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Wang D, He R, Song Q, Diao H, Jin Y, Zhang A. Calcitriol Inhibits NaAsO 2 Triggered Hepatic Stellate Cells Activation and Extracellular Matrix Oversecretion by Activating Nrf2 Signaling Pathway Through Vitamin D Receptor. Biol Trace Elem Res 2024; 202:3601-3613. [PMID: 37968493 DOI: 10.1007/s12011-023-03957-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/07/2023] [Accepted: 11/08/2023] [Indexed: 11/17/2023]
Abstract
Previous studies, including our own, have demonstrated that arsenic exposure can induce liver fibrosis, while the underlying mechanism remains unclear and there is currently no effective pharmacological intervention available. Recent research has demonstrated that vitamin D supplementation can ameliorate liver fibrosis caused by various etiologies, potentially through modulation of the Nrf2 signaling pathways. However, it remains unclear whether vitamin D intervention can mitigate arsenic-caused liver fibrosis. As is known hepatic stellate cells (HSCs) activation and extracellular matrix (ECM) deposition are pivotal in the pathogenesis of liver fibrosis. In this study, we investigated the intervention effect of calcitriol (a form of active vitamin D) on arsenite-triggered Lx-2 cells (a human hepatic stellate cell line) activation and ECM oversecretion. Additionally, we also elucidated the role and mechanism of Nrf2 antioxidant signaling pathway. Our results demonstrated that calcitriol intervention significantly inhibits Lx-2 cell activation and ECM oversecretion induced by arsenite exposure. Additionally, calcitriol activates Nrf2 and its downstream antioxidant enzyme expression in Lx-2 cells, thereby reducing ROS overproduction caused by arsenite exposure. Further investigation reveals that calcitriol activates the Nrf2 signaling pathway and inhibits arsenite-triggered Lx-2 cell activation and ECM oversecretion by targeting vitamin D receptor (VDR). In conclusion, this study has demonstrated that vitamin D intervention can effectively inhibit HSC activation and ECM oversecretion triggered by arsenite exposure through its antioxidant activity. This provides a novel strategy for targeted nutritional intervention in the treatment of arsenic-induced liver fibrosis.
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Affiliation(s)
- Dapeng Wang
- Key Laboratory of Environmental Pollution Monitoring and Disease Control, Ministry of Education, School of Public Health, Guizhou Medical University, Guiyang, 550025, Guizhou, People's Republic of China.
- Collaborative Innovation Center for Prevention and Control of Endemic and Ethnic Regional Diseases Co-Constructed By the Province and Ministry, Guizhou Medical University, Guiyang, 550025, Guizhou, People's Republic of China.
| | - Rui He
- Key Laboratory of Environmental Pollution Monitoring and Disease Control, Ministry of Education, School of Public Health, Guizhou Medical University, Guiyang, 550025, Guizhou, People's Republic of China
| | - Qian Song
- Key Laboratory of Environmental Pollution Monitoring and Disease Control, Ministry of Education, School of Public Health, Guizhou Medical University, Guiyang, 550025, Guizhou, People's Republic of China
| | - Heng Diao
- Key Laboratory of Environmental Pollution Monitoring and Disease Control, Ministry of Education, School of Public Health, Guizhou Medical University, Guiyang, 550025, Guizhou, People's Republic of China
| | - Ying Jin
- Key Laboratory of Environmental Pollution Monitoring and Disease Control, Ministry of Education, School of Public Health, Guizhou Medical University, Guiyang, 550025, Guizhou, People's Republic of China
| | - Aihua Zhang
- Key Laboratory of Environmental Pollution Monitoring and Disease Control, Ministry of Education, School of Public Health, Guizhou Medical University, Guiyang, 550025, Guizhou, People's Republic of China.
- Collaborative Innovation Center for Prevention and Control of Endemic and Ethnic Regional Diseases Co-Constructed By the Province and Ministry, Guizhou Medical University, Guiyang, 550025, Guizhou, People's Republic of China.
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Yılmaz HK, Türker M, Kutlu EY, Mercantepe T, Pınarbaş E, Tümkaya L, Atak M. Investigation of the effects of white tea on liver fibrosis: An experimental animal model. Food Sci Nutr 2024; 12:2998-3006. [PMID: 38628196 PMCID: PMC11016422 DOI: 10.1002/fsn3.3980] [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: 08/01/2023] [Revised: 01/05/2024] [Accepted: 01/10/2024] [Indexed: 04/19/2024] Open
Abstract
Liver fibrosis is a common, progressive disease that affects millions of patients worldwide. In this study, it was aimed at investigating the effect of white tea on liver fibrosis in an in-vivo environment by creating an experimental liver fibrosis model on rats. In this study, an experimental liver fibrosis model was created with carbon tetrachloride (CCl4) in Sprague-Dawley rats to investigate the effect of white tea on liver fibrosis. Rats are treated with CCl4 (1 mL/kg) to constitute the liver fibrosis model. White tea was given ad libitum with drinking water. As a result of the study, liver tissue hydroxyproline levels were found to be significantly lower (p = .001) in the white tea group. Histopathologically, it was found that the liver tissue histopathological damage score (LHDS) and fibrosis scoring were significantly lower (p < .001) in the white tea group. However, although it was not statistically significant in the group given white tea, compared with the fibrosis group, it was found that the malondialdehyde (MDA) level in the liver tissues was lower, the glutathione (GSH) level was higher, and the serum alanine aminotransferase (ALT) levels were lower. The study explained the effect of white tea on liver fibrosis and suggested that white tea might be beneficial in reducing the progression of liver fibrosis.
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Affiliation(s)
- Hülya Kılıç Yılmaz
- Department of Clinical Biochemistry, Faculty of MedicineRecep Tayyip Erdogan UniversityRizeTurkey
| | - Merve Türker
- Biochemistry LaboratoryGumushane State HospitalGumushaneTurkey
| | - Eda Yılmaz Kutlu
- Department of Clinical Biochemistry, Faculty of MedicineRecep Tayyip Erdogan UniversityRizeTurkey
| | - Tolga Mercantepe
- Department of Histology, Faculty of MedicineRecep Tayyip Erdogan UniversityRizeTurkey
| | - Esra Pınarbaş
- Department of Clinical Biochemistry, Faculty of MedicineRecep Tayyip Erdogan UniversityRizeTurkey
| | - Levent Tümkaya
- Department of Histology, Faculty of MedicineRecep Tayyip Erdogan UniversityRizeTurkey
| | - Mehtap Atak
- Department of Clinical Biochemistry, Faculty of MedicineRecep Tayyip Erdogan UniversityRizeTurkey
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3
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Hosseinzadeh A, Pourhanifeh MH, Amiri S, Sheibani M, Irilouzadian R, Reiter RJ, Mehrzadi S. Therapeutic potential of melatonin in targeting molecular pathways of organ fibrosis. Pharmacol Rep 2024; 76:25-50. [PMID: 37995089 DOI: 10.1007/s43440-023-00554-5] [Citation(s) in RCA: 6] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2023] [Revised: 10/29/2023] [Accepted: 10/31/2023] [Indexed: 11/24/2023]
Abstract
Fibrosis, the excessive deposition of fibrous connective tissue in an organ in response to injury, is a pathological condition affecting many individuals worldwide. Fibrosis causes the failure of tissue function and is largely irreversible as the disease progresses. Pharmacologic treatment options for organ fibrosis are limited, but studies suggest that antioxidants, particularly melatonin, can aid in preventing and controlling fibrotic damage to the organs. Melatonin, an indole nocturnally released from the pineal gland, is commonly used to regulate circadian and seasonal biological rhythms and is indicated for treating sleep disorders. While it is often effective in treating sleep disorders, melatonin's anti-inflammatory and antioxidant properties also make it a promising molecule for treating other disorders such as organ fibrosis. Melatonin ameliorates the necrotic and apoptotic changes that lead to fibrosis in various organs including the heart, liver, lung, and kidney. Moreover, melatonin reduces the infiltration of inflammatory cells during fibrosis development. This article outlines the protective effects of melatonin against fibrosis, including its safety and potential therapeutic effects. The goal of this article is to provide a summary of data accumulated to date and to encourage further experimentation with melatonin and increase its use as an anti-fibrotic agent in clinical settings.
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Affiliation(s)
- Azam Hosseinzadeh
- Razi Drug Research Center, Iran University of Medical Sciences, Tehran, Iran
| | - Mohammad Hossein Pourhanifeh
- Research Center for Biochemistry and Nutrition in Metabolic Diseases, Institute for Basic Sciences, Kashan University of Medical Sciences, Kashan, Iran
| | - Shiva Amiri
- Pharmaceutics Research Center, Institute of Neuropharmacology, Kerman University of Medical Sciences, Kerman, Iran
| | - Mohammad Sheibani
- Razi Drug Research Center, Iran University of Medical Sciences, Tehran, Iran
- Department of Pharmacology, School of Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Rana Irilouzadian
- Clinical Research Development Unit of Shohada-e Tajrish Hospital, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Russel J Reiter
- Department of Cell Systems and Anatomy, UT Health San Antonio, San Antonio, TX, USA
| | - Saeed Mehrzadi
- Razi Drug Research Center, Iran University of Medical Sciences, Tehran, Iran.
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Lapa Neto CJC, de Melo IMF, Alpiovezza PKBM, de Albuquerque YML, Francisco Soares A, Teixeira ÁAC, Wanderley-Teixeira V. Melatonin associated with a high-fat diet during pregnancy and lactation prevents liver changes in the offspring. Gen Comp Endocrinol 2023; 343:114357. [PMID: 37586542 DOI: 10.1016/j.ygcen.2023.114357] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/22/2023] [Accepted: 08/07/2023] [Indexed: 08/18/2023]
Abstract
In the present study, we set out to determine whether melatonin combined with a high-fat diet during pregnancy and lactation can prevent liver disorders in offspring. Forty rats were divided into four groups: DC - pregnant rats submitted to the standard diet; DC + Mel - pregnant rats submitted to the standard diet combined with melatonin; HFD - pregnant rats submitted to a high-fat diet; HFD + Mel - pregnant rats submitted to a high-fat diet combined with melatonin. Morphophysiological and biochemical parameters were analyzed. Melatonin (5 mg/kg) was administered intraperitoneally. The HFD group offspring showed an increase in AST, ALT, alkaline phosphatase, cholesterol, triglycerides, LDL and glucose levels, and a reduction in HDL and lipase levels. In the liver obseved steatosis, hepatocellular ballooning, increased lobular parenchyma and reduced non-lobular parenchyma, beside reduced liver glycogen and fibrosis. These changes were not observed in the HFD + Mel group. In conclusion, melatonin combined with a high-fat diet preserves the liver architecture and function in the offspring.
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Affiliation(s)
- Clovis J C Lapa Neto
- Department of Morphology and Animal Physiology, Federal Rural University of Pernambuco, Av. Dom Manoel de Medeiros s/n, Dois Irmãos, 52171-900 Recife, PE, Brazil
| | - Ismaela M F de Melo
- Department of Morphology and Animal Physiology, Federal Rural University of Pernambuco, Av. Dom Manoel de Medeiros s/n, Dois Irmãos, 52171-900 Recife, PE, Brazil
| | - Paloma K B M Alpiovezza
- Department of Morphology and Animal Physiology, Federal Rural University of Pernambuco, Av. Dom Manoel de Medeiros s/n, Dois Irmãos, 52171-900 Recife, PE, Brazil
| | - Yuri M L de Albuquerque
- Department of Morphology and Animal Physiology, Federal Rural University of Pernambuco, Av. Dom Manoel de Medeiros s/n, Dois Irmãos, 52171-900 Recife, PE, Brazil
| | - Anísio Francisco Soares
- Department of Morphology and Animal Physiology, Federal Rural University of Pernambuco, Av. Dom Manoel de Medeiros s/n, Dois Irmãos, 52171-900 Recife, PE, Brazil
| | - Álvaro A C Teixeira
- Department of Morphology and Animal Physiology, Federal Rural University of Pernambuco, Av. Dom Manoel de Medeiros s/n, Dois Irmãos, 52171-900 Recife, PE, Brazil
| | - Valéria Wanderley-Teixeira
- Department of Morphology and Animal Physiology, Federal Rural University of Pernambuco, Av. Dom Manoel de Medeiros s/n, Dois Irmãos, 52171-900 Recife, PE, Brazil.
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Zhang C, Shao Q, Liu M, Wang X, Loor JJ, Jiang Q, Cuan S, Li X, Wang J, Li Y, He L, Huang Y, Liu G, Lei L. Liver fibrosis is a common pathological change in the liver of dairy cows with fatty liver. J Dairy Sci 2023; 106:2700-2715. [PMID: 36823013 DOI: 10.3168/jds.2022-22021] [Citation(s) in RCA: 12] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2022] [Accepted: 10/24/2022] [Indexed: 02/23/2023]
Abstract
Fatty liver (i.e., hepatic lipidosis) is a prevalent metabolic disorder in dairy cows during the transition period, characterized by excess hepatic accumulation of triglyceride (TG), tissue dysfunction, and cell death. Detailed pathological changes, particularly hepatic fibrosis, during fatty liver remain to be determined. Liver fibrosis occurs as a consequence of liver damage, resulting from the excessive accumulation of extracellular matrix, which distorts the architecture of the normal liver, compromising its normal synthetic and metabolic functions. Thus, we aimed to investigate liver fibrosis status and its potential causal factors including oxidative stress, hepatocyte apoptosis, and production of inflammatory cytokines in the liver of cows with fatty liver. Forty-five dairy cows (parity, 3-5) were selected, and liver biopsy and blood were collected on the second week postpartum (days in milk, 10-14 d). On the basis of the degree of lipid accumulation in liver, selected cows were categorized into normal (n = 25; TG <1% wet wt), mild fatty liver (n = 15; 1% ≤ TG <5% wet wt), and moderate fatty liver (n = 5; 5% ≤ TG <10% wet wt). Compared with normal cows, blood concentrations of nonesterified fatty acids and β-hydroxybutyrate, along with alanine aminotransferase and aspartate aminotransferase activities, were greater in the cows with fatty liver (mild and moderate). Hepatic extracellular matrix deposition, as indicated by Picrosirius red staining, was greater in cows with fatty liver than those with normal ones. In addition, we observed an increased proportion of collagen type I fiber in extracellular matrix with increased lipid accumulation in the liver. Compared with normal cows, the area of α-smooth muscle actin (α-SMA)-positive staining along with the mRNA abundance of collagen type I α 1 (COL1A1), ACTA2 (gene encoding α-SMA), and transforming growth factor-β (TGFB) were greater in cows with fatty liver. Compared with normal cows, hepatic contents of malondialdehyde, glutathione disulfide, and 8-isoprostane were greater, whereas total antioxidant capacity, the hepatic content of glutathione, and activities of antioxidant indicators, including superoxide dismutase, glutathione peroxidase, and catalase, were lower in cows with fatty liver. The number of terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling-positive cells and abundance of apoptosis-related molecules BAX, CASP3, CASP8, and CASP9 were greater in cows with fatty liver. However, mRNA abundance of the anti-apoptotic gene BCL2 did not differ. The mRNA abundance of pro-inflammatory cytokines including tumor necrosis factor-α (TNFA), interleukin-1β (IL1B), and interleukin-6 (IL6) was greater in the liver of cows with fatty liver. Overall, the present study indicated that fibrosis is a common pathological response to liver damage and is associated with oxidative stress, hepatocyte death, and inflammation.
