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Yokus B, Maccioni L, Fu L, Haskó G, Nagy LE, Gao B, Pacher P. The Link Between Alcohol Consumption and Kidney Injury. THE AMERICAN JOURNAL OF PATHOLOGY 2025:S0002-9440(25)00193-2. [PMID: 40513821 DOI: 10.1016/j.ajpath.2025.05.011] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/10/2025] [Revised: 04/24/2025] [Accepted: 05/13/2025] [Indexed: 06/16/2025]
Abstract
Alcohol consumption contributes to systemic organ dysfunction, but its direct effect on kidney health is unclear. Epidemiological studies show inconsistent findings due to reliance on conventional markers like serum creatinine (sCr) and blood urea nitrogen (BUN), which are insensitive to early chronic kidney disease (CKD) and influenced by factors such as muscle mass, diet, and hydration status. Experimental studies indicate that alcohol may directly exacerbate renal damage through mitochondrial dysfunction, oxidative stress, and inflammation. Furthermore, indirect effects from alcohol-induced altered intestinal permeability and microbiome, liver injury, microcirculatory/cardiac dysfunction and muscle damage may also facilitate kidney damage. Notably, alcohol-related liver disease can lead to hepatorenal syndrome, a severe form of kidney dysfunction driven by circulatory disturbances and systemic inflammation. This overview explores the adverse effects of alcohol misuse on kidney health and disease, emphasizing the need for comprehensive epidemiological studies with more sensitive kidney injury biomarkers. It also highlights the importance of using clinically relevant preclinical models to clarify the underlying mechanisms of alcohol-related kidney injury and to enhance our understanding of its long-term clinical consequences.
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Affiliation(s)
- Burhan Yokus
- Laboratory of Cardiovascular Physiology and Tissue Injury, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD, USA
| | - Luca Maccioni
- Laboratory of Liver Diseases, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD, USA
| | - Lihong Fu
- Laboratory of Cardiovascular Physiology and Tissue Injury, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD, USA
| | - György Haskó
- Department of Anesthesiology, Columbia University, New York, New York, USA
| | - Laura E Nagy
- Departments of Inflammation and Immunity, Cleveland Clinic, Cleveland, OH, USA
| | - Bin Gao
- Laboratory of Liver Diseases, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD, USA
| | - Pal Pacher
- Laboratory of Cardiovascular Physiology and Tissue Injury, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD, USA.
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2
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Huang J, Zhou K, Li J, Xu Z, Wu X, Chen T, Wang D, Pan H, Huang S, Liu T, Luo Z, Gao Y. Poncirin ameliorates alcoholic liver injury by regulating lipid metabolism and inflammatory response in a PPARα dependent manner. PHYTOMEDICINE : INTERNATIONAL JOURNAL OF PHYTOTHERAPY AND PHYTOPHARMACOLOGY 2025; 140:156598. [PMID: 40056635 DOI: 10.1016/j.phymed.2025.156598] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/13/2024] [Revised: 01/27/2025] [Accepted: 03/01/2025] [Indexed: 03/10/2025]
Abstract
BACKGROUND Poncirin (PO) is a citrus flavonoid with various of functional effect including cardiac ischemia-reperfusion injury, colitis, cancer, et al. Considering the role of PO in improving inflammation and lipid metabolism, it may have potential therapeutic effects on alcoholic liver injury (ALI), but there are currently no relevant reports. PURPOSE Current study aimed to explore the protective effect of PO on preventing ALI. METHODS A chronic ethanol-fed mice was used as ALI-mice model and ethanol-induced mouse primary hepatocytes (MPHs) as ALI-cells model. Multiple molecular biology analysis methods are used to evaluate PO's efficacy. RESULTS Both in vivo and in vitro, PO improved the inflammatory response and lipid deposition induced by ethanol. According to RNA-seq analysis, Peroxisome proliferator activated receptor alpha (PPARα) had been found as a potential target, followed by the experiment validation using Cellular Thermal Shift Assay (CETSA), Western bolt analysis as well as qPCR analysis. In addition, the protective effect of PO was reduced or disappeared in PPARα-/- ALI mice, both in vivo and in vitro. CONCLUSION This is the first study to evaluate the role of PO in preventing ALI by targeting lipid metabolism and the inflammatory response by partly targeting the PPARα pathway, providing a fundamental basis for the use of PO as a functional food to alleviate ALI.
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Affiliation(s)
- Jiawen Huang
- Department of Gastroenterology, The Second Afliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou University of Chinese Medicine, Guangzhou 510000, PR China; State Key Laboratory of Traditional Chinese Medicine Syndrome, Science and Technology Innovation Center, Guangzhou University of Chinese Medicine, Guangzhou, 510405, PR China
| | - Kaili Zhou
- State Key Laboratory of Traditional Chinese Medicine Syndrome, Science and Technology Innovation Center, Guangzhou University of Chinese Medicine, Guangzhou, 510405, PR China
| | - Jiayu Li
- State Key Laboratory of Traditional Chinese Medicine Syndrome, Science and Technology Innovation Center, Guangzhou University of Chinese Medicine, Guangzhou, 510405, PR China
| | - Zaibin Xu
- State Key Laboratory of Traditional Chinese Medicine Syndrome, Science and Technology Innovation Center, Guangzhou University of Chinese Medicine, Guangzhou, 510405, PR China
| | - Xiaoqin Wu
- State Key Laboratory of Traditional Chinese Medicine Syndrome, Science and Technology Innovation Center, Guangzhou University of Chinese Medicine, Guangzhou, 510405, PR China
| | - Tingting Chen
- State Key Laboratory of Traditional Chinese Medicine Syndrome, Science and Technology Innovation Center, Guangzhou University of Chinese Medicine, Guangzhou, 510405, PR China
| | - Danna Wang
- State Key Laboratory of Traditional Chinese Medicine Syndrome, Science and Technology Innovation Center, Guangzhou University of Chinese Medicine, Guangzhou, 510405, PR China
| | - Huafeng Pan
- State Key Laboratory of Traditional Chinese Medicine Syndrome, Science and Technology Innovation Center, Guangzhou University of Chinese Medicine, Guangzhou, 510405, PR China
| | - Shuiqing Huang
- State Key Laboratory of Traditional Chinese Medicine Syndrome, Science and Technology Innovation Center, Guangzhou University of Chinese Medicine, Guangzhou, 510405, PR China.
| | - Tianwen Liu
- Department of Gastroenterology, The Second Afliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou University of Chinese Medicine, Guangzhou 510000, PR China.
| | - Zhuohui Luo
- Hainan Pharmaceutical Research and Development Science Park, Hainan Medical University, Haikou 571199, PR China; Research Center for Drug Safety Evaluation of Hainan Province, Hainan Medical University, Haikou 571199, PR China.
| | - Yong Gao
- Department of Gastroenterology, The Second Afliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou University of Chinese Medicine, Guangzhou 510000, PR China; State Key Laboratory of Traditional Chinese Medicine Syndrome, Science and Technology Innovation Center, Guangzhou University of Chinese Medicine, Guangzhou, 510405, PR China.
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Park SH, Seo W. Key mechanisms in alcohol-associated liver disease: hepatic ADH deficiency, dysregulated hepatic lipid metabolism, and nonoxidative ethanol metabolites. Am J Physiol Gastrointest Liver Physiol 2025; 328:G426-G428. [PMID: 40063038 DOI: 10.1152/ajpgi.00076.2025] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/03/2025] [Revised: 03/04/2025] [Accepted: 03/04/2025] [Indexed: 03/29/2025]
Affiliation(s)
- Seol Hee Park
- Department of Companion Animal Health, Hanyang Women's University, Seoul, Republic of Korea
| | - Wonhyo Seo
- Graduate School of Pharmaceutical Sciences, College of Pharmacy, Ewha Womans University, Seoul, Republic of Korea
- Graduate Program in Innovative Biomaterials Convergence, Ewha Womans University, Seoul, Republic of Korea
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Zhu YQ, Wang LL, Li ZH, Qian SS, Xu Z, Zhang J, Song YH, Pan XS, Du N, Abou-Elnour A, Tay LJ, Zhang JR, Li MX, Shen YX, Huang Y. Acid-sensing ion channel 1a promotes alcohol-associated liver disease in mice via regulating endoplasmic reticulum autophagy. Acta Pharmacol Sin 2025; 46:989-1001. [PMID: 39592735 PMCID: PMC11950321 DOI: 10.1038/s41401-024-01423-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/16/2024] [Accepted: 11/05/2024] [Indexed: 11/28/2024]
Abstract
Alcohol-associated liver disease (ALD) is a hepatocyte dysfunction disease caused by chronic or excessive alcohol consumption, which can lead to extensive hepatocyte necrosis and even liver failure. Currently, the pathogenesis of ALD and the anti-ALD mechanisms have not been fully elucidated yet. In this study, we investigated the effects of endoplasmic reticulum autophagy (ER-phagy) in ALD and the role of acid-sensing ion channel 1a (ASIC1a) in ER stress-mediated ER-phagy. A mouse model of ALD was established using the Gao-Binge method and the AML12 cell line treated with alcohol was used as an in vitro model. We showed that ASIC1a expression was significantly increased and ER-phagy was activated in both the in vivo and in vitro models. In alcohol-treated AML12 cells, we showed that blockade of ASIC1a with PcTx-1 or knockdown of ASIC1a reduced alcohol-induced intracellular Ca2+ accumulation and ER stress. In addition, inhibition of ER stress with 4-PBA reduced the level of ER-phagy. Furthermore, knockdown of the ER-phagy receptor family with sequence similarity 134 member B (FAM134B) alleviated alcohol-triggered hepatocyte injury and apoptosis. In conclusion, this study demonstrates that alcohol activates ER stress-induced ER-phagy and liver injury by increasing ASIC1a expression and ASIC1a-mediated Ca2+ influx, providing a novel strategy for the treatment of ALD.
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Affiliation(s)
- Yue-Qin Zhu
- Department of Pharmacy, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, 230001, China
- Office of Clinical Trial Institution, Anhui Provincial Cancer Hospital, Hefei, 230031, China
| | - Li-Li Wang
- Anhui Province Key Laboratory of Major Autoimmune Diseases, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, Hefei, 230032, China
| | - Zi-Hao Li
- Anhui Province Key Laboratory of Major Autoimmune Diseases, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, Hefei, 230032, China
| | - Shi-Shun Qian
- Anhui Province Key Laboratory of Major Autoimmune Diseases, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, Hefei, 230032, China
| | - Zhou Xu
- Anhui Province Key Laboratory of Major Autoimmune Diseases, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, Hefei, 230032, China
| | - Jin Zhang
- The First Affiliated Hospital of Anhui Medical University, Hefei, 230032, China
| | - Yong-Hu Song
- The First Affiliated Hospital of Anhui Medical University, Hefei, 230032, China
| | - Xue-Sheng Pan
- Department of Immunology, School of Basic Medical Sciences, Anhui Medical University, Hefei, 230032, China
| | - Na Du
- Department of Pharmacy, Shanghai Songjiang District Central Hospital, Shanghai, 201600, China
| | - Amira Abou-Elnour
- Anhui Province Key Laboratory of Major Autoimmune Diseases, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, Hefei, 230032, China
| | - Lynn Jia Tay
- Anhui Province Key Laboratory of Major Autoimmune Diseases, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, Hefei, 230032, China
| | - Jing-Rong Zhang
- Anhui Province Key Laboratory of Major Autoimmune Diseases, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, Hefei, 230032, China
| | - Meng-Xue Li
- Anhui Province Key Laboratory of Major Autoimmune Diseases, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, Hefei, 230032, China
| | - Yu-Xian Shen
- Department of Pharmacology, School of Basic Medical Sciences, Anhui Medical University, Hefei, 230032, China.
| | - Yan Huang
- Anhui Province Key Laboratory of Major Autoimmune Diseases, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, Hefei, 230032, China.
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Weng L, Zhang J, Peng J, Ru M, Liang H, Wei Q, Ruan J, Ali R, Yin C, Huang J. Functional remodeling of gut microbiota and liver in laying hens as affected by fasting and refeeding after fasting. Anim Biosci 2025; 38:692-706. [PMID: 39483011 PMCID: PMC11917430 DOI: 10.5713/ab.24.0299] [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: 05/06/2024] [Revised: 07/22/2024] [Accepted: 10/10/2024] [Indexed: 11/03/2024] Open
Abstract
OBJECTIVE Animals will experience energy deprivation processes such as moulting, clutching, migration and long-distance transportation under natural survival conditions and in production practices, and the body will trigger a series of adaptive metabolic changes during these processes. Fasting and refeeding after fasting can induce remodeling of nutrients and energy metabolism. This study aims to investigate the mechanisms by which the gut microbiota and liver of poultry respond to energy deprivation under specific conditions. METHODS Ninety 252-day-old laying hens were randomly divided into 3 groups: (1) fed ad libitum (control group); (2) fasted from day 13 to day 17 (fasting group); (3) fasted from day 1 to day 5, then refed on a specific feeding way (refeeding group). After that, the serum, liver, jejunum tissues, and cecum contents were sampled and sent for metabolome, transcriptome, morphology, and 16S rDNA sequencing analyses, respectively. RESULTS Results showed that food deprivation not only observably decreased the body weight, liver index, and the villus height and villus/crypt ratio of jejunum, but also significantly changed the gut microbiota compositions, serum metabolic profiles, and the hepatic gene expression patterns of laying hens, whereas these changes were effectively reversed by the following refeeding operation. At the same time, metabolome combined transcriptome analysis revealed that both serum differential metabolites and hepatic differential expressed genes (DEGs) were consistently enriched in the lipid and amino metabolism pathways, and strong correlations were synchronously found between the differential metabolites and both of the differential gut microbial genera and DEGs, suggesting the crosstalks among gut, liver and their resulting serum metabolic products. CONCLUSION The results suggested that the organism might coordinate to maintain metabolic homeostasis under energy deprivation through a combination of changes in gut microbial composition and hepatic gene expression.
