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Ezhilarasan D, Karthikeyan S, Najimi M, Vijayalakshmi P, Bhavani G, Jansi Rani M. Preclinical liver toxicity models: Advantages, limitations and recommendations. Toxicology 2025; 511:154020. [PMID: 39637935 DOI: 10.1016/j.tox.2024.154020] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2024] [Revised: 11/25/2024] [Accepted: 12/02/2024] [Indexed: 12/07/2024]
Abstract
Experimental animal models are crucial for elucidating the pathophysiology of liver injuries and for assessing new hepatoprotective agents. Drugs and chemicals such as acetaminophen, isoniazid, valproic acid, ethanol, carbon tetrachloride (CCl4), dimethylnitrosamine (DMN), and thioacetamide (TAA) are metabolized by the CYP2E1 enzyme, producing hepatotoxic metabolites that lead to both acute and chronic liver injuries. In experimental settings, acetaminophen (centrilobular necrosis), carbamazepine (centrilobular necrosis and inflammation), sodium valproate (necrosis, hydropic degeneration and mild inflammation), methotrexate (sinusoidal congestion and inflammation), and TAA (centrilobular necrosis and inflammation) are commonly used to induce various types of acute liver injuries. Repeated and intermittent low-dose administration of CCl4, TAA, and DMN activates quiescent hepatic stellate cells, transdifferentiating them into myofibroblasts, which results in abnormal extracellular matrix production and fibrosis induction, more rapidly with DMN and CCL4 than TAA (DMN > CCl4 > TAA). Regarding toxicity and mortality, CCl4 is more toxic than DMN and TAA (CCl4 > DMN > TAA). Models used to induce metabolic dysfunction-associated liver disease (MAFLD) vary, but MAFLD's multifactorial nature driven by factors like obesity, fatty liver, dyslipidaemia, type II diabetes, hypertension, and cardiovascular disease makes it challenging to replicate human metabolic dysfunction-associated steatohepatitis accurately. From an experimental point of view, the degree and pattern of liver injury are influenced by various factors, including the type of hepatotoxic agent, exposure duration, route of exposure, dosage, frequency of administration, and the animal model utilized. Therefore, there is a pressing need for standardized protocols and regulatory guidelines to streamline the selection of animal models in preclinical studies.
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Affiliation(s)
- Devaraj Ezhilarasan
- Department of Pharmacology, Hepatology and Molecular Medicine Lab, Saveetha Dental College and Hospitals, Saveetha Institute of Medical and Technical Sciences, Chennai, Tamil Nadu, India.
| | - Sivanesan Karthikeyan
- Department of Pharmacology and Environmental Toxicology, Dr. A.L.M. Postgraduate Institute of Basic Medical Sciences, University of Madras, Chennai, India
| | - Mustapha Najimi
- Laboratory of Pediatric Hepatology and Cell Therapy, Institute of Experimental and Clinical Research (IREC), UCLouvain, Brussels, Belgium
| | - Paramasivan Vijayalakshmi
- Department of Pharmacology and Environmental Toxicology, Dr. A.L.M. Postgraduate Institute of Basic Medical Sciences, University of Madras, Chennai, India; Department of Pharmacology, Asan Memorial Dental College and Hospital, Chengalpattu, Tamil Nadu, India
| | - Ganapathy Bhavani
- Department of Pharmacology and Environmental Toxicology, Dr. A.L.M. Postgraduate Institute of Basic Medical Sciences, University of Madras, Chennai, India; Department of Pharmacology, Meenakshi Ammal Dental College and Hospital, Meenakshi Academy of Higher Education and Research, Chennai, Tamil Nadu, India
| | - Muthukrishnan Jansi Rani
- Department of Pharmacology and Environmental Toxicology, Dr. A.L.M. Postgraduate Institute of Basic Medical Sciences, University of Madras, Chennai, India
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Ciceu A, Fenyvesi F, Hermenean A, Ardelean S, Dumitra S, Puticiu M. Advancements in Plant-Based Therapeutics for Hepatic Fibrosis: Molecular Mechanisms and Nanoparticulate Drug Delivery Systems. Int J Mol Sci 2024; 25:9346. [PMID: 39273295 PMCID: PMC11394827 DOI: 10.3390/ijms25179346] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2024] [Revised: 08/21/2024] [Accepted: 08/27/2024] [Indexed: 09/15/2024] Open
Abstract
Chronic liver injuries often lead to hepatic fibrosis, a condition characterized by excessive extracellular matrix accumulation and abnormal connective tissue hyperplasia. Without effective treatment, hepatic fibrosis can progress to cirrhosis or hepatocellular carcinoma. Current treatments, including liver transplantation, are limited by donor shortages and high costs. As such, there is an urgent need for effective therapeutic strategies. This review focuses on the potential of plant-based therapeutics, particularly polyphenols, phenolic acids, and flavonoids, in treating hepatic fibrosis. These compounds have demonstrated anti-fibrotic activities through various signaling pathways, including TGF-β/Smad, AMPK/mTOR, Wnt/β-catenin, NF-κB, PI3K/AKT/mTOR, and hedgehog pathways. Additionally, this review highlights the advancements in nanoparticulate drug delivery systems that enhance the pharmacokinetics, bioavailability, and therapeutic efficacy of these bioactive compounds. Methodologically, this review synthesizes findings from recent studies, providing a comprehensive analysis of the mechanisms and benefits of these plant-based treatments. The integration of novel drug delivery systems with plant-based therapeutics holds significant promise for developing effective treatments for hepatic fibrosis.
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Affiliation(s)
- Alina Ciceu
- "Aurel Ardelean" Institute of Life Sciences, Vasile Goldis Western University of Arad, 86 Rebreanu, 310414 Arad, Romania
| | - Ferenc Fenyvesi
- Department of Molecular and Nanopharmaceutics, Faculty of Pharmacy, University of Debrecen, 4032 Debrecen, Hungary
| | - Anca Hermenean
- "Aurel Ardelean" Institute of Life Sciences, Vasile Goldis Western University of Arad, 86 Rebreanu, 310414 Arad, Romania
| | - Simona Ardelean
- Faculty of Pharmacy, Vasile Goldis Western University of Arad, 86 Rebreanu, 310414 Arad, Romania
| | - Simona Dumitra
- Faculty of Medicine, Vasile Goldis Western University of Arad, 86 Rebreanu, 310414 Arad, Romania
| | - Monica Puticiu
- Faculty of Medicine, Vasile Goldis Western University of Arad, 86 Rebreanu, 310414 Arad, Romania
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Saygun I, Slezovic MÖ, Özkan CK, Bengi VU, Elçi P, Serdar M, Kantarci A. Anti-proliferative impact of resveratrol on gingival fibroblasts from juvenile hyaline fibromatosis. Clin Oral Investig 2024; 28:448. [PMID: 39060456 PMCID: PMC11281951 DOI: 10.1007/s00784-024-05771-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2024] [Accepted: 06/11/2024] [Indexed: 07/28/2024]
Abstract
AIM Resveratrol is a natural polyphenolic compound with biological activities such as anti-inflammation and antioxidation. Its anti-fibrotic effect has been experimentally demonstrated in the pancreas and liver. This study aims to determine the anti-proliferative effect of resveratrol on fibroblasts obtained from hyperplastic gingival tissues from a patient diagnosed with Juvenile Hyaline Fibromatosis (JHF). MATERIALS AND METHODS Primary gingival fibroblast cell lines were obtained from gingival growth tissues by the gingivectomy of a patient with JHF. Gingival fibroblasts were treated with or without 3 different doses of resveratrol (50, 100, 200 µM). Cytotoxicity and cell proliferation were evaluated after 24, 48, and 72 h. Collagen, TGF, and CTGF were analyzed by ELISA in the 48-hour supernatants. RESULTS All three doses of resveratrol suppressed the proliferation of JHF gingival fibroblasts at 24 and 48 h without showing any cytotoxic effect compared to the control group (p < 0.0001). At 72 h, 100 and 200 µM resveratrol showed significantly less proliferation (p < 0.0001), less collagen, CTGF, and TGF- β (p < 0.001) than the control group. CONCLUSION Resveratrol had a profound anti-proliferative effect on gingival fibroblasts obtained from gingival enlargements with JHF, suggesting that it can be used as a therapeutic to prevent excessive cell growth by suppressing collagen, CTGF, and TGF- β synthesis in the pathogenesis of hyperplasia.
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Affiliation(s)
- Işıl Saygun
- Department of Periodontology, Gulhane Faculty of Dental Medicine, University of Health Sciences, Ankara, Turkey.
| | - Melis Özgül Slezovic
- Department of Periodontology, Gulhane Faculty of Dental Medicine, University of Health Sciences, Ankara, Turkey.
| | - Cansel Köse Özkan
- Gulhane Faculty of Pharmacy, University of Health Sciences, Ankara, Turkey
| | - Vahdi Umut Bengi
- Department of Periodontology, Gulhane Faculty of Dental Medicine, University of Health Sciences, Ankara, Turkey
| | - Pınar Elçi
- Gulhane Health Sciences Institute, Stem Cell Lab, University of Health Sciences, Ankara, Turkey
| | - Muhittin Serdar
- Department of Medical Biochemistry, Acıbadem Mehmet Ali Aydınlar University, Ankara, Turkey
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Yang HW, Chun-Yu Ho D, Liao HY, Liao YW, Fang CY, Ng MY, Yu CC, Lin FC. Resveratrol inhibits arecoline-induced fibrotic properties of buccal mucosal fibroblasts via miR-200a activation. J Dent Sci 2024; 19:1028-1035. [PMID: 38618058 PMCID: PMC11010603 DOI: 10.1016/j.jds.2023.06.027] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/05/2023] [Revised: 06/26/2023] [Indexed: 04/16/2024] Open
Abstract
Background/purpose Oral submucous fibrosis (OSF) is a precancerous lesion in the oral cavity, commonly results from the Areca nut chewing habit. Arecoline, the main component of Areca nut, is known to stimulate the activation of myofibroblasts, which can lead to abnormal collagen I deposition. Meanwhile, Resveratrol is a non-flavonoid phenolic substance that can be naturally obtained from various berries and foods. Given that resveratrol has significant anti-fibrosis traits in other organs, but little is known about its effect on OSF, this study aimed to investigate the therapeutic impact of resveratrol on OSF and its underlying mechanism. Materials and methods The cytotoxicity of resveratrol was tested using normal buccal mucosal fibroblasts (BMFs). Myofibroblast phenotypes such as collagen contractile, enhanced migration, and wound healing capacities in dose-dependently resveratrol-treated fBMFs were examined. Results Current results showed that arecoline induced cell migration and contractile activity in BMFs as well as upregulated the expressions of α-SMA, type I collagen, and ZEB1 markers. Resveratrol intervention, on the other hand, was shown to inhibit arecoline-induced myofibroblast activation and reduce myofibroblast hallmarks and EMT markers. Additionally, resveratrol was also demonstrated to restore the downregulated miR-200a in the arecoline-stimulated cells. Conclusion In a nutshell, these findings implicate that resveratrol may have an inhibitory influence on arecoline-induced fibrosis via the regulation of miR-200a. Hence, resveratrol may be used as a therapeutic strategy for OSF intervention.
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Affiliation(s)
- Hui-Wen Yang
- School of Dentistry, Chung Shan Medical University, Taichung, Taiwan
- Department of Dentistry, Chung Shan Medical University Hospital, Taichung, Taiwan
| | - Dennis Chun-Yu Ho
- Division of Oral and Maxillofacial Surgery, Department of Dentistry, Wan Fang Hospital, Taipei Medical University, Taipei, Taiwan
- School of Dentistry, College of Oral Medicine, Taipei Medical University, Taipei, Taiwan
| | - Heng-Yi Liao
- School of Dentistry, Chung Shan Medical University, Taichung, Taiwan
| | - Yi-Wen Liao
- Institute of Oral Sciences, Chung Shan Medical University, Taichung, Taiwan
- Department of Medical Research, Chung Shan Medical University Hospital, Taichung, Taiwan
| | - Chih-Yuan Fang
- Division of Oral and Maxillofacial Surgery, Department of Dentistry, Wan Fang Hospital, Taipei Medical University, Taipei, Taiwan
- School of Dentistry, College of Oral Medicine, Taipei Medical University, Taipei, Taiwan
| | - Min Yee Ng
- School of Dentistry, Chung Shan Medical University, Taichung, Taiwan
| | - Cheng-Chia Yu
- School of Dentistry, Chung Shan Medical University, Taichung, Taiwan
- Department of Dentistry, Chung Shan Medical University Hospital, Taichung, Taiwan
- Institute of Oral Sciences, Chung Shan Medical University, Taichung, Taiwan
| | - Fu-Chen Lin
- Department of Otorhinolaryngology-Head and Neck Surgery, Changhua Christian Hospital, Changhua, Taiwan
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Li J, Koonyosying P, Korsieporn W, Paradee N, Hutachok N, Xu H, Ma Y, Chuljerm H, Srichairatanakool S. Deferiprone-resveratrol hybrid attenuates iron accumulation, oxidative stress, and antioxidant defenses in iron-loaded human Huh7 hepatic cells. Front Mol Biosci 2024; 11:1364261. [PMID: 38572444 PMCID: PMC10987756 DOI: 10.3389/fmolb.2024.1364261] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/02/2024] [Accepted: 03/07/2024] [Indexed: 04/05/2024] Open
Abstract
Chronic liver diseases are complications of thalassemia with iron overload. Iron chelators are required to remove excessive iron, and antioxidants are supplemented to diminish harmful reactive oxygen species (ROS), purposing to ameliorate oxidative liver damage and dysfunctions. The deferiprone-resveratrol hybrid (DFP-RVT) is a synthetic iron chelator possessing anti-β-amyloid peptide aggregation, anti-malarial activity, and hepatoprotection in plasmodium-infected mice. The study focuses on investigating the antioxidant, cytotoxicity, iron-chelating, anti-lipid peroxidation, and antioxidant defense properties of DFP-RVT in iron-loaded human hepatocellular carcinoma (Huh7) cells. In the findings, DFP-RVT dose dependently bound Fe(II) and Fe(III) and exerted stronger ABTS•- and DPPH•-scavenging (IC50 = 8.0 and 164 μM, respectively) and anti-RBC hemolytic activities (IC50 = 640 μM) than DFP but weaker than RVT (p < 0.01). DFP-RVT was neither toxic to Huh7 cells nor PBMCs. In addition, DFP-RVT diminished the level of redox-active iron (p < 0.01) and decreased the non-heme iron content (p < 0.01) in iron-loaded Huh7 cells effectively when compared without treatment in the order of DFP-RVT > RVT ∼ DFP treatments (50 µM each). Moreover, the compound decreased levels of hepatic ROS in a dose-dependent manner and the level of malondialdehyde, which was stronger than DFP but weaker than RVT. Furthermore, DFP-RVT restored the decrease in the GSH content and GPX and SOD activities (p < 0.01) in iron-loaded Huh7 cells in the dose-dependent manner, consistently in the order of RVT > DFP-RVT > DFP. Thus, the DFP-RVT hybrid possesses potent iron chelation, antioxidation, anti-lipid peroxidation, and antioxidant defense against oxidative liver damage under iron overload.
