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Zhang X, Wu W, Zhou G, Huang X, Xu M, Zhao Q, Yan H. Relationship between alcohol use and traumatic brain injury: evidence from Mendelian randomization. Brain Inj 2025:1-8. [PMID: 39894956 DOI: 10.1080/02699052.2025.2460740] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2024] [Revised: 01/13/2025] [Accepted: 01/25/2025] [Indexed: 02/04/2025]
Abstract
BACKGROUND Observational studies suggest that alcohol consumption increases the risk of traumatic brain injury (TBI); however, the causality of this association remains unclear. OBJECTIVES This study aimed to identify which drinking pattern is the primary factor influencing TBI. METHOD Two-sample Mendelian randomization (MR) was used to assess whether drinking patterns (alcohol consumption, abuse, and intake frequency) are causally associated with TBI risk. RESULTS MR analysis revealed causal effects of alcohol intake frequency [odds ratio (OR) 0.806, 95% confidence interval (CI): 0.665-0.978, p = 0.028, beta: -0.215, se: 0.098], alcohol drinks per week (OR 1.772, 95% CI: 1.140-2.753, p = 0.011, beta: 0.572, se: 0.225), and alcohol abuse (OR 1.095, 95% CI: 1.006-1.192, p = 0.035, beta: 0.091, se: 0.043) on TBI. Additionally, no causal effect of alcohol consumption (OR 0.730, 95% CI: 0.264-2.025, p = 0.546, beta: -0.314, se: 0.520) or average monthly alcohol intake (OR 1.138, 95% CI: 0.805-1.609, p = 0.463, beta: 0.130, se: 0.177) on TBI was observed. Similarly, the effects of TBI on alcohol intake were statistically non-significant. CONCLUSION Drinking patterns, including alcohol intake frequency and abuse, influence TBI, whereas TBI rarely influences drinking patterns.
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Affiliation(s)
- Xiaohang Zhang
- School of Integrated Medicine, Nanjing University of Chinese Medicine, Nanjing, China
| | - Wenze Wu
- Jiangsu Key Laboratory for High Technology Research of TCM Formulae, School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, China
| | - Guisheng Zhou
- Jiangsu Key Laboratory for High Technology Research of TCM Formulae, School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, China
- Jiangsu Collaborative Innovation Center of Chinese Medicinal Resource Industrialization, and National and Local Collaborative Engineering Center of Chinese Medicinal Resources Industrialization and Formulae Innovative Medicine, Nanjing University of Chinese Medicine, Nanjing, China
| | - Xi Huang
- School of Integrated Medicine, Nanjing University of Chinese Medicine, Nanjing, China
| | - Min Xu
- School of Integrated Medicine, Nanjing University of Chinese Medicine, Nanjing, China
| | - Qiulong Zhao
- Department of Pharmacy, Shenzhen Hospital of Integrated Traditional Chinese and Western Medicine, Shenzhen, China
| | - Hui Yan
- Jiangsu Key Laboratory for High Technology Research of TCM Formulae, School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, China
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Dhanarisi J, Eddleston M, Wunnapuk K, Gawarammana I, Mohamed F. The relationships of plasma profenofos and ethanol concentrations to clinical outcome in acute profenofos self-poisoning. Clin Toxicol (Phila) 2025; 63:83-91. [PMID: 39807620 DOI: 10.1080/15563650.2024.2437119] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2023] [Revised: 11/23/2024] [Accepted: 11/27/2024] [Indexed: 01/16/2025]
Abstract
INTRODUCTION Many patients acutely self-poisoned with organophosphorus insecticides have co-ingested ethanol. Currently, profenofos 50% emulsifiable concentrate (EC50) is commonly ingested for self-harm in Sri Lanka. Clinical experience suggests that ethanol co-ingestion makes management more difficult. Therefore, we aimed to determine the relationships between plasma ethanol concentration, plasma profenofos concentration and its toxicokinetics, and clinical outcome in acute profenofos self-poisoning. METHODS Demographic and clinical data, including a history of ethanol ingestion and blood samples, were prospectively collected from all cases of acute poisoning with profenofos EC50 presenting to Teaching Hospital Peradeniya, Sri Lanka, over four years. Plasma samples were analyzed by gas chromatography-mass spectrometry to quantify the ethanol (n = 99) and profenofos (n = 30 [15 with ethanol, 15 without ethanol]) concentrations. The PKSolver program was used to calculate the toxicokinetic parameters. RESULTS Of 99 patients (male 78/99) with acute profenofos self-poisoning, 50 reported a history of ethanol co-ingestion. Plasma from 44 of 99 profenofos-poisoned patients had detectable ethanol concentrations. No statistical difference was observed between the mortality in the ethanol group and the no ethanol group (5/44 [11.4%] versus 3/55 [5.5%]; P = 0.461). Similarly, the median half-lives of plasma profenofos absorption in the ethanol and no ethanol groups (0.1 h and 0.1 h, respectively; time 0-24 h) were not statistically different (P = 0.6594). However, the median half-life of plasma profenofos elimination was significantly longer in the ethanol group than the no ethanol group (23.1 h and 9.9 h, respectively; time 0-24 h; P = 0.0002). According to the regression analysis, the half-life of plasma profenofos elimination was longer by 29.4 h in the ethanol group (P = 0.013). DISCUSSION No significant differences in outcomes, including death and endotracheal intubation rates, were found between those who did and did not co-ingest ethanol. No differences were found in toxicokinetic variables between the ethanol and no ethanol groups, but the ethanol group had a longer elimination half-life. CONCLUSION The co-ingestion of ethanol leads to a slowing of the elimination kinetics of profenofos. However, the study did not reveal a significant impact of ethanol co-ingestion on clinical outcomes.
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Affiliation(s)
- Jeevan Dhanarisi
- Faculty of Medicine, South Asian Clinical Toxicology Research Collaboration, University of Peradeniya, Peradeniya, Sri Lanka
| | - Michael Eddleston
- Faculty of Medicine, South Asian Clinical Toxicology Research Collaboration, University of Peradeniya, Peradeniya, Sri Lanka
- Pharmacology, Toxicology, & Therapeutics, University/BHF Centre for Cardiovascular Science, and Centre for Pesticide Suicide Prevention, University of Edinburgh, Edinburgh, UK
| | - Klintean Wunnapuk
- Department of Forensic Medicine, Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand
| | - Indika Gawarammana
- Faculty of Medicine, South Asian Clinical Toxicology Research Collaboration, University of Peradeniya, Peradeniya, Sri Lanka
- Department of Medicine, Faculty of Medicine, University of Peradeniya, Peradeniya, Sri Lanka
| | - Fahim Mohamed
- Faculty of Medicine, South Asian Clinical Toxicology Research Collaboration, University of Peradeniya, Peradeniya, Sri Lanka
- Department of Pharmacology, Sydney Pharmacy School, Faculty of Medicine and Health, The University of Sydney, Sydney, Australia
- Edith Collins Centre for Translational Research, Royal Prince Alfred Hospital, Camperdown, Australia
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Cuomo RE. Health disparities in time to diagnosis and survival post-diagnosis of cirrhosis in individuals with alcohol use disorder: A retrospective cohort study. Alcohol 2024; 121:141-146. [PMID: 38408687 DOI: 10.1016/j.alcohol.2024.02.005] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2023] [Revised: 02/15/2024] [Accepted: 02/22/2024] [Indexed: 02/28/2024]
Abstract
OBJECTIVE This study investigates the impact of race, gender, and ethnicity on the progression from diagnosis to cirrhosis and subsequent survival in patients with alcohol use disorder, with a specific focus on identifying potential disparities in health outcomes. METHOD Employing a STROBE-compliant, retrospective cohort design, we analyzed data from patients diagnosed with alcohol use disorder from January 2000 to December 2022, using the University of California Health Data Warehouse. We estimated survival functions using the Kaplan-Meier method and assessed demographic associations using both bivariate and multivariate Cox proportional hazards models. RESULTS The analysis highlighted a significant association between Hispanic ethnicity and an accelerated timeline for both the diagnosis of alcohol-related cirrhosis following diagnosis of alcohol use disorder and mortality post-cirrhosis diagnosis. The former was evident only in bivariate analysis, but the latter association persisted in multivariate analysis. Gender did not demonstrate a significant correlation with the time to these outcomes, though multiracial identification emerged as a protective factor. CONCLUSIONS The study reveals critical health disparities in the progression and outcomes of cirrhosis, particularly between Hispanic and non-Hispanic patients. These findings underscore the urgent need for targeted healthcare interventions and policies that address these disparities. Future research should delve deeper into the multifaceted factors influencing these outcomes, facilitating the development of more nuanced and effective prevention and treatment strategies for alcohol use disorder and its severe complications.
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Affiliation(s)
- Raphael E Cuomo
- University of California, San Diego, School of Medicine, San Diego, California, United States.
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Sandoval C, Canobbi L, Orrego Á, Reyes C, Venegas F, Vera Á, Torrens F, Vásquez B, Godoy K, Zamorano M, Caamaño J, Farías J. Application of Integrated Optical Density in Evaluating Insulin Expression in the Endocrine Pancreas During Chronic Ethanol Exposure and β-Carotene Supplementation: A Novel Approach Utilizing Artificial Intelligence. Pharmaceuticals (Basel) 2024; 17:1478. [PMID: 39598390 PMCID: PMC11597364 DOI: 10.3390/ph17111478] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2024] [Revised: 10/29/2024] [Accepted: 11/01/2024] [Indexed: 11/26/2024] Open
Abstract
BACKGROUND β-carotene is an essential antioxidant, providing protection against type 2 diabetes mellitus, cardiovascular illnesses, obesity, and metabolic syndrome. This study investigates the impact of β-carotene on biochemical parameters and pancreatic insulin expression in mice exposed to ethanol. METHODS Thirty-six C57BL/6 mice (Mus musculus) were divided into six groups: 1. C (control), 2. LA (3% alcohol dose), 3. MA (7% alcohol dose), 4. B (0.52 mg/kg body weight/day β-carotene), 5. LA+B (3% alcohol dose + 0.52 mg/kg body weight/day β-carotene), and 6. MA+B (7% alcohol dose plus 0.52 mg/kg body weight/day β-carotene). After 28 days, the animals were euthanized for serum and pancreatic tissue collection. Biochemical analysis and pancreatic insulin expression were performed. One-way ANOVA was used. RESULTS The B, LA+B, and MA+B groups improved insulin levels and decreased HOMA-β versus the C group, with the LA+B and MA+B groups also showing lower ADH and ALDH levels than their nonsupplemented counterparts (p < 0.05). The B, LA+B, and MA+B groups showed a greater β-cell mass area compared to the unsupplemented groups. Additionally, the LA+B and MA+B groups demonstrated significantly increased β-cell area and integrated optical density compared to the LA and MA groups, respectively (p < 0.001). CONCLUSIONS In mice, β-cell loss led to increased glucose release due to decreased insulin levels. β-carotene appeared to mitigate ethanol's impact on these cells, resulting in reduced insulin degradation when integrated optical density was used. These findings suggest that antioxidant supplementation may be beneficial in treating ethanol-induced type 2 diabetes in animal models.
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Affiliation(s)
- Cristian Sandoval
- Escuela de Tecnología Médica, Facultad de Salud, Universidad Santo Tomás, Los Carreras 753, Osorno 5310431, Chile
- Departamento de Ingeniería Química, Facultad de Ingeniería y Ciencias, Universidad de La Frontera, Temuco 4811230, Chile;
- Departamento de Medicina Interna, Facultad de Medicina, Universidad de La Frontera, Temuco 4811230, Chile;
| | - Luciano Canobbi
- Carrera de Tecnología Médica, Facultad de Medicina, Universidad de La Frontera, Temuco 4811230, Chile; (L.C.); (Á.O.); (C.R.); (F.V.); (Á.V.)
| | - Álvaro Orrego
- Carrera de Tecnología Médica, Facultad de Medicina, Universidad de La Frontera, Temuco 4811230, Chile; (L.C.); (Á.O.); (C.R.); (F.V.); (Á.V.)
| | - Camila Reyes
- Carrera de Tecnología Médica, Facultad de Medicina, Universidad de La Frontera, Temuco 4811230, Chile; (L.C.); (Á.O.); (C.R.); (F.V.); (Á.V.)
| | - Felipe Venegas
- Carrera de Tecnología Médica, Facultad de Medicina, Universidad de La Frontera, Temuco 4811230, Chile; (L.C.); (Á.O.); (C.R.); (F.V.); (Á.V.)
| | - Ángeles Vera
- Carrera de Tecnología Médica, Facultad de Medicina, Universidad de La Frontera, Temuco 4811230, Chile; (L.C.); (Á.O.); (C.R.); (F.V.); (Á.V.)
| | - Francisco Torrens
- Institut Universitari de Ciència Molecular, Universitat de València, 46071 València, Spain;
| | - Bélgica Vásquez
- Departamento de Ciencias Básicas, Facultad de Medicina, Universidad de La Frontera, Temuco 4811230, Chile;
- Centro de Excelencia en Estudios Morfológicos y Quirúrgicos (CEMyQ), Facultad de Medicina, Universidad de La Frontera, Temuco 4811230, Chile
| | - Karina Godoy
- Núcleo Científico y Tecnológico en Biorecursos (BIOREN), Universidad de La Frontera, Temuco 4811230, Chile;
| | - Mauricio Zamorano
- Departamento de Ingeniería Química, Facultad de Ingeniería y Ciencias, Universidad de La Frontera, Temuco 4811230, Chile;
| | - José Caamaño
- Departamento de Medicina Interna, Facultad de Medicina, Universidad de La Frontera, Temuco 4811230, Chile;
| | - Jorge Farías
- Departamento de Ingeniería Química, Facultad de Ingeniería y Ciencias, Universidad de La Frontera, Temuco 4811230, Chile;
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Choi S, Ofosu-Boateng M, Kim S, Nnamani DO, Mah'moud M, Neequaye P, Gebreyesus LH, Twum E, Gonzalez FJ, Yue Cui J, Gyamfi MA. Molecular targets of PXR-dependent ethanol-induced hepatotoxicity in female mice. Biochem Pharmacol 2024; 228:116416. [PMID: 38986717 PMCID: PMC11410527 DOI: 10.1016/j.bcp.2024.116416] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2024] [Revised: 06/19/2024] [Accepted: 07/04/2024] [Indexed: 07/12/2024]
Abstract
The pregnane X receptor (PXR, NR1I2), a xenobiotic-sensing nuclear receptor signaling potentiates ethanol (EtOH)-induced hepatotoxicity in male mice, however, how PXR signaling modulates EtOH-induced hepatotoxicity in female mice is unknown. Wild type (WT) and Pxr-null mice received 5 % EtOH-containing diets or paired-fed control diets for 8 weeks followed by assessment of liver injury, EtOH elimination rates, histology, and changes in gene and protein expression; microarray and bioinformatic analyses were also employed to identify PXR targets in chronic EtOH-induced hepatotoxicity. In WT females, EtOH ingestion significantly increased serum ethanol and alanine aminotransferase (ALT) levels, hepatic Pxr mRNA, constitutive androstane receptor activation, Cyp2b10 mRNA and protein, oxidative stress, endoplasmic stress (phospho-elF2α) and pro-apoptotic (Bax) protein expression. Unexpectedly, EtOH-fed female Pxr-null mice displayed increased EtOH elimination and elevated levels of hepatic acetaldehyde detoxifying aldehyde dehydrogenase 1a1 (Aldh1a1) mRNA and protein, EtOH-metabolizing alcohol dehydrogenase 1 (ADH1), and lipid suppressing microsomal triglyceride transport protein (MTP) protein, aldo-keto reductase 1b7 (Akr1b7) and Cyp2a5 mRNA, but suppressed CYP2B10 protein levels, with evidence of protection against chronic EtOH-induced oxidative stress and hepatotoxicity. While liver injury was not different between the two WT sexes, female sex may suppress EtOH-induced macrovesicular steatosis in the liver. Several genes and pathways important in retinol and steroid hormone biosynthesis, chemical carcinogenesis, and arachidonic acid metabolism were upregulated by EtOH in a PXR-dependent manner in both sexes. Together, these data establish that female Pxr-null mice are resistant to chronic EtOH-induced hepatotoxicity and unravel the PXR-dependent and -independent mechanisms that contribute to EtOH-induced hepatotoxicity.
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Affiliation(s)
- Sora Choi
- Julius L. Chambers Biomedical Biotechnology Research Institute, North Carolina Central University, Durham, NC 27707, USA
| | - Malvin Ofosu-Boateng
- Department of Pharmaceutical Sciences, The University of Tennessee Health Science Center, 881 Madison Avenue, Memphis, TN 38163 USA
| | - Sarah Kim
- Department of Environmental and Occupational Health Sciences, University of Washington, Seattle, WA 98105, USA
| | - Daniel O Nnamani
- Department of Pharmaceutical Sciences, The University of Tennessee Health Science Center, 881 Madison Avenue, Memphis, TN 38163 USA
| | - Mia Mah'moud
- Julius L. Chambers Biomedical Biotechnology Research Institute, North Carolina Central University, Durham, NC 27707, USA
| | - Prince Neequaye
- Julius L. Chambers Biomedical Biotechnology Research Institute, North Carolina Central University, Durham, NC 27707, USA
| | - Lidya H Gebreyesus
- Department of Pharmaceutical Sciences, The University of Tennessee Health Science Center, 881 Madison Avenue, Memphis, TN 38163 USA
| | - Elizabeth Twum
- Department of Pharmaceutical Sciences, The University of Tennessee Health Science Center, 881 Madison Avenue, Memphis, TN 38163 USA
| | - Frank J Gonzalez
- Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, Building 37, Room 3106, Bethesda, MD 20892, USA
| | - Julia Yue Cui
- Department of Environmental and Occupational Health Sciences, University of Washington, Seattle, WA 98105, USA
| | - Maxwell A Gyamfi
- Julius L. Chambers Biomedical Biotechnology Research Institute, North Carolina Central University, Durham, NC 27707, USA; Department of Pharmaceutical Sciences, The University of Tennessee Health Science Center, 881 Madison Avenue, Memphis, TN 38163 USA.
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Rangra S, Rana D, Prajapati A, Benival D, Dwivedi P, Mandoli A. Nutritional and microbiota-based therapeutic interventions for alcohol-associated liver disease: From pathogenesis to therapeutic insights. Life Sci 2024; 352:122852. [PMID: 38909682 DOI: 10.1016/j.lfs.2024.122852] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/02/2024] [Revised: 06/06/2024] [Accepted: 06/14/2024] [Indexed: 06/25/2024]
Abstract
Alcohol-associated liver disease (ALD) manifests as a consequence of prolonged and excessive alcohol consumption. This disease is closely associated with the interplay between gut health and liver function, which can lead to complex pathophysiological changes in the body. This review offers a comprehensive exploration of ALD's multifaceted nature, with a keen focus on its pathogenesis and the potential of nutritional and microbiota-based therapies. Insights derived from diverse case studies are utilized to shed light on how interventions can rebalance the gut microbiome and enhance liver function in ALD patients. Furthermore, the feasibility of liver transplantation and stem cell therapy as ultimate measures for ALD has been discussed, with acknowledgment of the inherent risks and challenges accompanying them. ALD's complexity underscores the necessity for a thorough understanding of its etiology and progression to devise effective treatments that mitigate its profound impact on an individual's health.
