an increase in the proportion of harmful bacteria (Muribaculaceae and Verrucomicrobiota). The metabolomic analyses of the SCFAs demonstrated an increase in the contents of SCFAs, acetic acid, propionic acid, and butyric acid, following GRP supplementation. Furthermore, the metabolic levels of cholinergic synapses and glycolysis/gluconeogenesis were found to be modulated. In conclusion, these findings suggest that GRP may attenuate alcohol-induced oxidative damage in the liver by modulating the gut microbiota and hepatic metabolic pathways. This may position GRP as a potential functional component for ALD prevention.

The burden of gastrointestinal cancers in north east India with special reference to Helicobacter pylori infection

Gastrointestinal (GI) cancers, particularly gastric and esophageal cancers, are a significant health burden in North East (NE) India, with incidence rates substantially higher than the national average. This region is marked by high prevalence of () infection, a major risk factor for gastric cancer. Additionally, dietary habits, such as the consumption of smoked and fermented foods, widespread use of betel nut and tobacco, and excessive alcohol intake, contribute to the elevated cancer risk. This narrative review examines the burden of GI cancers in NE India, focusing on the role of in gastric carcinogenesis. The bacterium induces chronic inflammation that can progress to gastric adenocarcinoma, compounded by genetic predisposition in the region's population. Despite advances in diagnostic methods, healthcare infrastructure limitations and late-stage diagnoses hinder early detection. Preventive strategies, including eradication, public awareness campaigns, dietary modifications, and tobacco control, are essential to curb the rising cancer rates. Strengthening healthcare systems and promoting research are crucial for effective cancer control in this high-risk region.This review highlights the urgent need for a comprehensive public health approach to mitigate the growing burden of GI cancers in NE India.

Conceptual study of Non-Alcoholic Fatty Liver Disease and its management in Ayurveda

Non-alcoholic Fatty liver Disease (NAFLD) is a condition with excessive fat deposition in liver on refers to a broad spectrum of disorders characterized by fatty infiltration of the liver steatosis, steatohepatitis and cirrhosis. It is a growing cause of liver injury globally and is present in developed and developing countries. NAFLD is a broad term which describes the build up of excessive fat in the liver cells (hepatocytes) in the absence of excessive alcohol intake. It is a growing worldwide, due to obesity and insulin resistance leading to liver accumulation of triglycerides and free fatty acids. NAFLD encompasses a spectrum of liver Pathology with different clinical prognoses, from the simple accumulation of triglycerides within hepatocytes to more progressive steatosis with associated hepatitis, fibrosis, cirrhosis and in some cases hepatocellular Carcinoma. It is a global epidemic that ranges from isolated hepatic steatosis (NAFL) to Steatosis Plus inflammation (NASH) with or without fibrosis. Ayurveda described different types of Non-Communicable diseases, and NAFLD is one among them. In Ayurveda NAFLD can be interpreted as a Santarpanotha Vikara caused by Kapha Medo Dushti, getting Sthanasamshraya in Yakrit, which is Raktavaha Srotasmula and Pittasthana. In the initial stage of NAFLD, Kapha Meda Dushti occurs when Pitta gets involved in the pathogenesis, inflammatory changes occur which leads to the next stage of disease i.e., Non alcoholic steatohepatitis (NASH), When Vata comes involved fibrosis occurs which may end up in cirrhosis. So, the management should be the breakdown of pathological factors like Agnivaigunya, Srotorodha and Kaphamedo Dushti. This review will give a better knowledge of etiopathogenesis.

Transforming steatotic liver disease management: The emerging role of GLP-1 receptor agonists.

Chronic liver disease is a major cause of mortality, with approximately 2 million deaths worldwide each year, and it poses a significant economic burden. The most common cause of chronic liver disease in the United States and Europe is steatotic liver disease (SLD), which includes metabolic dysfunction-associated SLD, metabolic dysfunction and alcohol-associated SLD, and alcohol-associated liver disease (ALD). Effective treatment of these conditions is essential to reduce the liver disease burden, with promising approaches including treating cardiometabolic risk factors and excessive alcohol intake. Glucagon-like peptide 1 receptor agonists, both as monotherapy and in combination with other drugs, are gaining attention for their beneficial impact on cardiometabolic risk factors and excessive alcohol intake. In this review, we examine the molecular and clinical effects of glucagon-like peptide 1 receptor agonists, focusing on their direct hepatic steatohepatitis and liver fibrosis but also the indirect influence on cardiometabolic risk factors and excessive alcohol intake as key features of SLD. We also explore the future implications of glucagon-like peptide 1 receptor agonists for treating metabolic dysfunction-associated SLD, metabolic dysfunction and alcohol-associated SLD, alcohol-associated liver disease, and the potential challenges.