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Affiliation(s)
- Linjian Weng
- College of Animal Science and Technology, Jiangxi Agricultural University, Nanchang 330045,
China
| | - Jingyi Zhang
- College of Animal Science and Technology, Jiangxi Agricultural University, Nanchang 330045,
China
| | - Jianling Peng
- College of Animal Science and Technology, Jiangxi Agricultural University, Nanchang 330045,
China
| | - Meng Ru
- College of Animal Science and Technology, Jiangxi Agricultural University, Nanchang 330045,
China
| | - Haiping Liang
- College of Animal Science and Technology, Jiangxi Agricultural University, Nanchang 330045,
China
| | - Qing Wei
- College of Animal Science and Technology, Jiangxi Agricultural University, Nanchang 330045,
China
| | - Jiming Ruan
- College of Animal Science and Technology, Jiangxi Agricultural University, Nanchang 330045,
China
| | - Ramlat Ali
- College of Animal Science and Technology, Jiangxi Agricultural University, Nanchang 330045,
China
| | - Chao Yin
- College of Animal Science and Technology, Jiangxi Agricultural University, Nanchang 330045,
China
| | - Jianzhen Huang
- College of Animal Science and Technology, Jiangxi Agricultural University, Nanchang 330045,
China
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6
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Tang XH, Pesola G, Chen Q, Miller D, Nagy LE, McMullen MR, Schwartz RE, Tsoy S, Lim C, Chikara S, Gross SS, Trasino SE, Gudas LJ, Melis M. Ethanol causes rapid decreases in the hepatic retinoid levels shaping the early steps of alcohol-associated liver disease. ALCOHOL, CLINICAL & EXPERIMENTAL RESEARCH 2025; 49:754-770. [PMID: 40016864 PMCID: PMC12014373 DOI: 10.1111/acer.70011] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/29/2024] [Accepted: 01/31/2025] [Indexed: 03/01/2025]
Abstract
BACKGROUND Chronic alcohol drinking causes hepatic vitamin A (retinoids and derivatives) decreases, which correlate with the progression and severity of alcohol-associated liver disease (ALD). However, the effects of short-term ethanol (EtOH) intake on liver retinoids and ALD are still undefined. METHODS Using high-performance liquid chromatography and high-performance liquid chromatography coupled with tandem mass spectrometry (HPLC, HPLC-MS/MS), and molecular biology techniques in mice and cultured human hepatocytes, we investigated the temporal EtOH effects on retinoids and ALD. RESULTS In female and male mice, acute EtOH intake caused hepatic retinol (ROL) and retinyl palmitate (RP) decreases within hours, whereas it did not significantly change the retinoic acid (RA) levels, and those of the RA catabolism metabolite, 4-oxo-RA. After EtOH withdrawal, the liver recovered the ROL and RP levels within 48 h, whereas RA and 4-oxo-RA levels remained almost undetectable by this time point. Compared with control diet-fed mice, hepatic ROL and RP levels remained decreased in the 10-day and 3-week-long EtOH treatments, while retinyl oleate and linoleate increased. Interestingly, some of the RA signaling receptors, Rarβ, along with Cyp26a1, revealed dramatic transcript increases during the 10-day-long experiments that attenuated over time (up to 8 weeks), reflecting impaired RA signaling. Our work also showed that primary human hepatocytes serve as a model to better define the role of EtOH in retinoid biology. CONCLUSIONS This work reveals that acute and short-term exposures to EtOH disrupt retinoid homeostasis, identifying key events in the early pathogenesis of ALD.
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Affiliation(s)
- Xiao-Han Tang
- Department of Pharmacology, Weill Cornell Medicine, New York, NY, USA
| | - Glen Pesola
- Department of Pharmacology, Weill Cornell Medicine, New York, NY, USA
| | - Qiuying Chen
- Department of Pharmacology, Weill Cornell Medicine, New York, NY, USA
| | - Dawson Miller
- Department of Pharmacology, Weill Cornell Medicine, New York, NY, USA
| | - Laura E. Nagy
- Department of Gastroenterology and Hepatology, Cleveland Clinic, Cleveland, OH, USA
| | - Megan R. McMullen
- Department of Gastroenterology and Hepatology, Cleveland Clinic, Cleveland, OH, USA
| | - Robert E. Schwartz
- Division of Gastroenterology & Hepatology, Weill Cornell Medicine, New York, NY, USA
| | - Sergey Tsoy
- Division of Gastroenterology & Hepatology, Weill Cornell Medicine, New York, NY, USA
| | - Christine Lim
- Division of Gastroenterology & Hepatology, Weill Cornell Medicine, New York, NY, USA
| | - Shireen Chikara
- Department of Pharmacology, Weill Cornell Medicine, New York, NY, USA
| | - Steven S. Gross
- Department of Pharmacology, Weill Cornell Medicine, New York, NY, USA
| | - Steven E. Trasino
- Department of Nutrition and Public Health, Hunter College, City University of New York, New York, NY, USA
| | - Lorraine J. Gudas
- Department of Pharmacology, Weill Cornell Medicine, New York, NY, USA
| | - Marta Melis
- Department of Pharmacology, Weill Cornell Medicine, New York, NY, USA
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He J, Huang Z, Zou R. Andrographolide ameliorates sepsis-induced acute liver injury by attenuating endoplasmic reticulum stress through the FKBP1A-mediated NOTCH1/AK2 pathway. Cell Biol Toxicol 2025; 41:56. [PMID: 40053226 PMCID: PMC11889056 DOI: 10.1007/s10565-025-10007-9] [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] [Subscribe] [Scholar Register] [Received: 11/18/2024] [Accepted: 02/20/2025] [Indexed: 03/10/2025]
Abstract
Andrographolide (AP) has been shown to possess anti-inflammatory activities. In this study, the impact of AP in sepsis-induced acute liver injury (ALI) and the molecules involved were dissected. FKBP1A was predicted to be the sole target protein of AP that was also differentially expressed in the GSE166868 dataset. AP induced the protein expression of FKBP1A and suppressed that of NOTCH1 in a dose-dependent manner. AP ameliorated ALI in mice induced by D-galactosamine and LPS and inhibited LPS-induced liver parenchymal cell injury in vitro. By contrast, the protective effect of AP was significantly lost after the knockdown of FKBP1A. As a positive control, the therapeutic effect of dexamethasone on ALI may be related to NOTCH1, which was not related to FKBP1A. NOTCH1 promoted AK2 transcription in liver parenchymal cells, and FKBP1A inhibited endoplasmic reticulum (ER) stress by impairing NOTCH1/AK2 signaling. Restoration of NOTCH1 significantly reversed the hepatoprotective effect of AP in ALI mice and LPS-induced liver parenchymal cell injury by activating the ER stress pathway. Therefore, AP-promoted FKBP1A expression inhibits ALI progression by blocking the NOTCH1/AK2-mediated ER pathway.
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Affiliation(s)
- Jiaqi He
- Department of General Surgery, Huadong Hospital Affiliated to Fudan University, Shanghai, 200040, P.R. China
| | - Zepeng Huang
- Department of Hepatobiliary Surgery, Hainan Cancer Hospital, Haikou, 570000, Hainan, P.R. China
| | - Rui Zou
- Department of Hepatobiliary Surgery, Hainan Cancer Hospital, Haikou, 570000, Hainan, P.R. China.
- Hainan Clinical Research Center for Liver Disease and Liver Critical Illness, Haikou, 570000, Hainan, P.R. China.
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Liu T, Zhang F, Feng Y, Han P, Gao Y. Alcohol-Metabolizing Enzymes, Liver Diseases and Cancer. Semin Liver Dis 2025; 45:99-113. [PMID: 40157374 PMCID: PMC12031026 DOI: 10.1055/a-2551-3320] [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] [Indexed: 04/01/2025]
Abstract
Alcohol is generally believed to be metabolized in the liver by alcohol dehydrogenase (ADH), aldehyde dehydrogenase (ALDH), and to a much lesser extent cytochrome P450 2E1 (CYP2E1) and other enzymes. Recent studies suggest that gut also play important roles in the promotion of alcohol metabolism. ADH, ALDH, and CYP2E1 have several polymorphisms that markedly impact alcohol metabolism. These alcohol-metabolizing enzymes not only affect alcohol-associated liver disease (ALD), but may also modulate the pathogenesis of other liver diseases and cancer in the absence of alcohol consumption. In this review, we discuss alcohol metabolism and the roles of alcohol-metabolizing enzymes in the pathogenesis of ALD, metabolic dysfunction-associated steatotic liver disease, metabolic dysfunction and alcohol-associated liver disease, viral hepatitis, and liver cancer. We also discuss how alcohol-metabolizing enzymes may affect endogenous ethanol production, and how ethanol metabolism in the gut affects liver disease and cancer. Directions for future research on the roles of alcohol-metabolizing enzymes in liver disease and cancer are also elaborated.
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Affiliation(s)
- Tao Liu
- Department of Hepatology, Center of Infectious Diseases and Pathogen Biology, The First Hospital of Jilin University, Changchun, China
- China-Singapore Belt and Road Joint Laboratory on Liver Disease Research, Changchun, China
- Jilin Provincial Key Laboratory of Metabolic Liver Diseases, Jilin University, Changchun, China
| | - FeiYu Zhang
- Department of Hepatology, Center of Infectious Diseases and Pathogen Biology, The First Hospital of Jilin University, Changchun, China
- China-Singapore Belt and Road Joint Laboratory on Liver Disease Research, Changchun, China
- Jilin Provincial Key Laboratory of Metabolic Liver Diseases, Jilin University, Changchun, China
| | - Yue Feng
- Department of Hepatology, Center of Infectious Diseases and Pathogen Biology, The First Hospital of Jilin University, Changchun, China
- China-Singapore Belt and Road Joint Laboratory on Liver Disease Research, Changchun, China
- Jilin Provincial Key Laboratory of Metabolic Liver Diseases, Jilin University, Changchun, China
| | - PanShiLi Han
- Department of Hepatology, Center of Infectious Diseases and Pathogen Biology, The First Hospital of Jilin University, Changchun, China
- China-Singapore Belt and Road Joint Laboratory on Liver Disease Research, Changchun, China
- Jilin Provincial Key Laboratory of Metabolic Liver Diseases, Jilin University, Changchun, China
| | - YanHang Gao
- Department of Hepatology, Center of Infectious Diseases and Pathogen Biology, The First Hospital of Jilin University, Changchun, China
- China-Singapore Belt and Road Joint Laboratory on Liver Disease Research, Changchun, China
- Jilin Provincial Key Laboratory of Metabolic Liver Diseases, Jilin University, Changchun, China
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9
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Kang J, Park SH, Khanam M, Park SB, Shin S, Seo W. Impact of binge drinking on alcoholic liver disease. Arch Pharm Res 2025; 48:212-223. [PMID: 40035998 DOI: 10.1007/s12272-025-01537-1] [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: 05/30/2024] [Accepted: 02/13/2025] [Indexed: 03/06/2025]
Abstract
Numerous studies have examined the pathophysiological changes induced by chronic alcohol (ethanol) consumption and the underlying mechanisms, while much less attention has been devoted to understanding the health impacts of binge drinking. Binge drinking is defined as the excessive consumption of alcohol within a single drinking episode, and is the typical consumption pattern among young people in Western countries. While most young binge drinkers are not clinically alcohol dependent, binge drinking has emerged as a significant social and public health concern. The circulating alcohol consumed during binge episodes permeates cellular membranes throughout the body, exerting profound effects on multiple organs, and signaling pathways. Regular binge drinking eventually induces hepatic steatosis (fatty liver), initiates acute inflammation, and accelerates neutrophil infiltration, de novo lipogenesis, adipocyte death/lipolysis, and the production of nonoxidative alcohol metabolites, processes that synergize to damage liver tissue and impair liver function. Metabolic abnormalities such as diabetes and obesity can also exacerbate the progression of alcohol-related liver disease among binge drinkers. Several animal models have been developed to evaluate the pathophysiological changes resulting from binge drinking; however, the pathogenesis of binge drinking is not fully understood due to differences in alcohol metabolism between animal models and humans. Thus, given the high prevalence and severe health implications of binge drinking, there is an urgent need for comprehensive experimental and clinical investigations to unravel the associated pathophysiological changes. This review summarizes recent research findings on the impact of binge drinking, specifically focusing on its contributions to alcoholic liver injury.
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Affiliation(s)
- Jisoo Kang
- College of Pharmacy, Graduate School of Pharmaceutical Sciences, Ewha Womans University, Seoul, 03760, Republic of Korea
| | - Seol Hee Park
- Department of Companion Animal Health, Hanyang Women's University, Seoul, 04763, Republic of Korea
| | - Mushira Khanam
- College of Pharmacy, Graduate School of Pharmaceutical Sciences, Ewha Womans University, Seoul, 03760, Republic of Korea
| | - Seo Bhin Park
- College of Pharmacy, Graduate School of Pharmaceutical Sciences, Ewha Womans University, Seoul, 03760, Republic of Korea
| | - Sumin Shin
- College of Pharmacy, Graduate School of Pharmaceutical Sciences, Ewha Womans University, Seoul, 03760, Republic of Korea
| | - Wonhyo Seo
- College of Pharmacy, Graduate School of Pharmaceutical Sciences, Ewha Womans University, Seoul, 03760, Republic of Korea.
- Graduate Program in Innovative Biomaterials Convergence, Ewha Womans University, Seoul, 03760, Republic of Korea.
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10
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Wang T, Xia G, Li X, Gong M, Lv X. Endoplasmic reticulum stress in liver fibrosis: Mechanisms and therapeutic potential. Biochim Biophys Acta Mol Basis Dis 2025; 1871:167695. [PMID: 39864668 DOI: 10.1016/j.bbadis.2025.167695] [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: 09/29/2024] [Revised: 01/07/2025] [Accepted: 01/22/2025] [Indexed: 01/28/2025]
Abstract
This paper reviews the important role of endoplasmic reticulum stress in the patho mechanism of liver fibrosis and its potential as a potential target for the treatment of liver fibrosis. Liver fibrosis is the result of sustained inflammation and injury to the liver due to a variety of factors, triggering excessive deposition of extracellular matrix and fibrous scar formation, which in turn leads to loss of liver function and a variety of related complications. Endoplasmic reticulum stress is one of the characteristics of chronic liver disease and is closely related to the pathological process of chronic liver disease, including alcohol-related liver disease, viral hepatitis, and liver fibrosis. The unfolded protein response is one of the important response mechanisms to endoplasmic reticulum stress. It is associated with several pathological aspects of liver fibrosis and the maintenance of endoplasmic reticulum homeostasis. Interventions targeting endoplasmic reticulum stress for the treatment of liver fibrosis have potential research and application value. An in-depth understanding of the biological basis of endoplasmic reticulum stress is also needed in the treatment of liver fibrosis, as well as the development of more effective drugs and interventions to accurately regulate the endoplasmic reticulum signaling network, to achieve the restoration and maintenance of endoplasmic reticulum homeostasis at the cellular and organ levels, and to further promote the reversal of the pathological process of liver fibrosis.
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Affiliation(s)
- Tiantian Wang
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Institute of Innovative Drugs, Hefei, China; School of Pharmacy, Anhui Medical University, Hefei, China; Institute for Liver Diseases of Anhui Medical University, Hefei, China
| | - Guoqing Xia
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Institute of Innovative Drugs, Hefei, China; School of Pharmacy, Anhui Medical University, Hefei, China; Institute for Liver Diseases of Anhui Medical University, Hefei, China
| | - Xue Li
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Institute of Innovative Drugs, Hefei, China; School of Pharmacy, Anhui Medical University, Hefei, China; Institute for Liver Diseases of Anhui Medical University, Hefei, China
| | - Mingxu Gong
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Institute of Innovative Drugs, Hefei, China; School of Pharmacy, Anhui Medical University, Hefei, China; Institute for Liver Diseases of Anhui Medical University, Hefei, China
| | - Xiongwen Lv
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Institute of Innovative Drugs, Hefei, China; School of Pharmacy, Anhui Medical University, Hefei, China; Institute for Liver Diseases of Anhui Medical University, Hefei, China.