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Affiliation(s)
- Jin Li
- Department of Biochemistry, Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand
- Department of Biochemistry, Faculty of Basic Medicine, Youjiang Medical University for Nationalities, Baise, China
| | - Pimpisid Koonyosying
- Department of Biochemistry, Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand
| | - Woranontee Korsieporn
- Department of Biochemistry, Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand
| | - Narisara Paradee
- Department of Biochemistry, Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand
| | - Nuntouchaporn Hutachok
- Department of Biochemistry, Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand
| | - Honghong Xu
- Department of Biochemistry, Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand
- Department of Biochemistry, Faculty of Basic Medicine, Youjiang Medical University for Nationalities, Baise, China
| | - Yongmin Ma
- School of Pharmaceutical and Chemical Engineering, Taizhou University, Taizhou, China
| | - Hataichanok Chuljerm
- School of Health Sciences Research, Research Institute for Health Sciences, Chiang Mai University, Chiang Mai, Thailand
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Mostafa DK, Eissa MM, Ghareeb DA, Abdulmalek S, Hewedy WA. Resveratrol protects against Schistosoma mansoni-induced liver fibrosis by targeting the Sirt-1/NF-κB axis. Inflammopharmacology 2024; 32:763-775. [PMID: 38041753 PMCID: PMC10907480 DOI: 10.1007/s10787-023-01382-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2023] [Accepted: 10/19/2023] [Indexed: 12/03/2023]
Abstract
Hepatic schistosomiasis is a prevalent form of chronic liver disease that drastically affects human health. Nevertheless, an antifibrotic drug that could suppress the development of hepatic fibrosis does not exist yet. The current study aimed to evaluate the effect of resveratrol, a natural polyphenol with multiple biological activities, on Schistosoma mansoni (S. mansoni)-induced hepatic fibrosis and delineate the underlying molecular mechanism. Swiss male albino mice were randomly assigned into infected and non-infected groups. Hepatic schistosomiasis infection was induced via exposure to S. mansoni cercariae. 6 weeks later, resveratrol was administrated either as 20 mg/kg/day or 100 mg/kg/day for 4 weeks to two infected groups. Another group received vehicle and served as infected control group. At the end of the study, portal hemodynamic, biochemical, and histopathological evaluation of liver tissues were conducted. Remarkably, resveratrol significantly reduced portal pressure, portal and mesenteric flow in a dose-dependent manner. It improved several key features of hepatic injury as evidenced biochemically by a significant reduction of bilirubin and liver enzymes, and histologically by amelioration of the granulomatous and inflammatory reactions. In line, resveratrol reduced the expression of pro-inflammatory markers; TNF-α, IL-1β and MCP-1 mRNA, together with fibrotic markers; collagen-1, TGF-β1 and α-SMA. Moreover, resveratrol restored SIRT1/NF-κB balance in hepatic tissues which is the main switch-off control for all the fibrotic and inflammatory mechanisms. Taken together, it can be inferred that resveratrol possesses a possible anti-fibrotic effect that can halt the progression of hepatic schistosomiasis via targeting SIRT1/ NF-κB signaling.
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Affiliation(s)
- Dalia Kamal Mostafa
- Clinical Pharmacology Department, Faculty of Medicine, Alexandria University, Al-Moassat Medical Campus, Elhadara, Alexandria, 21561, Egypt
| | - Maha M Eissa
- Medical Parasitology Department, Faculty of Medicine, Alexandria University, Alexandria, Egypt
| | - Doaa A Ghareeb
- Biochemistry Department, Faculty of Science, Alexandria University, Alexandria, Egypt
| | - Shaymaa Abdulmalek
- Biochemistry Department, Faculty of Science, Alexandria University, Alexandria, Egypt
| | - Wafaa A Hewedy
- Clinical Pharmacology Department, Faculty of Medicine, Alexandria University, Al-Moassat Medical Campus, Elhadara, Alexandria, 21561, Egypt.
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Li T, Fan X, Cai M, Jiang Y, Wang Y, He P, Ni J, Mo A, Peng C, Liu J. Advances in investigating microcystin-induced liver toxicity and underlying mechanisms. THE SCIENCE OF THE TOTAL ENVIRONMENT 2023; 905:167167. [PMID: 37730048 DOI: 10.1016/j.scitotenv.2023.167167] [Citation(s) in RCA: 24] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/02/2023] [Revised: 08/27/2023] [Accepted: 09/15/2023] [Indexed: 09/22/2023]
Abstract
Microcystins (MCs) are a class of biologically active cyclic heptapeptide pollutants produced by the freshwater alga Microcystis aeruginosa. With increased environmental pollution, MCs have become a popular research topic. In recent years, the hepatotoxicity of MCs and associated effects and mechanisms have been studied extensively. Current epidemiological data indicate that long-term human exposure to MCs can lead to severe liver toxicity, acute toxicity, and death. In addition, current toxicological studies on the liver, a vital target organ of MCs, indicate that MC contamination is associated with the development of liver cancer, nonalcoholic fatty liver, and liver fibrosis. MCs produce hepatotoxicity that affects the metabolic homeostasis of the liver, induces apoptosis, and acts as a pro-cancer factor, leading to liver lesions. MCs mainly mediate the activation of signaling pathways, such as the ERK/JNK/p38 MAPK and IL-6-STAT3 pathways, which leads to oxidative damage and even carcinogenesis. Moreover, MCs can act synergistically with other pollutants to produce combined toxicity. However, few systematic reviews have been performed on these new findings. This review systematically summarizes the toxic effects and mechanisms of MCs on the liver and discusses the combined liver toxicity effects of MCs and other pollutants to provide reference for subsequent research. The toxicity of different MC isomers deserves further study. The detection methods and limit standards of MCs in agricultural and aquatic products will represent important research directions in the future. Standard protocols for fish sampling during harmful algal blooms or to evaluate the degree of MC toxicity in nature are lacking. In future, bioinformatics can be applied to offer insights into MC toxicology research and potential drug development for MC poisoning. Further research is essential to understand the molecular mechanisms of liver function damage in combined-exposure toxicology studies to establish treatment for MC-induced liver damage.
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Affiliation(s)
- Tong Li
- Department of Cell Biology and Genetics, Institute of Cytology and Genetics, School of Basic Medical Sciences, Hengyang Medical School, Key Laboratory of Hengyang City on Biological Toxicology and Ecological Restoration, Key Laboratory of Hengyang City on Ecological Impedance Technology of Heavy Metal Pollution in Cultivated Soil of Nonferrous Metal Mining Area, Key Laboratory of Ecological Environment and Critical Human Diseases Prevention of Hunan Province Department of Education, University of South China, Hengyang, Hunan 421001, China; School of Public Health, Hengyang Medical School, Hunan Key Laboratory of Typical Environmental Pollution and Health Hazards, University of South China, Hengyang, Hunan 421001, China
| | - Xinting Fan
- Department of Cell Biology and Genetics, Institute of Cytology and Genetics, School of Basic Medical Sciences, Hengyang Medical School, Key Laboratory of Hengyang City on Biological Toxicology and Ecological Restoration, Key Laboratory of Hengyang City on Ecological Impedance Technology of Heavy Metal Pollution in Cultivated Soil of Nonferrous Metal Mining Area, Key Laboratory of Ecological Environment and Critical Human Diseases Prevention of Hunan Province Department of Education, University of South China, Hengyang, Hunan 421001, China; School of Public Health, Hengyang Medical School, Hunan Key Laboratory of Typical Environmental Pollution and Health Hazards, University of South China, Hengyang, Hunan 421001, China
| | - Meihan Cai
- Department of Cell Biology and Genetics, Institute of Cytology and Genetics, School of Basic Medical Sciences, Hengyang Medical School, Key Laboratory of Hengyang City on Biological Toxicology and Ecological Restoration, Key Laboratory of Hengyang City on Ecological Impedance Technology of Heavy Metal Pollution in Cultivated Soil of Nonferrous Metal Mining Area, Key Laboratory of Ecological Environment and Critical Human Diseases Prevention of Hunan Province Department of Education, University of South China, Hengyang, Hunan 421001, China; School of Public Health, Hengyang Medical School, Hunan Key Laboratory of Typical Environmental Pollution and Health Hazards, University of South China, Hengyang, Hunan 421001, China
| | - Yuanyuan Jiang
- Department of Cell Biology and Genetics, Institute of Cytology and Genetics, School of Basic Medical Sciences, Hengyang Medical School, Key Laboratory of Hengyang City on Biological Toxicology and Ecological Restoration, Key Laboratory of Hengyang City on Ecological Impedance Technology of Heavy Metal Pollution in Cultivated Soil of Nonferrous Metal Mining Area, Key Laboratory of Ecological Environment and Critical Human Diseases Prevention of Hunan Province Department of Education, University of South China, Hengyang, Hunan 421001, China; School of Public Health, Hengyang Medical School, Hunan Key Laboratory of Typical Environmental Pollution and Health Hazards, University of South China, Hengyang, Hunan 421001, China
| | - Yaqi Wang
- Department of Cell Biology and Genetics, Institute of Cytology and Genetics, School of Basic Medical Sciences, Hengyang Medical School, Key Laboratory of Hengyang City on Biological Toxicology and Ecological Restoration, Key Laboratory of Hengyang City on Ecological Impedance Technology of Heavy Metal Pollution in Cultivated Soil of Nonferrous Metal Mining Area, Key Laboratory of Ecological Environment and Critical Human Diseases Prevention of Hunan Province Department of Education, University of South China, Hengyang, Hunan 421001, China; School of Public Health, Hengyang Medical School, Hunan Key Laboratory of Typical Environmental Pollution and Health Hazards, University of South China, Hengyang, Hunan 421001, China
| | - Peishuang He
- Department of Cell Biology and Genetics, Institute of Cytology and Genetics, School of Basic Medical Sciences, Hengyang Medical School, Key Laboratory of Hengyang City on Biological Toxicology and Ecological Restoration, Key Laboratory of Hengyang City on Ecological Impedance Technology of Heavy Metal Pollution in Cultivated Soil of Nonferrous Metal Mining Area, Key Laboratory of Ecological Environment and Critical Human Diseases Prevention of Hunan Province Department of Education, University of South China, Hengyang, Hunan 421001, China; School of Public Health, Hengyang Medical School, Hunan Key Laboratory of Typical Environmental Pollution and Health Hazards, University of South China, Hengyang, Hunan 421001, China
| | - Juan Ni
- Department of Cell Biology and Genetics, Institute of Cytology and Genetics, School of Basic Medical Sciences, Hengyang Medical School, Key Laboratory of Hengyang City on Biological Toxicology and Ecological Restoration, Key Laboratory of Hengyang City on Ecological Impedance Technology of Heavy Metal Pollution in Cultivated Soil of Nonferrous Metal Mining Area, Key Laboratory of Ecological Environment and Critical Human Diseases Prevention of Hunan Province Department of Education, University of South China, Hengyang, Hunan 421001, China; School of Public Health, Hengyang Medical School, Hunan Key Laboratory of Typical Environmental Pollution and Health Hazards, University of South China, Hengyang, Hunan 421001, China
| | - Aili Mo
- Department of Cell Biology and Genetics, Institute of Cytology and Genetics, School of Basic Medical Sciences, Hengyang Medical School, Key Laboratory of Hengyang City on Biological Toxicology and Ecological Restoration, Key Laboratory of Hengyang City on Ecological Impedance Technology of Heavy Metal Pollution in Cultivated Soil of Nonferrous Metal Mining Area, Key Laboratory of Ecological Environment and Critical Human Diseases Prevention of Hunan Province Department of Education, University of South China, Hengyang, Hunan 421001, China; School of Public Health, Hengyang Medical School, Hunan Key Laboratory of Typical Environmental Pollution and Health Hazards, University of South China, Hengyang, Hunan 421001, China
| | - Cuiying Peng
- Department of Cell Biology and Genetics, Institute of Cytology and Genetics, School of Basic Medical Sciences, Hengyang Medical School, Key Laboratory of Hengyang City on Biological Toxicology and Ecological Restoration, Key Laboratory of Hengyang City on Ecological Impedance Technology of Heavy Metal Pollution in Cultivated Soil of Nonferrous Metal Mining Area, Key Laboratory of Ecological Environment and Critical Human Diseases Prevention of Hunan Province Department of Education, University of South China, Hengyang, Hunan 421001, China; School of Public Health, Hengyang Medical School, Hunan Key Laboratory of Typical Environmental Pollution and Health Hazards, University of South China, Hengyang, Hunan 421001, China
| | - Jun Liu
- Department of Cell Biology and Genetics, Institute of Cytology and Genetics, School of Basic Medical Sciences, Hengyang Medical School, Key Laboratory of Hengyang City on Biological Toxicology and Ecological Restoration, Key Laboratory of Hengyang City on Ecological Impedance Technology of Heavy Metal Pollution in Cultivated Soil of Nonferrous Metal Mining Area, Key Laboratory of Ecological Environment and Critical Human Diseases Prevention of Hunan Province Department of Education, University of South China, Hengyang, Hunan 421001, China; School of Public Health, Hengyang Medical School, Hunan Key Laboratory of Typical Environmental Pollution and Health Hazards, University of South China, Hengyang, Hunan 421001, China.
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Li JZ, Chen N, Ma N, Li MR. Mechanism and Progress of Natural Products in the Treatment of NAFLD-Related Fibrosis. Molecules 2023; 28:7936. [PMID: 38067665 PMCID: PMC10707854 DOI: 10.3390/molecules28237936] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2023] [Revised: 11/22/2023] [Accepted: 11/29/2023] [Indexed: 12/18/2023] Open
Abstract
Nonalcoholic fatty liver disease (NAFLD) has emerged as the most prevalent chronic liver disorder worldwide, with liver fibrosis (LF) serving as a pivotal juncture in NAFLD progression. Natural products have demonstrated substantial antifibrotic properties, ushering in novel avenues for NAFLD treatment. This study provides a comprehensive review of the potential of natural products as antifibrotic agents, including flavonoids, polyphenol compounds, and terpenoids, with specific emphasis on the role of Baicalin in NAFLD-associated fibrosis. Mechanistically, these natural products have exhibited the capacity to target a multitude of signaling pathways, including Hedgehog, Wnt/β-catenin, TGF-β1, and NF-κB. Moreover, they can augment the activities of antioxidant enzymes, inhibit pro-fibrotic factors, and diminish fibrosis markers. In conclusion, this review underscores the considerable potential of natural products in addressing NAFLD-related liver fibrosis through multifaceted mechanisms. Nonetheless, it underscores the imperative need for further clinical investigation to authenticate their effectiveness, offering invaluable insights for future therapeutic advancements in this domain.
