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Ma C, Cheng X, Hu M, Wang W, Guo W, Li S. The role of bioactive compounds in the management of metabolic and alcohol-related liver disease. Life Sci 2025; 373:123660. [PMID: 40287054 DOI: 10.1016/j.lfs.2025.123660] [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: 03/07/2025] [Revised: 04/12/2025] [Accepted: 04/21/2025] [Indexed: 04/29/2025]
Abstract
Metabolic and alcohol-related liver disease (MetALD) is a newly defined category within the spectrum of steatotic liver diseases, designed to capture the interplay between metabolic dysfunction and alcohol consumption more effectively. Bioactive compounds, celebrated for their potent antioxidant, anti-inflammatory, and hepatoprotective properties, have emerged as promising therapeutic agents for the management of MetALD. This review comprehensively examines the underlying mechanisms by which these compounds exert their effects, including the modulation of oxidative stress pathways, the enhancement of lipid metabolism, and the promotion of liver regeneration. Specific bioactive constituents, such as polyphenols, flavonoids, and omega-3 fatty acids, have demonstrated potential in ameliorating hepatic steatosis and fibrosis associated with MetALD. Incorporating these natural compounds into treatment regimens presents a novel strategy for managing MetALD, with significant implications for both lifestyle modifications and pharmacological interventions. Future research should prioritize clinical trials, improvements in bioavailability, and investigations into the synergistic effects of multi-compound formulations to establish effective and sustainable treatment strategies for MetALD.
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Affiliation(s)
- Chang Ma
- School of Public Health, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China
| | - Xi Cheng
- School of Public Health, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China
| | - Min Hu
- Department of Pharmacy, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430074, China
| | - Wanyu Wang
- Department of Pharmacy, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430074, China
| | - Wei Guo
- Department of Pharmacy, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430074, China.
| | - Sha Li
- School of Public Health, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China.
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Madesh S, Gopi S, Ramamurthy K, Srivasan M, Kumaradoss KM, Shiny M, Elsadek MF, Elshikh MS, Arokiyaraj S, Chitra V, Vedula GS, Arockiaraj J. Development and evaluation of chitosan conjugated Isatin-linked Pyrazole derivative to target anti-inflammatory and anti-fibrotic in ethanol induced liver fibrosis using an in-vivo zebra fish model. Bioorg Chem 2025; 162:108584. [PMID: 40393354 DOI: 10.1016/j.bioorg.2025.108584] [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: 01/29/2025] [Revised: 05/09/2025] [Accepted: 05/11/2025] [Indexed: 05/22/2025]
Abstract
Alcoholic liver disease (ALD) remains a health burden, characterized by hepatic steatosis to fibrosis, a significant contributor to global morbidity and mortality, with limited therapeutic options for advanced stages like liver fibrosis. This study explores the antifibrotic and anti-inflammatory potential of a novel isatin-linked pyrazole derivative (3F) conjugated with chitosan-EDTA (CS) in mitigating ethanol (EtOH) induced liver fibrosis in zebrafish model. We demonstrated hepatic fibrosis using a chronic low-dose EtOH model (0.2 %), mimicking the ALD stage. CS-3F conjugates were synthesized using ionotropic gelation, exhibiting optimal drug-loading capacity, sustained drug release, and enhanced bioavailability. Morphological characterization revealed particle sizes ranging from 50 to 300 nm, facilitating efficient cellular uptake and liver-targeted drug distribution. EtOH exposure significantly elevated hepatic biomarkers (ALT, AST, and ALP), disrupted lipid metabolism (TC and TG), and impaired detoxification functions (ammonia and urea metabolism). Oxidative stress and inflammation were evident, with decreased SOD and CAT levels, increased MDA and LDH levels, and upregulation of pro-inflammatory and fibrotic genes (il-1β, tnfα, tgf-β, col1a1, and fasn). Treatment with CS-3F significantly ameliorated these alterations, restoring metabolic, detoxification, antioxidant functions and significantly reducing inflammation and fibrosis. Histopathological analysis confirmed improvements in liver architecture, including reduced parenchymal damage and ECM deposition. These results highlight the utility of CS-3F in reversing fibrosis and restoring liver function, offering a promising avenue for addressing the unmet therapeutic needs in ALD. However, further studies are needed to validate these findings in mammalian models and elucidate the underlying molecular mechanisms.
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Affiliation(s)
- S Madesh
- Toxicology and Pharmacology Laboratory, Department of Biotechnology, Faculty of Science and Humanities, SRM Institute of Science and Technology, Kattankulathur, 603203, Chengalpattu District, Tamil Nadu, India
| | - Sanjay Gopi
- Toxicology and Pharmacology Laboratory, Department of Biotechnology, Faculty of Science and Humanities, SRM Institute of Science and Technology, Kattankulathur, 603203, Chengalpattu District, Tamil Nadu, India
| | - Karthikeyan Ramamurthy
- Toxicology and Pharmacology Laboratory, Department of Biotechnology, Faculty of Science and Humanities, SRM Institute of Science and Technology, Kattankulathur, 603203, Chengalpattu District, Tamil Nadu, India
| | - Mukil Srivasan
- Toxicology and Pharmacology Laboratory, Department of Biotechnology, Faculty of Science and Humanities, SRM Institute of Science and Technology, Kattankulathur, 603203, Chengalpattu District, Tamil Nadu, India
| | - Kathiravan Muthu Kumaradoss
- Dr APJ Abdul Kalam Research Lab, Department of Pharmaceutical Chemistry, SRM College of Pharmacy, SRM Institute of Science and Technology, Kattankulathur, 603203, Chengalpattu District, Tamil Nadu, India
| | - Marapatla Shiny
- Department of Pharmaceutical Chemistry, AU College of Pharmaceutical Sciences, Andhra University, Visakhapatnam, 530003, Andhra Pradesh, India
| | - Mohamed Farouk Elsadek
- Department of Biochemistry, College of Science, King Saud University, P.O. 2455, Riyadh, 11451, Saudi Arabia
| | - Mohamed S Elshikh
- Department of Botany and Microbiology, College of Science, King Saud University, P.O. 2455, Riyadh, 11451, Saudi Arabia
| | - Selvaraj Arokiyaraj
- Department of Food Science and Biotechnology, Sejong University, Seoul, 05006, Republic of Korea
| | - Vellapandian Chitra
- Department of Pharmacology, SRM College of Pharmacy, SRM Institute of Science and Technology, Kattankulathur, 603203, Chengalpattu District, Tamil Nadu, India.
| | - Girija Sastry Vedula
- Department of Pharmaceutical Chemistry, AU College of Pharmaceutical Sciences, Andhra University, Visakhapatnam, 530003, Andhra Pradesh, India.
| | - Jesu Arockiaraj
- Toxicology and Pharmacology Laboratory, Department of Biotechnology, Faculty of Science and Humanities, SRM Institute of Science and Technology, Kattankulathur, 603203, Chengalpattu District, Tamil Nadu, India.
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Song S, Ning L, Yu J. Elucidating the causal relationship between gut microbiota, metabolites, and diabetic nephropathy in European patients: Revelations from genome-wide bidirectional mendelian randomization analysis. Front Endocrinol (Lausanne) 2025; 15:1391891. [PMID: 39845884 PMCID: PMC11750691 DOI: 10.3389/fendo.2024.1391891] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/26/2024] [Accepted: 12/17/2024] [Indexed: 01/24/2025] Open
Abstract
Objective Previous observational studies suggest a potential link between gut microbiota, metabolites, and diabetic nephropathy. However, the exact causal relationship among these factors remains unclear. Method We conducted a two-sample bidirectional Mendelian randomization study using summary statistics from the IEU OpenGWAS Project database to investigate gut microbiota, metabolites, and diabetic nephropathy. A range of methods, including inverse variance weighting, MR-Egger, weighted median, and simple median, were applied to examine causal associations. Sensitivity analyses were performed to assess the robustness of the results. Additionally, reverse Mendelian randomization analysis was conducted, treating significant gut microbiota as the outcome, to evaluate effects and perform sensitivity testing. This comprehensive approach provided an in-depth assessment of the interactions among gut microbiota, metabolites, and diabetic nephropathy. Result The Inverse Variance Weighted estimates revealed that the abundance of Lachnospiraceae, Parasutterella, and Eubacterium exhibited negative causal effects on diabetic nephropathy, while Coprococcus, Sutterella, Faecalibacterium prausnitzii, and Bacteroides vulgatus showed protective causal effects against the condition. However, reverse Mendelian randomization analysis did not identify any significant associations between diabetic nephropathy and the identified gut microbiota. Furthermore, the estimates indicated that Cholesterol, Pyridoxate, Hexanoylcarnitine, X-12007, Octanoylcarnitine, 10-nonadecenoate (19:1n9), X-12734, and the average number of double bonds in a fatty acid chain had negative causal effects on diabetic nephropathy. In contrast, Methionine, Glycodeoxycholate, X-06351, 1-stearoylglycerol (1-monostearin), 5-dodecenoate (12:1n7), X-13859, 2-hydroxyglutarate, Glycoproteins, Phospholipids in IDL, and the concentration of small HDL particles demonstrated protective causal effects. Notably, sensitivity analyses did not detect any heterogeneity or horizontal pleiotropy, ensuring the robustness of the findings. Conclusion Modulating gut microbiota diversity and composition offers a promising strategy for improving the incidence and prognosis of diabetic nephropathy. This highlights the need for future clinical trials focusing on microbiome-based interventions, potentially utilizing microbiome-dependent metabolites. Such approaches could transform the treatment and management of diabetic nephropathy and its associated risk factors, paving the way for more effective therapeutic strategies to combat this debilitating condition.
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Affiliation(s)
- Siyuan Song
- Department of Endocrinology, Jiangsu Province Hospital of Chinese Medicine, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, China
| | - Li Ning
- Department of Gynecology, Jiangsu Provincial Hospital of Traditional Chinese Medicine, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, China
| | - Jiangyi Yu
- Department of Endocrinology, Jiangsu Province Hospital of Chinese Medicine, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, China
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Overstreet AMC, Burge M, Bellar A, McMullen M, Czarnecki D, Huang E, Pathak V, Finney C, Vij R, Dasarathy S, Dasarathy J, Streem D, Welch N, Rotroff D, Schmitt AM, Nagy LE, Messer JS. Evidence that extracellular HSPB1 contributes to inflammation in alcohol-associated hepatitis. MEDRXIV : THE PREPRINT SERVER FOR HEALTH SCIENCES 2024:2024.09.06.24313193. [PMID: 39281760 PMCID: PMC11398598 DOI: 10.1101/2024.09.06.24313193] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 09/18/2024]
Abstract
Background and aims Alcohol-associated hepatitis (AH) is the most life-threatening form of alcohol-associated liver disease (ALD). AH is characterized by severe inflammation attributed to increased levels of ethanol, microbes or microbial components, and damage-associated molecular pattern (DAMP) molecules in the liver. HSPB1 (Heat Shock Protein Family B (Small) Member 1; also known as Hsp25/27) is a DAMP that is rapidly increased in and released from cells experiencing stress, including hepatocytes. The goal of this study was to define the role of HSPB1 in AH pathophysiology. Methods Serum HSPB1 was measured in a retrospective study of 184 heathy controls (HC), heavy alcohol consumers (HA), patients with alcohol-associated cirrhosis (AC), and patients with AH recruited from major hospital centers. HSPB1 was also retrospectively evaluated in liver tissue from 10 HC and AH patients and an existing liver RNA-seq dataset. Finally, HSPB1 was investigated in a murine Lieber-DeCarli diet model of early ALD as well as cellular models of ethanol stress in hepatocytes and hepatocyte-macrophage communication during ethanol stress. Results Circulating HSPB1 was significantly increased in AH patients and levels positively correlated with disease-severity scores. Likewise, HSPB1 was increased in the liver of patients with severe AH and in the liver of ethanol-fed mice. In vitro , ethanol-stressed hepatocytes released HSPB1, which then triggered TNFα-mediated inflammation in macrophages. Anti-HSPB1 antibody prevented TNFα release from macrophages exposed to media conditioned by ethanol-stressed hepatocytes. Conclusions Our findings support investigation of HSPB1 as both a biomarker and therapeutic target in ALD. Furthermore, this work demonstrates that anti-HSPB1 antibody is a rational approach to targeting HSPB1 with the potential to block inflammation and protect hepatocytes, without inactivating host defense. GRAPHICAL ABSTRACT HIGHLIGHTS HSPB1 is significantly increased in serum and liver of patients with alcohol-associated hepatitis.Ethanol consumption leads to early increases in HSPB1 in the mouse liver.Hepatocytes subjected to ethanol stress release HSPB1 into the extracellular environment where it activates TNFα-mediated inflammation in macrophages.Anti-HSPB1 antibody blocks hepatocyte-triggered TNFα in a model of hepatocyte-macrophage communication during ethanol stress.
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Yang Y, Tong M, de la Monte SM. Early-Stage Moderate Alcohol Feeding Dysregulates Insulin-Related Metabolic Hormone Expression in the Brain: Potential Links to Neurodegeneration Including Alzheimer's Disease. J Alzheimers Dis Rep 2024; 8:1211-1228. [PMID: 39247872 PMCID: PMC11380283 DOI: 10.3233/adr-240026] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2024] [Accepted: 08/01/2024] [Indexed: 09/10/2024] Open
Abstract
Background Alzheimer's disease (AD), one of the most prevalent causes of dementia, is mainly sporadic in occurrence but driven by aging and other cofactors. Studies suggest that excessive alcohol consumption may increase AD risk. Objective Our study examined the degree to which short-term moderate ethanol exposure leads to molecular pathological changes of AD-type neurodegeneration. Methods Long Evans male and female rats were fed for 2 weeks with isocaloric liquid diets containing 24% or 0% caloric ethanol (n = 8/group). The frontal lobes were used to measure immunoreactivity to AD biomarkers, insulin-related endocrine metabolic molecules, and proinflammatory cytokines/chemokines by duplex or multiplex enzyme-linked immunosorbent assays (ELISAs). Results Ethanol significantly increased frontal lobe levels of phospho-tau, but reduced Aβ, ghrelin, glucagon, leptin, PAI, IL-2, and IFN-γ. Conclusions Short-term effects of chronic ethanol feeding produced neuroendocrine molecular pathologic changes reflective of metabolic dysregulation, together with abnormalities that likely contribute to impairments in neuroplasticity. The findings suggest that chronic alcohol consumption rapidly establishes a platform for impairments in energy metabolism that occur in both the early stages of AD and alcohol-related brain degeneration.
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Affiliation(s)
- Yiwen Yang
- Molecular Pharmacology, Physiology and Biotechnology Graduate Program, Brown University, Providence, RI, USA
| | - Ming Tong
- Department of Medicine, Rhode Island Hospital, Lifespan Academic Institutions, and the Warren Alpert Medical School of Brown University, Providence, RI, USA
| | - Suzanne M. de la Monte
- Department of Medicine, Rhode Island Hospital, Lifespan Academic Institutions, and the Warren Alpert Medical School of Brown University, Providence, RI, USA
- Department of Pathology and Laboratory Medicine, Rhode Island Hospital, Lifespan Academic Institutions, the Providence VA Medical Center, and the Warren Alpert Medical School of Brown University, Providence, RI, USA
- Departments of Neurology and Neurosurgery, Rhode Island Hospital, and the Warren Alpert Medical School of Brown University, Providence, RI, USA
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Kumar H, Dhanjal DS, Guleria S, Nepovimova E, Sethi N, Dhalaria R, Kuca K. Hepatoprotective effects of fruits pulp, seed, and peel against chemical-induced toxicity: Insights from in vivo studies. Food Chem Toxicol 2024; 189:114742. [PMID: 38754807 DOI: 10.1016/j.fct.2024.114742] [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: 03/24/2024] [Revised: 05/11/2024] [Accepted: 05/13/2024] [Indexed: 05/18/2024]
Abstract
The liver is a vital organ in human physiology positioned in the upper right quadrant of the peritoneal cavity, which plats a critical role in metabolic processes, detoxification of various substances and overall homeostasis. Along with these critical functions, hepatic diseases impose as significant global health threat. Liver illness is the cause of two million fatalities every year, or 4% of all deaths. Traditionally, healthcare providers have prescribed antibacterial and antiviral medications to address liver illness. Nephrotoxicity is a frequently observed negative reaction to drugs, with the majority of such events happening in individuals who have advanced cirrhosis. Thus, recognizing this gap, there is a dire need of exploration of pharmaceutical alterative for hepatic diseases, with special focus on their efficacy and reduced toxicity. Fruits have long been known to therapeutic impact on human health, thus exploration of fruits components namely pulp, seeds and peels containing phytochemicals have emerged as a promising avenue for hepatoprotective interventions. Thus, review comprehends the information about worldwide burden of chemical induced toxicity and injuries as well as highlight the on-going challenges in hepatic disease management. It also shed light on the valuable contributions fruit parts and their phytocompounds obtained from different components of fruits. Fruit pulp, especially when rich in flavonoids, has demonstrated significant potential in animal model studies. It has been observed to enhance the activity of antioxidant enzymes and reduce the expression of pro-inflammatory markers. The methanolic and ethanolic extracts have demonstrated the most favorable outcomes. Further, this review also discusses about the safety assessments of fruits extracts for their utilization as hepatoprotective agents.
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Affiliation(s)
- Harsh Kumar
- Centre of Advanced Technologies, Faculty of Science, University of Hradec Kralove, Rokitanskeho 62, 50003, Hradec Kralove, Czech Republic
| | - Daljeet Singh Dhanjal
- School of Bioengineering and Biosciences, Lovely Professional University, Phagwara, Punjab, 144411, India
| | - Shivani Guleria
- Department of Biotechnology, TIFAC-Centre of Relevance and Excellence in Agro and Industrial Biotechnology (CORE), Thapar Institute of Engineering and Technology, Patiala, 147001, India.
| | - Eugenie Nepovimova
- Department of Chemistry, Faculty of Science, University of Hradec Kralove, 50003, Hradec Kralove, Czech Republic
| | - Nidhi Sethi
- Department of Pharmaceutical Sciences, Guru Nanak Dev University, Amritsar, 143005, India
| | - Rajni Dhalaria
- School of Biological and Environmental Sciences, Shoolini University of Biotechnology and Management Sciences, Solan, 173229, India.
| | - Kamil Kuca
- Department of Chemistry, Faculty of Science, University of Hradec Kralove, 50003, Hradec Kralove, Czech Republic.