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11
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Srinivasan M, Kota S, Bhopale K, Caracheo A, Kaphalia L, Linares J, Romsdahl T, Russell W, Popov V, Boor P, Kaphalia B. Dysregulated hepatic alcohol metabolism: a key factor involved in the pathogenesis of alcohol-associated liver disease. Am J Physiol Gastrointest Liver Physiol 2025; 328:G289-G308. [PMID: 39907561 DOI: 10.1152/ajpgi.00394.2024] [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: 12/17/2024] [Revised: 12/22/2024] [Accepted: 01/04/2025] [Indexed: 02/06/2025]
Abstract
Alcohol use disorder is a major risk factor for alcohol-associated liver disease (ALD), characterized by reduced hepatic alcohol dehydrogenase (ADH) activity, increased body burden of alcohol, and its nonoxidative metabolism to fatty acid ethyl esters (FAEEs). However, the mechanism(s) underlying ALD remain unclear. This study investigated the metabolic basis and mechanism(s) of ALD in chronic ethanol (EtOH)-fed hepatic ADH1-deficient (ADH-) deer mice administered with a single dose of binge EtOH with/without FAEEs. Hepatic ADH- and ADH normal (ADH+) deer mice fed chronic EtOH daily for 3 mo, followed by a single dose of binge EtOH (3 g/kg·body wt) with/without FAEEs (100 mg/kg·body wt), 1 wk before euthanasia. Blood alcohol and acetaldehyde and liver injury markers in the plasma, hepatic FAEEs, lipids, and inflammatory markers were analyzed. Hepatic histology, ultrastructure, protein/mRNA expression of genes involved in alcohol metabolism and lipogenesis, cyclic adenosine monophosphate (cAMP), phosphodiesterase (PDE) activity, and AMP-activated protein kinase (AMPKα) signaling were assessed. Blood alcohol, hepatic lipids and FAEEs, inflammation, oxidative stress, and the expression of lipogenic proteins/genes were significantly increased in various chronic EtOH-fed groups of ADH- versus ADH+ deer mice. In addition, hepatic cAMP levels were reduced, whereas PDE activity and plasma transaminases were elevated. Binge EtOH with/without FAEEs did not significantly exacerbate the liver injury in chronic EtOH-fed ADH- as well as ADH+ deer mice. Overall, an increased body burden of EtOH and endogenously formed FAEEs due to hepatic ADH deficiency, along with dysregulated cAMP and AMPKα signaling, could be the determining factors for EtOH-induced liver injury leading to ALD.NEW & NOTEWORTHY Using hepatic alcohol dehydrogenase deficient (ADH-) deer mouse, which mimics the metabolic conditions observed in chronic alcoholics, we found significant hepatic injury along with degenerative changes in endoplasmic reticulum and mitochondria. Our findings suggest that an increased nonoxidative alcohol metabolism under hepatic alcohol dehydrogenase deficiency and associated hepatic lipid dysregulation and injury appear to be the key factors involved in the pathogenesis of alcohol-associated liver disease.
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Affiliation(s)
- Mukund Srinivasan
- Department of Pathology, The University of Texas Medical Branch, Galveston, Texas, United States
| | - Sumedha Kota
- Department of Pathology, The University of Texas Medical Branch, Galveston, Texas, United States
| | - Kamlesh Bhopale
- Department of Pathology, The University of Texas Medical Branch, Galveston, Texas, United States
| | - Anna Caracheo
- Department of Pathology, The University of Texas Medical Branch, Galveston, Texas, United States
| | - Lata Kaphalia
- Department of Internal Medicine, The University of Texas Medical Branch, Galveston, Texas, United States
| | - Jennifer Linares
- Mass Spectrometry Facility, Department of Biochemistry and Molecular Biology, The University of Texas Medical Branch, Galveston, Texas, United States
| | - Trevor Romsdahl
- Mass Spectrometry Facility, Department of Biochemistry and Molecular Biology, The University of Texas Medical Branch, Galveston, Texas, United States
| | - William Russell
- Mass Spectrometry Facility, Department of Biochemistry and Molecular Biology, The University of Texas Medical Branch, Galveston, Texas, United States
| | - Vsevolod Popov
- Department of Pathology, The University of Texas Medical Branch, Galveston, Texas, United States
| | - Paul Boor
- Department of Pathology, The University of Texas Medical Branch, Galveston, Texas, United States
| | - Bhupendra Kaphalia
- Department of Pathology, The University of Texas Medical Branch, Galveston, Texas, United States
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12
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Ruiter-Lopez L, Khan MAS, Wang X, Song BJ. Roles of Oxidative Stress and Autophagy in Alcohol-Mediated Brain Damage. Antioxidants (Basel) 2025; 14:302. [PMID: 40227291 PMCID: PMC11939343 DOI: 10.3390/antiox14030302] [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: 02/01/2025] [Revised: 02/27/2025] [Accepted: 02/27/2025] [Indexed: 04/15/2025] Open
Abstract
Excessive alcohol consumption significantly impacts human health, particularly the brain, due to its susceptibility to oxidative stress, which contributes to neurodegenerative conditions. Alcohol metabolism in the brain occurs primarily via catalase, followed by CYP2E1 pathways. Excess alcohol metabolized by CYP2E1 generates reactive oxygen/nitrogen species (ROS/RNS), leading to cell injury via altering many different pathways. Elevated oxidative stress impairs autophagic processes, increasing post-translational modifications and further exacerbating mitochondrial dysfunction and ER stress, leading to cell death. The literature highlights that alcohol-induced oxidative stress disrupts autophagy and mitophagy, contributing to neuronal damage. Key mechanisms include mitochondrial dysfunction, ER stress, epigenetics, and the accumulation of oxidatively modified proteins, which lead to neuroinflammation and impaired cellular quality control. These processes are exacerbated by chronic alcohol exposure, resulting in the suppression of protective pathways like NRF2-mediated antioxidant responses and increased susceptibility to neurodegenerative changes in the brain. Alcohol-mediated neurotoxicity involves complex interactions between alcohol metabolism, oxidative stress, and autophagy regulation, which are influenced by various factors such as drinking patterns, nutritional status, and genetic/environmental factors, highlighting the need for further molecular studies to unravel these mechanisms and develop targeted interventions.
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Affiliation(s)
- Leon Ruiter-Lopez
- Section of Molecular Pharmacology and Toxicology, National Institute on Alcohol Abuse and Alcoholism, Bethesda, MD 20892, USA
| | - Mohammed A. S. Khan
- Department of Neurosurgery, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA 02115, USA; (M.A.S.K.); (X.W.)
| | - Xin Wang
- Department of Neurosurgery, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA 02115, USA; (M.A.S.K.); (X.W.)
| | - Byoung-Joon Song
- Section of Molecular Pharmacology and Toxicology, National Institute on Alcohol Abuse and Alcoholism, Bethesda, MD 20892, USA
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13
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Li J, Liu W, Zhang J, Sun C. The Role of Mitochondrial Quality Control in Liver Diseases: Dawn of a Therapeutic Era. Int J Biol Sci 2025; 21:1767-1783. [PMID: 39990657 PMCID: PMC11844277 DOI: 10.7150/ijbs.107777] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2024] [Accepted: 01/28/2025] [Indexed: 02/25/2025] Open
Abstract
The liver is a vital metabolic organ that detoxifies substances, produces bile, stores nutrients, and regulates versatile metabolic processes. Maintaining normal liver cell function requires the prompt and delicate modulation of mitochondrial quality control (MQC), which encompasses a spectrum of processes such as mitochondrial fission, fusion, biogenesis, and mitophagy. Recent studies have shown that disruptions to this homeostatic status are closely linked to the advent and progression of a variety of acute and chronic liver diseases, including but not limited to alcohol-associated liver disease and metabolic dysfunction-associated fatty liver disease. However, the explicit mechanisms by which mitochondrial dysfunction impacts inflammatory pathways and cell death in the context of liver diseases remain unclear. In this narrative review, we provide a detailed description of MQC, analyze the mechanisms underpinning mitochondrial dysfunction induced by different detrimental insults, and further elucidate how imbalanced/disrupted MQC promotes the progression and aggravation of liver diseases, ultimately shedding light on the mitochondrion-centric therapeutic strategies for these pathophysiological entities.
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Affiliation(s)
- Jia Li
- Department of Gastroenterology and Hepatology, Tianjin Medical University General Hospital, Anshan Road 154, Heping District, Tianjin 300052, China
| | - Wenqin Liu
- Department of Gastroenterology and Hepatology, Tianjin Medical University General Hospital, Anshan Road 154, Heping District, Tianjin 300052, China
| | - Jie Zhang
- Department of Gastroenterology and Hepatology, Tianjin Medical University General Hospital, Anshan Road 154, Heping District, Tianjin 300052, China
| | - Chao Sun
- Department of Gastroenterology and Hepatology, Tianjin Medical University General Hospital, Anshan Road 154, Heping District, Tianjin 300052, China
- Department of Gastroenterology, Tianjin Medical University General Hospital Airport Hospital, East Street 6, Tianjin Airport Economic Area, Tianjin 300308, China
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14
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Lu J, Wang C. Ferulic acid from Angelica sinensis (Oliv.) Diels ameliorates lipid metabolism in alcoholic liver disease via AMPK/ACC and PI3K/AKT pathways. JOURNAL OF ETHNOPHARMACOLOGY 2025; 338:119118. [PMID: 39551284 DOI: 10.1016/j.jep.2024.119118] [Citation(s) in RCA: 3] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/19/2024] [Revised: 11/02/2024] [Accepted: 11/14/2024] [Indexed: 11/19/2024]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE Angelica sinensis (Oliv.) Diels is a well-known traditional medicinal plant. In China, it is a common blood tonic drug that has been inherited for thousands of years. There is a consensus that Angelica sinensis (Oliv.) Diels has a protective effect against various liver diseases. However, the effects and mechanisms of Angelica sinensis (Oliv.) Diels and its active components on alcoholic liver disease (ALD) have not been clearly defined yet. AIM OF THE STUDY The aim of this study is to evaluate the effect and explore the mechanism of ferulic acid (FA) from Angelica sinensis (Oliv.) Diels ameliorates lipid metabolism in ALD. METHODS C57BL/6 mice were fed ethanol-containing liquid feeds to establish ALD model in vivo. The lipid metabolism-related indexes were detected by kits, H&E staining and oil red O staining were used to analyze liver histopathological changes and fat deposition, to evaluate the protective effect of water extraction and ethanol precipitation of Angelica sinensis radix (WEEPAS) on ethanol-induced liver injury. The active components and potential targets of Angelica sinensis (Oliv.) Diels for ALD were screened by network pharmacology and molecular docking. Ethanol was co-incubated with HepG2 cells to construct the ALD model in vitro, then the same approaches were used to explore the effect of FA for ALD in vivo and in vitro. The levels of proteins and mRNA related to AMPK/ACC and PI3K/AKT pathways were detected by Western Blotting and RT-qPCR. RESULTS WEEPAS could protect mice from ethanol-induced liver tissues injury by ameliorating fat deposition and inhibiting oxidative stress response. Network pharmacology and molecular docking results suggested that FA might be the main bioactive component in Angelica sinensis (Oliv.) Diels for ALD, and its mechanism might be related to the regulation of AMPK and PI3K/AKT signaling pathways. In vitro and in vivo experiments further demonstrated that FA regulated lipid metabolism via AMPK/ACC and PI3K/AKT pathways, thereby ameliorating ethanol-induced liver tissues injury and lipid metabolism disorders in HepG2 cells and mice, which were consistent with the network pharmacology results. CONCLUSION In summary, the results indicated that FA from Angelica sinensis (Oliv.) Diels was able to ameliorate ethanol-induced ALD. The mechanism may be related to the regulation of lipid metabolism via AMPK/ACC and PI3K/AKT pathways.
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Affiliation(s)
- Jun Lu
- School of Pharmaceutical Sciences, Zhejiang Chinese Medical University, Hangzhou, 311402, China; College of Pharmacy, Guilin Medical University, Guilin, 541104, China
| | - Chen Wang
- School of Pharmaceutical Sciences, Zhejiang Chinese Medical University, Hangzhou, 311402, China.
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15
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Liu M, Zhou M, Ren X, Xie Y. Establishment and application of murine models of alcoholic liver disease: A narrative review. ALCOHOL, CLINICAL & EXPERIMENTAL RESEARCH 2025; 49:271-284. [PMID: 39715699 DOI: 10.1111/acer.15520] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/02/2024] [Accepted: 11/29/2024] [Indexed: 12/25/2024]
Abstract
In recent years, there have been significant advances in pathological research on alcoholic liver disease (ALD), with suitable animal models making a significant contribution. However, the currently established animal ALD models still have some significant drawbacks, especially the inability to induce the entire human ALD lineage, which may be related to physiological differences between animals and humans. This review comprehensively summarized the most widely used experimental models of ALD, including voluntary drinking, Lieber-DeCarli, Meadows-Cook, Tsukamoto-French, NIAAA, and the "second hit" model. "Second hit" refers to an additional factor that damages the liver. There are various "second hit" models that fall into two main categories: particular diets and drugs. These models can either simulate human drinking patterns more accurately or produce varying degrees of ALD without significantly increasing animal mortality. We introduced the established method of the original models, discussed the advantages and disadvantages of the existing models from the aspects of operability and practicality, and provided existing improvement methods, hoping to provide a reference for future researchers.
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Affiliation(s)
- Mengsi Liu
- Peking University People's Hospital, Peking University Hepatology Institute, Beijing Key Laboratory of Hepatitis C and Immunotherapy for Liver Diseases, Beijing International Cooperation Base for Science and Technology on NAFLD Diagnosis, Beijing, China
| | - Mingying Zhou
- Peking University People's Hospital, Peking University Hepatology Institute, Beijing Key Laboratory of Hepatitis C and Immunotherapy for Liver Diseases, Beijing International Cooperation Base for Science and Technology on NAFLD Diagnosis, Beijing, China
| | - Xueyi Ren
- Peking University People's Hospital, Peking University Hepatology Institute, Beijing Key Laboratory of Hepatitis C and Immunotherapy for Liver Diseases, Beijing International Cooperation Base for Science and Technology on NAFLD Diagnosis, Beijing, China
| | - Yandi Xie
- Peking University People's Hospital, Peking University Hepatology Institute, Beijing Key Laboratory of Hepatitis C and Immunotherapy for Liver Diseases, Beijing International Cooperation Base for Science and Technology on NAFLD Diagnosis, Beijing, China
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16
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Zheng K, Yang L, Zhang RS, Qian YH, Zhou YG, Huang WF, Lin JC, Shi YJ, Kong XN. Puerarin Alleviates Alcoholic Liver Disease via Suppressing Lipolysis Induced by Sympathetic Outflow. THE AMERICAN JOURNAL OF CHINESE MEDICINE 2025; 53:863-888. [PMID: 40374377 DOI: 10.1142/s0192415x25500326] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/17/2025]
Abstract
The aim of this study was to evaluate the therapeutic effect of puerarin (PUE) on alcoholic liver disease (ALD) and elucidate the potential mechanism from the perspective of lipolysis and hepatic steatosis. Assessment of PUE efficacy against ALD was performed using serum biochemical parameters and the histological examination of liver and adipose tissue via Hematoxylin and eosin (H&E) staining. The potential mechanisms underlying the amelioration of ALD by PUE were investigated using Western blotting (WB) analysis and immunofluorescence (IHC) staining. We demonstrated that PUE attenuated steatosis in ALD by alleviating ethanol-induced liver damage and lipid accumulation, suppressing the expression of lipid synthesis genes, upregulating the expression of lipid metabolism genes, and reducing lipolysis by inhibiting adipose triglyceride lipase (ATGL) activation and the phosphorylation of hormone-sensitive lipase (HSL). In conclusion, PUE ameliorates ALD by inhibiting the sympathetic outflow-mediated activation of key lipolysis enzymes ATGL and HSL. These findings provide a solid theoretical foundation for the potential application of PUE in the clinical treatment of ALD.