Probenecid as a pharmacotherapy for alcohol use disorder: Arandomized placebo-controlled alcohol interaction trial.

This study shows the first evidence for pannexin 1 channels as a new target to develop medications for alcohol use disorder (AUD). Due to its history of long-term safe clinical use and preclinical evidence of reducing excessive alcohol intake in rodents, probenecid has clinical potential for AUD. We conducted a Phase I/IIa randomized, double-blind, placebo-controlled, crossover trial investigating the safety, tolerability, and efficacy of an oral dose of probenecid (2 g) when administered with alcohol (0.08 g/dL) in individuals who regularly consume alcohol to the 0.08 g/dL level (N = 35) and in individuals with mild to severe AUD. Alcohol pharmacokinetics and subjective responses were evaluated to assess potential interactions between probenecid and alcohol. Alcohol craving, inflammatory biomarkers, cognitive assessments, and hemodynamics were assessed as additional alcohol research domains. All outcomes were assessed both in the ascending and descending limb of alcohol intoxication using Generalized Estimating Equation. Probenecid did not exert any significant effect on alcohol pharmacokinetics and did not affect alcohol stimulation or sedation. Probenecid, compared to placebo, significantly decreased alcohol craving during the alcohol ascending limb. Inflammatory biomarkers, cognitive performance following alcohol ingestion, and hemodynamics were likewise not affected by probenecid administration. Analysis of sex as a biological variable revealed no differences of probenecid compared to placebo. Taken together, our data support the potential of probenecid for treatment of AUD and suggest that pannexin 1 channels represent a novel emerging therapeutic target for the development of new pharmacotherapies for treating AUD.

Excessive alcohol intake produces persistent mechanical allodynia and dysregulates the endocannabinoid system in the lumbar dorsal root ganglia of genetically-selected Marchigian Sardinian alcohol-preferring rats

Epidemiological data indicate a strong association between alcohol use disorder (AUD) and neuropathic pain. Genetically-selected Marchigian Sardinian alcohol-preferring (msP) rats exhibit a high preference for alcohol compared with their background strain (Wistar rats), but their sensitivity to mechanical allodynia after chronic alcohol exposure is unknown. The present study compared the development of mechanical allodynia between “low, non-pathological drinker” Wistar rats and “high drinker” msP rats using the two-bottle choice (2BC) free-access procedure. Several studies reported the involvement of endocannabinoids (eCBs) in modulating mechanical allodynia, but there are no data on their role in alcohol-related allodynia. Thus, the present study assessed eCBs and their related lipid species in lumbar dorsal root ganglia (DRG) and correlated them with mechanical allodynia in our model. We found that male and female msP rats developed persistent mechanical allodynia during protracted abstinence from alcohol, presenting no sign of recovery, as opposed to Wistar rats. This effect directly correlated with their total alcohol intake. Notably, we found a correlation between lower lumbar DRG 2-arachidonoylglycerol (2-AG) levels and the development of higher mechanical allodynia during abstinence in msP rats of both sexes but not in Wistar rats. Moreover, alcohol-exposed and abstinent msP and Wistar females but not males exhibited significant alterations of thromboxane B2 and prostaglandin E2/prostaglandin D2 compared with naive rats. These findings demonstrate that DRG 2-AG metabolism is altered in msP rats during prolonged abstinence and represents a potentially interesting pharmacological target for the treatment of mechanical allodynia during alcohol abstinence.

Galangin Alleviates Alcohol-Provoked Liver Injury Associated with Gut Microbiota Disorder and Intestinal Barrier Dysfunction in Mice.