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Liu S, Ge X, Xu X, Zhang K, Lu X. Alterations of Gut Microbiota in Pyogenic Liver Abscess Patients with and without Type 2 Diabetes Mellitus. Infect Drug Resist 2024; 17:2149-2158. [PMID: 38828371 PMCID: PMC11144416 DOI: 10.2147/idr.s456423] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2023] [Accepted: 05/08/2024] [Indexed: 06/05/2024] Open
Abstract
Purpose The clinical manifestations of pyogenic liver abscess (PLA) vary between patients with and without diabetes mellitus (DM). However, the relationship between PLA and the gut microbiome remains unknown. This study analyzed the composition of gut microbiota in PLA patients with and without DM and healthy controls (HCs) with the goal of identifying potential reasons for the observed variations in clinical manifestations. Patients and Methods Using 16S ribosomal RNA(16S rRNA) gene sequencing, we analyzed the compositions of gut microbiota in 32 PLA patients with DM, 32 PLA patients without DM, and 29 matched HCs. Results In PLA patients with DM, the D-dimer level, fibrinogen degradation products, and thrombin time were significantly higher compared to the PLA patients without DM (P < 0.05). The abundance and diversity of intestinal flora were reduced in both groups of PLA patients compared with the HCs (P < 0.05). Specifically, the PLA patients with DM showed significant decreases in the relative abundances of Bacteroides, Blautia, Prevotella9, and Faecalibacterium, whereas Enterococcus and Escherichia-Shigella were relatively more abundant (P < 0.05). Compared to PLA patients without DM, those with DM had lower relative abundances of Lactobacillus and Klebsiella (P < 0.05) and showed different bacterial flora, including Anaerosporobacter and Megamonas. Conclusion PLA patients with DM exhibited more severe clinical manifestations of PLA compared to patients without DM. It is important to monitor blood coagulation in PLA patients with DM to prevent the development of thrombotic diseases. Additionally, PLA patients with DM exhibit distinct differences in the composition and diversity of their intestinal flora compared to both PLA patients without DM and HCs.
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Affiliation(s)
- Shanshan Liu
- Department of Laboratory Medicine, Beijing Tongren Hospital, Capital Medical University, Beijing, People’s Republic of China
- Department of Infection Management, The Affiliated Lianyungang Hospital of Xuzhou Medical University, The First People’s Hospital of Lianyungang, Jiangsu, People’s Republic of China
| | - Xiaomeng Ge
- Microbial Resources and Big Data Center, Institute of Microbiology, Chinese Academy of Sciences, Beijing, People’s Republic of China
| | - Xizhan Xu
- Beijing Institute of Ophthalmology, Beijing Tongren Eye Center, Beijing Tongren Hospital, Capital Medical University, Beijing, People’s Republic of China
| | - Kang Zhang
- Department of Laboratory Medicine, Beijing Tongren Hospital, Capital Medical University, Beijing, People’s Republic of China
| | - Xinxin Lu
- Department of Laboratory Medicine, Beijing Tongren Hospital, Capital Medical University, Beijing, People’s Republic of China
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Choubey P, Sharma V, Joshi R, Upadhyaya A, Kumar D, Patial V. Hydroethanolic extract of Gentiana kurroo Royle rhizome ameliorates ethanol-induced liver injury by reducing oxidative stress, inflammation and fibrogenesis in rats. JOURNAL OF ETHNOPHARMACOLOGY 2024; 325:117866. [PMID: 38350504 DOI: 10.1016/j.jep.2024.117866] [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: 09/21/2023] [Revised: 01/30/2024] [Accepted: 02/03/2024] [Indexed: 02/15/2024]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE Gentiana kurroo Royle is a medicinal plant mentioned as Traymana in Ayurveda. In the folklore, it is used to cure fever, stomach ache, skin diseases and liver disorders. However, limited reports are available on the therapeutic potential of Gentiana kurroo Royle against alcohol-induced liver damage. AIM OF THE STUDY To assess the effectiveness of the hydroethanolic extract of Gentiana kurroo Royle rhizome (GKRE) against alcohol-induced liver injury and explore the mechanism of action. MATERIALS AND METHODS GKRE was characterized using UHPLC-QTOF-MS/MS. The binding affinity of the identified compound was studied in silico. In vitro studies were performed in the Huh-7 cell line. An acute oral toxicity study (2 g/kg BW) of GKRE was done in rats following OECD 420 guidelines. In the efficacy study, rats were treated with 50% ethanol (5 mL/kg BW, orally) for 4 weeks, followed by a single intraperitoneal dose of CCl4 (30%; 1 mL/kg BW) to induce liver injury. After 4th week, the rats were treated with GKRE at 100, 200 and 400 mg/kg BW doses for the next fifteen days. The biochemical and antioxidant parameters were analyzed using commercial kits and a biochemistry analyzer. Histopathology, gene and protein expressions were studied using qRT PCR and western blotting. RESULTS Thirteen compounds were detected in GKRE. Few compounds showed a strong interaction with the fibrotic and inflammatory proteins in silico. GKRE reduced (p < 0.05) the ethanol-induced ROS production and inflammation in Huh-7 cells. The acute oral toxicity study revealed no adverse effect of GKRE in rats at 2 g/kg BW. GKRE improved (p < 0.05) the body and liver weights in ethanol-treated rats. GKRE improved (p < 0.05) the mRNA levels of ADH, SREBP1c and mitochondrial biogenesis genes in the liver tissues. GKRE also improved (p < 0.05) the liver damage markers, lipid peroxidation and levels of antioxidant enzymes in the liver. A reduced severity (p < 0.05) of pathological changes, fibrotic tissue deposition and caspase 3/7 activity were observed in the liver tissues of GKRE-treated rats. Further, GKRE downregulated (p < 0.05) the expression of fibrotic (TGFβ, αSMA and SMADs) and inflammatory markers (TNFα, IL6, IL1β and NFκB) in the liver. CONCLUSION GKRE showed efficacy against alcohol-induced liver damage by inhibiting oxidative stress, apoptosis, inflammation and fibrogenesis in the liver.
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Affiliation(s)
- Pragya Choubey
- Pharmacology and Toxicology Laboratory, Dietetics & Nutrition Technology Division, CSIR-Institute of Himalayan Bioresource Technology, Palampur, 176061, HP, India; PG Department of Dravyaguna, Rajiv Gandhi Govt. Post Graduate Ayurvedic College and Hospital, Paprola, 176115, HP, India
| | - Vinesh Sharma
- Pharmacology and Toxicology Laboratory, Dietetics & Nutrition Technology Division, CSIR-Institute of Himalayan Bioresource Technology, Palampur, 176061, HP, India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, 201002, UP, India
| | - Robin Joshi
- Biotechnology Division, CSIR-Institute of Himalayan Bioresource Technology, Palampur, 176061, HP, India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, 201002, UP, India
| | - Ashwani Upadhyaya
- PG Department of Dravyaguna, Rajiv Gandhi Govt. Post Graduate Ayurvedic College and Hospital, Paprola, 176115, HP, India
| | - Dinesh Kumar
- Chemical Technology Division, CSIR-Institute of Himalayan Bioresource Technology, Palampur, 176061, HP, India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, 201002, UP, India
| | - Vikram Patial
- Pharmacology and Toxicology Laboratory, Dietetics & Nutrition Technology Division, CSIR-Institute of Himalayan Bioresource Technology, Palampur, 176061, HP, India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, 201002, UP, India.
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HAN M, YI X, YOU S, WU X, WANG S, HE D. Gehua Jiejiu Dizhi decoction ameliorates alcoholic fatty liver in mice by regulating lipid and bile acid metabolism and with exertion of antioxidant stress based on 4DLabel-free quantitative proteomic study. J TRADIT CHIN MED 2024; 44:277-288. [PMID: 38504534 PMCID: PMC10927405 DOI: 10.19852/j.cnki.jtcm.20231018.001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2022] [Accepted: 04/27/2023] [Indexed: 03/21/2024]
Abstract
OBJECTIVE To analyze the effect and molecular mechanism of Gehua Jiejiu Dizhi decoction (, GJDD) on alcoholic fatty live disease (AFLD) by using proteomic methods. METHODS The male C57BL/6J mouse were randomly divided into four groups: control group, model group, GJDD group and resveratrol group. After the AFLD model was successfully prepared by intragastric administration of alcohol once on the basis of the Lieber-DeCarli classical method, the GJDD group and resveratrol group were intragastrically administered with GJDD (4900 mg/kg) and resveratrol (400 mg/kg) respectively, once a day for 9 d. The fat deposition of liver tissue was observed and evaluated by oil red O (ORO) staining. 4DLabel-free quantitative proteome method was used to determine and quantify the protein expression in liver tissue of each experimental group. The differentially expressed proteins were screened according to protein expression differential multiples, and then analyzed by Gene ontology classification and Kyoto Encyclopedia of Genes and Genomes pathway enrichment. Finally, expression validation of the differentially co-expressed proteins from control group, model group and GJDD group were verified by targeted proteomics quantification techniques. RESULTS In semiquantitative analyses of ORO, all kinds of steatosis (ToS, MaS, and MiS) were evaluated higher in AFLD mice compared to those in GJDD or resveratrol-treated mice. 4DLabel-free proteomics analysis results showed that a total of 4513 proteins were identified, of which 3763 proteins were quantified and 946 differentially expressed proteins were screened. Compared with the control group, 145 proteins were up-regulated and 148 proteins were down-regulated in the liver tissue of model group. In addition, compared with the model group, 92 proteins were up-regulated and 135 proteins were down-regulated in the liver tissue of the GJDD group. 15 differentially co-expressed proteins were found between every two groups (model group vs control group, GJDD group vs model group and GJDD group vs control group), which were involved in many biological processes. Among them, 11 differentially co-expressed key proteins (Aox3, H1-5, Fabp5, Ces3a, Nudt7, Serpinb1a, Fkbp11, Rpl22l1, Keg1, Acss2 and Slco1a1) were further identified by targeted proteomic quantitative technology and their expression patterns were consistent with the results of 4D label-free proteomic analysis. CONCLUSIONS Our study provided proteomics-based evidence that GJDD alleviated AFLD by modulating liver protein expression, likely through the modulation of lipid metabolism, bile acid metabolism and with exertion of antioxidant stress.
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Affiliation(s)
- Min HAN
- 1 Guizhou University of Traditional Chinese Medicine, Graduate School, Guiyang 550025, China
| | - Xu YI
- 2 Department of Clinical medical laboratory, Department of Gastroenterology, the Second Affiliated Hospital of Guizhou University of Traditional Chinese Medicine, Guiyang 550003, China
| | - Shaowei YOU
- 2 Department of Clinical medical laboratory, Department of Gastroenterology, the Second Affiliated Hospital of Guizhou University of Traditional Chinese Medicine, Guiyang 550003, China
| | - Xueli WU
- 2 Department of Clinical medical laboratory, Department of Gastroenterology, the Second Affiliated Hospital of Guizhou University of Traditional Chinese Medicine, Guiyang 550003, China
| | - Shuoshi WANG
- 2 Department of Clinical medical laboratory, Department of Gastroenterology, the Second Affiliated Hospital of Guizhou University of Traditional Chinese Medicine, Guiyang 550003, China
| | - Diancheng HE
- 2 Department of Clinical medical laboratory, Department of Gastroenterology, the Second Affiliated Hospital of Guizhou University of Traditional Chinese Medicine, Guiyang 550003, China
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Chen L, Ye X, Yang L, Zhao J, You J, Feng Y. Linking fatty liver diseases to hepatocellular carcinoma by hepatic stellate cells. JOURNAL OF THE NATIONAL CANCER CENTER 2024; 4:25-35. [PMID: 39036388 PMCID: PMC11256631 DOI: 10.1016/j.jncc.2024.01.002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2023] [Revised: 01/05/2024] [Accepted: 01/07/2024] [Indexed: 07/23/2024] Open
Abstract
Hepatic stellate cells (HSCs), a distinct category of non-parenchymal cells in the liver, are critical for liver homeostasis. In healthy livers, HSCs remain non-proliferative and quiescent. However, under conditions of acute or chronic liver damage, HSCs are activated and participate in the progression and regulation of liver diseases such as liver fibrosis, cirrhosis, and liver cancer. Fatty liver diseases (FLD), including nonalcoholic (NAFLD) and alcohol-related (ALD), are common chronic inflammatory conditions of the liver. These diseases, often resulting from multiple metabolic disorders, can progress through a sequence of inflammation, fibrosis, and ultimately, cancer. In this review, we focused on the activation and regulatory mechanism of HSCs in the context of FLD. We summarized the molecular pathways of activated HSCs (aHSCs) in mediating FLD and their role in promoting liver tumor development from the perspectives of cell proliferation, invasion, metastasis, angiogenesis, immunosuppression, and chemo-resistance. We aimed to offer an in-depth discussion on the reciprocal regulatory interactions between FLD and HSC activation, providing new insights for researchers in this field.
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Affiliation(s)
- Liang'en Chen
- Zhejiang Provincial Key Laboratory of Pancreatic Disease, First Affiliated Hospital, and Institute of Translational Medicine, Zhejiang University School of Medicine, Hangzhou, China
- Cancer Center, Zhejiang University, Hangzhou, China
| | - Xiangshi Ye
- Zhejiang Provincial Key Laboratory of Pancreatic Disease, First Affiliated Hospital, and Institute of Translational Medicine, Zhejiang University School of Medicine, Hangzhou, China
- Cancer Center, Zhejiang University, Hangzhou, China
| | - Lixian Yang
- Cancer Center, Department of Radiation Oncology, Zhejiang Provincial People's Hospital (Hangzhou Medical College), Hangzhou, China
| | - Jiangsha Zhao
- Zhejiang Provincial Key Laboratory of Pancreatic Disease, First Affiliated Hospital, and Institute of Translational Medicine, Zhejiang University School of Medicine, Hangzhou, China
- Cancer Center, Zhejiang University, Hangzhou, China
| | - Jia You
- School of Life Sciences, Westlake University, Hangzhou, China
| | - Yuxiong Feng
- Zhejiang Provincial Key Laboratory of Pancreatic Disease, First Affiliated Hospital, and Institute of Translational Medicine, Zhejiang University School of Medicine, Hangzhou, China
- Cancer Center, Zhejiang University, Hangzhou, China
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Yan T, Zhang Y, Lu H, Zhao J, Wen C, Song S, Ai C, Yang J. The protective effect of Enteromorpha prolifera polysaccharide on alcoholic liver injury in C57BL/6 mice. Int J Biol Macromol 2024; 261:129908. [PMID: 38320642 DOI: 10.1016/j.ijbiomac.2024.129908] [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: 10/31/2023] [Revised: 01/28/2024] [Accepted: 01/30/2024] [Indexed: 02/08/2024]
Abstract
An alcohol-induced liver injury model was induced in C57BL/6 mice to assess the protective efficacy of Enteromorpha prolifera polysaccharides (EP) against liver damage. Histological alterations in the liver were examined following hematoxylin-eosin (H&E) staining. Biochemical assay kits and ELISA kits were employed to analyze serum and liver biochemical parameters, as well as the activity of antioxidant enzymes and alcohol metabolism-related enzymes. The presence of oxidative stress-related proteins in the liver was detected using western blotting. Liquid chromatography and mass spectrometry were used to profile serum metabolites in mice. The findings demonstrated that EP-H (100 mg/Kg) reduced serum ALT and AST activity by 2.31-fold and 2.32-fold, respectively, when compared to the alcohol-induced liver injury group. H&E staining revealed a significant attenuation of microvesicular steatosis and ballooning pathology in the EP-H group compared to the model group. EP administration was found to enhance alcohol metabolism by regulating metabolite-related enzymes (ADH and ALDH) and decreasing CYP2E1 expression. EP also modulated the Nrf2/HO-1 signaling pathway to bolster hepatic antioxidant capacity. Furthermore, EP restored the levels of lipid metabolites (Glycine, Butanoyl-CoA, and Acetyl-CoA) to normalcy. In summary, EP confers protection to the liver through the regulation of antioxidant activity and lipid metabolites in the murine liver.
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Affiliation(s)
- Tingting Yan
- SKL of Marine Food Processing & Safety Control, National Engineering Research Center of Seafood, School of Food Science and Technology, Dalian Polytechnic University, Dalian 116034, China
| | - Yuying Zhang
- SKL of Marine Food Processing & Safety Control, National Engineering Research Center of Seafood, School of Food Science and Technology, Dalian Polytechnic University, Dalian 116034, China
| | - Hengyu Lu
- West China School of Pharmacy, Sichuan University, Chengdu 610207, China
| | - Jun Zhao
- SKL of Marine Food Processing & Safety Control, National Engineering Research Center of Seafood, School of Food Science and Technology, Dalian Polytechnic University, Dalian 116034, China
| | - Chengrong Wen
- SKL of Marine Food Processing & Safety Control, National Engineering Research Center of Seafood, School of Food Science and Technology, Dalian Polytechnic University, Dalian 116034, China
| | - Shuang Song
- SKL of Marine Food Processing & Safety Control, National Engineering Research Center of Seafood, School of Food Science and Technology, Dalian Polytechnic University, Dalian 116034, China
| | - Chunqing Ai
- SKL of Marine Food Processing & Safety Control, National Engineering Research Center of Seafood, School of Food Science and Technology, Dalian Polytechnic University, Dalian 116034, China
| | - Jingfeng Yang
- SKL of Marine Food Processing & Safety Control, National Engineering Research Center of Seafood, School of Food Science and Technology, Dalian Polytechnic University, Dalian 116034, China.
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Yang HX, Jiang XL, Zuo RM, Wu YL, Nan JX, Lian LH. Targeting RXFP1 by Ligustilide: A novel therapeutic approach for alcoholic hepatic steatosis. Int Immunopharmacol 2024; 127:111460. [PMID: 38157696 DOI: 10.1016/j.intimp.2023.111460] [Citation(s) in RCA: 4] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/24/2023] [Revised: 12/21/2023] [Accepted: 12/25/2023] [Indexed: 01/03/2024]
Abstract
BACKGROUND Ligustilide (Lig) is the main active ingredient of Umbelliferae Angelicae Sinensis Radix (Chinese Angelica) and Chuanxiong Rhizoma (Sichuan lovase rhizome). Lig possesses various pharmacological properties and could treat obesity by regulating energy metabolism. However, the impact and regulatory mechanism of Lig on alcoholic hepatic steatosis remains unclear. PURPOSE This study aimed to explore the therapeutic effect of Lig on alcoholic hepatic steatosis and its related pharmacological mechanism. RESULTS With chronic and binge ethanol feeding, liver tissue damage and lipid accumulation in mice suffering alcoholic hepatic steatosis were significantly improved after Lig treatment. Lig effectively regulated the expression levels of lipid metabolism-related proteins in alcoholic hepatic steatosis. In addition, Lig reduced RXFP1 expression, inhibited the activation of NLRP3 inflammasome, and blocked NET formation. Lig reduced the infiltration of immune cells to the liver and the further prevented the occurrence of alcohol-stimulated inflammatory response in liver. Lig significantly regulated lipid accumulation in alcohol exposed AML12 cells via modulating PPARα and SREBP1. In MPMs, Lig decreased the expression of RXFP1, inhibited the activation of NLRP3 in macrophages stimulated by LPS/ATP, and slowed down the occurrence of inflammatory response. CONCLUSION Lig sustained lipid metabolism homeostasis in alcoholic hepatic steatosis, through inhibiting the activation of NLRP3 inflammasomes and the formation of NETs, especially targeting RXFP1 in macrophages.