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Affiliation(s)
- Ke Zheng
- Central Laboratory, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
| | - Liu Yang
- Central Laboratory, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
| | - Rui-Shuo Zhang
- Clinical Medicine Admitted Class of 2020, the First Affiliated Hospital of Anhui Medical University, Hefei, Anhui 230031, China
| | - Yi-Han Qian
- Central Laboratory, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
| | - Yu-Ge Zhou
- Central Laboratory, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
| | - Wei-Fan Huang
- Central Laboratory, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
| | - Jia-Cheng Lin
- Central Laboratory, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
| | - Yan-Jun Shi
- Abdominal Transplantation Center, General Surgery, Ruijin Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200025, China
| | - Xiao-Ni Kong
- Central Laboratory, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
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17
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Maccioni L, Dvorácskó S, Godlewski G, Cinar R, Iyer MR, Gao B, Kunos G. Gut cannabinoid receptor 1 regulates alcohol binge-induced intestinal permeability. EGASTROENTEROLOGY 2025; 3:e100173. [PMID: 40124989 PMCID: PMC11927431 DOI: 10.1136/egastro-2024-100173] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/09/2024] [Accepted: 01/29/2025] [Indexed: 03/25/2025]
Abstract
Background Endocannabinoids acting via cannabinoid receptor 1 (CB1R) can elicit increased intestinal permeability (a condition also called 'leaky gut'). Alcohol binge can adversely affect digestive functions, including intestinal permeability; however, the underlying mechanisms remain incompletely understood. The current study aimed at examining whether CB1R is involved in alcohol binge-induced intestinal permeability. Methods We developed intestinal epithelial-specific CB1R knockout (CB1IEC-/-) mice and evaluated the in vivo contribution of gut CB1R in alcohol binge-induced intestinal permeability. Results Alcohol binge increased anandamide levels in the proximal small intestine in association with increased intestinal permeability. Radioligand binding and functional assays confirmed that the genetic deletion of intestinal epithelial CB1R did not alter the density or functionality of CB1R in the brain. Additionally, a peripheral CB1R antagonist, (S)-MRI-1891 (INV-202/monlunabant), exhibited comparable binding affinity to CB1R in brain homogenates. An acute oral administration of (S)-MRI-1891 (3 mg/kg) reduced alcohol binge-induced intestinal permeability in littermate control CB1f/f (CB1 floxed/floxed) mice but had no effect in CB1IEC-/- mice, underscoring the role of intestinal CB1R in this phenomenon. Mechanistically, we found that alcohol activated intestinal epithelial CB1R-ERK1/2 pathway with subsequent downregulation of tight junction proteins and reduction in villi length. In addition, targeting intestinal CB1R and downstream ERK1/2 was able to reverse this process, with subsequent upregulation of tight junction proteins and increased villi length, thus improving gut barrier function. Despite the effects on intestinal permeability, deletion of intestinal CB1R did not significantly affect metabolic parameters and liver disease. Conclusion Our findings suggest that alcohol promotes leaky gut via the activation of gut epithelial CB1R and demonstrate that inhibition of CB1R with peripheral-restricted selective CB1R antagonists can prevent alcohol binge-induced intestinal permeability.
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Affiliation(s)
- Luca Maccioni
- Laboratory of Liver Diseases, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, Maryland, USA
- Laboratory of Physiologic Studies, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, Maryland, USA
| | - Szabolcs Dvorácskó
- Laboratory of Physiologic Studies, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, Maryland, USA
- Section on Fibrotic Disorders, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, Maryland, USA
- Section on Medicinal Chemistry, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, Maryland, USA
- Laboratory of Biomolecular Structure and Pharmacology, HUN-REN Biological Research Centre Szeged, Institute of Biochemistry, Szeged, Hungary
| | - Grzegorz Godlewski
- Laboratory of Physiologic Studies, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, Maryland, USA
| | - Resat Cinar
- Section on Fibrotic Disorders, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, Maryland, USA
| | - Malliga R Iyer
- Section on Medicinal Chemistry, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, Maryland, USA
| | - Bin Gao
- Laboratory of Liver Diseases, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, Maryland, USA
| | - George Kunos
- Laboratory of Physiologic Studies, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, Maryland, USA
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18
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Liu H, Ren Q, Gong M, Zuo F, Li Q, Huo D, Yuan Y, Zhang Y, Kong Y, Liu X, Lu C, Wu X. Enforced activation of the CREB/KDM2B axis prevents alcohol-induced embryonic developmental delay. Cell Rep 2024; 43:115075. [PMID: 39661511 DOI: 10.1016/j.celrep.2024.115075] [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: 05/17/2024] [Revised: 10/07/2024] [Accepted: 11/25/2024] [Indexed: 12/13/2024] Open
Abstract
Unintentional, early pregnancy alcohol consumption affects embryonic development. During the peri-implantation stage, coinciding with the transition from naive to primed pluripotency, the long isoform of KDM2B (KDM2BLF) underlies the de novo establishment of polycomb repressive complex (PRC) functions at promoters after fertilization. However, it remains unclear whether and how ethanol exposure affects this spatiotemporal chromatin setting. Here, we show that exposing peri-implantation mouse embryos to ethanol leads to impaired post-implantation development, mirrored by the delayed exit of naive pluripotency in acetaldehyde-treated embryonic stem cells. Remarkably, these abnormalities are linked to inadequate KDM2BLF expression and compromised deposition of PRC marks, which arise from cAMP response element-binding protein (CREB) inactivation. Accordingly, pharmacological activation of CREB effectively restores pluripotency transition partly dependent on KDM2BLF in vitro and ameliorates post-implantation embryonic defects in vivo. Therefore, our study highlights the pivotal role of the CREB/KDM2B axis in chromatin configuration and developmental programming, proposing potential preventive strategies against ethanol exposure-induced detrimental effects.
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Affiliation(s)
- Hang Liu
- State Key Laboratory of Experimental Hematology, the Province and Ministry Co-sponsored Collaborative Innovation Center for Medical Epigenetics, Key Laboratory of Immune Microenvironment and Disease (Ministry of Education), Tianjin Key Laboratory of Medical Epigenetics, Department of Cell Biology, Tianjin Medical University, Qixiangtai Road 22, Tianjin 300070, China
| | - Qiyu Ren
- Department of Genetics, National Research Institute for Family Planning, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100081, China
| | - Meihan Gong
- State Key Laboratory of Experimental Hematology, the Province and Ministry Co-sponsored Collaborative Innovation Center for Medical Epigenetics, Key Laboratory of Immune Microenvironment and Disease (Ministry of Education), Tianjin Key Laboratory of Medical Epigenetics, Department of Cell Biology, Tianjin Medical University, Qixiangtai Road 22, Tianjin 300070, China
| | - Feifei Zuo
- State Key Laboratory of Experimental Hematology, the Province and Ministry Co-sponsored Collaborative Innovation Center for Medical Epigenetics, Key Laboratory of Immune Microenvironment and Disease (Ministry of Education), Tianjin Key Laboratory of Medical Epigenetics, Department of Cell Biology, Tianjin Medical University, Qixiangtai Road 22, Tianjin 300070, China
| | - Qian Li
- State Key Laboratory of Experimental Hematology, the Province and Ministry Co-sponsored Collaborative Innovation Center for Medical Epigenetics, Key Laboratory of Immune Microenvironment and Disease (Ministry of Education), Tianjin Key Laboratory of Medical Epigenetics, Department of Cell Biology, Tianjin Medical University, Qixiangtai Road 22, Tianjin 300070, China
| | - Dawei Huo
- State Key Laboratory of Experimental Hematology, the Province and Ministry Co-sponsored Collaborative Innovation Center for Medical Epigenetics, Key Laboratory of Immune Microenvironment and Disease (Ministry of Education), Tianjin Key Laboratory of Medical Epigenetics, Department of Cell Biology, Tianjin Medical University, Qixiangtai Road 22, Tianjin 300070, China; Bone Marrow Transplantation Center, the First Affiliated Hospital, Zhejiang University School of Medicine, Liangzhu Laboratory, Institute of Hematology, Zhejiang University, Hangzhou 311113, China
| | - Ye Yuan
- State Key Laboratory of Experimental Hematology, the Province and Ministry Co-sponsored Collaborative Innovation Center for Medical Epigenetics, Key Laboratory of Immune Microenvironment and Disease (Ministry of Education), Tianjin Key Laboratory of Medical Epigenetics, Department of Cell Biology, Tianjin Medical University, Qixiangtai Road 22, Tianjin 300070, China
| | - Yutong Zhang
- Department of Genetics, National Research Institute for Family Planning, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100081, China
| | - Yu Kong
- State Key Laboratory of Experimental Hematology, the Province and Ministry Co-sponsored Collaborative Innovation Center for Medical Epigenetics, Key Laboratory of Immune Microenvironment and Disease (Ministry of Education), Tianjin Key Laboratory of Medical Epigenetics, Department of Cell Biology, Tianjin Medical University, Qixiangtai Road 22, Tianjin 300070, China
| | - Xiaozhi Liu
- Tianjin Key Laboratory of Epigenetics for Organ Development of Premature Infants, Tianjin 300450, China
| | - Cailing Lu
- Department of Genetics, National Research Institute for Family Planning, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100081, China.
| | - Xudong Wu
- State Key Laboratory of Experimental Hematology, the Province and Ministry Co-sponsored Collaborative Innovation Center for Medical Epigenetics, Key Laboratory of Immune Microenvironment and Disease (Ministry of Education), Tianjin Key Laboratory of Medical Epigenetics, Department of Cell Biology, Tianjin Medical University, Qixiangtai Road 22, Tianjin 300070, China; Tianjin Key Laboratory of Epigenetics for Organ Development of Premature Infants, Tianjin 300450, China.
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19
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Raya Tonetti F, Eguileor A, Mrdjen M, Pathak V, Travers J, Nagy LE, Llorente C. Gut-liver axis: Recent concepts in pathophysiology in alcohol-associated liver disease. Hepatology 2024; 80:1342-1371. [PMID: 38691396 PMCID: PMC11801230 DOI: 10.1097/hep.0000000000000924] [Citation(s) in RCA: 13] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/13/2024] [Accepted: 04/20/2024] [Indexed: 05/03/2024]
Abstract
The growing recognition of the role of the gut microbiome's impact on alcohol-associated diseases, especially in alcohol-associated liver disease, emphasizes the need to understand molecular mechanisms involved in governing organ-organ communication to identify novel avenues to combat alcohol-associated diseases. The gut-liver axis refers to the bidirectional communication and interaction between the gut and the liver. Intestinal microbiota plays a pivotal role in maintaining homeostasis within the gut-liver axis, and this axis plays a significant role in alcohol-associated liver disease. The intricate communication between intestine and liver involves communication between multiple cellular components in each organ that enable them to carry out their physiological functions. In this review, we focus on novel approaches to understanding how chronic alcohol exposure impacts the microbiome and individual cells within the liver and intestine, as well as the impact of ethanol on the molecular machinery required for intraorgan and interorgan communication.
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Affiliation(s)
| | - Alvaro Eguileor
- Department of Medicine, University of California San Diego, La Jolla, CA, USA
| | - Marko Mrdjen
- Department of Molecular Medicine, Case Western Reserve University, Cleveland, OH
- Department of Inflammation and Immunity, Cleveland Clinic, Cleveland, OH
| | - Vai Pathak
- Department of Quantitative Health Sciences, Cleveland Clinic, Cleveland, Ohio, USA
| | - Jared Travers
- Department of Inflammation and Immunity, Cleveland Clinic, Cleveland, OH
- Department of Gastroenterology and Hepatology, University Hospital, Cleveland OH
| | - Laura E Nagy
- Department of Molecular Medicine, Case Western Reserve University, Cleveland, OH
- Department of Inflammation and Immunity, Cleveland Clinic, Cleveland, OH
- Department of Gastroenterology and Hepatology, Cleveland Clinic, Cleveland OH
| | - Cristina Llorente
- Department of Medicine, University of California San Diego, La Jolla, CA, USA
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Genchi VA, Cignarelli A, Sansone A, Yannas D, Dalla Valentina L, Renda Livraghi D, Spaggiari G, Santi D. Understanding the Role of Alcohol in Metabolic Dysfunction and Male Infertility. Metabolites 2024; 14:626. [PMID: 39590862 PMCID: PMC11596383 DOI: 10.3390/metabo14110626] [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: 10/16/2024] [Revised: 11/08/2024] [Accepted: 11/12/2024] [Indexed: 11/28/2024] Open
Abstract
Purpose: Over the past 40-50 years, demographic shifts and the obesity epidemic have coincided with significant changes in lifestyle habits, including a rise in excessive alcohol consumption. This increase in alcohol intake is a major public health concern due to its far-reaching effects on human health, particularly on metabolic processes and male reproductive function. This narrative review focuses on the role of alcohol consumption in altering metabolism and impairing testicular function, emphasizing the potential damage associated with both acute and chronic alcohol intake. Conclusion: Chronic alcohol consumption has been shown to disrupt liver function, impair lipid metabolism, and dysregulate blood glucose levels, contributing to the development of obesity, metabolic syndrome, and related systemic diseases. In terms of male reproductive health, alcohol can significantly affect testicular function by lowering testosterone levels, reducing sperm quality, and impairing overall fertility. The extent of these effects varies, depending on the frequency, duration, and intensity of alcohol use, with chronic and abusive consumption posing greater risks. The complexity of alcohol's impact is further compounded by individual variability and the interaction with other lifestyle factors such as diet, stress, and physical activity. Despite growing concern, research on alcohol's effects remains inconclusive, with significant discrepancies across studies regarding the definition and reporting of alcohol consumption. These inconsistencies highlight the need for more rigorous, methodologically sound research to better understand how alcohol consumption influences metabolic and reproductive health. Ultimately, a clearer understanding is essential for developing targeted public health interventions, particularly in light of rising alcohol use, demographic changes, and the ongoing obesity crisis.
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Affiliation(s)
- Valentina Annamaria Genchi
- Department of Precision and Regenerative Medicine and Ionian Area-Section of Internal Medicine, Endocrinology, Andrology and Metabolic Diseases, University of Bari Aldo Moro, 70121 Bari, Italy
| | - Angelo Cignarelli
- Department of Precision and Regenerative Medicine and Ionian Area-Section of Internal Medicine, Endocrinology, Andrology and Metabolic Diseases, University of Bari Aldo Moro, 70121 Bari, Italy
| | - Andrea Sansone
- Chair of Endocrinology and Medical Sexology (ENDOSEX), Department of Systems Medicine, University of Rome Tor Vergata, Tower E South, Room E 413, Via Montpellier 1, 00133 Rome, Italy
| | - Dimitri Yannas
- Chair of Endocrinology and Medical Sexology (ENDOSEX), Department of Systems Medicine, University of Rome Tor Vergata, Tower E South, Room E 413, Via Montpellier 1, 00133 Rome, Italy
| | - Leonardo Dalla Valentina
- Department of Biomedical, Metabolic and Neural Sciences, University of Modena and Reggio Emilia, 41121 Modena, Italy (D.S.)