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Affiliation(s)
- Shagun Rangra
- Department of Pharmaceutics, National Institute of Pharmaceutical Education and Research- Ahmedabad (NIPER-A), 382355, India
| | - Dhwani Rana
- Department of Pharmaceutics, National Institute of Pharmaceutical Education and Research- Ahmedabad (NIPER-A), 382355, India
| | - Arvee Prajapati
- Department of Pharmaceutics, National Institute of Pharmaceutical Education and Research- Ahmedabad (NIPER-A), 382355, India
| | - Derajram Benival
- Department of Pharmaceutics, National Institute of Pharmaceutical Education and Research- Ahmedabad (NIPER-A), 382355, India
| | - Pradeep Dwivedi
- Department of Pharmacology, All India Institute of Medical Sciences (AIIMS) - Jodhpur, 342005, India
| | - Amit Mandoli
- Department of Biotechnology, National Institute of Pharmaceutical Education and Research- Ahmedabad (NIPER-A), 382355, India.
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Grodin EN, Burnette EM, Rodriguez C, Fulcher JA, Ray LA. The gut microbiome in alcohol use disorder and alcohol-associated liver disease: A systematic review of clinical studies. ALCOHOL, CLINICAL & EXPERIMENTAL RESEARCH 2024; 48:1221-1242. [PMID: 38719790 PMCID: PMC11827555 DOI: 10.1111/acer.15338] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/21/2024] [Revised: 04/01/2024] [Accepted: 04/10/2024] [Indexed: 07/11/2024]
Abstract
Evidence suggests that a relationship exists between the gut microbiome and the pathogenesis of alcohol use disorder (AUD) and alcohol-associated liver disease (AALD). This systematic review identified studies that investigated the gut microbiome in individuals with an AUD or an AALD. A search was conducted on October 27, 2022, in PubMed, Web of Science, and Embase databases. Fifty studies satisfied eligibility criteria. Most studies found evidence for gut dysbiosis in individuals with AUD and AALD. Microbiome intervention studies have mostly been conducted in AALD patients; fecal microbial transplant interventions show the most promise. Because most studies were conducted cross-sectionally, the causal relationship between the gut microbiome and alcohol use is unknown. Furthermore, almost all studies have been conducted in predominantly male populations, leaving critical questions regarding sex differences and generalizability of the findings. The study summaries and recommendations provided in this review seek to identify areas for further research and to highlight potential gut microbial interventions for treating AUD and AALD.
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Affiliation(s)
- Erica N. Grodin
- Department of Psychology, University of California, Los Angeles, Los Angeles, California, USA
- Department of Psychiatry and Biobehavioral Sciences, University of California, Los Angeles, Los Angeles, California, USA
- Brain Research Institute, University of California, Los Angeles, Los Angeles, California, USA
| | - Elizabeth M. Burnette
- Brain Research Institute, University of California, Los Angeles, Los Angeles, California, USA
| | - Crystal Rodriguez
- Department of Psychology, University of California, Los Angeles, Los Angeles, California, USA
| | - Jennifer A. Fulcher
- Division of Infectious Diseases, David Gefen School of Medicine at the University of California, Los Angeles, Los Angeles, CA, USA
| | - Lara A. Ray
- Department of Psychology, University of California, Los Angeles, Los Angeles, California, USA
- Department of Psychiatry and Biobehavioral Sciences, University of California, Los Angeles, Los Angeles, California, USA
- Brain Research Institute, University of California, Los Angeles, Los Angeles, California, USA
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Wu Z, Yu J, Lyu B, Lin H, Li S, Liu GG. Alcohol Consumption Patterns for Excessive Drinkers in a Multi-Ethnic Society Short Running Title: Drinking Patterns and Health Education. Risk Manag Healthc Policy 2024; 17:1577-1586. [PMID: 38882055 PMCID: PMC11180439 DOI: 10.2147/rmhp.s459188] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2024] [Accepted: 05/19/2024] [Indexed: 06/18/2024] Open
Abstract
Objective Culture and eating habits, which vary greatly across different ethnic groups, have a substantial impact on drinking behavior. This study aimed to examine whether the drinking patterns and reasons differ by ethnic groups, and provide useful insights for multi-ethnic areas that seek to cut down alcohol intake. Methods We recruited excessive drinkers and collected the drinking patterns and motivations by questionnaire in a multi-ethnic society. Multiple linear regressions were used to evaluate the variations in drinking characteristics among different ethnic groups. Results We recruited 1287 participants through convenience sampling (a non-probability sampling technique used in research where the researcher selects participants or units for a study based on their accessibility and proximity), among whom 439 excessive drinkers were eligible. The mean age was 38 years for the 439 participants, 92.9% were men, 36.0% were Han, and 64.0% were minorities mainly composed of the Yi. The majority of the participants were married (75.9%) and did physical work (58.1%). Ethnic minorities consumed more alcohol on a single occasion than Han people did (47.3 vs 41.8g/session) while drinking less frequently. For the minority and Han participants, 67% and 42% were not used to drinking with food, respectively. Peer pressure and fostering a good atmosphere were the most common drinking reasons for the minority and Han, respectively. Conclusion We found substantial differences in drinking patterns and reasons between ethnic minorities and Han ethnicity, attributable to their culture and customs. Findings highlight the importance of drinking habits and motivations in exploring alcohol control education strategies in the context of ethnic integration and population immigration.
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Affiliation(s)
- Ziting Wu
- National School of Development, Peking University, Beijing, 100871, People's Republic of China
- Institute for Global Health and Development, Peking University, Beijing, 100871, People's Republic of China
- PKU China Center for Health Economic Research, Peking University, Beijing, 100871, People's Republic of China
| | - Jiangxia Yu
- School of Medicine and Health Management, Guizhou Medical University, Guiyang, 550025, People's Republic of China
| | - Beini Lyu
- Institute for Global Health and Development, Peking University, Beijing, 100871, People's Republic of China
| | - Haoxiang Lin
- Institute for Global Health and Development, Peking University, Beijing, 100871, People's Republic of China
| | - Shanshan Li
- Center for International Cooperation and Disciplinary Innovation of Income Distribution and Public Finance (111 Center), Zhongnan University of Economics and Law, Wuhan, 430073, People's Republic of China
- Hubei Finance and Development Research Center, Zhongnan University of Economics and Law, Wuhan, 430073, People's Republic of China
| | - Gordon G Liu
- National School of Development, Peking University, Beijing, 100871, People's Republic of China
- Institute for Global Health and Development, Peking University, Beijing, 100871, People's Republic of China
- PKU China Center for Health Economic Research, Peking University, Beijing, 100871, People's Republic of China
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Lu Y, George J. Interaction between fatty acid oxidation and ethanol metabolism in liver. Am J Physiol Gastrointest Liver Physiol 2024; 326:G483-G494. [PMID: 38573193 PMCID: PMC11901390 DOI: 10.1152/ajpgi.00281.2023] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/22/2023] [Revised: 02/13/2024] [Accepted: 02/26/2024] [Indexed: 04/05/2024]
Abstract
Fatty acid oxidation (FAO) releases the energy stored in fat to maintain basic biological processes. Dehydrogenation is a major way to oxidize fatty acids, which needs NAD+ to accept the released H+ from fatty acids and form NADH, which increases the ratio of NADH/NAD+ and consequently inhibits FAO leading to the deposition of fat in the liver, which is termed fatty liver or steatosis. Consumption of alcohol (ethanol) initiates simple steatosis that progresses to alcoholic steatohepatitis, which constitutes a spectrum of liver disorders called alcohol-associated liver disease (ALD). ALD is linked to ethanol metabolism. Ethanol is metabolized by alcohol dehydrogenase (ADH), microsomal ethanol oxidation system (MEOS), mainly cytochrome P450 2E1 (CYP2E1), and catalase. ADH also requires NAD+ to accept the released H+ from ethanol. Thus, ethanol metabolism by ADH leads to increased ratio of NADH/NAD+, which inhibits FAO and induces steatosis. CYP2E1 directly consumes reducing equivalent NADPH to oxidize ethanol, which generates reactive oxygen species (ROS) that lead to cellular injury. Catalase is mainly present in peroxisomes, where very long-chain fatty acids and branched-chain fatty acids are oxidized, and the resultant short-chain fatty acids will be further oxidized in mitochondria. Peroxisomal FAO generates hydrogen peroxide (H2O2), which is locally decomposed by catalase. When ethanol is present, catalase uses H2O2 to oxidize ethanol. In this review, we introduce FAO (including α-, β-, and ω-oxidation) and ethanol metabolism (by ADH, CYP2E1, and catalase) followed by the interaction between FAO and ethanol metabolism in the liver and its pathophysiological significance.
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Affiliation(s)
- Yongke Lu
- Department of Biomedical Sciences, Joan C. Edwards College of Medicine, Marshall University, Huntington, West Virginia, United States
| | - Joseph George
- Department of Hepatology, Kanazawa Medical University, Uchinada, Ishikawa, Japan
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Torres Irizarry VC, Feng B, Yang X, Patel N, Schaul S, Ibrahimi L, Ye H, Luo P, Carrillo-Sáenz L, Lai P, Kota M, Dixit D, Wang C, Lasek AW, He Y, Xu P. Estrogen signaling in the dorsal raphe regulates binge-like drinking in mice. Transl Psychiatry 2024; 14:122. [PMID: 38413577 PMCID: PMC10899193 DOI: 10.1038/s41398-024-02821-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/19/2024] [Revised: 02/06/2024] [Accepted: 02/08/2024] [Indexed: 02/29/2024] Open
Abstract
Estrogens promote binge alcohol drinking and contribute to sex differences in alcohol use disorder. However, the mechanisms are largely unknown. This study aims to test if estrogens act on 5-hydroxytryptamine neurons in the dorsal raphe nucleus (5-HTDRN) to promote binge drinking. We found that female mice drank more alcohol than male mice in chronic drinking in the dark (DID) tests. This sex difference was associated with distinct alterations in mRNA expression of estrogen receptor α (ERα) and 5-HT-related genes in the DRN, suggesting a potential role of estrogen/ERs/5-HT signaling. In supporting this view, 5-HTDRN neurons from naïve male mice had lower baseline firing activity but higher sensitivity to alcohol-induced excitation compared to 5-HTDRN neurons from naïve female mice. Notably, this higher sensitivity was blunted by 17β-estradiol treatment in males, indicating an estrogen-dependent mechanism. We further showed that both ERα and ERβ are expressed in 5-HTDRN neurons, whereas ERα agonist depolarizes and ERβ agonist hyperpolarizes 5-HTDRN neurons. Notably, both treatments blocked the stimulatory effects of alcohol on 5-HTDRN neurons in males, even though they have antagonistic effects on the activity dynamics. These results suggest that ERs' inhibitory effects on ethanol-induced burst firing of 5-HTDRN neurons may contribute to higher levels of binge drinking in females. Consistently, chemogenetic activation of ERα- or ERβ-expressing neurons in the DRN reduced binge alcohol drinking. These results support a model in which estrogens act on ERα/β to prevent alcohol-induced activation of 5-HTDRN neurons, which in return leads to higher binge alcohol drinking.
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Affiliation(s)
- Valeria C Torres Irizarry
- Division of Endocrinology, Department of Medicine, The University of Illinois at Chicago, Chicago, IL, 60612, USA
- Department of Physiology and Biophysics, The University of Illinois at Chicago, Chicago, IL, 60612, USA
| | - Bing Feng
- Pennington Biomedical Research Center, Louisiana State University, Baton Rouge, LA, 70808, USA
| | - Xiaohua Yang
- Division of Endocrinology, Department of Medicine, The University of Illinois at Chicago, Chicago, IL, 60612, USA
- Guangdong Laboratory of Lingnan Modern Agriculture and Guangdong Province Key Laboratory of Animal Nutritional Regulation, National Engineering Research Center for Breeding Swine Industry, College of Animal Science, South China Agricultural University, 483 Wushan Road, Tianhe District, 510642, Guangzhou, Guangdong, China
| | - Nirali Patel
- Division of Endocrinology, Department of Medicine, The University of Illinois at Chicago, Chicago, IL, 60612, USA
| | - Sarah Schaul
- Division of Endocrinology, Department of Medicine, The University of Illinois at Chicago, Chicago, IL, 60612, USA
| | - Lucas Ibrahimi
- Division of Endocrinology, Department of Medicine, The University of Illinois at Chicago, Chicago, IL, 60612, USA
| | - Hui Ye
- Division of Endocrinology, Department of Medicine, The University of Illinois at Chicago, Chicago, IL, 60612, USA
| | - Pei Luo
- Division of Endocrinology, Department of Medicine, The University of Illinois at Chicago, Chicago, IL, 60612, USA
- Guangdong Laboratory of Lingnan Modern Agriculture and Guangdong Province Key Laboratory of Animal Nutritional Regulation, National Engineering Research Center for Breeding Swine Industry, College of Animal Science, South China Agricultural University, 483 Wushan Road, Tianhe District, 510642, Guangzhou, Guangdong, China
| | - Leslie Carrillo-Sáenz
- Division of Endocrinology, Department of Medicine, The University of Illinois at Chicago, Chicago, IL, 60612, USA
- Department of Physiology and Biophysics, The University of Illinois at Chicago, Chicago, IL, 60612, USA
| | - Penghua Lai
- Division of Endocrinology, Department of Medicine, The University of Illinois at Chicago, Chicago, IL, 60612, USA
| | - Maya Kota
- Division of Endocrinology, Department of Medicine, The University of Illinois at Chicago, Chicago, IL, 60612, USA
| | - Devin Dixit
- Division of Endocrinology, Department of Medicine, The University of Illinois at Chicago, Chicago, IL, 60612, USA
| | - Chunmei Wang
- Children's Nutrition Research Center, Department of Pediatrics, Baylor College of Medicine, One Baylor Plaza, Houston, TX, 77030, USA
| | - Amy W Lasek
- Center for Alcohol Research in Epigenetics and Department of Psychiatry, University of Illinois at Chicago, Chicago, IL, 60612, USA
- Department of Pharmacology and Toxicology, Virginia Commonwealth University, Richmond, VI, 23298, USA
| | - Yanlin He
- Pennington Biomedical Research Center, Louisiana State University, Baton Rouge, LA, 70808, USA.
| | - Pingwen Xu
- Division of Endocrinology, Department of Medicine, The University of Illinois at Chicago, Chicago, IL, 60612, USA.
- Department of Physiology and Biophysics, The University of Illinois at Chicago, Chicago, IL, 60612, USA.
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11
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Kipchumba B, Gitonga F, Jepchirchir C, Gitau GW, Okanya PW, Amwayi PW, Isaac AO, Nyabuga NJ. Alcohol spiked with zolpidem and midazolam potentiates inflammation, oxidative stress and organ damage in a mouse model. Forensic Toxicol 2024; 42:45-59. [PMID: 37814103 DOI: 10.1007/s11419-023-00674-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2023] [Accepted: 09/25/2023] [Indexed: 10/11/2023]
Abstract
PURPOSE Crime-related spiking of alcoholic drinks with prescription drugs is quite common and has been happening for centuries. This study, therefore, evaluated the effects of oral administration of alcohol spiked with the zolpidem and midazolam potent sedatives on inflammation, oxidative stress and various organ damage in male Swiss albino mice. METHODS Mice were randomly assigned into six treatment groups; the first group constituted the normal control, the second group received 50 mg/kg body weight of zolpidem only, the third group received 50 mg/kg body weight zolpidem dissolved in 5 g/kg alcohol, the fourth group received 50 mg/kg midazolam only, the fifth group received midazolam (50 mg/kg) dissolved in 5 g/kg alcohol and the sixth group received 5 g/kg alcohol. RESULTS Alcohol-induced significant reduction in neurological function and altered blood hematological indicators. Such neurological impairment and negative effects on blood were exacerbated in mice administered with spiked alcohol. Additionally, midazolam and zolpidem enhanced alcohol-driven elevation of liver function markers; the serum aspartate aminotransferase (AST), alanine aminotransferase (ALT) gamma glutamyltransferase (GGT), total bilirubin and alkaline phosphatase. Exposure to alcohol and/or spiked alcohol led to significant augmentation of nitric oxide and malonaldehyde, with concomitant depletion of liver glutathione (GSH) levels. Similarly, serum levels of pro-inflammatory cytokines tumor necrosis factor alpha and interferon-gamma were increased by co-exposure with midazolam or zolpidem. Alcohol-induced hepatotoxicity and nephrotoxicity were amplified by exposure to alcohol spiked with midazolam/zolpidem. CONCLUSION Exposure to alcohol spiked with midazolam or zolpidem appears to exacerbate neurological deficits, inflammation, oxidative stress, and organ damage.
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Affiliation(s)
- Biwott Kipchumba
- Department of Biochemistry and Biotechnology, Technical University of Kenya, 52428, Nairobi, 00200, Kenya
| | - Francis Gitonga
- Department of Biochemistry and Biotechnology, Technical University of Kenya, 52428, Nairobi, 00200, Kenya
| | - Careen Jepchirchir
- Department of Biochemistry and Biotechnology, Technical University of Kenya, 52428, Nairobi, 00200, Kenya
| | - Grace Wairimu Gitau
- Department of Biochemistry and Biotechnology, Technical University of Kenya, 52428, Nairobi, 00200, Kenya
| | - Patrick W Okanya
- Department of Biochemistry and Biotechnology, Technical University of Kenya, 52428, Nairobi, 00200, Kenya
| | - Peris Wanza Amwayi
- Department of Biochemistry and Biotechnology, Technical University of Kenya, 52428, Nairobi, 00200, Kenya
| | - Alfred Orina Isaac
- Department of Pharmaceutical Technology, School of Health Sciences and Technology, Technical University of Kenya, 52428, Nairobi, 00200, Kenya
| | - Nyariki James Nyabuga
- Department of Biochemistry and Biotechnology, Technical University of Kenya, 52428, Nairobi, 00200, Kenya.
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12
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Maheshwari S, Gu CN, Caserta MP, Kezer CA, Shah VH, Torbenson MS, Menias CO, Fidler JL, Venkatesh SK. Imaging of Alcohol-Associated Liver Disease. AJR Am J Roentgenol 2024; 222:e2329917. [PMID: 37729554 DOI: 10.2214/ajr.23.29917] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 09/22/2023]
Abstract
Alcohol-associated liver disease (ALD) continues to be a global health concern, responsible for a significant number of deaths worldwide. Although most individuals who consume alcohol do not develop ALD, heavy drinkers and binge drinkers are at increased risk. Unfortunately, ALD is often undetected until it reaches advanced stages, frequently associated with portal hypertension and hepatocellular carcinoma (HCC). ALD is now the leading indication for liver transplant. The incidence of alcohol-associated hepatitis (AH) surged during the COVID-19 pandemic. Early diagnosis of ALD is therefore important in patient management and determination of prognosis, as abstinence can halt disease progression. The spectrum of ALD includes steatosis, steatohepatitis, and cirrhosis, with steatosis the most common manifestation. Diagnostic techniques including ultrasound, CT, and MRI provide useful information for identifying ALD and excluding other causes of liver dysfunction. Heterogeneous steatosis and transient perfusion changes on CT and MRI in the clinical setting of alcohol-use disorder are diagnostic of severe AH. Elastography techniques are useful for assessing fibrosis and monitoring treatment response. These various imaging modalities are also useful in HCC surveillance and diagnosis. This review discusses the imaging modalities currently used in the evaluation of ALD, highlighting their strengths, limitations, and clinical applications.