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Affiliation(s)
- Hong-Xu Yang
- Key Laboratory of Traditional Chinese Korean Medicine Research (Yanbian University) of State Ethnic Affairs Commission, College of Pharmacy, Yanbian University, Yanji, Jilin Province 133002, China; Key Laboratory of Natural Medicines of the Changbai Mountain, Ministry of Education, College of Pharmacy, Yanbian University, Yanji, Jilin Province 133002, China
| | - Xue-Li Jiang
- Key Laboratory of Traditional Chinese Korean Medicine Research (Yanbian University) of State Ethnic Affairs Commission, College of Pharmacy, Yanbian University, Yanji, Jilin Province 133002, China; Key Laboratory of Natural Medicines of the Changbai Mountain, Ministry of Education, College of Pharmacy, Yanbian University, Yanji, Jilin Province 133002, China
| | - Rong-Mei Zuo
- Key Laboratory of Traditional Chinese Korean Medicine Research (Yanbian University) of State Ethnic Affairs Commission, College of Pharmacy, Yanbian University, Yanji, Jilin Province 133002, China; Key Laboratory of Natural Medicines of the Changbai Mountain, Ministry of Education, College of Pharmacy, Yanbian University, Yanji, Jilin Province 133002, China
| | - Yan-Ling Wu
- Key Laboratory of Traditional Chinese Korean Medicine Research (Yanbian University) of State Ethnic Affairs Commission, College of Pharmacy, Yanbian University, Yanji, Jilin Province 133002, China; Key Laboratory of Natural Medicines of the Changbai Mountain, Ministry of Education, College of Pharmacy, Yanbian University, Yanji, Jilin Province 133002, China
| | - Ji-Xing Nan
- Key Laboratory of Traditional Chinese Korean Medicine Research (Yanbian University) of State Ethnic Affairs Commission, College of Pharmacy, Yanbian University, Yanji, Jilin Province 133002, China; Key Laboratory of Natural Medicines of the Changbai Mountain, Ministry of Education, College of Pharmacy, Yanbian University, Yanji, Jilin Province 133002, China.
| | - Li-Hua Lian
- Key Laboratory of Traditional Chinese Korean Medicine Research (Yanbian University) of State Ethnic Affairs Commission, College of Pharmacy, Yanbian University, Yanji, Jilin Province 133002, China; Key Laboratory of Natural Medicines of the Changbai Mountain, Ministry of Education, College of Pharmacy, Yanbian University, Yanji, Jilin Province 133002, China.
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Mao J, Tan L, Tian C, Wang W, Zhang H, Zhu Z, Li Y. Research progress on rodent models and its mechanisms of liver injury. Life Sci 2024; 337:122343. [PMID: 38104860 DOI: 10.1016/j.lfs.2023.122343] [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: 09/21/2023] [Revised: 11/22/2023] [Accepted: 12/06/2023] [Indexed: 12/19/2023]
Abstract
The liver is the most important organ for biological transformation in the body and is crucial for maintaining the body's vital activities. Liver injury is a serious pathological condition that is commonly found in many liver diseases. It has a high incidence rate, is difficult to cure, and is prone to recurrence. Liver injury can cause serious harm to the body, ranging from mild to severe fatty liver disease. If the condition continues to worsen, it can lead to liver fibrosis and cirrhosis, ultimately resulting in liver failure or liver cancer, which can seriously endanger human life and health. Therefore, establishing an rodent model that mimics the pathogenesis and severity of clinical liver injury is of great significance for better understanding the pathogenesis of liver injury patients and developing more effective clinical treatment methods. The author of this article summarizes common chemical liver injury models, immune liver injury models, alcoholic liver injury models, drug-induced liver injury models, and systematically elaborates on the modeling methods, mechanisms of action, pathways of action, and advantages or disadvantages of each type of model. The aim of this study is to establish reliable rodent models for researchers to use in exploring anti-liver injury and hepatoprotective drugs. By creating more accurate theoretical frameworks, we hope to provide new insights into the treatment of clinical liver injury diseases.
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Affiliation(s)
- Jingxin Mao
- Chongqing Medical and Pharmaceutical College, Chongqing 400030, China; College of Pharmaceutical Sciences, Southwest University, Chongqing 400715, China
| | - Lihong Tan
- Chongqing Medical and Pharmaceutical College, Chongqing 400030, China; Chongqing Key Laboratory of High Active Traditional Chinese Drug Delivery System, Chongqing 400030, China
| | - Cheng Tian
- Chongqing Medical and Pharmaceutical College, Chongqing 400030, China; Chongqing Key Laboratory of High Active Traditional Chinese Drug Delivery System, Chongqing 400030, China
| | - Wenxiang Wang
- Chongqing Three Gorges Medical College, Chongqing 404120, China
| | - Hao Zhang
- Chongqing Medical and Pharmaceutical College, Chongqing 400030, China; Chongqing Key Laboratory of High Active Traditional Chinese Drug Delivery System, Chongqing 400030, China
| | - Zhaojing Zhu
- Chongqing Medical and Pharmaceutical College, Chongqing 400030, China; Chongqing Key Laboratory of High Active Traditional Chinese Drug Delivery System, Chongqing 400030, China
| | - Yan Li
- Chongqing Medical and Pharmaceutical College, Chongqing 400030, China; Chongqing Key Laboratory of High Active Traditional Chinese Drug Delivery System, Chongqing 400030, China.
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Jadhav PA, Thomas AB, Nanda RK, Chitlange SS. Unveiling the role of gut dysbiosis in non-alcoholic fatty liver disease. Eur J Gastroenterol Hepatol 2023; 35:1324-1333. [PMID: 37823422 DOI: 10.1097/meg.0000000000002654] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 10/13/2023]
Abstract
Non-alcoholic fatty liver disease (NAFLD) is a multifactorial complicated condition, reflected by the accumulation of extra fat in the liver. A detailed study of literature throws light on the fascinating connection between gut dysbiosis and NAFLD. The term 'gut dysbiosis' describes an imbalance in the harmony and operation of the gut microflora, which can upshoot a number of metabolic disorders. To recognize the underlying mechanisms and determine treatment options, it is essential to comprehend the connection between gut dysbiosis and NAFLD. This in-depth review discusses the normal gut microflora composition and its role in health, alterations in the gut microflora composition that leads to disease state focusing on NAFLD. The potential mechanisms influencing the advent and aggravation of NAFLD suggested disturbance of microbial metabolites, changes in gut barrier integrity, and imbalances in the composition of the gut microflora. Furthermore, it was discovered that gut dysbiosis affected immune responses, liver inflammation, and metabolic pathways, aggravating NAFLD.
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Affiliation(s)
- Pranali A Jadhav
- Department of Pharmaceutical Chemistry, Dr. D. Y. Patil Institute of Pharmaceutical Sciences and Research, Pimpri, Pune, Maharashtra, India
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Namachivayam A, Valsala Gopalakrishnan A. Effect of Lauric acid against ethanol-induced hepatotoxicity by modulating oxidative stress/apoptosis signalling and HNF4α in Wistar albino rats. Heliyon 2023; 9:e21267. [PMID: 37908709 PMCID: PMC10613920 DOI: 10.1016/j.heliyon.2023.e21267] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2023] [Revised: 10/12/2023] [Accepted: 10/18/2023] [Indexed: 11/02/2023] Open
Abstract
Ethanol (EtOH) is most widely used in alcoholic beverages to prepare alcohol. As EtOH is mainly metabolised in the liver, the excessive consumption of EtOH forms a primary toxic metabolic product called acetaldehyde, as the gradual increase in acetaldehyde leads to liver injury, as reported. Lauric acid (LA) is rich in antioxidant, antifungal, antibacterial, anticancer, and antiviral properties. LA is an edible component highly present in coconut oil. However, no report on LA protective effects against the EtOH-instigated hepatotoxicity exists. Therefore, the experiment is carried out to investigate the potency effects of LA on EtOH-instigated hepatotoxicity in thirty male albino rats. Rats were divided into five groups (n-6): control DMSO alone, EtOH -intoxicated, EtOH + LA 180 mg/kg, EtOH + LA 360 mg/kg, and LA alone were administered orally using oral gavage. The study measured body weight every weekend in all rat groups. The rats were sacrificed and assessed for serum markers (alkaline phosphatase, alanine aminotransferase, aspartate aminotransferase), antioxidant activity (superoxide dismutase, reduced glutathione, glutathione peroxidase), lipid peroxidation (malondialdehyde), histopathological, cytokine levels (TNF-α, IL-1β and IL-6), protein expression (caspase 3 and caspase 8 and Bcl-2 and HNF4α) were evaluated after the 56-days study period. The impact of EtOH intoxication reduces the rat's body weight by 90 g, upregulates the liver enzyme markers, depletes the antioxidant levels, produces malondialdehyde, changes the histoarchitecture (periportal inflammation and hepatocyte damage), downregulates the Bcl-2 expressions and HNF4α, and elevates the expression of cytokines and apoptotic markers. LA alleviated EtOH-induced liver toxicity by significant (p < 0.05) modulation of biochemical levels, caspase-8/3 signalling, reducing pro-inflammatory cytokines, and restoring the normal histoarchitecture, upregulating the Bcl-2 and HNF4α Expressions. In conclusion, LA treatment can protect the liver against EtOH-induced hepatotoxicity, evidenced by alleviating Oxidative stress, lipid peroxidation, inflammation, apoptosis, and upregulation of HNF4α.
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Affiliation(s)
- Arunraj Namachivayam
- Department of Biomedical Sciences, School of Bio-Sciences and Technology, Vellore Institute of Technology (VIT), Vellore 632014, India
| | - Abilash Valsala Gopalakrishnan
- Department of Biomedical Sciences, School of Bio-Sciences and Technology, Vellore Institute of Technology (VIT), Vellore 632014, India
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Subramaiyam N. Insights of mitochondrial involvement in alcoholic fatty liver disease. J Cell Physiol 2023; 238:2175-2190. [PMID: 37642259 DOI: 10.1002/jcp.31100] [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: 05/04/2023] [Revised: 07/31/2023] [Accepted: 08/04/2023] [Indexed: 08/31/2023]
Abstract
Alcoholic liver disease (ALD) is a global concern affecting most of the population and leading to the development of end-stage liver disease. Metabolic alterations due to increased alcohol consumption surge the hepatic accumulation of lipids and develop into a severe form of alcoholic steatohepatitis (ASH), depending on age and the consumption rate. The mitochondria in the hepatocyte actively regulate metabolic homeostasis and are disrupted in ALD pathogenesis. The increased NADH upon ethanol metabolism inhibits the mitochondrial oxidation of fatty acids, alters oxidative phosphorylation, and favors de novo lipogenesis. The higher mitochondrial respiration in early ALD increases free radical generation, whereas mitochondrial respiration is uncoupled in chronic ALD, affecting the cellular energy status. The defective glutathione importer due to excessive cholesterol loading and low adenosine triphosphate accounts for additional oxidative stress leading to hepatocyte apoptosis. The defective mitochondrial transcription machinery and sirtuins function in ALD affect mitochondrial function and biogenesis. The metabolites of ethanol metabolism epigenetically alter the gene expression profile of hepatic cell populations by modulating the promoters and sirtuins, aiding hepatic fibrosis and inflammation. The defect in mitophagy increases the accumulation of megamitochondria in hepatocytes and attracts immune cells by releasing mitochondrial damage-associated molecular patterns to initiate hepatic inflammation and ASH progression. Thus, maintaining mitochondrial lipid homeostasis and antioxidant capacity pharmacologically could provide a better outcome for ALD management.
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Affiliation(s)
- Nithyananthan Subramaiyam
- Division of Gastroenterology, Hepatology and Nutrition, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA
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Zhang L, Lu QY, Wu H, Cheng YL, Kang J, Xu ZG. The Intestinal Microbiota Composition in Early and Late Stages of Diabetic Kidney Disease. Microbiol Spectr 2023; 11:e0038223. [PMID: 37341590 PMCID: PMC10434009 DOI: 10.1128/spectrum.00382-23] [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: 01/25/2023] [Accepted: 05/31/2023] [Indexed: 06/22/2023] Open
Abstract
Many studies have suggested that gut microbiota dysbiosis may be one of the pathogenesis factors of diabetes mellitus (DM), while it is not clear whether it is involved in the development of diabetic kidney diseases (DKD). The objective of this study was to determine bacterial taxa biomarkers during the progression of DKD by investigating bacterial compositional changes in early and late DKD. 16S rRNA gene sequencing was performed on fecal samples, including the diabetes mellitus (DM), DNa (early DKD), and DNb (late DKD) groups. Taxonomic annotation of microbial composition was performed. Samples were sequenced on the Illumina NovaSeq platform. At the genus level, we found counts of Fusobacterium, Parabacteroides, and Ruminococcus_gnavus were significantly elevated both in the DNa group (P = 0.0001, 0.0007, and 0.0174, respectively) and the DNb group (P < 0.0001, 0.0012, and 0.0003, respectively) compared with those in the DM group. Only the level of Agathobacter was significantly decreased in the DNa group than the DM group and in the DNb group than the DNa group. Counts of Prevotella_9, Roseburia were significantly decreased in the DNa group compared with those in the DM group (P = 0.001 and 0.006, respectively) and in the DNb group compared with those in the DM group (P < 0.0001 and 0.003, respectively). Levels of Agathobacter, Prevotella_9, Lachnospira, and Roseburia were positively correlated with an estimated glomerular filtration rate (eGFR), but negatively correlated with microalbuminuria (MAU), 24 h urinary protein quantity (24hUP), and serum creatinine (Scr). Moreover, the areas under the curve (AUCs) of Agathobacter and Fusobacteria were 83.33% and 80.77%, respectively, for the DM and DNa cohorts, respectively. Notably, the largest AUC for DNa and DNb cohorts was also that of Agathobacter at 83.60%. Gut microbiota dysbiosis was found in the early and late stages of DKD, especially in the early stage. Agathobacter may be the most promising intestinal bacteria biomarker that can help distinguish different stages of DKD. IMPORTANCE It is not clear as to whether gut microbiota dysbiosis is involved in the progression of DKD. This study may be the first to explore gut microbiota compositional changes in diabetes, early-DKD, and late DKD. We identify different gut microbial characteristics during different stages of DKD. Gut microbiota dysbiosis is found in the early and late stages of DKD. Agathobacter may be the most promising intestinal bacteria biomarker that can help distinguish different stages of DKD, although further studies are warranted to illustrate these mechanisms.
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Affiliation(s)
- Li Zhang
- Department of Nephrology, The First Hospital of Jilin University, Changchun, Jilin Province, China
| | - Qi-Yu Lu
- Department of Thyroid Surgery, General surgery center, The First Hospital of Jilin University, Changchun, Jilin Province, China
| | - Hao Wu
- Department of Nephrology, The First Hospital of Jilin University, Changchun, Jilin Province, China
| | - Yan-Li Cheng
- Department of Nephrology, The First Hospital of Jilin University, Changchun, Jilin Province, China
| | - Jing Kang
- Department of Endocrinology, The Second Hospital of Jilin University, Changchun, Jilin Province, China
| | - Zhong-Gao Xu
- Department of Nephrology, The First Hospital of Jilin University, Changchun, Jilin Province, China
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Patil VS, Harish DR, Sampat GH, Roy S, Jalalpure SS, Khanal P, Gujarathi SS, Hegde HV. System Biology Investigation Revealed Lipopolysaccharide and Alcohol-Induced Hepatocellular Carcinoma Resembled Hepatitis B Virus Immunobiology and Pathogenesis. Int J Mol Sci 2023; 24:11146. [PMID: 37446321 DOI: 10.3390/ijms241311146] [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: 04/14/2023] [Revised: 06/05/2023] [Accepted: 06/07/2023] [Indexed: 07/15/2023] Open
Abstract
Hepatitis B infection caused by the hepatitis B virus is a life-threatening cause of liver fibrosis, cirrhosis, and hepatocellular carcinoma. Researchers have produced multiple in vivo models for hepatitis B virus (HBV) and, currently, there are no specific laboratory animal models available to study HBV pathogenesis or immune response; nonetheless, their limitations prevent them from being used to study HBV pathogenesis, immune response, or therapeutic methods because HBV can only infect humans and chimpanzees. The current study is the first of its kind to identify a suitable chemically induced liver cirrhosis/HCC model that parallels HBV pathophysiology. Initially, data from the peer-reviewed literature and the GeneCards database were compiled to identify the genes that HBV and seven drugs (acetaminophen, isoniazid, alcohol, D-galactosamine, lipopolysaccharide, thioacetamide, and rifampicin) regulate. Functional enrichment analysis was performed in the STRING server. The network HBV/Chemical, genes, and pathways were constructed by Cytoscape 3.6.1. About 1546 genes were modulated by HBV, of which 25.2% and 17.6% of the genes were common for alcohol and lipopolysaccharide-induced hepatitis. In accordance with the enrichment analysis, HBV activates the signaling pathways for apoptosis, cell cycle, PI3K-Akt, TNF, JAK-STAT, MAPK, chemokines, NF-kappa B, and TGF-beta. In addition, alcohol and lipopolysaccharide significantly activated these pathways more than other chemicals, with higher gene counts and lower FDR scores. In conclusion, alcohol-induced hepatitis could be a suitable model to study chronic HBV infection and lipopolysaccharide-induced hepatitis for an acute inflammatory response to HBV.
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Affiliation(s)
- Vishal S Patil
- ICMR-National Institute of Traditional Medicine, Nehru Nagar, Belagavi 590010, India
- KLE College of Pharmacy, Belagavi, KLE Academy of Higher Education and Research, Belagavi 590010, India
| | - Darasaguppe R Harish
- ICMR-National Institute of Traditional Medicine, Nehru Nagar, Belagavi 590010, India
| | - Ganesh H Sampat
- ICMR-National Institute of Traditional Medicine, Nehru Nagar, Belagavi 590010, India
- KLE College of Pharmacy, Belagavi, KLE Academy of Higher Education and Research, Belagavi 590010, India
| | - Subarna Roy
- ICMR-National Institute of Traditional Medicine, Nehru Nagar, Belagavi 590010, India
| | - Sunil S Jalalpure
- KLE College of Pharmacy, Belagavi, KLE Academy of Higher Education and Research, Belagavi 590010, India
| | - Pukar Khanal
- KLE College of Pharmacy, Belagavi, KLE Academy of Higher Education and Research, Belagavi 590010, India
| | - Swarup S Gujarathi
- ICMR-National Institute of Traditional Medicine, Nehru Nagar, Belagavi 590010, India
- KLE College of Pharmacy, Belagavi, KLE Academy of Higher Education and Research, Belagavi 590010, India
| | - Harsha V Hegde
- ICMR-National Institute of Traditional Medicine, Nehru Nagar, Belagavi 590010, India
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Mahdi WA, AlGhamdi SA, Alghamdi AM, Imam SS, Alshehri S, Almaniea MA, Hajjar BM, Al-Abbasi FA, Sayyed N, Kazmi I. Effect of Europinidin against Alcohol-Induced Liver Damage in Rats by Inhibiting the TNF-α/TGF-β/IFN-γ/NF-kB/Caspase-3 Signaling Pathway. ACS OMEGA 2023; 8:22656-22664. [PMID: 37396259 PMCID: PMC10308532 DOI: 10.1021/acsomega.3c01312] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 02/27/2023] [Accepted: 05/12/2023] [Indexed: 07/04/2023]
Abstract
BACKGROUND The effect of europinidin on alcoholic liver damage in rats was examined in this research. METHODS A total of 24 Wistar rats were grouped in the same way into four groups: normal control (normal), ethanol control (EtOH), europinidin low dose (10 mg/kg), and europinidin higher dose (20 mg/kg). The test group rats were orally treated with europinidin-10 and europinidin-20 for 4 weeks, whereas 5 mL/kg distilled water was administered to control rats. In addition, 1 h after the last dose of the above-mentioned oral treatment, 5 mL/kg (i.p.) EtOH was injected to induce liver injury. After 5 h of EtOH treatment, samples of blood were withdrawn for biochemical estimations. RESULTS Administration of europinidin at both doses restored all of the estimated serum, i.e., liver function tests (ALT, AST, ALP), biochemical test (Creatinine, albumin, BUN, direct bilirubin, and LDH), lipid assessment (TC and TG), endogenous antioxidants (GSH-Px, SOD, and CAT), malondialdehyde (MDA), nitric oxide (NO), cytokines (TGF-β, TNF-α, IL-1β, IL-6, IFN-γ, and IL-12), caspase-3, and nuclear factor kappa B (NF-κB) associated with the EtOH group. CONCLUSION The results of the investigation showed that europinidin had favorable effects in rats given EtOH and may have hepatoprotective potential property.