- Unit of Endocrinology, Department of Medical Specialties, Azienda Ospedaliero-Universitaria of Modena, 41125 Modena, Italy
| | - Daniele Renda Livraghi
- Department of Biomedical, Metabolic and Neural Sciences, University of Modena and Reggio Emilia, 41121 Modena, Italy (D.S.)
- Unit of Endocrinology, Department of Medical Specialties, Azienda Ospedaliero-Universitaria of Modena, 41125 Modena, Italy
| | - Giorgia Spaggiari
- Unit of Endocrinology, Department of Medical Specialties, Azienda Ospedaliero-Universitaria of Modena, 41125 Modena, Italy
| | - Daniele Santi
- Department of Biomedical, Metabolic and Neural Sciences, University of Modena and Reggio Emilia, 41121 Modena, Italy (D.S.)
- Unit of Endocrinology, Department of Medical Specialties, Azienda Ospedaliero-Universitaria of Modena, 41125 Modena, Italy
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Liang H, Zhou X, Zhang J, Xu W, Liu Y, Wang X, Hu Y, Xu R, Li X. The therapeutic potential of Apigenin in amyotrophic lateral sclerosis through ALDH1A2/Nrf2/ARE signaling. Mol Med 2024; 30:206. [PMID: 39521994 PMCID: PMC11550557 DOI: 10.1186/s10020-024-00977-7] [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: 07/18/2024] [Accepted: 10/27/2024] [Indexed: 11/16/2024] Open
Abstract
BACKGROUND Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease characterized by motor neuron loss leading to muscle weakness and atrophy. Apigenin (APG), known for its antioxidant properties, holds potential as a therapeutic compound in ALS. METHODS We used the Tg(SOD1*G93A)1Gur/J transgenic mouse model of ALS to investigate the therapeutic effects of APG. Key measured included motor function via the ALSTDI score, molecular markers of oxidative stress (OS) and apoptosis in spinal cord tissues. Techniques used included pathological, Western blotting, flow cytometry, and qRT-PCR to assess the effect of ALDH1A2. RESULTS APG treatment attenuated weight loss and improved motor function scores in ALS mice compared to untreated ALS models. Molecular analyses revealed a significant upregulation of ALDH1A2 in APG-treated groups, along with a reduction in markers of OS and apoptosis. In vitro studies in NSC34 cells further confirmed the protective effects of APG against SOD1*G93A mutation-induced cytotoxicity. In addition, suppression of ALDH1A2 by shRNA exacerbated disease markers that were ameliorated by APG treatment. CONCLUSIONS Our results suggest that APG attenuates the progression of ALS pathology by regulating OS and apoptosis through ALDH1A2. These results support further investigation of APG as a potential therapeutic agent for the treatment of ALS.
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Affiliation(s)
- Huiting Liang
- Department of Neurology, First Affiliated Hospital of Nanchang University, Nanchang, 330006, China
- Institute of Neurology, Jiangxi Academy of Clinical Medical Science, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, 330006, China
- Rare Disease Center, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, 330006, China
- Key Laboratory of Rare Neurological Diseases of Jiangxi Provincial Health Commission, Jiangxi Medical College, Nanchang University, Nanchang, 330006, China
| | - Xinhui Zhou
- Department of Neurosurgery, First Affiliated Hospital of Nanchang University, Nanchang, 330006, China
| | - Jie Zhang
- Department of Neurology, First Affiliated Hospital of Nanchang University, Nanchang, 330006, China
- Institute of Neurology, Jiangxi Academy of Clinical Medical Science, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, 330006, China
- Rare Disease Center, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, 330006, China
- Key Laboratory of Rare Neurological Diseases of Jiangxi Provincial Health Commission, Jiangxi Medical College, Nanchang University, Nanchang, 330006, China
| | - Wenyuan Xu
- Department of Neurology, First Affiliated Hospital of Nanchang University, Nanchang, 330006, China
- Institute of Neurology, Jiangxi Academy of Clinical Medical Science, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, 330006, China
- Rare Disease Center, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, 330006, China
- Key Laboratory of Rare Neurological Diseases of Jiangxi Provincial Health Commission, Jiangxi Medical College, Nanchang University, Nanchang, 330006, China
| | - Yi Liu
- Department of Neurology, First Affiliated Hospital of Nanchang University, Nanchang, 330006, China
- Institute of Neurology, Jiangxi Academy of Clinical Medical Science, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, 330006, China
- Rare Disease Center, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, 330006, China
- Key Laboratory of Rare Neurological Diseases of Jiangxi Provincial Health Commission, Jiangxi Medical College, Nanchang University, Nanchang, 330006, China
| | - Xinxin Wang
- Department of Neurology, Jiangxi Provincial People's Hospital, Nanchang, 330006, China
| | - Yushu Hu
- Department of Neurology, Jiangxi Provincial People's Hospital, Nanchang, 330006, China
| | - Renshi Xu
- Department of Neurology, Jiangxi Provincial People's Hospital, Nanchang, 330006, China.
| | - Xiaobing Li
- Department of Neurology, First Affiliated Hospital of Nanchang University, Nanchang, 330006, China.
- Institute of Neurology, Jiangxi Academy of Clinical Medical Science, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, 330006, China.
- Rare Disease Center, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, 330006, China.
- Key Laboratory of Rare Neurological Diseases of Jiangxi Provincial Health Commission, Jiangxi Medical College, Nanchang University, Nanchang, 330006, China.
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22
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Hur S, Jeong H, Kim K, Kim KH, Kim SH, Lee Y, Nam KT. MIST1 regulates endoplasmic reticulum stress-induced hepatic apoptosis as a candidate marker of fatty liver disease progression. Cell Death Dis 2024; 15:805. [PMID: 39516480 PMCID: PMC11549289 DOI: 10.1038/s41419-024-07217-0] [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: 01/03/2024] [Revised: 10/30/2024] [Accepted: 11/01/2024] [Indexed: 11/16/2024]
Abstract
The liver regenerates after injury; however, prolonged injury can lead to chronic inflammation, fatty liver disease, fibrosis, and cancer. The mechanism involving the complex pathogenesis of the progression of liver injury to chronic liver disease remains unclear. In this study, we investigated the dynamics of gene expression associated with the progression of liver disease. We analyzed changes in gene expression over time in a mouse model of carbon tetrachloride (CCl4)-induced fibrosis using high-throughput RNA sequencing. Prolonged CCl4-induced liver injury increased the expression levels of genes associated with the unfolded protein response (UPR), which correlated with the duration of injury, with substantial, progressive upregulation of muscle, intestine, and stomach expression 1 (Mist1, bhlha15) in the mouse fibrosis model and other liver-damaged tissues. Knockdown of MIST1 in HepG2 cells decreased tribbles pseudokinase 3 (TRIB3) levels and increased apoptosis, consistent with the patterns detected in Mist1-knockout mice. MIST1 expression was confirmed in liver tissues from patients with metabolic dysfunction-associated steatohepatitis and alcoholic steatohepatitis (MASH) and correlated with disease progression. In conclusion, MIST1 is expressed in hepatocytes in response to damage, suggesting a new indicator of liver disease progression. Our results suggest that MIST1 plays a key role in the regulation of apoptosis and TRIB3 expression contributing to progressive liver disease after injury.
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Affiliation(s)
- Sumin Hur
- Severance Biomedical Science Institute, Graduate School of Medical Science, Brain Korea 21 Project, Yonsei University College of Medicine, Seoul, Korea
| | - Haengdueng Jeong
- Severance Biomedical Science Institute, Graduate School of Medical Science, Brain Korea 21 Project, Yonsei University College of Medicine, Seoul, Korea
| | - Keunyoung Kim
- Department of Pharmacy, Kangwon National University College of Pharmacy, Chuncheon, Korea
| | - Kwang H Kim
- Severance Biomedical Science Institute, Graduate School of Medical Science, Brain Korea 21 Project, Yonsei University College of Medicine, Seoul, Korea
| | - Sung Hee Kim
- Severance Biomedical Science Institute, Graduate School of Medical Science, Brain Korea 21 Project, Yonsei University College of Medicine, Seoul, Korea
| | - Yura Lee
- Severance Biomedical Science Institute, Graduate School of Medical Science, Brain Korea 21 Project, Yonsei University College of Medicine, Seoul, Korea
| | - Ki Taek Nam
- Severance Biomedical Science Institute, Graduate School of Medical Science, Brain Korea 21 Project, Yonsei University College of Medicine, Seoul, Korea.
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23
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Yan M, Man S, Ma L, Guo L, Huang L, Gao W. Immunological mechanisms in steatotic liver diseases: An overview and clinical perspectives. Clin Mol Hepatol 2024; 30:620-648. [PMID: 38988278 PMCID: PMC11540396 DOI: 10.3350/cmh.2024.0315] [Citation(s) in RCA: 8] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/28/2024] [Revised: 07/10/2024] [Accepted: 07/10/2024] [Indexed: 07/12/2024] Open
Abstract
Steatotic liver diseases (SLD) are the principal worldwide cause of cirrhosis and end-stage liver cancer, affecting nearly a quarter of the global population. SLD includes metabolic dysfunction-associated alcoholic liver disease (MetALD) and metabolic dysfunction-associated steatotic liver disease (MASLD), resulting in asymptomatic liver steatosis, fibrosis, cirrhosis and associated complications. The immune processes include gut dysbiosis, adiposeliver organ crosstalk, hepatocyte death and immune cell-mediated inflammatory processes. Notably, various immune cells such as B cells, plasma cells, dendritic cells, conventional CD4+ and CD8+ T cells, innate-like T cells, platelets, neutrophils and macrophages play vital roles in the development of MetALD and MASLD. Immunological modulations targeting hepatocyte death, inflammatory reactions and gut microbiome include N-acetylcysteine, selonsertib, F-652, prednisone, pentoxifylline, anakinra, JKB-121, HA35, obeticholic acid, probiotics, prebiotics, antibiotics and fecal microbiota transplantation. Understanding the immunological mechanisms underlying SLD is crucial for advancing clinical therapeutic strategies.
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Affiliation(s)
- Mengyao Yan
- State Key Laboratory of Food Nutrition and Safety, Key Laboratory of Industrial Microbiology, Ministry of Education, Tianjin Key Laboratory of Industry Microbiology, National and Local United Engineering Lab of Metabolic Control Fermentation Technology, China International Science and Technology Cooperation Base of Food Nutrition/Safety and Medicinal Chemistry, College of Biotechnology, Tianjin University of Science & Technology, Tianjin, China
| | - Shuli Man
- State Key Laboratory of Food Nutrition and Safety, Key Laboratory of Industrial Microbiology, Ministry of Education, Tianjin Key Laboratory of Industry Microbiology, National and Local United Engineering Lab of Metabolic Control Fermentation Technology, China International Science and Technology Cooperation Base of Food Nutrition/Safety and Medicinal Chemistry, College of Biotechnology, Tianjin University of Science & Technology, Tianjin, China
| | - Long Ma
- State Key Laboratory of Food Nutrition and Safety, Key Laboratory of Industrial Microbiology, Ministry of Education, Tianjin Key Laboratory of Industry Microbiology, National and Local United Engineering Lab of Metabolic Control Fermentation Technology, China International Science and Technology Cooperation Base of Food Nutrition/Safety and Medicinal Chemistry, College of Biotechnology, Tianjin University of Science & Technology, Tianjin, China
| | - Lanping Guo
- National Resource Center for Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing, China
| | - Luqi Huang
- National Resource Center for Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing, China
| | - Wenyuan Gao
- Tianjin Key Laboratory for Modern Drug Delivery & High-Efficiency, School of Pharmaceutical Science and Technology, Tianjin University, Weijin Road, Tianjin, China
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24
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Shi H, Xu W, Liu Q, Li Y, Dong S, Zhao Z. AKR7A5 knockout promote acute liver injury by inducing inflammatory response, oxidative stress and apoptosis in mice. J Cell Mol Med 2024; 28:e70129. [PMID: 39365156 PMCID: PMC11451264 DOI: 10.1111/jcmm.70129] [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: 01/16/2024] [Revised: 04/22/2024] [Accepted: 09/20/2024] [Indexed: 10/05/2024] Open
Abstract
Alcohol liver disease has become a worldwide critical health problem. The ingested alcohol could be converted into acetaldehyde or combined with free fatty acids to induce the endoplasmic reticulum oxidative stress in the liver. Coincidentally, AKR7A5 has both aldehyde detoxification and antioxidant effects. Therefore, we discuss the possible role and mechanism of AKR7A5 in the acute alcohol injury of mice liver. There were four experiment groups, the C57BL/6 mice of wild-type mice (WT) or AKR7A5-/- mice (KO) were intragastrically administrated with saline or 50% ethanol at 14 mL/kg, respectively. Compared to the WT + alcohol group, abnormal liver function, disordered hepatic cord, severe congestion in the hepatic sinus and the space of the hepatic cord, occurrence of oxidative stress, DNA damage and different expressions of apoptosis-related proteins were detected in the KO + alcohol group. Meanwhile, the biological process enrichment analysis showed that the down-regulated proteins were related to the metabolism of fatty acid, the up-regulated proteins positive regulation of reactive oxygen species metabolic process, negative regulation of coagulation and haemostasis. In conclusion, single ethanol binge combined with the absence of AKR7A5 caused more severe inflammatory response, oxidative stress, apoptosis of endogenous pathways, abnormal lipids metabolism and disordered coagulation in mice liver.
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Affiliation(s)
- Hui Shi
- College of Life ScienceYantai UniversityYantaiChina
| | - Wenda Xu
- College of Life ScienceYantai UniversityYantaiChina
| | - Qingling Liu
- College of Life ScienceYantai UniversityYantaiChina
| | - Yan Li
- College of Life ScienceYantai UniversityYantaiChina
| | - Silin Dong
- College of Life ScienceYantai UniversityYantaiChina
| | - Zhenjun Zhao
- College of Life ScienceYantai UniversityYantaiChina
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25
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Kim SY, Oh KJ, Seo YR, Kim YW, Song PH, Song CH. Comparative Study on Hepatoprotective Effects of Traditional Herbs, Roots of Angelica gigas Nakai, Glycyrrhiza uralensis Fischer, Zizyphus jujuba Mill., and Fruits of Paeonia lactiflora Pall., on Ethanol-Induced Liver Injury in Mice. Antioxidants (Basel) 2024; 13:1137. [PMID: 39334796 PMCID: PMC11428478 DOI: 10.3390/antiox13091137] [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: 07/26/2024] [Revised: 09/10/2024] [Accepted: 09/18/2024] [Indexed: 09/30/2024] Open
Abstract
Alcohol-associated liver disease (ALD) is a major cause of chronic liver disease, with few effective treatments besides alcohol abstinence. Angelicae Gigantis Radix (AG), Glycyrrhizae Radix et Rhizoma (GR), Paeoniae Radix (PR), and Zizyphi Fructus (ZF) are traditional herbs used to treat various ailments, including liver diseases. While several studies have reported the beneficial effects of GR on ALD, the effects of AG, PR, and ZF remain underexplored. Therefore, their efficacy and mechanisms against ALD were investigated using an alcohol-related liver injury model. The model was induced by ethanol gavage in C57BL/6J mice for 14 days, followed by oral administration of AG, GR, PR, and ZF one hour post-induction. The administration of these herbs reduced liver weight, and improved serum biomarkers of liver injury (ALT, AST, albumin). The herbs enhanced hepatic antioxidant capacity (GSH, SOD, catalase) and suppressed the production of proinflammatory cytokines (TNF-α, IL-1β) and apoptotic changes (caspase-3). The mechanisms of action involved lipid-lowering gene modulation through regulation of the cytochrome P450 2E1/Sirtuin 1/Nrf2 pathways. Histopathological and immunohistochemical analyses revealed that these herbs attenuated hepatocyte damage and steatosis via antioxidant, anti-inflammatory, and antiapoptotic effects. These findings suggest that traditional herbs, particularly AG, could be promising alternative therapies for treating ALD.
