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Huang BH, Guo ZW, Lv BH, Zhao X, Li YB, Lv WL. A role for curcumin in preventing liver fibrosis in animals: a systematic review and meta-analysis. Front Pharmacol 2024; 15:1396834. [PMID: 38855740 PMCID: PMC11157132 DOI: 10.3389/fphar.2024.1396834] [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: 03/06/2024] [Accepted: 04/30/2024] [Indexed: 06/11/2024] Open
Abstract
Objective This meta-analysis aimed to determine the efficacy of curcumin in preventing liver fibrosis in animal models. Methods A systematic search was conducted on studies published from establishment to November 2023 in PubMed, Web of Science, Embase, Cochrane Library, and other databases. The methodological quality was assessed using Sycle's RoB tool. An analysis of sensitivity and subgroups were performed when high heterogeneity was observed. A funnel plot was used to assess publication bias. Results This meta-analysis included 24 studies involving 440 animals with methodological quality scores ranging from 4 to 6. The results demonstrated that curcumin treatment significantly improved Aspartate aminotransferase (AST) [standard mean difference (SMD) = -3.90, 95% confidence interval (CI) (-4.96, -2.83), p < 0.01, I2 = 85.9%], Alanine aminotransferase (ALT)[SMD = - 4.40, 95% CI (-5.40, -3.40), p < 0.01, I2 = 81.2%]. Sensitivity analysis of AST and ALT confirmed the stability and reliability of the results obtained. However, the funnel plot exhibited asymmetry. Subgroup analysis based on species and animal models revealed statistically significant differences among subgroups. Furthermore, curcumin therapy improved fibrosis degree, oxidative stress level, inflammation level, and liver synthesis function in animal models of liver fibrosis. Conclusion Curcumin intervention not only mitigates liver fibrosis but also enhances liver function, while concurrently modulating inflammatory responses and antioxidant capacity in animal models. This result provided a strong basis for further large-scale animal studies as well as clinical trials in humans in the future. Systematic Review Registration: https://www.crd.york.ac.uk/prospero/, identifier CRD42024502671.
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Affiliation(s)
- Bo-Hao Huang
- Department of Infection, Guang’an Men Hospital, China Academy of Chinese Medical Sciences, Beijing, China
- Graduate school, Beijing University of Chinese Medicine, Beijing, China
| | - Zi-Wei Guo
- Department of Infection, Guang’an Men Hospital, China Academy of Chinese Medical Sciences, Beijing, China
| | - Bo-Han Lv
- Department of Infection, Guang’an Men Hospital, China Academy of Chinese Medical Sciences, Beijing, China
| | - Xin Zhao
- Department of Infection, Guang’an Men Hospital, China Academy of Chinese Medical Sciences, Beijing, China
| | - Yan-Bo Li
- Department of Infection, Guang’an Men Hospital, China Academy of Chinese Medical Sciences, Beijing, China
| | - Wen-Liang Lv
- Department of Infection, Guang’an Men Hospital, China Academy of Chinese Medical Sciences, Beijing, China
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Chou AH, Lee HC, Liao CC, Yu HP, Liu FC. ERK/NF-kB/COX-2 Signaling Pathway Plays a Key Role in Curcumin Protection against Acetaminophen-Induced Liver Injury. Life (Basel) 2023; 13:2150. [PMID: 38004290 PMCID: PMC10672507 DOI: 10.3390/life13112150] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2023] [Revised: 10/23/2023] [Accepted: 10/30/2023] [Indexed: 11/26/2023] Open
Abstract
Recent experimental studies have highlighted the beneficial effects of curcumin on liver injury induced by acetaminophen (APAP). However, the specific molecular mechanisms underlying curcumin's hepatoprotective effects against APAP-induced liver injury remain to be fully elucidated. This study aimed to investigate the therapeutic effect of curcumin on APAP-induced liver injury using a mouse model. In the experiment, mice were subjected to an intraperitoneal hepatotoxic dose of APAP (300 mg/kg) to induce hepatotoxicity. After 30 min of APAP administration, the mice were treated with different concentrations of curcumin (0, 10, 25, or 50 mg/kg). After 16 h, mice with hepatotoxicity showed elevated levels of serum alanine transaminase (ALT), aspartate transaminase (AST), hepatic myeloperoxidase (MPO), TNF-α, and IL-6, and decreased levels of glutathione (GSH). Moreover, there was an increased infiltration of neutrophils and macrophages following intraperitoneal injection of APAP. However, curcumin-treated mice displayed a pronounced reduction in serum ALT, AST, hepatic MPO, TNF-α, and IL-6 levels, coupled with a notable elevation in GSH levels compared to the APAP-treated hepatotoxic mice. Moreover, curcumin treatment led to reduced infiltration of neutrophils and macrophages. Additionally, curcumin inhibited the phosphorylation of ERK and NF-kB proteins while reducing the expression of cyclooxygenase-2 (COX-2). These findings highlight the hepatoprotective potential of curcumin against APAP-induced liver injury through the suppression of the ERK, NF-kB, and COX-2 signaling pathways.
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Affiliation(s)
- An-Hsun Chou
- Department of Anesthesiology, Chang Gung Memorial Hospital, Linkou Branch, Taoyuan 333, Taiwan; (A.-H.C.); (H.-C.L.); (C.-C.L.); (H.-P.Y.)
- College of Medicine, Chang Gung University, Taoyuan 333, Taiwan
| | - Hung-Chen Lee
- Department of Anesthesiology, Chang Gung Memorial Hospital, Linkou Branch, Taoyuan 333, Taiwan; (A.-H.C.); (H.-C.L.); (C.-C.L.); (H.-P.Y.)
- College of Medicine, Chang Gung University, Taoyuan 333, Taiwan
| | - Chia-Chih Liao
- Department of Anesthesiology, Chang Gung Memorial Hospital, Linkou Branch, Taoyuan 333, Taiwan; (A.-H.C.); (H.-C.L.); (C.-C.L.); (H.-P.Y.)
- College of Medicine, Chang Gung University, Taoyuan 333, Taiwan
| | - Huang-Ping Yu
- Department of Anesthesiology, Chang Gung Memorial Hospital, Linkou Branch, Taoyuan 333, Taiwan; (A.-H.C.); (H.-C.L.); (C.-C.L.); (H.-P.Y.)
- College of Medicine, Chang Gung University, Taoyuan 333, Taiwan
| | - Fu-Chao Liu
- Department of Anesthesiology, Chang Gung Memorial Hospital, Linkou Branch, Taoyuan 333, Taiwan; (A.-H.C.); (H.-C.L.); (C.-C.L.); (H.-P.Y.)
- College of Medicine, Chang Gung University, Taoyuan 333, Taiwan
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Singh S, Sharma N, Shukla S, Behl T, Gupta S, Anwer MK, Vargas-De-La-Cruz C, Bungau SG, Brisc C. Understanding the Potential Role of Nanotechnology in Liver Fibrosis: A Paradigm in Therapeutics. Molecules 2023; 28:molecules28062811. [PMID: 36985782 PMCID: PMC10057127 DOI: 10.3390/molecules28062811] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2023] [Revised: 03/15/2023] [Accepted: 03/17/2023] [Indexed: 03/30/2023] Open
Abstract
The liver is a vital organ that plays a crucial role in the physiological operation of the human body. The liver controls the body's detoxification processes as well as the storage and breakdown of red blood cells, plasma protein and hormone production, and red blood cell destruction; therefore, it is vulnerable to their harmful effects, making it more prone to illness. The most frequent complications of chronic liver conditions include cirrhosis, fatty liver, liver fibrosis, hepatitis, and illnesses brought on by alcohol and drugs. Hepatic fibrosis involves the activation of hepatic stellate cells to cause persistent liver damage through the accumulation of cytosolic matrix proteins. The purpose of this review is to educate a concise discussion of the epidemiology of chronic liver disease, the pathogenesis and pathophysiology of liver fibrosis, the symptoms of liver fibrosis progression and regression, the clinical evaluation of liver fibrosis and the research into nanotechnology-based synthetic and herbal treatments for the liver fibrosis is summarized in this article. The herbal remedies summarized in this review article include epigallocathechin-3-gallate, silymarin, oxymatrine, curcumin, tetrandrine, glycyrrhetinic acid, salvianolic acid, plumbagin, Scutellaria baicalnsis Georgi, astragalosides, hawthorn extract, and andrographolides.
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Affiliation(s)
- Sukhbir Singh
- Department of Pharmaceutics, MM College of Pharmacy, Maharishi Markandeshwar (Deemed to be University), Mullana-Ambala 133207, Haryana, India
| | - Neelam Sharma
- Department of Pharmaceutics, MM College of Pharmacy, Maharishi Markandeshwar (Deemed to be University), Mullana-Ambala 133207, Haryana, India
| | - Saurabh Shukla
- Chitkara College of Pharmacy, Chitkara University, Punjab 140401, India
| | - Tapan Behl
- School of Health Sciences &Technology, University of Petroleum and Energy Studies, Dehradun 248007, Uttarakhand, India
| | - Sumeet Gupta
- Department of Pharmacology, MM College of Pharmacy, Maharishi Markandeshwar (Deemed to be University), Mullana-Ambala 133207, Haryana, India
| | - Md Khalid Anwer
- Department of Pharmaceutics, College of Pharmacy, Prince Sattam Bin Abdulaziz University, Alkharj 11942, Saudi Arabia
| | - Celia Vargas-De-La-Cruz
- Department of Pharmacology, Bromatology and Toxicology, Faculty of Pharmacy and Biochemistry, Universidad Nacional Mayor de San Marcos, Lima 150001, Peru
- E-Health Research Center, Universidad de Ciencias y Humanidades, Lima 15001, Peru
| | - Simona Gabriela Bungau
- Department of Pharmacy, Faculty of Medicine and Pharmacy, University of Oradea, 410028 Oradea, Romania
- Doctoral School of Biomedical Sciences, University of Oradea, 410087 Oradea, Romania
| | - Cristina Brisc
- Department of Medical Disciplines, Faculty of Medicine and Pharmacy, University of Oradea, 410073 Oradea, Romania
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Sharma V, Sharma S, Akarshit, Kumar R, Sharma P, Mittal A, Kumar R, Sharma M. Effect of curcumin and zingiberone on non alcoholic fatty liver disease (NAFLD). AIP CONFERENCE PROCEEDINGS 2023; 2804:020254. [DOI: 10.1063/5.0162870] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
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Zheng L, Zhao Z, Lin J, Li H, Wu G, Qi X, Lou X, Bao Y, Huo H, Luo M. Telmisartan relieves liver fibrosis and portal hypertension by improving vascular remodeling and sinusoidal dysfunction. Eur J Pharmacol 2022; 915:174713. [PMID: 34942161 DOI: 10.1016/j.ejphar.2021.174713] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2021] [Revised: 12/13/2021] [Accepted: 12/16/2021] [Indexed: 12/23/2022]
Abstract
BACKGROUNDS Telmisartan(TEL) has demonstrated anti-fibrotic and blood pressure lowering effect in various diseases. In this study, we aimed to explore the beneficial effects of TEL on portal hypertension(PHT). METHODS Two models of cirrhosis-induced PHT were involved including carbon tetrachloride injection(CCl4) and bile duct ligation(BDL). Rats were orally gavaged with TEL for 4 weeks. After that, the portal pressure(PP) was determined, and liver and mesenteric tissue specimens were collected to evaluate inflammatory response, liver fibrosis, vascular remodeling, angiogenesis, etc. RESULTS: In CCl4 PHT models, TEL decreased PP significantly from 12.79 ± 2.92 to 6.91 ± 1.19 mmHg(p < 0.05). In inflammatory response, hepatic expressions of interleukin(IL)-6, lipopolysaccharide(LPS), and tumor necrosis factor-α(TNF-α) were significantly decreased after TEL treatment. Moreover, in the liver fibrotic area, the expressions of α-smooth muscle actin(α-SMA), collagen1a1(Col1a1), desmin, transforming growth factor-β(TGF-β), and hydroxyproline, and serum hyaluronic acid were significantly decreased after TEL treatment. Additionally, the expressions of von Willebrand factor(vWF), vascular endothelial growth factor(VEGF) and platelet-derived growth factor-β(PDGF-β), matrix metallopeptidase(MMP)-2, and MMP-9 were ameliorated in liver sinusoid, while the expressions of MMP-2 and vWF were reduced in mesenteric arteries after TEL treatment. Meanwhile, TEL treatment up-regulated the hepatic expressions of an anti-fibrotic factor Krüppel-like factor-4(KLF-4) and its downstream endothelial nitric oxide synthase(eNOS) in rats with PHT. The performance of TEL in BDL model was similar but slightly weaker. CONCLUSIONS TEL ameliorated the cirrhosis-induced PHT by reducing liver fibrosis, inflammation responses, angiogenesis, and vascular remodeling. Collectively, KLF-4 and eNOS were the possible molecular targets for the management of cirrhosis-associated PHT.