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Affiliation(s)
- Jin-Zhong Li
- Division of Infectious Disease, The First Affiliated Hospital, Jinan University, Guangzhou 510632, China
| | - Ning Chen
- General Medicine, The First Affiliated Hospital, Jinan University, Guangzhou 510632, China
| | - Nan Ma
- Center for Bioactive Natural Molecules and Innovative Drugs Research, College of Pharmacy, Jinan University, Guangzhou 510632, China
- JNU-HKUST Joint Laboratory for Neuroscience and Innovative Drug Research, College of Pharmacy, Jinan University, Guangzhou 510632, China
| | - Min-Ran Li
- Division of Infectious Disease, The First Affiliated Hospital, Jinan University, Guangzhou 510632, China
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Novi S, Vestuto V, Campiglia P, Tecce N, Bertamino A, Tecce MF. Anti-Angiogenic Effects of Natural Compounds in Diet-Associated Hepatic Inflammation. Nutrients 2023; 15:2748. [PMID: 37375652 DOI: 10.3390/nu15122748] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2023] [Revised: 06/09/2023] [Accepted: 06/12/2023] [Indexed: 06/29/2023] Open
Abstract
Alcoholic liver disease (ALD) and non-alcoholic fatty liver disease (NAFLD) are the most common causes of chronic liver disease and are increasingly emerging as a global health problem. Such disorders can lead to liver damage, resulting in the release of pro-inflammatory cytokines and the activation of infiltrating immune cells. These are some of the common features of ALD progression in ASH (alcoholic steatohepatitis) and NAFLD to NASH (non-alcoholic steatohepatitis). Hepatic steatosis, followed by fibrosis, lead to a continuous progression accompanied by angiogenesis. This process creates hypoxia, which activates vascular factors, initiating pathological angiogenesis and further fibrosis. This forms a vicious cycle of ongoing damage and progression. This condition further exacerbates liver injury and may contribute to the development of comorbidities, such as metabolic syndrome as well as hepatocellular carcinoma. Increasing evidence suggests that anti-angiogenic therapy may have beneficial effects on these hepatic disorders and their exacerbation. Therefore, there is a great interest to deepen the knowledge of the molecular mechanisms of natural anti-angiogenic products that could both prevent and control liver diseases. In this review, we focus on the role of major natural anti-angiogenic compounds against steatohepatitis and determine their potential therapeutic benefits in the treatment of liver inflammation caused by an imbalanced diet.
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Affiliation(s)
- Sara Novi
- Department of Pharmacy, University of Salerno, Via G. Paolo II, 84084 Fisciano, Italy
| | - Vincenzo Vestuto
- Department of Pharmacy, University of Salerno, Via G. Paolo II, 84084 Fisciano, Italy
| | - Pietro Campiglia
- Department of Pharmacy, University of Salerno, Via G. Paolo II, 84084 Fisciano, Italy
| | - Nicola Tecce
- Unit of Endocrinology, Department of Clinical Medicine and Surgery, Medical School of Naples, Federico II University, Via Sergio Pansini 5, 80131 Napoli, Italy
| | - Alessia Bertamino
- Department of Pharmacy, University of Salerno, Via G. Paolo II, 84084 Fisciano, Italy
| | - Mario Felice Tecce
- Department of Pharmacy, University of Salerno, Via G. Paolo II, 84084 Fisciano, Italy
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10
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Soltani S, Sharifi-Zahabi E, Sangsefidi ZS, Ahmadi Vasmehjani A, Meshkini F, Clayton ZS, Abdollahi S. The effect of resveratrol supplementation on biomarkers of liver health: A systematic review and meta-analysis of randomized controlled trials. Phytother Res 2023; 37:1153-1166. [PMID: 36642444 DOI: 10.1002/ptr.7719] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2022] [Revised: 10/25/2022] [Accepted: 12/18/2022] [Indexed: 01/17/2023]
Abstract
This study aimed to evaluate the effect of resveratrol on liver biomarkers in adult participants, using systematic review and meta-analysis of randomized controlled trials. PubMed, Scopus, Web of Science and Cochran Library was searched, up to October 2021. The pooled effects were calculated using a random-effects model and expressed as weighted mean difference and 95% confidence interval. The methodological quality of studies as well as certainty of evidence were assessed by standard tools. Thirty-seven relevant trials were found. Although overall analysis found no significant change, subgroup analysis showed a significant improvement in alanine aminotransferase (ALT; -7.79 U/L) and glutamyl transferase (-6.0 U/L) in patients with liver disorders, and ALT (-2.22 U/L) in younger adults; however, high-dose supplementation (>1,000 mg/day) appeared to increase alkaline phosphatase concentration (+5.07 U/L). ALT also increased in older adults (+2.33 U/L) following resveratrol supplementation. We found resveratrol did not have a significant effect on liver health in the general population. However, resveratrol could be effective in patients with liver disorders. Our findings also suggest that high-dose resveratrol administration and supplementation in older adults should be performed with caution. Further high-quality clinical trials are also needed to firmly establish the clinical efficacy of resveratrol.
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Affiliation(s)
- Sepideh Soltani
- Yazd Cardiovascular Research Center, Non-Communicable Diseases Research Institute, Shahid Sadoughi University of Medical Sciences, Yazd, Iran
| | - Elham Sharifi-Zahabi
- School of Nutrition Sciences and Food Technology, Kermanshah University of Medical Sciences, Kermanshah, Iran
| | - Zohreh Sadat Sangsefidi
- Department of Nutrition, School of Public Health, North Khorasan University of Medical Sciences, Bojnurd, Iran
| | - Azam Ahmadi Vasmehjani
- Department of Nutrition, School of Public Health, Shahid Sadughi University of Medical Sciences, Yazd, Iran
| | - Fatemeh Meshkini
- Department of Biochemistry, School of Medicine, Shahid Sadoughi University of Medical Sciences, Yazd, Iran.,Student Research Committee, Shahid Sadoughi University of Medical Sciences, Yazd, Iran
| | - Zachary Stephen Clayton
- Department of Integrative Physiology, University of Colorado Boulder, Boulder, Colorado, USA
| | - Shima Abdollahi
- Department of Nutrition, School of Public Health, North Khorasan University of Medical Sciences, Bojnurd, Iran
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11
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Alshehri FS, Alorfi NM. Protective role of resveratrol against VCM-induced hepatotoxicity in male wistar rats. Front Pharmacol 2023; 14:1130670. [PMID: 36825158 PMCID: PMC9941161 DOI: 10.3389/fphar.2023.1130670] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2022] [Accepted: 01/30/2023] [Indexed: 02/10/2023] Open
Abstract
Background: Vancomycin is a glycopeptide antibiotic with a high risk of acute liver injury. Resveratrol is believed to protect the liver against toxicity. Aim: To investigate the ability of resveratrol to attenuate vancomycin-induced liver toxicity in rats injected with vancomycin. Method: Twenty-four adult male Wistar rats were distributed into three groups. The control group received only a vehicle, while the treated group received either vancomycin 200 (mg/kg, i. p.) only or vancomycin (200 mg/kg, i. p.) with resveratrol (20 mg/kg, oral gavage). All groups received their dose once daily for 7 days. Hepatic damage was assessed by measuring biochemical parameter levels in serum, aspartate transaminase (AST), alanine transaminase (ALT), alkaline phosphatase (ALP), and lactate dehydrogenase (LDH). Also, antioxidants and inflammation biomarkers such as Interleukin-6 (IL-6), malondialdehyde (MDA), nitric oxide (NO), and glutathione (GSH) were measured. Furthermore, the vancomycin-induced pathological changes in the liver were evaluated by histopathological studies. Results: In the vancomycin-treated group, hepatic serum biomarkers such as AST, ALT, ALP, IL-6, and MDA were elevated, while NO and GSH were depleted. However, resveratrol co-treatment with vancomycin prevented the elevation of AST, ALT, ALP, IL-6, and MDA and it protected the liver from NO and GSH depletion. Also, regarding vancomycin-induced degeneration of hepatocytes, resveratrol co-treatment with vancomycin prevented such degeneration and improved mononuclear cells in the liver. Conclusion: The results showed that oral administration of resveratrol has a significant hepatoprotective effect against vancomycin-induced hepatotoxicity.
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Affiliation(s)
| | - Nasser M. Alorfi
- Department of Pharmacology and Toxicology, College of Pharmacy, Umm Al-Qura University, Makkah, Saudi Arabia
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12
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Ma Z, Sheng L, Li J, Qian J, Wu G, Wang Z, Zhang Y. Resveratrol Alleviates Hepatic Fibrosis in Associated with Decreased Endoplasmic Reticulum Stress-Mediated Apoptosis and Inflammation. Inflammation 2022; 45:812-823. [PMID: 35080697 PMCID: PMC8956545 DOI: 10.1007/s10753-021-01586-w] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2021] [Revised: 10/14/2021] [Accepted: 10/18/2021] [Indexed: 11/24/2022]
Abstract
Hepatic fibrosis (HF) is the typical response to chronic liver disease and is characterized by deposition of abundant extracellular matrix. The aim of the present study was to investigate the protective effect of resveratrol (RSV) in a CCl4-induced rat model of HF. We demonstrate that the administration of RSV effectively improves liver function and ameliorates liver fibrosis by reducing collagen deposition and reversing the expression of COL1A1 and PPAR-γ. Treatment efficacy of RSV could be attributed to reversed epithelial-mesenchymal transition progress with upregulated expression of E-cadherin and downregulated N-cadherin, vimentin, and α-SMA. Moreover, RSV significantly decreased the levels of endoplasmic reticulum stress (ERS)-related proteins CHOP; Bip; cleaved caspase-3, caspase-7, and caspase-12; Bax; and Bak while promotes the expression of anti-apoptosis protein Bcl2. The important role of ERS in HF was confirmed by using 4-PBA, an ERS inhibitor, which markedly ameliorated CCl4-induced HF. Further, mechanistic studies demonstrated that RSV significantly decreased CCl4-induced transforming growth factor-β synthesis and inflammatory factor (tumor necrosis factor-α and interleukin-6) expression and reduced the inflammation of hepatic stellate cells by inhibiting the NF-κB pathway in vivo and in vitro. In conclusion, the results suggested that RSV ameliorated HF in associated with decreased ERS-induced apoptosis and inflammation in rats.
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Affiliation(s)
- Zhenyu Ma
- Department of General Surgery, Huashan Hospital, Fudan University, Shanghai, 200040, China
| | - Lulu Sheng
- Department of Emergency Medicine, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, 200233, China
| | - Juan Li
- Department of Nursing Center, Huashan Hospital, Fudan University, Shanghai, 200040, China
| | - Jianmin Qian
- Department of General Surgery, Huashan Hospital, Fudan University, Shanghai, 200040, China
| | - Gang Wu
- Department of General Surgery, Huashan Hospital, Fudan University, Shanghai, 200040, China
| | - Zhengxin Wang
- Department of General Surgery, Huashan Hospital, Fudan University, Shanghai, 200040, China.
| | - Yi Zhang
- Biomedical Research Center, Institute for Clinical Sciences, Zhongshan Hospital, Fudan University, Shanghai, 200032, China. .,Shanghai Key Laboratory of Organ Transplantation, Shanghai, China.
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13
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Das R, Mitra S, Tareq AM, Emran TB, Hossain MJ, Alqahtani AM, Alghazwani Y, Dhama K, Simal-Gandara J. Medicinal plants used against hepatic disorders in Bangladesh: A comprehensive review. JOURNAL OF ETHNOPHARMACOLOGY 2022; 282:114588. [PMID: 34480997 DOI: 10.1016/j.jep.2021.114588] [Citation(s) in RCA: 36] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/22/2021] [Revised: 08/19/2021] [Accepted: 08/29/2021] [Indexed: 06/13/2023]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE Liver disease is a major cause of illness and death worldwide which accounts for approximately 2 million deaths per year worldwide, 1 million due to complications of cirrhosis and 1 million due to viral hepatitis and hepatocellular carcinoma. That's why it is seeking the researchers' attention to find out the effective treatment strategies. Phytochemicals from natural resources are the main leads for the development of noble hepatoprotective drugs. The majority of the natural sources whose active compounds are currently employed actually have an ethnomedical use. Ethnopharmacological research is essential for the development of these bioactive compounds. These studies not only provide scientific evidence on medicinal plants utilized for particular therapeutic purposes, but they also ensure cultural heritage preservation. Plenty of experimental studies have been well-documented that the ethnomedicinal plants are of therapeutics' interest for the advanced pharmacological intervention in terms of hepatic disorders. AIM OF THE STUDY This study summarizes the processes of hepatotoxicity induced by various toxins and explores identified hepatoprotective plants and their phytoconstituents, which can guide the extraction of novel phytochemical constituents from plants to treat liver injury. This review aimed to summarize the hepatoprotective activity of Bangladeshi medicinal plants where the bioactive compounds may be leads for the drug discovery in future. MATERIALS AND METHODS Literature searches in electronic databases, such as Web of Science, Science Direct, SpringerLink, PubMed, Google Scholar, Semantic Scholar, Scopus, BanglaJOL, and so on, were performed using the keywords 'Bangladesh', 'ethnomedicinal plants', 'Hepatoprotective agents' as for primary searches, and secondary search terms were used as follows, either alone or in combination: traditional medicine, medicinal plants, folk medicine, liver, hepatitis, therapeutic uses, and anti-inflammatory. Besides, several books, including the book entitled "Medicinal plants of Bangladesh: chemical constituents and uses" authored by Abdul Ghani, were carefully considered, which contained pharmacological properties and phytoconstituents of many medicinal plants growing and traditionally available in Bangladesh. Among them, the most promising plant species with their latest therapeutic effects against hepatic disorders were deeply considered in this review. RESULTS The results of this study revealed that in most cases, therapy using plant extracts stabilized altered hepatic biochemical markers induced by hepatotoxins. Initially, we investigated 32 plant species for hepatoprotective activity, however after extensive literature searching; we observed that 20 plants offer good pharmacological evidence of hepatoprotective function. Consequently, most bioactive compounds derived from the herbs including berberine, thymoquinone, andrographolide, ursolic acid, luteolin, naringenin, genistein, quercetin, troxerutin, morin, epigallocatechin-3-gallate, chlorogenic acid, emodin, curcumin, resveratrol, capsaicin, ellagic acid, etc. are appeared to be effective against hepatic disorders. CONCLUSIONS Flavonoids, phenolic acids, monoterpenoids, diterpenoids, triterpenoids, alkaloids, chromenes, capsaicinoids, curcuminoids, and anthraquinones are among the phytoconstituents were appraised to have hepatoprotective activities. All the actions displayed by these ethnomedicinal plants could make them serve as leads in the formulation of drugs with higher efficacy to treat hepatic disorders.
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Affiliation(s)
- Rajib Das
- Department of Pharmacy, Faculty of Pharmacy, University of Dhaka, Dhaka, 1000, Bangladesh
| | - Saikat Mitra
- Department of Pharmacy, Faculty of Pharmacy, University of Dhaka, Dhaka, 1000, Bangladesh
| | - Abu Montakim Tareq
- Department of Pharmacy, International Islamic University Chittagong, Chittagong, 4318, Bangladesh
| | - Talha Bin Emran
- Department of Pharmacy, BGC Trust University Bangladesh, Chittagong, 4381, Bangladesh.
| | - Md Jamal Hossain
- Department of Pharmacy, State University of Bangladesh, 77 Satmasjid Road, Dhanmondi, Dhaka, 1205, Bangladesh
| | - Ali M Alqahtani
- Department of Pharmacology, College of Pharmacy, King Khalid University, Abha, 62529, Saudi Arabia
| | - Yahia Alghazwani
- Department of Pharmacology, College of Pharmacy, King Khalid University, Abha, 62529, Saudi Arabia
| | - Kuldeep Dhama
- Division of Pathology, ICAR-Indian Veterinary Research Institute, Izatnagar, Bareil-ly, 243122, Uttar Pradesh, India
| | - Jesus Simal-Gandara
- Nutrition and Bromatology Group, Department of Analytical and Food Chemistry, Faculty of Food Science and Technology, University of Vigo - Ourense Campus, E32004, Ourense, Spain.