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Affiliation(s)
- Wael A. Mahdi
- Department
of Pharmaceutics, College of Pharmacy, King
Saud University, Riyadh 11451, Saudi Arabia
| | - Shareefa A. AlGhamdi
- Department
of Biochemistry, Faculty of Sciences, King
Abdulaziz University, Jeddah 21589, Saudi Arabia
- Experimental
Biochemistry Unit, King Fahd Medical Research Center, King Abdulaziz University, Jeddah 21589, Saudi Arabia
| | - Amira M. Alghamdi
- Department
of Biochemistry, Faculty of Sciences, King
Abdulaziz University, Jeddah 21589, Saudi Arabia
| | - Syed Sarim Imam
- Department
of Pharmaceutics, College of Pharmacy, King
Saud University, Riyadh 11451, Saudi Arabia
| | - Sultan Alshehri
- Department
of Pharmaceutics, College of Pharmacy, King
Saud University, Riyadh 11451, Saudi Arabia
| | - Mohammad A. Almaniea
- Department
of Pharmaceutics, College of Pharmacy, King
Saud University, Riyadh 11451, Saudi Arabia
| | - Baraa Mohammed Hajjar
- Department
of Pharmaceutics, College of Pharmacy, King
Saud University, Riyadh 11451, Saudi Arabia
| | - Fahad A. Al-Abbasi
- Department
of Biochemistry, Faculty of Sciences, King
Abdulaziz University, Jeddah 21589, Saudi Arabia
| | - Nadeem Sayyed
- School
of Pharmacy, Glocal University, Saharanpur 247121, India
| | - Imran Kazmi
- Department
of Biochemistry, Faculty of Sciences, King
Abdulaziz University, Jeddah 21589, Saudi Arabia
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20
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Gao H, Li Z, Liu Y, Zhao YK, Cheng C, Qiu F, Gao Y, Lu YW, Song XH, Wang JB, Ma ZT. A clinical experience-based Chinese herbal formula improves ethanol-induced drunken behavior and hepatic steatohepatitis in mice models. Chin Med 2023; 18:47. [PMID: 37127639 PMCID: PMC10150545 DOI: 10.1186/s13020-023-00753-5] [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: 02/06/2023] [Accepted: 04/13/2023] [Indexed: 05/03/2023] Open
Abstract
BACKGROUND Bao-Gan-Xing-Jiu-Wan (BGXJW) is a clinical experience-based Chinese herbal formula. Its efficacy, pharmacological safety, targeted function, process quality, and other aspects have met the evaluation standards and the latest requirements of preparations. It could prevent and alleviate the symptoms of drunkenness and alcoholic liver injury clinically. The present work aims to elucidate whether BGXJW could protect against drunkenness and alcoholic liver disease in mice and explore the associated mechanism. MATERIAL AND METHODS We used acute-on-chronic (NIAAA) mice model to induce alcoholic steatosis, and alcohol binge-drinking model to reappear the drunk condition. BGXJW at indicated doses were administered by oral gavage respectively to analyze its effects on alcoholic liver injury and the associated molecular mechanisms. RESULTS BGXJW had no cardiac, hepatic, renal, or intestinal toxicity in mice. Alcoholic liver injury and steatosis in the NIAAA mode were effectively prevented by BGXJW treatment. BGXJW increased the expression of alcohol metabolizing enzymes ADH, CYP2E1, and ALDH2 to enhance alcohol metabolism, inhibited steatosis through regulating lipid metabolism, counteracted alcohol-induced upregulation of lipid synthesis related proteins SREBP1, FASN, and SCD1, meanwhile it enhanced fatty acids β-oxidation related proteins PPAR-α and CPT1A. Alcohol taken enhanced pro-inflammatory TNF-α, IL-6 and down-regulated the anti-inflammatory IL-10 expression in the liver, which were also reversed by BGXJW administration. Moreover, BGXJW significantly decreased the blood ethanol concentration and alleviated drunkenness in the alcohol binge-drinking mice model. CONCLUSIONS BGXJW could effectively relieve drunkenness and prevent alcoholic liver disease by regulating lipid metabolism, inflammatory response, and alcohol metabolism.
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Affiliation(s)
- Han Gao
- College of Pharmacy, Fujian University of Traditional Chinese Medicine, Fuzhou, 350122, Fujian, China
- School of Traditional Chinese Medicine, Capital Medical University, Beijing, 100069, China
- Department of Hepatology, Fifth Medical Center of Chinese, PLA General Hospital, Beijing, 100039, China
| | - Zhen Li
- School of Traditional Chinese Medicine, Capital Medical University, Beijing, 100069, China
- College of Pharmacy, Henan University of Traditional Chinese Medicine, Henan, 450046, Zhengzhou, China
| | - Yao Liu
- School of Traditional Chinese Medicine, Capital Medical University, Beijing, 100069, China
- Department of Infectious Disease, Beijing Hospital of Traditional Chinese Medicine, Capital Medical University, Beijing, 100010, China
| | - Yong-Kang Zhao
- School of Traditional Chinese Medicine, Capital Medical University, Beijing, 100069, China
- College of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, 611137, China
| | - Cheng Cheng
- School of Traditional Chinese Medicine, Capital Medical University, Beijing, 100069, China
- Department of Pharmacy, Jincheng General Hospital, Jincheng, 048006, Shanxi, China
| | - Feng Qiu
- School of Traditional Chinese Medicine, Capital Medical University, Beijing, 100069, China
| | - Yuan Gao
- School of Traditional Chinese Medicine, Capital Medical University, Beijing, 100069, China
| | - Ya-Wen Lu
- School of Traditional Chinese Medicine, Capital Medical University, Beijing, 100069, China
| | - Xin-Hua Song
- School of Traditional Chinese Medicine, Capital Medical University, Beijing, 100069, China
| | - Jia-Bo Wang
- College of Pharmacy, Fujian University of Traditional Chinese Medicine, Fuzhou, 350122, Fujian, China.
- School of Traditional Chinese Medicine, Capital Medical University, Beijing, 100069, China.
| | - Zhi-Tao Ma
- School of Traditional Chinese Medicine, Capital Medical University, Beijing, 100069, China.
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21
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Zhang X, Dong Z, Fan H, Yang Q, Yu G, Pan E, He N, Li X, Zhao P, Fu M, Dong J. Scutellarin prevents acute alcohol-induced liver injury via inhibiting oxidative stress by regulating the Nrf2/HO-1 pathway and inhibiting inflammation by regulating the AKT, p38 MAPK/NF-κB pathways. J Zhejiang Univ Sci B 2023; 24:617-631. [PMID: 37455138 PMCID: PMC10350365 DOI: 10.1631/jzus.b2200612] [Citation(s) in RCA: 26] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2022] [Accepted: 01/03/2023] [Indexed: 04/15/2023]
Abstract
Alcoholic liver disease (ALD) is the most frequent liver disease worldwide, resulting in severe harm to personal health and posing a serious burden to public health. Based on the reported antioxidant and anti-inflammatory capacities of scutellarin (SCU), this study investigated its protective role in male BALB/c mice with acute alcoholic liver injury after oral administration (10, 25, and 50 mg/kg). The results indicated that SCU could lessen serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels and improve the histopathological changes in acute alcoholic liver; it reduced alcohol-induced malondialdehyde (MDA) content and increased glutathione peroxidase (GSH-Px), catalase (CAT), and superoxide dismutase (SOD) activity. Furthermore, SCU decreased tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), and IL-1β messenger RNA (mRNA) expression levels, weakened inducible nitric oxide synthase (iNOS) activity, and inhibited nucleotide-binding oligomerization domain (NOD)-like receptor protein 3 (NLRP3) inflammasome activation. Mechanistically, SCU suppressed cytochrome P450 family 2 subfamily E member 1 (CYP2E1) upregulation triggered by alcohol, increased the expression of oxidative stress-related nuclear factor erythroid 2-related factor 2 (Nrf2) and heme oxygenase-1 (HO-1) pathways, and suppressed the inflammation-related degradation of inhibitor of nuclear factor-κB (NF-κB)-α (IκBα) as well as activation of NF-κB by mediating the protein kinase B (AKT) and p38 mitogen-activated protein kinase (MAPK) pathways. These findings demonstrate that SCU protects against acute alcoholic liver injury via inhibiting oxidative stress by regulating the Nrf2/HO-1 pathway and suppressing inflammation by regulating the AKT, p38 MAPK/NF-κB pathways.
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Affiliation(s)
- Xiao Zhang
- Jiangsu Key Laboratory of Marine Bioresources and Environment / Co-Innovation Center of Jiangsu Marine Bio-Industry Technology / Jiangsu Key Laboratory of Marine Pharmaceutical Compound Screening, College of Pharmacy, Jiangsu Ocean University, Lianyungang 222005, China
| | - Zhicheng Dong
- Department of Oncology, the Second People's Hospital of Lianyungang, Lianyungang 222000, China
| | - Hui Fan
- Jiangsu Key Laboratory of Marine Bioresources and Environment / Co-Innovation Center of Jiangsu Marine Bio-Industry Technology / Jiangsu Key Laboratory of Marine Pharmaceutical Compound Screening, College of Pharmacy, Jiangsu Ocean University, Lianyungang 222005, China
| | - Qiankun Yang
- Jiangsu Key Laboratory of Marine Bioresources and Environment / Co-Innovation Center of Jiangsu Marine Bio-Industry Technology / Jiangsu Key Laboratory of Marine Pharmaceutical Compound Screening, College of Pharmacy, Jiangsu Ocean University, Lianyungang 222005, China
| | - Guili Yu
- Jiangsu Key Laboratory of Marine Bioresources and Environment / Co-Innovation Center of Jiangsu Marine Bio-Industry Technology / Jiangsu Key Laboratory of Marine Pharmaceutical Compound Screening, College of Pharmacy, Jiangsu Ocean University, Lianyungang 222005, China
| | - Enzhuang Pan
- Jiangsu Key Laboratory of Marine Bioresources and Environment / Co-Innovation Center of Jiangsu Marine Bio-Industry Technology / Jiangsu Key Laboratory of Marine Pharmaceutical Compound Screening, College of Pharmacy, Jiangsu Ocean University, Lianyungang 222005, China
| | - Nana He
- Jiangsu Key Laboratory of Marine Bioresources and Environment / Co-Innovation Center of Jiangsu Marine Bio-Industry Technology / Jiangsu Key Laboratory of Marine Pharmaceutical Compound Screening, College of Pharmacy, Jiangsu Ocean University, Lianyungang 222005, China
| | - Xueqing Li
- Jiangsu Key Laboratory of Marine Bioresources and Environment / Co-Innovation Center of Jiangsu Marine Bio-Industry Technology / Jiangsu Key Laboratory of Marine Pharmaceutical Compound Screening, College of Pharmacy, Jiangsu Ocean University, Lianyungang 222005, China
| | - Panpan Zhao
- Jiangsu Key Laboratory of Marine Bioresources and Environment / Co-Innovation Center of Jiangsu Marine Bio-Industry Technology / Jiangsu Key Laboratory of Marine Pharmaceutical Compound Screening, College of Pharmacy, Jiangsu Ocean University, Lianyungang 222005, China
| | - Mian Fu
- Jiangsu Key Laboratory of Marine Bioresources and Environment / Co-Innovation Center of Jiangsu Marine Bio-Industry Technology / Jiangsu Key Laboratory of Marine Pharmaceutical Compound Screening, College of Pharmacy, Jiangsu Ocean University, Lianyungang 222005, China.
| | - Jingquan Dong
- Jiangsu Key Laboratory of Marine Bioresources and Environment / Co-Innovation Center of Jiangsu Marine Bio-Industry Technology / Jiangsu Key Laboratory of Marine Pharmaceutical Compound Screening, College of Pharmacy, Jiangsu Ocean University, Lianyungang 222005, China.
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22
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Smith SJ, Lopresti AL, Fairchild TJ. The effects of alcohol on testosterone synthesis in men: a review. Expert Rev Endocrinol Metab 2023; 18:155-166. [PMID: 36880700 DOI: 10.1080/17446651.2023.2184797] [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: 10/14/2022] [Accepted: 02/22/2023] [Indexed: 03/02/2023]
Abstract
INTRODUCTION Testosterone concentrations in men decline with advancing age, with low testosterone concentrations being associated with multiple morbidities, an increased risk of early mortality, and a reduced quality of life. The purpose of this study was to examine the effects of alcohol on testosterone synthesis in men by investigating its effects on each level of the hypothalamic-pituitary-gonadal axis. AREAS COVERED Acute consumption of a low-to-moderate amount of alcohol increases testosterone concentrations in men, while consumption of a large volume of alcohol is associated with a reduction in serum testosterone concentrations. Elevated testosterone concentrations result from the increased activity of detoxification enzymes in the liver. Conversely, the primary mechanisms of action involved in the reduction of testosterone are increased hypothalamic-pituitary-adrenal axis activity, inflammation, and oxidative stress. When alcohol is consumed in excess, particularly chronically, it negatively affects testosterone production in men. EXPERT OPINION Since testosterone is an important component of men's health and wellbeing, current levels of alcohol consumption in many countries of the world require urgent attention. Elucidating the relationship between alcohol consumption and testosterone may be useful in identifying strategies to attenuate the testosterone-reducing effects of excessive or chronic alcohol consumption.
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Affiliation(s)
- Stephen James Smith
- Clinical Research Australia, Perth, Australia
- The Centre for Molecular Medicine and Innovative Therapeutics, Murdoch University, Perth, Australia
| | - Adrian Leo Lopresti
- Clinical Research Australia, Perth, Australia
- The Centre for Molecular Medicine and Innovative Therapeutics, Murdoch University, Perth, Australia
| | - Timothy John Fairchild
- The Centre for Molecular Medicine and Innovative Therapeutics, Murdoch University, Perth, Australia
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23
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Zuo RM, Jiao JY, Chen N, Jiang XL, Wu YL, Nan JX, Lian LH. Carnosic acid suppressed the formation of NETs in alcoholic hepatosteatosis based on P2X7R-NLRP3 axis. PHYTOMEDICINE : INTERNATIONAL JOURNAL OF PHYTOTHERAPY AND PHYTOPHARMACOLOGY 2023; 110:154599. [PMID: 36577209 DOI: 10.1016/j.phymed.2022.154599] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/28/2022] [Revised: 11/24/2022] [Accepted: 12/10/2022] [Indexed: 06/17/2023]
Abstract
BACKGROUND Alcoholic liver disease (ALD) is accompanied by a disruption of lipid metabolism and an inflammatory response in the liver during the process of disease. Carnosic acid (CA), a natural diterpene extracted from Rosmarinus officinalis (rosemary) and Salvia officinalis (sage), has more pharmacological activities, which is known to be useful in the treatment of obesity and acts by regulating energy metabolism. However, the role and regulation mechanism of CA against ALD remain unclear. HYPOTHESIS We hypothesized that CA might improve alcoholic-induced hepatosteatosis. STUDY DESIGN AND METHODS The alcoholic liver disease model was established a mouse chronic ethanol feeding by Lieber-DeCarli control liquid feed (10 d) plus a single binge with or without CA administration. AML12 cells were exposed to ethanol for 24 h. Murine peritoneal macrophages (MPM) were stimulated with LPS and ATP. RESULTS CA ameliorated lipid accumulation in the liver of mice in the NIAAA model, acting by inhibiting the expression of genes related to lipid synthesis. CA reduced alcohol-induced immune cell infiltration in the liver, and inhibited the activation of P2X7R-NLRP3 inflammasome, meanwhile blocked the formation of NETs in mouse livers tissue. In AML12 cells, CA attenuated the lipid accumulation triggered by ethanol stimulation, which was achieved by inhibiting the expression of SREBP1 and CA reduced the release of inflammatory factor IL-1β by inhibiting the activation of P2X7R-NLRP3. In MPM, IL-1β and HMGB1 were reduced after LPS/ATP stimulation in CA-treated cells and supernatant. CONCLUSIONS CA attenuated alcohol-induced fat accumulation, suppressed the formation of NETs based on P2X7R-NLRP3 axis in mouse livers. Our data indicated that CA exerted hepatoprotective effects, which might be a promising candidate.
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Affiliation(s)
- Rong-Mei Zuo
- Key Laboratory of Traditional Chinese Korean Medicine Research (Yanbian University) of State Ethnic Affairs Commission, College of Pharmacy, Yanbian University, Yanji, Jilin 133002, China; Key Laboratory of Natural Medicines of the Changbai Mountain, Ministry of Education, College of Pharmacy, Yanbian University, Yanji, Jilin 133002, China
| | - Jing-Ya Jiao
- Key Laboratory of Traditional Chinese Korean Medicine Research (Yanbian University) of State Ethnic Affairs Commission, College of Pharmacy, Yanbian University, Yanji, Jilin 133002, China; Key Laboratory of Natural Medicines of the Changbai Mountain, Ministry of Education, College of Pharmacy, Yanbian University, Yanji, Jilin 133002, China
| | - Nan Chen
- Key Laboratory of Traditional Chinese Korean Medicine Research (Yanbian University) of State Ethnic Affairs Commission, College of Pharmacy, Yanbian University, Yanji, Jilin 133002, China; Key Laboratory of Natural Medicines of the Changbai Mountain, Ministry of Education, College of Pharmacy, Yanbian University, Yanji, Jilin 133002, China; Interdisciplinary of Biological Functional Molecules, College of Integration Science, Yanbian University, Yanji, Jilin 133002, China
| | - Xue-Li Jiang
- Key Laboratory of Traditional Chinese Korean Medicine Research (Yanbian University) of State Ethnic Affairs Commission, College of Pharmacy, Yanbian University, Yanji, Jilin 133002, China; Key Laboratory of Natural Medicines of the Changbai Mountain, Ministry of Education, College of Pharmacy, Yanbian University, Yanji, Jilin 133002, China
| | - Yan-Ling Wu
- Key Laboratory of Traditional Chinese Korean Medicine Research (Yanbian University) of State Ethnic Affairs Commission, College of Pharmacy, Yanbian University, Yanji, Jilin 133002, China; Key Laboratory of Natural Medicines of the Changbai Mountain, Ministry of Education, College of Pharmacy, Yanbian University, Yanji, Jilin 133002, China; Interdisciplinary of Biological Functional Molecules, College of Integration Science, Yanbian University, Yanji, Jilin 133002, China
| | - Ji-Xing Nan
- Key Laboratory of Traditional Chinese Korean Medicine Research (Yanbian University) of State Ethnic Affairs Commission, College of Pharmacy, Yanbian University, Yanji, Jilin 133002, China; Key Laboratory of Natural Medicines of the Changbai Mountain, Ministry of Education, College of Pharmacy, Yanbian University, Yanji, Jilin 133002, China; Interdisciplinary of Biological Functional Molecules, College of Integration Science, Yanbian University, Yanji, Jilin 133002, China.
| | - Li-Hua Lian
- Key Laboratory of Traditional Chinese Korean Medicine Research (Yanbian University) of State Ethnic Affairs Commission, College of Pharmacy, Yanbian University, Yanji, Jilin 133002, China; Key Laboratory of Natural Medicines of the Changbai Mountain, Ministry of Education, College of Pharmacy, Yanbian University, Yanji, Jilin 133002, China; Interdisciplinary of Biological Functional Molecules, College of Integration Science, Yanbian University, Yanji, Jilin 133002, China.