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Affiliation(s)
- Sharad Maheshwari
- Department of Radiology, Kokilaben Dhirubhai Ambani Hospital, Mumbai, India
| | - Chris N Gu
- Department of Radiology, Division of Abdominal Imaging, Mayo Clinic, 200 1st St SW, Rochester, MN 55905
| | - Melanie P Caserta
- Department of Radiology, Division of Abdominal Imaging, Mayo Clinic, Jacksonville, FL
| | - Camille A Kezer
- Department of Internal Medicine, Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN
| | - Vijay H Shah
- Department of Internal Medicine, Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN
| | - Michael S Torbenson
- Department of Laboratory Medicine and Pathology, Division of Anatomic Pathology, Mayo Clinic, Rochester, MN
| | - Christine O Menias
- Department of Radiology, Division of Abdominal Imaging, Mayo Clinic, Scottsdale, AZ
| | - Jeff L Fidler
- Department of Radiology, Division of Abdominal Imaging, Mayo Clinic, 200 1st St SW, Rochester, MN 55905
| | - Sudhakar K Venkatesh
- Department of Radiology, Division of Abdominal Imaging, Mayo Clinic, 200 1st St SW, Rochester, MN 55905
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13
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Namachivayam A, Valsala Gopalakrishnan A. Effect of Lauric acid against ethanol-induced hepatotoxicity by modulating oxidative stress/apoptosis signalling and HNF4α in Wistar albino rats. Heliyon 2023; 9:e21267. [PMID: 37908709 PMCID: PMC10613920 DOI: 10.1016/j.heliyon.2023.e21267] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2023] [Revised: 10/12/2023] [Accepted: 10/18/2023] [Indexed: 11/02/2023] Open
Abstract
Ethanol (EtOH) is most widely used in alcoholic beverages to prepare alcohol. As EtOH is mainly metabolised in the liver, the excessive consumption of EtOH forms a primary toxic metabolic product called acetaldehyde, as the gradual increase in acetaldehyde leads to liver injury, as reported. Lauric acid (LA) is rich in antioxidant, antifungal, antibacterial, anticancer, and antiviral properties. LA is an edible component highly present in coconut oil. However, no report on LA protective effects against the EtOH-instigated hepatotoxicity exists. Therefore, the experiment is carried out to investigate the potency effects of LA on EtOH-instigated hepatotoxicity in thirty male albino rats. Rats were divided into five groups (n-6): control DMSO alone, EtOH -intoxicated, EtOH + LA 180 mg/kg, EtOH + LA 360 mg/kg, and LA alone were administered orally using oral gavage. The study measured body weight every weekend in all rat groups. The rats were sacrificed and assessed for serum markers (alkaline phosphatase, alanine aminotransferase, aspartate aminotransferase), antioxidant activity (superoxide dismutase, reduced glutathione, glutathione peroxidase), lipid peroxidation (malondialdehyde), histopathological, cytokine levels (TNF-α, IL-1β and IL-6), protein expression (caspase 3 and caspase 8 and Bcl-2 and HNF4α) were evaluated after the 56-days study period. The impact of EtOH intoxication reduces the rat's body weight by 90 g, upregulates the liver enzyme markers, depletes the antioxidant levels, produces malondialdehyde, changes the histoarchitecture (periportal inflammation and hepatocyte damage), downregulates the Bcl-2 expressions and HNF4α, and elevates the expression of cytokines and apoptotic markers. LA alleviated EtOH-induced liver toxicity by significant (p < 0.05) modulation of biochemical levels, caspase-8/3 signalling, reducing pro-inflammatory cytokines, and restoring the normal histoarchitecture, upregulating the Bcl-2 and HNF4α Expressions. In conclusion, LA treatment can protect the liver against EtOH-induced hepatotoxicity, evidenced by alleviating Oxidative stress, lipid peroxidation, inflammation, apoptosis, and upregulation of HNF4α.
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Affiliation(s)
- Arunraj Namachivayam
- Department of Biomedical Sciences, School of Bio-Sciences and Technology, Vellore Institute of Technology (VIT), Vellore 632014, India
| | - Abilash Valsala Gopalakrishnan
- Department of Biomedical Sciences, School of Bio-Sciences and Technology, Vellore Institute of Technology (VIT), Vellore 632014, India
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14
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Salete-Granado D, Carbonell C, Puertas-Miranda D, Vega-Rodríguez VJ, García-Macia M, Herrero AB, Marcos M. Autophagy, Oxidative Stress, and Alcoholic Liver Disease: A Systematic Review and Potential Clinical Applications. Antioxidants (Basel) 2023; 12:1425. [PMID: 37507963 PMCID: PMC10376811 DOI: 10.3390/antiox12071425] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2023] [Revised: 07/06/2023] [Accepted: 07/12/2023] [Indexed: 07/30/2023] Open
Abstract
Ethanol consumption triggers oxidative stress by generating reactive oxygen species (ROS) through its metabolites. This process leads to steatosis and liver inflammation, which are critical for the development of alcoholic liver disease (ALD). Autophagy is a regulated dynamic process that sequesters damaged and excess cytoplasmic organelles for lysosomal degradation and may counteract the harmful effects of ROS-induced oxidative stress. These effects include hepatotoxicity, mitochondrial damage, steatosis, endoplasmic reticulum stress, inflammation, and iron overload. In liver diseases, particularly ALD, macroautophagy has been implicated as a protective mechanism in hepatocytes, although it does not appear to play the same role in stellate cells. Beyond the liver, autophagy may also mitigate the harmful effects of alcohol on other organs, thereby providing an additional layer of protection against ALD. This protective potential is further supported by studies showing that drugs that interact with autophagy, such as rapamycin, can prevent ALD development in animal models. This systematic review presents a comprehensive analysis of the literature, focusing on the role of autophagy in oxidative stress regulation, its involvement in organ-organ crosstalk relevant to ALD, and the potential of autophagy-targeting therapeutic strategies.
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Affiliation(s)
- Daniel Salete-Granado
- Instituto de Investigación Biomédica de Salamanca (IBSAL), 37007 Salamanca, Spain; (D.S.-G.); (C.C.); (D.P.-M.); (V.-J.V.-R.); (M.G.-M.); (A.B.H.)
| | - Cristina Carbonell
- Instituto de Investigación Biomédica de Salamanca (IBSAL), 37007 Salamanca, Spain; (D.S.-G.); (C.C.); (D.P.-M.); (V.-J.V.-R.); (M.G.-M.); (A.B.H.)
- Hospital Universitario de Salamanca, 37007 Salamanca, Spain
- Unidad de Medicina Molecular, Departamento de Medicina, Universidad de Salamanca, 37007 Salamanca, Spain
| | - David Puertas-Miranda
- Instituto de Investigación Biomédica de Salamanca (IBSAL), 37007 Salamanca, Spain; (D.S.-G.); (C.C.); (D.P.-M.); (V.-J.V.-R.); (M.G.-M.); (A.B.H.)
- Hospital Universitario de Salamanca, 37007 Salamanca, Spain
| | - Víctor-José Vega-Rodríguez
- Instituto de Investigación Biomédica de Salamanca (IBSAL), 37007 Salamanca, Spain; (D.S.-G.); (C.C.); (D.P.-M.); (V.-J.V.-R.); (M.G.-M.); (A.B.H.)
- Hospital Universitario de Salamanca, 37007 Salamanca, Spain
| | - Marina García-Macia
- Instituto de Investigación Biomédica de Salamanca (IBSAL), 37007 Salamanca, Spain; (D.S.-G.); (C.C.); (D.P.-M.); (V.-J.V.-R.); (M.G.-M.); (A.B.H.)
- Instituto de Biología Funcional y Genómica (IBFG), Universidad de Salamanca, 37007 Salamanca, Spain
| | - Ana Belén Herrero
- Instituto de Investigación Biomédica de Salamanca (IBSAL), 37007 Salamanca, Spain; (D.S.-G.); (C.C.); (D.P.-M.); (V.-J.V.-R.); (M.G.-M.); (A.B.H.)
- Unidad de Medicina Molecular, Departamento de Medicina, Universidad de Salamanca, 37007 Salamanca, Spain
| | - Miguel Marcos
- Instituto de Investigación Biomédica de Salamanca (IBSAL), 37007 Salamanca, Spain; (D.S.-G.); (C.C.); (D.P.-M.); (V.-J.V.-R.); (M.G.-M.); (A.B.H.)
- Hospital Universitario de Salamanca, 37007 Salamanca, Spain
- Unidad de Medicina Molecular, Departamento de Medicina, Universidad de Salamanca, 37007 Salamanca, Spain
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15
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Jung F, Sánchez V, Brandt A, Bergheim I. Alcohol-related liver disease: also a question of what you drink? EXPLORATION OF DIGESTIVE DISEASES 2023; 2:118-132. [PMID: 39404693 PMCID: PMC7616590 DOI: 10.37349/edd.2023.00022] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 02/15/2023] [Accepted: 04/06/2023] [Indexed: 11/28/2024]
Abstract
Excessive alcohol intake is still among the leading causes of chronic liver diseases. Epidemiological studies suggest that per capita consumption of alcohol from various alcohol beverages e.g., beer, wine, or spirits, differs markedly between different areas of the world. Studies further suggest that different alcoholic beverages may impact the development of alcohol-related liver diseases (ALD) differentially. Specifically, results of several more recent epidemiological studies suggest that consumption of wine and herein especially of red wine may be less harmful in relation to the development of liver diseases than the intake of hard spirits. Results of studies evaluating the effects of beer on the development of ALD in humans are rather contradictory. Here, results of studies assessing the impact of wine, beer, and spirits on the development of ALD as well as possible underlying mechanisms are summarized and discussed.
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Affiliation(s)
- Finn Jung
- Department of Nutritional Sciences, Molecular Nutritional Science, University of Vienna, A-1090Vienna, Austria
| | - Victor Sánchez
- Department of Nutritional Sciences, Molecular Nutritional Science, University of Vienna, A-1090Vienna, Austria
| | - Annette Brandt
- Department of Nutritional Sciences, Molecular Nutritional Science, University of Vienna, A-1090Vienna, Austria
| | - Ina Bergheim
- Department of Nutritional Sciences, Molecular Nutritional Science, University of Vienna, A-1090Vienna, Austria
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16
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Li Q, Wang O, Ji B, Zhao L, Zhao L. Alcohol, White Adipose Tissue, and Brown Adipose Tissue: Mechanistic Links to Lipogenesis and Lipolysis. Nutrients 2023; 15:2953. [PMID: 37447280 PMCID: PMC10346806 DOI: 10.3390/nu15132953] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2023] [Revised: 06/21/2023] [Accepted: 06/27/2023] [Indexed: 07/15/2023] Open
Abstract
According to data from the World Health Organization, there were about 3 million deaths caused by alcohol consumption worldwide in 2016, of which about 50% were related to liver disease. Alcohol consumption interfering with the normal function of adipocytes has an important impact on the pathogenesis of alcoholic liver disease. There has been increasing recognition of the crucial role of adipose tissue in regulating systemic metabolism, far beyond that of an inert energy storage organ in recent years. The endocrine function of adipose tissue is widely recognized, and the significance of the proteins it produces and releases is still being investigated. Alcohol consumption may affect white adipose tissue (WAT) and brown adipose tissue (BAT), which interact with surrounding tissues such as the liver and intestines. This review briefly introduces the basic concept and classification of adipose tissue and summarizes the mechanism of alcohol affecting lipolysis and lipogenesis in WAT and BAT. The adipose tissue-liver axis is crucial in maintaining lipid homeostasis within the body. Therefore, this review also demonstrates the effects of alcohol consumption on the adipose tissue-liver axis to explore the role of alcohol consumption in the crosstalk between adipose tissue and the liver.
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Affiliation(s)
- Qing Li
- Beijing Engineering and Technology Research Center of Food Additives, Beijing Technology and Business University, Beijing 100048, China;
| | - Ou Wang
- National Institute for Nutrition and Health, Chinese Center for Disease Control and Prevention, Beijing 100050, China;
| | - Baoping Ji
- Beijing Key Laboratory of Functional Food from Plant Resources, College of Food Science & Nutritional Engineering, China Agricultural University, Beijing 100083, China;
| | - Liang Zhao
- Beijing Engineering and Technology Research Center of Food Additives, Beijing Technology and Business University, Beijing 100048, China;
| | - Lei Zhao
- School of Food and Health, Beijing Technology and Business University, Beijing 100048, China
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17
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Chien TH, Lin CL, Chen LW, Chien CH, Hu CC. Patients with Non-Alcoholic Fatty Liver Disease and Alcohol Dehydrogenase 1B/Aldehyde Dehydrogenase 2 Mutant Gene Have Higher Values of Serum Alanine Transaminase. J Pers Med 2023; 13:jpm13050758. [PMID: 37240928 DOI: 10.3390/jpm13050758] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2023] [Revised: 04/23/2023] [Accepted: 04/24/2023] [Indexed: 05/28/2023] Open
Abstract
Patients with non-alcoholic fatty liver disease (NAFLD) share similar pathophysiologies to those of patients with alcohol liver disease. Alcoholic metabolic enzyme-related genes (alcohol dehydrogenase 1B (ADH1B) and aldehyde dehydrogenase 2 (ALDH2)) may be associated with pathophysiology in NAFLD patients. In this study, the association between ADH1B/ALDH2 gene polymorphism and serum metabolic factors, body statures, and hepatic steatosis/fibrosis status was evaluated in patients with NAFLD. Using biochemistry data, abdominal ultrasonography, fibrosis evaluation (Kpa), and steatosis evaluation (CAP), ADH1B gene SNP rs1229984 and ALDH2 gene SNP rs671 polymorphism were analyzed in sixty-six patients from 1 January 2022 to 31 December 2022. The percentage of the mutant type (GA + AA) was 87.9% (58/66) in the ADH1B allele and 45.5% (30/66) in the ALDH2 allele. Patients with the mutant-type ADH1B/ALDH2 allele had higher values of alanine aminotransferase (ALT) than the wild type (β = 0.273, p = 0.04). No association was observed between body mass index, serum metabolic factors (sugar and lipid profile), CAP, kPa, and ADH1B/ALDH2. A high proportion of the mutant-type ADH1B allele (87.9%) and ALDH2 allele (45.5%) was observed in patients with NAFLD. No association was observed between ADH1B/ALDH2 allele, BMI, and hepatic steatosis/fibrosis. Patients with the mutant-type ADH1B/ALDH2 allele had higher values of ALT than those with the wild type.
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Affiliation(s)
- Tsuo-Hsuan Chien
- Department of Gastroenterology and Hepatology, Chang-Gung Memorial Hospital and University, Keelung Branch, Keelung 204, Taiwan
| | - Chih-Lang Lin
- Department of Gastroenterology and Hepatology, Chang-Gung Memorial Hospital and University, Keelung Branch, Keelung 204, Taiwan
- Community Medicine Research Center, Chang-Gung Memorial Hospital and University, Keelung Branch, Keelung 204, Taiwan
| | - Li-Wei Chen
- Department of Gastroenterology and Hepatology, Chang-Gung Memorial Hospital and University, Keelung Branch, Keelung 204, Taiwan
- Community Medicine Research Center, Chang-Gung Memorial Hospital and University, Keelung Branch, Keelung 204, Taiwan
| | - Cheng-Hung Chien
- Department of Gastroenterology and Hepatology, Chang-Gung Memorial Hospital and University, Keelung Branch, Keelung 204, Taiwan
- Community Medicine Research Center, Chang-Gung Memorial Hospital and University, Keelung Branch, Keelung 204, Taiwan
| | - Ching-Chih Hu
- Department of Gastroenterology and Hepatology, Chang-Gung Memorial Hospital and University, Keelung Branch, Keelung 204, Taiwan
- Community Medicine Research Center, Chang-Gung Memorial Hospital and University, Keelung Branch, Keelung 204, Taiwan
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18
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Lesnewich LM, Lu SE, Weinreb KS, Sparks SO, Litke DR, Helmer DA, Pigeon WR, McAndrew LM. Associations between risky alcohol use, disability, and problem-solving impairment among Veterans with Gulf War Illness: Secondary data analysis of a randomized clinical trial. J Psychosom Res 2023; 170:111336. [PMID: 37087893 DOI: 10.1016/j.jpsychores.2023.111336] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/18/2023] [Revised: 03/30/2023] [Accepted: 04/09/2023] [Indexed: 04/25/2023]
Abstract
OBJECTIVE Gulf War Illness (GWI) and alcohol use are both major sources of disability among Gulf War Veterans. The goal of this secondary data analysis was to examine associations between risky alcohol use, problem-solving impairment, and disability among Veterans in a randomized clinical trial of problem-solving treatment (PST) for GWI. We examined cross-sectional associations and conducted longitudinal analyses to test if alcohol use moderated treatment outcome of PST. METHODS Participants were 268 United States military Veterans with GWI randomized to PST or a control intervention. Participants were assessed at four timepoints. Measures included the World Health Organization Disability Assessment Schedule 2.0 (WHO-DAS 2.0), Problem Solving Inventory (PSI), and Alcohol Use Disorders Identification Test-Concise (AUDIT-C). We conducted multivariate regression (cross-sectional) and mixed model analyses (longitudinal) with separate models for WHO-DAS 2.0 and PSI. All models included AUDIT-C and household income. This analysis was pre-registered on the Open Science Framework. RESULTS Cross-sectional analyses revealed a significant negative association with small effect size between AUDIT-C and WHO-DAS 2.0 (p = 0.006; f2 = 0.05); worse disability was associated with less risky alcohol use. There was no evidence that risky alcohol use moderated effects of PST on disability or PSI. CONCLUSION If replicated, the cross-sectional findings suggest high levels of disability may deter heavy drinking among Veterans with GWI. We did not find evidence that risky alcohol use moderated treatment outcome of PST for GWI. More research is needed to identify moderators of GWI interventions and to understand risky drinking among Veterans with complex health problems.