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14
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Olaso E, Benedicto A, Lopategi A, Cossio FP, Arteta B. A Synthetic Analog of Resveratrol Inhibits the Proangiogenic Response of Liver Sinusoidal Cells during Hepatic Metastasis. Biomol Ther (Seoul) 2021; 30:162-169. [PMID: 34873071 PMCID: PMC8902452 DOI: 10.4062/biomolther.2021.062] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2021] [Revised: 07/13/2021] [Accepted: 08/14/2021] [Indexed: 11/17/2022] Open
Abstract
We utilized Fas21, a resveratrol analog, to modulate the function of hepatic stellate cells (HSCs) and liver sinusoidal endothelial cells (LSECs) during the angiogenic phase of murine liver metastasis by B16 melanoma and 51b colorectal carcinoma. Preangiogenic micrometastases were treated with Fas21 (1 mg/kg/day) or vehicle during the development of intra-angiogenic tracts. Mice treated with Fas21 showed reduced liver tumor foci in both liver metastasis models. Micrometastases were classified immunohistochemically, as well as according to their position coordinates and connection to local microvasculature. The volume of liver occupied by sinusoidal-type foci, containing infiltrating angiogenic capillaries, decreased by ~50% in Fas21-treated mice compared to vehicle-treated ones in both tumor metastasis models. The volume of portal foci, containing peripheral neoangiogenesis within a discontinuous layer of myofibroblasts, was similar in all experimental groups in both tumor metastasis models, but displayed enhanced necrotic central areas devoid of angiogenesis following Fas21 treatment. As a result, sinusoidal tumors from mice treated with Fas21 showed a 50% reduction in desmin(+)/asma(+) HSCs and CD31(+) vessel density, and a 45% reduction in intrametastatic VEGF mRNA compared with sinusoidal tumors from vehicle-treated mice. Necrotic portal metastases increased 2-4-fold in treated mice. In vitro, Fas21 reduced VEGF secretion by HSCs and 51b cells dose-dependently. Additionally, HSCs migration in response to tumor soluble factors was dose-dependently diminished by Fas21, as was LSEC migration in response to HSCs and tumor soluble factors. Resveratrol analog Fas21 inhibits the proangiogenic response of HSCs and LSECs during the development of murine liver metastasis.
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Affiliation(s)
- Elvira Olaso
- Tumor Microenvironment Group, Department of Cell Biology and Histology, School of Medicine and Dentistry, University of the Basque Country, Leioa 48940, Spain
| | - Aitor Benedicto
- Tumor Microenvironment Group, Department of Cell Biology and Histology, School of Medicine and Dentistry, University of the Basque Country, Leioa 48940, Spain
| | - Aritz Lopategi
- Tumor Microenvironment Group, Department of Cell Biology and Histology, School of Medicine and Dentistry, University of the Basque Country, Leioa 48940, Spain
| | - Fernando P Cossio
- Department of Organic Chemistry, School of Sciences, University of the Basque Country, Donosti 20018, Spain
| | - Beatriz Arteta
- Tumor Microenvironment Group, Department of Cell Biology and Histology, School of Medicine and Dentistry, University of the Basque Country, Leioa 48940, Spain
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15
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Hung WL, Hsiao YT, Chiou YS, Nagabhushanam K, Ho CT, Pan MH. Hepatoprotective effect of piceatannol against carbon tetrachloride-induced liver fibrosis in mice. Food Funct 2021; 12:11229-11240. [PMID: 34676843 DOI: 10.1039/d1fo02545g] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/28/2022]
Abstract
Piceatannol (3,5,3',4'-trans-tetrahydroxystilbene) is a natural analog and a metabolite of resveratrol present in grapes and red wine. Previous studies have reported that piceatannol exerts a broad spectrum of health benefits including antioxidant, anti-inflammatory, chemopreventive, and neuroprotective effects. However, little is known about the hepatoprotective effect of piceatannol against toxin-induced liver fibrosis. Therefore, the objective of this study is to evaluate the protective effect of piceatannol in a mouse model of CCl4-induced hepatic fibrosis. Oral administration of piceatannol significantly improved the hepatic functions of CCl4-treated mice in both therapeutic and preventive models. Additionally, the immunohistochemical staining results revealed that collagen deposition in CCl4-injected mice was significantly reduced by treatment with piceatannol. Moreover, piceatannol remarkably suppressed the expressions of collagen I, α-smooth muscle protein (α-SMA), and tissue inhibitor of matrix metalloproteinases-1 (TIMP-1) induced by CCl4. The anti-fibrotic mechanism of piceatannol was associated with the regulation of the transforming growth factor-β (TGF-β)/Smad signaling pathway. Finally, piceatannol also profoundly alleviated CCl4-induced hepatic oxidative damage by elevating the level of glutathione and catalase activity. Altogether, our current findings suggest that piceatannol may serve as a bioactive agent that inhibits or alleviates toxic-induced fibroproliferative diseases, especially in the prevention of liver fibrosis.
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Affiliation(s)
- Wei-Lun Hung
- School of Food Safety, Taipei Medical University, Taipei, 11031, Taiwan
| | - Yi-Ting Hsiao
- Institute of Food Science and Technology, National Taiwan University, Taipei 10617, Taiwan.
| | - Yi-Shiou Chiou
- Institute of Food Science and Technology, National Taiwan University, Taipei 10617, Taiwan.
| | | | - Chi-Tang Ho
- Department of Food Science, Rutgers University, New Brunswick, New Jersey 08901, USA
| | - Min-Hsiung Pan
- Institute of Food Science and Technology, National Taiwan University, Taipei 10617, Taiwan. .,Department of Medical Research, China Medical University Hospital, China Medical University, Taichung 40402, Taiwan.,Department of Health and Nutrition Biotechnology, Asia University, Taichung, 41354, Taiwan
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16
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Kawakatsu-Hatada Y, Murata S, Mori A, Kimura K, Taniguchi H. Serous Membrane Detachment with Ultrasonic Homogenizer Improves Engraftment of Fetal Liver to Liver Surface in a Rat Model of Cirrhosis. Int J Mol Sci 2021; 22:11589. [PMID: 34769019 PMCID: PMC8584093 DOI: 10.3390/ijms222111589] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2021] [Revised: 10/23/2021] [Accepted: 10/24/2021] [Indexed: 11/16/2022] Open
Abstract
Liver transplantation is the most effective treatment for end-stage cirrhosis. However, due to serious donor shortages, new treatments to replace liver transplantation are sorely needed. Recent studies have focused on novel therapeutic methods using hepatocytes and induced pluripotent stem cells, we try hard to develop methods for transplanting these cells to the liver surface. In the present study, we evaluated several methods for their efficiency in the detachment of serous membrane covering the liver surface for transplantation to the liver surface. The liver surface of dipeptidyl peptidase IV (DPPIV)-deficient rats in a cirrhosis model was detached by various methods, and then fetal livers from DPPIV-positive rats were transplanted. We found that the engraftment rate and area as well as the liver function were improved in rats undergoing transplantation following serous membrane detachment with an ultrasonic homogenizer, which mimics the Cavitron Ultrasonic Surgical Aspirator® (CUSA), compared with no detachment. Furthermore, the bleeding amount was lower with the ultrasonic homogenizer method than with the needle and electric scalpel methods. These findings provide evidence that transplantation to the liver surface with serous membrane detachment using CUSA might contribute to the development of new treatments for cirrhosis using cells or tissues.
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Affiliation(s)
- Yumi Kawakatsu-Hatada
- Department of Regenerative Medicine, Yokohama City University Graduate School of Medicine, 3-9 Fukuura, Kanazawa-ku, Yokohama 236-0004, Japan; (Y.K.-H.); (A.M.); (K.K.); (H.T.)
| | - Soichiro Murata
- Department of Regenerative Medicine, Yokohama City University Graduate School of Medicine, 3-9 Fukuura, Kanazawa-ku, Yokohama 236-0004, Japan; (Y.K.-H.); (A.M.); (K.K.); (H.T.)
- Division of Regenerative Medicine, Center for Stem Cell Biology and Regenerative Medicine, The Institute of Medical Science, The University of Tokyo, 4-6-1 Shirokanedai, Minato-ku, Tokyo 108-8639, Japan
| | - Akihiro Mori
- Department of Regenerative Medicine, Yokohama City University Graduate School of Medicine, 3-9 Fukuura, Kanazawa-ku, Yokohama 236-0004, Japan; (Y.K.-H.); (A.M.); (K.K.); (H.T.)
| | - Kodai Kimura
- Department of Regenerative Medicine, Yokohama City University Graduate School of Medicine, 3-9 Fukuura, Kanazawa-ku, Yokohama 236-0004, Japan; (Y.K.-H.); (A.M.); (K.K.); (H.T.)
| | - Hideki Taniguchi
- Department of Regenerative Medicine, Yokohama City University Graduate School of Medicine, 3-9 Fukuura, Kanazawa-ku, Yokohama 236-0004, Japan; (Y.K.-H.); (A.M.); (K.K.); (H.T.)
- Division of Regenerative Medicine, Center for Stem Cell Biology and Regenerative Medicine, The Institute of Medical Science, The University of Tokyo, 4-6-1 Shirokanedai, Minato-ku, Tokyo 108-8639, Japan
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17
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Li J, Wang S, Duan J, Le P, Li C, Ding Y, Wang R, Gao Y. The protective mechanism of resveratrol against hepatic injury induced by iron overload in mice. Toxicol Appl Pharmacol 2021; 424:115596. [PMID: 34044072 DOI: 10.1016/j.taap.2021.115596] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/25/2020] [Revised: 05/19/2021] [Accepted: 05/21/2021] [Indexed: 12/14/2022]
Abstract
Excessive iron deposition can produce toxicity. Liver, as the main storage site of iron, is more vulnerable to excessive iron than other organs. Many studies have found that Resveratrol (RES) can effectively eliminate oxygen free radicals and resist lipid peroxide damage. However, studies investigating the mechanism of how RES prevents liver injury induced by iron overload are few. This study aims to observe the protective effect of RES on liver injury induced by iron overload in mice. Mice, except for the control group, received an intraperitoneal injection of iron dextran (50 mg/kg) every morning. The L-RES and H-RES groups received intragastric administration of low- and high-concentration RES solutions (20 or 50 mg/kg). The deferoxamine (DFO) group was intraperitoneally injected with DFO (50 mg/kg), while the control and iron overload groups were intraperitoneally injected with the same amount of normal saline every afternoon. Two weeks after continuous administration, iron-overloaded mice treated with high and low doses of RES significantly improved liver injury (GOT and GPT) and decreased LDH activity and MDA content and increased SOD and GSH activities (P < 0.01). Morphological tests showed that RES treatment can reduce liver iron deposition and improve liver pathological changes in iron-overloaded mice. Furthermore, RES treatment caused a significant decrease in Ft expression (P < 0.01). In conclusion, RES can alleviate liver injury in iron-overloaded mice. The mechanism may be related to improve the antioxidant capacity and reduce excess iron in the liver.
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Affiliation(s)
- Jinghan Li
- School of Basic Medicine, Hebei University of Chinese Medicine, Shijiazhuang 050200, China
| | - Simeng Wang
- College of Nursing, Hebei University of Chinese Medicine, Shijiazhuang 050200, China
| | - Jiaqi Duan
- College of Acupuncture and Massage, Hebei University of Chinese Medicine, Shijiazhuang 050200, China
| | - Peixin Le
- School of Basic Medicine, Hebei University of Chinese Medicine, Shijiazhuang 050200, China
| | - Chao Li
- College of Acupuncture and Massage, Hebei University of Chinese Medicine, Shijiazhuang 050200, China
| | - Yongpei Ding
- College of Acupuncture and Massage, Hebei University of Chinese Medicine, Shijiazhuang 050200, China
| | - Rui Wang
- School of Basic Medicine, Hebei University of Chinese Medicine, Shijiazhuang 050200, China.
| | - Yonggang Gao
- School of Basic Medicine, Hebei University of Chinese Medicine, Shijiazhuang 050200, China.
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18
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Gokkaya EO, Yesilot S, Ozgocmen M, Aslankoc R, Aydin Acar C. Protective effects of resveratrol and avocado oil against paracetamol-induced hepatotoxicity in rats. Drug Chem Toxicol 2021; 45:2131-2139. [PMID: 33832400 DOI: 10.1080/01480545.2021.1908716] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
This study sought to assess the protective effects of resveratrol and avocado oil in relation to paracetamol-induced hepatotoxicity in rats. The rats were divided into five groups, namely the control, paracetamol (600 mg/kg), resveratrol (RES; 10 mg/kg) + paracetamol, avocado oil (AVO; 200 mg/kg) + paracetamol, and RES + AVO + paracetamol groups. The hepatoprotective activity was evaluated by measuring biochemical parameters such as the total antioxidant status (TAS) and the total oxidant status (TOS) in each rat's liver homogenates. Any DNA damage was assessed by means of a comet assay. The results showed that the TOS levels were significantly increased in the paracetamol group when compared with the control group. The TOS levels were found to be significantly lower in the paracetamol groups, in comparison with the RES, AVO, and RES + AVO groups. Moreover, the TAS levels significantly increased in the RES and RES + AVO groups when compared with the paracetamol group. The histopathological examination revealed necrotic areas in the rats' livers. Pretreatment with both RES and RES + AVO was found to reverse the oxidative stress parameters, DNA damage, and necrosis induced by paracetamol. These results suggest that a combination of REV and AVO may protect against paracetamol-induced hepatotoxicity due to their antioxidant properties.