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Affiliation(s)
- Cai Zhang
- College of Animal Science and Technology, Henan University of Science and Technology, Luoyang 471003, China
| | - Qi Shao
- Key Laboratory of Zoonosis, Ministry of Education, College of Veterinary Medicine, Jilin University, 5333 Xi'an Road, Changchun, 130062, Jilin, China
| | - Mingchao Liu
- College of Veterinary Medicine, Hebei Agricultural University, Baoding, 071001, China
| | - Xueying Wang
- College of Animal Science and Technology, Henan University of Science and Technology, Luoyang 471003, China
| | - Juan J Loor
- Mammalian NutriPhysioGenomics, Department of Animal Sciences and Division of Nutritional Sciences, University of Illinois, Urbana 61801
| | - Qianming Jiang
- Mammalian NutriPhysioGenomics, Department of Animal Sciences and Division of Nutritional Sciences, University of Illinois, Urbana 61801
| | - Shunan Cuan
- College of Biological and Pharmaceutical Engineering, West Anhui University, Lu'an 237012, China
| | - Xinwei Li
- Key Laboratory of Zoonosis, Ministry of Education, College of Veterinary Medicine, Jilin University, 5333 Xi'an Road, Changchun, 130062, Jilin, China
| | - Jianguo Wang
- College of Veterinary Medicine, Northwest A&F University, Yangling 712100, Shanxi, China
| | - Yuanxiao Li
- College of Animal Science and Technology, Henan University of Science and Technology, Luoyang 471003, China
| | - Lei He
- College of Animal Science and Technology, Henan University of Science and Technology, Luoyang 471003, China
| | - Yong Huang
- College of Animal Science and Technology, Henan University of Science and Technology, Luoyang 471003, China
| | - Guowen Liu
- Key Laboratory of Zoonosis, Ministry of Education, College of Veterinary Medicine, Jilin University, 5333 Xi'an Road, Changchun, 130062, Jilin, China.
| | - Lin Lei
- Key Laboratory of Zoonosis, Ministry of Education, College of Veterinary Medicine, Jilin University, 5333 Xi'an Road, Changchun, 130062, Jilin, China.
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Hepatic Myofibroblasts: A Heterogeneous and Redox-Modulated Cell Population in Liver Fibrogenesis. Antioxidants (Basel) 2022; 11:antiox11071278. [PMID: 35883770 PMCID: PMC9311931 DOI: 10.3390/antiox11071278] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2022] [Revised: 06/22/2022] [Accepted: 06/24/2022] [Indexed: 12/19/2022] Open
Abstract
During chronic liver disease (CLD) progression, hepatic myofibroblasts (MFs) represent a unique cellular phenotype that plays a critical role in driving liver fibrogenesis and then fibrosis. Although they could originate from different cell types, MFs exhibit a rather common pattern of pro-fibrogenic phenotypic responses, which are mostly elicited or sustained both by oxidative stress and reactive oxygen species (ROS) and several mediators (including growth factors, cytokines, chemokines, and others) that often operate through the up-regulation of the intracellular generation of ROS. In the present review, we will offer an overview of the role of MFs in the fibrogenic progression of CLD from different etiologies by focusing our attention on the direct or indirect role of ROS and, more generally, oxidative stress in regulating MF-related phenotypic responses. Moreover, this review has the purpose of illustrating the real complexity of the ROS modulation during CLD progression. The reader will have to keep in mind that a number of issues are able to affect the behavior of the cells involved: a) the different concentrations of reactive species, b) the intrinsic state of the target cells, as well as c) the presence of different growth factors, cytokines, and other mediators in the extracellular microenvironment or of other cellular sources of ROS.
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Forsythiaside A Regulates Activation of Hepatic Stellate Cells by Inhibiting NOX4-Dependent ROS. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2022; 2022:9938392. [PMID: 35035671 PMCID: PMC8754607 DOI: 10.1155/2022/9938392] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/15/2021] [Revised: 07/27/2021] [Accepted: 12/03/2021] [Indexed: 11/30/2022]
Abstract
Hepatic stellate cells (HSCs) activation is an important step in the process of hepatic fibrosis. NOX4 and reactive oxygen species expressed in HSCs play an important role in liver fibrosis. Forsythiaside A (FA), a phenylethanoid glycoside extracted and isolated from Forsythiae Fructus, has significant antioxidant activities. However, it is not clear whether FA can play a role in inhibiting the HSCs activation through regulating NOX4/ROS pathway. Therefore, our purpose is to explore the effect and mechanism of FA on HSCs activation to alleviate liver fibrosis. LX2 cells were activated by TGF-β1 in vitro. MTT assay and Wound Healing assay were used to investigate the effect of FA on TGF-β1-induced LX2 cell proliferation and migration. Elisa kit was used to measure the expression of MMP-1 and TIMP-1. Western blot and RT-qPCR were used to investigate the expression of fibrosis-related COLI, α-SMA, MMP-1 and TIMP-1, and inflammation-related TNF-α, IL-6 and IL-1β. The hydroxyproline content was characterized using a biochemical kit. The mechanism of FA to inhibit HSCs activation and apoptosis was detected by DCF-DA probe, RT-qPCR, western blot and flow cytometry. NOX4 siRNA was used to futher verify the effect of FA on NOX4/ROS pathway. The results showed that FA inhibited the proliferation and migration of LX2 cells and adjusted the expression of MMP-1, TIMP-1, COLI, α-SMA, TNF-α, IL-6 and IL-1β as well as promoted collagen metabolism to show potential in anti-hepatic fibrosis. Mechanically, FA down-regulated NOX4/ROS signaling pathway to improve oxidation imbalances, and subsequently inhibited PI3K/Akt pathway to suppress proliferation. FA also promoted the apoptosis of LX2 cells by Bax/Bcl2 pathway. Furthermore, the effects of FA on TGF-β1-induced increased ROS levels and α-SMA and COLI expression were weaken by silencing NOX4. In conclusion, FA had potential in anti-hepatic fibrosis at least in part by remolding of extracellular matrix and improving oxidation imbalances to inhibit the activation of HSCs and promote HSCs apoptosis.
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Zhou J, Zheng Q, Chen Z. The Nrf2 Pathway in Liver Diseases. Front Cell Dev Biol 2022; 10:826204. [PMID: 35223849 PMCID: PMC8866876 DOI: 10.3389/fcell.2022.826204] [Citation(s) in RCA: 70] [Impact Index Per Article: 23.3] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2021] [Accepted: 01/17/2022] [Indexed: 12/11/2022] Open
Abstract
Oxidative stress is the leading cause of most liver diseases, such as drug-induced liver injury, viral hepatitis, and alcoholic hepatitis caused by drugs, viruses, and ethanol. The Kelch-like ECH-associated protein 1-NFE2-related factor 2 (Keap1-Nrf2) system is a critical defense mechanism of cells and organisms in response to oxidative stress. Accelerating studies have clarified that the Keap1-Nrf2 axis are involved in the prevention and attenuation of liver injury. Nrf2 up-regulation could alleviate drug-induced liver injury in mice. Moreover, many natural Nrf2 activators can regulate lipid metabolism and oxidative stress of liver cells to alleviate fatty liver disease in mice. In virus hepatitis, the increased Nrf2 can inhibit hepatitis C viral replication by up-regulating hemeoxygenase-1. In autoimmune liver diseases, the increased Nrf2 is essential for mice to resist liver injury. In liver cirrhosis, the enhanced Nrf2 reduces the activation of hepatic stellate cells by reducing reactive oxygen species levels to prevent liver fibrosis. Nrf2 plays a dual function in liver cancer progression. At present, a Nrf2 agonist has received clinical approval. Therefore, activating the Nrf2 pathway to induce the expression of cytoprotective genes is a potential option for treating liver diseases. In this review, we comprehensively summarized the relationships between oxidative stress and liver injury, and the critical role of the Nrf2 pathway in multiple liver diseases.
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Wang X, Liu D, Wang Z, Cai C, Jiang H, Yu G. Porphyran-derived oligosaccharides alleviate NAFLD and related cecal microbiota dysbiosis in mice. FASEB J 2021; 35:e21458. [PMID: 33948987 DOI: 10.1096/fj.202000763rrr] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2020] [Revised: 02/02/2021] [Accepted: 02/03/2021] [Indexed: 12/18/2022]
Abstract
Porphyran and its derivatives possess a variety of biological activities, such as ameliorations of oxidative stress, inflammation, hyperlipemia, and immune deficiencies. In this study, we evaluated the potential efficacy of porphyran-derived oligosaccharides from Porphyra yezoensis (PYOs) in alleviating nonalcoholic fatty liver disease (NAFLD) and preliminarily clarified the underlying mechanism. NAFLD was induced by a high-fat diet for six months in C57BL/6J mice, followed by treatment with PYOs (100 or 300 mg/kg/d) for another six weeks. We found that PYOs reduced hepatic oxidative stress in mice with NAFLD, which plays a critical role in the occurrence and development of NAFLD. In addition, PYOs could markedly decrease lipid accumulation in liver by activating the IRS-1/AKT/GSK-3β signaling pathway and the AMPK signaling pathway in mice with NAFLD. PYOs also apparently relieved the hepatic fibrosis induced by oxidative stress via downregulation of TGF-β and its related proteins, so that liver injury was markedly alleviated. Furthermore, PYOs treatment relieved cecal microbiota dysbiosis (such as increasing the relative abundance of Akkermansia, while decreasing the Helicobacter abundance), which could alleviate oxidative stress, inflammation, and lipid metabolism, and protect the liver to a certain degree. In summary, PYOs treatment remarkably improved NAFLD via a specific molecular mechanism and reshaped the cecal microbiota.
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Affiliation(s)
- Xueliang Wang
- Key Laboratory of Marine Drugs of Ministry of Education, Shandong Provincial Key Laboratory of Glycoscience and Glycotechnology, School of Medicine and Pharmacy, Ocean University of China, Qingdao, China.,Laboratory for Marine Drugs and Bioproducts, Pilot National Laboratory for Marine Science and Technology (Qingdao), Qingdao, China
| | - Di Liu
- Key Laboratory of Marine Drugs of Ministry of Education, Shandong Provincial Key Laboratory of Glycoscience and Glycotechnology, School of Medicine and Pharmacy, Ocean University of China, Qingdao, China.,Laboratory for Marine Drugs and Bioproducts, Pilot National Laboratory for Marine Science and Technology (Qingdao), Qingdao, China
| | - Zhe Wang
- Key Laboratory of Marine Drugs of Ministry of Education, Shandong Provincial Key Laboratory of Glycoscience and Glycotechnology, School of Medicine and Pharmacy, Ocean University of China, Qingdao, China.,Laboratory for Marine Drugs and Bioproducts, Pilot National Laboratory for Marine Science and Technology (Qingdao), Qingdao, China
| | - Chao Cai
- Key Laboratory of Marine Drugs of Ministry of Education, Shandong Provincial Key Laboratory of Glycoscience and Glycotechnology, School of Medicine and Pharmacy, Ocean University of China, Qingdao, China.,Laboratory for Marine Drugs and Bioproducts, Pilot National Laboratory for Marine Science and Technology (Qingdao), Qingdao, China
| | - Hao Jiang
- Key Laboratory of Marine Drugs of Ministry of Education, Shandong Provincial Key Laboratory of Glycoscience and Glycotechnology, School of Medicine and Pharmacy, Ocean University of China, Qingdao, China.,Laboratory for Marine Drugs and Bioproducts, Pilot National Laboratory for Marine Science and Technology (Qingdao), Qingdao, China
| | - Guangli Yu
- Key Laboratory of Marine Drugs of Ministry of Education, Shandong Provincial Key Laboratory of Glycoscience and Glycotechnology, School of Medicine and Pharmacy, Ocean University of China, Qingdao, China.,Laboratory for Marine Drugs and Bioproducts, Pilot National Laboratory for Marine Science and Technology (Qingdao), Qingdao, China
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Li T, Tuo B. Pathophysiology of hepatic Na +/H + exchange (Review). Exp Ther Med 2020; 20:1220-1229. [PMID: 32742358 PMCID: PMC7388279 DOI: 10.3892/etm.2020.8888] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2019] [Accepted: 05/15/2020] [Indexed: 02/06/2023] Open
Abstract
Na+/H+ exchangers (NHEs) are a family of membrane proteins that contribute to exchanging one intracellular proton for one extracellular sodium. The family of NHEs consists of nine known members, NHE1-9. Each isoform represents a different gene product that has unique tissue expression, membrane localization, physiological effects, pathological regulation and sensitivity to drug inhibitors. NHE1 was the first to be discovered and is often referred to as the 'housekeeping' isoform of the NHE family. NHEs are not only involved in a variety of physiological processes, including the control of transepithelial Na+ absorption, intracellular pH, cell volume, cell proliferation, migration and apoptosis, but also modulate complex pathological events. Currently, the vast majority of review articles have focused on the role of members of the NHE family in inflammatory bowel disease, intestinal infectious diarrhea and digestive system tumorigenesis, but only a few reviews have discussed the role of NHEs in liver disease. Therefore, the present review described the basic biology of NHEs and highlighted their physiological and pathological effects in the liver.
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Affiliation(s)
- Tingting Li
- Department of Gastroenterology, Affiliated Hospital, Zunyi Medical University, Zunyi, Guizhou 563000, P.R. China
| | - Biguang Tuo
- Department of Gastroenterology, Affiliated Hospital, Zunyi Medical University, Zunyi, Guizhou 563000, P.R. China
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11
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Fahmy SR, Sayed DA, Soliman AM, Almortada NY, Aal WEAE. Protective effect of Echinochrome against intrahepatic cholestasis induced by alpha-naphthylisothiocyanate in rats. BRAZ J BIOL 2020; 80:102-111. [DOI: 10.1590/1519-6984.192697] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2018] [Accepted: 11/10/2018] [Indexed: 12/20/2022] Open
Abstract
Abstract The present study was designed to evaluate the protective effects of echinochrome (Ech) on intrahepatic cholestasis in rats induced by a single (i.p.) injection of alpha-naphthylisothiocyanate (ANIT) (75 mg/kg body weight). The rats were pre-treated orally for 48hr (one dose / 24hr) with Ech (1, 5 and 10 mg/kg body weight) or ursodeoxycholic acid (UDCA) 80 mg/kg body weight drug then, injected with ANIT. ANIT markedly increased serum activities of alanine amino transaminase (ALT), aspartate amino transaminase (AST) and alkaline phosphatase (ALP), which was accompanied by a massive inflammation of epithelial cells on bile duct at 24h after ANIT injection. ANIT also increased the levels of total protein (TP), total bilirubin (TB), direct bilirubin (DB), indirect bilirubin (IB), however decrease albumin content (ALB). In addition ANIT increased hepatic MDA and NO level and decreased GSH level and GST activity. The Ech exerted hepatoprotective and anticholestatic effects as assessed by a significant decrease in the activities of serum AST, ALT and ALP, and the levels of TP, TB, DB and IB as well as liver MDA level and NO level. In conclusion, Ech was found to possess hepatoprotective effect against intrahepatic cholestasis induced by hepatotoxin such as ANIT.