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Affiliation(s)
- Lei Zheng
- Department of General Surgery, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Zhifeng Zhao
- Department of General Surgery, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Jiayun Lin
- Department of General Surgery, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Hongjie Li
- Department of General Surgery, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Guangbo Wu
- Department of General Surgery, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Xiaoliang Qi
- Department of General Surgery, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Xiaolou Lou
- Department of General Surgery, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Yongyang Bao
- Department of Pathology, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
| | - Haizhong Huo
- Department of General Surgery, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
| | - Meng Luo
- Department of General Surgery, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
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Hernández-Aquino E, Quezada-Ramírez MA, Silva-Olivares A, Ramos-Tovar E, Flores-Beltrán RE, Segovia J, Shibayama M, Muriel P. Curcumin downregulates Smad pathways and reduces hepatic stellate cells activation in experimental fibrosis. Ann Hepatol 2021; 19:497-506. [PMID: 32673649 DOI: 10.1016/j.aohep.2020.05.006] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/02/2020] [Revised: 05/06/2020] [Accepted: 05/28/2020] [Indexed: 02/04/2023]
Abstract
INTRODUCTION AND OBJECTIVES Curcumin, a polyphenol, is a natural compound that has been widely studied as a hepatoprotector; however, only a few studies have examined its ability to reduce fibrosis in previously established cirrhosis. The objective of this study was to investigate whether curcumin could reduce carbon tetrachloride (CCl4)-induced fibrosis and if so, to determine the action mechanisms involved in the reduction process. MATERIALS AND METHODS CCl4 was administered to male Wistar rats (400 mg/kg, three times a week, i. p.) for 12 weeks; curcumin (100 mg/kg body weight twice per day, p. o.) was administered from week 9-12 of CCl4 treatment. Biochemical markers of hepatic injury and oxidative stress were evaluated. Hematoxylin and eosin, Masson's trichrome stains, transmission electron microscopy; immunohistochemistry, and zymography assays were carried out. Moreover, Smad3 and α-SMA mRNA and protein levels were studied. Western blotting by TGF-β, CTGF, Col-I, MMP-13, NF-κB, IL-1, IL-10, Smad7, pSmad3, and pJNK proteins was developed. RESULTS AND CONCLUSIONS Curcumin reduced liver damage, oxidative stress, fibrosis, and restored normal activity of MMP-9 and MMP-2. Besides, curcumin restored NF-κB, IL-1, IL-10, TGF-β, CTGF, Col-I, MMP-13, and Smad7 protein levels. On the other hand, curcumin decreased JNK and Smad3 phosphorylation. Furthermore, curcumin treatment decreased α-SMA and Smad3 protein and mRNA levels. Curcumin normalized GSH, and NF-κB, JNK-Smad3, and TGF-β-Smad3 pathways, leading to a decrement in activated hepatic stellate cells, thereby producing its antifibrotic effects.
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Affiliation(s)
- Erika Hernández-Aquino
- Laboratory of Experimental Hepatology, Department of Pharmacology, Cinvestav-IPN, Av. Instituto Politécnico Nacional, Mexico City, Mexico
| | | | | | | | - Rosa E Flores-Beltrán
- Laboratory of Experimental Hepatology, Department of Pharmacology, Cinvestav-IPN, Av. Instituto Politécnico Nacional, Mexico City, Mexico
| | - José Segovia
- Department of Physiology, Biophysics and Neurosciences, Cinvestav-IPN, Mexico City, Mexico
| | - Mineko Shibayama
- Department of Infectomics and Molecular Pathogenesis, Cinvestav-IPN, Mexico City, Mexico
| | - Pablo Muriel
- Laboratory of Experimental Hepatology, Department of Pharmacology, Cinvestav-IPN, Av. Instituto Politécnico Nacional, Mexico City, Mexico.
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Khodarahmi A, Javidmehr D, Eshaghian A, Ghoreshi ZAS, Karimollah A, Yousefi H, Moradi A. Curcumin exerts hepatoprotection via overexpression of Paraoxonase-1 and its regulatory genes in rats undergone bile duct ligation. J Basic Clin Physiol Pharmacol 2020; 32:969-977. [PMID: 34592082 DOI: 10.1515/jbcpp-2020-0067] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2020] [Accepted: 08/14/2020] [Indexed: 01/08/2023]
Abstract
OBJECTIVES Curcumin is described as an antioxidant, hepato-protective and antifibrotic in liver fibrosis, although its mechanism is still not known. One of the models of the chronic liver disease stemming from oxidative stress and the generation of free radical has been considered to be bile duct ligation (BDL). Paraoxonase 1 (PON1) is a prominent antioxidant enzyme. Therefore, the objective of the present research is to assess the effects of curcumin on upregulation of PON1 in BDL rats. METHODS As predicted, the rats have been divided into the four groups of Sham, Sham + Cur (curcumin), BDL and BDL + Cur. We evaluated the efficacy of curcumin (100 mg/kg/day) on protein and gene expression of PON1 and regulatory genes contributed to the gene expression PON1 such as Sp1, PKCα, SREBP-2, AhR, JNK and regulation PON1 activity gene expression of Apo A1. RESULTS Curcumin attenuated alterations in liver histology, hepatic enzymes and the mRNA expression of fibrotic markers (p<0.05). In addition, curcumin increased significantly mRNA, protein expression of PON1 and mRNA of the genes that are contributed to the expression of PON1 such as Sp1, PKCα, SREBP-2, AhR, JNK and increased PON1 activity through upregulation of Apo A1 (p<0.05). CONCLUSIONS Cirrhosis progression may be inhibited by treatment with curcumin through the increased influence the expression and activity of PON1.
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Affiliation(s)
- Ameneh Khodarahmi
- Department of Biochemistry, School of Medicine, Shahid Sadoughi University of Medical Sciences and Health Services, Yazd, Iran
| | - Davoud Javidmehr
- Department of Biochemistry, School of Medicine, Shahid Sadoughi University of Medical Sciences and Health Services, Yazd, Iran
| | - Azam Eshaghian
- Department of Biochemistry, School of Medicine, Shahid Sadoughi University of Medical Sciences and Health Services, Yazd, Iran
| | - Zohreh-Al-Sadat Ghoreshi
- Department of Biochemistry, School of Medicine, Shahid Sadoughi University of Medical Sciences and Health Services, Yazd, Iran
| | - Alireza Karimollah
- Department of Pharmacology, School of Medicine, Shahid Sadoughi University of Medical Sciences, Yazd, Iran
| | - Hamidreza Yousefi
- Department of Biochemistry, School of Medicine, Shahid Sadoughi University of Medical Sciences and Health Services, Yazd, Iran
| | - Ali Moradi
- Department of Biochemistry, School of Medicine, Shahid Sadoughi University of Medical Sciences and Health Services, Yazd, Iran
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Ramos-Tovar E, Flores-Beltrán RE, Galindo-Gómez S, Camacho J, Tsutsumi V, Muriel P. An aqueous extract of Stevia rebaudiana variety Morita II prevents liver damage in a rat model of cirrhosis that mimics the human disease. Ann Hepatol 2020; 18:472-479. [PMID: 31053541 DOI: 10.1016/j.aohep.2018.10.002] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/13/2018] [Revised: 09/10/2018] [Accepted: 10/08/2018] [Indexed: 02/04/2023]
Abstract
INTRODUCTION AND AIM Stevia has exhibited antioxidant, antihyperglycemic, antihypertensive and anti-inflammatory properties in several in vivo and in vitro models. The objective of this study was to investigate the ability of an aqueous extract of stevia (AES) to prevent experimental cirrhosis in rats and to explore its mechanism of action. MATERIALS AND METHODS Liver cirrhosis was induced by administering carbon tetrachloride (CCl4) (400mg/kg by i.p. injection 3 times a week for 12 weeks); AES was administered (100mg/kg by gavage daily) during the CCl4 treatment. Fibrosis was evaluated with histological, biochemical and molecular approaches, and liver damage was assessed with standardized procedures. The profibrotic pathways were analyzed by western blotting, qRT-PCR and immunohistochemistry. RESULTS AND CONCLUSIONS Chronic CCl4 administration increased nuclear factor kappa B (NF-κB) and proinflammatory cytokine production as well as oxidative parameters such as lipid peroxidation and 4-hydroxynonenal levels, whereas GSH and nuclear factor-E2-related factor 2 (Nrf2) levels were decreased. CCl4 induced profibrogenic mediator expression, hepatic stellate cell (HSC) activation and, consequently, extracellular matrix production. AES exhibited antioxidant, anti-inflammatory and antifibrotic properties, probably because of its capacity to induce Nrf2 expression, reduce NF-κB expression and block several profibrogenic signaling pathways, subsequently inhibiting HSC activation and preventing fibrosis induced by chronic CCl4 administration.
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Affiliation(s)
- Erika Ramos-Tovar
- Laboratory of Experimental Hepatology, Department of Pharmacology, Cinvestav-IPN, Mexico City, Mexico
| | - Rosa E Flores-Beltrán
- Laboratory of Experimental Hepatology, Department of Pharmacology, Cinvestav-IPN, Mexico City, Mexico
| | - Silvia Galindo-Gómez
- Department of Infectomics and Molecular Pathogenesis, Cinvestav-IPN, Mexico City, Mexico
| | - Javier Camacho
- Department of Pharmacology, Cinvestav-IPN, Mexico City, Mexico
| | - Víctor Tsutsumi
- Department of Infectomics and Molecular Pathogenesis, Cinvestav-IPN, Mexico City, Mexico
| | - Pablo Muriel
- Laboratory of Experimental Hepatology, Department of Pharmacology, Cinvestav-IPN, Mexico City, Mexico.
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Chan YT, Wang N, Tan HY, Li S, Feng Y. Targeting Hepatic Stellate Cells for the Treatment of Liver Fibrosis by Natural Products: Is It the Dawning of a New Era? Front Pharmacol 2020; 11:548. [PMID: 32425789 PMCID: PMC7212390 DOI: 10.3389/fphar.2020.00548] [Citation(s) in RCA: 37] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2019] [Accepted: 04/09/2020] [Indexed: 12/12/2022] Open
Abstract
Liver fibrosis is a progressive liver damage condition that is worth studying widely. It is important to target and alleviate the disease at an early stage before turning into later cirrhosis or liver cancer. There are currently no direct medicines targeting the attenuation or reversal of liver fibrosis, and so there is an urgent need to look into this area. Traditional Chinese Medicine has a long history in using herbal medicines to treat liver diseases including fibrosis. It is time to integrate the ancient wisdom with modern science and technology to look for the best solution to the disease. In this review, the principal concept of the pathology of liver fibrosis will be described, and then some of the single compounds isolated from herbal medicines, including salvianolic acids, oxymatrine, curcumin, tetrandrine, etc. will be discussed from their effects to the molecular mechanism behind. Molecular targets of the compounds are analyzed by network pharmacology approach, and TGFβ/SMAD was identified as the most common pathway. This review serves to summarize the current findings of herbal medicines combining with modern medicines in the area of fibrosis. It hopefully provides insights in further pharmaceutical research directions.
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Affiliation(s)
| | | | | | | | - Yibin Feng
- School of Chinese Medicine, The University of Hong Kong, Hong Kong, Hong Kong
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YILDIRIM D, AKTÜRK OM, KOCAKUŞAK A, ÇAKIR M, SUNAMAK O, HUT A, ZENGİN AK, ÖZCAN M, AKI H, BALCI H. Skolosidal Ajanlardan Kaynaklanan Sklerozan Kolanjitin Önlenmesinde Halofuginon ve Ursodeoksikolik Asidin Etkileri. MUSTAFA KEMAL ÜNIVERSITESI TIP DERGISI 2020. [DOI: 10.17944/mkutfd.425288] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/11/2022] Open
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Nouri-Vaskeh M, Afshan H, Malek Mahdavi A, Alizadeh L, Fan X, Zarei M. Curcumin ameliorates health-related quality of life in patients with liver cirrhosis: A randomized, double-blind placebo-controlled trial. Complement Ther Med 2020; 49:102351. [PMID: 32147077 DOI: 10.1016/j.ctim.2020.102351] [Citation(s) in RCA: 22] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2019] [Revised: 02/16/2020] [Accepted: 02/18/2020] [Indexed: 02/07/2023] Open
Abstract
OBJECTIVES Current study aimed to find the effects of curcumin on quality of life (QoL) in liver cirrhotic patients. DESIGN In this randomized double-masked placebo-controlled trial, 70 cases with liver cirrhosis aged 20-70 years were randomly divided into two groups to receive 1000 mg/day curcumin (n = 35) or placebo (n = 35) for 12 weeks. The health-related QoL (HRQoL) was assessed by CLDQ, LDSI 2.0, and SF-36. RESULTS Fifty-eight patients (28 in curcumin and 30 in placebo groups) finished the research. Compared with baseline, overall scores as well as most of CLDQ domains (e.g. Fatigue, Emotional Function, Worry, Abdominal Symptoms, and Systemic Symptoms) and the Physical and Mental health (Total) scores and most of SF-36 domains (e.g. Physical Functioning, Bodily Pain, Vitality, Social Functioning, and Mental Health) increased considerably (P < 0.05) after curcumin administration. Furthermore, curcumin reduced most of LDSI 2.0 domains (e.g. Itch, Joint pain, Pain in the right upper abdomen, Sleeping during the day, Decreased appetite, Depression, Fear of complication, Jaundice, Hindrance in Financial Affairs, Change in use of time, Decreased sexual interest, and Decreased sexual activity) significantly (P < 0.05). Significant differences were noticed between two groups in CLDQ domains and overall scores, LDSI 2.0 domains and overall scores, SF-36 Physical and Mental health (total) scores and all its domains scores (P < 0.05), adjusting for baseline values and disease duration. CONCLUSIONS Curcumin improved QoL in liver cirrhotic patients according to CLDQ, LDSI 2.0, and SF-36 domains. Additional studies are warranted to consider curcumin as a safe, accessible, and low-cost complementary therapeutic option in cirrhosis.