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Affiliation(s)
- So-Yeon Kim
- Research Center for Herbal Convergence on Liver Disease, Gyeongsan 38610, Republic of Korea
| | - Kyung-Jin Oh
- Department of Urology, Chonnam National University Hospital, Chonnam National University Medical School, Gwangju 61469, Republic of Korea
| | - Yu-Ri Seo
- Research Center for Herbal Convergence on Liver Disease, Gyeongsan 38610, Republic of Korea
| | - Young-Woo Kim
- Department of Herbal Prescription, School of Korean Medicine, Dongguk University, Gyeongju 38066, Republic of Korea
| | - Phil Hyun Song
- Department of Urology, College of Medicine, Yeungnam University, Daegu 42415, Republic of Korea
| | - Chang-Hyun Song
- Research Center for Herbal Convergence on Liver Disease, Gyeongsan 38610, Republic of Korea
- Department of Anatomy and Histology, College of Korean Medicine, Daegu Haany University, Gyeongsan 38610, Republic of Korea
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26
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Liu M, Guo J, Lu J, Chen Y, Deng X, Zhang S, Guan S. Capsaicin alleviates acute alcohol-induced pyroptosis by activating ESCRT-III-dependent cell membrane repair in hepatocytes. Food Funct 2024; 15:8395-8407. [PMID: 39036891 DOI: 10.1039/d4fo00806e] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 07/23/2024]
Abstract
Capsaicin (CAP), the active ingredient in hot chilli peppers, has anti-inflammatory and hepatoprotection effects. Acute alcoholic liver injury (AALI) is liver damage caused by acute alcohol abuse, which can lead to severe liver lesions and even be life-threatening. Pyroptosis is inflammation-related programmed cell death characterized by membrane rupture and plays a key role in AALI. The endosomal sorting complexes required for transport (ESCRT) proteins can gather at damaged areas of the membrane to facilitate the process of sealing the membrane. In this study, we found that CAP could relieve acute alcohol-induced pyroptosis of hepatocytes in vitro and in vivo. Mechanically, we found that CAP could alleviate acute alcohol-induced pyroptosis by activating the ESCRT-III-dependent membrane repair machinery. Furthermore, the data showed that CAP induced ESCRT-III protein expression by activating transient receptor potential vanilloid member 1 (TRPV1) on the cell membrane and Ca2+ influx. TRPV1 inhibitor capsazepine (CPZ) inhibited the relief effect of CAP on acute alcohol-induced pyroptosis. Overall, these results showed that CAP might activate ESCRT-III-dependent membrane repair machinery through Ca2+ influx, which is regulated by TRPV1 calcium channels, therefore mitigating acute alcohol-induced pyroptosis. Our research provides a new perspective on a naturally active food product to promote cell repair and relieve AALI.
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Affiliation(s)
- Meitong Liu
- College of Food Science and Engineering, Jilin University, Changchun, Jilin 130012, China.
| | - Jiakang Guo
- College of Food Science and Engineering, Jilin University, Changchun, Jilin 130012, China.
| | - Jing Lu
- College of Food Science and Engineering, Jilin University, Changchun, Jilin 130012, China.
| | - Yuelin Chen
- College of Food Science and Engineering, Jilin University, Changchun, Jilin 130012, China.
| | - Xuming Deng
- State Key Laboratory for Zoonotic Diseases, Key Laboratory for Zoonosis Research, Ministry of Education, College of Veterinary Medicine, Jilin University, Changchun 130012, China
| | - Shengzhuo Zhang
- College of Food Science and Engineering, Jilin University, Changchun, Jilin 130012, China.
| | - Shuang Guan
- College of Food Science and Engineering, Jilin University, Changchun, Jilin 130012, China.
- State Key Laboratory for Zoonotic Diseases, Key Laboratory for Zoonosis Research, Ministry of Education, College of Veterinary Medicine, Jilin University, Changchun 130012, China
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27
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Zheng QX, Liu QL, Sun WN, Jiang XY, Zeng T. Biphasic effects of ethanol consumption on N,N-dimethylformamide-induced liver injury in mice. Toxicology 2024; 506:153872. [PMID: 38924947 DOI: 10.1016/j.tox.2024.153872] [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: 05/13/2024] [Revised: 06/19/2024] [Accepted: 06/24/2024] [Indexed: 06/28/2024]
Abstract
N,N-Dimethylformamide (DMF) is a well-documented occupational hazardous material, which can induce occupational liver injury. The current study was designed to investigate whether ethanol consumption can affect DMF-induced hepatotoxicity and the potential underlying mechanisms involved. We found that a single dose of ethanol (1.25, 2.5, or 5 g/kg bw by gavage) significantly repressed the increase in serum alanine transaminase (ALT) and aspartate transaminase (AST) activities and alleviated the liver histopathological changes in mice challenged with 3 g/kg DMF. In contrast, long-term moderate drinking (2.5 g/kg bw) significantly aggravated the repeated DMF (0.7 g/kg bw) exposure-induced increase in the serum ALT and AST activities. Mechanistically, acute ethanol consumption suppressed DMF-induced activation of the NLR family pyrin domain-containing protein 3 (NLRP3) inflammasome, while long-term moderate ethanol consumption promoted hepatocyte apoptosis in the mouse liver. Notably, cytochrome P4502E1 (CYP2E1) protein level and activity in mouse livers were not significantly affected by ethanol per se in the two models. These results confirm that regular drinking can increase the risk of DMF-induced hepatotoxicity, and suggest that DMF-handling workers should avoid consuming ethanol to reduce the risk of DMF-indued liver injury.
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Affiliation(s)
- Qing-Xiang Zheng
- School of Public Health, Cheeloo College of Medicine, Shandong University, Jinan, Shandong 250012, China
| | - Qing-Lin Liu
- School of Public Health, Cheeloo College of Medicine, Shandong University, Jinan, Shandong 250012, China
| | - Wen-Na Sun
- School of Public Health, Cheeloo College of Medicine, Shandong University, Jinan, Shandong 250012, China
| | - Xin-Yu Jiang
- School of Public Health, Cheeloo College of Medicine, Shandong University, Jinan, Shandong 250012, China
| | - Tao Zeng
- Institute of Toxicology, School of Public Health, Cheeloo College of Medicine, Shandong University, Jinan, Shandong 250012, China.
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28
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Yang Z, Gao H, Ma J, Liang NA, Liang SP, Huda N, Jiang Y, Thoudam T, Tu W, Su J, Hesler M, Chandler K, Liangpunsakul S. Unique urine and serum metabolomic signature in patients with excessive alcohol use: An exploratory study. ALCOHOL, CLINICAL & EXPERIMENTAL RESEARCH 2024; 48:1519-1528. [PMID: 38951043 DOI: 10.1111/acer.15398] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/31/2024] [Revised: 06/02/2024] [Accepted: 06/04/2024] [Indexed: 07/03/2024]
Abstract
BACKGROUND Excessive alcohol consumption has a multifaceted impact on the body's metabolic pathways and organ systems. The objectives of this study were to characterize global metabolomic changes and identify specific pathways that are altered in individuals with excessive alcohol use. METHODS This exploratory study included 22 healthy controls with no known history of excessive alcohol use and 38 patients identified as using alcohol excessively. A Fibrosis-4 score was used to determine the risk of underlying alcohol-associated liver disease among the excessive drinkers. RESULTS We found significantly altered urinary and serum metabolites among excessive drinkers, affecting various metabolic pathways including the metabolism of lipids, amino acids and peptides, cofactors and vitamins, carbohydrates, and nucleotides. Levels of two steroid hormones-5alpha-androstan-3beta,17beta-diol disulfate and androstenediol (3beta,17beta) disulfate-were significantly higher in both the serum and urine samples of excessive drinkers. These elevated levels may be associated with a higher risk of liver fibrosis in individuals with excessive alcohol use. CONCLUSION Alcohol consumption leads to marked alterations in multiple metabolic pathways, highlighting the systemic impact of alcohol on various tissues and organ systems. These findings provide a foundation for future mechanistic studies aimed at elucidating alcohol-induced changes in these metabolic pathways and their implications.
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Affiliation(s)
- Zhihong Yang
- Division of Gastroenterology and Hepatology, Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana, USA
| | - Hui Gao
- Division of Gastroenterology and Hepatology, Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana, USA
| | - Jing Ma
- Division of Gastroenterology and Hepatology, Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana, USA
| | | | | | - Nazmul Huda
- Division of Gastroenterology and Hepatology, Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana, USA
| | - Yanchao Jiang
- Division of Gastroenterology and Hepatology, Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana, USA
| | - Themis Thoudam
- Division of Gastroenterology and Hepatology, Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana, USA
| | - Wanzhu Tu
- Department of Biostatistics and Health Data Science, Richard M. Fairbanks School of Public Health, Indiana University, Indianapolis, Indiana, USA
| | - Jing Su
- Department of Biostatistics and Health Data Science, Richard M. Fairbanks School of Public Health, Indiana University, Indianapolis, Indiana, USA
| | - Maggie Hesler
- Division of Gastroenterology and Hepatology, Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana, USA
| | - Kristina Chandler
- Division of Gastroenterology and Hepatology, Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana, USA
| | - Suthat Liangpunsakul
- Division of Gastroenterology and Hepatology, Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana, USA
- Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, Indiana, USA
- Roudebush Veterans Administration Medical Center, Indianapolis, Indiana, USA
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Wang D, Zhou BY, Xiang L, Chen XY, Feng JX. Alanine aminotransferase as a risk marker for new-onset metabolic dysfunction-associated fatty liver disease. World J Gastroenterol 2024; 30:3132-3139. [PMID: 39006380 PMCID: PMC11238669 DOI: 10.3748/wjg.v30.i25.3132] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/06/2024] [Revised: 05/07/2024] [Accepted: 06/13/2024] [Indexed: 07/01/2024] Open
Abstract
In this editorial, we comment on the article by Chen et al. Metabolic dysfunction-associated fatty liver disease (MAFLD) is a global public health burden whose incidence has risen concurrently with overweight and obesity. Given its detrimental health impact, early identification of at-risk individuals is crucial. MAFLD diagnosis is based on evidence of hepatic steatosis indicated by liver biopsy, imaging, or blood biomarkers, and one of the following conditions: Overweight/ obesity, type 2 diabetes mellitus, or metabolic dysregulation. However, in large-scale epidemiological studies, liver biopsies are not feasible. The application of techniques such as ultrasonography, computed tomography, magnetic resonance imaging, and magnetic resonance spectroscopy is restricted by their limited sensitivity, low effectiveness, high costs, and need for specialized software. Blood biomarkers offer several advantages, particularly in large-scale epidemiological studies or clinical scenarios where traditional imaging techniques are impractical. Analysis of cumulative effects of excess high-normal blood alanine aminotransferase (ALT) levels of blood ALT levels could facilitate identification of at-risk patients who might not be detected through conventional imaging methods. Accordingly, investigating the utility of blood biomarkers in MAFLD should enhance early detection and monitoring, enabling timely intervention and management and improving patient outcomes.
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Affiliation(s)
- Di Wang
- Department of Pediatric Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, Hubei Province, China
| | - Bing-Yan Zhou
- Department of Pediatric Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, Hubei Province, China
| | - Lei Xiang
- Department of Pediatric Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, Hubei Province, China
| | - Xu-Yong Chen
- Department of Pediatric Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, Hubei Province, China
| | - Jie-Xiong Feng
- Department of Pediatric Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, Hubei Province, China
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Wang X, Sun Z, Wang X, Li M, Zhou B, Zhang X. Solanum nigrum L. berries extract ameliorated the alcoholic liver injury by regulating gut microbiota, lipid metabolism, inflammation, and oxidative stress. Food Res Int 2024; 188:114489. [PMID: 38823872 DOI: 10.1016/j.foodres.2024.114489] [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: 02/08/2024] [Revised: 05/02/2024] [Accepted: 05/07/2024] [Indexed: 06/03/2024]
Abstract
Solanum nigrum L. (SN) berry is an edible berry containing abundant polyphenols and bioactive compounds, which possess antioxidant and antiinflammatory properties. However, the effects of SN on alcohol-induced biochemical changes in the enterohepatic axis remain unclear. In the current study, a chronic ethanol-fed mice ALD model was used to test the protective mechanisms of SN berries. Microbiota composition was determined via 16S rRNA sequencing, we found that SN berries extract (SNE) improved intestinal imbalance by reducing the Firmicutes to Bacteroides ratio, restoring the abundance of Akkermansia microbiota, and reducing the abundance of Allobaculum and Shigella. SNE restored the intestinal short-chain fatty acids content. In addition, liver transcriptome data analysis revealed that SNE primarily affected the genes involved in lipid metabolism and inflammatory responses. Furthermore, SNE ameliorated hepatic steatosis in alcohol-fed mice by activating AMP-activated protein kinase (AMPK), acetyl-CoA carboxylase (ACC), peroxisome proliferator-activated receptor α (PPAR-α). SNE reduced the expression of toll-like receptor 4 (TLR4), myeloid differentiation factor-88 (MyD88) nuclear factor kappa-B (NF-κB), which can indicate that SNE mainly adjusted LPS/TLR4/MyD88/NF-κB pathway to reduce liver inflammation. SNE enhanced hepatic antioxidant capacity by regulating NRF2-related protein expression. SNE alleviates alcoholic liver injury by regulating of gut microbiota, lipid metabolism, inflammation, and oxidative stress. This study may provide a reference for the development and utilization of SN resources.
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Affiliation(s)
- Xueying Wang
- School of Functional Food and Wine, Shenyang Pharmaceutical University, Shenyang 110016, People's Republic of China
| | - Ziqi Sun
- School of Functional Food and Wine, Shenyang Pharmaceutical University, Shenyang 110016, People's Republic of China
| | - Xiaoli Wang
- School of Functional Food and Wine, Shenyang Pharmaceutical University, Shenyang 110016, People's Republic of China
| | - Minjie Li
- School of Functional Food and Wine, Shenyang Pharmaceutical University, Shenyang 110016, People's Republic of China
| | - Boru Zhou
- School of Functional Food and Wine, Shenyang Pharmaceutical University, Shenyang 110016, People's Republic of China
| | - Xiaoshu Zhang
- School of Functional Food and Wine, Shenyang Pharmaceutical University, Shenyang 110016, People's Republic of China.