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12
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Yang JH, Kim KM, Cho SS, Shin SM, Ka SO, Na CS, Park BH, Jegal KH, Kim JK, Ku SK, Lee HJ, Park SG, Cho IJ, Ki SH. Inhibitory Effect of Sestrin 2 on Hepatic Stellate Cell Activation and Liver Fibrosis. Antioxid Redox Signal 2019; 31:243-259. [PMID: 30909713 DOI: 10.1089/ars.2018.7559] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/05/2023]
Abstract
Aims: Hepatic fibrosis results from chronic liver injury and inflammatory responses. Sestrin 2 (Sesn2), an evolutionarily conserved antioxidant enzyme, reduces the severities of acute hepatitis and metabolic liver diseases. However, the role of Sesn2 in the pathogenesis of liver fibrosis remains obscure. Here, we used cultured hepatic stellate cells (HSCs) and chronic carbon tetrachloride (CCl4) and bile duct ligation (BDL) murine models to investigate the effects of Sesn2 on fibrogenesis. Results: Sesn2 protein and mRNA levels were upregulated in activated primary HSCs, and by increasing transcription, transforming growth factor-β (TGF-β) also increased Sesn2 expression in HSCs. Furthermore, Smad activation was primarily initiated by TGF-β signaling, and Smad3 activation increased Sesn2 luciferase activity. In silico analysis of the 5' upstream region of the Sesn2 gene revealed a putative Smad-binding element (SBE), and its deletion demonstrated that the SBE between -964 and -956 bp within human Sesn2 promoter was critically required for TGF-β-mediated response. Moreover, ectopic expression of Sesn2 reduced gene expressions associated with HSC activation, and this was accompanied by marked decreases in SBE luciferase activity and Smad phosphorylation. Infection of recombinant adenovirus Sesn2 reduced hepatic injury severity, as evidenced by reductions in CCl4- or BDL-induced alanine aminotransferase and aspartate aminotransferase, and inhibited collagen accumulation. Furthermore, HSC-specific lentiviral delivery of Sesn2 prevented CCl4-induced liver fibrosis. Finally, Sesn2 expression was downregulated in the livers of patients with liver cirrhosis and in mouse models of hepatic fibrosis. Innovation and Conclusion: Our findings suggest that Sesn2 has the potential to inhibit HSC activation and hepatic fibrosis.
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Affiliation(s)
- Ji Hye Yang
- 1 College of Pharmacy, Chosun University, Gwangju, Republic of Korea.,2 College of Korean Medicine, Dongshin University, Naju, Republic of Korea
| | - Kyu Min Kim
- 1 College of Pharmacy, Chosun University, Gwangju, Republic of Korea
| | - Sam Seok Cho
- 1 College of Pharmacy, Chosun University, Gwangju, Republic of Korea
| | - Sang Mi Shin
- 1 College of Pharmacy, Chosun University, Gwangju, Republic of Korea
| | - Sun O Ka
- 3 Department of Biochemistry, Chonbuk National University Medical School, Jeonju, Republic of Korea
| | - Chang-Su Na
- 2 College of Korean Medicine, Dongshin University, Naju, Republic of Korea
| | - Byung Hyun Park
- 3 Department of Biochemistry, Chonbuk National University Medical School, Jeonju, Republic of Korea
| | - Kyung Hwan Jegal
- 4 Research Center for Herbal Convergence on Liver Disease, College of Korean Medicine, Daegu Haany University, Gyeongsan, Republic of Korea.,5 College of Pharmacy, Seoul National University, Seoul, Republic of Korea
| | - Jae Kwang Kim
- 4 Research Center for Herbal Convergence on Liver Disease, College of Korean Medicine, Daegu Haany University, Gyeongsan, Republic of Korea
| | - Sae Kwang Ku
- 4 Research Center for Herbal Convergence on Liver Disease, College of Korean Medicine, Daegu Haany University, Gyeongsan, Republic of Korea
| | - Hee-Jeong Lee
- 6 Department of Internal Medicine, Hemato-oncology, Chosun University School of Medicine, Gwangju, Republic of Korea
| | - Sang-Gon Park
- 6 Department of Internal Medicine, Hemato-oncology, Chosun University School of Medicine, Gwangju, Republic of Korea
| | - Il Je Cho
- 4 Research Center for Herbal Convergence on Liver Disease, College of Korean Medicine, Daegu Haany University, Gyeongsan, Republic of Korea
| | - Sung Hwan Ki
- 1 College of Pharmacy, Chosun University, Gwangju, Republic of Korea
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Xu H, Hong S, Yan Z, Zhao Q, Shi Y, Song N, Xie J, Jiang X. RAP-8 ameliorates liver fibrosis by modulating cell cycle and oxidative stress. Life Sci 2019; 229:200-209. [DOI: 10.1016/j.lfs.2019.04.037] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2019] [Revised: 04/11/2019] [Accepted: 04/15/2019] [Indexed: 12/17/2022]
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14
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Luangmonkong T, Suriguga S, Mutsaers HAM, Groothuis GMM, Olinga P, Boersema M. Targeting Oxidative Stress for the Treatment of Liver Fibrosis. Rev Physiol Biochem Pharmacol 2019; 175:71-102. [PMID: 29728869 DOI: 10.1007/112_2018_10] [Citation(s) in RCA: 171] [Impact Index Per Article: 28.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Oxidative stress is a reflection of the imbalance between the production of reactive oxygen species (ROS) and the scavenging capacity of the antioxidant system. Excessive ROS, generated from various endogenous oxidative biochemical enzymes, interferes with the normal function of liver-specific cells and presumably plays a role in the pathogenesis of liver fibrosis. Once exposed to harmful stimuli, Kupffer cells (KC) are the main effectors responsible for the generation of ROS, which consequently affect hepatic stellate cells (HSC) and hepatocytes. ROS-activated HSC undergo a phenotypic switch and deposit an excessive amount of extracellular matrix that alters the normal liver architecture and negatively affects liver function. Additionally, ROS stimulate necrosis and apoptosis of hepatocytes, which causes liver injury and leads to the progression of end-stage liver disease. In this review, we overview the role of ROS in liver fibrosis and discuss the promising therapeutic interventions related to oxidative stress. Most importantly, novel drugs that directly target the molecular pathways responsible for ROS generation, namely, mitochondrial dysfunction inhibitors, endoplasmic reticulum stress inhibitors, NADPH oxidase (NOX) inhibitors, and Toll-like receptor (TLR)-affecting agents, are reviewed in detail. In addition, challenges for targeting oxidative stress in the management of liver fibrosis are discussed.
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Affiliation(s)
- Theerut Luangmonkong
- Department of Pharmaceutical Technology and Biopharmacy, University of Groningen, Groningen, The Netherlands.,Department of Pharmacology, Faculty of Pharmacy, Mahidol University, Bangkok, Thailand
| | - Su Suriguga
- Department of Pharmaceutical Technology and Biopharmacy, University of Groningen, Groningen, The Netherlands
| | - Henricus A M Mutsaers
- Department of Pharmaceutical Technology and Biopharmacy, University of Groningen, Groningen, The Netherlands.,Department of Clinical Medicine, Aarhus University, Aarhus, Denmark
| | - Geny M M Groothuis
- Department of Pharmacokinetics, Toxicology and Targeting, University of Groningen, Groningen, The Netherlands
| | - Peter Olinga
- Department of Pharmaceutical Technology and Biopharmacy, University of Groningen, Groningen, The Netherlands.
| | - Miriam Boersema
- Department of Pharmaceutical Technology and Biopharmacy, University of Groningen, Groningen, The Netherlands
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Elufioye TO, Habtemariam S. Hepatoprotective effects of rosmarinic acid: Insight into its mechanisms of action. Biomed Pharmacother 2019; 112:108600. [PMID: 30780110 DOI: 10.1016/j.biopha.2019.108600] [Citation(s) in RCA: 69] [Impact Index Per Article: 11.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2018] [Revised: 01/11/2019] [Accepted: 01/18/2019] [Indexed: 02/06/2023] Open
Abstract
Liver diseases such as hepatitis, fibrosis, cirrhosis, and hepatocellular carcinoma are one of the major health challenges in the world and many conditions such as inadequate nutrition, viral infection, ethanol and drug abuse, xenobiotic exposure, and metabolic diseases have been implicated in the development and progression of liver diseases. Several factors including lipid peroxidation, production of reactive oxygen species (ROS), peroxynitrite formation, complement factors and proinflammatory mediators, such as cytokines and chemokines, are involved in hepatic diseases. Rosmarinic acid (RA) is a natural phenolic compound found mainly in the family Lamiaceae consisting of several medicinal plants, herbs and spices. Several biological activities have been reported for RA and these include antioxidant properties as a ROS scavenger and lipid peroxidation inhibitor, anti-inflammatory, neuroprotective and antiangiogenic among others. This review is aimed at discussing the effects of RA on the liver, highlighting its hepatoprotective potential and the underlying mechanisms.
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Affiliation(s)
- Taiwo O Elufioye
- Department of Pharmacognosy, Faculty of Pharmacy, University of Ibadan, Nigeria.
| | - Solomon Habtemariam
- Pharmacognosy Research Laboratories & Herbal Analysis Services, University of Greenwich, Chatham, Maritime Kent, ME4 4TB, UK
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16
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Bessone F, Razori MV, Roma MG. Molecular pathways of nonalcoholic fatty liver disease development and progression. Cell Mol Life Sci 2019; 76:99-128. [PMID: 30343320 PMCID: PMC11105781 DOI: 10.1007/s00018-018-2947-0] [Citation(s) in RCA: 405] [Impact Index Per Article: 67.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2018] [Revised: 10/10/2018] [Accepted: 10/15/2018] [Indexed: 02/06/2023]
Abstract
Nonalcoholic fatty liver disease (NAFLD) is a main hepatic manifestation of metabolic syndrome. It represents a wide spectrum of histopathological abnormalities ranging from simple steatosis to nonalcoholic steatohepatitis (NASH) with or without fibrosis and, eventually, cirrhosis and hepatocellular carcinoma. While hepatic simple steatosis seems to be a rather benign manifestation of hepatic triglyceride accumulation, the buildup of highly toxic free fatty acids associated with insulin resistance-induced massive free fatty acid mobilization from adipose tissue and the increased de novo hepatic fatty acid synthesis from glucose acts as the "first hit" for NAFLD development. NAFLD progression seems to involve the occurrence of "parallel, multiple-hit" injuries, such as oxidative stress-induced mitochondrial dysfunction, endoplasmic reticulum stress, endotoxin-induced, TLR4-dependent release of inflammatory cytokines, and iron overload, among many others. These deleterious factors are responsible for the triggering of a number of signaling cascades leading to inflammation, cell death, and fibrosis, the hallmarks of NASH. This review is aimed at integrating the overwhelming progress made in the characterization of the physiopathological mechanisms of NAFLD at a molecular level, to better understand the factor influencing the initiation and progression of the disease.
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Affiliation(s)
- Fernando Bessone
- Hospital Provincial del Centenario, Facultad de Ciencias Médicas, Servicio de Gastroenterología y Hepatología, Universidad Nacional de Rosario, Rosario, Argentina
| | - María Valeria Razori
- Instituto de Fisiología Experimental (IFISE-CONICET), Facultad de Ciencias Bioquímicas y Farmacéuticas, Universidad Nacional de Rosario, Suipacha 570, 2000, Rosario, Argentina
| | - Marcelo G Roma
- Instituto de Fisiología Experimental (IFISE-CONICET), Facultad de Ciencias Bioquímicas y Farmacéuticas, Universidad Nacional de Rosario, Suipacha 570, 2000, Rosario, Argentina.
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17
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Marzhokhova MY, Hussein AAM, Marzhokhova AR. Indices of peroxidation of lipids of biological membranes and endogenous intoxication in patients with psoriasis on the background of chronic viral hepatitis С. VESTNIK DERMATOLOGII I VENEROLOGII 2018. [DOI: 10.25208/0042-4609-2018-94-6-22-30] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/02/2022] Open
Abstract
Aim. To study the features of lipid peroxidation of biological membranes and accumulation of toxic metabolites in the body of patients with psoriasis, depending on the presence of concomitant chronic viral hepatitis C.Materials and methods. In the survey, participated 56 patients with a vulgar form of psoriasis who received in-patient treatment at the Nalchik skin clinic in 2016–2017, divided into 2 groups, depending on the presence of concomitant chronic viral hepatitis C. In patients, the content of malonic dialdehyde in blood was determined as an indicator of the state of the prooxidant system, ceruloplasmin and erythrocyte catalase, as indicators of antioxidant protection, and also for the evaluation of the Intoxication Syndrome; the level of substances of low and medium molecular mass and oligopeptides in the biological environments of the organism in different periods of the disease.Results. It was found that the presence of concomitant chronic viral hepatitis C in patients with psoriasis was characterized by a more pronounced increase in the concentration of lipid peroxidation products than in the group of patients with hepatitis without psoriasis, accompanied by a decrease in the activity of antioxidant enzymes in the blood plasma and an increase in the activity of catalase in erythrocytes. Simultaneously, the presence of chronic hepatitis C led to a significantly higher content in the body fluids of patients with low and medium molecular weight substances and oligopeptides.
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18
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Bessone F, Dirchwolf M, Rodil MA, Razori MV, Roma MG. Review article: drug-induced liver injury in the context of nonalcoholic fatty liver disease - a physiopathological and clinical integrated view. Aliment Pharmacol Ther 2018; 48:892-913. [PMID: 30194708 DOI: 10.1111/apt.14952] [Citation(s) in RCA: 59] [Impact Index Per Article: 8.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/02/2018] [Revised: 03/25/2018] [Accepted: 07/30/2018] [Indexed: 12/15/2022]
Abstract
BACKGROUND Nonalcoholic fatty disease (NAFLD) is the most common liver disease, since it is strongly associated with obesity and metabolic syndrome pandemics. NAFLD may affect drug disposal and has common pathophysiological mechanisms with drug-induced liver injury (DILI); this may predispose to hepatoxicity induced by certain drugs that share these pathophysiological mechanisms. In addition, drugs may trigger fatty liver and inflammation per se by mimicking NAFLD pathophysiological mechanisms. AIMS To provide a comprehensive update on (a) potential mechanisms whereby certain drugs can be more hepatotoxic in NAFLD patients, (b) the steatogenic effects of drugs, and (c) the mechanism involved in drug-induced steatohepatitis (DISH). METHODS A language- and date-unrestricted Medline literature search was conducted to identify pertinent basic and clinical studies on the topic. RESULTS Drugs can induce macrovesicular steatosis by mimicking NAFLD pathogenic factors, including insulin resistance and imbalance between fat gain and loss. Other forms of hepatic fat accumulation exist, such as microvesicular steatosis and phospholipidosis, and are mostly associated with acute mitochondrial dysfunction and defective lipophagy, respectively. Drug-induced mitochondrial dysfunction is also commonly involved in DISH. Patients with pre-existing NAFLD may be at higher risk of DILI induced by certain drugs, and polypharmacy in obese individuals to treat their comorbidities may be a contributing factor. CONCLUSIONS The relationship between DILI and NAFLD may be reciprocal: drugs can cause NAFLD by acting as steatogenic factors, and pre-existing NAFLD could be a predisposing condition for certain drugs to cause DILI. Polypharmacy associated with obesity might potentiate the association between this condition and DILI.