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Affiliation(s)
- Laura M Lesnewich
- War Related Illness and Injury Study Center (WRIISC), Veterans Affairs New Jersey Health Care System, 385 Tremont Ave., East Orange, NJ 07018, USA.
| | - Shou-En Lu
- Rutgers School of Public Health, 683 Hoes Ln. W, Piscataway, NJ 08854, USA; Rutgers Cancer Institute of New Jersey, 195 Little Albany St., New Brunswick, NJ 08901, USA
| | - Karly S Weinreb
- War Related Illness and Injury Study Center (WRIISC), Veterans Affairs New Jersey Health Care System, 385 Tremont Ave., East Orange, NJ 07018, USA; Montclair State University, 1 Normal Ave., Montclair, NJ 07043, USA
| | - Sharron O Sparks
- War Related Illness and Injury Study Center (WRIISC), Veterans Affairs New Jersey Health Care System, 385 Tremont Ave., East Orange, NJ 07018, USA; Felician University, 1 Felician Way, Rutherford, NJ 07070, USA
| | - David R Litke
- War Related Illness and Injury Study Center (WRIISC), Veterans Affairs New Jersey Health Care System, 385 Tremont Ave., East Orange, NJ 07018, USA; Department of Rehabilitation Medicine, New York University Grossman School of Medicine, 240 E. 38th St., New York, NY 10016, USA
| | - Drew A Helmer
- Center for Innovations in Quality, Effectiveness & Safety (IQuESt), Michael E. DeBakey Veterans Affairs Medical Center, 2002 Holcombe Blvd. (152), Houston, TX 77030, USA; Department of Medicine, Baylor College of Medicine, 1 Taub Loop, Houston, TX 77030, USA
| | - Wilfred R Pigeon
- VISN 2 Center of Excellence for Suicide Prevention, 400 Fort Hill Ave., Canandaigua, New York 14424, USA; University of Rochester Medical Center, 300 Crittenden Blvd. - Box PSYCH, Rochester, NY 14642, USA
| | - Lisa M McAndrew
- War Related Illness and Injury Study Center (WRIISC), Veterans Affairs New Jersey Health Care System, 385 Tremont Ave., East Orange, NJ 07018, USA
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19
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Pontes Pereira TT, Fideles Duarte-Andrade F, Gardone Vitório J, do Espírito Santo Pereira T, Braga Martins FR, Marques Souza JA, Malacco NL, Mathias Melo E, Costa Picossi CR, Pinto E, Santiago Gomez R, Martins Teixeira M, Nori de Macedo A, André Baptista Canuto G, Soriani FM. Chronic alcohol administration alters metabolomic profile of murine bone marrow. Front Immunol 2023; 14:1128352. [PMID: 37090737 PMCID: PMC10113543 DOI: 10.3389/fimmu.2023.1128352] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2022] [Accepted: 03/06/2023] [Indexed: 04/25/2023] Open
Abstract
Introduction People with hazardous alcohol use are more susceptible to viral, bacterial, and fungal infections due to the effect of alcohol on immune system cell function. Metabolized ethanol reduces NAD+ to NADH, affecting critical metabolic pathways. Here, our aim was to investigate whether alcohol is metabolized by bone marrow cells and if it impacts the metabolic pathways of leukocyte progenitor cells. This is said to lead to a qualitative and quantitative alteration of key metabolites which may be related to the immune response. Methods We addressed this aim by using C57BL/6 mice under chronic ethanol administration and evaluating the metabolomic profile of bone marrow total cells by gas chromatography-coupled mass spectrometry (GC-MS). Results We identified 19 metabolites. Our data demonstrated that chronic ethanol administration alters the metabolomic profile in the bone marrow, resulting in a statistically diminished abundance of five metabolites in ethanol-treated animals: uracil, succinate, proline, nicotinamide, and tyrosine. Discussion Our results demonstrate for the first time in the literature the effects of alcohol consumption on the metabolome content of hematopoietic tissue and open a wide range of further studies to investigate mechanisms by which alcohol compromises the cellular function of the immune system.
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Affiliation(s)
| | | | - Jéssica Gardone Vitório
- Department of Clinic, Pathology and Dental Surgery, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil
| | | | | | | | | | - Eliza Mathias Melo
- Department of Biochemistry and Immunology, Federal University of Minas Gerais, Belo Horizonte, Brazil
| | | | - Ernani Pinto
- Nuclear Energy Center in Agriculture, Escola Superior de Agricultura Luiz de Queiroz, University of São Paulo, Piracicaba, Brazil
| | - Ricardo Santiago Gomez
- Department of Clinic, Pathology and Dental Surgery, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil
| | - Mauro Martins Teixeira
- Department of Biochemistry and Immunology, Federal University of Minas Gerais, Belo Horizonte, Brazil
| | | | - Gisele André Baptista Canuto
- Department of Analytical Chemistry of the Institute of Chemistry, Universidade Federal da Bahia, Salvador, Brazil
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20
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Kim KJ, Park SY, Park TG, Park HJ, Kim YJ, Kim EJ, Shin W, Kim A, Yoo H, Kweon M, Jang J, Choi SY, Kim JY. Noni fruit extract ameliorates alcohol-induced hangover symptoms by reducing the concentrations of alcohol and acetaldehyde in a Sprague Dawley rat model and a human intervention study. Food Funct 2023; 14:1750-1760. [PMID: 36727425 DOI: 10.1039/d2fo02835b] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/27/2023]
Abstract
Various studies have reported that Noni shows various health effects. This study aimed to assess the ability of Noni fruit extract to serve as a single active functional ingredient for the alleviation of hangover symptoms in Sprague Dawley rats and healthy subjects in a single-dose, randomized, double-blind, crossover, placebo-controlled study. The rats were orally administered Noni fruit extract at 50 or 100 mg per kg body weight (B.W.) and HOVENIA. The blood ethanol (EtOH) and acetaldehyde concentrations were significantly lower in the 100 mg per kg B.W. group than in the EtOH group. Alcohol dehydrogenase and aldehyde dehydrogenase activity tended to increase in the 100 mg kg-1 B.W. group. In the human study, 30 subjects received either a placebo or Noni fruit extract (1 g). The Noni fruit extract group showed significantly faster time point at which the maximum concentration (Tmax) of alcohol than in the placebo group. In addition, blood acetaldehyde levels and diarrhea at 40 and 720 min after alcohol intake and the area under the curve between 40 and 60 min of acetaldehyde were significantly decreased in the Noni fruit extract group compared to the placebo group. According to the QUalitative INteraction Trees, subjects who were ≤36 years old who consumed more alcohol (>15 drinks per week) and had a higher total hangover score (>27.5 and 33) presented significantly lower blood acetaldehyde levels and less severe hangover symptoms. These results indicate that Noni fruit extract has the potential to improve hangover symptoms by decreasing alcohol and acetaldehyde levels.
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Affiliation(s)
- Kyeong Jin Kim
- Department of Nano Bio Engineering, Seoul National University of Science and Technology, Seoul 01811, Republic of Korea
| | - Soo-Yeon Park
- Department of Food Science and Technology, Seoul National University of Science and Technology, Seoul 01811, Republic of Korea.
| | - Tae Gwon Park
- Department of Food Science and Technology, Seoul National University of Science and Technology, Seoul 01811, Republic of Korea.
| | - Hyeon-Ju Park
- Department of Food Science and Technology, Seoul National University of Science and Technology, Seoul 01811, Republic of Korea.
| | - Young-Jun Kim
- Department of Food Science and Technology, Seoul National University of Science and Technology, Seoul 01811, Republic of Korea.
| | - Eun Ji Kim
- Industry coupled Cooperation Center for Bio Healthcare Materials, Hallym University, Chuncheon 24252, Republic of Korea
| | - Wonsuk Shin
- Department of Clinical Pharmacology and Therapeutics, CHA Bundang Medical Center, CHA University School of Medicine, Seongnam-si, Gyeonggi-do, Republic of Korea
| | - Anhye Kim
- Department of Clinical Pharmacology and Therapeutics, CHA Bundang Medical Center, CHA University School of Medicine, Seongnam-si, Gyeonggi-do, Republic of Korea
| | - Hyounggyoon Yoo
- Department of Clinical Pharmacology and Therapeutics, CHA Bundang Medical Center, CHA University School of Medicine, Seongnam-si, Gyeonggi-do, Republic of Korea
| | - MinSon Kweon
- COSMAX NS, Seongnam-si, Gyeonggi-do, Republic of Korea
| | - Jihwan Jang
- COSMAX NS, Seongnam-si, Gyeonggi-do, Republic of Korea
| | - Su-Young Choi
- COSMAX NS, Seongnam-si, Gyeonggi-do, Republic of Korea
| | - Ji Yeon Kim
- Department of Nano Bio Engineering, Seoul National University of Science and Technology, Seoul 01811, Republic of Korea.,Department of Food Science and Technology, Seoul National University of Science and Technology, Seoul 01811, Republic of Korea.
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21
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Wu YC, Yao Y, Tao LS, Wang SX, Hu Y, Li LY, Hu S, Meng X, Yang DS, Li H, Xu T. The role of acetaldehyde dehydrogenase 2 in the pathogenesis of liver diseases. Cell Signal 2023; 102:110550. [PMID: 36464104 DOI: 10.1016/j.cellsig.2022.110550] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2022] [Revised: 11/12/2022] [Accepted: 11/28/2022] [Indexed: 12/04/2022]
Abstract
Common liver tissue damage is mainly due to the accumulation of toxic aldehydes in lipid peroxidation under oxidative stress. Cumulative toxic aldehydes in the liver can be effectively metabolized by acetaldehyde dehydrogenase 2 (ALDH2), thereby alleviating various liver diseases. Notably, gene mutation of ALDH2 leads to impaired ALDH2 enzyme activity, thus aggravating the progress of liver diseases. However, the relationship and specific mechanism between ALDH2 and liver diseases are not clear. Consequently, the review explains the relationship between ALDH2 and liver diseases such as alcoholic liver disease (ALD), non-alcoholic fatty liver disease (NAFLD), liver fibrosis and hepatocellular carcinoma (HCC). In addition, this review also discusses ALDH2 as a potential therapeutic target for various liver diseases,and focuses on summarizing the regulatory mechanism of ALDH2 in these liver diseases.
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Affiliation(s)
- Yin-Cui Wu
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, Hefei, 230032, China; Institute for Liver Diseases of Anhui Medical University, China
| | - Yan Yao
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, Hefei, 230032, China; Institute for Liver Diseases of Anhui Medical University, China
| | - Liang-Song Tao
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, Hefei, 230032, China; Institute for Liver Diseases of Anhui Medical University, China
| | - Shu-Xian Wang
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, Hefei, 230032, China; Institute for Liver Diseases of Anhui Medical University, China
| | - Ying Hu
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, Hefei, 230032, China; Institute for Liver Diseases of Anhui Medical University, China
| | - Liang-Yun Li
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, Hefei, 230032, China; Institute for Liver Diseases of Anhui Medical University, China
| | - Shuang Hu
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, Hefei, 230032, China; Institute for Liver Diseases of Anhui Medical University, China
| | - Xiang Meng
- College & Hospital of Stomatology, Anhui Medical University, Key Lab. of Oral Diseases Research of Anhui Province, Hefei 230032, China
| | - Da-Shuai Yang
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, Hefei, 230032, China; Institute for Liver Diseases of Anhui Medical University, China
| | - He Li
- The Second Hospital of Anhui Medical University, Hefei, Anhui Province 230001, China.
| | - Tao Xu
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, Hefei, 230032, China; Institute for Liver Diseases of Anhui Medical University, China.
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22
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Ma Y, Ding Q, Qian Q, Feng L, Zhu Q, Si C, Dou X, Li S. AMPK-Regulated Autophagy Contributes to Ursolic Acid Supplementation-Alleviated Hepatic Steatosis and Liver Injury in Chronic Alcohol-Fed Mice. ACS OMEGA 2023; 8:907-914. [PMID: 36643445 PMCID: PMC9835778 DOI: 10.1021/acsomega.2c06252] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/27/2022] [Accepted: 12/08/2022] [Indexed: 06/17/2023]
Abstract
Alcoholic liver disease (ALD) is a chronic liver disease caused by long-term heavy consumption of alcohol. The pathogenesis of ALD is complex, and there is no effective clinical treatment at present. Ursolic acid (UA), a general triterpenoid with multiple biological roles, is widely distributed in plants. This study aims to explore the therapeutic effect and potential mechanisms of UA that protect against liver injury and hepatic steatosis in an ALD mouse model. In this study, we analyzed the lipid accumulation and the effect of UA treatment in a mouse model of ALD; AML12 and HepG2 cells were used to study the biological effect and potential mechanisms of UA on ethanol-induced hepatotoxicity. The morphologic and histological detections showed that UA significantly reduced alcohol-induced liver injury and hepatic steatosis. In addition, UA dramatically ameliorated alcohol-induced metabolic disorders, oxidative stress, and inflammation. Furthermore, UA treatment activated autophagy via the AMPK-ACC pathway to protect hepatocytes from lipotoxicity. Thus, these findings demonstrate that UA treatment alleviates alcoholic-induced liver injury by activating autophagy through the AMPK-ACC pathway. Therefore, UA may represent a promising candidate for the treatment of ALD.
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Affiliation(s)
- Yue Ma
- Zhejiang
Provincial Laboratory of Experimental Animal’s & Nonclinical
Laboratory Studies, Hangzhou Medical College, Hangzhou, Zhejiang 310053, PR China
| | - Qinchao Ding
- School
of Public Health, Zhejiang Chinese Medical
University, Hangzhou, Zhejiang 310053, PR China
- Institute
of Dairy Science, College of Animal Sciences, Zhejiang University, Hangzhou, Zhejiang 310058, PR China
| | - Qianyu Qian
- School
of Life Science, Zhejiang Chinese Medical
University, Hangzhou, Zhejiang 310053, PR China
| | - Luyan Feng
- School
of Life Science, Zhejiang Chinese Medical
University, Hangzhou, Zhejiang 310053, PR China
| | - Qin Zhu
- Department
of Clinical Nutrition, Zhejiang Hospital, Hangzhou, Zhejiang 310013, PR China
| | - Caijuan Si
- Department
of Clinical Nutrition, Zhejiang Hospital, Hangzhou, Zhejiang 310013, PR China
| | - Xiaobing Dou
- School
of Life Science, Zhejiang Chinese Medical
University, Hangzhou, Zhejiang 310053, PR China
| | - Songtao Li
- School
of Public Health, Zhejiang Chinese Medical
University, Hangzhou, Zhejiang 310053, PR China
- Department
of Clinical Nutrition, Zhejiang Hospital, Hangzhou, Zhejiang 310013, PR China
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23
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Liu X, Yu S, Zhang Y, Zhang W, Zhong H, Lu X, Guan R. A review on the protective effect of active components in Antrodia camphorata against alcoholic liver injury. JOURNAL OF ETHNOPHARMACOLOGY 2023; 300:115740. [PMID: 36162549 DOI: 10.1016/j.jep.2022.115740] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/29/2022] [Revised: 09/02/2022] [Accepted: 09/15/2022] [Indexed: 06/16/2023]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE Antrodia camphorata is a genus of wood-rot basidiomycete in the family Fomitopsidaceae. It is a valuable medicinal fungus in China that contains more than 78 kinds of active compounds. A. camphorata has good protection effects on the liver, especially on alcoholic liver injury (ALI). AIM This paper summarizes the complex occurrence and development of alcoholic liver disease (ALD). In addition, the effect of ALD on the intestine through the gut-liver axis is summarized. The protective mechanism of A. camphorata on ALI is reviewed to reveal its therapeutic potential, offering insights into future research. MATERIALS AND METHODS A comprehensive search in the literature was obtained from books and online databases such as Web of Science, Google Scholar, PubMed, Scopus, Science direct, ACS Publications and Baidu Scholar. RESULTS The pathogenesis of ALD mainly includes oxidative stress injury, intestinal microflora imbalance, inflammatory mediator injury and nutritional imbalance. A. camphorata contains rich active components (e.g. polysaccharides, triterpenoids, maleic and succinic acid derivatives, amino acids, superoxide dismutase, vitamins, lignin and sterols). These components have good antioxidant, anti-inflammatory and intestinal protection activities. Therefore, A. camphorata has a wide application in the prevention and treatment of ALI. CONCLUSIONS ALD develops from a mild disease to alcoholic hepatitis and cirrhosis, which is the main reason of global morbidity and mortality. At present, there is no effective drug for the treatment of ALD. A. camphorata, as a valuable medicinal fungus unique to Taiwan, has a great protective effect on the liver. It is expected to be an effective drug for ALI treatment. Although many studies have performed the protective effects of A. camphorata on ALI, its regulatory effects on the gut-liver axis of ALD patients need to be further explored.
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Affiliation(s)
- Xiaofeng Liu
- College of Food Science and Technology, Zhejiang University of Technology, Zhejiang, Hangzhou, 310014, China.
| | - Shuzhen Yu
- College of Food Science and Technology, Zhejiang University of Technology, Zhejiang, Hangzhou, 310014, China.
| | - Yao Zhang
- Zhejiang Provincial Key Lab for Chem and Bio Processing Technology of Farm Produces, School of Biological and Chemical Engineering, Zhejiang University of Science and Technology, Zhejiang, Hangzhou, 310023, China.
| | - Wei Zhang
- College of Food Science and Technology, Zhejiang University of Technology, Zhejiang, Hangzhou, 310014, China.
| | - Hao Zhong
- College of Food Science and Technology, Zhejiang University of Technology, Zhejiang, Hangzhou, 310014, China.
| | - Xiaoqin Lu
- College of Food Science and Technology, Zhejiang University of Technology, Zhejiang, Hangzhou, 310014, China.
| | - Rongfa Guan
- College of Food Science and Technology, Zhejiang University of Technology, Zhejiang, Hangzhou, 310014, China.
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24
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Wang C, Zhang X, Li B, Mu D. A study of factors impacting disease based on the Charlson Comorbidity Index in UK Biobank. Front Public Health 2023; 10:1050129. [PMID: 36699869 PMCID: PMC9868818 DOI: 10.3389/fpubh.2022.1050129] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2022] [Accepted: 12/20/2022] [Indexed: 01/12/2023] Open
Abstract
Objective With advances in medical diagnosis, more people are diagnosed with more than one disease. The damage caused by different diseases varies, so relying solely on the number of diseases to represent multimorbidity is limited. The Charlson comorbidity index (CCI) is widely used to measure multimorbidity and has been validated in various studies. However, CCI's demographic and behavioral risk factors still need more exploration. Methods We conduct multivariate logistic regression analysis and restricted cubic splines to examine the influence factors of CCI and the relationship between covariates and risk of CCI, respectively. Our research employs the Multivariate Imputation by Chained Equations method to interpolate missing values. In addition, the CCI score for each participant is calculated based on the inpatient's condition using the International Classification of Diseases, edition 10 (ICD10). Considering the differences in the disease burden between males and females, the research was finally subgroup analyzed by sex. Results This study includes 5,02,411 participants (2,29,086 female) with CCI scores ranging from 0 to 98. All covariates differed between CCI groups. High waist-hip ratio (WHR) increases the risk of CCI in both males [OR = 19.439, 95% CI = (16.261, 23.241)] and females [OR = 12.575, 95% CI = (11.005, 14.370)], and the effect of WHR on CCI is more significant in males. Associations between age, Body Mass Index (BMI) and WHR, and CCI risk are J-shaped for all participants, males, and females. Concerning the association between Townsend deprivation index (TDI) and CCI risk, the U-shape was found in all participants and males and varied to a greater extent in males, but it is a J-shape in females. Conclusions Increased WHR, BMI, and TDI are significant predictors of poor health, and WHR showed a greater role. The impact of deprivation indices on health showed differences by sex. Socio-economic factors, such as income and TDI, are associated with CCI. The association of social status differences caused by these socioeconomic factors with health conditions should be considered. Factors might interact with each other; therefore, a comprehensive, rational, and robust intervention will be necessary for health.