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Fu Y, Mackowiak B, Lin YH, Maccioni L, Lehner T, Pan H, Guan Y, Godlewski G, Lu H, Chen C, Wei S, Feng D, Paloczi J, Zhou H, Pacher P, Zhang L, Kunos G, Gao B. Coordinated action of a gut-liver pathway drives alcohol detoxification and consumption. Nat Metab 2024; 6:1380-1396. [PMID: 38902331 DOI: 10.1038/s42255-024-01063-2] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/24/2023] [Accepted: 05/07/2024] [Indexed: 06/22/2024]
Abstract
Alcohol use disorder (AUD) affects millions of people worldwide, causing extensive morbidity and mortality with limited pharmacological treatments. The liver is considered as the principal site for the detoxification of ethanol metabolite, acetaldehyde (AcH), by aldehyde dehydrogenase 2 (ALDH2) and as a target for AUD treatment, however, our recent data indicate that the liver only plays a partial role in clearing systemic AcH. Here we show that a liver-gut axis, rather than liver alone, synergistically drives systemic AcH clearance and voluntary alcohol drinking. Mechanistically, we find that after ethanol intake, a substantial proportion of AcH generated in the liver is excreted via the bile into the gastrointestinal tract where AcH is further metabolized by gut ALDH2. Modulating bile flow significantly affects serum AcH level and drinking behaviour. Thus, combined targeting of liver and gut ALDH2, and manipulation of bile flow and secretion are potential therapeutic strategies to treat AUD.
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Affiliation(s)
- Yaojie Fu
- Laboratory of Liver Diseases, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD, USA
| | - Bryan Mackowiak
- Laboratory of Liver Diseases, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD, USA
| | - Yu-Hong Lin
- Laboratory of Liver Diseases, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD, USA
| | - Luca Maccioni
- Laboratory of Liver Diseases, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD, USA
- Laboratory of Physiologic Studies, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD, USA
| | - Taylor Lehner
- Laboratory of Liver Diseases, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD, USA
| | - Hongna Pan
- Laboratory of Liver Diseases, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD, USA
| | - Yukun Guan
- Laboratory of Liver Diseases, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD, USA
| | - Grzegorz Godlewski
- Laboratory of Physiologic Studies, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD, USA
| | - Hongkun Lu
- Laboratory of Liver Diseases, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD, USA
| | - Cheng Chen
- Laboratory of Liver Diseases, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD, USA
- Laboratory of Physiologic Studies, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD, USA
| | - Shoupeng Wei
- Laboratory for Integrative Neuroscience, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD, USA
| | - Dechun Feng
- Laboratory of Liver Diseases, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD, USA
| | - Janos Paloczi
- Laboratory of Cardiovascular Physiology and Tissue Injury, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD, USA
| | - Huiping Zhou
- Department of Microbiology and Immunology, Virginia Commonwealth University and Richmond Veterans Affairs Medical Center, Richmond, VA, USA
| | - Pal Pacher
- Laboratory of Cardiovascular Physiology and Tissue Injury, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD, USA
| | - Li Zhang
- Laboratory for Integrative Neuroscience, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD, USA
| | - George Kunos
- Laboratory of Physiologic Studies, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD, USA
| | - Bin Gao
- Laboratory of Liver Diseases, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD, USA.
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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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Feng D, Hwang S, Guillot A, Wang Y, Guan Y, Chen C, Maccioni L, Gao B. Inflammation in Alcohol-Associated Hepatitis: Pathogenesis and Therapeutic Targets. Cell Mol Gastroenterol Hepatol 2024; 18:101352. [PMID: 38697358 PMCID: PMC11234022 DOI: 10.1016/j.jcmgh.2024.04.009] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/09/2024] [Revised: 04/25/2024] [Accepted: 04/25/2024] [Indexed: 05/05/2024]
Abstract
Alcohol-associated hepatitis (AH) is an acute-on-chronic liver injury that occurs in patients with chronic alcohol-associated liver disease (ALD). Patients with severe AH have high short-term mortality and lack effective pharmacologic therapies. Inflammation is believed to be one of the key factors promoting AH progression and has been actively investigated as therapeutic targets over the last several decades, but no effective inflammatory targets have been identified so far. In this review, we discuss how inflammatory cells and the inflammatory mediators produced by these cells contribute to the development and progression of AH, with focus on neutrophils and macrophages. The crosstalk between inflammatory cells and liver nonparenchymal cells in the pathogenesis of AH is elaborated. We also deliberate the application of recent cutting-edge technologies in characterizing liver inflammation in AH. Finally, the potential therapeutic targets of inflammatory mediators for AH are briefly summarized.
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Affiliation(s)
- Dechun Feng
- Laboratory of Liver Diseases, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, Maryland.
| | - Seonghwan Hwang
- College of Pharmacy and Research Institute for Drug Development, Pusan National University, Busan, Republic of Korea
| | - Adrien Guillot
- Department of Hepatology and Gastroenterology, Charité Universitätsmedizin Berlin, Berlin, Germany
| | - Yang Wang
- Laboratory of Liver Diseases, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, Maryland
| | - Yukun Guan
- Laboratory of Liver Diseases, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, Maryland
| | - Cheng Chen
- Laboratory of Liver Diseases, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, Maryland
| | - Luca Maccioni
- Laboratory of Liver Diseases, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, Maryland
| | - Bin Gao
- Laboratory of Liver Diseases, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, Maryland.
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Ma X, Niu M, Ni HM, Ding WX. Mitochondrial dynamics, quality control, and mtDNA in alcohol-associated liver disease and liver cancer. Hepatology 2024:01515467-990000000-00861. [PMID: 38683546 DOI: 10.1097/hep.0000000000000910] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/24/2024] [Accepted: 04/05/2024] [Indexed: 05/01/2024]
Abstract
Mitochondria are intracellular organelles responsible for energy production, glucose and lipid metabolism, cell death, cell proliferation, and innate immune response. Mitochondria are highly dynamic organelles that constantly undergo fission, fusion, and intracellular trafficking, as well as degradation and biogenesis. Mitochondrial dysfunction has been implicated in a variety of chronic liver diseases including alcohol-associated liver disease, metabolic dysfunction-associated steatohepatitis, and HCC. In this review, we provide a detailed overview of mitochondrial dynamics, mitophagy, and mitochondrial DNA-mediated innate immune response, and how dysregulation of these mitochondrial processes affects the pathogenesis of alcohol-associated liver disease and HCC. Mitochondrial dynamics and mitochondrial DNA-mediated innate immune response may thereby represent an attractive therapeutic target for ameliorating alcohol-associated liver disease and alcohol-associated HCC.
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Affiliation(s)
- Xiaowen Ma
- Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City, Kansas, USA
| | - Mengwei Niu
- Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City, Kansas, USA
| | - Hong-Min Ni
- Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City, Kansas, USA
| | - Wen-Xing Ding
- Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City, Kansas, USA
- Department of Internal Medicine, Division of Gastroenterology, Hepatology and Mobility, University of Kansas Medical Center, Kansas City, Kansas, USA
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35
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Shen Y, Zhao Y, Zhong C, Huang H, Yang Z, Wu M, Lu L, Yang R, Ke X. Primary study on the effects and mechanisms of separate and combined decoctions of Scutellaria baicalensis Georgi - Coptis chinensis Franch extracts in relieving acute alcoholic liver injury in rats. JOURNAL OF ETHNOPHARMACOLOGY 2024; 324:117790. [PMID: 38253276 DOI: 10.1016/j.jep.2024.117790] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/10/2023] [Revised: 01/04/2024] [Accepted: 01/16/2024] [Indexed: 01/24/2024]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE Scutellaria baicalensis Georgi (SBG) and Coptis chinensis Franch (CCF) are traditional herbal medicine pairs used for clearing heat and eliminating dampness, stopping diarrhea, and detoxification. Traditionally, these two herbs are combined and decocted together, but the modern preparation procedures separate them to avoid the large amount of precipitation generated from co-decoction. Thus, a conflict lies between the traditional and modern extraction processes of Scutellaria baicalensis Georgi - Coptis chinensis Franch (SBG-CCF). AIM OF STUDY There is a conflict between traditional medical practices of SBG-CCF and the modern formulation industry. In this study, we investigated the differences in the effects and mechanisms of SBG-CCF extracted by decocting separately and combining decoctions, as well as the scientific effectiveness of traditional and modern treatment methods on both. Acute alcoholic liver injury (ALI) rats were used as the pathological model. MATERIALS AND METHODS SD rats were divided into 8 groups, including blank group, model group, low, medium, and high dose groups of SBG-CCF separated decoction, low, medium, and high dose groups of SBG-CCF combined decoction. Acute alcoholic liver injury model was induced in rats by gradually increasing the dose of alcohol through gavage everyday using white wine with an alcohol content 52%. Aspartate aminotransferase (AST), alanine aminotransferase (ALT), total cholesterol (TC), triglyceride (TG), lactate dehydrogenase (LDH), malondialdehyde (MDA), superoxide dismutase (SOD), and reduced glutathione (GSH) were used as indicators to assess the intervention effect of SBG-CCF. And the potential active ingredients of SBG-CCF and the targets related to ALI were screened using network pharmacology, and the prediction results of network pharmacology were verified by quantitative real-time fluorescence PCR (qRT-PCR). RESULTS SBG-CCF decoction alone and six combinations of decoctions have different degrees of improvement on alcoholic liver injury, with significant efficacy in the middle-dose group, and the combined decoction was superior to the individual decoction. SBG-CCF gavage can reduce the activity of AST, ALT, TC, TG, LDH, and MDA in the serum and liver of ALI rats, while increasing the levels of SOD and GSH. Network pharmacological analysis identified 39 active components, mainly flavonoids and alkaloids. Enrichment analysis suggested that SBG-CCF may treat ALI through the regulation of tumor necrosis factor (TNF), mitogen-activated protein kinase (MAPK), interleukin-17 (IL-17), apoptosis, and the Toll-like receptor signaling pathways. The key targets in the Disease-Signaling Pathway-Target Network were MAPK8, IKBKB, MAPK10, MAPK3, MAPK1, and AKT1. qRT-PCR results indicated that targets regulating inflammation and lipid metabolism are MAPK8, MAPK10, MAPK3, and AKT1. CONCLUSION SBG-CCF separately extracts and combines decoction can alleviate acute alcoholic liver injury, and the effect of combined decoction is more significant than separate decoction, implying that the precipitate produced by the combination of the two is also an active substance. The resistance mechanism of SBG-CCF ALI may be related to the modulation of lipid metabolism, inhibition of lipid peroxidation, and oxidative stress. SBG-CCF has the characteristics of multi-component, multi-pathway, and multi-target resistance to ALI.
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Affiliation(s)
- Yingyan Shen
- Key Laboratory Breeding Base of Systematic Research and Utilization on Chinese Meterial, Medical Resources Co-founded by Sichuan Province and Ministry of Science and Technology, Chengdu University of Traditional Chinese Medicine, Chendu, China
| | - Yixin Zhao
- Key Laboratory Breeding Base of Systematic Research and Utilization on Chinese Meterial, Medical Resources Co-founded by Sichuan Province and Ministry of Science and Technology, Chengdu University of Traditional Chinese Medicine, Chendu, China
| | - Chunxue Zhong
- Chongqing Key Laboratory of Chinese Medicine New Drug Screening, Southwest University, Chongqing, China
| | - Hanmei Huang
- Chongqing Key Laboratory of Chinese Medicine New Drug Screening, Southwest University, Chongqing, China
| | - Zaiqing Yang
- Chongqing Key Laboratory of Chinese Medicine New Drug Screening, Southwest University, Chongqing, China
| | - Mingxing Wu
- Chongqing Key Laboratory of Chinese Medicine New Drug Screening, Southwest University, Chongqing, China
| | - Lingzhi Lu
- Chongqing Key Laboratory of Chinese Medicine New Drug Screening, Southwest University, Chongqing, China
| | - Rongping Yang
- Chongqing Key Laboratory of Chinese Medicine New Drug Screening, Southwest University, Chongqing, China.
| | - Xiumei Ke
- College of Pharmacy, Chongqing Medical University, Chongqing, China.
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Abstract
Alcohol-associated liver disease (ALD) is a major cause of chronic liver disease worldwide, and comprises a spectrum of several different disorders, including simple steatosis, steatohepatitis, cirrhosis, and superimposed hepatocellular carcinoma. Although tremendous progress has been made in the field of ALD over the last 20 years, the pathogenesis of ALD remains obscure, and there are currently no FDA-approved drugs for the treatment of ALD. In this Review, we discuss new insights into the pathogenesis and therapeutic targets of ALD, utilizing the study of multiomics and other cutting-edge approaches. The potential translation of these studies into clinical practice and therapy is deliberated. We also discuss preclinical models of ALD, interplay of ALD and metabolic dysfunction, alcohol-associated liver cancer, the heterogeneity of ALD, and some potential translational research prospects for ALD.
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Walter MN, Montoya-Durango D, Rodriguez W, Wang Y, Zhang J, Chariker JH, Rouchka EC, Maldonado C, Bennett A, McClain CJ, Barve S, Gobejishvili L. Hepatocyte-specific mitogen-activated protein kinase phosphatase 1 in sexual dimorphism and susceptibility to alcohol induced liver injury. Front Immunol 2024; 15:1316228. [PMID: 38370409 PMCID: PMC10871047 DOI: 10.3389/fimmu.2024.1316228] [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: 10/10/2023] [Accepted: 01/03/2024] [Indexed: 02/20/2024] Open
Abstract
Background It is well established that females are more susceptible to the toxic effects of alcohol, although the exact mechanisms are still poorly understood. Previous studies noted that alcohol reduces the expression of mitogen-activated protein kinase phosphatase 1 (MKP1), a negative regulator of mitogen-activated protein kinases (MAPK) in the liver. However, the role of hepatocyte- specific MKP1 in the pathogenesis of alcohol-associated liver disease (ALD) remains uncharacterized. This study aimed to evaluate the role of hepatocyte-specific MKP1 in the susceptibility and sexual dimorphism in alcohol-induced liver injury. Methods C57Bl/6 mice were used in an intragastric ethanol feeding model of alcohol-associated steatohepatitis (ASH). Hepatocyte-specific Mkp1-/- knockout and (Mkp1+/+ "f/f" male and female mice were subjected to the NIAAA chronic plus binge model. Primary mouse hepatocytes were used for in vitro studies. Liver RNA sequencing was performed on an Illumina NextSeq 500. Liver injury was evaluated by plasma alanine transaminase (ALT), hepatic ER stress and inflammation markers. Statistical analysis was carried out using ANOVA and the unpaired Student's t-test. Results ASH was associated with the severe injury accompanied by increased endoplasmic reticulum (ER) stress and significant downregulation of Dusp1 mRNA expression. In vitro, ethanol treatment resulted in a time-dependent decrease in Dusp1 mRNA and protein expression in primary hepatocytes in both males and females; however, this effect was significantly more pronounced in hepatocytes from females. In vivo, female mice developed more liver injury in a chronic plus binge model which was accompanied by a significant decrease in liver Dusp1 mRNA expression. In comparison, liver Dusp1 was not changed in male mice, while they developed milder injury to alcohol. Mkp1 deletion in hepatocytes led to increased alcohol induced liver injury, ER stress and inflammation in both sexes. Conclusion Hepatocyte Mkp1 plays a significant role in alcohol induced liver injury. Alcohol downregulates Mkp1 expression in hepatocytes in a sex dependent manner and could play a role in sexual dimorphism in increased female susceptibility to alcohol.