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Affiliation(s)
- Fernando Bessone
- Hospital Provincial del Centenario, Facultad de Ciencias Médicas, Servicio de Gastroenterología y Hepatología, Universidad Nacional de Rosario, Rosario, Argentina
| | - Melisa Dirchwolf
- Unidad de Transplante Hepático, Servicio de Hepatología, Hospital Privado de Rosario, Rosario, Argentina
| | - María Agustina Rodil
- Hospital Provincial del Centenario, Facultad de Ciencias Médicas, Servicio de Gastroenterología y Hepatología, Universidad Nacional de Rosario, Rosario, Argentina
| | - María Valeria Razori
- Instituto de Fisiología Experimental (IFISE-CONICET), Facultad de Ciencias Bioquímicas y Farmacéuticas, Universidad Nacional de Rosario, Rosario, Argentina
| | - Marcelo G Roma
- Instituto de Fisiología Experimental (IFISE-CONICET), Facultad de Ciencias Bioquímicas y Farmacéuticas, Universidad Nacional de Rosario, Rosario, Argentina
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Wang ZF, Wang MY, Yu DH, Zhao Y, Xu HM, Zhong S, Sun WY, He YF, Niu JQ, Gao PJ, Li HJ. Therapeutic effect of chitosan on CCl4‑induced hepatic fibrosis in rats. Mol Med Rep 2018; 18:3211-3218. [PMID: 30085342 PMCID: PMC6102732 DOI: 10.3892/mmr.2018.9343] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2017] [Accepted: 06/19/2018] [Indexed: 12/15/2022] Open
Abstract
Chitosan is a linear polysaccharide that is made by treating the chitin shells of shrimp and crustaceans with an alkaline substance, for example sodium hydroxide. Due to its unique physical and chemical properties, chitosan has a wide range of applications in the medical field. Currently, there are no effective treatments for liver fibrosis; therefore, the aim of the present study was to investigate the therapeutic effect of chitosan in a CCl4‑induced hepatic fibrosis (HF) rat model. The serum levels of aspartate transaminase (AST), alanine transaminase (ALT) and alkaline phosphatase (ALP) were measured by ELISA. Collagen (COL) 3 and α‑smooth muscle actin (SMA) expression levels in the rat liver were detected by reverse transcription‑semiquantitative polymerase chain reaction and western blotting, respectively. The results demonstrated that treatment with chitosan significantly improved HF, by decreasing the serum levels of AST, ALT, and ALP; improving liver histology; and decreasing the expression levels of COL3 and α‑SMA. Chitosan may offer an alternative approach for the clinical treatment of HF.
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Affiliation(s)
- Zhong-Feng Wang
- Department of Geriatrics, The First Hospital, Jilin University, Changchun, Jilin 130021, P.R. China
| | - Mao-Yu Wang
- Department of CCU, The First People's Hospital of Aksu Prefecture in Xinjiang, Aksu, Xinjiang 843000, P.R. China
| | - De-Hai Yu
- Cancer Center, The First Hospital of Jilin University, Changchun, Jilin 130061, P.R. China
| | - Yan Zhao
- College of Chinese Medicinal Materials, Jilin Agriculture University, Changchun, Jilin 130061, P.R. China
| | - Hong-Mei Xu
- Department of Obstetrics, The First Hospital, Jilin University, Changchun, Jilin 130061, P.R. China
| | - Sheng Zhong
- Department of Geriatrics, The First Hospital, Jilin University, Changchun, Jilin 130021, P.R. China
| | - Wen-Yi Sun
- Department of Clinical Pharmacy and Pharmaceutical Management, School of Pharmaceutical Sciences, Jilin University, Changchun, Jilin 130021, P.R. China
| | - Yu-Fang He
- Institute of Phytochemistry, Jilin Academy of Chinese Medicine Sciences, Changchun, Jilin 130012, P.R. China
| | - Jun-Qi Niu
- Department of Geriatrics, The First Hospital, Jilin University, Changchun, Jilin 130021, P.R. China
| | - Pu-Jun Gao
- Department of Geriatrics, The First Hospital, Jilin University, Changchun, Jilin 130021, P.R. China
| | - Hai-Jun Li
- Institute of Translational Medicine, The First Hospital, Jilin University, Changchun, Jilin 130021, P.R. China
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Curcumin attenuates hepatic fibrosis and insulin resistance induced by bile duct ligation in rats. Br J Nutr 2018; 120:393-403. [PMID: 29880071 DOI: 10.1017/s0007114518001095] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Recent studies have strongly indicated the hepatoprotective effect of curcumin; however, the precise mechanisms are not well understood. This study aimed to determine the protective effect of curcumin on hepatic damage and hepatic insulin resistance in biliary duct ligated (BDL) fibrotic rat model. To accomplish this, male Wistar rats were divided into four groups (eight for each): sham group, BDL group, sham+Cur group and BDL+Cur group. The last two groups received curcumin at a dose of 100 mg/kg daily for 4 weeks. The mRNA/protein expression levels of Ras-related C3 botulinum toxin substrate 1 (Rac1), Rac1-GTP, dinucleotide phosphate oxidase 1 (NOX1), signal transducer and activator of transcription 3 (STAT3), suppressor of cytokine signalling 3 (SOCS3), insulin receptor substrate 1 (IRS1), extracellular signal-regulated kinase 1 (ERK1), specific protein 1 (Sp1) and hypoxia-inducible factor-1α (HIF-1α) were measured by real-time PCR and Western blotting, respectively. Fasting blood glucose, insulin and Leptin levels were determined and homoeostasis model assessment-estimated insulin resistance, as an index of insulin resistance, was calculated. Curcumin significantly attenuated liver injury and fibrosis, including amelioration of liver histological changes, reduction of hepatic enzymes, as well as decreased expression of liver fibrogenesis-associated variables, including Rac1, Rac1-GTP, NOX1, ERK1, HIF-1α and Sp1. Curcumin also attenuated leptin level and insulin resistance, which had increased in BDL rats (P<0·05). Furthermore, compared with the BDL group, we observed an increase in IRS1 and a decrease in SOCS3 and STAT3 expression in the curcumin-treated BDL group (P<0·05), indicating return of these parameters towards normalcy. In conclusion, Curcumin showed hepatoprotective activity against BDL-induced liver injury and hepatic insulin resistance by influencing the expression of some genes/proteins involved in these processes, and the results suggest that it can be used as a therapeutic option.
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Ma D, Zhang J, Zhang Y, Zhang X, Han X, Song T, Zhang Y, Chu L. Inhibition of myocardial hypertrophy by magnesium isoglycyrrhizinate through the TLR4/NF-κB signaling pathway in mice. Int Immunopharmacol 2017; 55:237-244. [PMID: 29274625 DOI: 10.1016/j.intimp.2017.12.019] [Citation(s) in RCA: 46] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/10/2017] [Revised: 12/12/2017] [Accepted: 12/14/2017] [Indexed: 11/25/2022]
Abstract
Magnesium isoglycyrrhizinate (MgIG) is a magnesium salt of the 18-α glycyrrhizic acid stereoisomer that has exhibited hepato-protective effects and has anti-inflammatory, antioxidant, and antiviral activities. Here, we have investigated the effects and potential mechanisms of action of MgIG, with respect to myocardial fibrosis induced by isoproterenol (ISO) in mice. Mice were administered MgIG for 14days, with concurrent ISO dosing, and were sacrificed two weeks later. Lactate dehydrogenase (LDH) and creatine kinase (CK) concentrations were measured in the blood. Pathological changes in the myocardium were observed via light microscopy. In addition, the expression of the Bax and Bcl-2 genes, and the basic fibroblast growth factor (bFGF) protein were measured via an immunohistochemical method. The RNA expression of atrial natriuretic peptide (ANP), brain natriuretic peptide (BNP), c-fos, and c-jun mRNA were quantified by reverse transcription-polymerase chain reaction (RT-PCR) in the myocardial tissue. The protein expression of toll-like receptor (TLR) 4, and nuclear factor kappa B (NF-κB) (p65) were measured using Western blot assays. Compared with the control group, the ISO group showed significant increases in bFGF, Bax, Bcl-2, TLR4, and NF-κB (p65) expressions, as well as increased serum levels of LDH and CK. MgIG had a protective effect on ISO-induced myocardial fibrosis, which might be ascribed, at least in part, to the inhibition of the TLR4/NF-κB (p65) signaling pathway.
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Affiliation(s)
- Donglai Ma
- School of Pharmacy, Hebei University of Chinese Medicine, Shijiazhuang 050200, Hebei, China; Collaborative Innovation Center of Integrative Reproductive Disorders, Hebei University of Chinese Medicine, Shijiazhuang 050200, Hebei, China; Hebei key laboratory of integrative Medicine on Liver-Kidney Patterns, Shijiazhuang 050200, Hebei, China
| | - Jianping Zhang
- School of Basic Medicine, Hebei University of Chinese Medicine, Shijiazhuang 050200, Hebei, China
| | - Yuanyuan Zhang
- School of Pharmacy, Hebei University of Chinese Medicine, Shijiazhuang 050200, Hebei, China; Hebei key laboratory of integrative Medicine on Liver-Kidney Patterns, Shijiazhuang 050200, Hebei, China
| | - Xuan Zhang
- School of Basic Medicine, Hebei University of Chinese Medicine, Shijiazhuang 050200, Hebei, China; Hebei key laboratory of integrative Medicine on Liver-Kidney Patterns, Shijiazhuang 050200, Hebei, China
| | - Xue Han
- School of Pharmacy, Hebei University of Chinese Medicine, Shijiazhuang 050200, Hebei, China
| | - Tao Song
- School of Pharmacy, Hebei University of Chinese Medicine, Shijiazhuang 050200, Hebei, China; Hebei key laboratory of integrative Medicine on Liver-Kidney Patterns, Shijiazhuang 050200, Hebei, China; School of Basic Medicine, Hebei Medical University, Shijiazhuang 050017, Hebei, China
| | - Ying Zhang
- School of Basic Medicine, Hebei University of Chinese Medicine, Shijiazhuang 050200, Hebei, China.
| | - Li Chu
- School of Pharmacy, Hebei University of Chinese Medicine, Shijiazhuang 050200, Hebei, China; Hebei key laboratory of integrative Medicine on Liver-Kidney Patterns, Shijiazhuang 050200, Hebei, China; School of Basic Medicine, Hebei Medical University, Shijiazhuang 050017, Hebei, China.
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Lin SY, Wang YY, Chen WY, Liao SL, Chou ST, Yang CP, Chen CJ. Hepatoprotective activities of rosmarinic acid against extrahepatic cholestasis in rats. Food Chem Toxicol 2017; 108:214-223. [PMID: 28789951 DOI: 10.1016/j.fct.2017.08.005] [Citation(s) in RCA: 52] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2017] [Revised: 06/30/2017] [Accepted: 08/04/2017] [Indexed: 12/29/2022]
Abstract
Though rosmarinic acid possesses nutritional, pharmaceutical, and toxic properties and shows therapeutic potential on liver diseases, its therapeutic effects against cholestatic liver diseases have not been proven. Using an extrahepatic cholestasis rat model by bile-duct ligation (BDL), daily oral administration of rosmarinic acid showed improvement effects on liver histology, serum biochemicals, ductular reaction, oxidative stress, inflammation, and fibrosis. Rosmarinic acid alleviated BDL-induced transforming growth factor beta-1 (TGF-β1) production and hepatic collagen deposition, and the anti-fibrotic effects were accompanied by reductions in matrix-producing cells and Smad2/3. BDL rats showed increased hepatic NF-κB/AP-1 activities, inflammatory cell infiltration/accumulation, and cytokine production, and these signs of hepatic inflammation were ameliorated by rosmarinic acid. Mechanistic study revealed an inhibitory effect of rosmarinic acid on the axis of the high mobility group box-1 (HMGB1)/toll-like receptor-4 (TLR4) in BDL rats. Results of cultured hepatic stellate cells further showed the impacts of rosmarinic acid which attenuated TGF-β1-induced stellate cell mitogenic and fibrogenic activation. Our findings support the concept that rosmarinic acid could serve as a hepatoprotective agent, and dietary rosmarinic acid supplementation may be beneficial in terms of improving cholestasis-related liver injury via mechanisms involving resolution of oxidative burden and down-regulation of HMGB1/TLR4, NF-κB, AP-1, and TGF-β1/Smad signaling.
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Affiliation(s)
- Shih-Yi Lin
- Center for Geriatrics and Gerontology, Taichung Veterans General Hospital, Taichung City 407, Taiwan; Institute of Clinical Medicine, National Yang-Ming University, Taipei City 112, Taiwan
| | - Ya-Yu Wang
- Institute of Clinical Medicine, National Yang-Ming University, Taipei City 112, Taiwan; Division of Family Medicine, Taichung Veterans General Hospital, Taichung City 407, Taiwan
| | - Wen-Ying Chen
- Department of Veterinary Medicine, National Chung Hsing University, Taichung City 402, Taiwan
| | - Su-Lan Liao
- Department of Medical Research, Taichung Veterans General Hospital, Taichung City 407, Taiwan
| | - Su-Tze Chou
- Department of Food and Nutrition, Providence University, Taichung City 433, Taiwan
| | - Ching-Ping Yang
- Department of Medical Research, Taichung Veterans General Hospital, Taichung City 407, Taiwan
| | - Chun-Jung Chen
- Department of Medical Research, Taichung Veterans General Hospital, Taichung City 407, Taiwan; Department of Medical Laboratory Science and Biotechnology, China Medical University, Taichung City 404, Taiwan.
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Wang YY, Lin SY, Chen WY, Liao SL, Wu CC, Pan PH, Chou ST, Chen CJ. Glechoma hederacea extracts attenuate cholestatic liver injury in a bile duct-ligated rat model. JOURNAL OF ETHNOPHARMACOLOGY 2017; 204:58-66. [PMID: 28416441 DOI: 10.1016/j.jep.2017.04.011] [Citation(s) in RCA: 30] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/07/2017] [Revised: 03/13/2017] [Accepted: 04/13/2017] [Indexed: 06/07/2023]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE In traditional Chinese medicine, Glechoma hederacea is frequently prescribed to patients with cholelithiasis, dropsy, abscess, diabetes, inflammation, and jaundice. Polyphenolic compounds are main bioactive components of Glechoma hederacea. AIM OF THE STUDY This study was aimed to investigate the hepatoprotective potential of hot water extract of Glechoma hederacea against cholestatic liver injury in rats. MATERIALS AND METHODS Cholestatic liver injury was produced by ligating common bile ducts in Sprague-Dawley rats. Saline and hot water extract of Glechoma hederacea were orally administrated using gastric gavages. Liver tissues and bloods were collected and subjected to evaluation using histological, molecular, and biochemical approaches. RESULTS Using a rat model of cholestasis caused by bile duct ligation (BDL), daily oral administration of Glechoma hederacea hot water extracts showed protective effects against cholestatic liver injury, as evidenced by the improvement of serum biochemicals, ductular reaction, oxidative stress, inflammation, and fibrosis. Glechoma hederacea extracts alleviated BDL-induced transforming growth factor beta-1 (TGF-β1), connective tissue growth factor, and collagen expression, and the anti-fibrotic effects were accompanied by reductions in α-smooth muscle actin-positive matrix-producing cells and Smad2/3 activity. Glechoma hederacea extracts attenuated BDL-induced inflammatory cell infiltration/accumulation, NF-κB and AP-1 activation, and inflammatory cytokine production. Further studies demonstrated an inhibitory effect of Glechoma hederacea extracts on the axis of high mobility group box-1 (HMGB1)/toll-like receptor-4 (TLR4) intracellular signaling pathways. CONCLUSIONS The hepatoprotective, anti-oxidative, anti-inflammatory, and anti-fibrotic effects of Glechoma hederacea extracts seem to be multifactorial. The beneficial effects of daily Glechoma hederacea extracts supplementation were associated with anti-oxidative, anti-inflammatory, and anti-fibrotic potential, as well as down-regulation of NF-κB, AP-1, and TGF-β/Smad signaling, probably via interference with the HMGB1/TLR4 axis.