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Affiliation(s)
- Changcong Wang
- Division of Clinical Research, The First Hospital of Jilin University, Changchun, China,Department of Medical Informatics, School of Public Health, Jilin University, Changchun, China
| | - Xinyue Zhang
- Division of Clinical Research, The First Hospital of Jilin University, Changchun, China,Department of Medical Informatics, School of Public Health, Jilin University, Changchun, China
| | - Bai Li
- Department of Colorectal and Anal Surgery, General Surgery Center, First Hospital of Jilin University, Changchun, China
| | - Dongmei Mu
- Division of Clinical Research, The First Hospital of Jilin University, Changchun, China,Department of Medical Informatics, School of Public Health, Jilin University, Changchun, China,*Correspondence: Dongmei Mu ✉
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25
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Lee W, Kim SJ. Protective effects of isoflavones on alcoholic liver diseases: Computational approaches to investigate the inhibition of ALDH2 with isoflavone analogues. Front Mol Biosci 2023; 10:1147301. [PMID: 36923641 PMCID: PMC10009234 DOI: 10.3389/fmolb.2023.1147301] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2023] [Accepted: 02/07/2023] [Indexed: 03/02/2023] Open
Abstract
Excessive and chronic alcohol intake can lead to the progression of alcoholic liver disease (ALD), which is a major cause of morbidity and mortality worldwide. ALD encompasses a pathophysiological spectrum such as simple steatosis, alcoholic steatohepatitis (ASH), fibrosis, alcoholic cirrhosis, and hepatocellular carcinoma (HCC). Aldehyde dehydrogenase (ALDH2) is the most vital enzyme that produces acetate from acetaldehyde and is expressed at high levels in the liver, kidneys, muscles, and heart. The ALDH2*2 allele is found in up to 40% of East Asian populations, and has a significant impact on alcohol metabolism. Interestingly, several studies have shown that individuals with ALDH2 deficiency are more susceptible to liver inflammation after drinking alcohol. Furthermore, there is growing evidence of an association between ALDH2 deficiency and the development of cancers in the liver, stomach, colon, and lung. Isoflavone analogues are low molecular-weight compounds derived from plants, similar in structure and activity to estrogen in mammals, known as phytoestrogens. Recent studies have reported that isoflavone analogues have beneficial effects on the progression of ALD. This mini-review summarizes the current knowledge about the roles of isoflavone analogues in ALD and discusses the therapeutic potential of isoflavone analogues in liver pathophysiology. In particular, we highlight the significance of computational approaches in this field.
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Affiliation(s)
- Wook Lee
- Department of Biochemistry, College of Natural Sciences, Kangwon National University, Chuncheon, Republic of Korea
| | - Seung-Jin Kim
- Kangwon Institute of Inclusive Technology, Kangwon National University, Chuncheon, Republic of Korea.,Global/Gangwon Innovative Biologics-Regional Leading Research Center (GIB-RLRC), Kangwon National University, Chuncheon, Republic of Korea
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26
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Kharbanda KK, Farokhnia M, Deschaine SL, Bhargava R, Rodriguez-Flores M, Casey CA, Goldstone AP, Jerlhag E, Leggio L, Rasineni K. Role of the ghrelin system in alcohol use disorder and alcohol-associated liver disease: A narrative review. Alcohol Clin Exp Res 2022; 46:2149-2159. [PMID: 36316764 PMCID: PMC9772086 DOI: 10.1111/acer.14967] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2022] [Revised: 10/21/2022] [Accepted: 10/28/2022] [Indexed: 11/07/2022]
Abstract
Unhealthy alcohol consumption is a global health problem. Adverse individual, public health, and socioeconomic consequences are attributable to harmful alcohol use. Epidemiological studies have shown that alcohol use disorder (AUD) and alcohol-associated liver disease (ALD) are the top two pathologies among alcohol-related diseases. Consistent with the major role that the liver plays in alcohol metabolism, uncontrolled drinking may cause significant damage to the liver. This damage is initiated by excessive fat accumulation in the liver, which can further progress to advanced liver disease. The only effective therapeutic strategies currently available for ALD are alcohol abstinence or liver transplantation. Any molecule with dual-pronged effects at the central and peripheral organs controlling addictive behaviors and associated metabolic pathways are a potentially important therapeutic target for treating AUD and ALD. Ghrelin, a hormone primarily derived from the stomach, has such properties, and regulates both behavioral and metabolic functions. In this review, we highlight recent advances in understanding the peripheral and central functions of the ghrelin system and its role in AUD and ALD pathogenesis. We first discuss the correlation between blood ghrelin concentrations and alcohol use or abstinence. Next, we discuss the role of ghrelin in alcohol-seeking behaviors and finally its role in the development of fatty liver by metabolic regulations and organ crosstalk. We propose that a better understanding of the ghrelin system could open an innovative avenue for improved treatments for AUD and associated medical consequences, including ALD.
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Affiliation(s)
- Kusum K. Kharbanda
- Research Service, Veterans Affairs Nebraska-Western Iowa Health Care System, Omaha, Nebraska, USA
- Department of Internal Medicine, University of Nebraska Medical Center, Omaha, Nebraska, USA
- Department of Biochemistry & Molecular Biology, University of Nebraska Medical Center, Omaha, Nebraska, USA
| | - Mehdi Farokhnia
- Clinical Psychoneuroendocrinology and Neuropsychopharmacology Section, Translational Addiction Medicine Branch, National Institute on Drug Abuse, Intramural Research Program and National Institute on Alcohol Abuse and Alcoholism, Division of Intramural Clinical and Biological Research, National Institutes of Health, Baltimore and Bethesda, Maryland, USA
- Johns Hopkins Bloomberg School of Public Health, Johns Hopkins University, Baltimore, Maryland, USA
| | - Sara L. Deschaine
- Clinical Psychoneuroendocrinology and Neuropsychopharmacology Section, Translational Addiction Medicine Branch, National Institute on Drug Abuse, Intramural Research Program and National Institute on Alcohol Abuse and Alcoholism, Division of Intramural Clinical and Biological Research, National Institutes of Health, Baltimore and Bethesda, Maryland, USA
| | - Raghav Bhargava
- PsychoNeuroEndocrinology Research Group, Division of Psychiatry, Department of Brain Sciences, Imperial College London, Hammersmith Hospital, London, UK
| | - Marcela Rodriguez-Flores
- PsychoNeuroEndocrinology Research Group, Division of Psychiatry, Department of Brain Sciences, Imperial College London, Hammersmith Hospital, London, UK
| | - Carol A. Casey
- Research Service, Veterans Affairs Nebraska-Western Iowa Health Care System, Omaha, Nebraska, USA
- Department of Internal Medicine, University of Nebraska Medical Center, Omaha, Nebraska, USA
- Department of Biochemistry & Molecular Biology, University of Nebraska Medical Center, Omaha, Nebraska, USA
| | - Anthony P. Goldstone
- PsychoNeuroEndocrinology Research Group, Division of Psychiatry, Department of Brain Sciences, Imperial College London, Hammersmith Hospital, London, UK
| | - Elisabet Jerlhag
- Department of Pharmacology, Institute of Neuroscience and Physiology, The Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden
| | - Lorenzo Leggio
- Clinical Psychoneuroendocrinology and Neuropsychopharmacology Section, Translational Addiction Medicine Branch, National Institute on Drug Abuse, Intramural Research Program and National Institute on Alcohol Abuse and Alcoholism, Division of Intramural Clinical and Biological Research, National Institutes of Health, Baltimore and Bethesda, Maryland, USA
- Medication Development Program, National Institute on Drug Abuse Intramural Research Program, National Institutes of Health, Baltimore, Maryland, USA
- Center for Alcohol and Addiction Studies, Department of Behavioral and Social Sciences, Brown University, Providence, Rhode Island, USA
- Division of Addiction Medicine, Department of Medicine, School of Medicine, Johns Hopkins University, Baltimore, Maryland, USA
- Department of Neuroscience, Georgetown University Medical Center, Washington DC, USA
| | - Karuna Rasineni
- Research Service, Veterans Affairs Nebraska-Western Iowa Health Care System, Omaha, Nebraska, USA
- Department of Internal Medicine, University of Nebraska Medical Center, Omaha, Nebraska, USA
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27
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Mackowiak B, Xu M, Lin Y, Guan Y, Seo W, Ren R, Feng D, Jones JW, Wang H, Gao B. Hepatic CYP2B10 is highly induced by binge ethanol and contributes to acute-on-chronic alcohol-induced liver injury. Alcohol Clin Exp Res 2022; 46:2163-2176. [PMID: 36224745 PMCID: PMC9771974 DOI: 10.1111/acer.14954] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2022] [Revised: 09/10/2022] [Accepted: 10/05/2022] [Indexed: 02/01/2023]
Abstract
BACKGROUND The chronic-plus-binge model of ethanol consumption, where chronically (8-week) ethanol-fed mice are gavaged a single dose of ethanol (E8G1), is known to induce steatohepatitis in mice. However, how chronically ethanol-fed mice respond to multiple binges of ethanol remains unknown. METHODS We extended the E8G1 model to three gavages of ethanol (E8G3) spaced 24 h apart, sacrificed each group 9 h after the final gavage, analyzed liver injury, and examined gene expression changes using microarray analyses in each group to identify mechanisms contributing to liver responses to binge ethanol. RESULTS Surprisingly, E8G3 treatment induced lower levels of liver injury, steatosis, inflammation, and fibrosis as compared to mice after E8G1 treatment. Microarray analyses identified several pathways that may contribute to the reduced liver injury after E8G3 treatment compared to E8G1 treatment. The gene encoding cytochrome P450 2B10 (Cyp2b10) was one of the top upregulated genes in the E8G1 group and was further upregulated in the E8G3 group, but only moderately induced after chronic ethanol consumption, as confirmed by RT-qPCR and western blot analyses. Genetic disruption of Cyp2b10 worsened liver injury in E8G1 and E8G3 mice with higher blood ethanol levels compared to wild-type control mice, while in vitro experiments revealed that CYP2b10 did not directly promote ethanol metabolism. Metabolomic analyses revealed significant differences in hepatic metabolites from E8G1-treated Cyp2b10 knockout and WT mice, and these metabolic alterations may contribute to the reduced liver injury in Cyp2b10 knockout mice. CONCLUSION Hepatic Cyp2b10 expression is highly induced after ethanol binge, and such upregulation reduces acute-on-chronic ethanol-induced liver injury via the indirect modification of ethanol metabolism.
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Affiliation(s)
- Bryan Mackowiak
- Laboratory of Liver Diseases, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD 20892, USA
| | - Mingjiang Xu
- Laboratory of Liver Diseases, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD 20892, USA
| | - Yuhong Lin
- Laboratory of Liver Diseases, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD 20892, USA
| | - Yukun Guan
- Laboratory of Liver Diseases, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD 20892, USA
| | - Wonhyo Seo
- Laboratory of Liver Diseases, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD 20892, USA
| | - Ruixue Ren
- Laboratory of Liver Diseases, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD 20892, USA
| | - Dechun Feng
- Laboratory of Liver Diseases, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD 20892, USA
| | - Jace W. Jones
- Department of Pharmaceutical Sciences, University of Maryland School of Pharmacy, 20 Penn Street, Baltimore, MD 21201, USA
| | - Hongbing Wang
- Department of Pharmaceutical Sciences, University of Maryland School of Pharmacy, 20 Penn Street, Baltimore, MD 21201, USA
| | - Bin Gao
- Laboratory of Liver Diseases, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD 20892, USA
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Osna NA, Rasineni K, Ganesan M, Donohue TM, Kharbanda KK. Pathogenesis of Alcohol-Associated Liver Disease. J Clin Exp Hepatol 2022; 12:1492-1513. [PMID: 36340300 PMCID: PMC9630031 DOI: 10.1016/j.jceh.2022.05.004] [Citation(s) in RCA: 32] [Impact Index Per Article: 10.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/17/2022] [Accepted: 05/25/2022] [Indexed: 12/12/2022] Open
Abstract
Excessive alcohol consumption is a global healthcare problem with enormous social, economic, and clinical consequences. While chronic, heavy alcohol consumption causes structural damage and/or disrupts normal organ function in virtually every tissue of the body, the liver sustains the greatest damage. This is primarily because the liver is the first to see alcohol absorbed from the gastrointestinal tract via the portal circulation and second, because the liver is the principal site of ethanol metabolism. Alcohol-induced damage remains one of the most prevalent disorders of the liver and a leading cause of death or transplantation from liver disease. Despite extensive research on the pathophysiology of this disease, there are still no targeted therapies available. Given the multifactorial mechanisms for alcohol-associated liver disease pathogenesis, it is conceivable that a multitherapeutic regimen is needed to treat different stages in the spectrum of this disease.
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Key Words
- AA, Arachidonic acid
- ADH, Alcohol dehydrogenase
- AH, Alcoholic hepatitis
- ALD, Alcohol-associated liver disease
- ALDH, Aldehyde dehydrogenase
- ALT, Alanine transaminase
- ASH, Alcohol-associated steatohepatitis
- AST, Aspartate transaminase
- AUD, Alcohol use disorder
- BHMT, Betaine-homocysteine-methyltransferase
- CD, Cluster of differentiation
- COX, Cycloxygenase
- CTLs, Cytotoxic T-lymphocytes
- CYP, Cytochrome P450
- CYP2E1, Cytochrome P450 2E1
- Cu/Zn SOD, Copper/zinc superoxide dismutase
- DAMPs, Damage-associated molecular patterns
- DC, Dendritic cells
- EDN1, Endothelin 1
- ER, Endoplasmic reticulum
- ETOH, Ethanol
- EVs, Extracellular vesicles
- FABP4, Fatty acid-binding protein 4
- FAF2, Fas-associated factor family member 2
- FMT, Fecal microbiota transplant
- Fn14, Fibroblast growth factor-inducible 14
- GHS-R1a, Growth hormone secretagogue receptor type 1a
- GI, GOsteopontinastrointestinal tract
- GSH Px, Glutathione peroxidase
- GSSG Rdx, Glutathione reductase
- GST, Glutathione-S-transferase
- GWAS, Genome-wide association studies
- H2O2, Hydrogen peroxide
- HA, Hyaluronan
- HCC, Hepatocellular carcinoma
- HNE, 4-hydroxynonenal
- HPMA, 3-hydroxypropylmercapturic acid
- HSC, Hepatic stellate cells
- HSD17B13, 17 beta hydroxy steroid dehydrogenase 13
- HSP 90, Heat shock protein 90
- IFN, Interferon
- IL, Interleukin
- IRF3, Interferon regulatory factor 3
- JAK, Janus kinase
- KC, Kupffer cells
- LCN2, Lipocalin 2
- M-D, Mallory–Denk
- MAA, Malondialdehyde-acetaldehyde protein adducts
- MAT, Methionine adenosyltransferase
- MCP, Macrophage chemotactic protein
- MDA, Malondialdehyde
- MIF, Macrophage migration inhibitory factor
- Mn SOD, Manganese superoxide dismutase
- Mt, Mitochondrial
- NK, Natural killer
- NKT, Natural killer T-lymphocytes
- OPN, Osteopontin
- PAMP, Pathogen-associated molecular patterns
- PNPLA3, Patatin-like phospholipase domain containing 3
- PUFA, Polyunsaturated fatty acid
- RIG1, Retinoic acid inducible gene 1
- SAH, S-adenosylhomocysteine
- SAM, S-adenosylmethionine
- SCD, Stearoyl-CoA desaturase
- STAT, Signal transduction and activator of transcription
- TIMP1, Tissue inhibitor matrix metalloproteinase 1
- TLR, Toll-like receptor
- TNF, Tumor necrosis factor-α
- alcohol
- alcohol-associated liver disease
- ethanol metabolism
- liver
- miRNA, MicroRNA
- p90RSK, 90 kDa ribosomal S6 kinase
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Affiliation(s)
- Natalia A. Osna
- Research Service, Veterans Affairs Nebraska-Western Iowa Health Care System, Omaha, NE, 68105, USA
- Department of Internal Medicine, Omaha, NE, 68198, USA
| | - Karuna Rasineni
- Research Service, Veterans Affairs Nebraska-Western Iowa Health Care System, Omaha, NE, 68105, USA
- Department of Internal Medicine, Omaha, NE, 68198, USA
| | - Murali Ganesan
- Research Service, Veterans Affairs Nebraska-Western Iowa Health Care System, Omaha, NE, 68105, USA
- Department of Internal Medicine, Omaha, NE, 68198, USA
| | - Terrence M. Donohue
- Research Service, Veterans Affairs Nebraska-Western Iowa Health Care System, Omaha, NE, 68105, USA
- Department of Internal Medicine, Omaha, NE, 68198, USA
- Department of Biochemistry & Molecular Biology, University of Nebraska Medical Center, Omaha, NE, 68198, USA
| | - Kusum K. Kharbanda
- Research Service, Veterans Affairs Nebraska-Western Iowa Health Care System, Omaha, NE, 68105, USA
- Department of Internal Medicine, Omaha, NE, 68198, USA
- Department of Biochemistry & Molecular Biology, University of Nebraska Medical Center, Omaha, NE, 68198, USA
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Warner JB, Zirnheld KH, Hu H, Floyd A, Kong M, McClain CJ, Kirpich IA. Analysis of alcohol use, consumption of micronutrient and macronutrients, and liver health in the 2017-2018 National Health and Nutrition Examination Survey. Alcohol Clin Exp Res 2022; 46:2025-2040. [PMID: 36124871 PMCID: PMC9722540 DOI: 10.1111/acer.14944] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2022] [Revised: 09/13/2022] [Accepted: 09/14/2022] [Indexed: 02/01/2023]
Abstract
BACKGROUND Alcohol use is a major global healthcare burden that contributes to numerous adverse health outcomes, including liver disease. Many factors influence individual susceptibility to alcohol-associated diseases, including nutritional factors. The objective of the current study was to examine inter-relations among alcohol, dietary micronutrients and macronutrient consumption, and liver health by analyzing data from the 2017-2018 National Health and Nutrition Examination Survey (NHANES). METHODS Based on self-reported alcohol consumption, NHANES respondents were assigned to one of four categories: never drinkers (lifetime abstainers), non-drinkers (past-year abstainers), moderate drinkers (1/2 drinks per day for females/males, respectively), and heavy drinkers (>1/>2 drinks per day for females/males, respectively, and/or frequent binge drinking). Survey-weighted regression analyses (adjusted for gender, age, race, education, and body mass index) were performed to examine associations between alcohol intake, dietary, and liver health characteristics. RESULTS Individuals categorized as heavy drinkers were significantly younger, most often well-educated males with low incidences of diabetes and other comorbidities. They consumed the most overall calories and various micronutrients, indicating a diet that was not necessarily nutrient poor. Neither moderate nor heavy drinkers had liver steatosis or fibrosis as measured by liver elastography, although heavy drinkers had modestly elevated plasma biomarkers of liver injury, including ALT, AST, and GGT, compared with the other groups. CONCLUSIONS Our findings suggest that the category of heavy drinkers in the 2017-2018 NHANES consisted of generally healthy individuals with high-energy intake and no evidence of liver steatosis or fibrosis. However, slightly increased plasma liver markers may indicate a risk of future progression to more advanced stages of liver disease over time in some individuals. Several limitations should be considered when interpreting these data, including the potential misclassification of drinking categories and the lack of standardized cutoff scores for fatty liver as assessed by elastography, among others.