Prolonged and excessive intake of alcohol results in the onset of alcoholic liver disease, which is marked by oxidative stress, intestinal barrier dysfunction, and disturbance in the intestinal microbiome. Galangin, a potent flavonoid from Alpinia officinarum Hance, has been recognized for its diverse biological properties; however, its ability for protecting against alcohol-stimulated hepatotoxicity remains unexplored in prior research. In the current study, a Gao-Binge mouse model was established to assess the positive role and mechanisms of galangin upon alcohol-induced liver injury. The administration of galangin relieved liver pathological damage, oxidative stress, and NLRP3-mediated inflammation induced by alcohol. In addition, galangin significantly reversed abnormal intestinal histopathological manifestations and damaged the intestinal barrier function. Furthermore, microbiota composition revealed that galangin improved intestinal imbalance by improving the gut microbiota dysbiosis and short-chain fatty acid level. Collectively, this study explored the interactions between phytochemical factors and virulence factors and discovered that galangin powerfully improved alcohol-induced liver disease by repressing the inflammatory cascade via the gut microbiota-mediated gut-liver axis. These results suggested that alcohol-targeted natural products could have potential applications in promoting food safety and human health and offer valuable insights into the possible use of these substances in these important areas.

Transcriptional Patterns in Stages of Alzheimer's Disease Are Cell-Type-Specific and Partially Converge with the Effects of Alcohol Use Disorder in Humans.

Advances in single-cell technologies have led to the discovery and characterization of new brain cell types, which in turn lead to a better understanding of the pathogenesis of Alzheimer's disease (AD). Here, we present a detailed analysis of single-nucleus (sn)RNA-seq data for three stages of AD from middle temporal gyrus and compare it with snRNA-seq data from the prefrontal cortices from individuals with alcohol use disorder (AUD). We observed a significant decrease in both inhibitory and excitatory neurons, in general agreement with previous reports. We observed several cell-type-specific gene expressions and pathway dysregulations that delineate AD stages. Endothelial and vascular leptomeningeal cells showed the greatest degree of gene expression changes. Cell-type-specific evidence of neurodegeneration was seen in multiple neuronal cell types particularly in somatostatin and Layer 5 extratelencephalic neurons, among others. Evidence of inflammatory responses was seen in non-neuronal cells, particularly in intermediate and advanced AD. We observed common perturbations in AD and AUD, particularly in pathways, like transcription, translation, apoptosis, autophagy, calcium signaling, neuroinflammation, and phosphorylation, that imply shared transcriptional pathogenic mechanisms and support the role of excessive alcohol intake in AD progression. Major AUD gene markers form and perturb a network of genes significantly associated with intermediate and advanced AD. Master regulator analysis from AUD gene markers revealed significant correlation with advanced AD of transcription factors that have implications in intellectual disability, neuroinflammation, and other neurodegenerative conditions, further suggesting a shared nexus of transcriptional changes between AD and AUD.

Bergenin inhibits hepatic fat deposition by activating the AMPK signaling pathway, thereby attenuating alcoholic liver disease

Alcoholic liver disease (ALD) is a prevalent liver condition that arises from prolonged and excessive alcohol intake. Bergenin (BER) is an effective phytotherapeutic agent that exhibits pharmacological properties, including anti-inflammatory and anti-oxidative effects. To establish an in vivo model of ALD, C57BL/6 mice were continuously fed a high-fat diet (HFD) and administered alcohol gavage for 8 weeks, while concurrently administering BER and evaluated for therapeutic effects. After modeling, the therapeutic effects of BER were evaluated by observing histopathological changes and the detection of relevant biochemical indicators in mice. In addition, RNA sequencing of liver tissues was performed to analyze differentially expressed genes and to investigate the associated signaling pathways in order to elucidate the protective mechanisms of BER. These differentially expressed genes were mainly enriched in lipid metabolism pathways and the cytochrome P450 metabolism of exogenous substances. Subsequently, HepG2 was co-treated with sodium oleate (NaOA) and ethanol to establish an in vitro model, and the specific mechanism by which BER ameliorates ALD was further analyzed in depth. AMPK inhibitor, Compound C (CC), was demonstrated to significantly inhibit the regulation of lipid metabolism by BER in vitro. Finally, the differentially expressed genes selected were validated through qRT-PCR and Western blot analysis. Collectively, our findings revealed that BER effectively alleviated liver injury caused by alcohol and HFD in mice, significantly suppressing lipid deposition in ALD, enhancing alcohol metabolism, and mitigating oxidative stress.