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24
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Wu MF, Zhang GD, Liu TT, Shen JH, Cheng JL, Shen J, Yang TY, Huang C, Zhang L. Hif-2α regulates lipid metabolism in alcoholic fatty liver disease through mitophagy. Cell Biosci 2022; 12:198. [PMID: 36476627 PMCID: PMC9730692 DOI: 10.1186/s13578-022-00889-1] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2022] [Accepted: 08/24/2022] [Indexed: 12/12/2022] Open
Abstract
BACKGROUND Disordered lipid metabolism plays an essential role in both the initiation and progression of alcoholic fatty liver disease (AFLD), and fatty acid β-oxidation is increasingly considered as a crucial factor for controlling lipid metabolism. Hif-2α is a member of the Hif family of nuclear receptors, which take part in regulating hepatic fatty acid β-oxidation. However, its functional role in AFLD and the underlying mechanisms remain unclear. RESULTS Hif-2α was upregulated in EtOH-fed mice and EtOH-treated AML-12 cells. Inhibition or silencing of Hif-2α led to increased fatty acid β-oxidation and BNIP3-dependent mitophagy. Downregulation of Hif-2α activates the PPAR-α/PGC-1α signaling pathway, which is involved in hepatic fatty acid β-oxidation, by mediating BNIP3-dependent mitophagy, ultimately delaying the progression of AFLD. CONCLUSIONS Hif-2α induces liver steatosis, which promotes the progression of AFLD. Here, we have described a novel Hif-2α-BNIP3-dependent mitophagy regulatory pathway interconnected with EtOH-induced lipid accumulation, which could be a potential therapeutic target for the prevention and treatment of AFLD.
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Affiliation(s)
- Mei-fei Wu
- grid.186775.a0000 0000 9490 772XSchool of Pharmacy, Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Medical University, Hefei, 230032 China ,grid.16821.3c0000 0004 0368 8293Sixth People’s Hospital South Campus, Shanghai Jiaotong University, Shanghai, 201400 China
| | - Guo-dong Zhang
- grid.186775.a0000 0000 9490 772XSchool of Pharmacy, Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Medical University, Hefei, 230032 China ,grid.186775.a0000 0000 9490 772XThe Key Laboratory of Anti-Inflammatory and Immune Medicines, Ministry of Education, Anhui Medical University, Hefei, 230032 China
| | - Tong-tong Liu
- grid.186775.a0000 0000 9490 772XSchool of Pharmacy, Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Medical University, Hefei, 230032 China ,grid.186775.a0000 0000 9490 772XThe Key Laboratory of Anti-Inflammatory and Immune Medicines, Ministry of Education, Anhui Medical University, Hefei, 230032 China
| | - Jun-hao Shen
- grid.186775.a0000 0000 9490 772XSchool of Pharmacy, Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Medical University, Hefei, 230032 China ,grid.186775.a0000 0000 9490 772XThe Key Laboratory of Anti-Inflammatory and Immune Medicines, Ministry of Education, Anhui Medical University, Hefei, 230032 China
| | - Jie-ling Cheng
- grid.186775.a0000 0000 9490 772XSchool of Pharmacy, Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Medical University, Hefei, 230032 China ,grid.186775.a0000 0000 9490 772XThe Key Laboratory of Anti-Inflammatory and Immune Medicines, Ministry of Education, Anhui Medical University, Hefei, 230032 China
| | - Jie Shen
- grid.186775.a0000 0000 9490 772XSchool of Pharmacy, Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Medical University, Hefei, 230032 China ,grid.186775.a0000 0000 9490 772XThe Key Laboratory of Anti-Inflammatory and Immune Medicines, Ministry of Education, Anhui Medical University, Hefei, 230032 China
| | - Tian-yu Yang
- grid.186775.a0000 0000 9490 772XSchool of Pharmacy, Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Medical University, Hefei, 230032 China ,grid.186775.a0000 0000 9490 772XThe Key Laboratory of Anti-Inflammatory and Immune Medicines, Ministry of Education, Anhui Medical University, Hefei, 230032 China
| | - Cheng Huang
- grid.186775.a0000 0000 9490 772XSchool of Pharmacy, Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Medical University, Hefei, 230032 China ,grid.186775.a0000 0000 9490 772XThe Key Laboratory of Anti-Inflammatory and Immune Medicines, Ministry of Education, Anhui Medical University, Hefei, 230032 China
| | - Lei Zhang
- grid.186775.a0000 0000 9490 772XSchool of Pharmacy, Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Medical University, Hefei, 230032 China ,grid.186775.a0000 0000 9490 772XThe Key Laboratory of Anti-Inflammatory and Immune Medicines, Ministry of Education, Anhui Medical University, Hefei, 230032 China
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25
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Abd El-Fattah EE, Zakaria AY. Targeting HSP47 and HSP70: promising therapeutic approaches in liver fibrosis management. J Transl Med 2022; 20:544. [DOI: 10.1186/s12967-022-03759-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2022] [Accepted: 11/06/2022] [Indexed: 11/28/2022] Open
Abstract
AbstractLiver fibrosis is a liver disease in which there is an excessive buildup of extracellular matrix proteins, including collagen. By regulating cytokine production and the inflammatory response, heat shock proteins (HSPs) contribute significantly to a wider spectrum of fibrotic illnesses, such as lung, liver, and idiopathic pulmonary fibrosis by aiding in the folding and assembly of freshly synthesized proteins, HSPs serve as chaperones. HSP70 is one of the key HSPs in avoiding protein aggregation which induces its action by sending unfolded and/or misfolded proteins to the ubiquitin–proteasome degradation pathway and antagonizing influence on epithelial-mesenchymal transition. HSP47, on the other hand, is crucial for boosting collagen synthesis, and deposition, and fostering the emergence of fibrotic disorders. The current review aims to provide light on how HSP70 and HSP47 affect hepatic fibrogenesis. Additionally, our review looks into new therapeutic approaches that target HSP70 and HSP47 and could potentially be used as drug candidates to treat liver fibrosis, especially in cases of comorbidities.
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26
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The effects of scoparone on alcohol and high-fat diet-induced liver injury revealed by RNA sequencing. Biomed Pharmacother 2022; 155:113770. [DOI: 10.1016/j.biopha.2022.113770] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2022] [Revised: 09/22/2022] [Accepted: 09/26/2022] [Indexed: 11/23/2022] Open
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27
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Pérez-Juárez A, Aguilar-Faisal JL, Posadas-Mondragón A, Santiago-Cruz JA, Barrientos-Alvarado C, Mojica-Villegas MA, Chamorro-Cevallos GA, Morales-González JA. Effect of Spirulina (Formerly Arthrospira) Maxima against Ethanol-Induced Damage in Rat Liver. APPLIED SCIENCES 2022; 12:8626. [DOI: 10.3390/app12178626] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/10/2024]
Abstract
Spirulina (formerly Arthrospira) maxima (SP) is a cyanobacterium reported to have great nutritional and pharmacological potential. The objective of this study was to evaluate the protective properties of SP against ethanol-induced toxicity. Male Wistar rats were used in the study and subjected to a 70% partial hepatectomy (PH); they were then divided into five groups. During the experiment, animals in two groups drank an aqueous solution of ethanol (EtOH) (40%, v/v). Additionally, they were administered an SP extract daily at a dose of 200 mg/kg body weight intragastrically. To explore possible mechanisms of action, we examined antioxidant defense enzymes, as well as serum biochemical parameters and histopathological changes in the liver. SP administration normalized elevated glutathione reductase (GR), glutathione (GSH), and superoxide dismutase (SOD) levels, in addition to increased catalase (CAT) and glutathione peroxidase (GPX) enzymes. Alterations in biochemical parameters were observed in the groups with PH treated with EtOH associated with a reduction in cholesterol and albumin levels, while glucose and triglyceride levels increased. The histological study supported the protective activity of SP, reducing apoptosis, necrosis, and congestion in the liver. Our findings demonstrated a protective effect of SP against EtOH that is related to less inflammation, a lesser antioxidant effect, and less free radical scavenging activity.
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Affiliation(s)
- Angélica Pérez-Juárez
- Laboratorio de Medicina de Conservación, Escuela Superior de Medicina, Instituto Politécnico Nacional, Ciudad de México 11340, Mexico
| | - José Leopoldo Aguilar-Faisal
- Laboratorio de Medicina de Conservación, Escuela Superior de Medicina, Instituto Politécnico Nacional, Ciudad de México 11340, Mexico
| | - Araceli Posadas-Mondragón
- Laboratorio de Medicina de Conservación, Escuela Superior de Medicina, Instituto Politécnico Nacional, Ciudad de México 11340, Mexico
| | - José Angel Santiago-Cruz
- Laboratorio de Medicina de Conservación, Escuela Superior de Medicina, Instituto Politécnico Nacional, Ciudad de México 11340, Mexico
| | - Cornelio Barrientos-Alvarado
- Laboratorio de Medicina de Conservación, Escuela Superior de Medicina, Instituto Politécnico Nacional, Ciudad de México 11340, Mexico
| | - María Angélica Mojica-Villegas
- Departamento de Farmacia, Escuela Nacional de Ciencias Biológicas, Instituto Politécnico Nacional, Ciudad de México 07738, Mexico
| | - Germán Alberto Chamorro-Cevallos
- Departamento de Farmacia, Escuela Nacional de Ciencias Biológicas, Instituto Politécnico Nacional, Ciudad de México 07738, Mexico
| | - José A. Morales-González
- Laboratorio de Medicina de Conservación, Escuela Superior de Medicina, Instituto Politécnico Nacional, Ciudad de México 11340, Mexico
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28
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Torres S, Segalés P, García-Ruiz C, Fernández-Checa JC. Mitochondria and the NLRP3 Inflammasome in Alcoholic and Nonalcoholic Steatohepatitis. Cells 2022; 11:1475. [PMID: 35563780 PMCID: PMC9105698 DOI: 10.3390/cells11091475] [Citation(s) in RCA: 24] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2022] [Revised: 04/18/2022] [Accepted: 04/25/2022] [Indexed: 12/12/2022] Open
Abstract
Alcoholic (ASH) and nonalcoholic steatohepatitis (NASH) are advanced stages of fatty liver disease and two of the most prevalent forms of chronic liver disease. ASH and NASH are associated with significant risk of further progression to cirrhosis and hepatocellular carcinoma (HCC), the most common type of liver cancer, and a major cause of cancer-related mortality. Despite extensive research and progress in the last decades to elucidate the mechanisms of the development of ASH and NASH, the pathogenesis of both diseases is still poorly understood. Mitochondrial damage and activation of inflammasome complexes have a role in inducing and sustaining liver damage. Mitochondrial dysfunction produces inflammatory factors that activate the inflammasome complexes. NLRP3 inflammasome (nucleotide-binding oligomerization domain-like receptor protein 3) is a multiprotein complex that activates caspase 1 and the release of pro-inflammatory cytokines, including interleukin-1β (IL-1β) and interleukin-18 (IL-18), and contributes to inflammatory pyroptotic cell death. The present review, which is part of the issue "Mitochondria in Liver Pathobiology", provides an overview of the role of mitochondrial dysfunction and NLRP3 activation in ASH and NASH.
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Affiliation(s)
- Sandra Torres
- Department of Cell Death and Proliferation, Institute of Biomedical Research of Barcelona (IIBB), Spanish National Research Council (CSIC), 08036 Barcelona, Spain; (S.T.); (P.S.)
- Liver Unit, Hospital Clinic I Provincial de Barcelona, Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), 08036 Barcelona, Spain
- Center for the Study of Liver and Gastrointestinal Diseases (CIBERehd), Carlos III National Institute of Health, 28029 Madrid, Spain
| | - Paula Segalés
- Department of Cell Death and Proliferation, Institute of Biomedical Research of Barcelona (IIBB), Spanish National Research Council (CSIC), 08036 Barcelona, Spain; (S.T.); (P.S.)
- Liver Unit, Hospital Clinic I Provincial de Barcelona, Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), 08036 Barcelona, Spain
- Center for the Study of Liver and Gastrointestinal Diseases (CIBERehd), Carlos III National Institute of Health, 28029 Madrid, Spain
| | - Carmen García-Ruiz
- Department of Cell Death and Proliferation, Institute of Biomedical Research of Barcelona (IIBB), Spanish National Research Council (CSIC), 08036 Barcelona, Spain; (S.T.); (P.S.)
- Liver Unit, Hospital Clinic I Provincial de Barcelona, Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), 08036 Barcelona, Spain
- Center for the Study of Liver and Gastrointestinal Diseases (CIBERehd), Carlos III National Institute of Health, 28029 Madrid, Spain
- Division of Gastrointestinal and Liver Diseases, Department of Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA
| | - José C. Fernández-Checa
- Department of Cell Death and Proliferation, Institute of Biomedical Research of Barcelona (IIBB), Spanish National Research Council (CSIC), 08036 Barcelona, Spain; (S.T.); (P.S.)
- Liver Unit, Hospital Clinic I Provincial de Barcelona, Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), 08036 Barcelona, Spain
- Center for the Study of Liver and Gastrointestinal Diseases (CIBERehd), Carlos III National Institute of Health, 28029 Madrid, Spain
- Division of Gastrointestinal and Liver Diseases, Department of Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA
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Lee SB, Kwon YJ, Jung DH, Kim JK. Association of Muscle Strength with Non-Alcoholic Fatty Liver Disease in Korean Adults. INTERNATIONAL JOURNAL OF ENVIRONMENTAL RESEARCH AND PUBLIC HEALTH 2022; 19:ijerph19031675. [PMID: 35162699 PMCID: PMC8834805 DOI: 10.3390/ijerph19031675] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/14/2021] [Revised: 01/25/2022] [Accepted: 01/27/2022] [Indexed: 02/01/2023]
Abstract
Sarcopenia is known to be associated with non-alcoholic fatty liver disease (NAFLD). However, few studies have revealed the association between muscle strength and prevalence of NAFLD. We investigated the association by using relative handgrip strength in a nationwide cross-sectional survey. The participants were recruited from the Korean National Health and Nutrition Examination Surveys (KNHANES). A total of 27,531 subjects from the KNHANES were selected in our study. We used normalized handgrip strength, which is called relative handgrip strength. The index was defined as handgrip strength divided by BMI. These subjects were divided into quartile groups according to relative handgrip strength. NAFLD was defined as hepatic steatosis index >36. Multinomial logistic regression was analysed to investigate the association between relative handgrip strength with prevalence of NAFLD. The mean age of study population was 45.8 ± 0.3 in men, and 48.3 ± 0.2 in women. The proportion of males was 37.5%. In multiple linear regression, relative handgrip strength was inversely associated with HSI index (Standardized β = −0.70; standard error (SE), 0.08; p < 0.001 in men, Standardized β = −0.94; standard error (SE), 0.07; p < 0.001 in women). According to the logistic regression model, the prevalence of NAFLD decreased with quartile 4 groups in relative handgrip strength, compared with quartile 1 groups (OR 0.42 [0.32–0.55] in men; OR 0.30 [0.22–0.40] in women). Relative handgrip strength, used as a biomarker of sarcopenia, is independently inversely associated with NAFLD.
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Affiliation(s)
- Sung-Bum Lee
- Department of Medicine, Graduate School, Yonsei University Wonju College of Medicine, Wonju 26426, Korea;
| | - Yu-Jin Kwon
- Department of Family Medicine, Yongin Severance Hospital, Yonsei University College of Medicine, Yongin 16995, Korea; (Y.-J.K.); (D.-H.J.)
| | - Dong-Hyuk Jung
- Department of Family Medicine, Yongin Severance Hospital, Yonsei University College of Medicine, Yongin 16995, Korea; (Y.-J.K.); (D.-H.J.)
| | - Jong-Koo Kim
- Department of Family Medicine, Yonsei University Wonju College of Medicine, Wonju 26426, Korea
- Research Group for Global Health and Medical Technology Development, Yonsei University Wonju College of Medicine, Wonju 26426, Korea
- Correspondence:
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Zhu YW, Li D, Ye TJ, Qiu FJ, Wang XL, Yan XF, Lu YL, Xu W, Li H, Hu XD. The Study of Yin-Chen-Hao-Tang Preventing and Treating Alcoholic Fatty Liver Disease through PPAR Signaling Pathway Based on Network Pharmacology and RNA-Seq Transcriptomics. EVIDENCE-BASED COMPLEMENTARY AND ALTERNATIVE MEDICINE : ECAM 2021; 2021:8917993. [PMID: 35003311 PMCID: PMC8741355 DOI: 10.1155/2021/8917993] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/25/2021] [Revised: 11/15/2021] [Accepted: 12/09/2021] [Indexed: 12/30/2022]
Abstract
BACKGROUND Alcoholic fatty liver disease (AFLD) is the first stage of the alcoholic liver disease course. Yin-Chen-Hao-Tang (YCHT) has a good clinical effect on the treatment of AFLD, but its molecular mechanism has not been elucidated. In this study, we tried to explore the molecular mechanism of YCHT in improving hepatocyte steatosis in AFLD mice through network pharmacology and RNA sequencing (RNA-Seq) transcriptomics. METHODS Network pharmacological methods were used to analyze the potential therapeutic signaling pathways and targets of YCHT on AFLD. Then, the AFLD mice model was induced and YCHT was administered concurrently. Liver injury was measured by serum alanine aminotransferase (ALT) activity and liver tissue H&E staining, and liver steatosis was determined by serum triglyceride (TG) level and liver tissue Oil Red staining. The molecular mechanism of YCHT on prevention and treatment of mice AFLD was investigated according to the Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis of the differential expression genes data obtained by liver tissue RNA-Seq. Finally, ethanol-induced AFLD AML12 hepatocyte model was established, YCHT with or without PPARα agonist pemafibrate or PPARγ inhibitor GW9662 was administered, Nile Red fluorescent staining was used to evaluate steatosis levels in AML12 hepatocytes, and qRT-PCR was used to detect PPARα and PPARγ gene expression. RESULTS The results of network pharmacology analysis showed that YCHT may exert its pharmacological effect on AFLD through 312 potential targets which are involved in many signaling pathways including the PPAR signaling pathway. AFLD mice experiments results showed that YCHT markedly decreased mice serum ALT activity and serum TG levels. YCHT also significantly improved alcohol-induced hepatic injury and steatosis in mice livers. Furthermore, KEGG pathway enrichment results of RNA-Seq showed that the PPAR signaling pathway should be the most relevant pathway of YCHT in the prevention and treatment of AFLD. AFLD hepatocyte model experiment results showed that YCHT could remarkably reduce hepatocyte steatosis through reducing PPARγ expression and increasing PPARα expression. CONCLUSIONS Our study discovered that PPARγ and PPARα are the key targets and the PPAR signaling pathway is the main signaling pathway for YCHT to prevent and treat AFLD.