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Affiliation(s)
- Erdi Onur Gokkaya
- Department of Health and Biomedical Sciences, Burdur Mehmet Akif Ersoy University, Burdur, Turkey
| | - Sukriye Yesilot
- Bucak School of Health, Department of Nursing, Burdur Mehmet Akif Ersoy University, Burdur, Turkey
| | - Meltem Ozgocmen
- Department of Histology and Embryology, Faculty of Medicine, Suleyman Demirel University, Burdur, Turkey
| | - Rahime Aslankoc
- Department of Physiology, Faculty of Medicine, Suleyman Demirel University, Burdur, Turkey
| | - Cigdem Aydin Acar
- Bucak School of Health, Department of Nursing, Burdur Mehmet Akif Ersoy University, Burdur, Turkey
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The Role of Resveratrol in Liver Disease: A Comprehensive Review from In Vitro to Clinical Trials. Nutrients 2021; 13:nu13030933. [PMID: 33805795 PMCID: PMC7999728 DOI: 10.3390/nu13030933] [Citation(s) in RCA: 63] [Impact Index Per Article: 15.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/16/2021] [Revised: 03/10/2021] [Accepted: 03/11/2021] [Indexed: 12/15/2022] Open
Abstract
Many studies have shown that resveratrol has a lot of therapeutic effects on liver disorders. Its administration can significantly increase the survival rate after liver transplantation, reduce fat deposition and ischemia-induced necrosis and apoptosis in Wistar rats. Resveratrol can provide Liver protection against chemical, cholestatic, and alcohol-mediated damage. It can improve glucose metabolism and lipid profile, reduce liver fibrosis, and steatosis. Additionally, it is capable of altering the fatty acid composition of the liver cells. Resveratrol may be a potential treatment option for the management of non-alcoholic fatty liver disease (NAFLD) due to its anti-inflammatory, antioxidant, and calorie-restricting effects. There are also studies that have evaluated the effect of resveratrol on lipid and liver enzyme profiles among patients with metabolic syndrome (MetS) and related disorders. Based on the extent of liver disease worldwide and the need to find new treatment possibilities, this review critically examines current in vitro and in vivo preclinical studies and human clinical studies related to liver protection.
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Darand M, Farrokhzad A, Ghavami A, Hadi A, Karimi E, Fadel A, Askari G. Effects of resveratrol supplementation on liver enzymes: A systematic review and meta-analysis of randomised controlled trials. Int J Clin Pract 2021; 75:e13692. [PMID: 32869460 DOI: 10.1111/ijcp.13692] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/17/2020] [Accepted: 08/21/2020] [Indexed: 12/30/2022] Open
Abstract
BACKGROUND The available evidence regarding the possible effects of resveratrol on liver function is inconsistent. Therefore, the present meta-analysis was performed to investigate the overall effects of resveratrol supplementation on liver enzymes in adults. METHODS A systematic and comprehensive search of the online medical databases including PubMed, Scupos, Web of Science and Cochran Library was performed up to February 2020. All RCTs using resveratrol supplements in adults were included in this systematic review and meta-analysis. The overall effect was presented as weighted mean difference (WMD) and 95% confidence interval (CI) in a random-effects meta-analysis model. RESULTS Finally, 15 randomised trials including 714 participants were selected for the present meta-analysis. Pooled analysis did not show any significant changes in alanine aminotransferase (ALT) (WMD: 0 IU/L, 95% CI: -3.17 to 3.17, P = .99; I2 = 74.2%), aspartate aminotransferase (AST) (WMD: -2.40 IU/L, 95% CI: -5.45 to 0.65, P = .11; I2 = 82.9%), gamma-glutamyl transferase (GGT) (WMD: -1.26 IU/L, 95% CI: -4.64 to 2.13, P = .64; I2 = 23.7%), alkaline phosphatase (ALP) (WMD: 3.80 IU/L, 95% CI: -4.65 to 12.25, P = .37; I2 = 29.9%) and bilirubin (WMD: 0.13 IU/L, 95% CI: -0.43 to 0.17, P = .39; I2 = 8.9%) after supplementation with resveratrol. CONCLUSION Overall, in our study, resveratrol does not affect liver enzyme levels significantly, but subgroup analysis indicates that these results may be influenced by resveratrol dose, duration of the study and population status, so future high-quality studies are necessary to get definitive results.
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Affiliation(s)
- Mina Darand
- Student Research Committee, Department of Clinical Nutrition, School of Nutrition and Food Science, Isfahan University of Medical Sciences, Isfahan, Iran
| | | | - Abed Ghavami
- Student Research Committee, Department of Clinical Nutrition, School of Nutrition and Food Science, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Amir Hadi
- Halal Research Center of IRI, FDA, Tehran, Iran
| | - Elham Karimi
- Student Research Committee, Department of Clinical Nutrition, School of Nutrition and Food Science, Isfahan University of Medical Sciences, Isfahan, Iran
- Research Development Center, Arash Women's Hospital, Tehran University of Medical Sciences, Tehran, Iran
| | - Abdulmnannan Fadel
- School of Sport and Exercise Sciences, Liverpool John Moores University, Liverpool, UK
| | - Gholamreza Askari
- Department of Community Nutrition, School of Nutrition and Food Science, Food Security Research Center, Isfahan University of Medical Sciences, Isfahan, Iran
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A Comprehensive Review of Natural Products against Liver Fibrosis: Flavonoids, Quinones, Lignans, Phenols, and Acids. EVIDENCE-BASED COMPLEMENTARY AND ALTERNATIVE MEDICINE 2020; 2020:7171498. [PMID: 33082829 PMCID: PMC7556091 DOI: 10.1155/2020/7171498] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/24/2020] [Revised: 07/23/2020] [Accepted: 07/25/2020] [Indexed: 12/18/2022]
Abstract
Liver fibrosis resulting from continuous long-term hepatic damage represents a heavy burden worldwide. Liver fibrosis is recognized as a complicated pathogenic mechanism with extracellular matrix (ECM) accumulation and hepatic stellate cell (HSC) activation. A series of drugs demonstrate significant antifibrotic activity in vitro and in vivo. No specific agents with ideally clinical efficacy for liver fibrosis treatment have been developed. In this review, we summarized the antifibrotic effects and molecular mechanisms of 29 kinds of common natural products. The mechanism of these compounds is correlated with anti-inflammatory, antiapoptotic, and antifibrotic activities. Moreover, parenchymal hepatic cell survival, HSC deactivation, and ECM degradation by interfering with multiple targets and signaling pathways are also involved in the antifibrotic effects of these compounds. However, there remain two bottlenecks for clinical breakthroughs. The low bioavailability of natural products should be improved, and the combined application of two or more compounds should be investigated for more prominent pharmacological effects. In summary, exploration on natural products against liver fibrosis is becoming increasingly extensive. Therefore, natural products are potential resources for the development of agents to treat liver fibrosis.
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Thuy LTT, Hai H, Kawada N. Role of cytoglobin, a novel radical scavenger, in stellate cell activation and hepatic fibrosis. Clin Mol Hepatol 2020; 26:280-293. [PMID: 32492766 PMCID: PMC7364355 DOI: 10.3350/cmh.2020.0037] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/20/2020] [Revised: 03/09/2020] [Accepted: 03/13/2020] [Indexed: 12/17/2022] Open
Abstract
Cytoglobin (Cygb), a stellate cell-specific globin, has recently drawn attention due to its association with liver fibrosis. In the livers of both humans and rodents, Cygb is expressed only in stellate cells and can be utilized as a marker to distinguish stellate cells from hepatic fibroblast-derived myofibroblasts. Loss of Cygb accelerates liver fibrosis and cancer development in mouse models of chronic liver injury including diethylnitrosamine-induced hepatocellular carcinoma, bile duct ligation-induced cholestasis, thioacetamide-induced hepatic fibrosis, and choline-deficient L-amino acid-defined diet-induced non-alcoholic steatohepatitis. This review focuses on the history of research into the role of reactive oxygen species and nitrogen species in liver fibrosis and discusses the current perception of Cygb as a novel radical scavenger with an emphasis on its role in hepatic stellate cell activation and fibrosis.
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Affiliation(s)
- Le Thi Thanh Thuy
- Department of Hepatology, Graduate School of Medicine, Osaka City University, Osaka, Japan
| | - Hoang Hai
- Department of Hepatology, Graduate School of Medicine, Osaka City University, Osaka, Japan
| | - Norifumi Kawada
- Department of Hepatology, Graduate School of Medicine, Osaka City University, Osaka, Japan
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Abbas MM, Al-Rawi N, Abbas MA, Al-Khateeb I. Naringenin potentiated β-sitosterol healing effect on the scratch wound assay. Res Pharm Sci 2019; 14:566-573. [PMID: 32038736 PMCID: PMC6937750 DOI: 10.4103/1735-5362.272565] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/26/2022] Open
Abstract
In the present investigation scratch wound assay was used to study the ability of several combinations of each flavonoid (chrysin, naringenin or resveratrol) with β-sitosterol to heal wounds in vitro. MTT test was performed to determine if the combination of flavonoid with β-sitosterol was toxic to fibroblasts or not. Also, superoxide dismutase (SOD) activity and interleukin-1β (IL-1β) concentrations were measured. The best closure rates were obtained with β-sitosterol combined with naringenin and β-sitosterol combined with resveratrol. The combination that produced the best closure rate namely β-sitosterol with naringenin increased SOD activity significantly. However, this combination was not better than naringenin or β-sitosterol alone in reducing IL-β concentration. The results of MTT test indicated that the combination as well as β-sitosterol alone or naringenin alone has no toxic effect on fibroblasts. In conclusion, the combination of β-sitosterol and naringenin exerted a synergistic effect on wound closure without decreasing the viability of fibroblasts, increased antioxidant defense mechanism and decreased IL-β.
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Affiliation(s)
- Manal Mohammad Abbas
- Faculty of Allied Medical Sciences, Al-Ahliyya Amman University, 19328, Amman, Jordan
| | - Naseer Al-Rawi
- Faculty of Pharmacy, Al-Ahliyya Amman University, 19328, Amman, Jordan
| | - Manal Ahmad Abbas
- Faculty of Allied Medical Sciences, Al-Ahliyya Amman University, 19328, Amman, Jordan
| | - Iqbal Al-Khateeb
- Faculty of Pharmacy, Al-Ahliyya Amman University, 19328, Amman, Jordan
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Yu B, Qin SY, Hu BL, Qin QY, Jiang HX, Luo W. Resveratrol improves CCL4-induced liver fibrosis in mouse by upregulating endogenous IL-10 to reprogramme macrophages phenotype from M(LPS) to M(IL-4). Biomed Pharmacother 2019; 117:109110. [DOI: 10.1016/j.biopha.2019.109110] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2019] [Revised: 06/05/2019] [Accepted: 06/10/2019] [Indexed: 12/23/2022] Open
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Ma Z, Zhang B, Fan Y, Wang M, Kebebe D, Li J, Liu Z. Traditional Chinese medicine combined with hepatic targeted drug delivery systems: A new strategy for the treatment of liver diseases. Biomed Pharmacother 2019; 117:109128. [PMID: 31234023 DOI: 10.1016/j.biopha.2019.109128] [Citation(s) in RCA: 36] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2019] [Revised: 06/12/2019] [Accepted: 06/12/2019] [Indexed: 12/18/2022] Open
Abstract
Liver diseases are clinically common and present a substantial public health issue. Many of the currently available drugs for the treatment of liver diseases suffer from limitations that include low hepatic distribution, lack of target effects, poor in vivo stability and adverse effects on other organs. Consequently, conventional treatment of hepatic diseases is ineffective. TCM is commonly used in the treatment of liver diseases worldwide, particularly in China, and has advantages over conventional therapy. HTDDS can be designed to enhance clinical efficacy in the treatment of liver diseases. We have conducted an extensive review of 335 studies reported since 1964. These included about 166 references involving the treatment of liver diseases with TCM (covering active components of TCM, single TCM and Chinese medicine formulas), 169 reports on HTDDS and background studies on liver-related diseases. Here we review the long history of TCM in the treatment of liver diseases.We have also reviewed the status of studies on active components of TCM using nanotechnology-based targeted delivery systems to provide support for further research and development of TCM-based targeted preparations for the treatment of liver disease.
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Affiliation(s)
- Zhe Ma
- Engineering Research Center of Modern Chinese Medicine Discovery and Preparation Technique, Ministry of Education, Tianjin University of Traditional Chinese Medicine, Tianjin, 300193, China; Institute of Traditional Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin, 300193, China
| | - Bing Zhang
- Engineering Research Center of Modern Chinese Medicine Discovery and Preparation Technique, Ministry of Education, Tianjin University of Traditional Chinese Medicine, Tianjin, 300193, China; Institute of Traditional Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin, 300193, China
| | - Yuqi Fan
- Institute of Traditional Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin, 300193, China; School of Integrative Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin, 300193, China
| | - Meng Wang
- Engineering Research Center of Modern Chinese Medicine Discovery and Preparation Technique, Ministry of Education, Tianjin University of Traditional Chinese Medicine, Tianjin, 300193, China; Institute of Traditional Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin, 300193, China
| | - Dereje Kebebe
- Engineering Research Center of Modern Chinese Medicine Discovery and Preparation Technique, Ministry of Education, Tianjin University of Traditional Chinese Medicine, Tianjin, 300193, China; Institute of Traditional Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin, 300193, China; School of Pharmacy, Institute of Health Sciences, Jimma University, Jimma, Ethiopia
| | - Jiawei Li
- Engineering Research Center of Modern Chinese Medicine Discovery and Preparation Technique, Ministry of Education, Tianjin University of Traditional Chinese Medicine, Tianjin, 300193, China; Institute of Traditional Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin, 300193, China; School of Chinese Materia Medica, Tianjin University of Traditional Chinese Medicine, Tianjin, 300193, China.
| | - Zhidong Liu
- Engineering Research Center of Modern Chinese Medicine Discovery and Preparation Technique, Ministry of Education, Tianjin University of Traditional Chinese Medicine, Tianjin, 300193, China; Institute of Traditional Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin, 300193, China.
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Thuy LTT, Hai H, Hieu VN, Dat NQ, Hoang DV, Kawada N. Antifibrotic Therapy for Liver Cirrhosis. THE EVOLVING LANDSCAPE OF LIVER CIRRHOSIS MANAGEMENT 2019:167-189. [DOI: 10.1007/978-981-13-7979-6_15] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/06/2025]
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Contribution of Red Wine Consumption to Human Health Protection. Molecules 2018; 23:molecules23071684. [PMID: 29997312 PMCID: PMC6099584 DOI: 10.3390/molecules23071684] [Citation(s) in RCA: 104] [Impact Index Per Article: 14.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2018] [Revised: 07/07/2018] [Accepted: 07/09/2018] [Indexed: 01/01/2023] Open
Abstract
Wine consumption has been popular worldwide for many centuries. Based on in vitro and in vivo studies, a certain amount of everyday wine consumption may prevent various chronic diseases. This is due, in part, to the presence and amount of important antioxidants in red wine, and, therefore, research has focused on them. Wine polyphenols, especially resveratrol, anthocyanins, and catechins, are the most effective wine antioxidants. Resveratrol is active in the prevention of cardiovascular diseases by neutralizing free oxygen radicals and reactive nitrogenous radicals; it penetrates the blood-brain barrier and, thus, protects the brain and nerve cells. It also reduces platelet aggregation and so counteracts the formation of blood clots or thrombi. The main aim of this review is to summarize the current findings about the positive influence of wine consumption on human organ function, chronic diseases, and the reduction of damage to the cardiovascular system.
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Zhu Y, Que RY, Li Y. Effects of resveratrol on activation of NLRP3 inflammasome in HSC-T6 cells. Shijie Huaren Xiaohua Zazhi 2018; 26:479-487. [DOI: 10.11569/wcjd.v26.i8.479] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [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 investigate the effect of resveratrol (Res) on the activation of nod-like receptor protein 3 (NLRP3) inflammasome in hepatic stellate cell (HSC)-T6 cells and to explore the anti-fibrotic mechanism of Res.