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Affiliation(s)
- Masoud Nouri-Vaskeh
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran; Connective Tissue Diseases Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Hossein Afshan
- Liver and Gastrointestinal Diseases Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Aida Malek Mahdavi
- Connective Tissue Diseases Research Center, Tabriz University of Medical Sciences, Tabriz, Iran.
| | - Leila Alizadeh
- Liver and Gastrointestinal Diseases Research Center, Tabriz University of Medical Sciences, Tabriz, Iran.
| | - Xiude Fan
- Department of Infectious Diseases, The First Affiliated Hospital of Xi 'an Jiaotong University, Xi'an, 710061 China; Department of Inflammation and Immunity, Cleveland Clinic, Cleveland, 44195, USA
| | - Mohammad Zarei
- Departrment of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, USA; Center for Mitochondrial and Epigenomic Medicine, Children's Hospital of Philadelphia, Philadelphia, USA
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Nouri-Vaskeh M, Malek Mahdavi A, Afshan H, Alizadeh L, Zarei M. Effect of curcumin supplementation on disease severity in patients with liver cirrhosis: A randomized controlled trial. Phytother Res 2020; 34:1446-1454. [PMID: 32017253 DOI: 10.1002/ptr.6620] [Citation(s) in RCA: 35] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2019] [Revised: 01/03/2020] [Accepted: 01/13/2020] [Indexed: 01/15/2023]
Abstract
Recent reports indicated that curcumin had beneficial effects in animal models of liver injury and cirrhosis. Current study aimed to investigate the effects of curcumin supplementation in patients with liver cirrhosis. In this randomized double-blind placebo-controlled trial, 70 patients with liver cirrhosis aged 20-70 years were randomly divided into two groups to receive 1,000 mg/day curcumin (n = 35) or placebo (n = 35) for 3 months. Model for end-stage liver disease (MELD) (i), MELD, MELD-Na, and Child-Pugh scores were used to assess the severity of cirrhosis. Sixty patients (29 in the curcumin group and 31 in the placebo group) completed the study. MELD(i) (15.55 ± 3.78 to 12.41 ± 3.07), MELD (15.31 ± 3.07 to 12.03 ± 2.79), MELD-Na (15.97 ± 4.02 to 13.55 ± 3.51), and Child-Pugh (7.17 ± 1.54 to 6.72 ± 1.31) scores decreased significantly in the curcumin group after 3-month intervention (p < .001, p < .001, p = .001, and p = .051, respectively), whereas they increased significantly in the placebo group (p < .001, p < .001, p < .001, p = .001, respectively). Significant differences were only observed between the two groups in MELD(i), MELD, MELD-Na, and Child-Pugh scores after 3-month intervention (p < .001 for all of them). In this pilot study, beneficial effects of curcumin supplementation were observed in decreasing disease activity scores and severity of cirrhosis in patients with cirrhosis.
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Affiliation(s)
- Masoud Nouri-Vaskeh
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran.,Connective Tissue Diseases Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Aida Malek Mahdavi
- Connective Tissue Diseases Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Hossein Afshan
- Liver and Gastrointestinal Diseases Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Leila Alizadeh
- Liver and Gastrointestinal Diseases Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Mohammad Zarei
- Department of Pathology and Laboratory Medicine, Perlman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania.,Center for Mitochondrial and Epigenomic Medicine, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania
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Abstract
The liver is one of the most complex organs of the human body and is involved in various metabolic processes. Due to its anatomical proximity to the digestive tract, its blood flow, and its contribution to the detoxification process, the liver is susceptible to a wide variety of disorders. Hepatic diseases can be caused by alcoholism, viral infections, malnutrition and xenobiotics, which result in a high frequency of patients with liver disease and subsequent increase in the number of deaths from these diseases, for which adequate treatments are not yet available. Therefore, the search for new alternatives to treat these liver conditions is mandatory. In recent decades, there has been an increase in interest in medicinal herbs due to their safety and hepatoprotective properties that arise from their anti-inflammatory, antioxidant, antifibrotic, antiviral, immunomodulatory and anticancer properties. Epidemiological and clinical studies have shown that the consumption of these compounds is associated with a decrease in the risk of developing liver diseases; thus, medicinal herbs have emerged as a viable option for the treatment of these hepatic pathologies. However, more basic and clinical studies are needed before reaching a final recommendation to treat human liver diseases. This review provides molecular and clinical information on some natural compounds and medicinal herbs that have hepatoprotective effects and could be useful for the treatment of hepatic disorders.
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14
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Li S, Li H, Xu X, Saw PE, Zhang L. Nanocarrier-mediated antioxidant delivery for liver diseases. Theranostics 2020; 10:1262-1280. [PMID: 31938064 PMCID: PMC6956819 DOI: 10.7150/thno.38834] [Citation(s) in RCA: 42] [Impact Index Per Article: 8.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2019] [Accepted: 10/30/2019] [Indexed: 12/12/2022] Open
Abstract
Liver is the principal detoxifying organ and metabolizes various compounds that produce free radicals (FR) constantly. To maintain the oxidative/antioxidative balance in the liver, antioxidants would scavenge FR by preventing tissue damage through FR formation, scavenging, or by enhancing their decomposition. The disruption of this balance therefore leads to oxidative stress and in turn leads to the onset of various diseases. Supplying the liver with exogeneous antioxidants is an effective way to recreate the oxidative/antioxidative balance in the liver homeostasis. Nevertheless, due to the short half-life and instability of antioxidants in circulation, the methodology for delivering antioxidants to the liver needs to be improved. Nanocarrier mediated delivery of antioxidants proved to be an ingenious way to safely and efficiently deliver a high payload of antioxidants into the liver for circumventing liver diseases. The objective of this review is to provide an overview of the role of reactive oxygen species (oxidant) and ROS scavengers (antioxidant) in liver diseases. Subsequently, current nanocarrier mediated antioxidant delivery methods for liver diseases are discussed.
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Affiliation(s)
- Senlin Li
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou 510120, People's Republic of China
- Department of Hepatobiliary Surgery, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou 510120, People's Republic of China
| | - Huiru Li
- Department of Hepatobiliary Surgery, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou 510120, People's Republic of China
| | - Xiaoding Xu
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou 510120, People's Republic of China
| | - Phei Er Saw
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou 510120, People's Republic of China
| | - Lei Zhang
- Department of Hepatobiliary Surgery, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou 510120, People's Republic of China
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15
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Mohseni R, Arab Sadeghabadi Z, Karimi J, Gholami H, Ghasemi H, Ghadimipour HR, Kheiripour N. Chlorella vulgaris supplementation attenuates the progression of liver fibrosis through targeting TGF-β-signaling pathway in the CCl4-induced liver fibrosis in rats. TOXIN REV 2019. [DOI: 10.1080/15569543.2019.1700525] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/07/2023]
Affiliation(s)
- Roohollah Mohseni
- Student research committee, Hamadan University of Medical Sciences, Hamadan, Iran
- Clinical Biochemistry Research Center, Basic Health Sciences Institute, Shahrekord University of Medical Sciences, Shahrekord, Iran
| | - Zahra Arab Sadeghabadi
- Department of Clinical Biochemistry, Hamadan University of Medical Sciences, Hamadan, Iran
| | - Jamshid Karimi
- Department of Clinical Biochemistry, Hamadan University of Medical Sciences, Hamadan, Iran
| | - Hamid Gholami
- Department of Clinical Biochemistry, Hamadan University of Medical Sciences, Hamadan, Iran
| | - Hadi Ghasemi
- Department of Clinical Biochemistry, Hamadan University of Medical Sciences, Hamadan, Iran
| | | | - Nejat Kheiripour
- Research Center for Biochemistry and Nutrition in Metabolic Diseases, Kashan University of Medical Sciences, Kashan, Iran
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16
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Buonomo AR, Scotto R, Nappa S, Arcopinto M, Salzano A, Marra AM, D’Assante R, Zappulo E, Borgia G, Gentile I. The role of curcumin in liver diseases. Arch Med Sci 2019; 15:1608-1620. [PMID: 31749891 PMCID: PMC6855174 DOI: 10.5114/aoms.2018.73596] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/17/2017] [Accepted: 10/20/2017] [Indexed: 01/11/2023] Open
Affiliation(s)
- Antonio Riccardo Buonomo
- Department of Clinical Medicine and Surgery – Section of Infectious Diseases, University of Naples “Federico II”, Naples, Italy
| | - Riccardo Scotto
- Department of Clinical Medicine and Surgery – Section of Infectious Diseases, University of Naples “Federico II”, Naples, Italy
| | - Salvatore Nappa
- Department of Clinical Medicine and Surgery – Section of Infectious Diseases, University of Naples “Federico II”, Naples, Italy
| | - Michele Arcopinto
- Department of Translational Medical Science, University of Naples “Federico II”, Naples, Italy
| | - Andrea Salzano
- Department of Translational Medical Science, University of Naples “Federico II”, Naples, Italy
- Department of Cardiovascular Sciences and NIHR Leicester Biomedical Research Centre, University of Leicester, Glenfield Hospital, Groby Road, Leicester, UK
| | | | | | - Emanuela Zappulo
- Department of Clinical Medicine and Surgery – Section of Infectious Diseases, University of Naples “Federico II”, Naples, Italy
| | - Guglielmo Borgia
- Department of Clinical Medicine and Surgery – Section of Infectious Diseases, University of Naples “Federico II”, Naples, Italy
| | - Ivan Gentile
- Department of Clinical Medicine and Surgery – Section of Infectious Diseases, University of Naples “Federico II”, Naples, Italy
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17
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Pickich MB, Hargrove MW, Phillips CN, Healy JC, Moore AN, Roberts MD, Martin JS. Effect of curcumin supplementation on serum expression of select cytokines and chemokines in a female rat model of nonalcoholic steatohepatitis. BMC Res Notes 2019; 12:496. [PMID: 31399137 PMCID: PMC6688243 DOI: 10.1186/s13104-019-4540-5] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/17/2019] [Accepted: 08/03/2019] [Indexed: 12/24/2022] Open
Abstract
Objective We recently reported that curcumin supplementation in a metabolically (i.e., Western diet [WD]) and chemically (i.e., CCl4) induced female rat model of non-alcoholic steatohepatitis (NASH) was associated with lower liver pathology scores and molecular markers of inflammation. This occurred when curcumin was given during induction of disease (preventative arm; 8-week WD with or without curcumin [8WD + C vs. 8WD]) as well as when given after disease development (treatment arm; 12-week WD with or without curcumin during weeks 9–12 [12WD + C vs. 12WD]). Herein, we sought to extend our findings from that study by determining the effects of curcumin supplementation on cytokine/chemokine expression in serum collected from these same rats. Results 24 cytokines/chemokines were assayed. IL-2 (+ 80%) and IL-13 (+ 83%) were greater with curcumin supplementation in the prevention arm. IL-2 (+ 192%), IL-13 (+ 87%), IL-17A (+ 81%) and fractalkine (+ 121%) were higher while RANTES was lower (− 22%) with curcumin supplementation in the treatment arm (p < 0.05 for all). RANTES concentrations also correlated significantly with hepatic pathology scores of inflammation (r = 0.417, p = 0.008). Select serum cytokines/chemokines were affected with curcumin supplementation in this female rat model of NASH. Moreover, curcumin’s effect(s) on RANTES and its association with liver disease pathogenesis and progression may warrant further investigation.
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Affiliation(s)
- Matthew B Pickich
- Department of Cell Biology and Physiology, Edward Via College of Osteopathic Medicine-Auburn Campus, Auburn, AL, 36832, USA
| | - Mark W Hargrove
- Department of Cell Biology and Physiology, Edward Via College of Osteopathic Medicine-Auburn Campus, Auburn, AL, 36832, USA
| | - C Niles Phillips
- Department of Cell Biology and Physiology, Edward Via College of Osteopathic Medicine-Auburn Campus, Auburn, AL, 36832, USA
| | - James C Healy
- Department of Cell Biology and Physiology, Edward Via College of Osteopathic Medicine-Auburn Campus, Auburn, AL, 36832, USA
| | - Angelique N Moore
- Department of Cell Biology and Physiology, Edward Via College of Osteopathic Medicine-Auburn Campus, Auburn, AL, 36832, USA
| | - Michael D Roberts
- Department of Cell Biology and Physiology, Edward Via College of Osteopathic Medicine-Auburn Campus, Auburn, AL, 36832, USA. .,School of Kinesiology, Auburn University, Auburn, AL, 36849, USA.
| | - Jeffrey S Martin
- Department of Cell Biology and Physiology, Edward Via College of Osteopathic Medicine-Auburn Campus, Auburn, AL, 36832, USA. .,School of Kinesiology, Auburn University, Auburn, AL, 36849, USA. .,Department of Basic Medical Sciences, Debusk College of Osteopathic Medicine, Knoxville, TN, 37932, USA.