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Affiliation(s)
- Yi-Wei Zhu
- Department of Biology, School of Basic Medical Science, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
| | - Du Li
- Department of Biology, School of Basic Medical Science, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
| | - Ting-Jie Ye
- Department of Biology, School of Basic Medical Science, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
| | - Feng-Jun Qiu
- Department of Biology, School of Basic Medical Science, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
| | - Xiao-Ling Wang
- Department of Biology, School of Basic Medical Science, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
| | - Xiao-Feng Yan
- Department of Biology, School of Basic Medical Science, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
| | - Yan-Lin Lu
- Department of Biology, School of Basic Medical Science, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
| | - Wei Xu
- Department of Biology, School of Basic Medical Science, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
| | - Hua Li
- Department of Biology, School of Basic Medical Science, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
| | - Xu-Dong Hu
- Department of Biology, School of Basic Medical Science, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
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Zhao Z, Guo Z, Yin Z, Qiu Y, Zhou B. Gut Microbiota Was Involved in the Process of Liver Injury During Intra-Abdominal Hypertension. Front Physiol 2021; 12:790182. [PMID: 34955896 PMCID: PMC8703017 DOI: 10.3389/fphys.2021.790182] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/06/2021] [Accepted: 11/12/2021] [Indexed: 11/22/2022] Open
Abstract
Background: Intestinal damage caused by intra-abdominal hypertension (IAH) and abdominal compartment syndrome (ACS) can lead to the ectopic gut microbiota, which can contribute to liver injury via portal veins. Therefore, it is speculated that gut microbiota disorder caused by IAH/ACS may result in liver injury. The relationship between gut microbiota and IAH/ACS-related liver injury was investigated in this study. Methods: A model of IAH was established in rats, and 16S rRNA sequencing was analyzed for gut microbiota in the feces of rats. The elimination of gut microbiota was completed by antibiotics gavage, and fecal microbiota transplantation (FMT) was used to change the composition of gut microbiota in rats. Results: In addition to the traditional cause of liver blood vessel compression, liver injury caused by IAH was also associated with gut microbiota dysbiosis. Gut microbiota clearance can relieve liver injury caused by IAH, while FMT from IAH-intervened rats can aggravate IAH-related liver injury. Conclusion: The gut microbiota was one of the most important factors contributing to the IAH-related liver injury, and the JNK/p38 signaling pathway was activated in this process.
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Affiliation(s)
- Zeyu Zhao
- Department of General Surgery, The First Affiliated Hospital of Anhui Medical University, Hefei, China
| | - Zhengchang Guo
- Department of General Surgery, The First Affiliated Hospital of Anhui Medical University, Hefei, China
| | - Zhengliang Yin
- Department of General Surgery, The First Affiliated Hospital of Anhui Medical University, Hefei, China
| | - Yue Qiu
- Department of General Surgery, The First Affiliated Hospital of Anhui Medical University, Hefei, China
| | - Bo Zhou
- Department of General Surgery, The First Affiliated Hospital of Anhui Medical University, Hefei, China
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32
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Dou JY, Jiang YC, Hu ZH, Yao KC, Yuan MH, Bao XX, Zhou MJ, Liu Y, Li ZX, Lian LH, Nan JX, Wu YL. Betulin Targets Lipin1/2-Meidated P2X7 Receptor as a Therapeutic Approach to Attenuate Lipid Accumulation and Metaflammation. Biomol Ther (Seoul) 2021; 30:246-256. [PMID: 34815367 PMCID: PMC9047492 DOI: 10.4062/biomolther.2021.136] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2021] [Revised: 10/19/2021] [Accepted: 11/01/2021] [Indexed: 11/06/2022] Open
Abstract
The present study focused on the potential mechanism of betulin (BT), a pentacyclic triterpenoid isolated from the bark of white birch (Betula pubescens), against chronic alcohol-induced lipid accumulation and metaflammation. AML-12 and RAW 264.7 cells were administered ethanol (EtOH), lipopolysaccharide (LPS) or BT. Male C57BL/6 mice were fed Lieber-DeCarli liquid diets containing 5% EtOH for 4 weeks, followed by single EtOH gavage on the last day and simultaneous treatment with BT (20 or 50 mg/kg) by oral gavage once per day. In vitro, MTT showed that 0-25 mM EtOH and 0-25 μM BT had no toxic effect on AML-12 cells. BT could regulate sterolregulatory-element-binding protein 1 (SREBP1), lipin1/2, P2X7 receptor (P2X7r) and NOD-like receptor family, pyrin domains-containing protein 3 (NLRP3) expressions again EtOH-stimulation. Oil Red O staining also indicated that BT significantly reduced lipid accumulation in EtOH-stimulated AML-12 cells. Lipin1/2 deficiency indicated that BT might mediate lipin1/2 to regulate SREBP1 and P2X7r expression and further alleviate lipid accumulation and inflammation. In vivo, BT significantly alleviated histopathological changes, reduced serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) and triglyceride (TG) levels, and regulated lipin1/2, SREBP1, peroxisome proliferator activated receptor α/γ (PPARα/γ) and PGC-1α expression compared with the EtOH group. BT reduced the secretion of inflammatory factors and blocked the P2X7r-NLRP3 signaling pathway. Collectively, BT attenuated lipid accumulation and metaflammation by regulating the lipin1/2-mediated P2X7r signaling pathway.
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Affiliation(s)
- Jia-Yi Dou
- Key Laboratory for Traditional Chinese Korean Medicine of Jilin Province, College of Pharmacy, Yanbian University, Yanji, Jilin Province 133002, China
| | - Yu-Chen Jiang
- Key Laboratory for Traditional Chinese Korean Medicine of Jilin Province, College of Pharmacy, Yanbian University, Yanji, Jilin Province 133002, China
| | - Zhong-He Hu
- Key Laboratory for Traditional Chinese Korean Medicine of Jilin Province, College of Pharmacy, Yanbian University, Yanji, Jilin Province 133002, China
| | - Kun-Chen Yao
- Key Laboratory for Traditional Chinese Korean Medicine of Jilin Province, College of Pharmacy, Yanbian University, Yanji, Jilin Province 133002, China
| | - Ming-Hui Yuan
- Key Laboratory for Traditional Chinese Korean Medicine of Jilin Province, College of Pharmacy, Yanbian University, Yanji, Jilin Province 133002, China
| | - Xiao-Xue Bao
- Key Laboratory for Traditional Chinese Korean Medicine of Jilin Province, College of Pharmacy, Yanbian University, Yanji, Jilin Province 133002, China
| | - Mei-Jie Zhou
- Key Laboratory for Traditional Chinese Korean Medicine of Jilin Province, College of Pharmacy, Yanbian University, Yanji, Jilin Province 133002, China
| | - Yue Liu
- Key Laboratory for Traditional Chinese Korean Medicine of Jilin Province, College of Pharmacy, Yanbian University, Yanji, Jilin Province 133002, China
| | - Zhao-Xu Li
- Key Laboratory for Traditional Chinese Korean Medicine of Jilin Province, College of Pharmacy, Yanbian University, Yanji, Jilin Province 133002, China
| | - Li-Hua Lian
- Key Laboratory for Traditional Chinese Korean Medicine of Jilin Province, College of Pharmacy, Yanbian University, Yanji, Jilin Province 133002, China
| | - Ji-Xing Nan
- Key Laboratory for Traditional Chinese Korean Medicine of Jilin Province, College of Pharmacy, Yanbian University, Yanji, Jilin Province 133002, China
| | - Yan-Ling Wu
- Key Laboratory for Traditional Chinese Korean Medicine of Jilin Province, College of Pharmacy, Yanbian University, Yanji, Jilin Province 133002, China
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Koga T, Peters JM. Targeting Peroxisome Proliferator-Activated Receptor-β/δ (PPARβ/δ) for the Treatment or Prevention of Alcoholic Liver Disease. Biol Pharm Bull 2021; 44:1598-1606. [PMID: 34719638 DOI: 10.1248/bpb.b21-00486] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
Excessive, chronic alcohol consumption can lead to alcoholic liver disease. The etiology of alcoholic liver disease is multifactorial and is influenced by alterations in gene expression and changes in fatty acid metabolism, oxidative stress, and insulin resistance. These events can lead to steatosis, fibrosis, and eventually to cirrhosis and liver cancer. Many of these functions are regulated by peroxisome proliferator-activated receptors (PPARs). Thus, it is not surprising that PPARs can modulate the mechanisms that cause alcoholic liver disease. While the roles of PPARα and PPARγ are clearer, the role of PPARβ/δ in alcoholic liver disease requires further clarification. This review summarizes the current understanding based on recent studies that indicate that PPARβ/δ can likely be targeted for the treatment and/or the prevention of alcoholic liver disease.
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Affiliation(s)
- Takayuki Koga
- Laboratory of Hygienic Chemistry, Department of Health Science and Hygiene, Daiichi University of Pharmacy
| | - Jeffrey M Peters
- Department of Veterinary and Biomedical Sciences and the Center of Molecular Toxicology and Carcinogenesis, The Pennsylvania State University
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34
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Cui ZY, Han X, Jiang YC, Dou JY, Yao KC, Hu ZH, Yuan MH, Bao XX, Zhou MJ, Liu Y, Lian LH, Zhang X, Nan JX, Wu YL. Allium victorialis L. Extracts Promote Activity of FXR to Ameliorate Alcoholic Liver Disease: Targeting Liver Lipid Deposition and Inflammation. Front Pharmacol 2021; 12:738689. [PMID: 34690775 PMCID: PMC8531498 DOI: 10.3389/fphar.2021.738689] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2021] [Accepted: 08/09/2021] [Indexed: 12/20/2022] Open
Abstract
Allium victorialis L. (AVL) is a traditional medicinal plant recorded in the Compendium of Materia Medica (the Ming Dynasty). In general, it is used for hemostasis, analgesia, anti-inflammation, antioxidation, and to especially facilitate hepatoprotective effect. In recent years, it has received more and more attention due to its special nutritional and medicinal value. The present study investigates the effect and potential mechanism of AVL against alcoholic liver disease (ALD). C57BL/6 mice were fed Lieber-DeCarli liquid diet containing 5% ethanol plus a single ethanol gavage (5 g/kg), and followed up with the administration of AVL or silymarin. AML12 cells were stimulated with ethanol and incubated with AVL. AVL significantly reduced serum transaminase and triglycerides in the liver and attenuated histopathological changes caused by ethanol. AVL significantly inhibited SREBP1 and its target genes, regulated lipin 1/2, increased PPARα and its target genes, and decreased PPARγ expression caused by ethanol. In addition, AVL significantly enhanced FXR, LXRs, Sirt1, and AMPK expressions compared with the EtOH group. AVL also inhibited inflammatory factors, NLRP3, and F4/80 and MPO, macrophage and neutrophil markers. In vitro, AVL significantly reduced lipid droplets, lipid metabolism enzymes, and inflammatory factors depending on FXR activation. AVL could ameliorate alcoholic steatohepatitis, lipid deposition and inflammation in ALD by targeting FXR activation.
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Affiliation(s)
- Zhen-Yu Cui
- Key Laboratory for Traditional Chinese Korean Medicine of Jilin Province, College of Pharmacy, Yanbian University, Yanji, China
| | - Xin Han
- Chinese Medicine Processing Centre, College of Pharmacy, Zhejiang Chinese Medical University, Hangzhou, China
| | - Yu-Chen Jiang
- Key Laboratory for Traditional Chinese Korean Medicine of Jilin Province, College of Pharmacy, Yanbian University, Yanji, China
| | - Jia-Yi Dou
- Key Laboratory for Traditional Chinese Korean Medicine of Jilin Province, College of Pharmacy, Yanbian University, Yanji, China
| | - Kun-Chen Yao
- Key Laboratory for Traditional Chinese Korean Medicine of Jilin Province, College of Pharmacy, Yanbian University, Yanji, China
| | - Zhong-He Hu
- Key Laboratory for Traditional Chinese Korean Medicine of Jilin Province, College of Pharmacy, Yanbian University, Yanji, China
| | - Ming-Hui Yuan
- Key Laboratory for Traditional Chinese Korean Medicine of Jilin Province, College of Pharmacy, Yanbian University, Yanji, China
| | - Xiao-Xue Bao
- Key Laboratory for Traditional Chinese Korean Medicine of Jilin Province, College of Pharmacy, Yanbian University, Yanji, China
| | - Mei-Jie Zhou
- Key Laboratory for Traditional Chinese Korean Medicine of Jilin Province, College of Pharmacy, Yanbian University, Yanji, China
| | - Yue Liu
- Key Laboratory for Traditional Chinese Korean Medicine of Jilin Province, College of Pharmacy, Yanbian University, Yanji, China
| | - Li-Hua Lian
- Key Laboratory for Traditional Chinese Korean Medicine of Jilin Province, College of Pharmacy, Yanbian University, Yanji, China
| | - Xian Zhang
- Agricultural College, Yanbian University, Yanji, China
| | - Ji-Xing Nan
- Key Laboratory for Traditional Chinese Korean Medicine of Jilin Province, College of Pharmacy, Yanbian University, Yanji, China.,Clinical Research Center, Affiliated Hospital of Yanbian University, Yanji, China
| | - Yan-Ling Wu
- Key Laboratory for Traditional Chinese Korean Medicine of Jilin Province, College of Pharmacy, Yanbian University, Yanji, China
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Wang R, Mu J. Arbutin attenuates ethanol-induced acute hepatic injury by the modulation of oxidative stress and Nrf-2/HO-1 signaling pathway. J Biochem Mol Toxicol 2021; 35:e22872. [PMID: 34346143 DOI: 10.1002/jbt.22872] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2021] [Revised: 03/20/2021] [Accepted: 07/21/2021] [Indexed: 12/17/2022]
Abstract
Alcoholic liver disease (ALD) is a pervasive ailment due to the excessive consumption of alcohol and there is no operative drug for its treatment. The current exploration was intended to examine the hepatoprotective efficacy of arbutin against ethanol-provoked liver injury in rats via the modulation of the Nrf-2/HO-1 signaling cascade. Wistar rats were challenged with the 3 g/kg/day (40% v/v) of ethanol for 4 weeks to provoke the ALD and concomitantly supplemented with 40 mg/kg of arbutin. The liver function markers enzymes, inflammatory cytokines, and oxidative stress markers levels were scrutinized by using the respective assay kits. The mRNA expression of Nrf-2/HO-1 signaling proteins was studied by reverse-transcription polymerase chain reaction. The histological alterations of liver tissues were examined. HepG2 cells were used for the in vitro studies. The levels of oxidative stress markers and liver marker enzymes were examined by using kits. Reactive oxygen species (ROS) and apoptotic cell death was detected by using fluorescent staining. There were no major differences in the body weight and liver weight of experimental animals. Arbutin treatment appreciably reduced the liver marker enzymes, upregulated superoxide dismutase, glutathione peroxidase, total antioxidant capacity, and the hydroxyl scavenging ability, and diminished the tumor necrosis factor-α and interleukin-6 levels in the serum of ethanol provoked animals. Arbutin triggered Nrf-2/HO-1 signaling cascade liver tissues of ethanol-provoked animals. Histological findings proved the preventing effects of arbutin. Arbutin did not demonstrate toxicity to the HepG2 cells. It reduced the aspartate aminotransferase and alanine aminotransferase, ROS, apoptotic cell death, lipid peroxidation and improved the antioxidants' levels in the ethanol-challenged HepG2 cells. In conclusion, our findings unveiled the hepatoprotective efficacy of arbutin against ethanol-provoked liver injury in rats. It could be a promising agent to treat alcoholic liver disease in the future.
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Affiliation(s)
- Rongsheng Wang
- Department of General Surgery, The Second Affiliated Hospital of Wannan Medical College, Wuhu, China
| | - Jinji Mu
- Department of Gastroenterology, People's Hospital of Tongchuan, Tongchuan, China
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Monroy-Ramirez HC, Galicia-Moreno M, Sandoval-Rodriguez A, Meza-Rios A, Santos A, Armendariz-Borunda J. PPARs as Metabolic Sensors and Therapeutic Targets in Liver Diseases. Int J Mol Sci 2021; 22:ijms22158298. [PMID: 34361064 PMCID: PMC8347792 DOI: 10.3390/ijms22158298] [Citation(s) in RCA: 47] [Impact Index Per Article: 11.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2021] [Revised: 07/28/2021] [Accepted: 07/29/2021] [Indexed: 12/12/2022] Open
Abstract
Carbohydrates and lipids are two components of the diet that provide the necessary energy to carry out various physiological processes to help maintain homeostasis in the body. However, when the metabolism of both biomolecules is altered, development of various liver diseases takes place; such as metabolic-associated fatty liver diseases (MAFLD), hepatitis B and C virus infections, alcoholic liver disease (ALD), and in more severe cases, hepatocelular carcinoma (HCC). On the other hand, PPARs are a family of ligand-dependent transcription factors with an important role in the regulation of metabolic processes to hepatic level as well as in other organs. After interaction with specific ligands, PPARs are translocated to the nucleus, undergoing structural changes to regulate gene transcription involved in lipid metabolism, adipogenesis, inflammation and metabolic homeostasis. This review aims to provide updated data about PPARs’ critical role in liver metabolic regulation, and their involvement triggering the genesis of several liver diseases. Information is provided about their molecular characteristics, cell signal pathways, and the main pharmacological therapies that modulate their function, currently engaged in the clinic scenario, or in pharmacological development.
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Affiliation(s)
- Hugo Christian Monroy-Ramirez
- Instituto de Biologia Molecular en Medicina, Centro Universitario de Ciencias de la Salud, Universidad de Guadalajara, Guadalajara 44340, Jalisco, Mexico; (H.C.M.-R.); (M.G.-M.); (A.S.-R.)
| | - Marina Galicia-Moreno
- Instituto de Biologia Molecular en Medicina, Centro Universitario de Ciencias de la Salud, Universidad de Guadalajara, Guadalajara 44340, Jalisco, Mexico; (H.C.M.-R.); (M.G.-M.); (A.S.-R.)
| | - Ana Sandoval-Rodriguez
- Instituto de Biologia Molecular en Medicina, Centro Universitario de Ciencias de la Salud, Universidad de Guadalajara, Guadalajara 44340, Jalisco, Mexico; (H.C.M.-R.); (M.G.-M.); (A.S.-R.)
| | - Alejandra Meza-Rios
- Tecnologico de Monterrey, Escuela de Medicina y Ciencias de la Salud, Zapopan 45138, Jalisco, Mexico; (A.M.-R.); (A.S.)
| | - Arturo Santos
- Tecnologico de Monterrey, Escuela de Medicina y Ciencias de la Salud, Zapopan 45138, Jalisco, Mexico; (A.M.-R.); (A.S.)
| | - Juan Armendariz-Borunda
- Instituto de Biologia Molecular en Medicina, Centro Universitario de Ciencias de la Salud, Universidad de Guadalajara, Guadalajara 44340, Jalisco, Mexico; (H.C.M.-R.); (M.G.-M.); (A.S.-R.)
