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Kim SY, Oh KJ, Seo YR, Kim YW, Song PH, Song CH. Comparative Study on Hepatoprotective Effects of Traditional Herbs, Roots of Angelica gigas Nakai, Glycyrrhiza uralensis Fischer, Zizyphus jujuba Mill., and Fruits of Paeonia lactiflora Pall., on Ethanol-Induced Liver Injury in Mice. Antioxidants (Basel) 2024; 13:1137. [PMID: 39334796 PMCID: PMC11428478 DOI: 10.3390/antiox13091137] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2024] [Revised: 09/10/2024] [Accepted: 09/18/2024] [Indexed: 09/30/2024] Open
Abstract
Alcohol-associated liver disease (ALD) is a major cause of chronic liver disease, with few effective treatments besides alcohol abstinence. Angelicae Gigantis Radix (AG), Glycyrrhizae Radix et Rhizoma (GR), Paeoniae Radix (PR), and Zizyphi Fructus (ZF) are traditional herbs used to treat various ailments, including liver diseases. While several studies have reported the beneficial effects of GR on ALD, the effects of AG, PR, and ZF remain underexplored. Therefore, their efficacy and mechanisms against ALD were investigated using an alcohol-related liver injury model. The model was induced by ethanol gavage in C57BL/6J mice for 14 days, followed by oral administration of AG, GR, PR, and ZF one hour post-induction. The administration of these herbs reduced liver weight, and improved serum biomarkers of liver injury (ALT, AST, albumin). The herbs enhanced hepatic antioxidant capacity (GSH, SOD, catalase) and suppressed the production of proinflammatory cytokines (TNF-α, IL-1β) and apoptotic changes (caspase-3). The mechanisms of action involved lipid-lowering gene modulation through regulation of the cytochrome P450 2E1/Sirtuin 1/Nrf2 pathways. Histopathological and immunohistochemical analyses revealed that these herbs attenuated hepatocyte damage and steatosis via antioxidant, anti-inflammatory, and antiapoptotic effects. These findings suggest that traditional herbs, particularly AG, could be promising alternative therapies for treating ALD.
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Affiliation(s)
- So-Yeon Kim
- Research Center for Herbal Convergence on Liver Disease, Gyeongsan 38610, Republic of Korea
| | - Kyung-Jin Oh
- Department of Urology, Chonnam National University Hospital, Chonnam National University Medical School, Gwangju 61469, Republic of Korea
| | - Yu-Ri Seo
- Research Center for Herbal Convergence on Liver Disease, Gyeongsan 38610, Republic of Korea
| | - Young-Woo Kim
- Department of Herbal Prescription, School of Korean Medicine, Dongguk University, Gyeongju 38066, Republic of Korea
| | - Phil Hyun Song
- Department of Urology, College of Medicine, Yeungnam University, Daegu 42415, Republic of Korea
| | - Chang-Hyun Song
- Research Center for Herbal Convergence on Liver Disease, Gyeongsan 38610, Republic of Korea
- Department of Anatomy and Histology, College of Korean Medicine, Daegu Haany University, Gyeongsan 38610, Republic of Korea
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Tarantino G, Citro V. What are the common downstream molecular events between alcoholic and nonalcoholic fatty liver? Lipids Health Dis 2024; 23:41. [PMID: 38331795 PMCID: PMC10851522 DOI: 10.1186/s12944-024-02031-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2023] [Accepted: 01/25/2024] [Indexed: 02/10/2024] Open
Abstract
Liver fat storage, also called hepatic steatosis, is increasingly common and represents a very frequent diagnosis in the medical field. Excess fat is not without consequences. In fact, hepatic steatosis contributes to the progression toward liver fibrosis. There are two main types of fatty liver disease, alcoholic fatty liver disease (AFLD) and nonalcoholic fatty liver disease (NAFLD). Although AFLD and NAFLD are similar in their initial morphological features, both conditions involve the same evolutive forms. Moreover, there are various common mechanisms underlying both diseases, including alcoholic liver disease and NAFLD, which are commonalities. In this Review, the authors explore similar downstream signaling events involved in the onset and progression of the two entities but not completely different entities, predominantly focusing on the gut microbiome. Downstream molecular events, such as the roles of sirtuins, cytokeratins, adipokines and others, should be considered. Finally, to complete the feature, some new tendencies in the therapeutic approach are presented.
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Affiliation(s)
| | - Vincenzo Citro
- Department of General Medicine, Umberto I Hospital, Nocera Inferiore, SA, 84014, Italy
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Mancak M, Altintas D, Balaban Y, Caliskan UK. Evidence-based herbal treatments in liver diseases. HEPATOLOGY FORUM 2024; 5:50-60. [PMID: 38283267 PMCID: PMC10809338 DOI: 10.14744/hf.2022.2022.0052] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/29/2023] [Revised: 01/09/2024] [Accepted: 01/12/2024] [Indexed: 01/30/2024]
Abstract
The liver is the main organ for metabolic and detoxification reactions in the body. Therefore, its diseases can be associated with both metabolic disorders, such as insulin resistance, obesity, diabetes, or dyslipidemia, and exogenous insults such as drugs, xenobiotics, or alcohol. Indeed, lifestyle changes are the primary approaches for the prevention and treatment of liver diseases. Since ancient times, herbals have also been used for preventive and therapeutic purposes, because of their anti-apoptotic, anti-inflammatory, and antioxidant effects. Here, the literature was reviewed for potential therapeutic effects of plants and their compounds by including in vitro and in vivo studies, as well as clinical trials. Although the available data imply some beneficial roles of herbals on the liver, the indications and posology of specific plants need to be clarified through multicenter, randomized clinical trials.
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Affiliation(s)
- Methiye Mancak
- Department of Pharmacognosy and Pharmaceutical Botany, Gazi University Faculty of Pharmacy, Ankara, Turkiye
| | - Dudu Altintas
- Department of Pharmacognosy, Duzce University Faculty of Pharmacy, Duzce, Turkiye
| | - Yasemin Balaban
- Division of Gastroenterology, Department of Internal Medical Sciences, Hacettepe University School of Medicine, Ankara, Turkiye
| | - Ufuk Koca Caliskan
- Department of Pharmacognosy and Pharmaceutical Botany, Gazi University Faculty of Pharmacy, Ankara, Turkiye
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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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Guo C, Zheng L, Chen S, Liang X, Song X, Wang Y, Hua B, Qiu L. Thymol ameliorates ethanol-induced hepatotoxicity via regulating metabolism and autophagy. Chem Biol Interact 2023; 370:110308. [PMID: 36535314 DOI: 10.1016/j.cbi.2022.110308] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2022] [Revised: 11/22/2022] [Accepted: 12/14/2022] [Indexed: 12/23/2022]
Abstract
Alcoholic liver disease represents a serious threat to human health. In terms of safety and acceptability, thymol is widely used in or on foodstuffs to generate odour and taste. The present study aimed to investigate the therapeutic effect and mechanism of thymol against ethanol-induced injury in liver cells. Here we found that thymol is an effective agent for reducing ethanol-induced reactive oxygen species production in mouse liver cells. Thymol improves ethanol-induced lipid accumulation, and this corresponded to altered DGAT2 mRNA expression levels. Metabolomics data analysis showed that thymol alleviated ethanol-induced changes in the levels of thirty-four metabolites including nicotinic acid and l-arginine. By utilizing pathway enrichment analysis, altered metabolites in cells treated with ethanol and ethanol plus thymol were enriched in fourteen pathways including metabolic pathways and arginine and proline metabolism. We further confirmed the alleviation of overdose nitric oxide production in cells treated with ethanol plus thymol compared with that in ethanol-treated cells. It was interesting that up-regulated LC3-II/LC3-I ratio together with higher SQSTM1 protein abundance in ethanol-treated cells were attenuated by treatment with ethanol plus thymol. Thymol ameliorated ethanol-induced reduction of HSPA8 protein abundance. In addition, chloroquine-treated cells exhibited lower HSPA8 protein abundance compared with cells simulated with ethanol plus thymol. These data reveal that improving effect of thymol on ethanol-induced metabolic alteration is related to autophagic flux restoration. Our findings indicate that thymol is an attractive option for treating ethanol-induced liver damage.
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Affiliation(s)
- Chang Guo
- School of Life Sciences, Longyan University, Longyan, 364012, PR China; Fujian Provincial Key Laboratory for the Prevention and Control of Animal Infectious Diseases and Biotechnology, Longyan, 364012, PR China; Key Laboratory of Preventive Veterinary Medicine and Biotechnology (Longyan University), Fujian Province University, Longyan, 364012, PR China
| | - Linyan Zheng
- School of Life Sciences, Longyan University, Longyan, 364012, PR China
| | - Shuyu Chen
- School of Life Sciences, Longyan University, Longyan, 364012, PR China
| | - Xuxuan Liang
- School of Life Sciences, Longyan University, Longyan, 364012, PR China
| | - Xue Song
- School of Life Sciences, Longyan University, Longyan, 364012, PR China
| | - Yue Wang
- School of Life Sciences, Longyan University, Longyan, 364012, PR China
| | - Baoyu Hua
- School of Life Sciences, Longyan University, Longyan, 364012, PR China; Fujian Provincial Key Laboratory for the Prevention and Control of Animal Infectious Diseases and Biotechnology, Longyan, 364012, PR China; Key Laboratory of Preventive Veterinary Medicine and Biotechnology (Longyan University), Fujian Province University, Longyan, 364012, PR China
| | - Longxin Qiu
- School of Life Sciences, Longyan University, Longyan, 364012, PR China; Fujian Provincial Key Laboratory for the Prevention and Control of Animal Infectious Diseases and Biotechnology, Longyan, 364012, PR China; Key Laboratory of Preventive Veterinary Medicine and Biotechnology (Longyan University), Fujian Province University, Longyan, 364012, PR China.