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Affiliation(s)
- Jeffrey B. Warner
- Division of Gastroenterology, Hepatology, and Nutrition, Department of Medicine, School of Medicine, University of Louisville, 505 South Hancock Street, Louisville KY, 40202, United States
- Department of Pharmacology and Toxicology, School of Medicine, University of Louisville, 505 South Hancock Street, Louisville KY, 40202, United States
| | - Kara H. Zirnheld
- Division of Gastroenterology, Hepatology, and Nutrition, Department of Medicine, School of Medicine, University of Louisville, 505 South Hancock Street, Louisville KY, 40202, United States
| | - Huirong Hu
- Department of Bioinformatics and Biostatistics, School of Public Health and Information Sciences, University of Louisville, 485 East Gray Street, Louisville, KY 40202, United States
| | - Alison Floyd
- Division of Gastroenterology, Hepatology, and Nutrition, Department of Medicine, School of Medicine, University of Louisville, 505 South Hancock Street, Louisville KY, 40202, United States
| | - Maiying Kong
- Department of Bioinformatics and Biostatistics, School of Public Health and Information Sciences, University of Louisville, 485 East Gray Street, Louisville, KY 40202, United States
- Robley Rex Veterans Affairs Medical Center, 800 Zorn Avenue, Louisville, KY 40206, United States
| | - Craig J. McClain
- Division of Gastroenterology, Hepatology, and Nutrition, Department of Medicine, School of Medicine, University of Louisville, 505 South Hancock Street, Louisville KY, 40202, United States
- Department of Pharmacology and Toxicology, School of Medicine, University of Louisville, 505 South Hancock Street, Louisville KY, 40202, United States
- Alcohol Research Center, School of Medicine, University of Louisville, 505 South Hancock Street, Louisville KY, 40202, United States
- Hepatobiology and Toxicology Center, School of Medicine, University of Louisville, 505 South Hancock Street, Louisville KY, 40202, United States
- Robley Rex Veterans Affairs Medical Center, 800 Zorn Avenue, Louisville, KY 40206, United States
| | - Irina A. Kirpich
- Division of Gastroenterology, Hepatology, and Nutrition, Department of Medicine, School of Medicine, University of Louisville, 505 South Hancock Street, Louisville KY, 40202, United States
- Department of Pharmacology and Toxicology, School of Medicine, University of Louisville, 505 South Hancock Street, Louisville KY, 40202, United States
- Alcohol Research Center, School of Medicine, University of Louisville, 505 South Hancock Street, Louisville KY, 40202, United States
- Hepatobiology and Toxicology Center, School of Medicine, University of Louisville, 505 South Hancock Street, Louisville KY, 40202, United States
- Department of Microbiology and Immunology, School of Medicine, University of Louisville, 505 South Hancock Street, Louisville KY, 40202, United States
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30
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Alcohol-Related Liver Disease: An Overview on Pathophysiology, Diagnosis and Therapeutic Perspectives. Biomedicines 2022; 10:biomedicines10102530. [PMID: 36289791 PMCID: PMC9599689 DOI: 10.3390/biomedicines10102530] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2022] [Revised: 10/01/2022] [Accepted: 10/08/2022] [Indexed: 11/19/2022] Open
Abstract
Alcohol-related liver disease (ALD) refers to a spectrum of liver manifestations ranging from fatty liver diseases, steatohepatitis, and fibrosis/cirrhosis with chronic inflammation primarily due to excessive alcohol use. Currently, ALD is considered as one of the most prevalent causes of liver disease-associated mortality worldwide. Although the pathogenesis of ALD has been intensively investigated, the present understanding of its biomarkers in the context of early clinical diagnosis is not complete, and novel therapeutic targets that can significantly alleviate advanced forms of ALD are limited. While alcohol abstinence remains the primary therapeutic intervention for managing ALD, there are currently no approved medications for treating ALD. Furthermore, given the similarities and the differences between ALD and non-alcoholic fatty liver disease in terms of disease progression and underlying molecular mechanisms, numerous studies have demonstrated that many therapeutic interventions targeting several signaling pathways, including oxidative stress, inflammatory response, hormonal regulation, and hepatocyte death play a significant role in ALD treatment. Therefore, in this review, we summarized several key molecular targets and their modes of action in ALD progression. We also described the updated therapeutic options for ALD management with a particular emphasis on potentially novel signaling pathways.
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31
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Li Y, Jiang JX, Fan W, Fish SR, Das S, Gupta P, Mozes G, Vancza L, Sarkar S, Kunimoto K, Chen D, Park H, Clemens D, Tomilov A, Cortopassi G, Török NJ. Shc Is Implicated in Calreticulin-Mediated Sterile Inflammation in Alcoholic Hepatitis. Cell Mol Gastroenterol Hepatol 2022; 15:197-211. [PMID: 36122677 PMCID: PMC9676381 DOI: 10.1016/j.jcmgh.2022.09.005] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/29/2021] [Revised: 09/12/2022] [Accepted: 09/12/2022] [Indexed: 12/23/2022]
Abstract
BACKGROUND & AIMS Src homology and collagen (Shc) proteins are major adapters to extracellular signals, however, the regulatory role of Shc isoforms in sterile inflammatory responses in alcoholic hepatitis (AH) has not been fully investigated. We hypothesized that in an isoform-specific manner Shc modulates pre-apoptotic signals, calreticulin (CRT) membrane exposure, and recruitment of inflammatory cells. METHODS Liver biopsy samples from patients with AH vs healthy subjects were studied for Shc expression using DNA microarray data and immunohistochemistry. Shc knockdown (hypomorph) and age-matched wild-type mice were pair-fed according to the chronic-plus-binge alcohol diet. To analyze hepatocyte-specific effects, adeno-associated virus 8-thyroxine binding globulin-Cre (hepatocyte-specific Shc knockout)-mediated deletion was performed in flox/flox Shc mice. Lipid peroxidation, proinflammatory signals, redox radicals, reduced nicotinamide adenine dinucleotide/oxidized nicotinamide adenine dinucleotide ratio, as well as cleaved caspase 8, B-cell-receptor-associated protein 31 (BAP31), Bcl-2-associated X protein (Bax), and Bcl-2 homologous antagonist killer (Bak), were assessed in vivo. CRT translocation was studied in ethanol-exposed p46ShcẟSH2-transfected hepatocytes by membrane biotinylation in conjunction with phosphorylated-eukaryotic initiation factor 2 alpha, BAP31, caspase 8, and Bax/Bak. The effects of idebenone, a novel Shc inhibitor, was studied in alcohol/pair-fed mice. RESULTS Shc was significantly induced in patients with AH (P < .01). Alanine aminotransferase, reduced nicotinamide adenine dinucleotide/oxidized nicotinamide adenine dinucleotide ratios, production of redox radicals, and lipid peroxidation improved (P < .05), and interleukin 1β, monocyte chemoattractant protein 1, and C-X-C chemokine ligand 10 were reduced in Shc knockdown and hepatocyte-specific Shc knockout mice. In vivo, Shc-dependent induction, and, in hepatocytes, a p46Shc-dependent increase in pre-apoptotic proteins Bax/Bak, caspase 8, BAP31 cleavage, and membrane translocation of CRT/endoplasmic reticulum-resident protein 57 were seen. Idebenone protected against alcohol-mediated liver injury. CONCLUSIONS Alcohol induces p46Shc-dependent activation of pre-apoptotic pathways and translocation of CRT to the membrane, where it acts as a damage-associated molecular pattern, instigating immunogenicity. Shc inhibition could be a novel treatment strategy in AH.
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Affiliation(s)
- Yuan Li
- Gastroenterology and Hepatology, Stanford University, VA Palo Alto, Palo Alto, California
| | - Joy X Jiang
- Gastroenterology and Hepatology, University of California Davis Medical Center, Sacramento, California
| | - Weiguo Fan
- Gastroenterology and Hepatology, Stanford University, VA Palo Alto, Palo Alto, California
| | - Sarah R Fish
- Gastroenterology and Hepatology, University of California Davis Medical Center, Sacramento, California
| | - Suvarthi Das
- Gastroenterology and Hepatology, Stanford University, VA Palo Alto, Palo Alto, California
| | - Parul Gupta
- Gastroenterology and Hepatology, Stanford University, VA Palo Alto, Palo Alto, California
| | - Gergely Mozes
- Gastroenterology and Hepatology, Stanford University, VA Palo Alto, Palo Alto, California
| | - Lorand Vancza
- Gastroenterology and Hepatology, Stanford University, VA Palo Alto, Palo Alto, California
| | - Sutapa Sarkar
- Gastroenterology and Hepatology, Stanford University, VA Palo Alto, Palo Alto, California
| | - Koshi Kunimoto
- Gastroenterology and Hepatology, Stanford University, VA Palo Alto, Palo Alto, California
| | - Dongning Chen
- Gastroenterology and Hepatology, Stanford University, VA Palo Alto, Palo Alto, California
| | - Hyesuk Park
- Gastroenterology and Hepatology, Stanford University, VA Palo Alto, Palo Alto, California
| | - Dahn Clemens
- Internal Medicine, University of Nebraska Medical Center, Omaha, Nebraska
| | - Alexey Tomilov
- Molecular Biosciences, School of Veterinary Medicine, University of California Davis, Davis, California
| | - Gino Cortopassi
- Molecular Biosciences, School of Veterinary Medicine, University of California Davis, Davis, California
| | - Natalie J Török
- Gastroenterology and Hepatology, Stanford University, VA Palo Alto, Palo Alto, California.
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Tarantino G, Cataldi M, Citro V. Could Alcohol Abuse and Dependence on Junk Foods Inducing Obesity and/or Illicit Drug Use Represent Danger to Liver in Young People with Altered Psychological/Relational Spheres or Emotional Problems? Int J Mol Sci 2022; 23:ijms231810406. [PMID: 36142317 PMCID: PMC9499369 DOI: 10.3390/ijms231810406] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2022] [Revised: 09/02/2022] [Accepted: 09/05/2022] [Indexed: 11/16/2022] Open
Abstract
Recent data show that young people, mainly due to the pressure of some risk factors or due to disrupted interpersonal relationships, utilise greater reward value and display greater sensitivity to the reinforcing properties of “pleasurable stimuli”, specifically in those situations in which an enhanced dopamine release is present. Alcoholic beverages, foods rich in sugar and fat, and illicit drug use are pleasurable feelings associated with rewards. Research shows that there is a link between substance abuse and obesity in brain functioning. Still, alcohol excess is central in leading to obesity and obesity-related morbidities, such as hepatic steatosis, mainly when associated with illicit drug dependence and negative eating behaviours in young people. It is ascertained that long-term drinking causes mental damage, similarly to drug abuse, but also affects liver function. Indeed, beyond the pharmacokinetic interactions of alcohol with drugs, occurring in the liver due to the same metabolic enzymes, there are also pharmacodynamic interactions of both substances in the CNS. To complicate matters, an important noxious effect of junk foods consists of inducing obesity and obesity-related NAFLD. In this review, we focus on some key mechanisms underlying the impact of these addictions on the liver, as well as those on the CNS.
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Affiliation(s)
- Giovanni Tarantino
- Department of Clinical Medicine and Surgery, “Federico II” University Medical School of Naples, 80131 Naples, Italy
- Correspondence:
| | - Mauro Cataldi
- Section of Pharmacology, Department of Neuroscience, Reproductive Sciences and Dentistry, “Federico II” University of Naples, 80138 Naples, Italy
| | - Vincenzo Citro
- Department of General Medicine, “Umberto I” Hospital, 84014 Nocera Inferiore, Italy
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Waddell JT, Jager J, Chassin L. Maturing out of alcohol and cannabis co-use: A test of patterns and personality predictors. Alcohol Clin Exp Res 2022; 46:1603-1615. [PMID: 35994040 PMCID: PMC10325930 DOI: 10.1111/acer.14898] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/11/2022] [Revised: 06/23/2022] [Accepted: 06/24/2022] [Indexed: 01/31/2023]
Abstract
OBJECTIVE Reductions in substance involvement into adulthood are thought to represent a normative maturing out of substance use. However, patterns and predictors of maturing out of alcohol and cannabis co-use remain largely unstudied. Therefore, the current study tested developmental trajectories of alcohol and cannabis use from late adolescence into adulthood and whether late adolescent personality traits predicted trajectory class membership. METHODS Data come from a longitudinal study of family history of alcohol disorder (N = 458). Age bands were created to model trajectories of drinking quantity, negative alcohol consequences, and cannabis use frequency from late adolescence (age 18-22) to young adulthood (age 23-28) and adulthood (age 29-36). Participants reported on their sensation seeking, conscientiousness, and neuroticism during late adolescence and their typical drinking quantity, negative alcohol consequences, and cannabis use frequency at each age band. RESULTS Three trajectory classes were derived from an initial Parallel Process Growth Mixture Model: (1) low-risk maturing out of alcohol-only use, (2) high-risk maturing out of co-use, and (3) high-risk switchers who increased their cannabis use into adulthood. Late adolescent sensation seeking was associated with higher odds of being in both co-use trajectories, whereas a lack of conscientiousness was associated with higher odds of being a co-use switcher. CONCLUSIONS We identified heterogeneity in trajectories of co-use, which suggests that a lack of maturing out of alcohol involvement may be accompanied by increased cannabis use. Moreover, late adolescent personality traits may predispose individuals toward riskier developmental trajectories of substance use into adulthood.
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Affiliation(s)
- Jack T Waddell
- Department of Psychology, Arizona State University, Tempe, Arizona, USA
| | - Justin Jager
- Department of Psychology, Arizona State University, Tempe, Arizona, USA
| | - Laurie Chassin
- Department of Psychology, Arizona State University, Tempe, Arizona, USA
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34
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Shafqat M, Jo JH, Moon HH, Choi YI, Shin DH. Alcohol-related liver disease and liver transplantation. KOSIN MEDICAL JOURNAL 2022. [DOI: 10.7180/kmj.22.108] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/11/2022] Open
Abstract
Alcohol-related liver disease (ALD) has become the major cause of liver transplantation (LT) in Korea, and is currently the most common cause of LT in Europe and the United States. Although, ALD is one of the most common indications for LT, it is traditionally not considered as an option for patients with ALD due to organ shortages and concerns about relapse. To select patients with terminal liver disease due to ALD for transplants, most LT centers in the United States and European countries require a 6-month sober period before transplantation. However, Korea has a different social and cultural background than Western countries, and most organ transplants are made from living donors, who account for approximately twice as many procedures as deceased donors. Most LT centers in Korea do not require a specific period of sobriety before transplantation in patients with ALD. As per the literature, 8%–20% of patients resume alcohol consumption 1 year after LT, and this proportion increases to 30%–40% at 5 years post-LT, among which 10%–15% of patients resume heavy drinking. According to previous studies, the risk factors for alcohol relapse after LT are as follows: young age, poor familial and social support, family history of alcohol use disorder, previous history of alcohol-related treatment, shorter abstinence before LT, smoking, psychiatric disorders, irregular follow-up, and unemployment. Recognition of the risk factors, early detection of alcohol consumption after LT, and regular follow-up by a multidisciplinary team are important for improving the short- and long-term outcomes of LT patients with ALD.
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Effect of Porcine Placental Extract Mixture on Alcohol-Induced Hepatotoxicity in Rats. Curr Issues Mol Biol 2022; 44:2029-2037. [PMID: 35678666 PMCID: PMC9164070 DOI: 10.3390/cimb44050137] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2022] [Revised: 04/28/2022] [Accepted: 04/29/2022] [Indexed: 11/18/2022] Open
Abstract
This study was conducted to examine the effect of porcine placenta extract mixture (pPEM, enzymatic/acidic extract = 1/3) on alcoholic hepatotoxicity after pPEM dosing with alcohol in rats. The experimental groups were normal, control, silymarin, three pPEM (590, 1771, and 2511 mg/kg/day, po), and silymarin (100 mg/kg/day, po) groups (n = 10). Alcoholic hepatotoxicity was caused by a liquid ethanol diet for 4 weeks. The effect of pPEM and silymarin on alcoholic hepatotoxicity was evaluated by serology, hepatic ADH and ALDH activities, and histopathological findings. After oral dosing with alcohol for 4 weeks, ALT and AST were significantly increased to 33.7 → 115.6 and 81.37 → 235.0 in the alcohol group, respectively. These levels were decreased significantly to 83.9 and 126.7 in the silymarin group and dose-dependently to 73.6–56.9 and 139.2–122.8 in all pPEM groups. Hepatic ADH and ALDH might have been increased in the control and not in the silymarin and pPEM groups for hepatic ADH. All pPEM groups exhibited no effects on hepatic ALDH except for the high pPEM group. Mild inflammation and fatty lesions were observed in the alcohol group and were attenuated in the silymarin and pPEM groups. As a results, the pPEM showed protective activities against alcoholic hepatotoxicity on the serological markers, hepatic ADH and ALDH, and pathological findings.
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Sun R, Lei C, Chen L, He L, Guo H, Zhang X, Feng W, Yan J, McClain CJ, Deng Z. Alcohol-driven metabolic reprogramming promotes development of RORγt-deficient thymic lymphoma. Oncogene 2022; 41:2287-2302. [PMID: 35246617 PMCID: PMC9018612 DOI: 10.1038/s41388-022-02257-2] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/22/2021] [Revised: 02/10/2022] [Accepted: 02/17/2022] [Indexed: 11/23/2022]
Abstract
RORγt is a master regulator of Th17 cells. Despite evidence linking RORγt deficiency/inhibition with metastatic thymic T cell lymphomas, the role of RORγt in lymphoma metabolism is unknown. Chronic alcohol consumption plays a causal role in many human cancers. The risk of T cell lymphoma remains unclear in humans with alcohol use disorders (AUD) after chronic RORγt inhibition. Here we demonstrated that alcohol consumption accelerates RORγt deficiency-induced lymphomagenesis. Loss of RORγt signaling in the thymus promotes aerobic glycolysis and glutaminolysis and increases allocation of glutamine carbon into lipids. Importantly, alcohol consumption results in a shift from aerobic glycolysis to glutaminolysis. Both RORγt deficiency- and alcohol-induced metabolic alterations are mediated by c-Myc, as silencing of c-Myc decreases the effects of alcohol consumption and RORγt deficiency on glutaminolysis, biosynthesis, and tumor growth in vivo. The ethanol-mediated c-Myc activation coupled with increased glutaminolysis underscore the critical role of RORγt-Myc signaling and translation in lymphoma.
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Affiliation(s)
- Rui Sun
- Department of Surgery, Division of Immunotherapy, University of Louisville, Louisville, KY, USA
- Department of Oncology, Wuhan Fourth Hospital, Puai Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430033, China
- Brown Cancer Center, University of Louisville, Louisville, KY, USA
| | - Chao Lei
- Department of Surgery, Division of Immunotherapy, University of Louisville, Louisville, KY, USA
- Brown Cancer Center, University of Louisville, Louisville, KY, USA
| | - Liang Chen
- Department of Surgery, Division of Immunotherapy, University of Louisville, Louisville, KY, USA
- Brown Cancer Center, University of Louisville, Louisville, KY, USA
| | - Liqing He
- Department of Chemistry, University of Louisville, Louisville, KY, USA
| | - Haixun Guo
- Department of Radiology, University of Louisville, Louisville, KY, USA
| | - Xiang Zhang
- Department of Chemistry, University of Louisville, Louisville, KY, USA
- Alcohol Research Center, University of Louisville, Louisville, KY, USA
- Hepatobiology & Toxicology Center, University of Louisville, Louisville, KY, USA
| | - Wenke Feng
- Alcohol Research Center, University of Louisville, Louisville, KY, USA
- Hepatobiology & Toxicology Center, University of Louisville, Louisville, KY, USA
- Department of Medicine, University of Louisville, Louisville, KY, USA
| | - Jun Yan
- Department of Surgery, Division of Immunotherapy, University of Louisville, Louisville, KY, USA
- Brown Cancer Center, University of Louisville, Louisville, KY, USA
| | - Craig J McClain
- Alcohol Research Center, University of Louisville, Louisville, KY, USA
- Hepatobiology & Toxicology Center, University of Louisville, Louisville, KY, USA
- Department of Medicine, University of Louisville, Louisville, KY, USA
- Robley Rex VA Medical Center, Louisville, KY, USA
| | - Zhongbin Deng
- Department of Surgery, Division of Immunotherapy, University of Louisville, Louisville, KY, USA.
- Brown Cancer Center, University of Louisville, Louisville, KY, USA.
- Alcohol Research Center, University of Louisville, Louisville, KY, USA.