- Tecnologico de Monterrey, Escuela de Medicina y Ciencias de la Salud, Zapopan 45138, Jalisco, Mexico; (A.M.-R.); (A.S.)
- Correspondence:
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37
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Liu Q, Xu L, Wu M, Zhou Y, Yang J, Huang C, Xu T, Li J, Zhang L. Rev-erbα exacerbates hepatic steatosis in alcoholic liver diseases through regulating autophagy. Cell Biosci 2021; 11:129. [PMID: 34246287 PMCID: PMC8272374 DOI: 10.1186/s13578-021-00622-4] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2021] [Accepted: 05/31/2021] [Indexed: 12/20/2022] Open
Abstract
Background and aims Alcoholic fatty liver (AFL) is a liver disease caused by long-term excessive drinking and is characterized by hepatic steatosis. Understanding the regulatory mechanism of steatosis is essential for the treatment of AFL. Rev-erbα is a member of the Rev-erbs family of nuclear receptors, playing an important role in regulating lipid metabolism. However, its functional role in AFL and its underlying mechanism remains unclear. Results Rev-erbα was upregulated in the liver of EtOH-fed mice and EtOH-treated L-02 cells. Further, Rev-erbα activation exacerbates steatosis in L-02 cells. Inhibition/downexpression of Rev-erbα improved steatosis. Mechanistically, autophagy activity was inhibited in vivo and vitro. Interestingly, inhibition/downexpression of Rev-erbα enhanced autophagy. Furthermore, silencing of Rev-erbα up-regulated the nuclear expression of Bmal1. Autophagy activity was inhibited and steatosis was deteriorated after EtOH-treated L-02 cells were cotransfected with Rev-erbα shRNA and Bmal1 siRNA. Conclusions Rev-erbα induces liver steatosis, which promotes the progression of AFL. Our study reveals a novel steatosis regulatory mechanism in AFL and suggest that Rev-erbα might be a potential therapeutic target for AFL. Supplementary Information The online version contains supplementary material available at 10.1186/s13578-021-00622-4.
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Affiliation(s)
- Qingxue Liu
- School of Pharmacy, Anhui Institute of Innovative Drugs, Anhui Medical University, Hefei, 230032, Anhui, China.,Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Hefei, 230032, People's Republic of China.,The Key Laboratory of Anti-Inflammatory and Immune Medicines, Ministry of Education, Hefei, 230032, China
| | - Lei Xu
- School of Pharmacy, Anhui Institute of Innovative Drugs, Anhui Medical University, Hefei, 230032, Anhui, China.,Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Hefei, 230032, People's Republic of China.,The Key Laboratory of Anti-Inflammatory and Immune Medicines, Ministry of Education, Hefei, 230032, China
| | - Meifei Wu
- School of Pharmacy, Anhui Institute of Innovative Drugs, Anhui Medical University, Hefei, 230032, Anhui, China.,Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Hefei, 230032, People's Republic of China.,The Key Laboratory of Anti-Inflammatory and Immune Medicines, Ministry of Education, Hefei, 230032, China
| | - Yiwen Zhou
- School of Pharmacy, Anhui Institute of Innovative Drugs, Anhui Medical University, Hefei, 230032, Anhui, China.,Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Hefei, 230032, People's Republic of China.,The Key Laboratory of Anti-Inflammatory and Immune Medicines, Ministry of Education, Hefei, 230032, China
| | - Junfa Yang
- School of Pharmacy, Anhui Institute of Innovative Drugs, Anhui Medical University, Hefei, 230032, Anhui, China.,Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Hefei, 230032, People's Republic of China.,The Key Laboratory of Anti-Inflammatory and Immune Medicines, Ministry of Education, Hefei, 230032, China
| | - Cheng Huang
- School of Pharmacy, Anhui Institute of Innovative Drugs, Anhui Medical University, Hefei, 230032, Anhui, China.,Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Hefei, 230032, People's Republic of China.,The Key Laboratory of Anti-Inflammatory and Immune Medicines, Ministry of Education, Hefei, 230032, China
| | - Tao Xu
- School of Pharmacy, Anhui Institute of Innovative Drugs, Anhui Medical University, Hefei, 230032, Anhui, China.,Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Hefei, 230032, People's Republic of China.,The Key Laboratory of Anti-Inflammatory and Immune Medicines, Ministry of Education, Hefei, 230032, China
| | - Jun Li
- School of Pharmacy, Anhui Institute of Innovative Drugs, Anhui Medical University, Hefei, 230032, Anhui, China.,Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Hefei, 230032, People's Republic of China.,The Key Laboratory of Anti-Inflammatory and Immune Medicines, Ministry of Education, Hefei, 230032, China
| | - Lei Zhang
- School of Pharmacy, Anhui Institute of Innovative Drugs, Anhui Medical University, Hefei, 230032, Anhui, China. .,Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Hefei, 230032, People's Republic of China. .,The Key Laboratory of Anti-Inflammatory and Immune Medicines, Ministry of Education, Hefei, 230032, China.
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Byun J, Shin JE, Choi Y, Choung S. Oyster hydrolysate ameliorates ethanol diet‐induced alcoholic fatty liver by regulating lipid metabolism in rats. Int J Food Sci Technol 2021. [DOI: 10.1111/ijfs.14983] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/22/2023]
Affiliation(s)
- Jae‐Hyuk Byun
- Department of Life and Nanopharmaceutical Sciences Graduate School Kyung Hee University Seoul02447Korea
| | - Ji Eun Shin
- Department of Life and Nanopharmaceutical Sciences Graduate School Kyung Hee University Seoul02447Korea
| | - Yeung‐Joon Choi
- Department of Seafood Science and Technology/Institute of Marine Industry Gyeongsang National University Gyeongnam650‐160Korea
| | - Se‐Young Choung
- Department of Life and Nanopharmaceutical Sciences Graduate School Kyung Hee University Seoul02447Korea
- Department of Preventive Pharmacy and Toxicology College of Pharmacy Kyung Hee University Seoul Korea
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39
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Vasques-Monteiro IML, Silva-Veiga FM, Miranda CS, de Andrade Gonçalves ÉCB, Daleprane JB, Souza-Mello V. A rise in Proteobacteria is an indicator of gut-liver axis-mediated nonalcoholic fatty liver disease in high-fructose-fed adult mice. Nutr Res 2021; 91:26-35. [PMID: 34130208 DOI: 10.1016/j.nutres.2021.04.008] [Citation(s) in RCA: 40] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2020] [Revised: 04/17/2021] [Accepted: 04/30/2021] [Indexed: 01/12/2023]
Abstract
Current evidence suggests that high fructose intake results in gut dysbiosis, leading to endotoxemia and NAFLD onset. Thus, the hypothesis of the study was that an enhanced Proteobacteria proportion in the cecal microbiota could be the most prominent trigger of NAFLD through enhanced endotoxin (LPS) in adult high-fructose-fed C57BL/6 mice. Male C57BL/6 mice received a control diet (n = 10, C: 76% of energy as carbohydrates, 0% as fructose) or high-fructose diet (n = 10, HFRU: 76% of energy as carbohydrate, 50% as fructose) for 12 weeks. Outcomes included biochemical analyses, 16S rDNA PCR amplification, hepatic stereology, and RT-qPCR. The groups showed similar body masses during the whole experiment. However, the HFRU group showed greater water intake and blood pressure than the C group. The HFRU group showed a significantly lower amount of Bacteroidetes and a predominant rise in Proteobacteria, implying increased LPS. The HFRU group also showed enhanced de novo lipogenesis (Chrebp expression), while beta-oxidation was decreased (Ppar-alpha expression). These results agree with the deposition of fat droplets within hepatocytes and the enhanced hepatic triacylglycerol concentrations, as observed in the photomicrographs, where the HFRU group had a higher volume density of steatosis than the C group. Thus, we confirmed that a rise in the Proteobacteria phylum proportion was the most prominent alteration in gut-liver axis-induced hepatic steatosis in HFRU-fed C57BL/6 mice. Gut dysbiosis and fatty liver were observed even in the absence of overweight in this dietary adult mouse model.
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Affiliation(s)
- Isabela Macedo Lopes Vasques-Monteiro
- Laboratory of Morphometry, Metabolism, and Cardiovascular Diseases, Biomedical Center, Institute of Biology, Rio de Janeiro State University, Rio de Janeiro, Brazil; Laboratory of bioactive compounds, LABBIO, School of Nutrition, Federal University of the State of Rio de Janeiro, Rio de Janeiro, Brazil
| | - Flávia Maria Silva-Veiga
- Laboratory of Morphometry, Metabolism, and Cardiovascular Diseases, Biomedical Center, Institute of Biology, Rio de Janeiro State University, Rio de Janeiro, Brazil
| | - Carolline Santos Miranda
- Laboratory of Morphometry, Metabolism, and Cardiovascular Diseases, Biomedical Center, Institute of Biology, Rio de Janeiro State University, Rio de Janeiro, Brazil
| | | | - Julio Beltrame Daleprane
- Laboratory for Studies of Interactions Between Nutrition and Genetics, LEING, Institute of Nutrition, Rio de Janeiro State University, Rio de Janeiro, Brazil
| | - Vanessa Souza-Mello
- Laboratory of Morphometry, Metabolism, and Cardiovascular Diseases, Biomedical Center, Institute of Biology, Rio de Janeiro State University, Rio de Janeiro, Brazil.
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40
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Tokuhara D. Role of the Gut Microbiota in Regulating Non-alcoholic Fatty Liver Disease in Children and Adolescents. Front Nutr 2021; 8:700058. [PMID: 34250000 PMCID: PMC8267179 DOI: 10.3389/fnut.2021.700058] [Citation(s) in RCA: 43] [Impact Index Per Article: 10.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2021] [Accepted: 06/04/2021] [Indexed: 01/18/2023] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD) is the most common form of chronic liver disease in children and adolescents. Although obesity is the leading cause of NAFLD, the etiologies of NAFLD are multifactorial (e.g., high-fat diet, a lack of exercise, gender, maternal obesity, the antibiotic use), and each of these factors leads to dysbiosis of the gut microbiota community. The gut microbiota is a key player in the development and regulation of the gut mucosal immune system as well as the regulation of both NAFLD and obesity. Dysbiosis of the gut microbiota promotes the development of NAFLD via alteration of gut-liver homeostasis, including disruption of the gut barrier, portal transport of bacterial endotoxin (lipopolysaccharide) to the liver, altered bile acid profiles, and decreased concentrations of short-chain fatty acids. In terms of prevention and treatment, conventional approaches (e.g., dietary and exercise interventions) against obesity and NAFLD have been confirmed to recover the dysbiosis and dysbiosis-mediated altered metabolism. In addition, increased understanding of the importance of gut microbiota-mediated homeostasis in the prevention of NAFLD suggests the potential effectiveness of gut microbiota-targeted preventive and therapeutic strategies (e.g., probiotics and fecal transplantation) against NAFLD in children and adolescents. This review comprehensively summarizes our current knowledge of the gut microbiota, focusing on its interaction with NAFLD and its potential therapeutic role in obese children and adolescents with this disorder.
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Affiliation(s)
- Daisuke Tokuhara
- Department of Pediatrics, Osaka City University Graduate School of Medicine, Osaka, Japan
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41
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Liu SY, Tsai IT, Hsu YC. Alcohol-Related Liver Disease: Basic Mechanisms and Clinical Perspectives. Int J Mol Sci 2021; 22:5170. [PMID: 34068269 PMCID: PMC8153142 DOI: 10.3390/ijms22105170] [Citation(s) in RCA: 80] [Impact Index Per Article: 20.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/17/2021] [Revised: 05/07/2021] [Accepted: 05/12/2021] [Indexed: 12/12/2022] Open
Abstract
Alcohol-related liver disease (ALD) refers to the liver damage occurring due to excessive alcohol consumption and involves a broad spectrum of diseases that includes liver steatosis, steatohepatitis, hepatitis, cirrhosis, and hepatocellular carcinoma (HCC). The progression of ALD is mainly associated with the amount and duration of alcohol usage; however, it is also influenced by genetic, epigenetic, and environmental factors. The definite diagnosis of ALD is based on a liver biopsy, although several non-invasive diagnostic tools and serum biomarkers have emerging roles in the early detection of ALD. While alcohol abstinence and nutritional support remain the cornerstone of ALD treatment, growing evidence has revealed that the therapeutic agents that target oxidative stress or gut-liver axis, inflammatory response inhibition, and liver regeneration enhancement also play a role in ALD management. Furthermore, microRNAs modulation and mesenchymal stem cell-based therapy have emerging potential as ALD therapeutic options. This review summarizes the updated understanding of the pathophysiology, diagnosis, and novel therapeutic approaches for ALD.
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Affiliation(s)
- Szu-Yi Liu
- Department of Emergency Medicine, E-Da Hospital, I-Shou University, Kaohsiung 82445, Taiwan; (S.-Y.L.); (I.-T.T.)
| | - I-Ting Tsai
- Department of Emergency Medicine, E-Da Hospital, I-Shou University, Kaohsiung 82445, Taiwan; (S.-Y.L.); (I.-T.T.)
- School of Medicine for International Student, I-Shou University, Kaohsiung 82445, Taiwan
| | - Yin-Chou Hsu
- Department of Emergency Medicine, E-Da Hospital, I-Shou University, Kaohsiung 82445, Taiwan; (S.-Y.L.); (I.-T.T.)
- School of Medicine for International Student, I-Shou University, Kaohsiung 82445, Taiwan
- School of Chinese Medicine for Post Baccalaureate, I-Shou University, Kaohsiung 82445, Taiwan
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42
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Jiang ZB, Gao J, Chai YH, Li W, Luo YF, Chen YZ. Astragaloside alleviates alcoholic fatty liver disease by suppressing oxidative stress. Kaohsiung J Med Sci 2021; 37:718-729. [PMID: 33973356 DOI: 10.1002/kjm2.12390] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2020] [Revised: 02/24/2021] [Accepted: 03/17/2021] [Indexed: 12/17/2022] Open
Abstract
Alcoholic fatty liver disease (AFLD) is the most common liver disease and can progress to fatal liver cirrhosis and carcinoma, affecting millions of patients worldwide. The functions of astragaloside on the cardiovascular system have been elucidated. However, its role in AFLD is unclear. Ethanol-treated AML-12 cells were used as a cell model of alcoholic fatty liver. Real-time quantitative reverse transcription-PCR and Western blotting detected genes and proteins expressions. Reactive oxygen species (ROS), triglyceride, total cholesterol, low-density lipoprotein, albumin, ferritin, bilirubin, superoxide dismutase, aspartate aminotransferase (AST), and alanine aminotransferase (ALT) were examined using commercial kits. Lipid accumulation was assessed by Oil red O staining. MTT and flow cytometry measured cell viability and apoptosis. JC-1 was used to analyze mitochondrial membrane potential. A rat model of AFLD was established by treating rats with ethanol. Astragaloside suppressed ethanol-induced lipid accumulation, oxidative stress, and the production of AST and ALT in AML-12 cells. Ethanol induced TNF-α and reduced IL-10 expression, which were reversed by astragaloside. Ethanol promoted Bax expression and cytochrome C release and inhibited Bcl-2 and ATP expression. Astragaloside hampered these apoptosis effects in AML-12 cells. Impaired mitochondrial membrane potential was recovered by astragaloside. However, all these astragaloside-mediated beneficial effects were abolished by the ROS inducer pyocyanin. Ethanol-induced activation of NF-κB signaling was suppressed by astragaloside in vitro and in vivo, suggesting that astragaloside inhibited oxidative stress by suppressing the activation of NF-κB signaling, thus improving liver function and alleviating AFLD in rats. Our study elucidates the pharmacological mechanism of astragaloside and provides potential therapeutic strategies for AFLD.
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Affiliation(s)
- Zhi-Bin Jiang
- College of Pharmacy, Guizhou University of Traditional Chinese Medicine, Guiyang, China
| | - Jie Gao
- Department of Preclinical Medicine, Guizhou University of Traditional Chinese Medicine, Guiyang, China
| | - Yi-Hui Chai
- Department of Preclinical Medicine, Guizhou University of Traditional Chinese Medicine, Guiyang, China
| | - Wen Li
- Department of Preclinical Medicine, Guizhou University of Traditional Chinese Medicine, Guiyang, China
| | - Yun-Feng Luo
- Department of Preclinical Medicine, Guizhou University of Traditional Chinese Medicine, Guiyang, China
| | - Yun-Zhi Chen
- Department of Preclinical Medicine, Guizhou University of Traditional Chinese Medicine, Guiyang, China
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Zhou Y, Wu M, Xu L, Cheng J, Shen J, Yang T, Zhang L. Bmal1 Regulates Macrophage Polarize Through Glycolytic Pathway in Alcoholic Liver Disease. Front Pharmacol 2021; 12:640521. [PMID: 33790796 PMCID: PMC8006279 DOI: 10.3389/fphar.2021.640521] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2020] [Accepted: 01/29/2021] [Indexed: 12/12/2022] Open
Abstract
Hepatic macrophages play a critical role in inflammation caused by alcohol feeding. During this process, variation of macrophage phenotypes triggers inflammatory responses in a variety of ways. Moreover, there is increasing evidence that Brain and Muscle Arnt-Like Protein-1 (Bmal1) is regarded as a key regulator of macrophage transformation. In our study, Bmal1 was detected to be low expressed in EtOH-fed mice tissue samples and ethanol-induced RAW264.7 cells. After hepatic specific overexpression of Bmal1, M1 macrophage markers were evidently down-regulated, while M2 markers were on the contrary, showing an upward trend. Furthermore, alcoholic liver lesions were also improved in alcohol feeding mice with overexpressed Bmal1. On this basis, we also found that the glycolytic pathway can regulate macrophage polarization. In vitro, blocking of glycolytic pathway can significantly inhibit M1-type polarization. Importantly, glycolysis levels were also restrained after Bmal1 overexpression. What’s more, Bmal1 exerts a negative regulatory effect on glycolysis by interacting with S100A9 protein. Further studies showed that the alleviation of alcoholic liver disease (ALD) by Bmal1 was associated with glycolytic pathway suppression and M1 macrophage polarization. In summary, we demonstrated that Bmal1 is a gene capable of relieving ALD, and this effect may provide new insights for altering macrophage phenotypes to regulate inflammatory responses in ALD.