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Affiliation(s)
- Mary Nancy Walter
- Department of Physiology, School of Medicine, University of Louisville, Louisville, KY, United States
| | - Diego Montoya-Durango
- Department of Physiology, School of Medicine, University of Louisville, Louisville, KY, United States
| | - Walter Rodriguez
- Department of Physiology, School of Medicine, University of Louisville, Louisville, KY, United States
| | - Yali Wang
- Department of Physiology, School of Medicine, University of Louisville, Louisville, KY, United States
| | - JingWen Zhang
- Department of Medicine, School of Medicine, University of Louisville, Louisville, KY, United States
| | - Julia H. Chariker
- Department of Neuroscience Training, University of Louisville, Louisville, KY, United States
- Kentucky IDeA Networks of Biomedical Research Excellence, (KY INBRE) Bioinformatics Core, University of Louisville, Louisville, KY, United States
| | - Eric C. Rouchka
- Kentucky IDeA Networks of Biomedical Research Excellence, (KY INBRE) Bioinformatics Core, University of Louisville, Louisville, KY, United States
- Department of Biochemistry and Molecular Genetics, University of Louisville, Louisville, KY, United States
| | - Claudio Maldonado
- Department of Physiology, School of Medicine, University of Louisville, Louisville, KY, United States
| | - Anton Bennett
- Department of Pharmacology, Yale University School of Medicine, New Haven, CT, United States
| | - Craig James McClain
- Department of Medicine, School of Medicine, University of Louisville, Louisville, KY, United States
- Robley Rex Veterans Affairs (VA) Medical Center, Louisville, KY, United States
- Department of Pharmacology and Toxicology, University of Louisville, Louisville, KY, United States
- Alcohol Research Center, University of Louisville, Louisville, KY, United States
- Hepatobiology and Toxicology Center, University of Louisville, Louisville, KY, United States
| | - Shirish Barve
- Department of Medicine, School of Medicine, University of Louisville, Louisville, KY, United States
- Alcohol Research Center, University of Louisville, Louisville, KY, United States
- Hepatobiology and Toxicology Center, University of Louisville, Louisville, KY, United States
| | - Leila Gobejishvili
- Department of Physiology, School of Medicine, University of Louisville, Louisville, KY, United States
- Department of Medicine, School of Medicine, University of Louisville, Louisville, KY, United States
- Alcohol Research Center, University of Louisville, Louisville, KY, United States
- Hepatobiology and Toxicology Center, University of Louisville, Louisville, KY, United States
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Warner JB, Hardesty JE, Song YL, Floyd AT, Deng Z, Jebet A, He L, Zhang X, McClain CJ, Hammock BD, Warner DR, Kirpich IA. Hepatic Transcriptome and Its Regulation Following Soluble Epoxide Hydrolase Inhibition in Alcohol-Associated Liver Disease. THE AMERICAN JOURNAL OF PATHOLOGY 2024; 194:71-84. [PMID: 37925018 PMCID: PMC10768534 DOI: 10.1016/j.ajpath.2023.09.016] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/08/2023] [Revised: 09/02/2023] [Accepted: 09/27/2023] [Indexed: 11/06/2023]
Abstract
Alcohol-associated liver disease (ALD) is a serious public health problem with limited pharmacologic options. The goal of the current study was to investigate the efficacy of pharmacologic inhibition of soluble epoxide hydrolase (sEH), an enzyme involved in lipid metabolism, in experimental ALD, and to examine the underlying mechanisms. C57BL/6J male mice were subjected to acute-on-chronic ethanol (EtOH) feeding with or without the sEH inhibitor 4-[[trans-4-[[[[4-trifluoromethoxy phenyl]amino]carbonyl]-amino]cyclohexyl]oxy]-benzoic acid (TUCB). Liver injury was assessed by multiple end points. Liver epoxy fatty acids and dihydroxy fatty acids were measured by targeted metabolomics. Whole-liver RNA sequencing was performed, and free modified RNA bases were measured by mass spectrometry. EtOH-induced liver injury was ameliorated by TUCB treatment as evidenced by reduced plasma alanine aminotransferase levels and was associated with attenuated alcohol-induced endoplasmic reticulum stress, reduced neutrophil infiltration, and increased numbers of hepatic M2 macrophages. TUCB altered liver epoxy and dihydroxy fatty acids and led to a unique hepatic transcriptional profile characterized by decreased expression of genes involved in apoptosis, inflammation, fibrosis, and carcinogenesis. Several modified RNA bases were robustly changed by TUCB, including N6-methyladenosine and 2-methylthio-N6-threonylcarbamoyladenosine. These findings show the beneficial effects of sEH inhibition by TUCB in experimental EtOH-induced liver injury, warranting further mechanistic studies to explore the underlying mechanisms, and highlighting the translational potential of sEH as a drug target for this disease.
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Affiliation(s)
- Jeffrey B Warner
- Division of Gastroenterology, Hepatology, and Nutrition, Department of Medicine, University of Louisville School of Medicine, Louisville, Kentucky; Department of Pharmacology and Toxicology, University of Louisville School of Medicine, Louisville, Kentucky
| | - Josiah E Hardesty
- Division of Gastroenterology, Hepatology, and Nutrition, Department of Medicine, University of Louisville School of Medicine, Louisville, Kentucky; Department of Pharmacology and Toxicology, University of Louisville School of Medicine, Louisville, Kentucky
| | - Ying L Song
- Division of Gastroenterology, Hepatology, and Nutrition, Department of Medicine, University of Louisville School of Medicine, Louisville, Kentucky
| | - Alison T Floyd
- Division of Gastroenterology, Hepatology, and Nutrition, Department of Medicine, University of Louisville School of Medicine, Louisville, Kentucky
| | - Zhongbin Deng
- Division of Immunotherapy, Department of Surgery, University of Louisville, Louisville, Kentucky; Brown Cancer Center, University of Louisville, Louisville, Kentucky
| | - Audriy Jebet
- Department of Chemistry, University of Louisville, Louisville, Kentucky
| | - Liqing He
- Department of Chemistry, University of Louisville, Louisville, Kentucky
| | - Xiang Zhang
- Department of Chemistry, University of Louisville, Louisville, Kentucky
| | - Craig J McClain
- Division of Gastroenterology, Hepatology, and Nutrition, Department of Medicine, University of Louisville School of Medicine, Louisville, Kentucky; Department of Pharmacology and Toxicology, University of Louisville School of Medicine, Louisville, Kentucky; University of Louisville Alcohol Center, University of Louisville School of Medicine, Louisville, Kentucky; University of Louisville Hepatobiology & Toxicology Center, University of Louisville School of Medicine, Louisville, Kentucky; Robley Rex Veterans Medical Center, Louisville, Kentucky
| | - Bruce D Hammock
- Department of Entomology and Nematology, Comprehensive Cancer Center, University of California, Davis, California
| | - Dennis R Warner
- Division of Gastroenterology, Hepatology, and Nutrition, Department of Medicine, University of Louisville School of Medicine, Louisville, Kentucky
| | - Irina A Kirpich
- Division of Gastroenterology, Hepatology, and Nutrition, Department of Medicine, University of Louisville School of Medicine, Louisville, Kentucky; Department of Pharmacology and Toxicology, University of Louisville School of Medicine, Louisville, Kentucky; University of Louisville Alcohol Center, University of Louisville School of Medicine, Louisville, Kentucky; University of Louisville Hepatobiology & Toxicology Center, University of Louisville School of Medicine, Louisville, Kentucky; Department of Microbiology and Immunology, University of Louisville School of Medicine, Louisville, Kentucky.
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Robea MA, Balmus IM, Girleanu I, Huiban L, Muzica C, Ciobica A, Stanciu C, Cimpoesu CD, Trifan A. Coagulation Dysfunctions in Non-Alcoholic Fatty Liver Disease-Oxidative Stress and Inflammation Relevance. MEDICINA (KAUNAS, LITHUANIA) 2023; 59:1614. [PMID: 37763733 PMCID: PMC10535217 DOI: 10.3390/medicina59091614] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/02/2023] [Revised: 08/29/2023] [Accepted: 09/04/2023] [Indexed: 09/29/2023]
Abstract
Non-alcoholic fatty liver disease (NAFLD) is one of the most common liver diseases. Its incidence is progressively rising and it is possibly becoming a worldwide epidemic. NAFLD encompasses a spectrum of diseases accounting for the chronic accumulation of fat within the hepatocytes due to various causes, excluding excessive alcohol consumption. In this study, we aimed to focus on finding evidence regarding the implications of oxidative stress and inflammatory processes that form the multifaceted pathophysiological tableau in relation to thrombotic events that co-occur in NAFLD and associated chronic liver diseases. Recent evidence on the pathophysiology of NAFLD suggests that a complex pattern of multidirectional components, such as prooxidative, proinflammatory, and prothrombotic components, better explains the multiple factors that promote the mechanisms underlying the fatty acid excess and subsequent processes. As there is extensive evidence on the multi-component nature of NAFLD pathophysiology, further studies could address the complex interactions that underlie the development and progression of the disease. Therefore, this study aimed to describe possible pathophysiological mechanisms connecting the molecular impairments with the various clinical manifestations, focusing especially on the interactions among oxidative stress, inflammation, and coagulation dysfunctions. Thus, we described the possible bidirectional modulation among coagulation homeostasis, oxidative stress, and inflammation that occurs in the various stages of NAFLD.
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Affiliation(s)
- Madalina Andreea Robea
- CENEMED Platform for Interdisciplinary Research, “Grigore T. Popa” University of Medicine and Pharmacy, 700115 Iasi, Romania; (M.A.R.); (I.-M.B.); (C.D.C.)
| | - Ioana-Miruna Balmus
- CENEMED Platform for Interdisciplinary Research, “Grigore T. Popa” University of Medicine and Pharmacy, 700115 Iasi, Romania; (M.A.R.); (I.-M.B.); (C.D.C.)
- Department of Exact Sciences and Natural Sciences, Institute of Interdisciplinary Research, “Alexandru Ioan Cuza” University of Iasi, Alexandru Lapusneanu Street, No. 26, 700057 Iasi, Romania
| | - Irina Girleanu
- Department of Gastroenterology, “Grigore T. Popa” University of Medicine and Pharmacy, 700115 Iasi, Romania; (I.G.); (L.H.); (C.M.); (A.T.)
- Institute of Gastroenterology and Hepatology, “St. Spiridon” University Hospital, 700111 Iasi, Romania
| | - Laura Huiban
- Department of Gastroenterology, “Grigore T. Popa” University of Medicine and Pharmacy, 700115 Iasi, Romania; (I.G.); (L.H.); (C.M.); (A.T.)
- Institute of Gastroenterology and Hepatology, “St. Spiridon” University Hospital, 700111 Iasi, Romania
| | - Cristina Muzica
- Department of Gastroenterology, “Grigore T. Popa” University of Medicine and Pharmacy, 700115 Iasi, Romania; (I.G.); (L.H.); (C.M.); (A.T.)
- Institute of Gastroenterology and Hepatology, “St. Spiridon” University Hospital, 700111 Iasi, Romania
| | - Alin Ciobica
- Department of Biology, Faculty of Biology, “Alexandru Ioan Cuza” University, Carol I Avenue, No. 20A, 700505 Iasi, Romania
- Centre of Biomedical Research, Romanian Academy, Carol I Avenue, No. 8, 700506 Iasi, Romania;
- Academy of Romanian Scientists, Splaiul Independentei nr. 54, Sector 5, 050094 Bucuresti, Romania
| | - Carol Stanciu
- Centre of Biomedical Research, Romanian Academy, Carol I Avenue, No. 8, 700506 Iasi, Romania;
| | - Carmen Diana Cimpoesu
- CENEMED Platform for Interdisciplinary Research, “Grigore T. Popa” University of Medicine and Pharmacy, 700115 Iasi, Romania; (M.A.R.); (I.-M.B.); (C.D.C.)
- Department of Emergency Medicine, Emergency County Hospital “Sf. Spiridon”, 700111 Iasi, Romania
- Faculty of Medicine, University of Medicine and Pharmacy “Grigore T. Popa” Iasi, Blvd. Independentei 1, 700111 Iasi, Romania
| | - Anca Trifan
- Department of Gastroenterology, “Grigore T. Popa” University of Medicine and Pharmacy, 700115 Iasi, Romania; (I.G.); (L.H.); (C.M.); (A.T.)
- Institute of Gastroenterology and Hepatology, “St. Spiridon” University Hospital, 700111 Iasi, Romania
- Centre of Biomedical Research, Romanian Academy, Carol I Avenue, No. 8, 700506 Iasi, Romania;
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Wang H, Shen H, Seo W, Hwang S. Experimental models of fatty liver diseases: Status and appraisal. Hepatol Commun 2023; 7:e00200. [PMID: 37378635 DOI: 10.1097/hc9.0000000000000200] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/24/2023] [Accepted: 05/16/2023] [Indexed: 06/29/2023] Open
Abstract
Fatty liver diseases, including alcohol-associated liver disease (ALD) and nonalcoholic fatty liver disease nonalcoholic fatty liver disease (NAFLD), affect a large number of people worldwide and become one of the major causes of end-stage liver disease, such as liver cirrhosis and hepatocellular carcinoma (HCC). Unfortunately, there are currently no approved pharmacological treatments for ALD or NAFLD. This situation highlights the urgent need to explore new intervention targets and discover effective therapeutics for ALD and NAFLD. The lack of properly validated preclinical disease models is a major obstacle to the development of clinical therapies. ALD and NAFLD models have been in the development for decades, but there are still no models that recapitulate the full spectrum of ALD and NAFLD. Throughout this review, we summarize the current in vitro and in vivo models used for research on fatty liver diseases and discuss the advantages and limitations of these models.
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Affiliation(s)
- Hua Wang
- Department of Oncology, The First Affiliated Hospital of Anhui Medical University, Hefei, China
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Medical University, Hefei, China
| | - Haiyuan Shen
- Department of Oncology, The First Affiliated Hospital of Anhui Medical University, Hefei, China
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Medical University, Hefei, China
| | - Wonhyo Seo
- Laboratory of Hepatotoxicity, College of Pharmacy, Ewha Womans University, Seoul, Republic of Korea
| | - Seonghwan Hwang
- College of Pharmacy and Research Institute for Drug Development, Pusan National University, Busan, Republic of Korea
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41
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Anton P, Rutt LN, Twardy SM, McCullough RL. Fatty Acid Ethyl Ethers: New Modulators of Acute Ethanol-Mediated Hepatotoxicity? Cell Mol Gastroenterol Hepatol 2022; 15:505-506. [PMID: 36435276 PMCID: PMC9880973 DOI: 10.1016/j.jcmgh.2022.11.002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/25/2022] [Revised: 10/28/2022] [Accepted: 11/03/2022] [Indexed: 11/24/2022]
Affiliation(s)
| | | | | | - Rebecca L McCullough
- Skaggs School of Pharmacy and Pharmaceutical Sciences, GI and Liver Innate Immune Program, School of Medicine, CU Alcohol Research Program, University of Colorado Anschutz Medical Campus, Aurora, Colorado.
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