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Affiliation(s)
- Ya-Yu Wang
- Division of Family Medicine, Taichung Veterans General Hospital, Taichung 407, Taiwan; Institute of Clinical Medicine, National Yang-Ming University, Taipei 112, Taiwan.
| | - Shih-Yi Lin
- Institute of Clinical Medicine, National Yang-Ming University, Taipei 112, Taiwan; Center for Geriatrics and Gerontology, Taichung Veterans General Hospital, Taichung 407, Taiwan.
| | - Wen-Ying Chen
- Department of Veterinary Medicine, National Chung Hsing University, Taichung 402, Taiwan.
| | - Su-Lan Liao
- Department of Medical Research, Taichung Veterans General Hospital, Taichung 407, Taiwan.
| | - Chih-Cheng Wu
- Department of Anesthesiology, Taichung Veterans General Hospital, Taichung 407, Taiwan.
| | - Pin-Ho Pan
- Department of Pediatrics, Tungs' Taichung MetroHarbor Hospital, Taichung 435, Taiwan.
| | - Su-Tze Chou
- Department of Cosmetic Science, Providence University, Taichung 433, Taiwan.
| | - Chun-Jung Chen
- Department of Medical Research, Taichung Veterans General Hospital, Taichung 407, Taiwan; Department of Medical Laboratory Science and Biotechnology, China Medical University, Taichung 404, Taiwan.
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van der Veen JN, Lingrell S, Gao X, Takawale A, Kassiri Z, Vance DE, Jacobs RL. Fenofibrate, but not ezetimibe, prevents fatty liver disease in mice lacking phosphatidylethanolamine N-methyltransferase. J Lipid Res 2017; 58:656-667. [PMID: 28159867 PMCID: PMC5392742 DOI: 10.1194/jlr.m070631] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2016] [Revised: 02/01/2017] [Indexed: 01/24/2023] Open
Abstract
Mice lacking phosphatidylethanolamine N-methyltransferase (PEMT) are protected from high-fat diet (HFD)-induced obesity and insulin resistance. However, these mice develop severe nonalcoholic fatty liver disease (NAFLD) when fed the HFD, which is mainly due to inadequate secretion of VLDL particles. Our aim was to prevent NAFLD development in mice lacking PEMT. We treated Pemt−/− mice with either ezetimibe or fenofibrate to see if either could ameliorate liver disease in these mice. Ezetimibe treatment did not reduce fat accumulation in Pemt−/− livers, nor did it reduce markers for hepatic inflammation or fibrosis. Fenofibrate, conversely, completely prevented the development of NAFLD in Pemt−/− mice: hepatic lipid levels, as well as markers of endoplasmic reticulum stress, inflammation, and fibrosis, in fenofibrate-treated Pemt−/− mice were similar to those in Pemt+/+ mice. Importantly, Pemt−/− mice were still protected against HFD-induced obesity and insulin resistance. Moreover, fenofibrate partially reversed hepatic steatosis and fibrosis in Pemt−/− mice when treatment was initiated after NAFLD had already been established. Increasing hepatic fatty acid oxidation can compensate for the lower VLDL-triacylglycerol secretion rate and prevent/reverse fatty liver disease in mice lacking PEMT.
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Affiliation(s)
- Jelske N van der Veen
- Group on the Molecular and Cell Biology of Lipids, University of Alberta, Edmonton, Alberta, Canada; Department of Biochemistry, University of Alberta, Edmonton, Alberta, Canada
| | - Susanne Lingrell
- Group on the Molecular and Cell Biology of Lipids, University of Alberta, Edmonton, Alberta, Canada; Department of Biochemistry, University of Alberta, Edmonton, Alberta, Canada
| | - Xia Gao
- Group on the Molecular and Cell Biology of Lipids, University of Alberta, Edmonton, Alberta, Canada; Department of Biochemistry, University of Alberta, Edmonton, Alberta, Canada
| | - Abhijit Takawale
- Department of Physiology, University of Alberta, Edmonton, Alberta, Canada
| | - Zamaneh Kassiri
- Department of Physiology, University of Alberta, Edmonton, Alberta, Canada
| | - Dennis E Vance
- Group on the Molecular and Cell Biology of Lipids, University of Alberta, Edmonton, Alberta, Canada; Department of Biochemistry, University of Alberta, Edmonton, Alberta, Canada
| | - René L Jacobs
- Group on the Molecular and Cell Biology of Lipids, University of Alberta, Edmonton, Alberta, Canada; Department of Biochemistry, University of Alberta, Edmonton, Alberta, Canada; Department of Agricultural, Food, and Nutritional Science, University of Alberta, Edmonton, Alberta, Canada.
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25
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Yoshioka Y, Li X, Zhang T, Mitani T, Yasuda M, Nanba F, Toda T, Yamashita Y, Ashida H. Black soybean seed coat polyphenols prevent AAPH-induced oxidative DNA-damage in HepG2 cells. J Clin Biochem Nutr 2016; 60:108-114. [PMID: 28366989 PMCID: PMC5370529 DOI: 10.3164/jcbn.16-48] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2016] [Accepted: 08/12/2016] [Indexed: 12/01/2022] Open
Abstract
Black soybean seed coat extract (BE), which contains abundant polyphenols such as procyanidins, cyanidin 3-glucoside, (+)-catechin, and (−)epicatechin, has been reported on health beneficial functions such as antioxidant activity, anti-inflammatory, anti-obesity, and anti-diabetic activities. In this study, we investigated that prevention of BE and its polyphenols on 2,2'-azobis(2-methylpropionamide) dihydrochloride (AAPH)-induced oxidative DNA damage, and found that these polyphenols inhibited AAPH-induced formation of 8-hydroxy-2'-deoxyguanosine (8-OHdG) as a biomarker for oxidative DNA damage in HepG2 cells. Under the same conditions, these polyphenols also inhibited AAPH-induced accumulation of reactive oxygen species (ROS) in the cells. Inhibition of ROS accumulation was observed in both cytosol and nucleus. It was confirmed that these polyphenols inhibited formation of AAPH radical using oxygen radical absorbance capacity assay under the cell-free conditions. These results indicate that polyphenols in BE inhibit free radical-induced oxidative DNA damages by their potent antioxidant activity. Thus, BE is an effective food material for prevention of oxidative stress and oxidative DNA damages.
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Affiliation(s)
- Yasukiyo Yoshioka
- Organization of Advanced Science and Technology, Kobe University, Kobe, Hyogo 657-8501, Japan
| | - Xiu Li
- Graduate School of Agricultural Science, Kobe University, Kobe, Hyogo 657-8501, Japan
| | - Tianshun Zhang
- Graduate School of Agricultural Science, Kobe University, Kobe, Hyogo 657-8501, Japan
| | - Takakazu Mitani
- Organization of Advanced Science and Technology, Kobe University, Kobe, Hyogo 657-8501, Japan; Graduate School of Agricultural Science, Kobe University, Kobe, Hyogo 657-8501, Japan
| | - Michiko Yasuda
- Organization of Advanced Science and Technology, Kobe University, Kobe, Hyogo 657-8501, Japan
| | - Fumio Nanba
- Research & Development Department, Fujicco Co., Ltd., Kobe, Hyogo 650-8558, Japan
| | - Toshiya Toda
- Research & Development Department, Fujicco Co., Ltd., Kobe, Hyogo 650-8558, Japan
| | - Yoko Yamashita
- Graduate School of Agricultural Science, Kobe University, Kobe, Hyogo 657-8501, Japan
| | - Hitoshi Ashida
- Organization of Advanced Science and Technology, Kobe University, Kobe, Hyogo 657-8501, Japan; Graduate School of Agricultural Science, Kobe University, Kobe, Hyogo 657-8501, Japan
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Kim J, Jung Y. Thymosin Beta 4 Is a Potential Regulator of Hepatic Stellate Cells. VITAMINS AND HORMONES 2016; 102:121-149. [PMID: 27450733 DOI: 10.1016/bs.vh.2016.04.011] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/18/2023]
Abstract
Liver fibrosis, a major characteristic of chronic liver disease, is inappropriate tissue remodeling caused by prolonged parenchymal cell injury and inflammation. During liver injury, hepatic stellate cells (HSCs) undergo transdifferentiation from quiescent HSCs into activated HSCs, which promote the deposition of extracellular matrix proteins, leading to liver fibrosis. Thymosin beta 4 (Tβ4), a major actin-sequestering protein, is the most abundant member of the highly conserved β-thymosin family and controls cell morphogenesis and motility by regulating the dynamics of the actin cytoskeleton. Tβ4 is known to be involved in various cellular responses, including antiinflammation, wound healing, angiogenesis, and cancer progression. Emerging evidence suggests that Tβ4 is expressed in the liver; however, its biological roles are poorly understood. Herein, we introduce liver fibrogenesis and recent findings regarding the function of Tβ4 in various tissues and discuss the potential role of Tβ4 in liver fibrosis with a special focus on the effects of exogenous and endogenous Tβ4. Recent studies have revealed that activated HSCs express Tβ4 in vivo and in vitro. Treatment with the exogenous Tβ4 peptide inhibits the proliferation and migration of activated HSCs and reduces liver fibrosis, indicating it has an antifibrotic action. Meanwhile, the endogenously expressed Tβ4 in activated HSCs is shown to promote HSCs activation. Although the role of Tβ4 has not been elucidated, it is apparent that Tβ4 is associated with HSC activation. Therefore, understanding the potential roles and regulatory mechanisms of Tβ4 in liver fibrosis may provide a novel treatment for patients.
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Affiliation(s)
- J Kim
- Pusan National University, Pusan, Republic of Korea
| | - Y Jung
- Pusan National University, Pusan, Republic of Korea.
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Abstract
Spaceflight affects numerous organ systems in the body, leading to metabolic dysfunction that may have long-term consequences. Microgravity-induced alterations in liver metabolism, particularly with respect to lipids, remain largely unexplored. Here we utilize a novel systems biology approach, combining metabolomics and transcriptomics with advanced Raman microscopy, to investigate altered hepatic lipid metabolism in mice following short duration spaceflight. Mice flown aboard Space Transportation System -135, the last Shuttle mission, lose weight but redistribute lipids, particularly to the liver. Intriguingly, spaceflight mice lose retinol from lipid droplets. Both mRNA and metabolite changes suggest the retinol loss is linked to activation of PPARα-mediated pathways and potentially to hepatic stellate cell activation, both of which may be coincident with increased bile acids and early signs of liver injury. Although the 13-day flight duration is too short for frank fibrosis to develop, the retinol loss plus changes in markers of extracellular matrix remodeling raise the concern that longer duration exposure to the space environment may result in progressive liver damage, increasing the risk for nonalcoholic fatty liver disease.
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Stiffening hydrogels for investigating the dynamics of hepatic stellate cell mechanotransduction during myofibroblast activation. Sci Rep 2016; 6:21387. [PMID: 26906177 PMCID: PMC4764908 DOI: 10.1038/srep21387] [Citation(s) in RCA: 164] [Impact Index Per Article: 18.2] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2015] [Accepted: 01/22/2016] [Indexed: 12/15/2022] Open
Abstract
Tissue fibrosis contributes to nearly half of all deaths in the developed world and is characterized by progressive matrix stiffening. Despite this, nearly all in vitro disease models are mechanically static. Here, we used visible light-mediated stiffening hydrogels to investigate cell mechanotransduction in a disease-relevant system. Primary hepatic stellate cell-seeded hydrogels stiffened in situ at later time points (following a recovery phase post-isolation) displayed accelerated signaling kinetics of both early (Yes-associated protein/Transcriptional coactivator with PDZ-binding motif, YAP/TAZ) and late (alpha-smooth muscle actin, α-SMA) markers of myofibroblast differentiation, resulting in a time course similar to observed in vivo activation dynamics. We further validated this system by showing that α-SMA inhibition following substrate stiffening resulted in attenuated stellate cell activation, with reduced YAP/TAZ nuclear shuttling and traction force generation. Together, these data suggest that stiffening hydrogels may be more faithful models for studying myofibroblast activation than static substrates and could inform the development of disease therapeutics.
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29
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Kim JK, Lee JI, Paik YH, Yun CO, Chang HY, Lee SY, Lee KS. A single adenovirus-mediated relaxin delivery attenuates established liver fibrosis in rats. J Gene Med 2016; 18:16-26. [DOI: 10.1002/jgm.2872] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2015] [Revised: 01/08/2016] [Accepted: 01/12/2016] [Indexed: 01/09/2023] Open
Affiliation(s)
- Ja Kyung Kim
- Department of Internal Medicine; Yonsei University College of Medicine; Seoul Republic of Korea
| | - Jung Il Lee
- Department of Internal Medicine; Yonsei University College of Medicine; Seoul Republic of Korea
| | - Yong-Han Paik
- Department of Internal Medicine Samsung Medical Centre; Sungkyunkwan University School of Medicine; Seoul Republic of Korea
| | - Chae-Ok Yun
- Department of Bioengineering, College of Engineering; Hanyang University; Seoul Republic of Korea
| | - Hye Young Chang
- Medical Research Centre, Gangnam Severance Hospital; Yonsei University College of Medicine; Seoul Republic of Korea
| | - Su Yeon Lee
- Medical Research Centre, Gangnam Severance Hospital; Yonsei University College of Medicine; Seoul Republic of Korea
| | - Kwan Sik Lee
- Department of Internal Medicine; Yonsei University College of Medicine; Seoul Republic of Korea
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30
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Kawano Y, Ohta M, Iwashita Y, Komori Y, Inomata M, Kitano S. Effects of the dihydrolipoyl histidinate zinc complex against carbon tetrachloride-induced hepatic fibrosis in rats. Surg Today 2015; 44:1744-50. [PMID: 24121950 DOI: 10.1007/s00595-013-0749-4] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2013] [Accepted: 08/22/2013] [Indexed: 02/07/2023]
Abstract
PURPOSE This study investigated the effects of an antioxidant, dihydrolipoyl histidinate zinc complex (DHLHZn), on the hepatic fibrosis in the carbon tetrachloride (CCl4) rat model. METHODS The animals were divided into three groups: control, CCl4, and CCl4+DHLHZn. A histological assessment of the liver fibrosis was performed using stained liver samples. The oxidative stress and antioxidant levels were evaluated by measuring the malondialdehyde (MDA) and glutathione (GSH) levels in the liver. In addition, cultured human hepatic stellate cells (LI90) were exposed to antimycin-A (AMA) and divided into four groups: control, DHLHZn, AMA, and AMA+DHLHZn. The effects of DHLHZn on AMA-induced fibrosis were evaluated by measuring the expression of transforming growth factor (TGF)-β1 and collagen α1 (I). RESULTS The hepatic fibrosis in the CCl4+DHLHZn group was attenuated compared to that in the CCl4 group. The MDA levels in the CCl4+DHLHZn group were significantly lower than those of the CCl4 group, whereas the GSH levels in the CCl4+DHLHZn group were significantly higher than those of the CCl4 group. Furthermore, the relative mRNA expression of TGF-β1 and collagen α1 (I) in the AMA+DHLHZn group was significantly lower than that in the AMA group. CONCLUSION DHLHZn may attenuate the hepatic fibrosis induced by CCl4 by decreasing the degree of oxidative stress.