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AHMAD M, ALI SW, HAMEED A, AMIR M, ASHRAF J, Afzal MI, UMER M, ALSAGABY SA, AWAIS M, IMRAN M, IQBAL S, AHMED A, RIAZ M. Functional potential of Aloe vera juice against CCl4 induced hepatotoxicity in animal model. FOOD SCIENCE AND TECHNOLOGY 2023. [DOI: 10.1590/fst.110321] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Affiliation(s)
| | | | | | | | | | | | | | | | | | - Muhammad IMRAN
- University of Narowal, Pakistan; King Abdulaziz University, Saudi Arabia
| | | | - Aftab AHMED
- Government College University Faisalabad, Pakistan
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7
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Shen Y, Huang H, Wang Y, Yang R, Ke X. Antioxidant effects of Se-glutathione peroxidase in alcoholic liver disease. J Trace Elem Med Biol 2022; 74:127048. [PMID: 35963055 DOI: 10.1016/j.jtemb.2022.127048] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/09/2022] [Revised: 07/11/2022] [Accepted: 07/27/2022] [Indexed: 02/07/2023]
Abstract
Oxidative damage induced by ethanol and its metabolites is one of the factors that fuels the development of alcoholic liver disease (ALD). Selenium (Se) is an effective cofactor for glutathione peroxidase (GPx), and has antioxidant effects that improve ALD. In patients with ALD, ethanol-induced oxidative damage inhibits the synthesis of related Se-containing proteins such as: selenoprotein P (Sepp1), albumin (ALB), and GPx in the liver, thus decreasing the overall Se level in patients. Both Se deficiency and excess can affect the expression of GPx, resulting in damage to the antioxidant defense system. This damage enhances oxidative stress by increasing the levels of reactive oxygen species (ROS) in the body, which aggravates the inflammatory response, lipid metabolism disorder, and lipid peroxidation and worsens ALD symptoms. A cascade of oxidative damages caused by ALD will deplete selenium deposition in the body, stimulate the expression of Gpx1, Sepp1, and Gpx4, and thus mobilize systemic selenoproteins, which can restore GPx activity in the hepatocytes of ALD patients, reduce the levels of reactive oxygen species and alleviate oxidative stress, the inflammatory response, lipid metabolism disorder, and lipid peroxidation, thus helping to mitigate ALD. This review provides a reference for future ALD studies that evaluate the regulation of Se levels and contributes to studies on the potential pathological mechanisms of Se imbalance in ALD.
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Affiliation(s)
- Yingyan Shen
- Key Laboratory Breeding Base of Systematic Research and Utilization on Chinese Meterial, Medical Resources Co-founded by Sichuan Province and Ministry of Science and Technology, Chengdu University of Traditional Chinese Medicine, Chendu, China
| | - Hanmei Huang
- Chongqing Key Laboratory of Chinese Medicine New Drug Screening, Southwest University, Chongqing, China
| | - Yunhong Wang
- Chongqing Academy of Chinese Materia Medica, Chongqing, China
| | - Rongping Yang
- Chongqing Key Laboratory of Chinese Medicine New Drug Screening, Southwest University, Chongqing, China.
| | - Xiumei Ke
- Chongqing Key Laboratory of Traditional Chinese Medicine for Prevention and Cure of Metabolic Diseases, Chongqing Medical University, Chongqing, China.
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Wang Q, Duan X, Li S, Lai H, Cheng W, Ao J, Zhang J, Duan C. Active Compounds Screening and Hepatoprotective Mechanism of Shuganning Injection Based on Network Pharmacology and Experimental Validation. Nat Prod Commun 2022. [DOI: 10.1177/1934578x221124756] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022] Open
Abstract
Objective: The study aimed to analyze the core active compounds and the potential mechanism of Shuganning injection (SGNI) through network pharmacology with biological experiments. Methods: Active compounds and targets of SGNI were screened from the Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform (TCMSP) and Targetnet database, whereas the liver disease-related targets were identified through the Genecards and Online Mendelian Inheritance in Man databases. The “compound-target” and “protein-protein interaction” networks construction, core target identification, and pathway enrichment were then performed. Finally, the exploration of the mechanism of action for SGNI against acetaminophen (APAP)-induced liver injury in the HepaRG cells and validation of three identified protein targets was also carried out through western blot assay, including tumor protein p53 (p53, TP53), transcription factor Jun (Jun), and Caspase 3 (CASP3). Results: The result showed that a total of 312 active compounds of SGNI and 408 liver disease-related targets, as well as 131 core targets were revealed through databases, such as prostaglandin G/H synthase 1, prostaglandin G/H synthase 2, and nuclear factor NF-kappa B (NF-kB) p65 subunit (RELA). The core targets of SGNI were involved in regulating hepatitis B signaling pathway, NF-kB signaling pathway, Toll-like receptor signaling pathway, and tumor necrosis factor (TNF) signaling pathway. Moreover, results of molecular docking in this study indicated that chlorogenic acid, geniposide, baicalin, indirubin, and ganoderic acid A could act on RELA, JUN, TP53, TNF, CASP3, Caspase 8 (CASP8) and nuclear factor NF-kB p105 subunit (NFKB1). Similarly, results of western blot revealed that SGNI reduced the expression of p53, Jun, and Caspase 3 proteins in HepaRG cells as compared with the APAP group ( P < 0.01 or P < 0.05). Conclusion: The present study verified the therapeutic effects and mechanism of SGNI on liver diseases and pointed out new directions for further research.
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Affiliation(s)
- Qiyi Wang
- School of Pharmacy, Zunyi Medical University, Zunyi, Guizhou, China
| | - Xiaotong Duan
- School of Basic Medical Sciences, Zunyi Medical University, Zunyi, Guizhou, China
| | - Shan Li
- School of Basic Medical Sciences, Zunyi Medical University, Zunyi, Guizhou, China
| | - Huaqing Lai
- School of Pharmacy, Zunyi Medical University, Zunyi, Guizhou, China
| | - Weina Cheng
- School of Pharmacy, Zunyi Medical University, Zunyi, Guizhou, China
| | - Jingwen Ao
- School of Pharmacy, Zunyi Medical University, Zunyi, Guizhou, China
| | - Jianyong Zhang
- School of Pharmacy, Zunyi Medical University, Zunyi, Guizhou, China
- Key Laboratory of Basic Pharmacology of Ministry of Education and Joint International Research Laboratory of Ethnomedicine of Ministry of Education, Zunyi Medical University, Zunyi, China
| | - Cancan Duan
- School of Pharmacy, Zunyi Medical University, Zunyi, Guizhou, China
- Key Laboratory of Basic Pharmacology of Ministry of Education and Joint International Research Laboratory of Ethnomedicine of Ministry of Education, Zunyi Medical University, Zunyi, China
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Raphani Semen ( Raphanus sativus L.) Ameliorates Alcoholic Fatty Liver Disease by Regulating De Novo Lipogenesis. Nutrients 2021; 13:nu13124448. [PMID: 34959999 PMCID: PMC8705906 DOI: 10.3390/nu13124448] [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: 10/14/2021] [Revised: 11/25/2021] [Accepted: 12/07/2021] [Indexed: 12/13/2022] Open
Abstract
In this study, we investigated the pharmacological effect of a water extract of Raphani Semen (RSWE) on alcoholic fatty liver disease (AFLD) using ethanol-induced AFLD mice (the NIAAA model) and palmitic acid (PA)-induced steatosis HepG2 cells. An RSWE supplement improved serum and hepatic triglyceride (TG) levels of AFLD mice, as well as their liver histological structure. To explore the molecular action of RSWE in the improvement of AFLD, we investigated the effect of RSWE on four major pathways for lipid homeostasis in the liver: free fatty acid transport, lipogenesis, lipolysis, and β-oxidation. Importantly, RSWE decreased the mRNA expression of de novo lipogenesis-related genes, such as Srebf1, Cebpa, Pparg, and Lpin1, as well as the protein levels of these factors, in the liver of AFLD mice. That these actions of RSWE affect lipogenesis was confirmed using PA-induced steatosis HepG2 cells. Overall, our findings suggest that RSWE has the potential for improvement of AFLD by inhibiting de novo lipogenesis.
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Chlorogenic Acid Protects against Advanced Alcoholic Steatohepatitis in Rats via Modulation of Redox Homeostasis, Inflammation, and Lipogenesis. Nutrients 2021; 13:nu13114155. [PMID: 34836410 PMCID: PMC8617701 DOI: 10.3390/nu13114155] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2021] [Revised: 11/16/2021] [Accepted: 11/19/2021] [Indexed: 11/17/2022] Open
Abstract
The aim of this study was to evaluate the therapeutic effects of chlorogenic acid (CGA) in rats with advanced alcoholic steatohepatitis. The rats were fed on a high-fat diet and gavaged with ethanol (4 g/kg) for 8 weeks. The livers of ethanol-treated rats showed steatosis; necrosis and mononuclear infiltration; and significant upregulation of the mRNA expression of the prooxidant (Cyp2e1, iNos), lipogenic (Srebp1, Acc), proinflammatory (Tlr4, Nf-κb, TnfA, Il-1B, and Il-6), and profibrogenic (TgfB, Col1, VegfA) genes. Simultaneously, a downregulation of level of Sod and Nrf2 was observed, which was accompanied by increased serum transaminase, TnfA, and serum and liver triglycerides levels. CGA administration (40 and 80 mg/kg, 8 weeks) to ethanol-fed group reduced the liver expression levels of Cyp2e1 and iNos, whereas it markedly enhanced the expression of Sod, Nrf2, and Ho-1. CGA at both doses downregulated the expressions of lipogenic, proinflammatory, and profibrogenic genes, while the expression of Tlr4 was lowered only after the higher dose of CGA. The higher dose of CGA efficiently prevented the progression of alcohol-induced steatosis and reduced inflammation through regulation of the expression of genes encoding the proteins involved in the Tlr4/Nf-κB signaling pathway and fibrosis. The study revealed hepatoprotective and anti-inflammatory effects of CGA through the regulation of expression of genes encoding Cyp2e1/Nrf2 involved in oxidative stress modulation. These results demonstrate CGA as a therapeutic candidate for the prevention and treatment of alcoholic steatohepatitis.
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Abdelhamid AM, Elsheakh AR, Suddek GM, Abdelaziz RR. Telmisartan alleviates alcohol-induced liver injury by activation of PPAR-γ/ Nrf-2 crosstalk in mice. Int Immunopharmacol 2021; 99:107963. [PMID: 34273638 DOI: 10.1016/j.intimp.2021.107963] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2021] [Revised: 07/01/2021] [Accepted: 07/04/2021] [Indexed: 02/07/2023]
Abstract
Excessive consumption of alcohol may induce severe liver damage, in part via oxidative stress and inflammatory responses, which implicates these processes as potential therapeutic approaches. Prior literature has shown that Telmisartan (TEL) may provide protective effects, presumably mediated by its anti-oxidant and anti-inflammatory activities. The purpose of this study was to determine TEL's hepatoprotective effects and to identify its possible curative mechanisms in alcoholic liver disease. A mouse chronic alcohol plus binge feedings model was used in the current study for induction of alcoholic liver disease (ALD). Our results showed that TEL (10 mg/kg/day) has the ability to reduce serum levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), and alkaline phosphatase (ALP). TEL also increased the activity of superoxide dismutase (SOD) and glutathione (GSH) with concomitant reduction of nitric oxide (NO) malonaldehyde (MDA) in the liver homogenate. Moreover, TEL downregulated nuclear factor kappa B (NF-κB) expression and decreased liver content of interleukin-6 (IL-6), interleukin-1β (IL-1β), and tumor necrosis factor-α (TNF-α). These anti-inflammatory and anti-oxidant activities were associated with a significant increase in the expression of nuclear factor erythroid 2-related factor 2 (Nrf-2), peroxisome proliferator-activated receptors -γ (PPAR-γ), and heme oxygenase-1 (Hmox-1). In conclusion, TEL's hepatoprotective effects against ALD may be attributable to its anti-inflammatory and anti-oxidant activities which may be in part via the modulation of PPAR-γ/ Nrf-2/ NF-κB crosstalk.