Risk Factors and Prevention of Stomach Cancer, Excluding Helicobacter pylori

Gastric cancer is a significant health problem owing to its high incidence and mortality rate. The risk factors for gastric cancer include both uncontrollable (e.g., age, sex, and genetic predisposition) and controllable factors (e.g., <i>Helicobacter pylori</i> infection, smoking, alcohol consumption, obesity, and high-salt diets). Although treatment of <i>H. pylori</i> infections has been implemented as a primary preventive measure, the risk of gastric cancer may persist, highlighting the need for additional preventive measures. This review discusses various risks and protective factors associated with gastric cancer, studies conducted on these factors, and chemoprevention. Smoking is a risk factor for this disease; thus, is not recommended and current smokers are encouraged to quit because cessation can reduce the risk of gastric cancer. Excessive alcohol intake has been reported to increase the risk of gastric cancer as has the consumption of high-salt foods that can damage the gastric mucosa. Additionally, increasing the intake of fruits and vegetables, known for their protective effects against gastric cancer, can aid in its prevention. Studies on chemopreventive agents, including nonsteroidal anti-inflammatory drugs (e.g., aspirin), statins, and metformin, have been reported; however, evidence of their effectiveness remains insufficient to recommend these agents as preventive treatments. Additional well-planned studies on preventive medications and dietary approaches are necessary.

Alcohol-associated liver disease - a current overview.

Alcohol-associated liver disease (ALD) remains a major and increasingly pressing concern in hepatology. ALD includes spectrum of conditions, each with unique diagnostic and therapeutic challenges. Excessive alcohol intake is a leading preventable cause of physical harm, including ALD. The pathogenesis of ALD involves oxidative stress, inflammation, and lipid metabolism disruptions, with genetic predispositions playing a major role. ALD progresses from hepatic steatosis to steatohepatitis, and finally liver cirrhosis, which is marked by severe fibrosis and impaired liver function. Advanced ALD stages, particularly alcoholic hepatitis and liver cirrhosis, are characterized by high mortality rates. Management of ALD primarily involves strict abstinence from alcohol, which can reverse early-stage disease or halt progression. Nutritional support, vitamin supplementation, and symptomatic treatment are also essential. Liver transplantation is the only definitive treatment for alcoholic liver cirrhosis, but it is difficult for patients with a history of alcohol abuse to qualify for the procedure. Epidemiological data indicate a growing burden of ALD, especially among younger populations, exacerbated by increased alcohol consumption trends and the COVID-19 pandemic's influence on drinking behaviors. Despite ALD's significant impact, current therapies are limited, highlight- ing the need for innovative treatments and comprehensive patient management strategies. Individualized care, enhanced epidemiological research, and new therapeutic approaches are crucial to improving outcomes for ALD patients.

From risk to reward: Japan’s potential for health and economic improvements

This study examines the relationship between risky consumption behaviors, non-communicable diseases (NCDs), and socioeconomic costs in Japan using the Preventable Risk Integrated ModEl (PRIME). We assess the potential impact of healthier lifestyle choices on NCD incidences and costs in 2019. Japan's rising healthcare expenditures threaten its economic future. Excessive intake of salt, tobacco, and alcohol, along with insufficient fiber and fruit consumption, significantly contribute to high NCD rates. Our analysis shows that healthier behaviors could have prevented 564,000 NCD cases, potentially saving $35 billion in health costs and economic losses in 2019. We consider scenarios where smokers switch to heated tobacco products (HTPs), applying conservative risk reduction estimates. Higher risk reduction levels could triple smoking-attributable savings. Projecting these savings over ten years would increase economic benefits tenfold. The study emphasizes the need for comprehensive public health strategies promoting healthier lifestyles. Targeted interventions, such as stricter regulation of high-risk products and incentives for healthier alternatives, could reduce NCD incidences and healthcare costs. While PRIME provides valuable insights, further research is needed to refine our understanding of risk factor-disease relationships.

Alcohol Consumption and Cardiovascular Disease: A Narrative Review of Evolving Perspectives and Long-Term Implications.

Cardiovascular illnesses remain the primary cause of death, accounting for at least 17.9 million fatalities per year and posing a significant public health problem because of its extensive predominance and effect on healthcare systems. The etiology of cardiovascular disease is complex and involves several environmental and lifestyle factors. Alcohol use is a highly important determinant because of its dual-edged effect on cardiovascular health. Multiple studies indicate that moderate alcohol consumption may have certain advantages, such as slight enhancements in lipid profiles. Conversely, excessive alcohol intake is associated with serious negative consequences, including cardiomyopathy, hypertension, arrhythmias, and even mortality. The aim of this study is to provide a comprehensive analysis of the several effects of alcohol on cardiovascular health and their understanding within the medical field over time. It uses an interpretative narrative review methodology and analyzes studies that focus on genetic risk factors, gender differences, and shifts in paradigms in recent years. This article highlights the need for obtaining a thorough understanding of the effects of alcohol on cardiovascular health to support public health guidelines and clinical practice, and it underscores the significance of including alcohol consumption into the broader context of cardiovascular risk management and identifies important subjects for further study.