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Kim KE, Kim H, Heo RW, Shin HJ, Yi CO, Lee DH, Kim HJ, Kang SS, Cho GJ, Choi WS, Roh GS. Myeloid-specific SIRT1 Deletion Aggravates Hepatic Inflammation and Steatosis in High-fat Diet-fed Mice. THE KOREAN JOURNAL OF PHYSIOLOGY & PHARMACOLOGY : OFFICIAL JOURNAL OF THE KOREAN PHYSIOLOGICAL SOCIETY AND THE KOREAN SOCIETY OF PHARMACOLOGY 2015; 19:451-60. [PMID: 26330758 PMCID: PMC4553405 DOI: 10.4196/kjpp.2015.19.5.451] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/10/2015] [Revised: 05/04/2015] [Accepted: 05/31/2015] [Indexed: 01/23/2023]
Abstract
Sirtuin 1 (SIRT1) is a mammalian NAD+-dependent protein deacetylase that regulates cellular metabolism and inflammatory response. The organ-specific deletion of SIRT1 induces local inflammation and insulin resistance in dietary and genetic obesity. Macrophage-mediated inflammation contributes to insulin resistance and metabolic syndrome, however, the macrophage-specific SIRT1 function in the context of obesity is largely unknown. C57/BL6 wild type (WT) or myeloid-specific SIRT1 knockout (KO) mice were fed a high-fat diet (HFD) or normal diet (ND) for 12 weeks. Metabolic parameters and markers of hepatic steatosis and inflammation in liver were compared in WT and KO mice. SIRT1 deletion enhanced HFD-induced changes on body and liver weight gain, and increased glucose and insulin resistance. In liver, SIRT1 deletion increased the acetylation, and enhanced HFD-induced nuclear translocation of nuclear factor kappa B (NF-κB), hepatic inflammation and macrophage infiltration. HFD-fed KO mice showed severe hepatic steatosis by activating lipogenic pathway through sterol regulatory element-binding protein 1 (SREBP-1), and hepatic fibrogenesis, as indicated by induction of connective tissue growth factor (CTGF), alpha-smooth muscle actin (α-SMA), and collagen secretion. Myeloid-specific deletion of SIRT1 stimulates obesity-induced inflammation and increases the risk of hepatic fibrosis. Targeted induction of macrophage SIRT1 may be a good therapy for alleviating inflammation-associated metabolic syndrome.
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Affiliation(s)
- Kyung Eun Kim
- Department of Anatomy and Convergence Medical Science, Institute of Health Sciences, Gyeongsang National University School of Medicine, Jinju 660-751, Korea
| | - Hwajin Kim
- Department of Anatomy and Convergence Medical Science, Institute of Health Sciences, Gyeongsang National University School of Medicine, Jinju 660-751, Korea
| | - Rok Won Heo
- Department of Anatomy and Convergence Medical Science, Institute of Health Sciences, Gyeongsang National University School of Medicine, Jinju 660-751, Korea
| | - Hyun Joo Shin
- Department of Anatomy and Convergence Medical Science, Institute of Health Sciences, Gyeongsang National University School of Medicine, Jinju 660-751, Korea
| | - Chin-Ok Yi
- Department of Anatomy and Convergence Medical Science, Institute of Health Sciences, Gyeongsang National University School of Medicine, Jinju 660-751, Korea
| | - Dong Hoon Lee
- Department of Anatomy and Convergence Medical Science, Institute of Health Sciences, Gyeongsang National University School of Medicine, Jinju 660-751, Korea
| | - Hyun Joon Kim
- Department of Anatomy and Convergence Medical Science, Institute of Health Sciences, Gyeongsang National University School of Medicine, Jinju 660-751, Korea
| | - Sang Soo Kang
- Department of Anatomy and Convergence Medical Science, Institute of Health Sciences, Gyeongsang National University School of Medicine, Jinju 660-751, Korea
| | - Gyeong Jae Cho
- Department of Anatomy and Convergence Medical Science, Institute of Health Sciences, Gyeongsang National University School of Medicine, Jinju 660-751, Korea
| | - Wan Sung Choi
- Department of Anatomy and Convergence Medical Science, Institute of Health Sciences, Gyeongsang National University School of Medicine, Jinju 660-751, Korea
| | - Gu Seob Roh
- Department of Anatomy and Convergence Medical Science, Institute of Health Sciences, Gyeongsang National University School of Medicine, Jinju 660-751, Korea
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Zhou DJ, Mu D, Jiang MD, Zheng SM, Zhang Y, He S, Weng M, Zeng WZ. Hepatoprotective effect of juglone on dimethylnitrosamine-induced liver fibrosis and its effect on hepatic antioxidant defence and the expression levels of α-SMA and collagen III. Mol Med Rep 2015; 12:4095-4102. [PMID: 26126609 PMCID: PMC4526056 DOI: 10.3892/mmr.2015.3992] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2014] [Accepted: 04/14/2015] [Indexed: 12/22/2022] Open
Abstract
The present study aimed to investigate the antifibrotic effects of juglone on dimethylnitrosamine (DMN)‑induced fibrosis in rats. Juglone, which is a quinone, significantly decreased DMN‑induced rat hepatic fibrosis, which was associated with increased superoxide dismutase (SOD) activity, decreased oxidative stress and reduced levels of α‑smooth muscle actin (α‑SMA) and collagen (Col) III in the liver. Serum levels of alanine aminotransferase, aspartate aminotransferase, hyaluronic acid, laminin, type III precollagen and type IV collagen were significantly reduced by treatment with juglone. Liver fibrosis was induced in male Sprague‑Dawley rats by subcutaneous injections of DMN solution and hepatic fibrosis was assessed using Massons trichome staining. The expression levels of α‑SMA and Col III were determined using immunohistochemical techniques. The activities of SOD and malondialdehyde in liver homogenates were also determined. The results suggested that juglone augmented the antioxidative capability of the liver, possibly by stimulating the activity of SOD, which promoted the inactivation of hepatic stellate cells (HSCs) and decreased the accumulation of extracellular matrix collagen in the liver, thereby alleviating hepatic fibrosis. Silymarin was used as a positive control for liver fibrosis protection. It was hypothesized that juglone alleviates or mitigates oxidative stress‑mediated hepatic fibrosis by upregulating the expression of peroxisome proliferator‑activated receptor γ and inhibiting the activation of HSC.
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Affiliation(s)
- De-Jiang Zhou
- Internal Medicine Department of Digestion, General Hospital of Chengdu Military Region, Chengdu, Sichuan 610083, P.R. China
| | - Dong Mu
- Internal Medicine Department of Digestion, General Hospital of Chengdu Military Region, Chengdu, Sichuan 610083, P.R. China
| | - Ming-De Jiang
- Internal Medicine Department of Digestion, General Hospital of Chengdu Military Region, Chengdu, Sichuan 610083, P.R. China
| | - Shu-Mei Zheng
- Internal Medicine Department of Digestion, General Hospital of Chengdu Military Region, Chengdu, Sichuan 610083, P.R. China
| | - Yong Zhang
- Internal Medicine Department of Digestion, General Hospital of Chengdu Military Region, Chengdu, Sichuan 610083, P.R. China
| | - Sheng He
- Internal Medicine Department of Digestion, General Hospital of Chengdu Military Region, Chengdu, Sichuan 610083, P.R. China
| | - Min Weng
- Internal Medicine Department of Digestion, General Hospital of Chengdu Military Region, Chengdu, Sichuan 610083, P.R. China
| | - Wei-Zheng Zeng
- Internal Medicine Department of Digestion, General Hospital of Chengdu Military Region, Chengdu, Sichuan 610083, P.R. China
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Li M, Wang XF, Shi JJ, Li YP, Yang N, Zhai S, Dang SS. Caffeic acid phenethyl ester inhibits liver fibrosis in rats. World J Gastroenterol 2015; 21:3893-3903. [PMID: 25852274 PMCID: PMC4385536 DOI: 10.3748/wjg.v21.i13.3893] [Citation(s) in RCA: 43] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/24/2014] [Revised: 10/25/2014] [Accepted: 12/05/2014] [Indexed: 02/06/2023] Open
Abstract
AIM To investigate the hepatoprotective effects and antioxidant activity of caffeic acid phenethyl ester (CAPE) in rats with liver fibrosis. METHODS A total of 75 male Sprague-Dawley rats were randomly assigned to seven experimental groups: a normal group (n = 10), a vehicle group (n = 10), a model group (n = 15), a vitamin E group (n = 10), and three CAPE groups (CAPE 3, 6 and 12 mg/kg, n = 10, respectively). Liver fibrosis was induced in rats by injecting CCl4 subcutaneously, feeding with high fat forage, and administering 30% alcohol orally for 10 wk. Concurrently, CAPE (3, 6 and 12 mg/kg) was intraperitoneally administered daily for 10 wk. After that, serum total bilirubin (TBil), aminotransferase (ALT) and aspartate aminotransferase (AST) levels were measured to assess hepatotoxicity. To investigate antioxidant activity of CAPE, malondialdehyde (MDA), glutathione (GSH) levels, catalase (CAT) and superoxide dismutase (SOD) activities in liver tissue were determined. Moreover, the effect of CAPE on α-smooth muscle actin (α-SMA), a characteristic hallmark of activated hepatic stellate cells (HSCs), and NF-E2-related factor 2 (Nrf2), a key transcription factor for antioxidant systems, was investigated by immunohistochemistry. RESULTS Compared to the model group, intraperitoneal administration of CAPE decreased TBil, ALT, and AST levels in liver fibrosis rats (P < 0.05), while serum TBil was decreased by CAPE in a dose-dependent manner. In addition, the liver hydroxyproline contents in both the 6 and 12 mg/kg CAPE groups were markedly lower than that in the model group (P < 0.05 and P < 0.001, respectively). CAPE markedly decreased MDA levels and, in turn, increased GSH levels, as well as CAT and SOD activities in liver fibrosis rats compared to the model group (P < 0.05). Moreover, CAPE effectively inhibited α-SMA expression while increasing Nrf2 expression compared to the model group (P < 0.01). CONCLUSION The protective effects of CAPE against liver fibrosis may be due to its ability to suppress the activation of HSCs by inhibiting oxidative stress.
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Jia D, Duan F, Peng P, Sun L, Ruan Y, Gu J. Pyrroloquinoline-quinone suppresses liver fibrogenesis in mice. PLoS One 2015; 10:e0121939. [PMID: 25822822 PMCID: PMC4379100 DOI: 10.1371/journal.pone.0121939] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2014] [Accepted: 02/09/2015] [Indexed: 02/07/2023] Open
Abstract
Liver fibrosis represents the consequences of a sustained wound healing response to chronic liver injuries, and its progression toward cirrhosis is the major cause of liver-related morbidity and mortality worldwide. However, anti-fibrotic treatment remains an unconquered area for drug development. Accumulating evidence indicate that oxidative stress plays a critical role in liver fibrogenesis. In this study, we found that PQQ, a natural anti-oxidant present in a wide variety of human foods, exerted potent anti-fibrotic and ROS-scavenging activity in Balb/C mouse models of liver fibrosis. The antioxidant activity of PQQ was involved in the modulation of multiple steps during liver fibrogenesis, including chronic liver injury, hepatic inflammation, as well as activation of hepatic stellate cells and production of extracellular matrix. PQQ also suppressed the up-regulation of RACK1 in activated HSCs in vivo and in vitro. Our data suggest that PQQ suppresses oxidative stress and liver fibrogenesis in mice, and provide rationale for the clinical application of PQQ in the prevention and treatment of liver fibrosis.
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Affiliation(s)
- Dongwei Jia
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Fudan University, Shanghai, P.R.China
| | - Fangfang Duan
- Institute of Biomedical Science, Fudan University, Shanghai, P.R.China
| | - Peike Peng
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Fudan University, Shanghai, P.R.China
| | - Linlin Sun
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Fudan University, Shanghai, P.R.China
| | - Yuanyuan Ruan
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Fudan University, Shanghai, P.R.China
- * E-mail: (YR); (JG)
| | - Jianxin Gu
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Fudan University, Shanghai, P.R.China
- Institute of Biomedical Science, Fudan University, Shanghai, P.R.China
- * E-mail: (YR); (JG)
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Pawlak M, Lefebvre P, Staels B. Molecular mechanism of PPARα action and its impact on lipid metabolism, inflammation and fibrosis in non-alcoholic fatty liver disease. J Hepatol 2015; 62:720-33. [PMID: 25450203 DOI: 10.1016/j.jhep.2014.10.039] [Citation(s) in RCA: 1110] [Impact Index Per Article: 111.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/28/2014] [Revised: 09/22/2014] [Accepted: 10/26/2014] [Indexed: 02/07/2023]
Abstract
Peroxisome proliferator-activated receptor α (PPARα) is a ligand-activated transcription factor belonging, together with PPARγ and PPARβ/δ, to the NR1C nuclear receptor subfamily. Many PPARα target genes are involved in fatty acid metabolism in tissues with high oxidative rates such as muscle, heart and liver. PPARα activation, in combination with PPARβ/δ agonism, improves steatosis, inflammation and fibrosis in pre-clinical models of non-alcoholic fatty liver disease, identifying a new potential therapeutic area. In this review, we discuss the transcriptional activation and repression mechanisms by PPARα, the spectrum of target genes and chromatin-binding maps from recent genome-wide studies, paying particular attention to PPARα-regulation of hepatic fatty acid and plasma lipoprotein metabolism during nutritional transition, and of the inflammatory response. The role of PPARα, together with other PPARs, in non-alcoholic steatohepatitis will be discussed in light of available pre-clinical and clinical data.
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Affiliation(s)
- Michal Pawlak
- European Genomic Institute for Diabetes (EGID), FR 3508, F-59000 Lille, France; Université Lille 2, F-59000 Lille, France; Inserm UMR 1011, F-59000 Lille, France; Institut Pasteur de Lille, F-59000 Lille, France
| | - Philippe Lefebvre
- European Genomic Institute for Diabetes (EGID), FR 3508, F-59000 Lille, France; Université Lille 2, F-59000 Lille, France; Inserm UMR 1011, F-59000 Lille, France; Institut Pasteur de Lille, F-59000 Lille, France
| | - Bart Staels
- European Genomic Institute for Diabetes (EGID), FR 3508, F-59000 Lille, France; Université Lille 2, F-59000 Lille, France; Inserm UMR 1011, F-59000 Lille, France; Institut Pasteur de Lille, F-59000 Lille, France.
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Fahmy SR. Anti-fibrotic effect of Holothuria arenicola extract against bile duct ligation in rats. BMC COMPLEMENTARY AND ALTERNATIVE MEDICINE 2015; 15:14. [PMID: 25652675 PMCID: PMC4328034 DOI: 10.1186/s12906-015-0533-7] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 02/21/2014] [Accepted: 01/19/2015] [Indexed: 02/08/2023]
Abstract
BACKGROUND Holothuria arenicola is the most important and abundant sea cucumber species in the Mediterranean Sea on the Egyptian coast. The present study aims to assess the anti-oxidative and anticholestatic effects of the sea cucumber Holothuria arenicola extract (HaE) in a model of bile duct ligation in male albino rats. METHODS Fifty four male Wistar albino rats were assigned into two main groups, the Sham-operated control and bile duct ligated (BDL) group. After 14 days of surgery, the animals of the group I (Sham control) received distilled water only for 7, 14 and 28 days. Second group (BDL group) was divided into 2 subgroups, animals of these subgroups treated for 7, 14 and 28 consecutive days as follow: subgroup I (BDL), rats of this subgroup administered distilled water orally. Subgroup II (HaE), animals of this subgroup treated orally with HaE (200 mg/kg body weight). RESULTS The HaE revealed significant antifibrotic effect as evident by decreasing the levels of total conjugated and unconjugated bilirubin and the activities of serum aminotransferases (ASAT and ALAT) and alkaline phosphatase (ALP) as well as malondialdehyde (MDA) level, and increasing the serum albumin, glutathione reduced (GSH) levels. Treatment with HaE normalized the antioxidant enzyme, glutathione-S-transferase (GST), superoxide dismutase (SOD) and catalase (CAT) activities activities. CONCLUSION The present prospective study correlated the antifibrotic effect of HaE to its direct antioxidant effect that can be related to its contents of phenolic compounds specially chlorogenic acid, pyrogallol, rutin and coumaric acid.