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Affiliation(s)
- Amir Mohamed Abdelhamid
- Department of Pharmacology & Toxicology, Faculty of Pharmacy, Mansoura University, Egypt; Department of Pharmacology and Biochemistry, Faculty of Pharmacy, Delta University for Science and Technology, Egypt
| | - Ahmed Ramadan Elsheakh
- Department of Pharmacology & Toxicology, Faculty of Pharmacy, Mansoura University, Egypt
| | - Ghada Mohamed Suddek
- Department of Pharmacology & Toxicology, Faculty of Pharmacy, Mansoura University, Egypt
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Michalak A, Lach T, Cichoż-Lach H. Oxidative Stress-A Key Player in the Course of Alcohol-Related Liver Disease. J Clin Med 2021; 10:3011. [PMID: 34300175 PMCID: PMC8303854 DOI: 10.3390/jcm10143011] [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: 06/08/2021] [Revised: 07/04/2021] [Accepted: 07/05/2021] [Indexed: 12/12/2022] Open
Abstract
Oxidative stress is known to be an inseparable factor involved in the presentation of liver disorders. Free radicals interfere with DNA, proteins, and lipids, which are crucial in liver metabolism, changing their expression and biological functions. Additionally, oxidative stress modifies the function of micro-RNAs, impairing the metabolism of hepatocytes. Free radicals have also been proven to influence the function of certain transcriptional factors and to alter the cell cycle. The pathological appearance of alcohol-related liver disease (ALD) constitutes an ideal example of harmful effects due to the redox state. Finally, ethanol-induced toxicity and overproduction of free radicals provoke irreversible changes within liver parenchyma. Understanding the underlying mechanisms associated with the redox state in the course of ALD creates new possibilities of treatment for patients. The future of hepatology may become directly dependent on the effective action against reactive oxygen species. This review summarizes current data on the redox state in the natural history of ALD, highlighting the newest reports on this topic.
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Affiliation(s)
- Agata Michalak
- Department of Gastroenterology with Endoscopy Unit, Medical University of Lublin, Jaczewskiego 8, 20-090 Lublin, Poland;
| | - Tomasz Lach
- Department of Orthopedics and Traumatology, Medical University of Lublin, Jaczewskiego 8, 20-090 Lublin, Poland;
| | - Halina Cichoż-Lach
- Department of Gastroenterology with Endoscopy Unit, Medical University of Lublin, Jaczewskiego 8, 20-090 Lublin, Poland;
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Lai Y, Tan Q, Xv S, Huang S, Wang Y, Li Y, Zeng T, Mo C, Chen Y, Huang S, Zhou C, Gao L, Lv Z. Ginsenoside Rb1 Alleviates Alcohol-Induced Liver Injury by Inhibiting Steatosis, Oxidative Stress, and Inflammation. Front Pharmacol 2021; 12:616409. [PMID: 33716743 PMCID: PMC7952325 DOI: 10.3389/fphar.2021.616409] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/23/2020] [Accepted: 01/12/2021] [Indexed: 12/12/2022] Open
Abstract
Alcoholic liver disease (ALD) has become a heavy burden on health worldwide. Ginsenoside Rb1 (GRb1), extracted from Panax quinquefolium L., has protective effects on many diseases, but the effect and mechanisms of GRb1 on ALD remain unknown. This study aimed to investigate the protective effects of GRb1 on ALD and to discover the potential mechanisms. Zebrafish larvae were exposed to 350 mM ethanol for 32 h to establish a model of acute alcoholic liver injury, and the larvae were then treated with 6.25, 12.5, or 25 μM GRb1 for 48 h. The human hepatocyte cell line was stimulated by 100 mM ethanol and meanwhile incubated with 6.25, 12.5, and 25 μM GRb1 for 24 h. The lipid changes were detected by Oil Red O staining, Nile Red staining, and triglyceride determination. The antioxidant capacity was assessed by fluorescent probes in vivo, and the expression levels of inflammatory cytokines were detected by immunohistochemistry, immunofluorescence, and quantitative real-time PCR. The results showed that GRb1 alleviated lipid deposition in hepatocytes at an optimal concentration of 12.5 μM in vivo. GRb1 reversed the reactive oxygen species accumulation caused by alcohol consumption and partially restored the level of glutathione. Furthermore, GRb1 ameliorated liver inflammation by inhibiting neutrophil infiltration in the liver parenchyma and downregulating the expression of nuclear factor-kappa B pathway-associated proinflammatory cytokines, including tumor necrosis factor-α and interleukin-1β. This study revealed that GRb1 has a protective effect on alcohol-induced liver injury due to its resistance to lipid deposition as well as antioxidant and anti-inflammatory actions. These findings suggest that GRb1 may be a promising candidate against ALD.
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Affiliation(s)
- Yuqi Lai
- School of Traditional Chinese Medicine, Southern Medical University, Guangzhou, China
| | - Qinxiang Tan
- Renal Division, Beijing University of Chinese Medicine Shenzhen Hospital (Longgang), Shenzhen, China
| | - Shu Xv
- Oncology Department of Shenzhen Hospital of University of Chinese Academy of Sciences, Shenzhen, China
| | - Sha Huang
- School of Traditional Chinese Medicine, Southern Medical University, Guangzhou, China
| | - Yuhua Wang
- School of Traditional Chinese Medicine, Southern Medical University, Guangzhou, China
| | - Yunjia Li
- School of Traditional Chinese Medicine, Southern Medical University, Guangzhou, China.,The Key Laboratory of Molecular Biology, State Administration of Traditional Chinese Medicine, School of Traditional Chinese Medicine, Southern Medical University, Guangzhou, China
| | - Ting Zeng
- School of Traditional Chinese Medicine, Southern Medical University, Guangzhou, China
| | - Chan Mo
- School of Traditional Chinese Medicine, Southern Medical University, Guangzhou, China
| | - Yuyao Chen
- School of Traditional Chinese Medicine, Southern Medical University, Guangzhou, China
| | - Shaohui Huang
- School of Traditional Chinese Medicine, Southern Medical University, Guangzhou, China
| | - Chuying Zhou
- School of Traditional Chinese Medicine, Southern Medical University, Guangzhou, China
| | - Lei Gao
- School of Traditional Chinese Medicine, Southern Medical University, Guangzhou, China.,The Key Laboratory of Molecular Biology, State Administration of Traditional Chinese Medicine, School of Traditional Chinese Medicine, Southern Medical University, Guangzhou, China
| | - Zhiping Lv
- School of Traditional Chinese Medicine, Southern Medical University, Guangzhou, China
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Salehi E, Mashayekh M, Taheri F, Gholami M, Motaghinejad M, Safari S, Sepehr A. Curcumin Can be Acts as Effective agent for Prevent or Treatment of Alcohol-induced Toxicity in Hepatocytes: An Illustrated Mechanistic Review. IRANIAN JOURNAL OF PHARMACEUTICAL RESEARCH : IJPR 2021; 20:418-436. [PMID: 34400970 PMCID: PMC8170768 DOI: 10.22037/ijpr.2020.112852.13985] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Previous studies have shown that alcohol abuse can cause serious liver damage and cirrhosis. The main pathway for these types of hepatocellular cell neurodegeneration is mitochondrial dysfunction, which causes lipid peroxidation and dysfunction of the glutathione ring and the defect of antioxidant enzymes in alcoholic hepatic cells. Alcohol can also initiate malicious inflammatory pathways and trigger the initiation and activation of intestinal and extrinsic apoptosis pathways in hepatocellular tissues that lead to cirrhosis. Previous studies have shown that curcumin may inhibit lipid peroxidation, glutathione dysfunction and restore antioxidant enzymes. Curcumin also modulates inflammation and the production of alcohol-induced biomarkers. Curcumin has been shown to play a critical role in the survival of alcoholic hepatocellular tissue. It has been shown that curcumin can induce and trigger mitochondrial biogenesis and, by this mechanism, prevent the occurrence of both intrinsic and extrinsic apoptosis pathways in liver cells that have been impaired by alcohol. According to this mechanism, curcumin may protect hepatocellular tissue from alcohol-induced cell degeneration and may therefore survive alcoholic hepatocellular tissue. . Based on these mechanisms, the protective functions of curcumin against alcohol-induced cell degeneration due to oxidative stress, inflammation, and apoptosis events in hepatocellular tissue have been recorded. Hence, in this research, we have attempted to evaluate and analyze the main contribution mechanism of curcumin cell defense properties against alcohol-induced hepatocellular damage, according to previous experimental and clinical studies, and in this way we report findings from major studies.
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Affiliation(s)
- Elham Salehi
- Department of Pharmaceutical Chemistry, Faculty of Pharmaceutical Chemistry, Pharmaceutical Sciences Branch, Islamic Azad University (IUAPS), Tehran, Iran.
| | - Mohammad Mashayekh
- Department of Pharmaceutical Chemistry, Faculty of Pharmaceutical Chemistry, Pharmaceutical Sciences Branch, Islamic Azad University (IUAPS), Tehran, Iran.
| | - Fereshteh Taheri
- Razi Drug Research Center, Iran University of Medical Sciences, Tehran, Iran.
| | - Mina Gholami
- Department of Medicinal Chemistry, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran.
| | - Majid Motaghinejad
- Razi Drug Research Center, Iran University of Medical Sciences, Tehran, Iran.
| | - Sepideh Safari
- Razi Drug Research Center, Iran University of Medical Sciences, Tehran, Iran.
| | - Afrah Sepehr
- Razi Drug Research Center, Iran University of Medical Sciences, Tehran, Iran.