Hepatologists' Awareness and Knowledge of NAFLD and the Familiarity with Renaming NAFLD to MAFLD.

Non-alcoholic fatty liver disease (NAFLD) is an emerging epidemic; it is a negative diagnosis that depends mainly on the presence of hepatic steatosis with or without inflammation after the exclusion of other chronic liver diseases and excess alcohol intake. However, the new definition of MAFLD is a shift towards a diagnosis of inclusion based on the presence of metabolic dysfunction, regardless of alcohol consumption or other concomitant liver diseases. Given the growing relevance of the disease, data on hepatologists' views and understanding of NAFLD are limited, we aimed to determine hepatologists' awareness and expertise of NAFLD screening, diagnosis, and therapeutic options as well as the influence of changing the NAFLD name to MAFLD on awareness of the fatty liver disease (FLD). Most of the hepatologists agreed that NAFLD can cause serious hepatic illness and may be linked to metabolic risk factors, necessitating a multidisciplinary approach to treatment. Hepatologists have a poor understanding of NAFLD care. The shift in terminology from NAFLD to MAFLD will be more known to hepatologists, and it may offer better awareness of FLD. A multicenter online questionnaire of 655 hepatologists was carried out, giving a sample of 207 respondents. A survey composed of 36 questions was used to assess the level of hepatologists' awareness and practices in the screening, diagnosis, and management of NAFLD/MAFLD, as well as their familiarity with the nomenclature change from NAFLD to MAFLD. A total of 207 hepatologists were included, of which 107 (51.4%) were males, with a mean age was 36.4 years. 50.2% (n = 104) of the hepatologists were oriented with NAFLD. Only 41 (19.8%) realized that NAFLD may frequently result in severe hepatic disease. NAFLD is rarely screened by the majority of the participating hepatologists (118, 57%), and (135, 65.2%) of them use liver biopsy for diagnosis of NAFLD. In (104, 50.2%) hepatologists, changing the nomenclature of NAFLD was relatively familiar. Furthermore, 71.9% of hepatologists thought that the new nomenclature offers a better awareness of FLD. A small percentage of hepatologists agreed that NAFLD can cause serious hepatic illness and may be linked to metabolic risk factors, and around half of them realize that NAFLD necessitates a multidisciplinary approach to treatment. Hepatologists have a poor understanding of NAFLD care. The shift in terminology from NAFLD to MAFLD will be more known to hepatologists, and it may offer better awareness of FLD.

Quantification of alcohol intake in patients with steatotic liver disease and excessive alcohol intake

Quantification of alcohol intake in patients with steatotic liver disease and excessive alcohol intake

Exploring the interplay between kidney function and urinary metabolites in young adults: the African-PREDICT study

The exposure to modifiable risk factors at young ages have been linked to premature fatal and non-fatal cardiovascular and kidney outcomes. The use of urinary metabolomics has shown strong predictability of kidney function and cardiovascular disease (CVD). We therefore determined the associations between estimated glomerular filtration rate (eGFR) and urinary metabolites in young adults with and without CVD risk factors. Apparently healthy Black and White sexes were included (aged 20–30 years) and categorised by the presence or absence of risk factors, i.e., obesity, physical inactivity, smoking, excessive alcohol intake, masked hypertension, hyperglycemia, dyslipidemia and low socio-economic status, forming the CVD risk group (N = 1036), CVD risk clusters (i.e. presenting with 1 CVD risk factor (N = 344), 2 CVD risk factors (N = 360) and 3 + CVD risk factors (N = 332)) and the control group (N = 166). eGFR was calculated with CKD-EPI equations. A targeted metabolomics approach using liquid chromatography-tandem mass spectrometry was used to measure amino acids and acylcarnitines. Lower cystatin C-based eGFR were indicated in the CVD risk group, 2 and 3 + CVD risk clusters compared to the control group (all P ≤ 0.033). In the CVD risk group, eGFR associated positively with histidine, lysine, asparagine, glycine, serine, glutamine, dimethylglycine, threonine, alanine, creatine, cystine, methionine, tyrosine, pyroglutamic acid, leucine/isoleucine, aspartic acid, tryptophan, glutamic acid, free carnitine, acetylcarnitine, propionylcarnitine, isovalerylcarnitine, octanoylcarnitine and decanoylcarnitine (all P ≤ 0.044), with similar results found in the CVD risk clusters, particularly the 2 CVD risk cluster. eGFR was positively associated with metabolites linked to aromatic amino acid and branched-chain amino acid metabolism, energy metabolism and oxidative stress. These findings may indicate altered reabsorption of these metabolites or altered metabolic regulation to preserve renal health in the setting of CVD risk factors at this young age without established CVD.