METHODS Rat hepatic stellate cell (HSC) line HSC-T6 was used. HSC-T6 cells were seeded into cell culture plates with high glucose DMEM medium containing 10% fetal bovine serum for 24 h. Then, the cells were incubated with Res (4, 8, and 16 μmol/L) or acetylcysteine (NAC; 5 mmol/L) for 24 h. Oxidative stress (OS) was induced by exposure to hydrogen peroxide (H2O2; 0.2 mmol/L) for 4 h. MTT method was used to observe the effect of Res on HSC-T6 cell proliferation. ELISA was used to detect the contents of type I collagen (COL-I), transforming growth factor β1 (TGF-β1), interleukin (IL)-1β, IL-18, malondialdehyde (MDA), and superoxide dismutase (SOD) in cell culture supernatant. Reactive oxygen species (ROS) production was measured with a fluorescence microplate reader following staining with DCFH-DA probe. Western blot analysis was used to detect the expression of alpha-smooth muscle actin (α-SMA), NLRP3, apoptosis-associated speck-like protein (ASC), and cysteinyl aspartate specific proteinase 1 (caspase 1) in HSC-T6 cells.
RESULTS Compared with control cells, Res at concentrations from 4 μmol/L to 64 μmol/L significantly suppressed the proliferation of HSC-T6 cells. Compared with control cells, OS induction significantly increased the proliferation of HSC-T6 cells, the contents of COL-1, TGF-β1, MDA, IL-1β, and IL-18 in cell culture supernatant, intracellular ROS production, and the protein expression of α-SMA, NLRP3, ASC, and caspase 1-p10 (P < 0.01), but decreased the content of SOD in cell culture supernatant (P < 0.01). Compared with the OS group, treatment with low-, medium-, or high-dose Res or positive control NAC significantly decreased the proliferation of HSC-T6 cells, the contents of COL-1, TGF-β1, MDA, IL-1β, and IL-18 in cell culture supernatant, intracellcular ROS production, and the protein expression of α-SMA, NLRP3, ASC, and caspase 1-p10 (P < 0.01), but increased the content of SOD in cell culture supernatant (P < 0.01).
CONCLUSION Res could suppress the proliferation and activation of HSC-T6 cells via down-regulation of ROS-NLRP3 inflammasome signaling.
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Que R, Shen Y, Ren J, Tao Z, Zhu X, Li Y. Estrogen receptor‑β‑dependent effects of saikosaponin‑d on the suppression of oxidative stress‑induced rat hepatic stellate cell activation. Int J Mol Med 2017; 41:1357-1364. [PMID: 29286085 PMCID: PMC5819932 DOI: 10.3892/ijmm.2017.3349] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2016] [Accepted: 12/06/2017] [Indexed: 11/22/2022] Open
Abstract
Saikosaponin-d (SSd) is one of the major triterpenoid saponins derived from Bupleurum falcatum L., which has been reported to possess antifibrotic activity. At present, there is little information regarding the potential target of SSd in hepatic stellate cells (HSCs), which serve an important role in excessive extracellular matrix (ECM) deposition during the pathogenesis of hepatic fibrosis. Our recent study indicated that SSd may be considered a novel type of phytoestrogen with estrogen-like actions. Therefore, the present study aimed to investigate the effects of SSd on the proliferation and activation of HSCs, and the underlying mechanisms associated with estrogen receptors. In the present study, a rat HSC line (HSC-T6) was used and cultured with dimethyl sulfoxide, SSd, or estradiol (E2; positive control), in the presence or absence of three estrogen receptor (ER) antagonists [ICI-182780, methylpiperidinopyrazole (MPP) or (R,R)-tetrahydrochrysene (THC)], for 24 h as pretreatment. Oxidative stress was induced by exposure to hydrogen peroxide for 4 h. Cell proliferation was assessed by MTT growth assay. Malondialdehyde (MDA), CuZn-superoxide dismutase (CuZn-SOD), tissue inhibitor of metalloproteinases-1 (TIMP- 1), matrix metalloproteinase-1 (MMP-1), transforming growth factor-β1 (TGF-β1), hydroxyproline (Hyp) and collagen-1 (COL1) levels in cell culture supernatants were determined by ELISA. Reactive oxygen species (ROS) was detected by flow cytometry. Total and phosphorylated mitogen-activated protein kinases (MAPKs) and α-smooth muscle actin (α-SMA) were examined by western blot analysis. TGF-β1 mRNA expression was determined by RT-quantitative (q)PCR. SSd and E2 were able to significantly suppress oxidative stress-induced proliferation and activation of HSC-T6 cells. Furthermore, SSd and E2 were able to reduce ECM deposition, as demonstrated by the decrease in transforming growth factor-β1, hydroxyproline, collagen-1 and tissue inhibitor of metalloproteinases-1, and by the increase in matrix metalloproteinase-1. These results suggested that the possible molecular mechanism could involve downregulation of the reactive oxygen species/mitogen-activated protein kinases signaling pathway. Finally, the effects of SSd and E2 could be blocked by co-incubation with ICI-182780 or THC, but not MPP, thus indicating that ERβ may be the potential target of SSd in HSC-T6 cells. In conclusion, these findings suggested that SSd may suppress oxidative stress-induced activation of HSCs, which relied on modulation of ERβ.
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Affiliation(s)
- Renye Que
- Department of Gastroenterology, Shanghai Municipal Hospital of Traditional Chinese Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai 200071, P.R. China
| | - Yanting Shen
- Department of Gastroenterology, Shanghai Municipal Hospital of Traditional Chinese Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai 200071, P.R. China
| | - Jianlin Ren
- Department of Scientific Research, Shanghai Municipal Hospital of Traditional Chinese Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai 200071, P.R. China
| | - Zhihui Tao
- Department of Gastroenterology, Shanghai Municipal Hospital of Traditional Chinese Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai 200071, P.R. China
| | - Xiaoyan Zhu
- Department of Physiology, The Second Military Medical University, Shanghai 200433, P.R. China
| | - Yong Li
- Department of Gastroenterology, Shanghai Municipal Hospital of Traditional Chinese Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai 200071, P.R. China
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Resveratrol pretreatment reduces circulating inflammatory interleukins in CCl 4 -induced hepatotoxicity rats. ACTA ACUST UNITED AC 2017. [DOI: 10.1016/j.bfopcu.2017.09.005] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/19/2022]
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Elbe H, Gul M, Cetin A, Taslidere E, Ozyalin F, Turkoz Y, Otlu A. Resveratrol reduces light and electron microscopic changes in acetaminophen-induced hepatotoxicity in rats: Role of iNOS expression. Ultrastruct Pathol 2017; 42:39-48. [PMID: 29192844 DOI: 10.1080/01913123.2017.1374313] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/15/2023]
Abstract
INTRODUCTION Hepatotoxicity is a major complication of acetaminophen (APAP), a widely used analgesic and antipyretic drug. Resveratrol (RSV) is a naturally occurring diphenol and it has anticancer, antioxidant, and anti-inflammatory properties. OBJECTIVES In this study, the beneficial effects of RSV on APAP-induced hepatotoxicity was investigated in rats. MATERIALS AND METHODS Group 1: Ethanol, Group 2: Saline, Group 3: RSV (10 mg/kg/ip), Group 4: APAP (1000 mg/kg/ip/single dose), Group 5: APAP+RSV (20 min after administration of APAP). The rats were sacrificed 24 h after administration of APAP. Light and electron microscopic changes were evaluated. Levels of malondialdehyde (MDA) and glutathione (GSH), catalase (CAT), and superoxide dismutase (SOD) activities were determined in liver tissue. RESULTS Rats of the ethanol, saline, and RSV groups did not present any histopathological alterations. In the APAP group, we observed vascular congestion, necrosis, inflammation, sinusoidal dilatation, and loss of glycogen content. In the APAP+RSV group, these changes were markedly reduced. iNOS immunostaining showed very weak positive stained hepatocytes the sections of control, saline, and RSV groups. However, in the APAP group, iNOS immunostaining was most evident in pericentral hepatocytes. In the same areas in APAP+RSV group, intensity of iNOS immunostaining decreased. A significant increase in MDA and decreases in GSH level, CAT, and SOD activity indicated that APAP-induced hepatotoxicity was mediated through oxidative stress. Significant beneficial changes were noted in tissue oxidative stress indicators in rats treated with RSV. CONCLUSION These biochemical, histopathological, and ultrastructural findings revealed that RSV reduced the severity of APAP-induced alterations in liver.
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Affiliation(s)
- Hulya Elbe
- a Faculty of Medicine, Department of Histology and Embryology , Mugla Sıtkı Kocman University , Mugla , Turkey
| | - Mehmet Gul
- b Faculty of Medicine, Department of Histology and Embryology , Inonu University , Malatya , Turkey
| | - Asli Cetin
- b Faculty of Medicine, Department of Histology and Embryology , Inonu University , Malatya , Turkey
| | - Elif Taslidere
- c Faculty of Medicine, Department of Histology and Embryology , Bezmialem Vakif University , Istanbul , Turkey
| | - Fatma Ozyalin
- d Faculty of Medicine, Department of Medical Biochemistry , Inonu University , Malatya , Turkey
| | - Yusuf Turkoz
- d Faculty of Medicine, Department of Medical Biochemistry , Inonu University , Malatya , Turkey
| | - Ali Otlu
- b Faculty of Medicine, Department of Histology and Embryology , Inonu University , Malatya , Turkey
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Bae M, Park YK, Lee JY. Food components with antifibrotic activity and implications in prevention of liver disease. J Nutr Biochem 2017; 55:1-11. [PMID: 29268106 DOI: 10.1016/j.jnutbio.2017.11.003] [Citation(s) in RCA: 59] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2017] [Revised: 09/18/2017] [Accepted: 11/11/2017] [Indexed: 12/26/2022]
Abstract
Increasing prevalence of nonalcoholic fatty liver disease (NAFLD) in parallel with the obesity epidemic has been a major public health concern. NAFLD is the most common chronic liver disease in the United States, ranging from fatty liver to steatohepatitis, fibrosis and cirrhosis in the liver. In response to chronic liver injury, fibrogenesis in the liver occurs as a protective response; however, prolonged and dysregulated fibrogenesis can lead to liver fibrosis, which can further progress to cirrhosis and eventually hepatocellular carcinoma. Interplay of hepatocytes, macrophages and hepatic stellate cells (HSCs) in the hepatic inflammatory and oxidative milieu is critical for the development of NAFLD. In particular, HSCs play a major role in the production of extracellular matrix proteins. Studies have demonstrated that bioactive food components and natural products, including astaxanthin, curcumin, blueberry, silymarin, coffee, vitamin C, vitamin E, vitamin D, resveratrol, quercetin and epigallocatechin-3-gallate, have antifibrotic effects in the liver. This review summarizes current knowledge of the mechanistic insight into the antifibrotic actions of the aforementioned bioactive food components.
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Affiliation(s)
- Minkyung Bae
- Department of Nutritional Sciences, University of Connecticut, Storrs, CT 06269, USA
| | - Young-Ki Park
- Department of Nutritional Sciences, University of Connecticut, Storrs, CT 06269, USA
| | - Ji-Young Lee
- Department of Nutritional Sciences, University of Connecticut, Storrs, CT 06269, USA; Department of Food and Nutrition, Kyung Hee University, Seoul, South Korea.
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Abdu SB, Al-Bogami FM. Influence of resveratrol on liver fibrosis induced by dimethylnitrosamine in male rats. Saudi J Biol Sci 2017; 26:201-209. [PMID: 30622427 PMCID: PMC6319027 DOI: 10.1016/j.sjbs.2017.09.003] [Citation(s) in RCA: 28] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2017] [Revised: 05/03/2017] [Accepted: 09/20/2017] [Indexed: 01/29/2023] Open
Abstract
Liver fibrosis is a significant health problem which represents the liver’s scarring process and response to injury through deposition of collagen and extracellular matrix, and ultimately leads to cirrhosis. Resveratrol is a naturally occurring phytoalexin found predominantly in grapes. This study aimed to investigate the antifibrotic role of resveratrol on dimethylnitrosamine (DMN)-induced liver fibrosis in rats. Rats were divided into four groups and treated for three weeks; control, resveratrol administered orally (20 mg/kg daily), DMN intraperitoneally injected (10 mg/kg 3 days/week), and the last group was pre-treated daily with resveratrol then injected with DMN, 3 days/week. DMN administration induced severe liver pathological alterations. However, oral administration of resveratrol before DMN significantly prevented the induced loss in body weight, as well as the increase in liver weight which arise from DMN administration. Resveratrol has also inhibited the elevation of serum aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase (ALP) and bilirubin levels. Furthermore, resveratrol significantly increased hepatic reduced glutathione (GSH) levels and reduced the levels of malondialdehyde (MDA) due to its antioxidants effect as well as increased serum protein levels. In addition, DMN induced elevation in hydroxyproline content. On the other hand, hydroxyproline level was significantly reduced in the resveratrol pretreated rats. Resveratrol has also remarkably maintained the normal liver lobular architecture. Moreover, resveratrol had displayed potent potentials to prevent collagen deposition, lymphocytic infiltration, necrosis, steatosis, vascular damage, blood hypertention, cholangiocyte proliferation. It can be concluded that resveratrol has a marked protective role on DMN-induced liver fibrosis in rats, and can be considered as antiproliferative, antihypertensive, as well as antifibrotic agent and may be used to block the development of liver fibrosis.
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Affiliation(s)
- Suzan B Abdu
- Department of Biological Sciences, Faculty of Sciences, King Abdulaziz University, P.O. Box 80200, Jeddah 21589, Saudi Arabia
| | - Fatima M Al-Bogami
- Department of Biological Sciences, Faculty of Sciences, King Abdulaziz University, P.O. Box 80200, Jeddah 21589, Saudi Arabia
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Weiskirchen S, Weiskirchen R. Resveratrol: Is It Really Good for Liver Health? HEPATITIS MONTHLY 2017; 17. [DOI: 10.5812/hepatmon.12074] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 08/30/2023]
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35
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Peron G, Uddin J, Stocchero M, Mammi S, Schievano E, Dall’Acqua S. Studying the effects of natural extracts with metabolomics: A longitudinal study on the supplementation of healthy rats with Polygonum cuspidatum Sieb. et Zucc. J Pharm Biomed Anal 2017; 140:62-70. [DOI: 10.1016/j.jpba.2017.03.015] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2016] [Revised: 03/10/2017] [Accepted: 03/10/2017] [Indexed: 01/27/2023]
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Barros PP, Gonçalves GMS, Silva GHD, Bastos MCVD, Ramos LN, Fernandes MM. Lycopene and resveratrol pretreatment did not interfere with the liver of hepatectomized rats. Acta Cir Bras 2017; 32:194-202. [PMID: 28403343 DOI: 10.1590/s0102-865020170030000003] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2016] [Accepted: 02/21/2017] [Indexed: 11/22/2022] Open
Abstract
Purpose: To investigate the effects of lycopene and resveratrol pretreatment on hepatic hyperplasia in partially hepatectomized rats. Methods: The lycopene group and the resveratrol group received 40 mg/kg/day of lycopene or resveratrol, respectively (dissolved in olive oil or in saline solution, respectively) and administered via a gastric tube for 30 days. The partially hepatectomzed (PH) control groups received saline or olive oil via a gastric tube for 30 days, respectively, and the normal control group received no treatment. Liver tissue and intracardiac blood samples were obtained 24, 36 or 48 h after PH. Results: No areas of fibrosis were detected. No significant changes in mitotic index, in the number of apoptosis events or in aspartate aminotransferase and alanine aminotransferase levels were observed. Conclusions: Lycopene and resveratrol pretreatment did not interfere on hepatic hyperplasia in partially hepatectomized rats.