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18
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Curcumin and α/ β-Adrenergic Antagonists Cotreatment Reverse Liver Cirrhosis in Hamsters: Participation of Nrf-2 and NF- κB. J Immunol Res 2019; 2019:3019794. [PMID: 31183386 PMCID: PMC6515016 DOI: 10.1155/2019/3019794] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/28/2018] [Accepted: 04/02/2019] [Indexed: 12/20/2022] Open
Abstract
Liver cirrhosis is the result of an uncontrolled fibrogenetic process, due to the activation and subsequent differentiation into myofibroblasts of the hepatic stellate cells (HSC). It is known that HSC express adrenoreceptors (AR), and the use of AR antagonists protects experimental animals from cirrhosis. However, several studies suggest that the toxicity generated by metabolism of these antagonists would hinder its use in cirrhotic patients. In addition, liver fibrosis may be associated with a decrease of the antioxidant response of the nuclear factor erythroid 2-related factor 2 (Nrf-2) and the overregulation of the proinflammatory pathway of nuclear factor kappa B (NF-κB). Therefore, in the present work, the capacity of doxazosin (α1 antagonist), carvedilol (nonselective beta-adrenoceptor blocker with alpha 1-blocking properties), and curcumin (antioxidant and anti-inflammatory compound) to reverse liver cirrhosis and studying the possible modulation of Nrf-2 and NF-κB were evaluated. Hamsters received CCl4 for 20 weeks, and then treatments were immediately administered for 4 weeks more. The individual administration of doxazosin or carvedilol showed less ability to reverse cirrhosis in relation to concomitantly curcumin administration. However, the best effect was the combined effect of doxazosin, carvedilol, and curcumin, reversing liver fibrosis and decreasing the amount of collagen I (Sirius red stain) without affecting the morphology of hepatocytes (hematoxylin and eosin stain), showing normal hepatic function (glucose, albumin, AST, ALT, total bilirubin, and total proteins). In addition, carvedilol treatment and the combination of doxazosin with curcumin increased Nrf-2/NF-κB mRNA ratio and its protein expression in the inflammatory cells in the livers, possibly as another mechanism of hepatoprotection. Therefore, these results suggest for the first time that α/β adrenergic blockers with curcumin completely reverse hepatic damage, possibly as a result of adrenergic antagonism on HSC and conceivably by the increase of Nrf-2/NF-κB mRNA ratio.
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19
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Curcumin Provides Hepatoprotection against Amoebic Liver Abscess Induced by Entamoeba histolytica in Hamster: Involvement of Nrf2/HO-1 and NF- κB/IL-1 β Signaling Pathways. J Immunol Res 2019; 2019:7431652. [PMID: 31275999 PMCID: PMC6561665 DOI: 10.1155/2019/7431652] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/28/2018] [Revised: 02/28/2019] [Accepted: 03/06/2019] [Indexed: 12/20/2022] Open
Abstract
Amoebic liver abscess (ALA) is the most common extraintestinal amoebiasis caused by Entamoeba histolytica (E. histolytica). However, despite current knowledge and scientific advances about this infection, there are no effective treatments to prevent it. Herein, the antiamoebic capacity of curcumin in a hamster model was evaluated. Curcumin (150 mg/kg, p.o., daily during 10 days before infection) considerably prevents liver damage induced at 12 and 48 h post-intrahepatic inoculation of trophozoites and decreases ALT, ALP, and γ-GTP activities, and macroscopic and microscopic observations were consistent with these results. On the other hand, after one week of intraportal inoculation, liver damage was prevented by curcumin (150 mg/kg, p.o., daily, 20 days before amoebic inoculation and during the week of infection); liver/body weight ratios and tissue and histological stains showed normal appearance; in addition, the increases in ALT, ALP, and γ-GTP activities were prevented; the depletion of glycogen content induced by the amoebic damage was partially but significantly prevented, while NF-κB activity was inhibited and the expression of IL-1β was reduced; Nrf2 production showed a tendency to increase it, and HO-1 protein was overexpressed. These results suggest for the first time that curcumin can be a compound with antiamoebic effect in the liver, suggesting that its daily use could help greatly decrease the incidence of this type of infection.
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20
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Patel SS, Acharya A, Ray RS, Agrawal R, Raghuwanshi R, Jain P. Cellular and molecular mechanisms of curcumin in prevention and treatment of disease. Crit Rev Food Sci Nutr 2019; 60:887-939. [PMID: 30632782 DOI: 10.1080/10408398.2018.1552244] [Citation(s) in RCA: 264] [Impact Index Per Article: 44.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
Curcumin is a naturally occurring polyphenolic compound present in rhizome of Curcuma longa belonging to the family zingiberaceae. Growing experimental evidence revealed that curcumin exhibit multitarget biological implications signifying its crucial role in health and disease. The current review highlights the recent progress and mechanisms underlying the wide range of pharmacological effects of curcumin against numerous diseases like neuronal, cardiovascular, metabolic, kidney, endocrine, skin, respiratory, infectious, gastrointestinal diseases and cancer. The ability of curcumin to modulate the functions of multiple signal transductions are linked with attenuation of acute and chronic diseases. Numerous preclinical and clinical studies have revealed that curcumin modulates several molecules in cell signal transduction pathway including PI3K, Akt, mTOR, ERK5, AP-1, TGF-β, Wnt, β-catenin, Shh, PAK1, Rac1, STAT3, PPARγ, EBPα, NLRP3 inflammasome, p38MAPK, Nrf2, Notch-1, AMPK, TLR-4 and MyD-88. Curcumin has a potential to prevent and/or manage various diseases due to its anti-inflammatory, anti-oxidant and anti-apoptotic properties with an excellent safety profile. In contrast, the anti-cancer effects of curcumin are reflected due to induction of growth arrest and apoptosis in various premalignant and malignant cells. This review also carefully emphasized the pharmacokinetics of curcumin and its interaction with other drugs. Clinical studies have shown that curcumin is safe at the doses of 12 g/day but exhibits poor systemic bioavailability. The use of adjuvant like piperine, liposomal curcumin, curcumin nanoparticles and curcumin phospholipid complex has shown enhanced bioavailability and therapeutic potential. Further studies are warranted to prove the potential of curcumin against various ailments.
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Affiliation(s)
- Sita Sharan Patel
- Department of Pharmacy, Sagar Institute of Research and Technology, Bhopal, India
| | - Ashish Acharya
- Department of Pharmacy, Sagar Institute of Research and Technology, Bhopal, India
| | - R S Ray
- Pharmacology Research Laboratory, University Institute of Pharmaceutical Sciences, Panjab University, Chandigarh, India
| | - Ritesh Agrawal
- Department of Pharmacy, Sagar Institute of Research and Technology, Bhopal, India
| | - Ramsaneh Raghuwanshi
- Department of Pharmacy, Sagar Institute of Research and Technology, Bhopal, India
| | - Priyal Jain
- Department of Pharmacy, Sagar Institute of Research and Technology, Bhopal, India
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21
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Farzaei MH, Zobeiri M, Parvizi F, El-Senduny FF, Marmouzi I, Coy-Barrera E, Naseri R, Nabavi SM, Rahimi R, Abdollahi M. Curcumin in Liver Diseases: A Systematic Review of the Cellular Mechanisms of Oxidative Stress and Clinical Perspective. Nutrients 2018; 10:855. [PMID: 29966389 PMCID: PMC6073929 DOI: 10.3390/nu10070855] [Citation(s) in RCA: 268] [Impact Index Per Article: 38.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2018] [Revised: 06/23/2018] [Accepted: 06/28/2018] [Indexed: 12/12/2022] Open
Abstract
Oxidative stress has been considered a key causing factor of liver damage induced by a variety of agents, including alcohol, drugs, viral infections, environmental pollutants and dietary components, which in turn results in progression of liver injury, non-alcoholic steatohepatitis, non-alcoholic liver disease, liver fibrosis and cirrhosis. During the past 30 years and even after the major progress in the liver disease management, millions of people worldwide still suffer from an acute or chronic liver condition. Curcumin is one of the most commonly used indigenous molecules endowed by various shielding functionalities that protects the liver. The aim of the present study is to comprehensively review pharmacological effects and molecular mechanisms, as well as clinical evidence, of curcumin as a lead compound in the prevention and treatment of oxidative associated liver diseases. For this purpose, electronic databases including “Scopus,” “PubMed,” “Science Direct” and “Cochrane library” were extensively searched with the keywords “curcumin or curcuminoids” and “hepatoprotective or hepatotoxicity or liver” along with “oxidative or oxidant.” Results showed that curcumin exerts remarkable protective and therapeutic effects of oxidative associated liver diseases through various cellular and molecular mechanisms. Those mechanisms include suppressing the proinflammatory cytokines, lipid perodixation products, PI3K/Akt and hepatic stellate cells activation, as well as ameliorating cellular responses to oxidative stress such as the expression of Nrf2, SOD, CAT, GSH, GPx and GR. Taking together, curcumin itself acts as a free radical scavenger over the activity of different kinds of ROS via its phenolic, β-diketone and methoxy group. Further clinical studies are still needed in order to recognize the structure-activity relationships and molecular mechanisms of curcumin in oxidative associated liver diseases.
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Affiliation(s)
- Mohammad Hosein Farzaei
- Pharmaceutical Sciences Research Center, Kermanshah University of Medical Sciences, Kermanshah 6734667149, Iran.
| | - Mahdi Zobeiri
- Internal Medicine Department, Imam Reza Hospital, Kermanshah University of Medical Sciences, Kermanshah 6734667149, Iran.
| | - Fatemeh Parvizi
- Pharmaceutical Sciences Research Center, Kermanshah University of Medical Sciences, Kermanshah 6734667149, Iran.
| | - Fardous F El-Senduny
- Biochemistry division, Chemistry Department, Faculty of Science, Mansoura University, Mansoura 35516, Egypt.
| | - Ilias Marmouzi
- Laboratory of Pharmacology and Toxicology Faculty of Medicine and Pharmacy, Mohammed V University in Rabat, Rabat 10100, Morocco.
| | - Ericsson Coy-Barrera
- Bioorganic Chemistry Laboratory, Facultad de Ciencias Básicas y Aplicadas, Universidad Militar Nueva Granada, Campus Nueva Granada, Cajicá 250247, Colombia.
| | - Rozita Naseri
- Internal Medicine Department, Imam Reza Hospital, Kermanshah University of Medical Sciences, Kermanshah 6734667149, Iran.
| | - Seyed Mohammad Nabavi
- Applied Biotechnology Research Center, Baghyatollah University of Medical Sciences, Tehran 1435916471, Iran.
| | - Roja Rahimi
- Department of Persian Pharmacy, School of Traditional Medicine, Tehran University of Medical Sciences, Tehran 1416663361, Iran.
| | - Mohammad Abdollahi
- Toxicology and Diseases Group, The Institute of Pharmaceutical Sciences (TIPS) and Department of Toxicology and Pharmacology, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran 1417614411, Iran.
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22
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Cunningham RP, Moore MP, Moore AN, Healy JC, Roberts MD, Rector RS, Martin JS. Curcumin supplementation mitigates NASH development and progression in female Wistar rats. Physiol Rep 2018; 6:e13789. [PMID: 30009570 PMCID: PMC6046645 DOI: 10.14814/phy2.13789] [Citation(s) in RCA: 36] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2018] [Revised: 06/12/2018] [Accepted: 06/17/2018] [Indexed: 02/07/2023] Open
Abstract
Curcumin, a naturally occurring plant polyphenolic compound, may have beneficial effects in nonalcoholic steatohepatitis (NASH) development. We examined whether curcumin supplementation could be used in both prevention and treatment of NASH with fibrosis. Female Wistar rats were provided ad libitum access to a "western diet" (WD) high in fat (43% kcal), sucrose (29% kcal), and cholesterol (2% w/v), as well as 15% fructose drinking water. Intraperitoneal CC14 injections (0.5 mL/kg) were also administered at weeks 1, 2, 4, and 6 to accelerate development of a NASH with fibrosis phenotype. Rats were randomized to four groups (n = 9-12/group) and fed ad libitum: (1) WD for 8-weeks (8WD), (2) WD enriched with curcumin for 8-weeks (8WD+C; 0.2% curcumin, BCM-95, DolCas Biotech) to assess prevention, (3) WD for 12-weeks (12WD), (4) WD for 8-weeks followed by 4-weeks WD+C (12WD+C) to assess treatment. Curcumin prevention (8WD vs. 8WD+C) attenuated (P < 0.05) histological liver inflammation, molecular markers of fibrosis (Col1a1 mRNA) and a serum marker of liver injury (AST). Curcumin treatment (12WD vs. 12WD+C) reduced (P < 0.05) hepatocellular inflammation, steatosis, NAFLD Activity Scores, and serum markers of liver injury (AST, ALP). Moreover, curcumin treatment also increased hepatic pACC/ACC, ApoB100, and SOD1 protein, and decreased hepatic FGF-21 levels; whereas, curcumin prevention increased hepatic glutathione levels. Both curcumin prevention and treatment reduced molecular markers of hepatic fibrosis (Col1a1 mRNA) and inflammation (TNF-α, SPP1 mRNA). Curcumin supplementation beneficially altered the NASH phenotype in female Wistar rats, particularly the reversal of hepatocellular inflammation.