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15
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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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16
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Zhu X, Yang L, He Y, Sun Y, Shi W, Ou C. Liver Function of Male Rats Exposed to Manganese at Different Time Points. Biol Trace Elem Res 2020; 198:224-230. [PMID: 32100273 DOI: 10.1007/s12011-020-02067-1] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/17/2019] [Accepted: 01/30/2020] [Indexed: 01/15/2023]
Abstract
As an essential trace element in the human body, manganese (Mn) is involved in many important biochemical reactions. However, excessive exposure to manganese can cause multiple systematic damages to the body. This study aims to investigate the effects of manganese exposure on serum hepatic enzymes in male rats at different time points. After adaptive feeding for 7 days, male Sprague-Dawley (SD) rats were injected intraperitoneally with 30 mg/kg MnCl2·4H2O once a day for 21 days at zeitgeber time point 2 (ZT2), ZT8, ZT14, and ZT20, respectively. We found that short-term repeated exposure to manganese caused slower body weight gain and increased relative liver and spleen weight index in male rats at different time points. Moreover, serum total bile acid (TBA) increased while aspartate aminotransferase (AST) decreased at ZT2, ZT8, and ZT20. Cholinesterase (ChE) decreased at ZT2 and ZT20, lactic dehydrogenase (LDH) decreased at ZT2, ZT14, and ZT20, and acid phosphatase (ACP) decreased at ZT2 and ZT14. Alkaline phosphatase (ALP) decreased at ZT2, ZT14, and ZT20, but increased at ZT8. Alanine amino transferase (ALT) decreased at ZT2 and ZT20, but increased at ZT8. There was a negative correlation between relative liver weight index with AST, ACP, ALP, and LDH, while a positive correlation with TBA. However, relative spleen weight index had a positive correlation with relative liver weight index and TBA, while a negative correlation with ALT, AST, ACP, ALP, LDH, and ChE. Our study shows that the injury of liver function is caused by short-term repeated manganese exposure at different time points. The time effect should be considered in manganese toxicity evaluation.
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Affiliation(s)
- Xiaonian Zhu
- Department of Health Toxicology, School of Public Health, Guilin Medical University, 109 Huancheng North Road 2, Guilin, Guangxi, 541004, People's Republic of China
| | - Lin Yang
- Department of Health Toxicology, School of Public Health, Guilin Medical University, 109 Huancheng North Road 2, Guilin, Guangxi, 541004, People's Republic of China
| | - Yonghua He
- Department of Health Toxicology, School of Public Health, Guilin Medical University, 109 Huancheng North Road 2, Guilin, Guangxi, 541004, People's Republic of China
| | - Yi Sun
- Department of Health Toxicology, School of Public Health, Guilin Medical University, 109 Huancheng North Road 2, Guilin, Guangxi, 541004, People's Republic of China
| | - Wenxiang Shi
- Department of Health Toxicology, School of Public Health, Guilin Medical University, 109 Huancheng North Road 2, Guilin, Guangxi, 541004, People's Republic of China
| | - Chaoyan Ou
- Department of Health Toxicology, School of Public Health, Guilin Medical University, 109 Huancheng North Road 2, Guilin, Guangxi, 541004, People's Republic of China.
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Effects of taraxasterol against ethanol and high-fat diet-induced liver injury by regulating TLR4/MyD88/NF-κB and Nrf2/HO-1 signaling pathways. Life Sci 2020; 262:118546. [PMID: 33035580 DOI: 10.1016/j.lfs.2020.118546] [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: 07/14/2020] [Revised: 09/22/2020] [Accepted: 09/30/2020] [Indexed: 12/13/2022]
Abstract
Studies have reported that taraxasterol (TAR) is effective in the treatment of immune liver injury and alcoholic liver injury. The mechanism of action is mainly related to the inhibition of inflammation. To determine the key molecular mechanisms for the effect of TAR on alleviating ethanol and high-fat diet-induced liver injury, pathological morphology, biochemistry, oxidative stress, inflammatory response and lipid metabolism were examined. Our results showed that TAR could inhibit ethanol-induced hepatocyte death or lipid accumulation, and suppress oxidative stress, inflammatory response and lipid metabolism disorders. More specifically, ethanol-induced TLR-4 and MyD88 inflammatory response were down-regulated, when treated with TAR. Production of CYP2E1, Nrf2 and HO-1, which produced in response to increased oxidative stress, were regulated in TAR treated, ethanol-induced hepatocytes. In summary, TAR could inhibit the inflammatory response and oxidative stress, which was related to the regulation of TAR on TLR-4/MyD88/NF-κB and Nrf2/HO-1 pathways.
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18
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Abdelhamid AM, Elsheakh AR, Abdelaziz RR, Suddek GM. Empagliflozin ameliorates ethanol-induced liver injury by modulating NF-κB/Nrf-2/PPAR-γ interplay in mice. Life Sci 2020; 256:117908. [PMID: 32512011 DOI: 10.1016/j.lfs.2020.117908] [Citation(s) in RCA: 38] [Impact Index Per Article: 7.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2020] [Revised: 05/25/2020] [Accepted: 06/01/2020] [Indexed: 02/07/2023]
Abstract
BACKGROUND Excessive alcohol intake contributes to severe liver damage involving oxidative stress and inflammatory responses, which make them promising therapeutic targets. Previous studies have demonstrated that empagliflozin (EMPA) showed cardiovascular, renal, and cerebral benefits potentially mediated through its antioxidant and anti-inflammatory actions. AIMS This experiment aimed to evaluate the hepatoprotective effect of EMPA on alcoholic liver disease (ALD) and the possible underlying mechanisms. MATERIALS AND METHODS Serum biochemical parameters and the liver contents of malondialdehyde (MDA), nitric oxide (NO), reduced glutathione (GSH), and superoxide dismutase (SOD) were measured. Real-time qPCR was conducted to determine the gene expression of peroxisome proliferator-activated receptor gamma (PPAR-γ), nuclear factor erythroid 2-related factor 2 (Nrf-2), and heme oxygenase-1 (Hmox-1). In addition, ELISA was performed to measure tumor necrosis factor-α (TNF-α), interleukin (IL)-1β, IL-6, Nrf-2, and PPAR-γ. Nuclear factor-kappa B (NF-κB) was detected by immunohistochemical staining using an anti-NF-κB p65 antibody. KEY FINDINGS Our results revealed that the serum levels of alanine aminotransferase, aspartate aminotransferase, and alkaline phosphatase were significantly reduced by EMPA. EMPA also decreased the content of MDA and NO and increased the activities of SOD and GSH in liver homogenates. Moreover, EMPA inhibited the release of proinflammatory cytokines, including TNF-α, IL-1β, and IL-6, via the downregulation of NF-κB. These changes were associated with an improvement in histopathological deterioration. The protective effect of EMPA against oxidative stress and inflammation was associated with the upregulation of PPAR-γ, Nrf-2, and their target gene Hmox-1. SIGNIFICANCE EMPA showed protective activities against ethanol-induced liver injury by suppressing inflammation and oxidative stress via modulation of the NF-κB/Nrf-2/PPAR-γ axis.
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Affiliation(s)
- Amir Mohamed Abdelhamid
- Department of Pharmacology and Biochemistry, Faculty of Pharmacy, Delta University for Science & Technology, Egypt.
| | - Ahmed Ramadan Elsheakh
- Department of Pharmacology & Toxicology, Faculty of Pharmacy, Mansoura University, Egypt
| | | | - Ghada Mohamed Suddek
- Department of Pharmacology & Toxicology, Faculty of Pharmacy, Mansoura University, Egypt
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Empagliflozin ameliorates ethanol-induced liver injury by modulating NF-κB/Nrf-2/PPAR-γ interplay in mice. Life Sci 2020. [DOI: 10.1016/j.lfs.2020.117908
expr 913773998 + 879574250] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/16/2023]
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Diesinger T, Buko V, Lautwein A, Dvorsky R, Belonovskaya E, Lukivskaya O, Naruta E, Kirko S, Andreev V, Buckert D, Bergler S, Renz C, Schneider E, Kuchenbauer F, Kumar M, Günes C, Büchele B, Simmet T, Müller-Enoch D, Wirth T, Haehner T. Drug targeting CYP2E1 for the treatment of early-stage alcoholic steatohepatitis. PLoS One 2020; 15:e0235990. [PMID: 32701948 PMCID: PMC7377376 DOI: 10.1371/journal.pone.0235990] [Citation(s) in RCA: 22] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2020] [Accepted: 06/25/2020] [Indexed: 02/07/2023] Open
Abstract
Background and aims Alcoholic steatohepatitis (ASH)—the inflammation of fatty liver—is caused by chronic alcohol consumption and represents one of the leading chronic liver diseases in Western Countries. ASH can lead to organ dysfunction or progress to hepatocellular carcinoma (HCC). Long-term alcohol abstinence reduces this probability and is the prerequisite for liver transplantation—the only effective therapy option at present. Elevated enzymatic activity of cytochrome P450 2E1 (CYP2E1) is known to be critically responsible for the development of ASH due to excessively high levels of reactive oxygen species (ROS) during metabolization of ethanol. Up to now, no rational drug discovery process was successfully initiated to target CYP2E1 for the treatment of ASH. Methods In this study, we applied a rational drug design concept to develop drug candidates (NCE) including preclinical studies. Results A new class of drug candidates was generated successfully. Two of the most promising small compounds named 12-Imidazolyl-1-dodecanol (abbr.: I-ol) and 1-Imidazolyldodecane (abbr.: I-an) were selected at the end of this process of drug discovery and developability. These new ω-imidazolyl-alkyl derivatives act as strong chimeric CYP2E1 inhibitors at a nanomolar range. They restore redox balance, reduce inflammation process as well as the fat content in the liver and rescue the physiological liver architecture of rats consuming continuously a high amount of alcohol. Conclusions Due to its oral application and therapeutic superiority over an off-label use of the hepatoprotector ursodeoxycholic acid (UDCA), this new class of inhibitors marks the first rational, pharmaceutical concept in long-term treatment of ASH.