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Affiliation(s)
- Pedro Paulo Barros
- PhD, Full Professor, Researcher, Faculty of Pharmaceutical Sciences, Pontifícia Universidade Católica de Campinas (PUC-Campinas), Brazil. Conception of the study, interpretation of data
| | - Gisele Mara Silva Gonçalves
- PhD, Full Professor, Researcher, Faculty of Pharmaceutical Sciences, PUC-Campinas, Brazil. Conception of the study, interpretation of data
| | - Gustavo Henrique da Silva
- PhD, Full Professor, Researcher, Faculty of Pharmaceutical Sciences, PUC-Campinas, Brazil. Conception of the study, interpretation of data
| | | | - Loren Nogaroto Ramos
- Graduate student, School of Medicine, FAPIC, PUC-Campinas, Brazil. Interpretation of data
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Kim NH, Heo JD, Kim TB, Rho JR, Yang MH, Jeong EJ. Protective Effects of Ethyl Acetate Soluble Fraction of Limonium tetragonum on Diethylnitrosamine-Induced Liver Fibrosis in Rats. Biol Pharm Bull 2017; 39:1022-8. [PMID: 27251505 DOI: 10.1248/bpb.b15-01047] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
Diethylnitrosamine (DEN) is a potent toxic material that can cause necrosis and subsequent fibrosis in the liver. Based on the previously reported hepatoprotective effect of Limonium tetragonum against the proliferation of hepatic stellate cells, we tested the EtOAc soluble fraction of L. tetragonum extract (EALT) in a DEN-induced hepatotoxic rat model. The development of hepatotoxicity including mononuclear cell infiltration and fibrosis induced by intraperitoneal injections of DEN (70 mg/2 mL/kg body weight (b.w.) per week) was observed at 4, 6 and 8 weeks after the first DEN treatment. Administration of EALT (200 mg/kg body weight, per os (p.o.)) induced significant reductions in serum alanine transaminase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP), gamma glutamyl transferase (GGT), and triglycerides (TG) in DEN-injected rats. Increased oxidative stress in DEN-induced liver fibrosis rats was diminished by EALT treatment through a decrease in malondialdehyde (MDA) and increase in superoxide dismutase (SOD). Histologic findings that included markedly attenuated mononuclear cell infiltration and fibrosis could be observed in liver samples from the EALT-treated groups. An extract of Hovenia dulcis fruit and Sylimarin were used as positive controls. The present study provides direct experimental evidence for EALT attenuated hepatic injury and fibrosis in DEN-treated mice. The L. tetragonum EtOAc fraction might be useful in treating fibrotic liver diseases.
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Affiliation(s)
- Na-Hyun Kim
- Gyeongnam Department of Environment & Toxicology, Korea Institute of Toxicology
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Jang CH, Kim KM, Yang JH, Cho SS, Kim SJ, Shin SM, Cho IJ, Ki SH. The Role of Lipin-1 in the Regulation of Fibrogenesis and TGF-β Signaling in Hepatic Stellate Cells. Toxicol Sci 2016; 153:28-38. [PMID: 27345520 DOI: 10.1093/toxsci/kfw109] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2022] Open
Abstract
The adipogenic transcriptional regulation was reported to inhibit transdifferentiation of hepatic stellate cells (HSCs), which constitute the main fibrogenic cell type in the liver. Lipin-1 exhibits a dual function: an enzyme that catalyzes the conversion of phosphatidate to diacylglycerol and a transcriptional regulator. However, the involvement of Lipin-1 in the regulation of transforming growth factor-β (TGF-β) signaling and fibrogenesis in HSCs is not fully understood. Here, we showed that Lipin-1 was downregulated in activated primary HSCs and TGF-β-treated LX-2 cells, immortalized human HSC cell lines. The downregulation of Lipin-1 by TGF-β was not dependent on altered mRNA stability but rather on protein stability. Treatment of LX-2 cells with the proteasome inhibitor led to the accumulation of Lipin-1. Moreover, we observed a significant increase in Lipin-1 polyubiquitination. Overexpression of Lipin-1 attenuated TGF-β-induced fibrogenic gene expression. In addition, Lipin-1 inhibited TGF-β-mediated activation of Sma and Mad-related family (SMAD), a major transcription factor that transduces intracellular signals from TGF-β. Resveratrol, a well-known natural polyphenolic antioxidant, is known to inhibit liver fibrosis, although its mechanism of action remains unknown. Our data showed that resveratrol significantly increased the levels of Lipin-1 protein and mRNA in HSCs. Further investigation revealed that resveratrol blocked the polyubiquitination of Lipin-1. Resveratrol inhibited TGF-β-induced fibrogenic gene expression. TGF-β-induced SMAD binding element-luciferase reporter activity was significantly diminished by resveratrol with a simultaneous decrease in SMAD3 phosphorylation. Consistently, knockdown of the Lipin-1 gene using siRNA abolished the inhibitory effect of resveratrol. We conclude that Lipin-1 can antagonize HSC activation through the inhibition of TGF-β/SMAD signaling and that resveratrol may affect Lipin-1 gene induction and contribute to the inhibition of TGF-β-mediated hepatic fibrogenesis.
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Affiliation(s)
- Chang Ho Jang
- *College of Pharmacy, Chosun University, Gwangju, 61452, Korea
| | - Kyu Min Kim
- *College of Pharmacy, Chosun University, Gwangju, 61452, Korea College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul, 08826, Korea
| | - Ji Hye Yang
- *College of Pharmacy, Chosun University, Gwangju, 61452, Korea
| | - Sam Seok Cho
- *College of Pharmacy, Chosun University, Gwangju, 61452, Korea
| | - Seung Jung Kim
- *College of Pharmacy, Chosun University, Gwangju, 61452, Korea
| | - Sang Mi Shin
- *College of Pharmacy, Chosun University, Gwangju, 61452, Korea
| | - Il Je Cho
- MRC-GHF, College of Korean Medicine, Daegu Haany University, Gyeongsan, 38610, Korea
| | - Sung Hwan Ki
- *College of Pharmacy, Chosun University, Gwangju, 61452, Korea
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Bai XZ, Liu JQ, Yang LL, Fan L, He T, Su LL, Shi JH, Tang CW, Zheng Z, Hu DH. Identification of sirtuin 1 as a promising therapeutic target for hypertrophic scars. Br J Pharmacol 2016; 173:1589-601. [PMID: 26891034 DOI: 10.1111/bph.13460] [Citation(s) in RCA: 29] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2015] [Revised: 01/31/2016] [Accepted: 02/14/2016] [Indexed: 01/08/2023] Open
Abstract
BACKGROUND AND PURPOSE Sirtuin1 (SIRT1), the founding member of mammalian class III histone deacetylases, is reported to be a drug target involved in fibrotic diseases. However, whether it is an effective drug target in hypertrophic scar treatment is still not known. EXPERIMENTAL APPROACH In the present study, we observed that SIRT1 localized to both the epidermis and the dermis of skin tissues by immunohistochemistry. After knock-down of SIRT1 by shRNA or up-regulating SIRT1 by resveratrol, the expression of α-SMA, Col1 and Col3 in fibroblasts were detected by western blots. A mouse excision wound healing model was used to observe the changes in collagen fibre associated with the different expression levels of SIRT1. KEY RESULTS SIRT1 expression was inhibited in hypertrophic scar tissue. The down-regulation of SIRT1 resulted in an increased expression of α-SMA, Col1 and Col3 in hypertrophic scar-derived fibroblasts. In contrast, the up-regulation of SIRT1 not only inhibited the expression of α-SMA, Col1 and Col3 in hypertrophic scar-derived fibroblasts but also blocked the activation of TGFβ1-induced normal skin-derived fibroblasts. In the mouse model of wound healing, the deletion of SIRT1 resulted in denser collagen fibres and a more disordered structure, whereas resveratrol treatment led to a more organized and thinner collagen fibre, which was similar to that observed during normal wound healing. CONCLUSIONS AND IMPLICATIONS The results revealed that SIRT1 negatively regulates TGFβ1-induced fibroblast activation and inhibits excessive scar formation and is, therefore, a promising drug target for hypertrophic scar formation.
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Affiliation(s)
- Xiao-Zhi Bai
- Department of Burns and Cutaneous Surgery, Xijing Hospital, the Fourth Military Medical University, Xi'an, Shaanxi, China
| | - Jia-Qi Liu
- Department of Burns and Cutaneous Surgery, Xijing Hospital, the Fourth Military Medical University, Xi'an, Shaanxi, China
| | - Long-Long Yang
- Department of Burns and Cutaneous Surgery, Xijing Hospital, the Fourth Military Medical University, Xi'an, Shaanxi, China
| | - Lei Fan
- Department of Burns and Cutaneous Surgery, Xijing Hospital, the Fourth Military Medical University, Xi'an, Shaanxi, China
| | - Ting He
- Department of Burns and Cutaneous Surgery, Xijing Hospital, the Fourth Military Medical University, Xi'an, Shaanxi, China
| | - Lin-Lin Su
- Department of Burns and Cutaneous Surgery, Xijing Hospital, the Fourth Military Medical University, Xi'an, Shaanxi, China
| | - Ji-Hong Shi
- Department of Burns and Cutaneous Surgery, Xijing Hospital, the Fourth Military Medical University, Xi'an, Shaanxi, China
| | - Chao-Wu Tang
- Department of Burns and Cutaneous Surgery, Xijing Hospital, the Fourth Military Medical University, Xi'an, Shaanxi, China
| | - Zhao Zheng
- Department of Burns and Cutaneous Surgery, Xijing Hospital, the Fourth Military Medical University, Xi'an, Shaanxi, China
| | - Da-Hai Hu
- Department of Burns and Cutaneous Surgery, Xijing Hospital, the Fourth Military Medical University, Xi'an, Shaanxi, China
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Balata GF, Essa EA, Shamardl HA, Zaidan SH, Abourehab MAS. Self-emulsifying drug delivery systems as a tool to improve solubility and bioavailability of resveratrol. Drug Des Devel Ther 2016; 10:117-28. [PMID: 26792979 PMCID: PMC4708959 DOI: 10.2147/dddt.s95905] [Citation(s) in RCA: 66] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/23/2022] Open
Abstract
Resveratrol is a nonflavonoid polyphenolic compound which has a broad range of desirable biological actions which include antioxidant, anti-inflammatory, antidiabetic, cardioprotective, and antitumor activities. However, there is concern that the bioavailability of resveratrol may limit some of its clinical utility. So, the aim of this study was to enhance the dissolution rate and oral hypoglycemic and hypolipidemic effect of resveratrol. This was achieved using self-emulsifying drug delivery system. The solubility of resveratrol was determined in various oils, surfactants, and cosurfactants. Phase diagram was plotted to identify the efficient self-emulsification regions using olive oil, Tween 80, and propylene glycol. The prepared self-emulsifying drug delivery system formulations were tested for thermodynamic stability, emulsification efficiency, droplet size, zeta potential, and in vitro drug release. Self-emulsification time averaged 17-99 seconds without precipitation and the mean droplet sizes ranged from 285 to 823 nm with overall zeta potential of -2.24 to -15.4 mv. All formulations improved drug dissolution in relation to unprocessed drug with a trend of decreased dissolution parameters with increasing oil content. The optimized formula, F19, with dissolution efficiency of 94% compared to only 42% of pure drug was used to study the in vivo hypoglycemic and hypolipidemic effects of resveratrol in diabetic-induced albino rats and comparing these effects with that of pure resveratrol in different doses. Treatment with the optimized formula, F19, at 10 mg/kg had significant hypoglycemic and hypolipidemic effects in diabetic-induced albino rats which were nearly similar to the high dose (20 mg/kg) of unprocessed resveratrol. From the study, it was concluded that formulation F19 has good emulsification property with uniform globule size, satisfactory in vitro drug release profile, and significant in vivo hypoglycemic effects which identify future opportunities for resveratrol delivery.
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Affiliation(s)
- Gehan F Balata
- Department of Pharmaceutics, Faculty of Pharmacy, Umm Al-Qura University, Makkah, Saudi Arabia
| | - Ebtessam A Essa
- Department of Pharmaceutics, Faculty of Pharmacy, Umm Al-Qura University, Makkah, Saudi Arabia
- Department of Pharmaceutics, Faculty of Pharmacy, Tanta University, Tanta, Egypt
| | - Hanan A Shamardl
- Department of Pharmacology, Faculty of Pharmacy, Umm Al-Qura University, Makkah, Saudi Arabia
- Department of Pharmacology, Faculty of Medicine, El Fayoom University
| | - Samira H Zaidan
- Department of Pharmacognosy, Faculty of Pharmacy, Umm Al-Qura University, Makkah, Saudi Arabia
| | - Mohammed AS Abourehab
- Department of Pharmaceutics, Faculty of Pharmacy, Umm Al-Qura University, Makkah, Saudi Arabia
- Department of Pharmaceutics, Faculty of Pharmacy, El-Minia University, Egypt
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41
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Faghihzadeh F, Hekmatdoost A, Adibi P. Resveratrol and liver: A systematic review. JOURNAL OF RESEARCH IN MEDICAL SCIENCES 2015; 20:797-810. [PMID: 26664429 PMCID: PMC4652315 DOI: 10.4103/1735-1995.168405] [Citation(s) in RCA: 82] [Impact Index Per Article: 8.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 12/26/2022]
Abstract
Background: Recent studies demonstrated that resveratrol has many therapeutic effects on liver disorders. Resveratrol significantly increased survival after liver transplantation, decreased fat deposition, necrosis, and apoptosis which induced by ischemia in Wistar rats. It provided liver protection against chemical, cholestatic, and alcohol injury. Resveratrol can improve glucose metabolism and lipid profile and decrease liver fibrosis and steatosis. Furthermore, it was able to alter hepatic cell fatty acid composition. According to extension of liver disease around the world and necessity of finding new threat, this review critically examines the current preclinical in vitro and in vivo studies on the preventive and therapeutic effects of resveratrol in liver disorders. Materials and Methods: A search in PubMed, Google Scholar, and Scopus was undertaken to identify relevant literature using search terms, including “liver,” “hepatic,” and “Resveratrol.” Both in vivo and in vitro studies were included. No time limiting considered for this search. Results: A total of 76 articles were eligible for this review. In these articles, resveratrol shows antioxidative properties in different models of hepatitis resulting in reducing of hepatic fibrosis. Conclusion: Resveratrol could reduce hepatic steatosis through modulating the insulin resistance and lipid profile in animals. These high quality preclinical studies propose the potential therapeutic implication of resveratrol in liver disorders especially those with hepatic steatosis. Resveratrol can play a pivotal role in prevention and treatment of liver disorders by reducing hepatic fibrosis.