- Hepatobiology & Toxicology Center, University of Louisville, Louisville, KY, USA.
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Sohal A, Khalid S, Green V, Gulati A, Roytman M. The Pandemic Within the Pandemic: Unprecedented Rise in Alcohol-related Hepatitis During the COVID-19 Pandemic. J Clin Gastroenterol 2022; 56:e171-e175. [PMID: 34653062 PMCID: PMC8843054 DOI: 10.1097/mcg.0000000000001627] [Citation(s) in RCA: 31] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/21/2021] [Accepted: 08/21/2021] [Indexed: 02/07/2023]
Abstract
BACKGROUND AND AIM The third leading preventable cause of death in the United States is excessive alcohol consumption. Our study sought to assess the impact of the coronavirus disease 2019 (COVID-19) on hospitalizations for alcohol-related hepatitis at a community hospital system. We hypothesized an increase in cases of alcohol-related hepatitis requiring inpatient management, mirroring the strain on economic and societal norms imposed by the COVID-19 pandemic. APPROACH/RESULTS We performed a retrospective chart review to study the incidence of alcohol-related hepatitis in patients presenting to 3 community hospitals in Fresno, California, before and during the COVID-19. Data including patient demographics, markers of disease severity, and clinical course were extracted from electronic medical records for 329 patients included in the study. There was a 51% increase in the overall incidence of alcohol-related hepatitis requiring hospitalization between 2019 and 2020 (P=0.003) and 69% increase (P<0.001) after implementation of the stay-at-home orders. In addition, 94% (P=0.028) increase in rehospitalizations was noted in 2020 (P=0.028), a 100% increase in patients under the age of 40 (P=0.0028), as well as a trend towards a 125% increase (P=0.06) of female patients admitted with this diagnosis during the COVID-19 pandemic. CONCLUSIONS Our study revealed drastic increases in severe alcohol-related hepatitis requiring inpatient management, specifically in patients under the age of 40 and in women during the COVID-19 pandemic. Given the high morbidity and mortality associated with severe alcohol-related hepatitis, these findings have far-reaching and lasting implications for our already strained health care system extending beyond the COVID-19 pandemic timeframe. Urgent public health interventions are needed to combat the rising misuse of alcohol and its consequences.
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Affiliation(s)
| | | | | | - Alakh Gulati
- Gastroenterology and Hepatology, UCSF Fresno, Fresno, CA
| | - Marina Roytman
- Gastroenterology and Hepatology, UCSF Fresno, Fresno, CA
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38
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Xie L, Huang W, Li J, Chen G, Xiao Q, Zhang Y, He H, Wang Q, He J. The protective effects and mechanisms of modified Lvdou Gancao decoction on acute alcohol intoxication in mice. JOURNAL OF ETHNOPHARMACOLOGY 2022; 282:114593. [PMID: 34480998 DOI: 10.1016/j.jep.2021.114593] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/15/2021] [Revised: 08/02/2021] [Accepted: 08/31/2021] [Indexed: 06/13/2023]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE Acute alcohol intoxication (AAI) is a ubiquitous emergency worldwide, whereas the searching for both effective and safe drugs is still a task to be completed. Modified Lvdou Gancao decoction (MLG), a traditional Chinese medicine decoction, has been confirmed to be valid to alcohol-induced symptoms and hepatotoxicity clinically, whereas its protective mechanisms have not been determined. MATERIALS AND METHODS AAI mice model was established by alcohol gavage (13.25 mL/kg) and MLG (5, 10, 20 g/kg BW) was administered to mice 2 h before and 30 min after the alcohol exposure. Assay kits for alcohol dehydrogenase (ADH), aldehyde dehydrogenase (ALDH), aspartate aminotransferase (AST), alanine aminotransferase (ALT), glutamine transferase (GGT), total superoxide dismutase (T-SOD), malondialdehyde (MDA), nitric oxide (NO), and glutathione peroxidase (GSH-Px), as well as histopathology were used to explore the effects of MLG on acute alcohol-induced intoxication and hepatotoxicity. Mechanisms of MLG on oxidative stress and inflammatory were evaluated with RT-qPCR and Western Blot. RESULTS MLG remarkably decreased the drunkenness rate, prolonged the tolerance time and shortened the sober-up time of AAI mice. After acute alcohol exposure, MLG treatment induced significant increment of ADH, ALDH, T-SOD and GSH-Px activities in liver, while serum ALT, AST, GGT and NO levels as well as hepatic MDA activity were reduced, in a dose-dependent manner. In contrast to the model group, the mRNA expression of TNFα, IL-1β and NF-κB in the MLG treated groups had a downward trend while the Nrf-2 showed an upward trend simultaneously. Furthermore, the protein levels of p65, p-p65, p-IκBα in the MLG treated groups were considerably diminished, with HO-1 and Nrf2 elevated. To sum up, our results suggested that MLG could efficaciously ameliorate AAI via accelerating the metabolism of alcohol, alleviating acute hepatotoxicity, and weakening the oxidative stress coupled with inflammation response, which might be attributed to the inhibition of the NF-κB signaling pathway and the activation of the Nrf2/HO-1 signaling pathway. CONCLUSIONS Taken together, our present study verified the protective effect and mechanisms of MLG to AAI mice, and we further conclude that MLG may be a potent and reliable candidate for the prevention and treatment of AAI.
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Affiliation(s)
- Lei Xie
- Science and Technology Innovation Center, Guangzhou University of Chinese Medicine, Guangzhou, 510080, Guangdong, China.
| | - Wenguan Huang
- Science and Technology Innovation Center, Guangzhou University of Chinese Medicine, Guangzhou, 510080, Guangdong, China.
| | - Junlin Li
- Science and Technology Innovation Center, Guangzhou University of Chinese Medicine, Guangzhou, 510080, Guangdong, China.
| | - Guirong Chen
- Science and Technology Innovation Center, Guangzhou University of Chinese Medicine, Guangzhou, 510080, Guangdong, China.
| | - Qiao Xiao
- Science and Technology Innovation Center, Guangzhou University of Chinese Medicine, Guangzhou, 510080, Guangdong, China.
| | - Yan Zhang
- First Clinical Medical College, Guangzhou University of Chinese Medicine, Guangzhou, 510080, Guangdong, China.
| | - Haolan He
- Guangzhou Eighth People's Hospital, Guangzhou, 510080, Guangdong, China.
| | - Qi Wang
- Science and Technology Innovation Center, Guangzhou University of Chinese Medicine, Guangzhou, 510080, Guangdong, China.
| | - Jinyang He
- Science and Technology Innovation Center, Guangzhou University of Chinese Medicine, Guangzhou, 510080, Guangdong, China.
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Khan S, Cain O, Rajoriya N. Alcohol Related Liver Disease. MEN’S HEALTH AND WELLBEING 2022:163-191. [DOI: 10.1007/978-3-030-84752-4_11] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/04/2025]
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40
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Edwards AC, Sundquist K, Sundquist J, Kendler KS, Lönn SL. Genetic and environmental influences on the progression from alcohol use disorder to alcohol-related medical conditions. Alcohol Clin Exp Res 2021; 45:2528-2535. [PMID: 34923650 PMCID: PMC8712390 DOI: 10.1111/acer.14731] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2021] [Revised: 09/27/2021] [Accepted: 10/21/2021] [Indexed: 12/15/2022]
Abstract
BACKGROUND Medical conditions related to alcohol use disorders (AUD) represent a substantial public health concern. However, only a subset of individuals with AUD develop these conditions and the extent to which genetic and environmental factors that are shared with AUD, versus those distinct from it, contribute to this progression has not yet been determined. METHODS Using data from Swedish national registries for a cohort born from 1932 to 1970 (N = 1,319,214, 48.9% women), we conducted twin-sibling biometric model fitting to examine the genetic and environmental sources of variance that contribute to the liability to alcohol-related medical conditions (AMC). Progression to AMC, determined using medical registry data, was contingent on an AUD registration, which was determined using medical and criminal registry data. RESULTS We identified AUD registrations in 3.2% of women and 9.2% of men. Among individuals with an AUD registration, 14.4% of women and 15.4% of men had an AMC registration. In the final models, we constrained the beta pathway from AUD to AMC and the genetic and unique environmental paths to be equal across sexes. The beta path was estimated at 0.59. AMC was modestly heritable in women (A = 0.32) and men (A = 0.30). The proportion of total heritability unique to AMC was 39.6% among women and 41.3% among men. A higher proportion of total environmental variance was unique to AMC: 76.7% for women and 77.2% for men. In a sensitivity analysis limited to liver-related AMC, we observed similar results, with a slightly lower beta path from AUD to AMC (0.46) and higher proportions of AMC-specific genetic (70.0% in women; 71.7% in men) and environmental (84.5% in both sexes) variance. CONCLUSIONS A moderate-to-substantial proportion of genetic and environmental variance that contributes to AMC risk is not shared with AUD, underscoring the need for additional gene identification efforts for AMC. Furthermore, the prominent influence of environmental factors specific to AMC provides a promising area for the identification of prevention targets. We did not observe significant sex differences in the etiology of AMC, although follow-up is warranted in other well-powered studies.
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Affiliation(s)
- Alexis C. Edwards
- Department of Psychiatry, Virginia Commonwealth University School of Medicine, Richmond, VA, US
- Virginia Institute for Psychiatric and Behavioral Genetics, Virginia Commonwealth University, Richmond, VA, US
| | | | - Jan Sundquist
- Center for Primary Health Care Research, Lund University, Malmö, Sweden
| | - Kenneth S. Kendler
- Department of Psychiatry, Virginia Commonwealth University School of Medicine, Richmond, VA, US
- Virginia Institute for Psychiatric and Behavioral Genetics, Virginia Commonwealth University, Richmond, VA, US
- Department of Human and Molecular Genetics, Virginia Commonwealth University School of Medicine, Richmond, VA, US
| | - Sara Larsson Lönn
- Center for Primary Health Care Research, Lund University, Malmö, Sweden
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41
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Willms J, Popp L, Jones BG, Babb F, Cook R, Nedumaran S, Littlefield AK, Trotter D. Implementation of Screening, Brief Intervention, and Referral to Treatment (SBIRT) Training in Large Cohorts of Second Year Medical Students. ALCOHOLISM TREATMENT QUARTERLY 2021. [DOI: 10.1080/07347324.2021.1972775] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/20/2022]
Affiliation(s)
- Joshua Willms
- Pharmacology & Neuroscience, Texas Tech University Health Sciences Center, Lubbock, USA
| | - Lisa Popp
- Department of Medical Education, Texas Tech University Health Sciences Center, Lubbock, USA
| | - Betsy G. Jones
- Department of Medical Education, Texas Tech University Health Sciences Center, Lubbock, USA
| | - Franklyn Babb
- Department of Medical Education, Texas Tech University Health Sciences Center, Lubbock, USA
| | - Ronal Cook
- Department of Medical Education, Texas Tech University Health Sciences Center, Lubbock, USA
| | | | | | - David Trotter
- Family and Community Medicine, Texas Tech Unvierity Health Sciences Center, Lubbock, USA
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Pi A, Jiang K, Ding Q, Lai S, Yang W, Zhu J, Guo R, Fan Y, Chi L, Li S. Alcohol Abstinence Rescues Hepatic Steatosis and Liver Injury via Improving Metabolic Reprogramming in Chronic Alcohol-Fed Mice. Front Pharmacol 2021; 12:752148. [PMID: 34603062 PMCID: PMC8481816 DOI: 10.3389/fphar.2021.752148] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2021] [Accepted: 09/01/2021] [Indexed: 12/12/2022] Open
Abstract
Background: Alcoholic liver disease (ALD) caused by chronic ethanol overconsumption is a common type of liver disease with a severe mortality burden throughout the world. The pathogenesis of ALD is complex, and no effective clinical treatment for the disease has advanced so far. Prolonged alcohol abstinence is the most effective therapy to attenuate the clinical course of ALD and even reverse liver damage. However, the molecular mechanisms involved in alcohol abstinence-improved recovery from alcoholic fatty liver remain unclear. This study aims to systematically evaluate the beneficial effect of alcohol abstinence on pathological changes in ALD. Methods: Using the Lieber-DeCarli mouse model of ALD, we analysed whether 1-week alcohol withdrawal reversed alcohol-induced detrimental alterations, including oxidative stress, liver injury, lipids metabolism, and hepatic inflammation, by detecting biomarkers and potential targets. Results: Alcohol withdrawal ameliorated alcohol-induced hepatic steatosis by improving liver lipid metabolism reprogramming via upregulating phosphorylated 5'-AMP -activated protein kinase (p-AMPK), peroxisome proliferator-activated receptor-α (PPAR-α), and carnitine palmitoyltransferase-1 (CPT-1), and downregulating fatty acid synthase (FAS) and diacylglycerol acyltransferase-2 (DGAT-2). The activities of antioxidant enzymes, including superoxide dismutase (SOD) and glutathione peroxidase (GSH-px), were significantly enhanced by alcohol withdrawal. Importantly, the abstinence recovered alcohol-fed induced liver injury, as evidenced by the improvements in haematoxylin and eosin (H&E) staining, plasma alanine aminotransferase (ALT) levels, and liver weight/body weight ratio. Alcohol-stimulated toll-like receptor 4/mitogen-activated protein kinases (TLR4/MAPKs) were significantly reversed by alcohol withdrawal, which might mechanistically contribute to the amelioration of liver injury. Accordingly, the hepatic inflammatory factor represented by tumour necrosis factor-alpha (TNF-α) was improved by alcohol abstinence. Conclusion: In summary, we reported that alcohol withdrawal effectively restored hepatic lipid metabolism and reversed liver injury and inflammation by improving metabolism reprogramming. These findings enhanced our understanding of the biological mechanisms involved in the beneficial role of alcohol abstinence as an effective treatment for ALD.
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Affiliation(s)
- Aiwen Pi
- School of Public Health, Zhejiang Chinese Medical University, Hangzhou, China
- School of Life Science, Zhejiang Chinese Medical University, Hangzhou, China
- Academy of Chinese Medical Science, Zhejiang Chinese Medical University, Hangzhou, China
| | - Kai Jiang
- School of Life Science, Zhejiang Chinese Medical University, Hangzhou, China
- Molecular Medicine Institute, Zhejiang Chinese Medical University, Hangzhou, China
| | - Qinchao Ding
- School of Public Health, Zhejiang Chinese Medical University, Hangzhou, China
- Academy of Chinese Medical Science, Zhejiang Chinese Medical University, Hangzhou, China
| | - Shanglei Lai
- School of Public Health, Zhejiang Chinese Medical University, Hangzhou, China
- School of Life Science, Zhejiang Chinese Medical University, Hangzhou, China
| | - Wenwen Yang
- School of Public Health, Zhejiang Chinese Medical University, Hangzhou, China
- School of Life Science, Zhejiang Chinese Medical University, Hangzhou, China
| | - Jinyan Zhu
- School of Public Health, Zhejiang Chinese Medical University, Hangzhou, China
- Academy of Chinese Medical Science, Zhejiang Chinese Medical University, Hangzhou, China
| | - Rui Guo
- School of Public Health, Zhejiang Chinese Medical University, Hangzhou, China
- Academy of Chinese Medical Science, Zhejiang Chinese Medical University, Hangzhou, China
| | - Yibin Fan
- Department of Dermatology, People’s Hospital of Hangzhou Medical College, Zhejiang Provincial People’s Hospital, Hangzhou, China
| | - Linfeng Chi
- School of Basic Medicine, Zhejiang Chinese Medical University, Hangzhou, China
| | - Songtao Li
- School of Public Health, Zhejiang Chinese Medical University, Hangzhou, China
- Academy of Chinese Medical Science, Zhejiang Chinese Medical University, Hangzhou, China
- Molecular Medicine Institute, Zhejiang Chinese Medical University, Hangzhou, China
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Ren Y, Chase E, d'Almeida T, Allègre J, Latino-Martel P, Deschamps V, Arwidson P, Etilé F, Hercberg S, Touvier M, Julia C. Modelling the number of avoidable new cancer cases in France attributable to alcohol consumption by following official recommendations: a simulation study. Addiction 2021; 116:2316-2325. [PMID: 33565659 DOI: 10.1111/add.15426] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/10/2020] [Revised: 10/20/2020] [Accepted: 01/20/2021] [Indexed: 11/29/2022]
Abstract
AIMS To predict the effects of perfect adherence to the French alcohol consumption guidelines, a maximum of 10 standard alcoholic drinks per week with no more than two standard alcoholic drinks per day, during a 36-year period (2014-50). DESIGN This simulation study is an adaption of the Sheffield Alcohol Policy Model. The dose-response relationship between alcohol consumption and alcohol-attributable cancer risks was defined by cancer site-specific risk functions, each modelled as a continuous risk. These estimates were used to compute the potential impact fraction (PIF) associated with alcohol consumption by cancer site. SETTING The French general adult population during a 36-year period (2014-50). PARTICIPANTS For the baseline scenario, the current distribution of consumption levels, the counterfactual scenario and perfect adherence to the French alcohol consumption guidelines, we generated for each gender and age group 1000 randomly distributed alcohol consumption values from calibrated group-specific gamma distribution. MEASUREMENTS The predicted number of new cancer cases among men and women in France between 2015 and 2050 that could have been prevented by following the French government's alcohol consumption guidelines. FINDINGS The simulation predicted that perfect adherence to the French government's alcohol consumption guidelines would prevent, on average, an estimated 15 952 cancer cases per year after the PIF reached its full effect, which would have represented 4.5% of new cancer cases in 2015. The number of averted cancer cases over the study period were highest for oral cavity, oropharynx and hypopharynx cancer (respectively, 118 462, 95% CI = 113 803-123 022 and 11 167, 95% CI = 10 149-12 229] for men and women; liver and intrahepatic bile ducts cancer (123 447, 95% CI = 112 581-133 404 and 2825, 95% CI = 2208,4095); colorectal cancer (89 859, 95% CI = 84 651-95 355 and 12 847, 95% CI = 11 545-14 245); and female breast cancer (61 649, 95% CI = 56 330-67 452). CONCLUSION This simulation study of the French general population predicted that perfect adherence to the French government's alcohol consumption guidelines (no more than 10 standard alcoholic drinks per week and two per day) would prevent almost 16 000 cancer cases per year.