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Affiliation(s)
- Yiwen Zhou
- School of Pharmacy, Anhui Medical University, Hefei, China.,Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Hefei, China.,The Key Laboratory of Anti-inflammatory and Immune Medicines, Ministry of Education, Hefei, China
| | - Meifei Wu
- School of Pharmacy, Anhui Medical University, Hefei, China.,Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Hefei, China.,The Key Laboratory of Anti-inflammatory and Immune Medicines, Ministry of Education, Hefei, China
| | - Lei Xu
- School of Pharmacy, Anhui Medical University, Hefei, China.,Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Hefei, China.,The Key Laboratory of Anti-inflammatory and Immune Medicines, Ministry of Education, Hefei, China
| | - Jieling Cheng
- School of Pharmacy, Anhui Medical University, Hefei, China.,Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Hefei, China.,The Key Laboratory of Anti-inflammatory and Immune Medicines, Ministry of Education, Hefei, China
| | - Jie Shen
- School of Pharmacy, Anhui Medical University, Hefei, China.,Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Hefei, China.,The Key Laboratory of Anti-inflammatory and Immune Medicines, Ministry of Education, Hefei, China
| | - Tianyu Yang
- School of Pharmacy, Anhui Medical University, Hefei, China.,Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Hefei, China.,The Key Laboratory of Anti-inflammatory and Immune Medicines, Ministry of Education, Hefei, China
| | - Lei Zhang
- School of Pharmacy, Anhui Medical University, Hefei, China.,Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Hefei, China.,The Key Laboratory of Anti-inflammatory and Immune Medicines, Ministry of Education, Hefei, China
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44
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Namachivayam A, Valsala Gopalakrishnan A. A review on molecular mechanism of alcoholic liver disease. Life Sci 2021; 274:119328. [PMID: 33711388 DOI: 10.1016/j.lfs.2021.119328] [Citation(s) in RCA: 23] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/24/2020] [Revised: 02/13/2021] [Accepted: 03/01/2021] [Indexed: 02/06/2023]
Abstract
Excessive alcohol consumption leads to damage to the organs of the body. More importantly, the liver is majorly affected organ upon alcohol consumption for most of the people; it causes inflammation and affects various pathways involved in metabolism. If the person is with high response of inflammatory in conduct with alcohol leads to the liver damage, which involves the creating effects with major cycle leads to homeostasis. In this review, we summarize the molecular mechanisms of alcoholic liver disease, such as the important role of genes, risk factors, pathogenicity, and role of micro RNA, the role of inflammation in the liver, and alcoholic fibrosis in the liver. There is increased oxidative stress, change in the biochemical alterations, and reduction in the antioxidant enzymes. These changes in the mechanism lead to liver injury. Hepatocyte nuclear factor-4 is the major transcriptional factor for the regulation of some genes involved in the lipid metabolism and oxidation process; with the help of the agonist, we can attenuate the level of the gene in the site of hepatic tissues, which will prevent the homeostatic condition. This review shows a clear view of the various pathways involved in alcohol consumption, which helps in the prevention of ALD using an agonist.
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Affiliation(s)
- Arunraj Namachivayam
- Department of Biomedical Sciences, School of Bio Sciences and Technology, Vellore Institute of Technology (VIT), Vellore, Tamil Nadu 632014, India
| | - Abilash Valsala Gopalakrishnan
- Department of Biomedical Sciences, School of Bio Sciences and Technology, Vellore Institute of Technology (VIT), Vellore, Tamil Nadu 632014, India.
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45
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Xia T, Zhang B, Li S, Fang B, Duan W, Zhang J, Song J, Wang M. Vinegar extract ameliorates alcohol-induced liver damage associated with the modulation of gut microbiota in mice. Food Funct 2021; 11:2898-2909. [PMID: 32242560 DOI: 10.1039/c9fo03015h] [Citation(s) in RCA: 44] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
Vinegar extract is rich in phenolic compounds, which can prevent free radical-induced diseases. The aim of the present study was to explore the effects of vinegar extract on gut microbiota in alcohol-treated mice and their correlation with alcohol-induced liver damage. These results showed that vinegar extract regulated the gut microbiota composition and improved intestinal homeostasis through increasing the expression levels of ZO-1, occludin, claudin-1, Reg3b, and Reg3g in alcohol-treated mice. In addition, vinegar extract inhibited the alcohol-induced production of ROS and inflammatory factors. Moreover, Bacteroidetes, Verrucomicrobia, Akkermansia, and Lactobacillus showed a significant positive correlation with Reg3b, Reg3g, ZO-1, occludin, and claudin-1 and a negative correlation with hepatic inflammation and oxidative stress parameters. However, Firmicutes, Proteobacteria, Butyricimonas, Parabacteroides, and Bilophila exhibited the opposite effect. These findings suggest that vinegar extract modulates gut microbiota and improves intestinal homeostasis, and can be used as a novel gut microbiota manipulator against alcohol-induced liver damage.
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Affiliation(s)
- Ting Xia
- State Key Laboratory of Food Nutrition and Safety, Key Laboratory of Industrial Fermentation Microbiology, College of Biotechnology, Tianjin University of Science and Technology, Tianjin, China.
| | - Bo Zhang
- State Key Laboratory of Food Nutrition and Safety, Key Laboratory of Industrial Fermentation Microbiology, College of Biotechnology, Tianjin University of Science and Technology, Tianjin, China.
| | - Shaopeng Li
- State Key Laboratory of Food Nutrition and Safety, Key Laboratory of Industrial Fermentation Microbiology, College of Biotechnology, Tianjin University of Science and Technology, Tianjin, China.
| | - Bin Fang
- State Key Laboratory of Food Nutrition and Safety, Key Laboratory of Industrial Fermentation Microbiology, College of Biotechnology, Tianjin University of Science and Technology, Tianjin, China.
| | - Wenhui Duan
- State Key Laboratory of Food Nutrition and Safety, Key Laboratory of Industrial Fermentation Microbiology, College of Biotechnology, Tianjin University of Science and Technology, Tianjin, China.
| | - Jin Zhang
- State Key Laboratory of Food Nutrition and Safety, Key Laboratory of Industrial Fermentation Microbiology, College of Biotechnology, Tianjin University of Science and Technology, Tianjin, China.
| | - Jia Song
- State Key Laboratory of Food Nutrition and Safety, Key Laboratory of Industrial Fermentation Microbiology, College of Biotechnology, Tianjin University of Science and Technology, Tianjin, China.
| | - Min Wang
- State Key Laboratory of Food Nutrition and Safety, Key Laboratory of Industrial Fermentation Microbiology, College of Biotechnology, Tianjin University of Science and Technology, Tianjin, China.
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46
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Hylocereus polyrhizus Peel Extract Retards Alcoholic Liver Disease Progression by Modulating Oxidative Stress and Inflammatory Responses in C57BL/6 Mice. Nutrients 2020; 12:nu12123884. [PMID: 33353102 PMCID: PMC7767216 DOI: 10.3390/nu12123884] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2020] [Revised: 12/15/2020] [Accepted: 12/15/2020] [Indexed: 02/07/2023] Open
Abstract
Alcoholic liver disease (ALD) has become a health problem as alcohol consumption has increased annually. Hepatic lipid accumulation, oxidative stress, and inflammation are important factors in the progression of ALD. Red pitaya (Hylocereus polyrhizus (Weber) Britt. & Rose) peel is rich in polyphenols and betanins, which possess antioxidative and anti-inflammatory properties. Therefore, the aim of this study was to investigate the effects of red pitaya peel extract (PPE) on ALD and explore the associated mechanisms. C57BL/6 J mice were administered an ethanol liquid diet for 11 weeks with or without two different doses of PPE (500 and 1000 mg/kg BW). PPE treatment significantly ameliorated liver injury and hepatic fat accumulation, and it improved hepatic lipid metabolism via increases in AMPK and PPAR-α protein expression and a decrease in SREBP-1 expression. In addition, PPE inhibited CYP2E1 and Nrf2 protein expression, reduced endotoxin levels in the serum, and decreased TLR4 and MyD88 expression and inflammatory cytokine TNF-α and IL-1β levels in the liver. In conclusion, these findings suggest that PPE may prevent the progression of ALD by modulating lipid metabolism and reducing oxidative stress and inflammatory responses.
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47
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Wen B, Zhang C, Zhou J, Zhang Z, Che Q, Cao H, Bai Y, Guo J, Su Z. Targeted treatment of alcoholic liver disease based on inflammatory signalling pathways. Pharmacol Ther 2020; 222:107752. [PMID: 33253739 DOI: 10.1016/j.pharmthera.2020.107752] [Citation(s) in RCA: 22] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2020] [Revised: 11/15/2020] [Accepted: 11/20/2020] [Indexed: 02/06/2023]
Abstract
Targeted therapy is an emerging treatment strategy for alcoholic liver disease (ALD). Inflammation plays an important role in the occurrence and development of ALD, and is a key choice for its targeted treatment, and anti-inflammatory treatment has been considered beneficial for liver disease. Surprisingly, immune checkpoint inhibitors have become important therapeutic agents for hepatocellular carcinoma (HCC). Moreover, studies have shown that the combination of inflammatory molecule inhibitors and immune checkpoint inhibitors can exert better effects than either alone in mouse models of HCC. This review discusses the mechanism of hepatic ethanol metabolism and the conditions under which inflammation occurs. In addition, we focus on the potential molecular targets in inflammatory signalling pathways and summarize the potential targeted inhibitors and immune checkpoint inhibitors, providing a theoretical basis for the targeted treatment of ALD and the development of new combination therapy strategies for HCC.
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Affiliation(s)
- Bingjian Wen
- Guangdong Engineering Research Center of Natural Products and New Drugs, Guangdong Provincial University Engineering Technology Research Center of Natural Products and Drugs, Guangdong Pharmaceutical University, Guangzhou 510006, China; Guangdong Metabolic Diseases Research Centre of Integrated Chinese and Western Medicine, Guangdong Pharmaceutical University, Guangzhou 510006, China
| | - Chengcheng Zhang
- Guangdong Engineering Research Center of Natural Products and New Drugs, Guangdong Provincial University Engineering Technology Research Center of Natural Products and Drugs, Guangdong Pharmaceutical University, Guangzhou 510006, China; Guangdong Metabolic Diseases Research Centre of Integrated Chinese and Western Medicine, Guangdong Pharmaceutical University, Guangzhou 510006, China
| | - Jingwen Zhou
- Guangdong Engineering Research Center of Natural Products and New Drugs, Guangdong Provincial University Engineering Technology Research Center of Natural Products and Drugs, Guangdong Pharmaceutical University, Guangzhou 510006, China; Guangdong Metabolic Diseases Research Centre of Integrated Chinese and Western Medicine, Guangdong Pharmaceutical University, Guangzhou 510006, China
| | - Zhengyan Zhang
- Guangdong Engineering Research Center of Natural Products and New Drugs, Guangdong Provincial University Engineering Technology Research Center of Natural Products and Drugs, Guangdong Pharmaceutical University, Guangzhou 510006, China; Guangdong Metabolic Diseases Research Centre of Integrated Chinese and Western Medicine, Guangdong Pharmaceutical University, Guangzhou 510006, China
| | - Qishi Che
- Guangzhou Rainhome Pharm & Tech Co., Ltd., Guangzhou 510663, China
| | - Hua Cao
- School of Chemistry and Chemical Engineering, Guangdong Pharmaceutical University, Zhongshan 528458, China
| | - Yan Bai
- School of Public Health, Guangdong Pharmaceutical University, Guangzhou 510310, China
| | - Jiao Guo
- Guangdong Metabolic Diseases Research Centre of Integrated Chinese and Western Medicine, Guangdong Pharmaceutical University, Guangzhou 510006, China.
| | - Zhengquan Su
- Guangdong Engineering Research Center of Natural Products and New Drugs, Guangdong Provincial University Engineering Technology Research Center of Natural Products and Drugs, Guangdong Pharmaceutical University, Guangzhou 510006, China; Guangdong Metabolic Diseases Research Centre of Integrated Chinese and Western Medicine, Guangdong Pharmaceutical University, Guangzhou 510006, China.
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48
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Microbiota reprogramming for treatment of alcohol-related liver disease. Transl Res 2020; 226:26-38. [PMID: 32687975 PMCID: PMC7572584 DOI: 10.1016/j.trsl.2020.07.004] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/30/2020] [Revised: 07/01/2020] [Accepted: 07/13/2020] [Indexed: 02/08/2023]
Abstract
In the past decade knowledge has expanded regarding the importance of the gut microbiota in maintaining intestinal homeostasis and overall health. During this same time, we have also gained appreciation for the role of the gut-liver axis in the development of liver diseases. Alcohol overconsumption is one of the leading causes of liver failure globally. However, not all people with alcohol use disorder progress to advanced stages of liver disease. With advances in technology to investigate the gut microbiome and metabolome, we are now beginning to delineate alcohol's effects on the gut microbiome in relation to liver disease. This review presents our current understanding on the role of the gut microbiota during alcohol exposure, and various therapeutic attempts that have been made to reprogram the gut microbiota with the goal of alleviating alcoholic-related liver disease.
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Nie W, Zhou K, Wang Y, Wang ZM, Xie Y, Zhou H, Xu BC. Isolation and identification of bioactive peptides from Xuanwei ham that rescue oxidative stress damage induced by alcohol in HHL-5 hepatocytes. Food Funct 2020; 11:9710-9720. [PMID: 33057513 DOI: 10.1039/d0fo02329a] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/17/2023]
Abstract
Peptides extracted from Xuanwei ham (XHP) can prevent free radical-induced diseases. The aim of the present study was to isolate and identify bioactive peptides from Xuanwei hams that rescue the oxidative stress damage induced by alcohol in HHL-5 hepatocytes. Alcohol-treated HHL-5 human hepatocytes were utilized as the alcohol-induced hepatocyte damage model to evaluate the effects of XHP on amounts of aminotransferase (ALT), aspartate aminotransferase (AST) and malondialdehyde (MDA). The result showed that XHP could significantly reduce ALT, AST and MDA, the major biomarkers of liver damage. The crude XHP was separated by size exclusion chromatography, followed by the evaluation of respective activities. Then, the most active components were further separated by RP-HPLC, and their activities were evaluated according to the above method. The peptide was identified as a hexapeptide with the sequence of Asn-Pro-Pro-Lys-Phe-Asp (NPPKFD) through LC-MS/MS. Further, the molecular mechanisms by which NPPKFD prevents alcohol-induced oxidative stress damage were revealed. Results showed that the hexapeptide could downregulate CYP2E1 expression, reduce generation of ROS and enhance oxidant defense systems via the activation of NrF2/HO-1 pathway. The findings suggest that Xuanwei ham can be used as a new source of bioactive peptides for protection from alcohol-induced liver damage.
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Affiliation(s)
- Wen Nie
- School of Food and Biological Engineering, Hefei University of Technology, Hefei 230601, China.
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Slevin E, Baiocchi L, Wu N, Ekser B, Sato K, Lin E, Ceci L, Chen L, Lorenzo SR, Xu W, Kyritsi K, Meadows V, Zhou T, Kundu D, Han Y, Kennedy L, Glaser S, Francis H, Alpini G, Meng F. Kupffer Cells: Inflammation Pathways and Cell-Cell Interactions in Alcohol-Associated Liver Disease. THE AMERICAN JOURNAL OF PATHOLOGY 2020; 190:2185-2193. [PMID: 32919978 PMCID: PMC7587925 DOI: 10.1016/j.ajpath.2020.08.014] [Citation(s) in RCA: 70] [Impact Index Per Article: 14.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/15/2020] [Revised: 07/11/2020] [Accepted: 08/12/2020] [Indexed: 02/08/2023]
Abstract
Chronic alcohol consumption is linked to the development of alcohol-associated liver disease (ALD). This disease is characterized by a clinical spectrum ranging from steatosis to hepatocellular carcinoma. Several cell types are involved in ALD progression, including hepatic macrophages. Kupffer cells (KCs) are the resident macrophages of the liver involved in the progression of ALD by activating pathways that lead to the production of cytokines and chemokines. In addition, KCs are involved in the production of reactive oxygen species. Reactive oxygen species are linked to the induction of oxidative stress and inflammation in the liver. These events are activated by the bacterial endotoxin, lipopolysaccharide, that is released from the gastrointestinal tract through the portal vein to the liver. Lipopolysaccharide is recognized by receptors on KCs that are responsible for triggering several pathways that activate proinflammatory cytokines involved in alcohol-induced liver injury. In addition, KCs activate hepatic stellate cells that are involved in liver fibrosis. Novel strategies to treat ALD aim at targeting Kupffer cells. These interventions modulate Kupffer cell activation or macrophage polarization. Evidence from mouse models and early clinical studies in patients with ALD injury supports the notion that pathogenic macrophage subsets can be successfully translated into novel treatment options for patients with this disease.
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Affiliation(s)
- Elise Slevin
- Research Service, Richard L. Roudebush VA Medical Center, Indianapolis, Indiana; Indiana Center for Liver Research and Division of Gastroenterology and Hepatology, Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana
| | - Leonardo Baiocchi
- Liver Unit, Department of Medicine, University of Rome Tor Vergata, Rome, Italy
| | - Nan Wu
- Indiana Center for Liver Research and Division of Gastroenterology and Hepatology, Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana
| | - Burcin Ekser
- Division of Transplant Surgery, Department of Surgery, Indiana University School of Medicine, Indianapolis, Indiana
| | - Keisaku Sato
- Indiana Center for Liver Research and Division of Gastroenterology and Hepatology, Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana
| | - Emily Lin
- Texas College of Osteopathic Medicine, The University of North Texas Health Science Center, Fort Worth, Texas
| | - Ludovica Ceci
- Indiana Center for Liver Research and Division of Gastroenterology and Hepatology, Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana
| | - Lixian Chen
- Indiana Center for Liver Research and Division of Gastroenterology and Hepatology, Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana
| | | | - Wenjuan Xu
- Indiana Center for Liver Research and Division of Gastroenterology and Hepatology, Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana
| | - Konstantina Kyritsi
- Indiana Center for Liver Research and Division of Gastroenterology and Hepatology, Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana
| | - Victoria Meadows
- Indiana Center for Liver Research and Division of Gastroenterology and Hepatology, Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana
| | - Tianhao Zhou
- Research Service, Richard L. Roudebush VA Medical Center, Indianapolis, Indiana; Indiana Center for Liver Research and Division of Gastroenterology and Hepatology, Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana
| | - Debiyoti Kundu
- Indiana Center for Liver Research and Division of Gastroenterology and Hepatology, Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana
| | - Yuyan Han
- School of Biological Sciences, Natural and Health Sciences, University of Northern Colorado, Greeley, Colorado
| | - Lindsey Kennedy
- Indiana Center for Liver Research and Division of Gastroenterology and Hepatology, Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana
| | - Shannon Glaser
- Department of Medical Physiology, Texas A&M University College of Medicine, Bryan, Texas
| | - Heather Francis
- Research Service, Richard L. Roudebush VA Medical Center, Indianapolis, Indiana; Indiana Center for Liver Research and Division of Gastroenterology and Hepatology, Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana
| | - Gianfranco Alpini
- Research Service, Richard L. Roudebush VA Medical Center, Indianapolis, Indiana; Indiana Center for Liver Research and Division of Gastroenterology and Hepatology, Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana
| | - Fanyin Meng
- Research Service, Richard L. Roudebush VA Medical Center, Indianapolis, Indiana; Indiana Center for Liver Research and Division of Gastroenterology and Hepatology, Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana.
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