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Affiliation(s)
- Sohair R Fahmy
- Department of Zoology, Faculty of Science, Cairo University, 12613, Giza, Egypt.
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Liu YL, Liu WH, Sun J, Hou TJ, Liu YM, Liu HR, Luo YH, Zhao NN, Tang Y, Deng FM. Mesenchymal stem cell-mediated suppression of hypertrophic scarring is p53 dependent in a rabbit ear model. Stem Cell Res Ther 2014; 5:136. [PMID: 25510921 PMCID: PMC4293008 DOI: 10.1186/scrt526] [Citation(s) in RCA: 31] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2014] [Accepted: 12/11/2014] [Indexed: 02/06/2023] Open
Abstract
Introduction Mesenchymal stem cells (MSCs) are considered to play important roles in wound repair and tissue remodeling. Hypertrophic scar (HTS) is a cutaneous condition characterized by deposits of excessive amount of collagen after an acute skin injury. However, currently there is little knowledge about the direct relationship between MSCs and HTS. Methods The hypertrophic scar model was established on rabbit ears. MSCs were isolated from rabbit femur bone marrow and transplanted through ear artery injection. Hypertrophic scar formation was examined using frozen-section analysis, hematoxylin and eosin (HE) staining, Masson’s trichrome staining, and scar elevation index. The role of p53 in the MSCs-mediated anti-scarring effect was examined by gene knockdown using p53 shRNA. Results In this study, MSCs engraftment through ear artery injection significantly inhibited the hypertrophic scarring in a rabbit ear hypertrophic scar model, while this anti-scarring function could be abrogated by p53 gene knockdown in MSCs. Additionally, we found that MSCs down-regulated the expression of TGF-β receptor I (TβRI) and alpha-smooth muscle actin (α-SMA) at both mRNA and protein levels in a paracrine manner, and this down-regulation was rescued by p53 gene knockdown. Moreover, our results showed that MSCs with p53 gene knockdown promoted the proliferation of fibroblasts through increasing nitric oxide (NO) production. Conclusions These results suggest that MSCs inhibit the formation of HTS in a p53 dependent manner through at least two mechanisms: inhibition of the transformation of HTS fibroblast to myofibroblast; and inhibition of the proliferation of fibroblasts through inhibition of NO production.
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Zhai X, Qiao H, Guan W, Li Z, Cheng Y, Jia X, Zhou Y. Curcumin regulates peroxisome proliferator-activated receptor-γ coactivator-1α expression by AMPK pathway in hepatic stellate cells in vitro. Eur J Pharmacol 2014; 746:56-62. [PMID: 25445048 DOI: 10.1016/j.ejphar.2014.10.055] [Citation(s) in RCA: 43] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/24/2014] [Revised: 10/23/2014] [Accepted: 10/27/2014] [Indexed: 12/21/2022]
Abstract
Curcumin exerts an inhibitory effect on hepatic stellate cell (HSC) activation, a key step for liver fibrogenesis, and on liver fibrosis by up-regulation of peroxisome proliferator-activated receptor-γ (PPARγ) expression. PPARγ plays a crucial role in suppression of HSC activation. Peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α) functions as a co-activator for PPARγ. Therefore, researches on the effect of curcumin on PGC-1α might contribute to understanding of the mechanisms underlying curcumin inhibition of HSC activation and liver fibrosis through PPARγ. The present study aimed to investigate the effect of curcumin on PGC-1α expression in HSCs in vitro and examine the underlying molecular mechanisms by western blot, reat-time PCR, and transfection. Our results showed that curcumin stimulation increased PGC-1α expression and the effects of curcumin on PGC-1α expression were correlated with the activation of adenosine monophosphate-activated protein kinase (AMPK). Curcumin increased superoxide dimutase-2 (SOD2) transcription and activity by AMPK/PGC-1α axis. Moreover, PGC-1α was demonstrated to inhibit α1(I) collagen (a marker for liver fibrosis) transcription in cultured HSCs. These results demonstrated the promotion effect of curcumin on PGC-1α expression through AMPK pathway, which led to the increases in PPARγ activity and in SOD-2 transcription and activity. These data might suggest a possible new explanation for the inhibitory effect of curcumin on HSC activation and on liver fibrogenesis.
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Affiliation(s)
- Xuguang Zhai
- Department of Biochemistry & Molecular Biology, Medical College, Nantong University, Nantong 226001, Jiangsu, China
| | - Haowen Qiao
- Department of Biochemistry & Molecular Biology, Medical College, Nantong University, Nantong 226001, Jiangsu, China
| | - Wei Guan
- Department of Pharmacology, School of Pharmacy, Nantong University, Qi xiou road 19, Nantong 226001, Jiangsu, China
| | - Ziqiang Li
- Department of Biochemistry & Molecular Biology, Medical College, Nantong University, Nantong 226001, Jiangsu, China
| | - Yuanyuan Cheng
- Department of Pharmacology, School of Pharmacy, Nantong University, Qi xiou road 19, Nantong 226001, Jiangsu, China
| | - Xin Jia
- Department of Biochemistry & Molecular Biology, Medical College, Nantong University, Nantong 226001, Jiangsu, China
| | - Yajun Zhou
- Department of Biochemistry & Molecular Biology, Medical College, Nantong University, Nantong 226001, Jiangsu, China.
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Lin SY, Wang YY, Chen WY, Chuang YH, Pan PH, Chen CJ. Beneficial effect of quercetin on cholestatic liver injury. J Nutr Biochem 2014; 25:1183-1195. [PMID: 25108658 DOI: 10.1016/j.jnutbio.2014.06.003] [Citation(s) in RCA: 58] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2013] [Revised: 05/29/2014] [Accepted: 06/04/2014] [Indexed: 12/15/2022]
Abstract
Bile duct obstruction and subsequent cholestasis are associated with hepatocellular injury, cholangiocyte proliferation, stellate cell activation, Kupffer cell activation, oxidative stress, inflammation and fibrosis. Flavonoids have been shown to confer beneficial health effects, including hepatoprotection. However, the molecular mechanism of flavonoid-mediated hepatoprotection is incompletely understood. In this study, we report the protective effect of quercetin on cholestatic liver injury. Cholestasis was produced by bile duct ligation (BDL) in male Sprague-Dawley rats for 3 weeks. Daily oral administration of quercetin was started 1 week before injury and lasted for 4 weeks. In comparison with the control group, the BDL group showed liver injury, as evidenced by histological changes, and elevation in serum biochemicals, ductular reaction, fibrosis, inflammation and oxidative stress. These pathophysiological changes were attenuated by daily quercetin supplementation. Quercetin alleviated BDL-induced transforming growth factor beta-1 (TGF-β1), interleukin-1 beta, connective tissue growth factor and collagen expression. The antifibrotic effect of quercetin was accompanied by reductions in α-smooth muscle actin-positive matrix-producing cells and Smad 2/3 activity critical to the fibrogenic potential of TGF-β1. Quercetin also attenuated BDL-induced oxidative stress, leukocyte accumulation, nuclear factor (NF)-κB activation and proinflammatory cytokine production. Further studies demonstrated an inhibitory effect of quercetin on MyD88 and TGF-β-activated kinase-1 critical for linking toll-like receptor (TLR) and NF-κB. Taken together, the hepatoprotective, anti-inflammatory and antifibrotic effects of quercetin seem to be multifactorial. The beneficial effects of daily quercetin supplementation are associated with antioxidative and anti-inflammatory potential as well as down-regulation of NF-κB and TGF-β/Smad signaling, probably via interference with TLR signaling.
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Affiliation(s)
- Shih-Yi Lin
- Division of Endocrinology and Metabolism, Taichung Veterans General Hospital, Taichung 407, Taiwan; School of Medicine, National Yang-Ming University, Taipei 112, Taiwan
| | - Ya-Yu Wang
- School of Medicine, National Yang-Ming University, Taipei 112, Taiwan; Division of Family Medicine, Taichung Veterans General Hospital, Taichung 407, Taiwan
| | - Wen-Ying Chen
- Department of Veterinary Medicine, National Chung Hsing University, Taichung 402, Taiwan
| | - Yu-Han Chuang
- Division of Endocrinology and Metabolism, Taichung Veterans General Hospital, Taichung 407, Taiwan
| | - Pin-Ho Pan
- Department of Pediatrics, Tungs' Taichung MetroHarbor Hospital, Taichung 435, Taiwan
| | - Chun-Jung Chen
- Department of Medical Research, Taichung Veterans General Hospital, Taichung 407, Taiwan; Institute of Biomedical Sciences, National Chung Hsing University, Taichung 402, Taiwan; Center for General Education, Tunghai University, Taichung 407, Taiwan; Department of Nursing, HungKuang University, Taichung 433, Taiwan.
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Lee JH, Jang EJ, Seo HL, Ku SK, Lee JR, Shin SS, Park SD, Kim SC, Kim YW. Sauchinone attenuates liver fibrosis and hepatic stellate cell activation through TGF-β/Smad signaling pathway. Chem Biol Interact 2014; 224:58-67. [PMID: 25451574 DOI: 10.1016/j.cbi.2014.10.005] [Citation(s) in RCA: 51] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2014] [Revised: 09/11/2014] [Accepted: 10/06/2014] [Indexed: 12/28/2022]
Abstract
Hepatic stellate cells (HSCs) are key mediators of fibrogenesis, and the regulation of their activation is now viewed as an attractive target for the treatment of liver fibrosis. Here, the authors investigated the ability of sauchinone, an active lignan found in Saururus chinensis, to regulate the activation of HSCs, to prevent liver fibrosis, and to inhibit oxidative stress in vivo and in vitro. Blood biochemistry and histopathology were assessed in CCl4-induced mouse model of liver fibrosis to investigate the effects of sauchinone. In addition, transforming growth factor-β1 (TGF-β1)-activated LX-2 cells (a human HSC line) were used to investigate the in vitro effects of sauchinone. Sauchinone significantly inhibited liver fibrosis, as indicated by decreases in regions of hepatic degeneration, inflammatory cell infiltration, and the intensity of α-smooth muscle actin staining in mice. Sauchinone blocked the TGF-β1-induced phosphorylation of Smad 2/3 and the transcript levels of plasminogen activator inhibitor-1 and matrix metalloproteinase-2 as well as autophagy in HSCs. Furthermore, sauchinone inhibited oxidative stress, as assessed by stainings of 4-hydroxynonenal and nitrotyrosine: these events may have a role in its inhibitory effects on HSCs activation. Sauchinone attenuated CCl4-induced liver fibrosis and TGF-β1-induced HSCs activation, which might be, at least in part, mediated by suppressing autophagy and oxidative stress in HSCs.
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Affiliation(s)
- Ju-Hee Lee
- College of Oriental Medicine, Daegu Haany University, Daegu 706-828, Republic of Korea
| | - Eun Jeong Jang
- College of Oriental Medicine, Daegu Haany University, Daegu 706-828, Republic of Korea
| | - Hye Lim Seo
- College of Oriental Medicine, Daegu Haany University, Daegu 706-828, Republic of Korea
| | - Sae Kwang Ku
- College of Oriental Medicine, Daegu Haany University, Daegu 706-828, Republic of Korea
| | - Jong Rok Lee
- College of Oriental Medicine, Daegu Haany University, Daegu 706-828, Republic of Korea
| | - Soon Shik Shin
- College of Oriental Medicine, Dongeui University, Busan 614-851, Republic of Korea
| | - Sun-Dong Park
- College of Oriental Medicine, Dongguk University, Gyeongju, Gyeongbuk 780-714, Republic of Korea
| | - Sang Chan Kim
- College of Oriental Medicine, Daegu Haany University, Daegu 706-828, Republic of Korea
| | - Young Woo Kim
- College of Oriental Medicine, Daegu Haany University, Daegu 706-828, Republic of Korea.
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Peverill W, Powell LW, Skoien R. Evolving concepts in the pathogenesis of NASH: beyond steatosis and inflammation. Int J Mol Sci 2014; 15:8591-638. [PMID: 24830559 PMCID: PMC4057750 DOI: 10.3390/ijms15058591] [Citation(s) in RCA: 287] [Impact Index Per Article: 26.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2014] [Revised: 03/20/2014] [Accepted: 04/17/2014] [Indexed: 12/12/2022] Open
Abstract
Non-alcoholic steatohepatitis (NASH) is characterised by hepatic steatosis and inflammation and, in some patients, progressive fibrosis leading to cirrhosis. An understanding of the pathogenesis of NASH is still evolving but current evidence suggests multiple metabolic factors critically disrupt homeostasis and induce an inflammatory cascade and ensuing fibrosis. The mechanisms underlying these changes and the complex inter-cellular interactions that mediate fibrogenesis are yet to be fully elucidated. Lipotoxicity, in the setting of excess free fatty acids, obesity, and insulin resistance, appears to be the central driver of cellular injury via oxidative stress. Hepatocyte apoptosis and/or senescence contribute to activation of the inflammasome via a variety of intra- and inter-cellular signalling mechanisms leading to fibrosis. Current evidence suggests that periportal components, including the ductular reaction and expansion of the hepatic progenitor cell compartment, may be involved and that the Th17 response may mediate disease progression. This review aims to provide an overview of the pathogenesis of NASH and summarises the evidence pertaining to key mechanisms implicated in the transition from steatosis and inflammation to fibrosis. Currently there are limited treatments for NASH although an increasing understanding of its pathogenesis will likely improve the development and use of interventions in the future.
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Affiliation(s)
- William Peverill
- Department of Gastroenterology and Hepatology, Royal Brisbane and Women's Hospital, Brisbane 4029, Australia.
| | - Lawrie W Powell
- Department of Gastroenterology and Hepatology, Royal Brisbane and Women's Hospital, Brisbane 4029, Australia.
| | - Richard Skoien
- Department of Gastroenterology and Hepatology, Royal Brisbane and Women's Hospital, Brisbane 4029, Australia.
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Morin ameliorates chemically induced liver fibrosis in vivo and inhibits stellate cell proliferation in vitro by suppressing Wnt/β-catenin signaling. Toxicol Appl Pharmacol 2014; 277:210-20. [PMID: 24657339 DOI: 10.1016/j.taap.2014.03.008] [Citation(s) in RCA: 63] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2014] [Revised: 03/05/2014] [Accepted: 03/10/2014] [Indexed: 12/11/2022]
Abstract
The anti-fibrotic effect of morin was examined in LX-2 cells (culture-activated human hepatic stellate cells) and in diethylnitrosamine induced rat model of liver fibrosis. The in vitro study was designed to determine whether morin affects the survival of cultured LX-2 cells, while the in vivo study was designed to evaluate the antioxidant and anti-fibrotic efficacy of morin on diethylnitrosamine induced liver fibrosis in male albino Wistar rat. The activities of liver function enzymes in serum, liver lipid peroxide levels, activities of serum antioxidant enzymes and liver architecture were monitored to cast light on the antioxidant and hepatoprotective nature of morin. To establish the anti-fibrotic effects of morin, the levels of key Wnt signaling molecules which are strongly associated with the signal transduction pathway of HSC activation were measured. Overall, from the in vitro results, it was observed that morin at 50 μM concentration inhibited the proliferation of cultured LX-2 cells, inhibited Wnt signaling and induced G1 cell cycle arrest. The in vivo results further confirmed that morin by downregulating the expressions of GSK-3β, β-catenin and cyclin D1 ameliorated DEN-induced liver fibrosis. Hence morin could be employed as a promising chemopreventive natural supplement for liver fibrosis.