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Affiliation(s)
- Rory P. Cunningham
- Research Service‐Harry S Truman Memorial VA HospitalColumbiaMissouri
- Department of Nutrition and Exercise PhysiologyUniversity of MissouriColumbiaMissouri
| | - Mary P. Moore
- Research Service‐Harry S Truman Memorial VA HospitalColumbiaMissouri
- Department of Nutrition and Exercise PhysiologyUniversity of MissouriColumbiaMissouri
| | - Angelique N. Moore
- Department of Biomedical SciencesEdward Via College of Osteopathic Medicine – Auburn CampusAuburnAlabama
| | - James C. Healy
- Department of Biomedical SciencesEdward Via College of Osteopathic Medicine – Auburn CampusAuburnAlabama
| | - Michael D. Roberts
- Department of Biomedical SciencesEdward Via College of Osteopathic Medicine – Auburn CampusAuburnAlabama
- School of KinesiologyAuburn UniversityAuburnAlabama
| | - R. Scott Rector
- Research Service‐Harry S Truman Memorial VA HospitalColumbiaMissouri
- Department of Nutrition and Exercise PhysiologyUniversity of MissouriColumbiaMissouri
- Department of Medicine‐GIUniversity of MissouriColumbiaMissouri
| | - Jeffrey S. Martin
- Department of Biomedical SciencesEdward Via College of Osteopathic Medicine – Auburn CampusAuburnAlabama
- School of KinesiologyAuburn UniversityAuburnAlabama
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23
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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: 17] [Impact Index Per Article: 2.4] [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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Kabirifar R, Ghoreshi ZAS, Rezaifar A, Binesh F, Bamdad K, Moradi A. Curcumin, quercetin and atorvastatin protected against the hepatic fibrosis by activating AMP-activated protein kinase. J Funct Foods 2018. [DOI: 10.1016/j.jff.2017.11.020] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023] Open
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25
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Hu RW, Carey EJ, Lindor KD, Tabibian JH. Curcumin in Hepatobiliary Disease: Pharmacotherapeutic Properties and Emerging Potential Clinical Applications. Ann Hepatol 2017; 16:835-841. [PMID: 29055920 DOI: 10.5604/01.3001.0010.5273] [Citation(s) in RCA: 35] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
Curcumin, an aromatic phytoextract from the turmeric (Curcuma longa) rhizome, has been used for centuries for a variety of purposes, not the least of which is medicinal. A growing body of evidence suggests that curcumin has a broad range of potentially therapeutic pharmacological properties, including anti-inflammatory, anti-fibrotic, and anti-neoplastic effects, among others. Clinical applications of curcumin have been hampered by quality control concerns and limited oral bioavailability, although novel formulations appear to have largely overcome these issues. Recent in vitro and in vivo studies have found that curcumin's cytoprotective and other biological activities may play a role in an array of benign and malignant hepatobiliary conditions, including but not limited to non-alcoholic fatty liver disease, cholestatic liver disease (e.g. primary sclerosing cholangitis), and cholangiocarcinoma. Here we provide an overview of fundamental principles, recent discoveries, and potential clinical hepatobiliary applications of this pleiotropic phytocompound.
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Affiliation(s)
- Robert W Hu
- Department of Biology, College of Arts and Sciences, University of Pennsylvania, Philadelphia, PA, USA
| | - Elizabeth J Carey
- Division of Gastroenterology and Hepatology, Mayo Clinic, Scottsdale, AZ, USA
| | - Keith D Lindor
- Division of Gastroenterology and Hepatology, Mayo Clinic, Scottsdale, AZ, USA Executive Vice Provost and Dean, College of Health Solutions, Arizona State University, Phoenix, AZ, USA
| | - James H Tabibian
- Division of Gastroenterology, Department of Medicine, Hospital of the University of Pennsylvania, Philadelphia, PA, USA Division of Gastroenterology, Department of Medicine, Olive View-UCLA Medical Center, Sylmar, CA, USA
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26
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Khedr NF, Khedr EG. Branched chain amino acids supplementation modulates TGF-β1/Smad signaling pathway and interleukins in CCl4-induced liver fibrosis. Fundam Clin Pharmacol 2017; 31:534-545. [PMID: 28544244 DOI: 10.1111/fcp.12297] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/01/2016] [Revised: 05/13/2017] [Accepted: 05/19/2017] [Indexed: 12/19/2022]
Affiliation(s)
- Naglaa F. Khedr
- Faculty of Pharmacy; Tanta University; Postal number: 31527 Tanta Egypt
| | - Eman G. Khedr
- Faculty of Pharmacy; Tanta University; Postal number: 31527 Tanta Egypt
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Sant'Anna L, Brito F, Barja P, Nicodemo M. Long-term effects of human amniotic membrane in a rat model of biliary fibrosis. Braz J Med Biol Res 2017; 50:e5692. [PMID: 28678914 PMCID: PMC5496151 DOI: 10.1590/1414-431x20175692] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2016] [Accepted: 04/18/2017] [Indexed: 12/11/2022] Open
Abstract
Liver fibrosis is the most common outcome of chronic liver diseases, and its progression to cirrhosis can only be effectively treated with liver transplantation. The amniotic membrane (AM) has been studied as an alternative therapy for fibrosis diseases mainly for its favorable properties, including anti-inflammatory, anti-scaring and immunomodulatory properties. It was recently demonstrated that the AM reduces the progression of biliary fibrosis to its advanced stage, cirrhosis, when applied on the liver for 6 weeks after fibrosis induction. Here, we investigated the effects of AM on rat fibrotic liver, during a prolonged period of time. Fibrosis was induced by bile duct ligation (BDL), and at the same time, a fragment of AM was applied around the liver. After 1, 3, 6, and 9 weeks, the degree of fibrosis was assessed by qualitative Knodell scoring, and by quantitative image analysis to quantify the area of collagen deposition in hepatic tissue. While fibrosis progressed rapidly in untreated BDL animals, leading to cirrhosis within 6 weeks, AM-treated livers showed confined fibrosis at the periportal area with few and thin fibrotic septa, but without cirrhosis. In addition, collagen deposition was reduced to about 36 and 55% of levels observed in BDL at 6 and 9 weeks after BDL, respectively, which shows that the longer the period of AM application, the lower the collagen deposition. These results suggested that AM applied as a patch onto the liver surface for longer periods attenuated the severity of biliary fibrosis and protected against liver degeneration caused by excessive collagen deposition.
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Affiliation(s)
- L.B. Sant'Anna
- Laboratório de Histologia e Terapia Regenerativa, Instituto de Pesquisa e Desenvolvimento, Universidade do Vale do Paraiba, São José dos Campos, SP, Brasil
| | - F.S. Brito
- Laboratório de Histologia e Terapia Regenerativa, Instituto de Pesquisa e Desenvolvimento, Universidade do Vale do Paraiba, São José dos Campos, SP, Brasil
| | - P.R. Barja
- Laboratório de Fotoacústica Aplicada aos Sistemas Biológicos, Instituto de Pesquisa e Desenvolvimento, Universidade do Vale do Paraiba, São José dos Campos, SP, Brasil
| | - M.C. Nicodemo
- Laboratório de Histologia e Terapia Regenerativa, Instituto de Pesquisa e Desenvolvimento, Universidade do Vale do Paraiba, São José dos Campos, SP, Brasil
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Xie YL, Chu JG, Jian XM, Dong JZ, Wang LP, Li GX, Yang NB. Curcumin attenuates lipopolysaccharide/d-galactosamine-induced acute liver injury by activating Nrf2 nuclear translocation and inhibiting NF-kB activation. Biomed Pharmacother 2017; 91:70-77. [PMID: 28448872 DOI: 10.1016/j.biopha.2017.04.070] [Citation(s) in RCA: 85] [Impact Index Per Article: 10.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2017] [Revised: 04/13/2017] [Accepted: 04/17/2017] [Indexed: 12/12/2022] Open
Abstract
Curcumin, a polyphenol in curry spice isolated from the rhizome of turmeric, has been reported to possess versatile biological properties including anti-inflammatory, anti-oxidant, antifibrotic, and anticancer activities. In this study, the hepatoprotective effect of curcumin was investigated in lipopolysaccharide (LPS)/d-galactosamine (d-GalN)-induced acute liver injury (ALI) in rats. Experimental ALI was induced with an intraperitoneal (ip) injection of sterile 0.9% sodium chloride (NaCl) solution containing 8μg LPS and 800mg/kg d-GalN. Curcumin was administered once daily starting three days prior to LPS/d-GalN treatment. Results indicated that curcumin could attenuate hepatic pathological damage, decrease serum ALT and AST levels, and reduce malondialdehyde (MDA) content in experimental ALI rats. Moreover, higher dosages of curcumin pretreatment inhibited NF-κB activation and reduced serum TNF-α and liver TNF-α levels induced by LPS/d-GalN ip injection. Furthermore, we found that curcumin up-regulated the expression of nuclear Nrf2 and Nrf2-dependent antioxidant defense genes including heme oxygenase-1 (HO-1), glutamate-cysteine ligase (GCLC), NAD(P)H dehydrogenase, and quinone (NQO-1) in a dose-dependent manner. Our results showed that curcumin protected experimental animals against LPS/d-GalN-induced ALI through activation of Nrf2 nuclear translocation and inhibition of NF-κB activation.
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Affiliation(s)
- Yi-Lian Xie
- Department of Infection and Liver Diseases, Ningbo First Hospital, Ningbo, China; Department of General Internal Medicine, Ningbo First Hospital, Ningbo, China
| | - Jin-Guo Chu
- Department of Infection and Liver Diseases, Ningbo First Hospital, Ningbo, China; Department of General Internal Medicine, Ningbo First Hospital, Ningbo, China
| | - Xiao-Min Jian
- Department of the First Clinical Medicine, Wenzhou Medical University, Wenzhou, China
| | - Jin-Zhong Dong
- Department of Intensive Care Unit, Ningbo First Hospital, Ningbo, China
| | - Li-Ping Wang
- Department of Infection and Liver Diseases, Ningbo First Hospital, Ningbo, China; Department of General Internal Medicine, Ningbo First Hospital, Ningbo, China
| | - Guo-Xiang Li
- Department of Infection and Liver Diseases, Ningbo First Hospital, Ningbo, China; Department of General Internal Medicine, Ningbo First Hospital, Ningbo, China.
| | - Nai-Bin Yang
- Department of Infection and Liver Diseases, Ningbo First Hospital, Ningbo, China; Department of General Internal Medicine, Ningbo First Hospital, Ningbo, China.
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29
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Cao L, Ding W, Jia R, Du J, Wang T, Zhang C, Gu Z, Yin G. Anti-inflammatory and hepatoprotective effects of glycyrrhetinic acid on CCl 4-induced damage in precision-cut liver slices from Jian carp (Cyprinus carpio var. jian) through inhibition of the nf-kƁ pathway. FISH & SHELLFISH IMMUNOLOGY 2017; 64:234-242. [PMID: 28288912 DOI: 10.1016/j.fsi.2017.03.007] [Citation(s) in RCA: 28] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/12/2016] [Revised: 03/02/2017] [Accepted: 03/03/2017] [Indexed: 06/06/2023]
Abstract
In order to evaluate the antioxidant and anti-inflammatory effects of glycyrrhetinic acid (GA) on carbon tetrachloride (CCl4)-induced damage in precision-cut liver slices (PCLS) from Jian carp (Cyprinus carpio. Jian), an acute liver damage model was established in this study. The viability of PCLS, levels of anti-oxidases in liver homogenates, expression of inflammation-related genes including nuclear factor-κB (nf-κB)/c-rel, inducible nitric oxide synthase (inos), interleukin-1β (il-1β), interleukin-6 (il-6) and interleukin-8 (il-8), and protein levels of (nf-κB)/c-rel in liver tissues were measured. The results showed that pretreatment of PCLS with GA at 5 and 10 μg/mL for 6 h significantly inhibited the cytotoxicity of CCl4. GA attenuated CCl4-induced oxidative stress in PCLS through promoting the recovery of superoxide dismutase (SOD) and glutathione (GSH) levels, and inhibiting malondialdehyde (MDA) synthesis. In inflammatory response, GA at both 5 and 10 μg/mL significantly inhibited the increase in mRNA levels of inflammatory cytokines including nf-kƁ/c-rel, inos, il-1β, il-6 and il-8, and the protein level of Nf-kƁ/C-rel induced by CCl4. Furthermore, treatment with pyrrolyl dithiocarbamate (PDTC, 4 μg/mL), an inhibitor of nuclear transcription factor nf-kB, significantly inhibited nf-kB levels, and transcription of downstream cytokines inos, il-1β, il-6 and il-8, also the viability of PCLS was significantly increased. These results indicated that GA suppressed inflammation and reduced cytotoxicity by inhibiting the nf-kƁ signaling pathway, and plays a role in liver protection.
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Affiliation(s)
- Liping Cao
- International Joint Research Laboratory for Fish Immunopharmacology, Freshwater Fisheries Research Center, Chinese Academy of Fishery Sciences, Wuxi 214081, China; Key Laboratory of Freshwater Fisheries and Germplasm Resources Utilization, Ministry of Agriculture, Freshwater Fisheries Research Center, Chinese Academy of Fishery Sciences, Wuxi 214081, China
| | - Weidong Ding
- International Joint Research Laboratory for Fish Immunopharmacology, Freshwater Fisheries Research Center, Chinese Academy of Fishery Sciences, Wuxi 214081, China; Key Laboratory of Freshwater Fisheries and Germplasm Resources Utilization, Ministry of Agriculture, Freshwater Fisheries Research Center, Chinese Academy of Fishery Sciences, Wuxi 214081, China
| | - Rui Jia
- International Joint Research Laboratory for Fish Immunopharmacology, Freshwater Fisheries Research Center, Chinese Academy of Fishery Sciences, Wuxi 214081, China; Key Laboratory of Freshwater Fisheries and Germplasm Resources Utilization, Ministry of Agriculture, Freshwater Fisheries Research Center, Chinese Academy of Fishery Sciences, Wuxi 214081, China
| | - Jingliang Du
- International Joint Research Laboratory for Fish Immunopharmacology, Freshwater Fisheries Research Center, Chinese Academy of Fishery Sciences, Wuxi 214081, China; Key Laboratory of Freshwater Fisheries and Germplasm Resources Utilization, Ministry of Agriculture, Freshwater Fisheries Research Center, Chinese Academy of Fishery Sciences, Wuxi 214081, China
| | - Tao Wang
- International Joint Research Laboratory for Fish Immunopharmacology, Freshwater Fisheries Research Center, Chinese Academy of Fishery Sciences, Wuxi 214081, China; Key Laboratory of Freshwater Fisheries and Germplasm Resources Utilization, Ministry of Agriculture, Freshwater Fisheries Research Center, Chinese Academy of Fishery Sciences, Wuxi 214081, China
| | - Chunyun Zhang
- International Joint Research Laboratory for Fish Immunopharmacology, Freshwater Fisheries Research Center, Chinese Academy of Fishery Sciences, Wuxi 214081, China; Key Laboratory of Freshwater Fisheries and Germplasm Resources Utilization, Ministry of Agriculture, Freshwater Fisheries Research Center, Chinese Academy of Fishery Sciences, Wuxi 214081, China
| | - Zhengyan Gu
- International Joint Research Laboratory for Fish Immunopharmacology, Freshwater Fisheries Research Center, Chinese Academy of Fishery Sciences, Wuxi 214081, China; Key Laboratory of Freshwater Fisheries and Germplasm Resources Utilization, Ministry of Agriculture, Freshwater Fisheries Research Center, Chinese Academy of Fishery Sciences, Wuxi 214081, China
| | - Guojun Yin
- International Joint Research Laboratory for Fish Immunopharmacology, Freshwater Fisheries Research Center, Chinese Academy of Fishery Sciences, Wuxi 214081, China; Key Laboratory of Freshwater Fisheries and Germplasm Resources Utilization, Ministry of Agriculture, Freshwater Fisheries Research Center, Chinese Academy of Fishery Sciences, Wuxi 214081, China.