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Affiliation(s)
- Yan Ren
- Nutritional Epidemiology Research Team, University of Paris, Sorbonne Paris Nord University, Bobigny, France
| | - Earl Chase
- Nutritional Epidemiology Research Team, University of Paris, Sorbonne Paris Nord University, Bobigny, France
| | - Tania d'Almeida
- Nutritional Epidemiology Research Team, University of Paris, Sorbonne Paris Nord University, Bobigny, France
| | - Julien Allègre
- Nutritional Epidemiology Research Team, University of Paris, Sorbonne Paris Nord University, Bobigny, France
| | - Paule Latino-Martel
- Nutritional Epidemiology Research Team, University of Paris, Sorbonne Paris Nord University, Bobigny, France
| | | | | | - Fabrice Etilé
- Paris School of Economics and Institut National de Recherche pour l'Agriculture, l'Alimentation et l'Environnement, Paris, France
| | - Serge Hercberg
- Nutritional Epidemiology Research Team, University of Paris, Sorbonne Paris Nord University, Bobigny, France.,Public Health Department, Avicenne Hospital, Bobigny, France
| | - Mathilde Touvier
- Nutritional Epidemiology Research Team, University of Paris, Sorbonne Paris Nord University, Bobigny, France
| | - Chantal Julia
- Nutritional Epidemiology Research Team, University of Paris, Sorbonne Paris Nord University, Bobigny, France.,Public Health Department, Avicenne Hospital, Bobigny, France
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Wang R, Mu J. Arbutin attenuates ethanol-induced acute hepatic injury by the modulation of oxidative stress and Nrf-2/HO-1 signaling pathway. J Biochem Mol Toxicol 2021; 35:e22872. [PMID: 34346143 DOI: 10.1002/jbt.22872] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2021] [Revised: 03/20/2021] [Accepted: 07/21/2021] [Indexed: 12/17/2022]
Abstract
Alcoholic liver disease (ALD) is a pervasive ailment due to the excessive consumption of alcohol and there is no operative drug for its treatment. The current exploration was intended to examine the hepatoprotective efficacy of arbutin against ethanol-provoked liver injury in rats via the modulation of the Nrf-2/HO-1 signaling cascade. Wistar rats were challenged with the 3 g/kg/day (40% v/v) of ethanol for 4 weeks to provoke the ALD and concomitantly supplemented with 40 mg/kg of arbutin. The liver function markers enzymes, inflammatory cytokines, and oxidative stress markers levels were scrutinized by using the respective assay kits. The mRNA expression of Nrf-2/HO-1 signaling proteins was studied by reverse-transcription polymerase chain reaction. The histological alterations of liver tissues were examined. HepG2 cells were used for the in vitro studies. The levels of oxidative stress markers and liver marker enzymes were examined by using kits. Reactive oxygen species (ROS) and apoptotic cell death was detected by using fluorescent staining. There were no major differences in the body weight and liver weight of experimental animals. Arbutin treatment appreciably reduced the liver marker enzymes, upregulated superoxide dismutase, glutathione peroxidase, total antioxidant capacity, and the hydroxyl scavenging ability, and diminished the tumor necrosis factor-α and interleukin-6 levels in the serum of ethanol provoked animals. Arbutin triggered Nrf-2/HO-1 signaling cascade liver tissues of ethanol-provoked animals. Histological findings proved the preventing effects of arbutin. Arbutin did not demonstrate toxicity to the HepG2 cells. It reduced the aspartate aminotransferase and alanine aminotransferase, ROS, apoptotic cell death, lipid peroxidation and improved the antioxidants' levels in the ethanol-challenged HepG2 cells. In conclusion, our findings unveiled the hepatoprotective efficacy of arbutin against ethanol-provoked liver injury in rats. It could be a promising agent to treat alcoholic liver disease in the future.
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Affiliation(s)
- Rongsheng Wang
- Department of General Surgery, The Second Affiliated Hospital of Wannan Medical College, Wuhu, China
| | - Jinji Mu
- Department of Gastroenterology, People's Hospital of Tongchuan, Tongchuan, China
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45
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Kim D, Adeniji N, Latt N, Kumar S, Bloom PP, Aby ES, Perumalswami P, Roytman M, Li M, Vogel AS, Catana AM, Wegermann K, Carr RM, Aloman C, Chen VL, Rabiee A, Sadowski B, Nguyen V, Dunn W, Chavin KD, Zhou K, Lizaola-Mayo B, Moghe A, Debes J, Lee TH, Branch AD, Viveiros K, Chan W, Chascsa DM, Kwo P, Dhanasekaran R. Predictors of Outcomes of COVID-19 in Patients With Chronic Liver Disease: US Multi-center Study. Clin Gastroenterol Hepatol 2021; 19:1469-1479.e19. [PMID: 32950749 PMCID: PMC7497795 DOI: 10.1016/j.cgh.2020.09.027] [Citation(s) in RCA: 174] [Impact Index Per Article: 43.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/10/2020] [Revised: 09/14/2020] [Accepted: 09/15/2020] [Indexed: 02/07/2023]
Abstract
BACKGROUND & AIMS Chronic liver disease (CLD) represents a major global health burden. We undertook this study to identify the factors associated with adverse outcomes in patients with CLD who acquire the novel coronavirus-2019 (COVID-19). METHODS We conducted a multi-center, observational cohort study across 21 institutions in the United States (US) of adult patients with CLD and laboratory-confirmed diagnosis of COVID-19 between March 1, 2020 and May 30, 2020. We performed survival analysis to identify independent predictors of all-cause mortality and COVID-19 related mortality, and multivariate logistic regression to determine the risk of severe COVID-19 in patients with CLD. RESULTS Of the 978 patients in our cohort, 867 patients (mean age 56.9 ± 14.5 years, 55% male) met inclusion criteria. The overall all-cause mortality was 14.0% (n = 121), and 61.7% (n = 535) had severe COVID-19. Patients presenting with diarrhea or nausea/vomiting were more likely to have severe COVID-19. The liver-specific factors associated with independent risk of higher overall mortality were alcohol-related liver disease (ALD) (hazard ratio [HR] 2.42, 95% confidence interval [CI] 1.29-4.55), decompensated cirrhosis (HR 2.91 [1.70-5.00]) and hepatocellular carcinoma (HCC) (HR 3.31 [1.53-7.16]). Other factors were increasing age, diabetes, hypertension, chronic obstructive pulmonary disease and current smoker. Hispanic ethnicity (odds ratio [OR] 2.33 [1.47-3.70]) and decompensated cirrhosis (OR 2.50 [1.20-5.21]) were independently associated with risk for severe COVID-19. CONCLUSIONS The risk factors which predict higher overall mortality among patients with CLD and COVID-19 are ALD, decompensated cirrhosis and HCC. Hispanic ethnicity and decompensated cirrhosis are associated with severe COVID-19. Our results will enable risk stratification and personalization of the management of patients with CLD and COVID-19. Clinicaltrials.gov number NCT04439084.
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Affiliation(s)
| | | | - Nyann Latt
- Ochsner Medical Center, New Orleans, Louisiana
| | | | | | - Elizabeth S. Aby
- Hennepin County Medical Center, Minneapolis, Minnesota,University of Minnesota, Minneapolis, Minnesota
| | | | - Marina Roytman
- University of California San Francisco, Fresno, California
| | - Michael Li
- Brigham and Women’s Hospital, Boston, Massachusetts
| | | | | | | | | | | | | | | | | | | | - Winston Dunn
- University of Kansas Medical Center, Kansas City, Kansas
| | | | - Kali Zhou
- University of Southern California, Los Angeles, California
| | | | - Akshata Moghe
- University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania
| | - José Debes
- Hennepin County Medical Center, Minneapolis, Minnesota,University of Minnesota, Minneapolis, Minnesota
| | | | | | | | - Walter Chan
- Brigham and Women’s Hospital, Boston, Massachusetts
| | | | - Paul Kwo
- Stanford University, Stanford, California
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Efe C, Dhanasekaran R, Lammert C, Ebik B, Higuera‐de la Tijera F, Aloman C, Rıza Calışkan A, Peralta M, Gerussi A, Massoumi H, Catana AM, Torgutalp M, Purnak T, Rigamonti C, Gomez Aldana AJ, Khakoo N, Kacmaz H, Nazal L, Frager S, Demir N, Irak K, Ellik ZM, Balaban Y, Atay K, Eren F, Cristoferi L, Batıbay E, Urzua Á, Snijders R, Kıyıcı M, Akyıldız M, Ekin N, Carr RM, Harputluoğlu M, Hatemi I, Mendizabal M, Silva M, Idilman R, Silveira M, Drenth JP, Assis DN, Björnsson E, Boyer JL, Invernizzi P, Levy C, Schiano TD, Ridruejo E, Wahlin S. Outcome of COVID-19 in Patients With Autoimmune Hepatitis: An International Multicenter Study. Hepatology 2021; 73:2099-2109. [PMID: 33713486 PMCID: PMC8250536 DOI: 10.1002/hep.31797] [Citation(s) in RCA: 41] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/23/2020] [Revised: 03/01/2021] [Accepted: 03/04/2021] [Indexed: 02/06/2023]
Abstract
BACKGROUND AND AIMS Data regarding outcome of COVID-19 in patients with autoimmune hepatitis (AIH) are lacking. APPROACH AND RESULTS We performed a retrospective study on patients with AIH and COVID-19 from 34 centers in Europe and the Americas. We analyzed factors associated with severe COVID-19 outcomes, defined as the need for mechanical ventilation, intensive care admission, and/or death. The outcomes of patients with AIH were compared to a propensity score-matched cohort of patients without AIH but with chronic liver diseases (CLD) and COVID-19. The frequency and clinical significance of new-onset liver injury (alanine aminotransferase > 2 × the upper limit of normal) during COVID-19 was also evaluated. We included 110 patients with AIH (80% female) with a median age of 49 (range, 18-85) years at COVID-19 diagnosis. New-onset liver injury was observed in 37.1% (33/89) of the patients. Use of antivirals was associated with liver injury (P = 0.041; OR, 3.36; 95% CI, 1.05-10.78), while continued immunosuppression during COVID-19 was associated with a lower rate of liver injury (P = 0.009; OR, 0.26; 95% CI, 0.09-0.71). The rates of severe COVID-19 (15.5% versus 20.2%, P = 0.231) and all-cause mortality (10% versus 11.5%, P = 0.852) were not different between AIH and non-AIH CLD. Cirrhosis was an independent predictor of severe COVID-19 in patients with AIH (P < 0.001; OR, 17.46; 95% CI, 4.22-72.13). Continuation of immunosuppression or presence of liver injury during COVID-19 was not associated with severe COVID-19. CONCLUSIONS This international, multicenter study reveals that patients with AIH were not at risk for worse outcomes with COVID-19 than other causes of CLD. Cirrhosis was the strongest predictor for severe COVID-19 in patients with AIH. Maintenance of immunosuppression during COVID-19 was not associated with increased risk for severe COVID-19 but did lower the risk for new-onset liver injury during COVID-19.
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Hyun J, Han J, Lee C, Yoon M, Jung Y. Pathophysiological Aspects of Alcohol Metabolism in the Liver. Int J Mol Sci 2021; 22:ijms22115717. [PMID: 34071962 PMCID: PMC8197869 DOI: 10.3390/ijms22115717] [Citation(s) in RCA: 146] [Impact Index Per Article: 36.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2021] [Revised: 05/22/2021] [Accepted: 05/24/2021] [Indexed: 12/12/2022] Open
Abstract
Alcoholic liver disease (ALD) is a globally prevalent chronic liver disease caused by chronic or binge consumption of alcohol. The liver is the major organ that metabolizes alcohol; therefore, it is particularly sensitive to alcohol intake. Metabolites and byproducts generated during alcohol metabolism cause liver damage, leading to ALD via several mechanisms, such as impairing lipid metabolism, intensifying inflammatory reactions, and inducing fibrosis. Despite the severity of ALD, the development of novel treatments has been hampered by the lack of animal models that fully mimic human ALD. To overcome the current limitations of ALD studies and therapy development, it is necessary to understand the molecular mechanisms underlying alcohol-induced liver injury. Hence, to provide insights into the progression of ALD, this review examines previous studies conducted on alcohol metabolism in the liver. There is a particular focus on the occurrence of ALD caused by hepatotoxicity originating from alcohol metabolism.
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Affiliation(s)
- Jeongeun Hyun
- Institute of Tissue Regeneration Engineering (ITREN), Dankook University, Cheonan 31116, Korea;
- Department of Nanobiomedical Science and BK21 PLUS NBM Global Research Center for Regenerative Medicine, Dankook University, Cheonan 31116, Korea
- Department of Regenerative Dental Medicine, College of Dentistry, Dankook University, Cheonan 31116, Korea
| | - Jinsol Han
- Department of Integrated Biological Science, Pusan National University, Pusan 46241, Korea; (J.H.); (C.L.)
| | - Chanbin Lee
- Department of Integrated Biological Science, Pusan National University, Pusan 46241, Korea; (J.H.); (C.L.)
| | - Myunghee Yoon
- Department of Surgery, Division of Hepatobiliary and Pancreas Surgery, Biomedical Research Institute, Pusan National University, Pusan 46241, Korea;
| | - Youngmi Jung
- Department of Integrated Biological Science, Pusan National University, Pusan 46241, Korea; (J.H.); (C.L.)
- Department of Biological Sciences, Pusan National University, Pusan 46241, Korea
- Correspondence: ; Tel.: +82-51-510-2262
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Gut Microbiota at the Intersection of Alcohol, Brain, and the Liver. J Clin Med 2021; 10:jcm10030541. [PMID: 33540624 PMCID: PMC7867253 DOI: 10.3390/jcm10030541] [Citation(s) in RCA: 23] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2020] [Revised: 01/20/2021] [Accepted: 01/26/2021] [Indexed: 12/12/2022] Open
Abstract
Over the last decade, increased research into the cognizance of the gut-liver-brain axis in medicine has yielded powerful evidence suggesting a strong association between alcoholic liver diseases (ALD) and the brain, including hepatic encephalopathy or other similar brain disorders. In the gut-brain axis, chronic, alcohol-drinking-induced, low-grade systemic inflammation is suggested to be the main pathophysiology of cognitive dysfunctions in patients with ALD. However, the role of gut microbiota and its metabolites have remained unclear. Eubiosis of the gut microbiome is crucial as dysbiosis between autochthonous bacteria and pathobionts leads to intestinal insult, liver injury, and neuroinflammation. Restoring dysbiosis using modulating factors such as alcohol abstinence, promoting commensal bacterial abundance, maintaining short-chain fatty acids in the gut, or vagus nerve stimulation could be beneficial in alleviating disease progression. In this review, we summarize the pathogenic mechanisms linked with the gut-liver-brain axis in the development and progression of brain disorders associated with ALD in both experimental models and humans. Further, we discuss the therapeutic potential and future research directions as they relate to the gut-liver-brain axis.
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Du XY, Wen L, Hu YY, Deng SQ, Xie LC, Jiang GB, Yang GL, Niu YM. Association Between the Aldehyde Dehydrogenase-2 rs671 G>A Polymorphism and Head and Neck Cancer Susceptibility: A Meta-Analysis in East Asians. Alcohol Clin Exp Res 2021; 45:307-317. [PMID: 33283290 DOI: 10.1111/acer.14527] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2020] [Accepted: 11/23/2020] [Indexed: 12/11/2022]
Abstract
BACKGROUND Aldehyde dehydrogenase-2 (ALDH2) plays an important role in the alcohol detoxification and acetaldehyde metabolism. Published studies have demonstrated some inconsistent associations between ALDH2 rs671 G>A polymorphism and head and neck cancer (HNC) risk. METHODS A meta-analysis was performed to provide pooled data on the association between the ALDH2 rs671 G>A polymorphism and HNC risk. Electronic databases were searched to identify relevant studies. Odds ratios and 95% confidence intervals (CIs) were used to examine the pooled effect size of each genetic model. In addition, heterogeneity test, accumulative analysis, sensitivity analysis, and publication bias were conducted to test the statistical power. RESULTS Thirteen publications (14 independent case-control studies) involving 10,939 subjects were selected. The stratified analysis indicated that both light/moderated drinking (e.g., GA vs. GG: OR = 1.47, 95% CI = 1.16 to 1.86, p < 0.01, I2 = 81.1%) and heavy drinking would increase HNC risk with rs671 G>A mutation (e.g., GA vs. GG: OR = 2.30, 95% CI = 1.11 to 4.77, p = 0.03, I2 = 81.9%). CONCLUSIONS In summary, this meta-analysis suggested that the ALDH2 rs671 G>A polymorphism may play an important synergistic effect in the pathogenesis of HNC development in East Asians.
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Affiliation(s)
- Xin-Ya Du
- From the, Department of Stomatology, (X-YD, G-LY, Y-MN), The People's Hospital of Longhua Shenzhen, Affiliated Longhua People's Hospital, Southern Medicine University, Shenzhen, China
| | - Li Wen
- Department of Dermatology, (LW), Suizhou Hospital, Hubei University of Medicine, Suizhou, China
| | - Yuan-Yuan Hu
- Department of Stomatology, (Y-YH, L-CX, Y-MN), Center for Evidence-Based Medicine and Clinical Research, Taihe Hospital, Hubei Key Laboratory of Embryonic Stem Cell Research, Hubei University of Medicine, Shiyan, China.,Department of Research Affair Management, (Y-YH, S-QD), Gongli Hospital, the Secondary Military Medical University, Shanghai, China.,Department of Radiology and Stomatology, (Y-YH, G-BJ), Suizhou Hospital, Hubei University of Medicine, Suizhou, China
| | - Sheng-Qiong Deng
- Department of Research Affair Management, (Y-YH, S-QD), Gongli Hospital, the Secondary Military Medical University, Shanghai, China
| | - Long-Chuan Xie
- Department of Stomatology, (Y-YH, L-CX, Y-MN), Center for Evidence-Based Medicine and Clinical Research, Taihe Hospital, Hubei Key Laboratory of Embryonic Stem Cell Research, Hubei University of Medicine, Shiyan, China
| | - Guang-Bin Jiang
- Department of Radiology and Stomatology, (Y-YH, G-BJ), Suizhou Hospital, Hubei University of Medicine, Suizhou, China
| | - Gong-Li Yang
- From the, Department of Stomatology, (X-YD, G-LY, Y-MN), The People's Hospital of Longhua Shenzhen, Affiliated Longhua People's Hospital, Southern Medicine University, Shenzhen, China.,Department of Gastroenterology, (G-Li Y), Shenzhen University General Hospital, Shenzhen University, Shenzhen, China
| | - Yu-Ming Niu
- From the, Department of Stomatology, (X-YD, G-LY, Y-MN), The People's Hospital of Longhua Shenzhen, Affiliated Longhua People's Hospital, Southern Medicine University, Shenzhen, China.,Department of Stomatology, (Y-YH, L-CX, Y-MN), Center for Evidence-Based Medicine and Clinical Research, Taihe Hospital, Hubei Key Laboratory of Embryonic Stem Cell Research, Hubei University of Medicine, Shiyan, China
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Recent Advances of Microbiome-Associated Metabolomics Profiling in Liver Disease: Principles, Mechanisms, and Applications. Int J Mol Sci 2021; 22:ijms22031160. [PMID: 33503844 PMCID: PMC7865944 DOI: 10.3390/ijms22031160] [Citation(s) in RCA: 23] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2020] [Revised: 01/17/2021] [Accepted: 01/22/2021] [Indexed: 02/06/2023] Open
Abstract
Advances in high-throughput screening of metabolic stability in liver and gut microbiota are able to identify and quantify small-molecule metabolites (metabolome) in different cellular microenvironments that are closest to their phenotypes. Metagenomics and metabolomics are largely recognized to be the “-omics” disciplines for clinical therapeutic screening. Here, metabolomics activity screening in liver disease (LD) and gut microbiomes has significantly delivered the integration of metabolomics data (i.e., a set of endogenous metabolites) with metabolic pathways in cellular environments that can be tested for biological functions (i.e., phenotypes). A growing literature in LD and gut microbiomes reports the use of metabolites as therapeutic targets or biomarkers. Although growing evidence connects liver fibrosis, cirrhosis, and hepatocellular carcinoma, the genetic and metabolic factors are still mainly unknown. Herein, we reviewed proof-of-concept mechanisms for metabolomics-based LD and gut microbiotas’ role from several studies (nuclear magnetic resonance, gas/lipid chromatography, spectroscopy coupled with mass spectrometry, and capillary electrophoresis). A deeper understanding of these axes is a prerequisite for optimizing therapeutic strategies to improve liver health.
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