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Affiliation(s)
- Torsten Diesinger
- Donauklinik Neu-Ulm, Abteilung für Innere Medizin, Neu-Ulm, Germany
- Institute of Physiological Chemistry, Ulm University, Ulm, Germany
- Department of Internal Medicine, Neu-Ulm Hospital, Neu-Ulm, Germany
- * E-mail:
| | - Vyacheslav Buko
- Division of Biochemical Pharmacology, Institute of Biochemistry of Biologically Active Substances, Grodno, Belarus
- Department of Biotechnology, University of Medical Sciences, Bialystok, Poland
| | - Alfred Lautwein
- Institute of Physiological Chemistry, Ulm University, Ulm, Germany
| | - Radovan Dvorsky
- Institut für Biochemie und Molekularbiologie II, Medizinische Fakultät der Heinrich-Heine-Universität Düsseldorf, Düsseldorf, Germany
- Max Planck Institute of Molecular Physiology, Dortmund, Germany
| | - Elena Belonovskaya
- Division of Biochemical Pharmacology, Institute of Biochemistry of Biologically Active Substances, Grodno, Belarus
| | - Oksana Lukivskaya
- Division of Biochemical Pharmacology, Institute of Biochemistry of Biologically Active Substances, Grodno, Belarus
| | - Elena Naruta
- Division of Biochemical Pharmacology, Institute of Biochemistry of Biologically Active Substances, Grodno, Belarus
| | - Siarhei Kirko
- Division of Biochemical Pharmacology, Institute of Biochemistry of Biologically Active Substances, Grodno, Belarus
| | - Viktor Andreev
- Department of Medical Biology and Genetics, Grodno State Medical University, Grodno, Belarus
| | - Dominik Buckert
- Institute of Physiological Chemistry, Ulm University, Ulm, Germany
- Department of Internal Medicine II, University Hospital Ulm, Ulm, Germany
| | | | - Christian Renz
- Institute of Physiological Chemistry, Ulm University, Ulm, Germany
| | - Edith Schneider
- Department of Internal Medicine III, University Hospital Ulm, Ulm, Germany
| | - Florian Kuchenbauer
- Department of Internal Medicine III, University Hospital Ulm, Ulm, Germany
- University of British Columbia, Terry Fox Laboratory, Vancouver, Canada
| | - Mukesh Kumar
- Department of Urology, University Hospital Ulm, Ulm, Germany
| | - Cagatay Günes
- Department of Urology, University Hospital Ulm, Ulm, Germany
| | - Berthold Büchele
- Institute of Pharmacology of Natural Products and Clinical Pharmacology, University Ulm, Ulm, Germany
| | - Thomas Simmet
- Institute of Pharmacology of Natural Products and Clinical Pharmacology, University Ulm, Ulm, Germany
| | | | - Thomas Wirth
- Institute of Physiological Chemistry, Ulm University, Ulm, Germany
| | - Thomas Haehner
- Institute of Physiological Chemistry, Ulm University, Ulm, Germany
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Choi RY, Ham JR, Ryu HS, Lee SS, Miguel MA, Paik MJ, Ji M, Park KW, Kang KY, Lee HI, Lee MK. Defatted Tenebrio molitor Larva Fermentation Extract Modifies Steatosis, Inflammation and Intestinal Microflora in Chronic Alcohol-Fed Rats. Nutrients 2020; 12:nu12051426. [PMID: 32423176 PMCID: PMC7284378 DOI: 10.3390/nu12051426] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2020] [Revised: 05/10/2020] [Accepted: 05/11/2020] [Indexed: 02/07/2023] Open
Abstract
This study examined the effects of defatted mealworm fermentation extract (MWF) on alcoholic liver injury in rats. The rats were fed either a Lieber-DeCarli control (Con) or alcohol liquid diet (EtOH). The alcohol-fed rats were administered MWF (50, 100, or 200 mg/kg/day) and silymarin (200 mg/kg/day) orally for eight weeks. MWF prevented alcohol-induced hepatocellular damage by decreasing their serum aspartate transaminase, alanine transaminase, and gamma-glutamyl transpeptidase levels significantly compared to the EtOH group. MWF effectively reduced the relative hepatic weight, lipid contents, and fat deposition, along with the down-regulation of transcriptional factors and genes involved in lipogenesis compared to the EtOH group. It also enhanced the antioxidant defense system by elevating the glutathione level and glutathione reductase activity. MWF attenuated the alcohol-induced inflammatory response by down-regulating hepatic inflammation-associated proteins expression, such as phosphorylated-inhibitor of nuclear factor-kappa B-alpha and tumor necrosis factor-alpha, in chronic alcohol-fed rats. Furthermore, sequencing analysis in the colonic microbiota showed that MWF tended to increase Lactobacillus johnsonii reduced by chronic alcohol consumption. These findings suggest that MWF can attenuate alcoholic liver injury by regulating the lipogenic and inflammatory pathway and antioxidant defense system, as well as by partially altering the microbial composition.
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Affiliation(s)
- Ra-Yeong Choi
- Department of Food and Nutrition, Sunchon National University, Suncheon 57922, Korea; (R.-Y.C.); (J.R.H.); (H.-S.R.)
| | - Ju Ri Ham
- Department of Food and Nutrition, Sunchon National University, Suncheon 57922, Korea; (R.-Y.C.); (J.R.H.); (H.-S.R.)
| | - Hyo-Seon Ryu
- Department of Food and Nutrition, Sunchon National University, Suncheon 57922, Korea; (R.-Y.C.); (J.R.H.); (H.-S.R.)
| | - Sang Suk Lee
- Department of Animal Science and Technology, Sunchon National University, Suncheon 57922, Korea; (S.S.L.); (M.A.M.)
| | - Michelle A. Miguel
- Department of Animal Science and Technology, Sunchon National University, Suncheon 57922, Korea; (S.S.L.); (M.A.M.)
| | - Man-Jeong Paik
- College of Pharmacy, Sunchon National University, Suncheon 57922, Korea; (M.-J.P.); (M.J.)
| | - Moongi Ji
- College of Pharmacy, Sunchon National University, Suncheon 57922, Korea; (M.-J.P.); (M.J.)
| | - Kyung-Wuk Park
- Suncheon Research Center for Natural Medicines, Suncheon 57922, Korea; (K.-W.P.); (K.-Y.K.)
| | - Kyung-Yun Kang
- Suncheon Research Center for Natural Medicines, Suncheon 57922, Korea; (K.-W.P.); (K.-Y.K.)
| | - Hae-In Lee
- Mokpo Marin Food-Industry Research Center, Mokpo 58621, Korea;
| | - Mi-Kyung Lee
- Department of Food and Nutrition, Sunchon National University, Suncheon 57922, Korea; (R.-Y.C.); (J.R.H.); (H.-S.R.)
- Correspondence: ; Tel.: +82-61-750-3656
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Liu X, Wang Y, Wu D, Li S, Wang C, Han Z, Wang J, Wang K, Yang Z, Wei Z. Magnolol Prevents Acute Alcoholic Liver Damage by Activating PI3K/Nrf2/PPARγ and Inhibiting NLRP3 Signaling Pathway. Front Pharmacol 2019; 10:1459. [PMID: 31920652 PMCID: PMC6915046 DOI: 10.3389/fphar.2019.01459] [Citation(s) in RCA: 48] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2019] [Accepted: 11/13/2019] [Indexed: 12/15/2022] Open
Abstract
Alcoholic liver damage (ALD) is a toxic liver damage caused by excessive drinking. Oxidative stress is one of the most crucial pathogenic factors leading to ALD. Magnolol is one of the main active constituents of traditional Chinese medicine Magnolia officinalis, which has been reported to possess many pharmacological effects including anti-inflammatory, anti-oxidant, and anti-tumor. However, the effects of magnolol on ALD remain unclear. In this study, we firstly evaluated the protective effects of magnolol on ALD, and then tried to clarify the mechanism underlying the pharmacological activities. AST, ALT, GSH-Px, and SOD were detected by respective kits. Histopathological changes of liver tissue were analyzed by H&E staining. The activities of PI3K, Nrf2, and NLRP3 signaling pathways activation were detected by western blotting analysis. It was showed that alcohol-induced ALT and AST levels were significantly reduced by magnolol, but the antioxidant enzymes of GSH-Px and SOD levels were significantly increased. Magnolol attenuated alcohol-induced pathologic damage such as decreasing hepatic cord swelling, hepatocyte necrosis, and inflammatory cell infiltration. Furthermore, it was found that magnolol inhibited oxidative stress through up-regulating the activities of HO-1, Nrf2, and PPARγ and the phosphorylation of PI3K and AKT. And magnolol also decreased inflammatory response by inhibiting the activation of NLRP3inflammasome, caspase-1, and caspase-3 signaling pathway. Above results showed that magnolol could prevent alcoholic liver damage, and the underlying mechanism was through activating PI3K/Nrf2/PPARγ signaling pathways as well as inhibiting NLRP3 inflammasome, which also suggested magnolol might be used as a potential drug for ALD.
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Affiliation(s)
- Xiao Liu
- College of Life Sciences and Engineering, Foshan University, Foshan, China.,College of Veterinary Medicine, Jilin University, Changchun, China
| | - Yanan Wang
- College of Veterinary Medicine, Jilin University, Changchun, China
| | - Di Wu
- College of Veterinary Medicine, Jilin University, Changchun, China
| | - Shuangqiu Li
- College of Veterinary Medicine, Jilin University, Changchun, China
| | - Chaoqun Wang
- College of Veterinary Medicine, Jilin University, Changchun, China
| | - Zhen Han
- College of Veterinary Medicine, Jilin University, Changchun, China
| | - Jingjing Wang
- College of Veterinary Medicine, Jilin University, Changchun, China
| | - Kai Wang
- College of Life Sciences and Engineering, Foshan University, Foshan, China
| | - Zhengtao Yang
- College of Life Sciences and Engineering, Foshan University, Foshan, China
| | - Zhengkai Wei
- College of Life Sciences and Engineering, Foshan University, Foshan, China
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Iahtisham-Ul-Haq, Butt MS, Randhawa MA, Shahid M. Hepatoprotective effects of red beetroot-based beverages against CCl 4 -induced hepatic stress in Sprague Dawley rats. J Food Biochem 2019; 43:e13057. [PMID: 31583751 DOI: 10.1111/jfbc.13057] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2019] [Revised: 09/08/2019] [Accepted: 09/10/2019] [Indexed: 12/30/2022]
Abstract
Red beetroot (Beta vulgaris L.) is considered important to improve hepatic health but its use is primarily limited to fresh salads in Pakistan. This study was aimed at exploring prophylactic role of red beetroot-based beverages against carbon tetrachloride (CCl4 )-induced hepatic stress. Purposely, red beetroot-based beverages (8 ml/kg b.w. per day) were administered to normal and hepatotoxicity-induced rats for 8 weeks. The biochemical analyses revealed significantly higher levels of superoxide dismutase (25%-28%), catalase (21%-24%), and hepatic enzymes (15%-19%) alongside reduced lipid peroxidation (27%-32%) in liver tissues of hepatotoxicity-induced rats treated with beetroot-based beverages compared to control. Similarly, hepatic injury was reduced by 19%-26% as indicated by concentrations of serum hepatic health biomarkers. Moreover, histological architecture of hepatocytes also portrayed promising effects of beetroot-based beverages to preserve hepatocellular portfolio. It was concluded that red beetroot-based beverages considerably assuage negative impacts of hepatic stress. PRACTICAL APPLICATIONS: Functional foods and nutraceuticals are considered vital in controlling the oxidative stress-mediated metabolic disorders as safer alternatives to pharmaceutical agents. The current research explored the protective effects of red beetroot-based beverages which can be utilized as an effective approach to prevent liver injuries. Also, the outcomes of this research endorsed the defensive role of these beverages against oxidative stress-induced hepatic stress, so dietary supplementation of such products can be synchronized in clinical practices to alleviate oxidative stress. However, there is a need to further explore the safety aspects of such products in their long-term usage before implementing this module in humans for disease prevention/cure.