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Houldsworth A, Metzner M, Shaw S, Kaminski E, Demaine AG, Cramp ME. Polymorphic differences in SOD-2 may influence HCV viral clearance. J Med Virol 2014; 86:941-7. [PMID: 24610415 DOI: 10.1002/jmv.23923] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 02/11/2014] [Indexed: 02/06/2023]
Abstract
Hepatitis C virus (HCV) is a pathogen causing chronic hepatitis, cirrhosis, and liver cancer occurring in about 3% of the world's population. Most individuals infected with HCV develop persistent viremia. Oxidative stress may play an important role in the pathogenesis of a number of diseases including HCV infection and diabetes mellitus. Polymorphisms in the antioxidant genes may determine cellular oxidative stress levels as a primary pathogenic role in HCV and/or in its complications. Patients with HCV and normal, healthy controls were investigated for a superoxide dismutase (SOD-2) polymorphism in the mitochondrial targeting sequence with Ala/Val (C-9T) substitution. Polymorphisms in antioxidant gene SOD-2 were carried out by PCR, restriction fragment length polymorphism assays and by polyacrylamide gel electrophoresis. For the SOD-2 polymorphism, the RNA positive group showed a higher percentage of "CT" genotype than the RNA negative group (89.3% vs. 66.1%, P = 0.001, χ(2) = 11.9). The RNA negative group had more TT genotypes than the RNA positive group (27.4% vs. 6.80%, P = 0.01, χ(2) = 11.6). The exposed uninfected group had an increased frequency of the "CT" genotype (86.2% vs. 66.1%, P = 0.02, χ(2) = 5.5). The RNA positives had a higher frequency of the "CT" from the normal controls (72.1% vs. 89.2%, P = 0.005, χ(2) = 7.8).
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Affiliation(s)
- Annwyne Houldsworth
- Hepatology and Molecular Medicine Research Groups, Plymouth University Peninsula School of Medicine and Dentistry (PU-PSMD), Plymouth, United Kingdom
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Gressner OA, Gao C. Monitoring fibrogenic progression in the liver. Clin Chim Acta 2014; 433:111-22. [PMID: 24607331 DOI: 10.1016/j.cca.2014.02.021] [Citation(s) in RCA: 35] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/26/2013] [Revised: 02/21/2014] [Accepted: 02/23/2014] [Indexed: 02/07/2023]
Abstract
The clinical course of chronic liver diseases is significantly dependent on the progression rate of fibrosis which is the unstructured replacement of injured parenchyma by extracellular matrix. Despite intensive studies, the clinical opportunities for patients with fibrosing liver diseases have not improved. This will be changed by increasing knowledge of new pathogenetic mechanisms, which complement the "canonical principle" of fibrogenesis. The latter is based on the activation of hepatic stellate cells and their transdifferentiation to myofibroblasts induced by hepatocellular injury and consecutive inflammatory mediators such as TGF-β. Stellate cells express a broad spectrum of matrix components. New mechanisms indicate that the heterogeneous pool of (myo-)fibroblasts can be supplemented by epithelial-mesenchymal transition (EMT) from cholangiocytes and potentially also from hepatocytes to fibroblasts, by influx of bone marrow-derived fibrocytes in the damaged liver tissue and by differentiation of a subgroup of monocytes to fibroblasts after homing in the damaged tissue. These processes are regulated by the cytokines TGF-β and BMP-7, chemokines, colony-stimulating factors, metalloproteinases and numerous trapping proteins. They offer innovative diagnostic and therapeutic options. As an example, modulation of TGF-β/BMP-7 ratio changes the rate of EMT, and so the simultaneous determination of these parameters and of the connective tissue growth factor (CTGF) in serum might provide information on fibrogenic activity. Also, proteomic and glycomic approaches of serum are under investigation to set up specific protein profiles in patients with liver fibrosis. The aim of this article is to present the current pathogenetic concepts of liver fibrosis and to discuss established and novel diagnostic approaches to reflect the process of hepatic fibrogenesis in the medical laboratory.
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Affiliation(s)
| | - Chunfang Gao
- Department of Laboratory Medicine, Eastern Hepatobiliary Surgical Hospital, Second Military Medical University, Shanghai, China.
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Ji HF, Sun Y, Shen L. Effect of vitamin E supplementation on aminotransferase levels in patients with NAFLD, NASH, and CHC: results from a meta-analysis. Nutrition 2014; 30:986-91. [PMID: 24976430 DOI: 10.1016/j.nut.2014.01.016] [Citation(s) in RCA: 50] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/04/2013] [Revised: 01/25/2014] [Accepted: 01/25/2014] [Indexed: 01/06/2023]
Abstract
OBJECTIVE The antioxidant vitamin E has been extensively employed to treat chronic liver diseases. The aim of this study was to assess the effect of vitamin E supplementation in lowering alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels in patients with nonalcoholic fatty liver disease (NAFLD), nonalcoholic steatohepatitis (NASH), and chronic hepatitis C (CHC). METHODS We searched all publications in PubMed, Web of Science, and Cochrane Library databases up to June 2013. In total, eight articles met the eligibility criteria, among which, two studies about NAFLD, four studies about NASH, and three studies about CHC, were identified and included in the meta-analysis. RESULTS According to standardized mean difference and 95% confidence interval, 12.19 (-4.08 to 28.46) for ALT and 6.84 (-3.18 to 16.86) for AST in patients with NAFLD, 4.54 (1.62-7.46) for ALT and 3.55 (1.39-5.71) for AST in patients with NASH, and 0.61 (0.20-1.02) for ALT and 0.68 (0.07-1.29) for AST in patients with CHC, vitamin E supplementation could optimize ALT and AST levels in patients with NASH and CHC, although it was not statistically significantly associated with reduced ALT and AST levels in patients with NAFLD. CONCLUSION To summarize, the evidence currently available supported the theory that vitamin E supplementation can optimize aminotransferase levels for patients with NAFLD, NASH, and CHC, and more well-designed, large-scale clinical trials are encouraged to examine the therapeutic effect of vitamin E for these disorders.
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Affiliation(s)
- Hong-Fang Ji
- Shandong Provincial Research Center for Bioinformatic Engineering and Technique, Shandong University of Technology, Zibo, P. R. China.
| | - Yan Sun
- Shandong Provincial Research Center for Bioinformatic Engineering and Technique, Shandong University of Technology, Zibo, P. R. China
| | - Liang Shen
- Shandong Provincial Research Center for Bioinformatic Engineering and Technique, Shandong University of Technology, Zibo, P. R. China.
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Najimi M, Stéphenne X, Sempoux C, Sokal E. Regulation of hepatic EAAT-2 glutamate transporter expression in human liver cholestasis. World J Gastroenterol 2014; 20:1554-1564. [PMID: 24587631 PMCID: PMC3925864 DOI: 10.3748/wjg.v20.i6.1554] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/23/2013] [Revised: 08/27/2013] [Accepted: 09/17/2013] [Indexed: 02/06/2023] Open
Abstract
AIM: To investigate the activity and expression of EAAT2 glutamate transporter in both in vitro and in vivo models of cholestasis.
METHODS: This study was conducted on human hepatoblastoma HepG2 cell cultures, the liver of bile duct ligated rats and human specimens from cholestatic patients. EAAT2 glutamate transporter activity and expression were analyzed using a substrate uptake assay, immunofluorescence, reverse transcription-polymerase chain reaction, and immunohistochemistry, respectively.
RESULTS: In HepG2 cells, cholestasis was mimicked by treating cells with the protein kinase C activator, phorbol 12-myristate 13-acetate. Under such conditions, EAAT2 transporter activity was decreased both at the level of substrate affinity and maximal transport velocity. The decreased uptake was correlated with intracellular translocation of EAAT2 molecules as demonstrated using immunofluorescence. In the liver of bile duct ligated rats, an increase in EAAT2 transporter protein expression in hepatocytes was demonstrated using immunohistochemistry. The same findings were observed in human liver specimens of cholestasis in which high levels of γ-glutamyl transpeptidase were documented in patients with biliary atresia and progressive familial intrahepatic cholestasis type 3.
CONCLUSION: This study demonstrates the alteration in glutamate handling by hepatocytes in liver cholestasis and suggests a potential cross-talk between glutamatergic and bile systems.
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Kang KH, Qian ZJ, Ryu B, Karadeniz F, Kim D, Kim SK. Hepatic Fibrosis Inhibitory Effect of Peptides Isolated from Navicula incerta on TGF-β1 Induced Activation of LX-2 Human Hepatic Stellate Cells. Prev Nutr Food Sci 2014; 18:124-32. [PMID: 24471121 PMCID: PMC3892505 DOI: 10.3746/pnf.2013.18.2.124] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/07/2013] [Accepted: 05/27/2013] [Indexed: 12/31/2022] Open
Abstract
In this study, novel peptides (NIPP-1, NIPP-2) derived from Navicula incerta (microalgae) protein hydrolysate were explored for their inhibitory effects on collagen release in hepatic fibrosis with the investigation of its underlying mechanism of action. TGF-β1 activated fibrosis in LX-2 cells was examined in the presence or absence of purified peptides NIPP-1 and NIPP-2. Besides the mechanisms of liver cell injury, protective effects of NIPP-1 and NIPP-2 were studied to show the protective mechanism against TGF-β1 stimulated fibrogenesis. Our results showed that the core protein of NIPP-1 peptide prevented fibril formation of type I collagen, elevated the MMP level and inhibited TIMP production in a dose-dependent manner. The treatment of NIPP-1 and NIPP-2 on TGF-β1 induced LX-2 cells alleviated hepatic fibrosis. Moreover, α-SMA, TIMPs, collagen and PDGF in the NIPP-1 treated groups were significantly decreased. Therefore, it could be suggested that NIPP-1 has potential to be used in anti-fibrosis treatment.
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Affiliation(s)
- Kyong-Hwa Kang
- Marine Bioprocess Research Center, Pukyong National University, Busan 608-737, Korea
| | - Zhong-Ji Qian
- Oceanic Life Research Center, Chosun University, Jeonnam 543-700, Korea
| | - Bomi Ryu
- Marine Bioprocess Research Center, Pukyong National University, Busan 608-737, Korea
| | - Fatih Karadeniz
- Marine Bioprocess Research Center, Pukyong National University, Busan 608-737, Korea
| | - Daekyung Kim
- Marine Bio Research Team, Korea Basic Science Institute (KBSI), Jeju 690-140, Korea
| | - Se-Kwon Kim
- Marine Bioprocess Research Center, Pukyong National University, Busan 608-737, Korea ; Department of Chemistry, Pukyong National University, Busan 608-737, Korea
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den Hartog GJM, Qi S, van Tilburg JHO, Koek GH, Bast A. Superoxide anion radicals activate hepatic stellate cells after entry through chloride channels: a new target in liver fibrosis. Eur J Pharmacol 2013; 724:140-4. [PMID: 24378345 DOI: 10.1016/j.ejphar.2013.12.033] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2013] [Revised: 12/17/2013] [Accepted: 12/19/2013] [Indexed: 12/13/2022]
Abstract
It is generally accepted that reactive oxygen species (ROS) play an important role in the pathogenesis of liver fibrosis. ROS, however, constitute a group of species with varying properties making it likely that their contribution to the pathological mechanism varies. LX-2 hepatic stellate cells (HSCs) were exposed to superoxide anion radicals (O2(·-)) generated by xanthine and xanthine oxidase. To rule out that the activation of HSCs is due to hydrogen peroxide derived from O2(·-), control incubations with copper, zinc-superoxide dismutase and tempol were studied as well. Influx of O2(·-) activated HSCs, evidenced by the expression of α-smooth muscle actin and the secretion of transforming growth factor β1 and collagen. We further found that blockade of chloride channels with 4,4'-diisothiocyanatostilbene-2,2'-disulfonic acid (DIDS), 5-nitro-2-(3-phenylpropyl-amino) benzoic acid (NPPB) or indanyloxyacetic acid (IAA-94) prevented the increase of intracellular O2(·-) levels as well as the activation of HSCs. These findings suggest that O2(·-) is involved in the development of liver fibrosis and that entry of O2(·-), through chloride channels, in stellate cells is critical for their activation. This study provides new insight into the mechanism by which ROS induce liver fibrosis. Furthermore, our data suggest that chloride channels constitute a potential target for new anti-fibrotic drugs.
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Affiliation(s)
- Gertjan J M den Hartog
- Maastricht University, Faculty of Health, Medicine and Life Sciences, Department of Toxicology, Maastricht, The Netherlands.
| | - Shufan Qi
- Maastricht University, Faculty of Health, Medicine and Life Sciences, Department of Toxicology, Maastricht, The Netherlands
| | - Jonathan H O van Tilburg
- Maastricht University, Faculty of Health, Medicine and Life Sciences, Department of Human Biology, Maastricht, The Netherlands
| | - Ger H Koek
- Department of Internal Medicine, Division of Gastroenterology and Hepatology, Maastricht University Medical Centre, Maastricht, The Netherlands
| | - Aalt Bast
- Maastricht University, Faculty of Health, Medicine and Life Sciences, Department of Toxicology, Maastricht, The Netherlands
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Zhao Y, Zhou G, Wang J, Jia L, Zhang P, Li R, Shan L, Liu B, Song X, Liu S, Xiao X. Paeoniflorin protects against ANIT-induced cholestasis by ameliorating oxidative stress in rats. Food Chem Toxicol 2013; 58:242-8. [DOI: 10.1016/j.fct.2013.04.030] [Citation(s) in RCA: 56] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2012] [Revised: 04/06/2013] [Accepted: 04/15/2013] [Indexed: 12/14/2022]
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Li R, Dai G, Zhao M, Zhang Y, Hui L, Zhang X, Jin B. Preventative effect of Astragalus flavescens on hepatic fibrosis in rats and its mechanism of action. Exp Ther Med 2013; 6:904-908. [PMID: 24137287 PMCID: PMC3797310 DOI: 10.3892/etm.2013.1232] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2013] [Accepted: 06/27/2013] [Indexed: 01/11/2023] Open
Abstract
The aim of this study was to investigate the preventative effect of Astragalus flavescens on hepatic fibrosis in rats and its mechanism of action. A total of 60 rats were randomly divided into normal control, model control, high-dose treatment and low-dose treatment groups, and a hepatic fibrosis model was established. The high- and low-dose treatment groups were treated with 2 g/100 g and 0.5 g/100 g Astragalus flavescens, respectively, once a day. Eight weeks following the initiation of treatment, the liver specimens of the rats were stained and observed under a light microscope. Hepatic fibrosis indices, specifically, type III precollagen (PC III), type IV collagen (C IV), hyaluronic acid (HA) and laminin (LN), were detected. Furthermore, the expression and localization of the hepatic fibrosis-related factors transforming growth factor-β1 (TGF-β1), connective tissue growth factor (CTGF) and platelet-derived growth factor-BB (PDGF-BB) were determined. The serum levels of hepatic fibrosis indices, and the liver tissue levels of hepatic fibrosis-related factors and collagen surface density in the model control group and the high- and low-dose treatment groups were significantly higher compared with those of the normal control group (P<0.05). In addition, the values in the two treatment groups were significantly lower compared with those of the model control group (P<0.05). The present study demonstrated that Astragalus flavescens effectively prevents hepatic fibrosis in rats. A possible mechanism for this is that it may reduce the expression levels of TGF-β1, PDGF-BB and CTGF, thereby inhibiting the activation of hepatic stellate cells and specifically blocking the signal transduction pathway of hepatic fibrosis.
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Affiliation(s)
- Rong Li
- Department of Gastroenterology, The First Hospital of Xi'an City, Xi'an, Shaanxi 710002; ; The Third Department of Internal Medicine, The Fifth Hospital of Xi'an City, Xi'an, Shaanxi 710082
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