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30
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Hepatoprotective effects of curcumin in rats after bile duct ligation via downregulation of Rac1 and NOX1. Nutrition 2017; 36:72-78. [DOI: 10.1016/j.nut.2016.06.006] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2016] [Revised: 05/24/2016] [Accepted: 06/05/2016] [Indexed: 02/08/2023]
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Cai Y, Lu D, Zou Y, Zhou C, Liu H, Tu C, Li F, Liu L, Zhang S. Curcumin Protects Against Intestinal Origin Endotoxemia in Rat Liver Cirrhosis by Targeting PCSK9. J Food Sci 2017; 82:772-780. [PMID: 28196290 DOI: 10.1111/1750-3841.13647] [Citation(s) in RCA: 32] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/03/2016] [Revised: 12/16/2016] [Accepted: 01/10/2017] [Indexed: 12/13/2022]
Abstract
Intestinal origin endotoxemia always occurs in severe liver injury. The aim of the current study was to test antiendotoxemia effect of curcumin on tetrachloride (CCl4 )-induced liver cirrhosis rats, and to elucidate the underlying molecular mechanism. Rat cirrhosis models were constructed with CCl4 subcutaneous injections with curcumin (200 mg/kg/d) administered via gavages for 12 wk until the rats were sacrificed. We found that the administration of curcumin improved the physiological condition pertaining to activity index and temperature, and ameliorated the liver injury in CCl4 -induced cirrhosis rats. Enzyme-linked immunosorbent assay (ELISA) and real-time quantitative polymerase chain reaction (qRT-PCR) showed that curcumin could reduce c-reaction protein levels and inflammatory cytokine (TNF-α, IL-1β, IL-6, and CINC-1/IL-8) concentrations in peripheral serum and liver tissue. Furthermore, curcumin treatment decreased lipopolysaccharide (LPS) levels in peripheral vein, but not in portal vein. As low-density lipoprotein receptor (LDLR) is the important receptor on the surface of hepatocyte during LPS detoxification process, we used qRT-PCR, western blot, and immunohistochemistry (IHC), finding that curcumin significantly increased LDLR protein levels, but not gene levels in the liver tissues. We also tested proprotein convertase subtilisin/kexin type 9 (PCSK9), one negative regulator of LDLR, by qRT-PCR, western blot, and IHC. The results showed that PCSK9 significantly decreased both gene and protein levels in the rat liver tissues of curcumin treatment. Thus, we concluded that curcumin could function to protect against intestinal origin endotoxemia by inhibiting PCSK9 to promote LDLR expression, thereby enhancing LPS detoxification as one pathogen lipid through LDLR in the liver.
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Affiliation(s)
- Yu Cai
- Dept. of Gastroenterology and Hepatology, Zhongshan Hospital, Fudan Univ., 180 Fenglin Rd., Xuhui District, Shanghai, P.R. China
| | - Di Lu
- Dept. of Gastroenterology and Hepatology, Zhongshan Hospital, Fudan Univ., 180 Fenglin Rd., Xuhui District, Shanghai, P.R. China
| | - Yanting Zou
- Dept. of Gastroenterology and Hepatology, Zhongshan Hospital, Fudan Univ., 180 Fenglin Rd., Xuhui District, Shanghai, P.R. China
| | - Chaohui Zhou
- Dept. of Gastroenterology and Hepatology, Zhongshan Hospital, Fudan Univ., 180 Fenglin Rd., Xuhui District, Shanghai, P.R. China
| | - Hongchun Liu
- Dept. of Gastroenterology and Hepatology, Zhongshan Hospital, Fudan Univ., 180 Fenglin Rd., Xuhui District, Shanghai, P.R. China
| | - Chuantao Tu
- Dept. of Gastroenterology and Hepatology, Zhongshan Hospital, Fudan Univ., 180 Fenglin Rd., Xuhui District, Shanghai, P.R. China
| | - Feng Li
- Dept. of Gastroenterology and Hepatology, Zhongshan Hospital, Fudan Univ., 180 Fenglin Rd., Xuhui District, Shanghai, P.R. China
| | - Lili Liu
- Dept. of Gastroenterology and Hepatology, Zhongshan Hospital, Fudan Univ., 180 Fenglin Rd., Xuhui District, Shanghai, P.R. China
| | - Shuncai Zhang
- Dept. of Gastroenterology and Hepatology, Zhongshan Hospital, Fudan Univ., 180 Fenglin Rd., Xuhui District, Shanghai, P.R. China
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Liqustri lucidi Fructus inhibits hepatic injury and functions as an antioxidant by activation of AMP-activated protein kinase in vivo and in vitro. Chem Biol Interact 2017; 262:57-68. [DOI: 10.1016/j.cbi.2016.11.031] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2016] [Revised: 11/14/2016] [Accepted: 11/30/2016] [Indexed: 12/27/2022]
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Yang F, Tang X, Ding L, zhou Y, Yang Q, Gong J, Wang G, Wang Z, Yang L. Curcumin protects ANIT-induced cholestasis through signaling pathway of FXR-regulated bile acid and inflammation. Sci Rep 2016; 6:33052. [PMID: 27624003 PMCID: PMC5021964 DOI: 10.1038/srep33052] [Citation(s) in RCA: 41] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2016] [Accepted: 08/15/2016] [Indexed: 12/16/2022] Open
Abstract
Cholestasis is a clinically significant symptom and widely associated with liver diseases, however, there are very few effective therapies for cholestasis. Danning tablet (DNT, a Chinese patent medicine preparation) has been clinically used to treat human liver and gallbladder diseases for more than 20 years in China. However, which ingredients of DNT contributed to this beneficial effect and their mechanistic underpinnings have been largely unknown. In the present study, we discovered that DNT not only demonstrated greater benefits for cholecystitis patients after cholecystectomy surgery in clinic but also showed protective effect against alpha-naphthylisothiocyanate (ANIT)-induced cholestasis model in rodent. Curcumin, one major compound derived from DNT, exerted the protective effect against cholestasis through farnesoid X receptor (FXR), which has been focused as potential therapeutic targets for treating cholestasis. The underlying mechanism of curcumin against cholestasis was restoring bile acid homeostasis and antagonizing inflammatory responses in a FXR-dependent manner and in turn contributed to overall cholestasis attenuation. Collectively, curcumin can be served as a potential treatment option for liver injury with cholestasis.
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Affiliation(s)
- Fan Yang
- The MOE Key Laboratory for Standardization of Chinese Medicines and the Shanghai Key Laboratory of Compound Chinese Medicines Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
| | - Xiaowen Tang
- The MOE Key Laboratory for Standardization of Chinese Medicines and the Shanghai Key Laboratory of Compound Chinese Medicines Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
| | - Lili Ding
- The MOE Key Laboratory for Standardization of Chinese Medicines and the Shanghai Key Laboratory of Compound Chinese Medicines Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
| | - Yue zhou
- The MOE Key Laboratory for Standardization of Chinese Medicines and the Shanghai Key Laboratory of Compound Chinese Medicines Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
| | - Qiaoling Yang
- The MOE Key Laboratory for Standardization of Chinese Medicines and the Shanghai Key Laboratory of Compound Chinese Medicines Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
| | - Junting Gong
- The MOE Key Laboratory for Standardization of Chinese Medicines and the Shanghai Key Laboratory of Compound Chinese Medicines Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
| | - Guangyun Wang
- The MOE Key Laboratory for Standardization of Chinese Medicines and the Shanghai Key Laboratory of Compound Chinese Medicines Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
| | - Zhengtao Wang
- The MOE Key Laboratory for Standardization of Chinese Medicines and the Shanghai Key Laboratory of Compound Chinese Medicines Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
| | - Li Yang
- The MOE Key Laboratory for Standardization of Chinese Medicines and the Shanghai Key Laboratory of Compound Chinese Medicines Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
- Center for Chinese Medical Therapy and Systems Biology, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
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SantAnna LB, Hage R, Cardoso MAG, Arisawa EAL, Cruz MM, Parolini O, Cargnoni A, SantAnna N. Antifibrotic Effects of Human Amniotic Membrane Transplantation in Established Biliary Fibrosis Induced in Rats. Cell Transplant 2016; 25:2245-2257. [PMID: 27480080 DOI: 10.3727/096368916x692645] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/05/2023] Open
Abstract
Liver fibrosis is characterized by excessive accumulation of extracellular matrix components in the liver parenchyma that distorts the normal architecture and hepatic function. Progressive fibrosis could end in the advanced stage known as cirrhosis, resulting in the need to resort to liver transplantation. Amniotic membrane (AM) has emerged as an innovative therapeutic approach for chronic liver diseases due to its anti-inflammatory, antiscarring, and wound-healing effects. We have recently shown that AM can be used as a patch on the liver surface at the same time of fibrosis induction, resulting in significantly reduced progression and severity of biliary fibrosis. Here we investigated the effects of human AM on the established rat model of liver fibrosis, induced by the bile duct ligation (BDL). We also explored the effect of AM on the expression of transforming growth factor-1 (TGF-1), the main profibrogenic factor in hepatic fibrosis, and the proinflammatory cytokines, tumor necrosis factor- (TNF-), interleukin-6 (IL-6), and anti-inflammatory cytokine IL-10. Two weeks after BDL, the liver was covered with a fragment of AM or left untreated. Six weeks later, the fibrosis was first assessed by the semiquantitative Knodell and the METAVIR scoring systems and, thereafter, by CellProfiler digital image analysis to quantify the area occupied by collagen deposition, ductular reactions (DRs), activated myofibroblasts, and TGF-1. The hepatic cytokines were determined by ELISA. AM-treated rats showed a significantly lower score compared to the control BDL rats (2.50.9 vs. 3.50.3, respectively; p0.05). The collagen deposition, DRs, number of activated myofibroblasts, and TGF-1 were all reduced to about 50% of levels observed in untreated BDL rats. These findings suggest that AM, when applied as a patch onto the liver surface, is useful for treating well-established cholestatic fibrosis, and the mechanism was partly by means of downregulating the profibrotic factor TGF-1 and IL-6.
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35
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Al-Rasheed NM, Fadda LM, Ali HM, Abdel Baky NA, El-Orabi NF, Al-Rasheed NM, Yacoub HI. New mechanism in the modulation of carbon tetrachloride hepatotoxicity in rats using different natural antioxidants. Toxicol Mech Methods 2016; 26:243-50. [DOI: 10.3109/15376516.2016.1159769] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/18/2023]
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Kheradpezhouh E, Barritt GJ, Rychkov GY. Curcumin inhibits activation of TRPM2 channels in rat hepatocytes. Redox Biol 2016; 7:1-7. [PMID: 26609559 PMCID: PMC4683391 DOI: 10.1016/j.redox.2015.11.001] [Citation(s) in RCA: 47] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2015] [Revised: 11/06/2015] [Accepted: 11/08/2015] [Indexed: 01/15/2023] Open
Abstract
Oxidative stress is a hallmark of many liver diseases including viral and drug-induced hepatitis, ischemia-reperfusion injury, and non-alcoholic steatohepatitis. One of the consequences of oxidative stress in the liver is deregulation of Ca(2+) homeostasis, resulting in a sustained elevation of the free cytosolic Ca(2+) concentration ([Ca(2+)]c) in hepatocytes, which leads to irreversible cellular damage. Recently it has been shown that liver damage induced by paracetamol and subsequent oxidative stress is, in large part, mediated by Ca(2+) entry through Transient Receptor Potential Melastatin 2 (TRPM2) channels. Involvement of TRPM2 channels in hepatocellular damage induced by oxidative stress makes TRPM2 a potential therapeutic target for treatment of a range of oxidative stress-related liver diseases. We report here the identification of curcumin ((1E,6E)-1,7-bis(4-hydroxy-3-methoxyphenyl)-1,6-heptadiene-3,5-dione), a natural plant-derived polyphenol in turmeric spice, as a novel inhibitor of TRPM2 channel. Presence of 5µM curcumin in the incubation medium prevented the H2O2- and paracetamol-induced [Ca(2+)]c rise in rat hepatocytes. Furthermore, in patch clamping experiments incubation of hepatocytes with curcumin inhibited activation of TRPM2 current by intracellular ADPR with IC50 of approximately 50nM. These findings enhance understanding of the actions of curcumin and suggest that the known hepatoprotective properties of curcumin are, at least in part, mediated through inhibition of TRPM2 channels.