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Affiliation(s)
- Iahtisham-Ul-Haq
- National Institute of Food Science & Technology, Faculty of Food, Nutrition & Home Sciences, University of Agriculture, Faisalabad, Pakistan
| | - Masood Sadiq Butt
- National Institute of Food Science & Technology, Faculty of Food, Nutrition & Home Sciences, University of Agriculture, Faisalabad, Pakistan
| | - Muhammad Atif Randhawa
- National Institute of Food Science & Technology, Faculty of Food, Nutrition & Home Sciences, University of Agriculture, Faisalabad, Pakistan
| | - Muhammad Shahid
- Medicinal Biochemistry Research Laboratory, Department of Biochemistry, University of Agriculture, Faisalabad, Pakistan
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24
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Kong LZ, Chandimali N, Han YH, Lee DH, Kim JS, Kim SU, Kim TD, Jeong DK, Sun HN, Lee DS, Kwon T. Pathogenesis, Early Diagnosis, and Therapeutic Management of Alcoholic Liver Disease. Int J Mol Sci 2019; 20:ijms20112712. [PMID: 31159489 PMCID: PMC6600448 DOI: 10.3390/ijms20112712] [Citation(s) in RCA: 112] [Impact Index Per Article: 18.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2019] [Revised: 05/30/2019] [Accepted: 05/31/2019] [Indexed: 02/08/2023] Open
Abstract
Alcoholic liver disease (ALD) refers to the damages to the liver and its functions due to alcohol overconsumption. It consists of fatty liver/steatosis, alcoholic hepatitis, steatohepatitis, chronic hepatitis with liver fibrosis or cirrhosis, and hepatocellular carcinoma. However, the mechanisms behind the pathogenesis of alcoholic liver disease are extremely complicated due to the involvement of immune cells, adipose tissues, and genetic diversity. Clinically, the diagnosis of ALD is not yet well developed. Therefore, the number of patients in advanced stages has increased due to the failure of proper early detection and treatment. At present, abstinence and nutritional therapy remain the conventional therapeutic interventions for ALD. Moreover, the therapies which target the TNF receptor superfamily, hormones, antioxidant signals, and MicroRNAs are used as treatments for ALD. In particular, mesenchymal stem cells (MSCs) are gaining attention as a potential therapeutic target of ALD. Therefore, in this review, we have summarized the current understandings of the pathogenesis and diagnosis of ALD. Moreover, we also discuss the various existing treatment strategies while focusing on promising therapeutic approaches for ALD.
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Affiliation(s)
- Ling-Zu Kong
- Laboratory of Animal Genetic Engineering and Stem Cell Biology, Advanced Convergence Technology and Science, Jeju National University, Jeju 63243, Korea.
- Immunotherapy Convergence Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon 34141, Korea.
| | - Nisansala Chandimali
- Laboratory of Animal Genetic Engineering and Stem Cell Biology, Advanced Convergence Technology and Science, Jeju National University, Jeju 63243, Korea.
- Immunotherapy Convergence Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon 34141, Korea.
| | - Ying-Hao Han
- Department of Disease Model Animal Research Center, College of Life Science and Technology, Heilongjiang Bayi Agricultural University, Daqing 163319, China.
| | - Dong-Ho Lee
- Primate Resources Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Jeongeup-si, Jeonbuk 56216, Korea.
| | - Ji-Su Kim
- Primate Resources Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Jeongeup-si, Jeonbuk 56216, Korea.
| | - Sun-Uk Kim
- Futuristic Animal Resource & Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Cheongju-si, Chungcheongbuk-do 28116, Korea.
| | - Tae-Don Kim
- Immunotherapy Convergence Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon 34141, Korea.
| | - Dong Kee Jeong
- Laboratory of Animal Genetic Engineering and Stem Cell Biology, Advanced Convergence Technology and Science, Jeju National University, Jeju 63243, Korea.
- Subtropical/Tropical Organism Gene Bank, Jeju National University, Jeju 63243, Korea.
| | - Hu-Nan Sun
- Department of Disease Model Animal Research Center, College of Life Science and Technology, Heilongjiang Bayi Agricultural University, Daqing 163319, China.
- Subtropical/Tropical Organism Gene Bank, Jeju National University, Jeju 63243, Korea.
| | - Dong Sun Lee
- Subtropical/Tropical Organism Gene Bank, Jeju National University, Jeju 63243, Korea.
- Department of Biotechnology, College of Applied Life Science, Jeju National University, Jeju 63243, Korea.
| | - Taeho Kwon
- Primate Resources Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Jeongeup-si, Jeonbuk 56216, Korea.
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Zhao N, Guo FF, Xie KQ, Zeng T. Targeting Nrf-2 is a promising intervention approach for the prevention of ethanol-induced liver disease. Cell Mol Life Sci 2018; 75:3143-3157. [PMID: 29947925 PMCID: PMC11105722 DOI: 10.1007/s00018-018-2852-6] [Citation(s) in RCA: 35] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2018] [Revised: 05/18/2018] [Accepted: 06/06/2018] [Indexed: 02/07/2023]
Abstract
Alcoholic liver disease (ALD) remains to be a worldwide health problem. It is generally accepted that oxidative stress plays critical roles in the pathogenesis of ALD, and antioxidant therapy represents a logical strategy for the prevention and treatment of ALD. Nuclear factor erythroid-derived 2-like 2 (NFE2L2 or Nrf-2) is essential for the antioxidant responsive element (ARE)-mediated induction of endogenous antioxidant enzymes such as heme oxygenase 1 (HO-1) and glutamate-cysteine ligase [GCL, the rate-limiting enzyme in the synthesis of glutathione (GSH)]. Activation of Nrf-2 pathway by genetic manipulation or pharmacological agents has been demonstrated to provide protection against ALD, which suggests that targeting Nrf-2 may be a promising approach for the prevention and treatment of ALD. Herein, we review the relevant literature about the potential hepatoprotective roles of Nrf-2 activation against ALD.
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Affiliation(s)
- Ning Zhao
- Institute of Toxicology, School of Public Health, Shandong University, 44 Wenhua West Road, Jinan, 250012, Shandong, China
| | - Fang-Fang Guo
- Department of Pharmacy, Qilu Hospital of Shandong University, 107 Wenhua West Road, Jinan, 250012, Shandong, China
| | - Ke-Qin Xie
- Institute of Toxicology, School of Public Health, Shandong University, 44 Wenhua West Road, Jinan, 250012, Shandong, China
| | - Tao Zeng
- Institute of Toxicology, School of Public Health, Shandong University, 44 Wenhua West Road, Jinan, 250012, Shandong, China.
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26
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Chigurupati H, Auddy B, Biyani M, Chakrabarti S, Stohs SJ. Prevention of alcohol-induced DNA damage by a proprietary glycyrrhizin/D-mannitol product: A randomized, placebo-controlled, cross-over human study. Alcohol 2018; 69:33-39. [PMID: 29609113 DOI: 10.1016/j.alcohol.2017.11.001] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/27/2016] [Revised: 10/31/2017] [Accepted: 11/01/2017] [Indexed: 01/12/2023]
Abstract
OBJECTIVES The purpose of the present study was to evaluate the ability of a proprietary combination of glycyrrhizin and D-mannitol to protect against oxidative damage to DNA associated with acute alcohol consumption by human subjects in a randomized, placebo-controlled cross-over designed study. Excessive alcohol consumption is associated with numerous diseases. Alcohol has been shown to generate reactive oxygen species that can result in DNA damage, leading to genetic and epigenetic changes. METHODS A total of 25 subjects (13 male and 12 female) were enrolled. Alcohol intake in the form of vodka (40% ethanol) was adjusted based on 1.275 g of 100% ethanol/kg body weight for men and 1.020 g/kg body weight for women, which was consumed with and without the study product. Blood samples were drawn at 2 h after alcohol consumption, lymphocytes were isolated, and were subjected to DNA comet electrophoresis on a blinded basis. RESULTS Acute alcohol consumption increased lymphocyte DNA damage by approximately 8.36%. Co-consumption of the glycyrrhizin/D-mannitol study product with alcohol reduced DNA damage to baseline levels. No adverse effects were associated with use of the study product, and no differences were observed in blood alcohol concentrations in the presence or absence of the study product in males and females. CONCLUSIONS Acute alcohol ingestion resulted in measurable increases in DNA damage, which were prevented by the addition of the proprietary glycyrrhizin/D-mannitol (NTX®) study product to the alcohol, suggesting that the tissue-damaging effects of alcohol consumption can be ameliorated.
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Affiliation(s)
| | - Biswajit Auddy
- Chigurupati Technologies Private Limited, Hyderabad, India
| | - Manish Biyani
- Chigurupati Technologies Private Limited, Hyderabad, India
| | | | - Sidney J Stohs
- Creighton University, 7068 Maumee Valley Court, Frisco, TX 75034, United States.
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27
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Tong J, Sun CY, Yang LB, Kang YN. Clinical efficacy of tauroursodeoxycholic acid combined with S-adenosyl methionine in treatment of cholestasis in patients with compensated alcoholic cirrhosis. Shijie Huaren Xiaohua Zazhi 2018; 26:31-35. [DOI: 10.11569/wcjd.v26.i1.31] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM To observe the clinical effects of taursodeoxycholic acid combined with S-adenosyl methionine in the treatment of cholestasis in patients with compensated alcoholic cirrhosis.
METHODS One hundred patients with compensated alcoholic cirrhosis treated at our hospital from January 2012 to January 2017 were randomly divided into an experimental group and a control group, with 50 cases in each group. Both groups of patients were given S-adenosyl methionine and hepatoprotective drugs, and the experimental group was additionally given tauroursodeoxycholic acid. After 12 wk of treatment, the changes of liver biochemical indicators [alkaline phosphatase (ALP), gamma glutamyl transaminase (GGT), and total bilirubin (TBIL)] and prothrombin activity (PTA) were detected to evaluate the therapeutic effect.
RESULTS The total effective rate in the experimental group was significantly higher than that of the control group (92% vs 56%, P < 0.05). After treatment, ALP, GGT, and TBIL in both groups decreased significantly compared with pretreatment values (P < 0.05), and the thereapeutic effect in the experimental group was better than that in the control group (P < 0.05).
CONCLUSION Tauroursodeoxycholic acid combined with S-adenosyl methionine is effective in treating cholestasis in patients with compensated alcoholic cirrhosis, and can effectively improve the clinical symptoms and biochemical indexes.