Abstract Mo065: An Anti-arrhythmic Action and Novel Molecular Mechanisms of Alda-1 in Holiday Heart Syndrome

Introduction: Holiday Heart Syndrome (HHS) is caused by excessive binge alcohol intake. Atrial fibrillation (AF) is the most common arrhythmia in HHS patients. With a worldwide rising trend in heavy alcohol consumption despite significant prevention efforts, effective drugs against alcohol-evoked AF are in urgent need. Methods: We assessed the effect of Alda-1, a cardiac protective agent, on mitigating binge alcohol-evoked AF and alcohol-activated stress kinase JNK2 in 50mM alcohol-exposed (24hr) H9c2 differentiated myocytes and in a well-characterized HHS mouse model (2g/kg ethanol i.p., 4 injections, every other day). Alda-1’s effect on alcohol-evoked RyR2 channel-mediated Ca 2+ waves/sparks & tachycardia/fibrillation (AT/AF) incidence were measured in intact mouse atria. RyR2 channel open probability was assessed in human RyR2 single-channel recordings. Results: We found that Alda-1 significantly reduced atrial arrhythmia inducibility in HHS mouse atria, as evidenced by a decreased incidence of alcohol-evoked AT/AF (0 vs. 0.21 incidences/pacing attempts/animal; n=6, 8). Alda-1 is an agonist of aldehyde dehydrogenase 2 (ALDH2; a key enzyme in alcohol detoxification), which inhibits cellular apoptosis. We found that ALDH2 was increased by 42%±6 in HHS mice compared to controls, and which remained elevated upon Alda-1 treatment (n=6,7,7; p<0.05). HHS hearts showed unchanged apoptotic signaling pathways, suggesting alternative mechanisms in AF genesis. Our lab recently revealed a critical role of activated cardiac stress kinase JNK2 in AF risk. Intriguingly, Alda-1 suppressed alcohol-activated JNK2 by 70%±13 (immunoprecipitated JNK2-specific activity; n=9,9, p<0.001) (but not JNK1, the other cardiac JNK isoform) in cells, while JNK2 inhibition alleviated alcohol-evoked RyR2 channel dysfunction in human RyR2 channels as well as Ca 2+ -triggered atrial arrhythmic activities and AT/AF (0 out of 8; p<0.05) in intact mouse hearts. Conclusion: Alda-1 effectively mitigates binge alcohol-evoked atrial arrhythmogenesis by suppressing JNK2 activity independently of an ALDH2-mediated anti-apoptosis effect. Our findings highlight the potential of Alda-1 as a therapeutic agent for the increasing incidence of alcohol-evoked AF.

The Effect of Morning Care Products Administration on Ethanol-Induced Hangover in Mice

Hangovers, resulting from excessive alcohol intake, manifest hours after drinking, causing symptoms like thirst, headache, and fatigue. Alcohol is metabolized in the liver by alcohol dehydrogenase (ADH) and aldehyde dehydrogenase (ALDH), with acetaldehyde and reactive oxygen species contributing to toxic effects. Morning Care (MC) products were evaluated in male and female mice to assess their impact on alcohol metabolism and hangover alleviation. The study revealed that pre-administration of MC products led to a significant reduction in blood ethanol and acetaldehyde concentrations postalcohol ingestion. This remarkable finding suggests a potential breakthrough in hangover relief. Enhanced ADH and ALDH activities were observed in blood and liver samples, indicating improved alcohol metabolism. Interestingly, gene expression levels of ADH and ALDH in the liver did not show significant differences, suggesting that MC products likely enhance enzyme activities through post-translational modifications rather than altering gene expression. These findings underscore the potential of MC products to mitigate hangover symptoms by enhancing alcohol metabolism.