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Affiliation(s)
- E Kheradpezhouh
- Discipline of Physiology, School of Medical Sciences, University of Adelaide, Adelaide, SA 5005, Australia
| | - G J Barritt
- Department of Medical Biochemistry, School of Medicine, Flinders University, Adelaide, SA 5001, Australia
| | - G Y Rychkov
- Discipline of Physiology, School of Medical Sciences, University of Adelaide, Adelaide, SA 5005, Australia; Discipline of Medicine, School of Medicine, University of Adelaide, Adelaide, SA 5005, Australia
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37
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Varatharajalu R, Garige M, Leckey LC, Reyes-Gordillo K, Shah R, Lakshman MR. Protective Role of Dietary Curcumin in the Prevention of the Oxidative Stress Induced by Chronic Alcohol with respect to Hepatic Injury and Antiatherogenic Markers. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2016; 2016:5017460. [PMID: 26881029 PMCID: PMC4736425 DOI: 10.1155/2016/5017460] [Citation(s) in RCA: 39] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/18/2015] [Revised: 11/10/2015] [Accepted: 11/12/2015] [Indexed: 12/15/2022]
Abstract
Curcumin, an antioxidant compound found in Asian spices, was evaluated for its protective effects against ethanol-induced hepatosteatosis, liver injury, antiatherogenic markers, and antioxidant status in rats fed with Lieber-deCarli low menhaden (2.7% of total calories from ω-3 polyunsaturated fatty acids (PUFA)) and Lieber-deCarli high menhaden (13.8% of total calories from ω-3 PUFA) alcohol-liquid (5%) diets supplemented with or without curcumin (150 mg/kg/day) for 8 weeks. Treatment with curcumin protected against high ω-3 PUFA and ethanol-induced hepatosteatosis and increase in liver injury markers, alanine aminotransferase, and aspartate aminotransferase. Curcumin upregulated paraoxonase 1 (PON1) mRNA and caused significant increase in serum PON1 and homocysteine thiolactonase activities as compared to high ω-3 PUFA and ethanol group. Moreover, treatment with curcumin protected against ethanol-induced oxidative stress by increasing the antioxidant glutathione and decreasing the lipid peroxidation adduct 4-hydroxynonenal. These results strongly suggest that chronic ethanol in combination with high ω-3 PUFA exacerbated hepatosteatosis and liver injury and adversely decreases antiatherogenic markers due to increased oxidative stress and depletion of glutathione. Curcumin supplementation significantly prevented these deleterious actions of chronic ethanol and high ω-3 PUFA. Therefore, we conclude that curcumin may have therapeutic potential to protect against chronic alcohol-induced liver injury and atherosclerosis.
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Affiliation(s)
- Ravi Varatharajalu
- Lipid Research Laboratory, VA Medical Center and Department of Biochemistry and Molecular Medicine, The George Washington University, Washington, DC 20422, USA
| | - Mamatha Garige
- Lipid Research Laboratory, VA Medical Center and Department of Biochemistry and Molecular Medicine, The George Washington University, Washington, DC 20422, USA
| | - Leslie C. Leckey
- Lipid Research Laboratory, VA Medical Center and Department of Biochemistry and Molecular Medicine, The George Washington University, Washington, DC 20422, USA
| | - Karina Reyes-Gordillo
- Lipid Research Laboratory, VA Medical Center and Department of Biochemistry and Molecular Medicine, The George Washington University, Washington, DC 20422, USA
| | - Ruchi Shah
- Lipid Research Laboratory, VA Medical Center and Department of Biochemistry and Molecular Medicine, The George Washington University, Washington, DC 20422, USA
| | - M. Raj Lakshman
- Lipid Research Laboratory, VA Medical Center and Department of Biochemistry and Molecular Medicine, The George Washington University, Washington, DC 20422, USA
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Strilakou A, Perelas A, Lazaris A, Papavdi A, Karkalousos P, Giannopoulou I, Kriebardis A, Panayiotides I, Liapi C. Immunohistochemical determination of the extracellular matrix modulation in a rat model of choline-deprived myocardium: the effects of carnitine. Fundam Clin Pharmacol 2015; 30:47-57. [PMID: 26501493 DOI: 10.1111/fcp.12163] [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] [Received: 03/25/2015] [Revised: 09/06/2015] [Accepted: 10/20/2015] [Indexed: 12/18/2022]
Abstract
Choline has been identified as an essential nutrient with crucial role in many vital biological functions. Recent studies have demonstrated that heart dysfunction can develop in the setting of choline deprivation even in the absence of underlying heart disease. Matrix metalloproteinases (MMPs) are responsible for extracellular matrix degradation, and the dysregulation of MMP-2 and MMP-9 has been involved in the pathogenesis of various cardiovascular disorders. The aim of the study was to investigate the role of MMPs and their inhibitors (TIMPs), in the pathogenesis of choline deficiency-induced cardiomyopathy, and the way they are affected by carnitine supplementation. Male Wistar Albino adult rats were divided into four groups and received standard or choline-deficient diet with or without L-carnitine in drinking water (0.15% w/v) for 1 month. Heart tissue immunohistochemistry for MMP-2, MMP-9, TIMP-1, and TIMP-2 was performed. Choline deficiency was associated with suppressed immunohistochemical expression of MMP-2 and an increased expression of TIMP-2 compared to control, while it had no impact on TIMP-1. MMP-9 expression was decreased without, however, reaching statistical significance. Carnitine did not affect MMP-2, MMP-9, TIMP-1 or TIMP-2 expression. The pattern of TIMP and MMP modulation observed in a choline deficiency setting appears to promote fibrosis. Carnitine, although shown to suppress fibrosis, does not seem to affect MMP-2, MMP-9, TIMP-1 or TIMP-2 expression. Further studies will be required to identify the mechanism underlying the beneficial effects of carnitine.
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Affiliation(s)
- Athina Strilakou
- Department of Pharmacology, Medical School, National and Kapodistrian University of Athens, 75 Mikras Asias Street, Goudi, 11527, Athens, Greece
| | - Apostolos Perelas
- Department of Pharmacology, Medical School, National and Kapodistrian University of Athens, 75 Mikras Asias Street, Goudi, 11527, Athens, Greece
| | - Andreas Lazaris
- 1st Department of Pathology, Medical School, National and Kapodistrian University of Athens, 75 Mikras Asias Street, Goudi, 11527, Athens, Greece
| | - Asteria Papavdi
- 1st Department of Pathology, Medical School, National and Kapodistrian University of Athens, 75 Mikras Asias Street, Goudi, 11527, Athens, Greece
| | - Petros Karkalousos
- Department of Medical Laboratories, Technological Institute of Athens, Agiou Spyridonos and Dimitsanas Street, Egaleo, 12210, Athens, Greece
| | - Ioanna Giannopoulou
- 1st Department of Pathology, Medical School, National and Kapodistrian University of Athens, 75 Mikras Asias Street, Goudi, 11527, Athens, Greece
| | - Anastasios Kriebardis
- Department of Medical Laboratories, Technological Institute of Athens, Agiou Spyridonos and Dimitsanas Street, Egaleo, 12210, Athens, Greece
| | - Ioannis Panayiotides
- 2nd Department of Pathology, Medical School, National and Kapodistrian University of Athens, Attikon Hospital, 1Rimini Street, Chaidari, 12462, Athens, Greece
| | - Charis Liapi
- Department of Pharmacology, Medical School, National and Kapodistrian University of Athens, 75 Mikras Asias Street, Goudi, 11527, Athens, Greece
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Effect of aflatoxin B1 on the seminiferous tubules and the possible protective role of curcumin in adult albino rats (Light and electron microscopic study). ACTA ACUST UNITED AC 2015. [DOI: 10.1097/01.ehx.0000481141.52450.03] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
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Casas-Grajales S, Muriel P. Antioxidants in liver health. World J Gastrointest Pharmacol Ther 2015; 6:59-72. [PMID: 26261734 PMCID: PMC4526841 DOI: 10.4292/wjgpt.v6.i3.59] [Citation(s) in RCA: 75] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/04/2015] [Revised: 06/04/2015] [Accepted: 06/18/2015] [Indexed: 02/06/2023] Open
Abstract
Liver diseases are a worldwide medical problem because the liver is the principal detoxifying organ and maintains metabolic homeostasis. The liver metabolizes various compounds that produce free radicals (FR). However, antioxidants scavenge FR and maintain the oxidative/antioxidative balance in the liver. When the liver oxidative/antioxidative balance is disrupted, the state is termed oxidative stress. Oxidative stress leads to deleterious processes in the liver and produces liver diseases. Therefore, restoring antioxidants is essential to maintain homeostasis. One method of restoring antioxidants is to consume natural compounds with antioxidant capacity. The objective of this review is to provide information pertaining to various antioxidants found in food that have demonstrated utility in improving liver diseases.
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Zhen YZ, Li NR, He HW, Zhao SS, Zhang GL, Hao XF, Shao RG. Protective effect of bicyclol against bile duct ligation-induced hepatic fibrosis in rats. World J Gastroenterol 2015; 21:7155-7164. [PMID: 26109801 PMCID: PMC4476876 DOI: 10.3748/wjg.v21.i23.7155] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/03/2015] [Revised: 02/13/2015] [Accepted: 04/09/2015] [Indexed: 02/06/2023] Open
Abstract
AIM: To evaluate the protective effect of bicyclol against bile duct ligation (BDL)-induced hepatic fibrosis in rats.
METHODS: Sprague-Dawley male rats underwent BDL and sham-operated animals were used as healthy controls. The BDL rats were divided into two groups which received sterilized PBS or bicyclol (100 mg/kg per day) orally for two consecutive weeks. Serum, urine and bile were collected for biochemical determinations. Liver tissues were collected for histological analysis and a whole genome oligonucleotide microarray assay. Reverse transcription-polymerase chain reaction and Western blotting were used to verify the expression of liver fibrosis-related genes.
RESULTS: Treatment with bicyclol significantly reduced liver fibrosis and bile duct proliferation after BDL. The levels of alanine aminotransferase (127.7 ± 72.3 vs 230.4 ± 69.6, P < 0.05) and aspartate aminotransferase (696.8 ± 232.6 vs 1032.6 ± 165.8, P < 0.05) were also decreased by treatment with bicyclol in comparison to PBS. The expression changes of 45 fibrogenic genes and several fibrogenesis-related pathways were reversed by bicyclol in the microarray assay. Bicyclol significantly reduced liver mRNA and/or protein expression levels of collagen 1a1, matrix metalloproteinase 2, tumor necrosis factor, tissue inhibitors of metalloproteinases 2, transforming growth factor-β1 and α-smooth muscle actin.
CONCLUSION: Bicyclol significantly attenuates BDL-induced liver fibrosis by reversing fibrogenic gene expression. These findings suggest that bicyclol might be an effective anti-fibrotic drug for the treatment of cholestatic liver disease.
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Tang Y. Curcumin targets multiple pathways to halt hepatic stellate cell activation: updated mechanisms in vitro and in vivo. Dig Dis Sci 2015; 60:1554-64. [PMID: 25532502 DOI: 10.1007/s10620-014-3487-6] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/21/2014] [Accepted: 12/07/2014] [Indexed: 12/12/2022]
Abstract
Nonalcoholic steatohepatitis (NASH) is the advanced form of nonalcoholic fatty liver disease, which is often accompanied by obese and/or type II diabetes mellitus. Approximately one-third of NASH patients develop hepatic fibrosis. Hepatic stellate cells are the major effector cells during liver fibrogenesis. Advanced liver fibrosis usually proceeds to cirrhosis and even hepatocellular carcinoma, leading to liver failure, portal hypertension and even death. Currently, there are no approved agents for treatment and prevention of liver fibrosis in human beings. Curcumin, the principal curcuminoid of turmeric, has been reported to show antitumor, antioxidant, and anti-inflammatory properties both in in vitro and in vivo systems. Accumulating data shows that curcumin plays a critical role in combating liver fibrogenesis. This review will discuss the inhibitory roles of curcumin and update the underlying mechanisms by which curcumin targets in inhibiting hepatic stellate cell activation.
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Affiliation(s)
- Youcai Tang
- Department of Pediatrics, The Second Affiliated Hospital, Zhengzhou University, 2 Jingba Road, Zhengzhou, 450014, Henan, China,
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43
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Strategies to prevent and reverse liver fibrosis in humans and laboratory animals. Arch Toxicol 2015; 89:1727-50. [PMID: 25963329 DOI: 10.1007/s00204-015-1525-6] [Citation(s) in RCA: 46] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2015] [Accepted: 04/28/2015] [Indexed: 02/07/2023]
Abstract
Liver fibrosis results from chronic damage to the liver in conjunction with various pathways and is mediated by a complex microenvironment. Based on clinical observations, it is now evident that fibrosis is a dynamic, bidirectional process with an inherent capacity for recovery and remodeling. The major mechanisms involved in liver fibrosis include the repetitive injury of hepatocytes, the activation of the inflammatory response after injury stimulation, and the activation and proliferation of hepatic stellate cells (HSCs), which represents the major extracellular matrix (ECM)-producing cells, stimulated by hepatocyte injury and inflammation. The microenvironment in the liver is synergistically regulated abnormal ECM deposition, scar formation, angiogenesis, and fibrogenesis. Moreover, recent studies have clarified novel mechanism in fibrosis such as epigenetic regulation of HSCs, the leptin and PPARγ pathways, the coagulation system, and even autophagy. Uncovering the mechanisms of liver fibrogenesis provides a basis to develop potential therapies to reverse and treat the fibrotic response, thereby improving the outcomes of patients with chronic liver disease. Although both scientific and clinical challenges remain, emerging studies attempt to reveal the ideal anti-fibrotic drug that could be easily delivered to the liver with high specificity and low toxicity. This review highlights the mechanisms, including novel pathways underlying fibrogenesis that may be translated into preventive and treatment strategies, reviews both current and novel agents that target specific pathways or multiple targets, and discusses novel drug delivery systems such as nanotechnology that can be applied in the treatment of liver fibrosis. In addition, we also discuss some current treatment strategies that are being applied in animal models and in clinical trials.