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Affiliation(s)
- Jing Tong
- Department of Infectious Diseases, the First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, He'nan Province, China
| | - Chang-Yu Sun
- Department of Infectious Diseases, the First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, He'nan Province, China
| | - Li-Bing Yang
- Department of Infectious Diseases, the First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, He'nan Province, China
| | - Yan-Nan Kang
- Department of Infectious Diseases, the First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, He'nan Province, China
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Polydatin Protects Rat Liver against Ethanol-Induced Injury: Involvement of CYP2E1/ROS/Nrf2 and TLR4/NF-κB p65 Pathway. EVIDENCE-BASED COMPLEMENTARY AND ALTERNATIVE MEDICINE 2017; 2017:7953850. [PMID: 29250126 PMCID: PMC5698823 DOI: 10.1155/2017/7953850] [Citation(s) in RCA: 45] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/05/2017] [Revised: 10/11/2017] [Accepted: 10/17/2017] [Indexed: 12/20/2022]
Abstract
Excessive alcohol consumption leads to serious liver injury, associating with oxidative stress and inflammatory response. Previous study has demonstrated that polydatin (PD) exerted antioxidant and anti-inflammatory effects and attenuated ethanol-induced liver damage, but the research remained insufficient. Hence, this experiment aimed to evaluate the hepatoprotective effect and potential mechanisms of PD on ethanol-induced hepatotoxicity. Our results showed that PD pretreatment dramatically decreased the levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP), and lactate dehydrogenase (LDH) in the serum, suppressed the malonaldehyde (MDA) and triglyceride (TG) content and the production of reactive oxygen species (ROS), and enhanced the activities of superoxide dismutase (SOD), glutathione peroxidase (GSH-Px), catalase (CAT), andalcohol dehydrogenase (ADH), and aldehyde dehydrogenase (ALDH), paralleled by an improvement of histopathology alterations. The protective effect of PD against oxidative stress was probably associated with downregulation of cytochrome P450 2E1 (CYP2E1) and upregulation of nuclear factor erythroid 2-related factor 2 (Nrf2) and its target gene haem oxygenase-1 (HO-1). Moreover, PD inhibited the release of proinflammatory cytokines (TNF-α, IL-1β, and IL-6) via downregulating toll-like receptor 4 (TLR4) and nuclear factor kappa B (NF-κB) p65. To conclude, PD pretreatment protects against ethanol-induced liver injury via suppressing oxidative stress and inflammation.
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29
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Jarido V, Kennedy L, Hargrove L, Demieville J, Thomson J, Stephenson K, Francis H. The emerging role of mast cells in liver disease. Am J Physiol Gastrointest Liver Physiol 2017; 313:G89-G101. [PMID: 28473331 PMCID: PMC5582878 DOI: 10.1152/ajpgi.00333.2016] [Citation(s) in RCA: 30] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/07/2016] [Revised: 04/12/2017] [Accepted: 04/24/2017] [Indexed: 01/31/2023]
Abstract
The depth of our knowledge regarding mast cells has widened exponentially in the last 20 years. Once thought to be only important for allergy-mediated events, mast cells are now recognized to be important regulators of a number of pathological processes. The revelation that mast cells can influence organs, tissues, and cells has increased interest in mast cell research during liver disease. The purpose of this review is to refresh the reader's knowledge of the development, type, and location of mast cells and to review recent work that demonstrates the role of hepatic mast cells during diseased states. This review focuses primarily on liver diseases and mast cells during autoimmune disease, hepatitis, fatty liver disease, liver cancer, and aging in the liver. Overall, these studies demonstrate the potential role of mast cells in disease progression.
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Affiliation(s)
- Veronica Jarido
- Baylor Scott & White Health and Medicine, Temple, Texas; and
| | - Lindsey Kennedy
- Research, Central Texas Veterans Health Care System, Temple, Texas
- Texas A & M Health Science Center, Temple, Texas
| | | | | | - Joanne Thomson
- Research, Central Texas Veterans Health Care System, Temple, Texas
| | | | - Heather Francis
- Research, Central Texas Veterans Health Care System, Temple, Texas;
- Baylor Scott & White Health and Medicine, Temple, Texas; and
- Texas A & M Health Science Center, Temple, Texas
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30
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Chigurupati H, Auddy B, Biyani M, Chakrabarti S, Pandit S, Biswas TK, Mondal T, Stohs SJ. Antioxidant and DNA protective effects of NTX, a proprietary glycyrrhizin/ d -mannitol product, in association with alcohol consumption: A randomized, placebo-controlled, double-blind, crossover study. J Funct Foods 2017. [DOI: 10.1016/j.jff.2017.04.011] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
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Abstract
酒精性肝病(alcoholic liver disease, ALD)是一种慢性肝脏疾病, 包括肝脂肪变性、酒精性脂肪性肝炎、肝硬化、肝细胞癌和肝衰竭. 许多因素被认为能促进ALD的发展, 特别是氧化应激, 在酒精代谢期间活性氧物质的产生, 来自内脏脂肪组织的脂肪因子和来自肠道的内毒素等. 目前, ALD的发病机制已被广泛研究, 精确的机制尚待阐明. 在我国随着人类生活水平提高和生活方式的改变, 人群中的嗜酒者的比率逐年上升, 乙醇也已成为导致肝脏损害的第二大原因. 因此, ALD相关治疗也受到人们的广泛关注. 在本文中, 我们就ALD的发病机制、治疗等方面的最新研究进展作一综述.
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Abstract
Malnutrition is associated with alcoholic liver disease (ALD) and related complications such as hepatic encephalopathy and increased rate of infections. Avoidance of prolonged fasting and overly restrictive diets is important to avoid poor nutrition. Adequate intake of calories, protein, and micronutrients via frequent small meals and evening supplements and/or enteral and parenteral nutrition when indicated has been associated with reduced mortality and morbidity in patients with ALD. Modification of protein/fat sources and composition in addition to probiotic supplementation are promising interventions for decreased progression of ALD and its complications.
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Rishi P, Arora S, Kaur UJ, Chopra K, Kaur IP. Better Management of Alcohol Liver Disease Using a 'Microstructured Synbox' System Comprising L. plantarum and EGCG. PLoS One 2017; 12:e0168459. [PMID: 28060832 PMCID: PMC5217831 DOI: 10.1371/journal.pone.0168459] [Citation(s) in RCA: 28] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2016] [Accepted: 12/01/2016] [Indexed: 02/06/2023] Open
Abstract
Synergistic combination of probiotics with carbohydrate based prebiotics is widely employed for the treatment of various gut related disorders. However, such carbohydrate based prebiotics encourage the growth of pathogens and probiotics, equally. Aim of the study was (i) to explore the possibility of using epigallocatechin gallate (EGCG) a phenolic compound, as a prebiotic for L.plantarum; (ii) to develop and evaluate a microstructured synbox (microencapsulating both probiotic and EGCG together) in rat model of alcohol liver disease (ALD); and, (iii) to confirm whether the combination can address issues of EGCG bioavailability and probiotic survivability in adverse gut conditions. Growth enhancing effect of EGCG on L. plantarum (12.8±0.5 log 10 units) was significantly (p≤0.05) better than inulin (11.4±0.38 log 10 units), a natural storage carbohydrate. The formulated synbox significantly modulated the levels of alcohol, endotoxin, hepatic enzymes and restored the hepatoarchitecture in comparison to simultaneous administration of free agents. Additionally, using a battery of techniques, levels of various cellular and molecular markers viz. NF-kB/p50, TNF-α, IL12/p40, and signalling molecules TLR4, CD14, MD2, MyD88 and COX-2 were observed to be suppressed. Developed microbead synbox, as a single delivery system for both the agents showed synergism and hence, holds promise as a therapeutic option for ALD management.
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Affiliation(s)
- Praveen Rishi
- Department of Microbiology, Basic Medical Sciences Block, South Campus, Panjab University, Chandigarh, India
| | - Sumeha Arora
- Department of Microbiology, Basic Medical Sciences Block, South Campus, Panjab University, Chandigarh, India
| | - Ujjwal Jit Kaur
- Department of Microbiology, Basic Medical Sciences Block, South Campus, Panjab University, Chandigarh, India
| | - Kanwaljit Chopra
- University Institute of Pharmaceutical Sciences, Panjab University, Chandigarh, India
| | - Indu Pal Kaur
- University Institute of Pharmaceutical Sciences, Panjab University, Chandigarh, India
- * E-mail:
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34
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Tlili N, Feriani A, Saadoui E, Nasri N, Khaldi A. Capparis spinosa leaves extract: Source of bioantioxidants with nephroprotective and hepatoprotective effects. Biomed Pharmacother 2017; 87:171-179. [PMID: 28056421 DOI: 10.1016/j.biopha.2016.12.052] [Citation(s) in RCA: 41] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/24/2016] [Revised: 12/01/2016] [Accepted: 12/14/2016] [Indexed: 01/15/2023] Open
Abstract
Capparis spinosa, Capparidaceae, is largely distributed all over the Mediterranean Basin and is traditionally used to treat many illnesses, such as liver and kidney diseases. The aim of the current study was to explore the antioxidant, nephroprotective and hepatoprotective effects of methanolic extract of Capparis spinosa leaves (MECS) associated with its phytochemical content. The levels of total phenolics, flavonoids and condensed tannins were 23.37mgGAE/g, 9.05mgQE/g and 9.35mgTAE/g, respectively. HPLC analysis revealed nine compounds, namely rutin, resveratrol, coumarin, epicatechin, luteolin, catechin, kaempferol, vanillic acid and gallic acid. The MECS showed interesting antioxidant capacity. The MECS-treatment significantly reduced the increased plasma levels of creatinine, urea and uric acid, reduced the elevated MDA levels, significantly reduced the antioxidant enzyme activities and restored the kidney damage, provoked by cisplatin-treatment. Furthermore, MECS-treatment significantly prevented the increase in serum ALT, AST and LDH levels in acute liver damage induced by CCl4, decreased the amount of hepatic malondialdehyde (MDA) formation and elevated the activities of SOD, CAT and GPx, and restored liver injury. This study supports the traditionally use of C. spinosa to cure kidney and liver diseases. The obtained results highlighted the possible use of C. spinosa as a source of phytochemical with important biological advantages.
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Affiliation(s)
- Nizar Tlili
- Laboratoire de biochimie, Faculté des Sciences de Tunis, Université Tunis El-Manar, 2092 Tunis, Tunisie; Institut National de Recherches en Génie Rural, Eaux et Forêts, Université de Carthage, BP 10, Ariana 2080, Tunisie.
| | - Anouar Feriani
- Unité de Biochimie Macromoléculaire et Génétique, Faculté des Sciences de Gafsa, cité Zarroug, Université de Gafsa, 2112 Gafsa, Tunisie; Laboratoire d'Ecophysiologie Animale, Faculté des Sciences de Sfax, Tunisia
| | - Ezzeddine Saadoui
- Institut National de Recherches en Génie Rural, Eaux et Forêts, Université de Carthage, BP 10, Ariana 2080, Tunisie
| | - Nizar Nasri
- Laboratoire de biochimie, Faculté des Sciences de Tunis, Université Tunis El-Manar, 2092 Tunis, Tunisie
| | - Abdelhamid Khaldi
- Institut National de Recherches en Génie Rural, Eaux et Forêts, Université de Carthage, BP 10, Ariana 2080, Tunisie
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Zulkawi N, Ng KH, Zamberi R, Yeap SK, Jaganath IB, Satharasinghe D, Yeah Yong C, Jamaluddin AB, Tan SW, Ho WY, Alitheen NB, Long K. The in vivo hepato-recovery effects of the polyphenol-rich fermented food Xeniji™ on ethanol-induced liver damage. RSC Adv 2017. [DOI: 10.1039/c7ra04616b] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022] Open
Abstract
Xeniji that rich in caffeoylquinic acid and sakuranetin promoted recovery of the ethanol induced liver damage.