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Affiliation(s)
- Forouzan Faghihzadeh
- Department of Clinical Nutrition and Dietetics, Faculty of Nutrition and Food Technology, National Nutrition and Food Technology Research Institute, Shahid Beheshti University of Medical Science, Tehran, Iran
| | - Azita Hekmatdoost
- Department of Clinical Nutrition and Dietetics, Faculty of Nutrition and Food Technology, National Nutrition and Food Technology Research Institute, Shahid Beheshti University of Medical Science, Tehran, Iran
| | - Payman Adibi
- Department of Medicine, Integrative Functional Gastroenterology Research Center, Isfahan University of Medical Sciences, Isfahan, Iran
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McGill MR, Du K, Weemhoff JL, Jaeschke H. Critical review of resveratrol in xenobiotic-induced hepatotoxicity. Food Chem Toxicol 2015; 86:309-18. [PMID: 26561740 DOI: 10.1016/j.fct.2015.11.003] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2015] [Revised: 10/30/2015] [Accepted: 11/02/2015] [Indexed: 02/07/2023]
Abstract
Use of natural products is increasingly popular. In fact, many patients with liver diseases self-medicate with herbal supplements. Resveratrol (RSV), in particular, is a common natural product that can reduce injury in experimental models of liver disease. Xenobiotic hepatotoxicity is a particularly important area-of-need for therapeutics. Drug-induced liver injury, for example, is the most common cause of acute liver failure (ALF) and ALF-induced deaths in many countries. Importantly, RSV protects against hepatotoxicity in animal models in vivo caused by several drugs and chemicals and may be an effective intervention. Although many mechanisms have been proposed to explain the protection, not all are consistent with other data. Furthermore, RSV suffers from other issues, including limited bioavailability due to extensive hepatic metabolism. The purpose of this article is to summarize recent findings on the protective effects of RSV in xenobiotic-induced liver injury and other forms of liver injury and to provide a critical review of the underlying mechanisms. New mechanisms that are more consistent with data emerging from the toxicology field are suggested. Efforts to move RSV into clinical use are also considered. Overall, RSV is a promising candidate for therapeutic use, but additional studies are needed to better understand its effects.
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Affiliation(s)
- Mitchell R McGill
- Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City, KS, USA.
| | - Kuo Du
- Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City, KS, USA
| | - James L Weemhoff
- Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City, KS, USA
| | - Hartmut Jaeschke
- Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City, KS, USA
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43
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Silva P, Fernandes E, Carvalho F. Dual effect of red wine on liver redox status: a concise and mechanistic review. Arch Toxicol 2015; 89:1681-1693. [PMID: 26026610 DOI: 10.1007/s00204-015-1538-1] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/07/2015] [Accepted: 05/12/2015] [Indexed: 01/09/2023]
Abstract
Chronic ethanol consumption is a strong risk factor for the development of liver disease. Multiple mechanisms are involved in ethanol-mediated liver injury; oxidative stress being pointed has an important factor. However, it should be noted that moderate consumption of red wine has been associated with hepatoprotective effects, mainly due to the antioxidant effect of resveratrol, one of its polyphenolic compounds. In this paper, the potential molecular mechanisms through which the protective effects of resveratrol counteract the oxidative effect of ethanol and the way as this dual effect impacts liver oxidative stress are reviewed. Mechanistic evaluation of modulation of oxidative signaling pathways by ethanol and resveratrol may explain the pathogenesis of various liver diseases and ultimately to disclose possible pharmacological therapies.
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Affiliation(s)
- Paula Silva
- UCIBIO-REQUIMTE, Laboratory of Histology and Embryology, Institute of Biomedical Sciences Abel Salazar (ICBAS), University of Porto, Rua de Jorge Viterbo Ferreira no. 228, 4050-313, Porto, Portugal.
| | - Eduarda Fernandes
- UCIBIO-REQUIMTE, Department of Chemical Sciences, Faculty of Pharmacy, University of Porto, Porto, Portugal
| | - Félix Carvalho
- UCIBIO-REQUIMTE, Department of Biological Sciences, Laboratory of Toxicology, Faculty of Pharmacy, University of Porto, Rua de Jorge Viterbo Ferreira no. 228, 4050-313, Porto, Portugal.
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Domitrović R, Potočnjak I. A comprehensive overview of hepatoprotective natural compounds: mechanism of action and clinical perspectives. Arch Toxicol 2015; 90:39-79. [DOI: 10.1007/s00204-015-1580-z] [Citation(s) in RCA: 74] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2015] [Accepted: 08/11/2015] [Indexed: 12/22/2022]
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45
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Strategies to prevent and reverse liver fibrosis in humans and laboratory animals. Arch Toxicol 2015; 89:1727-50. [PMID: 25963329 DOI: 10.1007/s00204-015-1525-6] [Citation(s) in RCA: 46] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2015] [Accepted: 04/28/2015] [Indexed: 02/07/2023]
Abstract
Liver fibrosis results from chronic damage to the liver in conjunction with various pathways and is mediated by a complex microenvironment. Based on clinical observations, it is now evident that fibrosis is a dynamic, bidirectional process with an inherent capacity for recovery and remodeling. The major mechanisms involved in liver fibrosis include the repetitive injury of hepatocytes, the activation of the inflammatory response after injury stimulation, and the activation and proliferation of hepatic stellate cells (HSCs), which represents the major extracellular matrix (ECM)-producing cells, stimulated by hepatocyte injury and inflammation. The microenvironment in the liver is synergistically regulated abnormal ECM deposition, scar formation, angiogenesis, and fibrogenesis. Moreover, recent studies have clarified novel mechanism in fibrosis such as epigenetic regulation of HSCs, the leptin and PPARγ pathways, the coagulation system, and even autophagy. Uncovering the mechanisms of liver fibrogenesis provides a basis to develop potential therapies to reverse and treat the fibrotic response, thereby improving the outcomes of patients with chronic liver disease. Although both scientific and clinical challenges remain, emerging studies attempt to reveal the ideal anti-fibrotic drug that could be easily delivered to the liver with high specificity and low toxicity. This review highlights the mechanisms, including novel pathways underlying fibrogenesis that may be translated into preventive and treatment strategies, reviews both current and novel agents that target specific pathways or multiple targets, and discusses novel drug delivery systems such as nanotechnology that can be applied in the treatment of liver fibrosis. In addition, we also discuss some current treatment strategies that are being applied in animal models and in clinical trials.
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46
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Lee SE, Kim KH, Kim JW. Flow Cytometric Analysis of the Effects of Resveratrol on the Survival of Human Tennon's Capsule Fibroblasts. JOURNAL OF THE KOREAN OPHTHALMOLOGICAL SOCIETY 2015. [DOI: 10.3341/jkos.2015.56.8.1268] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/23/2022]
Affiliation(s)
- See Eun Lee
- Department of Ophthalmology, Catholic University of Daegu School of Medicine, Daegu, Korea
| | - Keun Hae Kim
- Department of Ophthalmology, Catholic University of Daegu School of Medicine, Daegu, Korea
| | - Jae Woo Kim
- Department of Ophthalmology, Catholic University of Daegu School of Medicine, Daegu, Korea
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47
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Ahmed RF, Abdel-Rahman RF, Farid OA, El-Marasy SA, Hessin AF. Combined hepatoprotective and antidepressant effects of resveratrol in an acute model of depression. ACTA ACUST UNITED AC 2014. [DOI: 10.1016/j.bfopcu.2014.06.002] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/28/2022]
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48
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Somi MH, Fatahi E, Panahi J, Havasian MR, judaki A. Data from a randomized and controlled trial of LCarnitine prescription for the treatment for Non- Alcoholic Fatty Liver Disease. Bioinformation 2014; 10:575-9. [PMID: 25352725 PMCID: PMC4209366 DOI: 10.6026/97320630010575] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2014] [Accepted: 08/21/2014] [Indexed: 02/07/2023] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD) consists of a range of complication. The disease describes clinical , para clinical and pathological conditions from simple steatosis in non-alcoholic steato hepatitis (NASH) to fibrosis, cirrhosis and hepato cellular carcinoma. Therefore, it is of interest to evaluate the grade of fatty liver and Liver Function Test in NAFLD patients. We collected samples and data from 80 patients referred to gastrointestinal clinic of Emam Reza hospital with sonography diagnosed NAFLD and were evaluated in two groups in a randomized clinical trial. The effects of L-Carnitine (500 mg) prescription twice a day on liver enzymes and echogenicity changes in case group was documented and compared with the control group. The mean age of the patients was 40.7±8 in the age range of 25 to 62 years old with 66 (82.5%) male and 14 (17.5%) female patients. Data show that fatty liver changes were not significantly different in the two groups (P=0.23). It is observed that the ALT was the only enzyme with significant changes (P=0.01) after a 24-week interval. It is also noted that the difference in fatty liver sonographic grading was also significant in the two groups (P=0.0001). Thus, proper therapeutic protocols can be adopted beside diet and weight loss to control the disease trend in consideration to the significant changes observed both in enzymatic levels and sonographic grading between the two groups of patients with NAFLD.
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Affiliation(s)
- Mohamad Hosein Somi
- Department of Gastroenterology, Emam Reza Hospital, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz/Iran
| | - Ebrahim Fatahi
- Department of Gastroenterology, Emam Reza Hospital, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz/Iran
| | - Jafar Panahi
- Student Research of Committee, Ilam University of Medical Sciences, Ilam/Iran
| | | | - Arezo judaki
- Department of Gastroenterology, Faculty of Medicine, Ilam University of Medical Sciences, Ilam/Iran
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Ahmad A, Ahmad R. Resveratrol mitigate structural changes and hepatic stellate cell activation in N'-nitrosodimethylamine-induced liver fibrosis via restraining oxidative damage. Chem Biol Interact 2014; 221:1-12. [PMID: 25064540 DOI: 10.1016/j.cbi.2014.07.007] [Citation(s) in RCA: 62] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2014] [Revised: 06/13/2014] [Accepted: 07/16/2014] [Indexed: 01/30/2023]
Abstract
Resveratrol, a polyphenol, found in skin of red grapes, peanuts and berries possesses anti-inflammatory, anti-carcinogenic and lipid modulation properties. Here, we demonstrate in vivo antifibrotic activity of resveratrol in a mammalian model, wherein hepatic fibrosis was induced by N'-nitrosodimethylamine (NDMA) administration. Apart from being a potent hepatotoxin, NDMA is a known mutagen and carcinogen, as well. To induce hepatic fibrosis, rats were administered NDMA (i.p.) in 10mg/kgb.wt thrice/week for 21 days. Another group of animals received resveratrol supplement (10mg/kgb.wt) subsequent to NDMA administration and were sacrificed weekly. The changes in selected biomarkers were monitored to compare profibrotic effects of NDMA and antifibrotic activity of resveratrol. The selected biomarkers were: sera transaminases, ALP, bilirubin, liver glycogen, LPO, SOD, protein carbonyl content, ATPases (Ca(2+), Mg(2+), Na(+)/K(+)) and hydroxyproline/collagen content. Alterations in liver architecture were assessed by H&E, Masson's trichrome and reticulin staining of liver biopsies. Immuno-histochemistry and immunoblotting were employed to examine expression of α-SMA. Our results demonstrate that during NDMA-induced liver fibrosis transaminases, ALP, bilirubin, hydroxyproline and liver collagen increases, while liver glycogen is depleted. The decline in SOD (>65%) and ATPases, which were concomitant with the elevation in MDA and protein carbonyls, strongly indicate oxidative damage. Fibrotic transformation of liver in NDMA-treated rats was verified by histopathology, immuno-histochemistry and immunoblotting data, with the higher expressivity of α-SMA-positive HSCs being most established diagnostic immuno-histochemical marker of HSCs. Resveratrol-supplement refurbished liver architecture by significantly restoring levels of biomarkers of oxidative damage (MDA, SOD, protein carbonyls and membrane-bound ATPases). Therefore, we conclude that antifibrotic effect of resveratrol is due to restrained oxidative damage and down-regulation of α-SMA, which inhibits HSC activation to obstruct liver fibrosis.
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Affiliation(s)
- Areeba Ahmad
- Biochemical and Clinical Genetics Laboratory, Section of Genetics, Department of Zoology, Aligarh Muslim University, Aligarh 202002, U.P., India
| | - Riaz Ahmad
- Biochemical and Clinical Genetics Laboratory, Section of Genetics, Department of Zoology, Aligarh Muslim University, Aligarh 202002, U.P., India.
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Buchner I, Medeiros N, Lacerda DDS, Normann CABM, Gemelli T, Rigon P, Wannmacher CMD, Henriques JAP, Dani C, Funchal C. Hepatoprotective and Antioxidant Potential of Organic and Conventional Grape Juices in Rats Fed a High-Fat Diet. Antioxidants (Basel) 2014; 3:323-38. [PMID: 26784874 PMCID: PMC4665483 DOI: 10.3390/antiox3020323] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2014] [Revised: 04/02/2014] [Accepted: 04/02/2014] [Indexed: 02/07/2023] Open
Abstract
The objective of this study was to investigate the antioxidant and hepatoprotective effect of the chronic use of conventional (CGJ) or organic (OGJ) grape juice from the Bordeaux variety grape on oxidative stress and cytoarchitecture in the liver of rats supplemented with a high-fat diet (HFD) for three months. The results demonstrated that HFD induced an increase in thiobarbituric acid-reactive substances (TBARS), catalase (CAT) activity and 2′,7′-dihydrodichlorofluorescein (DCFH) oxidation and a decrease in sulfhydryl content and superoxide dismutase (SOD) and glutathione peroxidase (GPx) activities. HFD also induced hepatocellular degeneration and steatosis. These alterations were prevented by CGJ and OGJ, where OGJ was more effective. Therefore, it was concluded that HFD induced oxidative stress and liver damage and that the chronic use of grape juice was able to prevent these alterations.
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Affiliation(s)
- Iselde Buchner
- Centro Universitário Metodista do IPA, 90420-060 Porto Alegre, Brazil.
| | - Niara Medeiros
- Centro Universitário Metodista do IPA, 90420-060 Porto Alegre, Brazil.
| | | | | | - Tanise Gemelli
- Departamento de Bioquímica, Universidade Federal do Rio Grande do Sul, 90035-003 Porto Alegre, Brazil.
| | - Paula Rigon
- Departamento de Ciências Morfológicas, Universidade Federal do Rio Grande do Sul, 90040-060 Porto Alegre, Brazil.
| | | | - João Antônio Pegas Henriques
- Departamento de Biofísica, Centro de Biotecnologia, Universidade Federal do Rio Grande do Sul, 91501-970 Porto Alegre, Brazil.
- Instituto de Biotecnologia, Universidade de Caxias do Sul, Caxias do Sul, 95070-560 Porto Alegre, Brazil.
| | - Caroline Dani
- Centro Universitário Metodista do IPA, 90420-060 Porto Alegre, Brazil.
| | - Cláudia Funchal
- Centro Universitário Metodista do IPA, 90420-060 Porto Alegre, Brazil.
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