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Cao L, Ding W, Du J, Jia R, Liu Y, Zhao C, Shen Y, Yin G. Effects of curcumin on antioxidative activities and cytokine production in Jian carp (Cyprinus carpio var. Jian) with CCl4-induced liver damage. FISH & SHELLFISH IMMUNOLOGY 2015; 43:150-157. [PMID: 25549934 DOI: 10.1016/j.fsi.2014.12.025] [Citation(s) in RCA: 42] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/22/2014] [Revised: 12/18/2014] [Accepted: 12/19/2014] [Indexed: 06/04/2023]
Abstract
We investigated the protective effects of curcumin on liver-damaged Cyprinus carpio var. Jian (Jian carp). The carp were fed 0.1%, 0.5%, or 1.0% curcumin for 60 days, then injected intraperitoneally with 30% carbon tetrachloride solution. Liver and blood samples were collected to measure the liver index, serum- and liver-associated enzymes, liver histology, nuclear factor-κB (NF-κB)/c-Rel, interleukin-1β (IL-1β), tumor necrosis factor-α (TNF-α), and IL-12 mRNA expression, and the level of NF-κB/c-Rel protein in the liver, and for a comet assay. We found that 0.5% and 1.0% curcumin significantly reduced the CCl(4)-induced increase in the liver index. The comet assay showed that the tail moment, olive tail moment, tail length, and tail DNA% improved in fish pretreated with 0.5 or 1.0% curcumin. CCl(4)-induced histological changes, including extensive hepatocyte degeneration, indistinct cell borders, nuclear condensation, and karyolysis were clearly reduced after treatment with 0.5% and 1.0% curcumin. Moreover, 0.5% and 1.0% curcumin significantly inhibited the CCl(4)-induced increase in serum glutamic oxaloacetic transaminase and promoted the restoration of superoxide dismutase in the liver; 1.0% curcumin significantly reduced serum glutamic pyruvic transaminase and lactate dehydrogenase and hepatic malondialdehyde, but significantly increased the total antioxidant capacity and glutathione levels in the liver. The CCl(4)-induced upregulation of NF-κB/c-Rel, IL-1β, and TNF-α mRNAs and NF-κB/c-Rel protein levels was inhibited by 0.5% and 1.0% curcumin, and IL-12 mRNA was reduced by all three doses of curcumin. The effects of curcumin on the liver index, enzymes, histological changes, and cytokines were dose-dependent. Our results indicate that curcumin reduces CCl(4)-induced liver damage in Jian carp by upregulating antioxidative activities and inhibiting NF-κB, IL-1β, TNF-α, and IL-12 expression.
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Affiliation(s)
- Liping Cao
- International Joint Research Laboratory for Fish Immunopharmacology, Freshwater Fisheries Research Center, Chinese Academy of Fishery Sciences, Wuxi 214081, China; Key Laboratory of Freshwater Fisheries and Germplasm Resource Utilization, Ministry of Agriculture, Freshwater Fisheries Research Center, Chinese Academy of Fishery Sciences, Wuxi 214081, China
| | - Weidong Ding
- International Joint Research Laboratory for Fish Immunopharmacology, Freshwater Fisheries Research Center, Chinese Academy of Fishery Sciences, Wuxi 214081, China
| | - Jingliang Du
- International Joint Research Laboratory for Fish Immunopharmacology, Freshwater Fisheries Research Center, Chinese Academy of Fishery Sciences, Wuxi 214081, China; Key Laboratory of Freshwater Fisheries and Germplasm Resource Utilization, Ministry of Agriculture, Freshwater Fisheries Research Center, Chinese Academy of Fishery Sciences, Wuxi 214081, China
| | - Rui Jia
- International Joint Research Laboratory for Fish Immunopharmacology, Freshwater Fisheries Research Center, Chinese Academy of Fishery Sciences, Wuxi 214081, China; Key Laboratory of Freshwater Fisheries and Germplasm Resource Utilization, Ministry of Agriculture, Freshwater Fisheries Research Center, Chinese Academy of Fishery Sciences, Wuxi 214081, China
| | - Yingjuan Liu
- International Joint Research Laboratory for Fish Immunopharmacology, Freshwater Fisheries Research Center, Chinese Academy of Fishery Sciences, Wuxi 214081, China; Key Laboratory of Freshwater Fisheries and Germplasm Resource Utilization, Ministry of Agriculture, Freshwater Fisheries Research Center, Chinese Academy of Fishery Sciences, Wuxi 214081, China
| | - Caiyuan Zhao
- International Joint Research Laboratory for Fish Immunopharmacology, Freshwater Fisheries Research Center, Chinese Academy of Fishery Sciences, Wuxi 214081, China; Key Laboratory of Freshwater Fisheries and Germplasm Resource Utilization, Ministry of Agriculture, Freshwater Fisheries Research Center, Chinese Academy of Fishery Sciences, Wuxi 214081, China
| | - Yujin Shen
- International Joint Research Laboratory for Fish Immunopharmacology, Freshwater Fisheries Research Center, Chinese Academy of Fishery Sciences, Wuxi 214081, China; Key Laboratory of Freshwater Fisheries and Germplasm Resource Utilization, Ministry of Agriculture, Freshwater Fisheries Research Center, Chinese Academy of Fishery Sciences, Wuxi 214081, China
| | - Guojun Yin
- International Joint Research Laboratory for Fish Immunopharmacology, Freshwater Fisheries Research Center, Chinese Academy of Fishery Sciences, Wuxi 214081, China; Key Laboratory of Freshwater Fisheries and Germplasm Resource Utilization, Ministry of Agriculture, Freshwater Fisheries Research Center, Chinese Academy of Fishery Sciences, Wuxi 214081, China.
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Duval F, Moreno-Cuevas JE, González-Garza MT, Rodríguez-Montalvo C, Cruz-Vega DE. Protective mechanisms of medicinal plants targeting hepatic stellate cell activation and extracellular matrix deposition in liver fibrosis. Chin Med 2014; 9:27. [PMID: 25606051 PMCID: PMC4299307 DOI: 10.1186/s13020-014-0027-4] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2014] [Accepted: 11/26/2014] [Indexed: 01/18/2023] Open
Abstract
During chronic liver injury, hepatic stellate cells (HSC) are activated and proliferate, which causes excessive extracellular matrix (ECM) deposition, leading to scar formation and fibrosis. Medicinal plants are gaining popularity as antifibrotic agents, and are often safe, cost-effective, and versatile. This review aims to describe the protective role and mechanisms of medicinal plants in the inhibition of HSC activation and ECM deposition during the pathogenesis of liver fibrosis. A systematic literature review on the anti-fibrotic mechanisms of hepatoprotective plants was performed in PubMed, which yielded articles about twelve relevant plants. Many of these plants act via disruption of the transforming growth factor beta 1 signaling pathway, possibly through reduction in oxidative stress. This reduction could explain the inhibition of HSC activation and reduction in ECM deposition. Medicinal plants could be a source of anti-liver fibrosis compounds.
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Affiliation(s)
- Florent Duval
- Cell Therapy Department, School of Medicine, Tecnológico de Monterrey, Monterrey, NL CP 63710 Mexico
| | - Jorge E Moreno-Cuevas
- Cell Therapy Department, School of Medicine, Tecnológico de Monterrey, Monterrey, NL CP 63710 Mexico
| | | | | | - Delia Elva Cruz-Vega
- Cell Therapy Department, School of Medicine, Tecnológico de Monterrey, Monterrey, NL CP 63710 Mexico
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Abouzied MMM, Eltahir HM, Abdel Aziz MA, Ahmed NS, Abd El-Ghany AA, Abd El-Aziz EA, Abd El-Aziz HO. Curcumin ameliorate DENA-induced HCC via modulating TGF-β, AKT, and caspase-3 expression in experimental rat model. Tumour Biol 2014; 36:1763-71. [PMID: 25519685 DOI: 10.1007/s13277-014-2778-z] [Citation(s) in RCA: 32] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2014] [Accepted: 10/21/2014] [Indexed: 12/20/2022] Open
Abstract
Hepatocellular carcinoma (HCC) is one of the most common malignancies worldwide. In laboratory animal models, diethylnitrosamine (DENA) is a well-known agent that has a potent hepatocarcinogenic effect that is used to induce HCC. As curcumin has a potent anti-inflammatory effect with strong therapeutic potential against a variety of cancers, our present study aims to investigate its curative effects and the possible mechanisms of action against DENA-induced HCC in male rats. Investigation of biochemical and molecular parameters of HCC animal model liver showed an overexpression of TGF-β and Akt proteins accompanied with a significant reduction of the proapoptotic marker caspase-3. DENA-induced hepatic cellular injury resulted also in a significant increase in liver function marker enzymes aspartate aminotransferase (AST), alanine aminotransferase (ALT), and lipid peroxides in this group. Curcumin treatment partially reversed DENA-induced damage as it reduced the overexpression of the angiogenic and anti-apoptotic factors TGF-β and Akt and improved caspase-3 expression. Also, it could partially normalize the serum values of liver marker enzymes and lipid peroxidation and improve liver architecture. Curcumin shows a unique chemotherapeutic effect in reversing DENA-induced HCC in rat model. This effect is possibly mediated through its proapoptotic, antioxidant, anti-angiogenic, as well as antimitotic effects. It interferes and modulates cell signaling pathways and hence turns death signals and apoptosis on within tumor cells.
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Affiliation(s)
- Mekky M M Abouzied
- Department of Pharmacology and Toxicology, College of Pharmacy, Taibah University, El- Madinah El-Munawarah, P.O. Box 30001, Saudi Arabia,
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Hofni A, El-Moselhy MA, Taye A, Khalifa MM. Combination therapy with spironolactone and candesartan protects against streptozotocin-induced diabetic nephropathy in rats. Eur J Pharmacol 2014; 744:173-82. [DOI: 10.1016/j.ejphar.2014.10.021] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2014] [Revised: 10/05/2014] [Accepted: 10/08/2014] [Indexed: 01/13/2023]
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The protective effect of curcumin on paracetamol-induced liver damage in adult male rabbits. ACTA ACUST UNITED AC 2014. [DOI: 10.1097/01.ehx.0000455822.82783.4b] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
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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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Meng Z, Yu XH, Chen J, Li L, Li S. Curcumin attenuates cardiac fibrosis in spontaneously hypertensive rats through PPAR-γ activation. Acta Pharmacol Sin 2014; 35:1247-56. [PMID: 25132338 DOI: 10.1038/aps.2014.63] [Citation(s) in RCA: 41] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/01/2014] [Accepted: 06/05/2014] [Indexed: 02/06/2023]
Abstract
AIM To investigate the effects of curcumin (Cur) on cardiac fibrosis in spontaneously hypertensive rats (SHRs) and the mechanisms underlying the anti-fibrotic effect of Cur in rat cardiac fibroblasts (CFs) in vitro. METHODS SHRs were orally treated with Cur (100 mg·kg(-1)·d(-1)) or Cur (100 mg·kg(-1)·d(-1)) plus the PPAR-γ antagonist GW9662 (1 mg·kg(-1)·d(-1)) for 12 weeks. Cultured CFs were treated with angiotensin II (Ang II, 0.1 μmol/L) in vitro. The expression of relevant proteins and mRNAs was analyzed using Western blotting and real-time PCR, respectively. The expression and activity of peroxisome proliferator-activated receptor-γ (PPAR-γ) were detected using Western blotting and a DNA-binding assay, respectively. RESULTS Treatment of SHRs with Cur significantly decreased systolic blood pressure, blood Ang II concentration, heart weight/body weight ratio and left ventricle weight/body weight ratio, with concurrently decreased expression of connective tissue growth factor (CTGF), plasminogen activator inhibitor (PAI)-1, collagen III (Col III) and fibronectin (FN), and increased expression and activity of PPAR-γ in the left ventricle. Co-treatment with GW9662 partially abrogated the anti-fibrotic effects of Cur in SHRs. Pretreatment of CFs with Cur (5, 10, 20 μmol/L) dose-dependently inhibited Ang II-induced expression of CTGF, PAI-1, Col III and FN, and increased the expression and binding activity of PPAR-γ. Pretreatment with GW9662 partially reversed anti-fibrotic effects of Cur in vitro. Furthermore, pretreatment of CFs with Cur inhibited Ang II-induced expression of transforming growth factor-β1 (TGF-β1) and phosphorylation of Smad2/3, which were reversed by GW9662. CONCLUSION Cur attenuates cardiac fibrosis in SHRs and inhibits Ang II-induced production of CTGF, PAI-1 and ECM in CFs in vitro. The crosstalk between PPAR-γ and TGF-β1/Smad2/3 signaling is involved in the anti-fibrotic and anti-proliferative effects of Cur.
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