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Affiliation(s)
| | | | - Rizi Zamberi
- Institute of Bioscience
- Universiti Putra Malaysia
- Serdang
- Malaysia
- Malaysian Agricultural Research and Development Institute (MARDI)
| | | | - Indu Bala Jaganath
- Malaysian Agricultural Research and Development Institute (MARDI)
- Serdang
- Malaysia
| | - Dilan Satharasinghe
- Department of Basic Veterinary Sciences
- Faculty of Veterinary Medicine & Animal Science
- University of Peradeniya
- Peradeniya 20400
- Sri Lanka
| | - Chean Yeah Yong
- Institute of Bioscience
- Universiti Putra Malaysia
- Serdang
- Malaysia
| | | | - Sheau Wei Tan
- Institute of Bioscience
- Universiti Putra Malaysia
- Serdang
- Malaysia
| | - Wan Yong Ho
- School of Biomedical Sciences
- The University of Nottingham Malaysia Campus
- 43500 Semenyih
- Malaysia
| | - Noorjahan Banu Alitheen
- Institute of Bioscience
- Universiti Putra Malaysia
- Serdang
- Malaysia
- Department of Cell and Molecular Biology
| | - Kamariah Long
- Malaysian Agricultural Research and Development Institute (MARDI)
- Serdang
- Malaysia
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36
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Osna NA, Donohue TM, Kharbanda KK. Alcoholic Liver Disease: Pathogenesis and Current Management. Alcohol Res 2017; 38:147-161. [PMID: 28988570 PMCID: PMC5513682] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023] Open
Abstract
Excessive alcohol consumption is a global healthcare problem. The liver sustains the greatest degree of tissue injury by heavy drinking because it is the primary site of ethanol metabolism. Chronic and excessive alcohol consumption produces a wide spectrum of hepatic lesions, the most characteristic of which are steatosis, hepatitis, and fibrosis/cirrhosis. Steatosis is the earliest response to heavy drinking and is characterized by the deposition of fat in hepatocytes. Steatosis can progress to steatohepatitis, which is a more severe, inflammatory type of liver injury. This stage of liver disease can lead to the development of fibrosis, during which there is excessive deposition of extracellular matrix proteins. The fibrotic response begins with active pericellular fibrosis, which may progress to cirrhosis, characterized by excessive liver scarring, vascular alterations, and eventual liver failure. Among problem drinkers, about 35 percent develop advanced liver disease because a number of disease modifiers exacerbate, slow, or prevent alcoholic liver disease progression. There are still no FDA-approved pharmacological or nutritional therapies for treating patients with alcoholic liver disease. Cessation of drinking (i.e., abstinence) is an integral part of therapy. Liver transplantation remains the life-saving strategy for patients with end-stage alcoholic liver disease.
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Affiliation(s)
- Natalia A Osna
- Natalia A. Osna, Ph.D., is a Research Biologist in the Research Service, Veterans Affairs Nebraska-Western Iowa Health Care System, and an Associate Professor in the Department of Internal Medicine, University of Nebraska Medical Center, both in Omaha, Nebraska. Terrence M. Donohue, Jr., Ph.D., is a Research Biochemist in the Research Service, Veterans Affairs Nebraska-Western Iowa Health Care System, and a Professor in the Departments of Internal Medicine and Biochemistry and Molecular Biology, University of Nebraska Medical Center, both in Omaha, Nebraska. Kusum K. Kharbanda, Ph.D., is a Research Biologist in the Research Service, Veterans Affairs Nebraska-Western Iowa Health Care System, and a Professor in the Departments of Internal Medicine and Biochemistry and Molecular Biology, University of Nebraska Medical Center, both in Omaha, Nebraska
| | - Terrence M Donohue
- Natalia A. Osna, Ph.D., is a Research Biologist in the Research Service, Veterans Affairs Nebraska-Western Iowa Health Care System, and an Associate Professor in the Department of Internal Medicine, University of Nebraska Medical Center, both in Omaha, Nebraska. Terrence M. Donohue, Jr., Ph.D., is a Research Biochemist in the Research Service, Veterans Affairs Nebraska-Western Iowa Health Care System, and a Professor in the Departments of Internal Medicine and Biochemistry and Molecular Biology, University of Nebraska Medical Center, both in Omaha, Nebraska. Kusum K. Kharbanda, Ph.D., is a Research Biologist in the Research Service, Veterans Affairs Nebraska-Western Iowa Health Care System, and a Professor in the Departments of Internal Medicine and Biochemistry and Molecular Biology, University of Nebraska Medical Center, both in Omaha, Nebraska
| | - Kusum K Kharbanda
- Natalia A. Osna, Ph.D., is a Research Biologist in the Research Service, Veterans Affairs Nebraska-Western Iowa Health Care System, and an Associate Professor in the Department of Internal Medicine, University of Nebraska Medical Center, both in Omaha, Nebraska. Terrence M. Donohue, Jr., Ph.D., is a Research Biochemist in the Research Service, Veterans Affairs Nebraska-Western Iowa Health Care System, and a Professor in the Departments of Internal Medicine and Biochemistry and Molecular Biology, University of Nebraska Medical Center, both in Omaha, Nebraska. Kusum K. Kharbanda, Ph.D., is a Research Biologist in the Research Service, Veterans Affairs Nebraska-Western Iowa Health Care System, and a Professor in the Departments of Internal Medicine and Biochemistry and Molecular Biology, University of Nebraska Medical Center, both in Omaha, Nebraska
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Trovato FM, Martines GF, Brischetto D, Trovato G, Catalano D. Neglected features of lifestyle: Their relevance in non-alcoholic fatty liver disease. World J Hepatol 2016; 8:1459-1465. [PMID: 27957244 PMCID: PMC5124717 DOI: 10.4254/wjh.v8.i33.1459] [Citation(s) in RCA: 33] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/30/2016] [Revised: 08/04/2016] [Accepted: 10/24/2016] [Indexed: 02/06/2023] Open
Abstract
AIM To investigated in non-alcoholic-fatty-liver-disease (NAFLD), with ultrasound (US)-detected fatty liver, and in a group of non-alcoholic and otherwise healthy subjects, relationship of neglected features of lifestyle with NAFLD and obesity.
METHODS Five hundred and thirty-two NAFLD and 667 non-NAFLD healthy subjects, age 21-60 years were studied. Severity of liver steatosis was assessed by US bright liver score. The adherence to mediterranean diet score (AMDS) was assessed on the basis of a 1-wk recall computerized questionnaire which included a detailed physical activity reports (Baecke questionnaire). The western dietary profile score, as a simplified paradigm of unhealthy diet, a questionnaire quantifying sun exposure score and a sleep habits questionnaires provided a further comprehensive lifestyle assessment.
RESULTS Body mass index (BMI), insulin resistance (HOMA), and triglycerides, poorer adherence to a mediterranean diet profile, sedentary habits, minor sun exposure and use of “western diet” foods are greater in NAFLD. Multiple linear regression analysis, weighted by years of age, displays BMI, HOMA and AMDS as the most powerful independent predictors of fatty liver severity; however, also the physical activity score, the western diet habit and the sun exposure score are acting inside the model with significant independent effects.
CONCLUSION Articulated clinical intervention, according to our results, are justified in NAFLD and can be pursued addressing by focused intervention nutritional profile, physical exercise mainly in open-air subsets for enhancing sun exposure and healthier sleep duration and rhythm.
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Chigurupati H, Auddy B, Biyani M, Stohs SJ. Hepatoprotective Effects of a Proprietary Glycyrrhizin Product during Alcohol Consumption: A Randomized, Double-Blind, Placebo-Controlled, Crossover Study. Phytother Res 2016; 30:1943-1953. [DOI: 10.1002/ptr.5699] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2016] [Revised: 07/18/2016] [Accepted: 07/22/2016] [Indexed: 12/14/2022]
Affiliation(s)
| | - Biswajit Auddy
- Chigurupati Technologies Private Limited; Hyderabad India
| | - M. Biyani
- Chigurupati Technologies Private Limited; Hyderabad India
| | - Sidney J. Stohs
- Creighton University; 7068 Maumee Valley Court Frisco TX 75034 USA
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Differential contribution of complement receptor C5aR in myeloid and non-myeloid cells in chronic ethanol-induced liver injury in mice. Mol Immunol 2016; 75:122-32. [PMID: 27280845 DOI: 10.1016/j.molimm.2016.05.006] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2016] [Revised: 05/05/2016] [Accepted: 05/07/2016] [Indexed: 01/06/2023]
Abstract
BACKGROUND Complement is implicated in the development of alcoholic liver disease. C3 and C5 contribute to ethanol-induced liver injury; however, the role of C5a receptor (C5aR) on myeloid and non-myeloid cells to progression of injury is not known. METHODS C57BL/6 (WT), global C5aR-/-, myeloid-specific C5aR-/-, and non-myeloid-specific C5aR-/- mice were fed a Lieber-DeCarli diet (32%kcal EtOH) for 25 days. Cultured hepatocytes were challenged with ethanol, TNFα, and C5a. RESULTS Chronic ethanol feeding increased expression of pro-inflammatory mediators in livers of WT mice; this response was completely blunted in C5aR-/- mice. However, C5aR-/- mice were not protected from other measures of hepatocellular damage, including ethanol-induced increases in hepatic triglycerides, plasma alanine aminotransferase and hepatocyte apoptosis. CYP2E1 and 4-hydroxynonenal protein adducts were induced in WT and C5aR-/- mice. Myeloid-specific C5aR-/- mice were protected from ethanol-induced increases in hepatic TNFα, whereas non-myeloid-specific C5aR-/- displayed increased hepatocyte apoptosis and inflammation after chronic ethanol feeding. In cultured hepatocytes, cytotoxicity induced by challenge with ethanol and TNFα was completely eliminated by treatment with C5a in cells from WT, but not C5aR-/- mice. Further, treatment with C5a enhanced activation of pro-survival signal AKT in hepatocytes challenged with ethanol and TNFα. CONCLUSION Taken together, these data reveal a differential role for C5aR during ethanol-induced liver inflammation and injury, with C5aR on myeloid cells contributing to ethanol-induced inflammatory cytokine expression, while non-myeloid C5aR protects hepatocytes from death after chronic ethanol feeding.
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