|
1
|
Han S, Wan J, Zhang X, Ding J, Li X, Cheng Y, Sun Y, Xu Z, Wu J, Chen R. Proteomic profiling of spleen in rat infected with clonorchissinensis using liquid chromatography tandem mass spectrometry analysis. Acta Trop 2025:107594. [PMID: 40127806 DOI: 10.1016/j.actatropica.2025.107594] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/07/2025] [Revised: 03/09/2025] [Accepted: 03/20/2025] [Indexed: 03/26/2025]
Abstract
Clonorchiasis, caused by Clonorchissinensis, remains a significant yet neglected tropical disease with substantial global health implications. As the largest immune organ in mammals, the spleen plays a crucial role in defending against C. sinensis infection; however, the molecular mechanisms underlying spleen pathogenesis during such infections are poorly understood. To address this gap, quantitative Tandem Mass Tags (TMT) liquid chromatography-tandem mass spectrometry was employed to profile protein changes in the spleens of rats infected with C. sinensis. This analysis identified 40,664 peptides from 6,817 proteins, including 371 and 464 differentially expressed proteins at 4 and 8 weeks post-infection (wpi) compared to the control groups, respectively. Clustering analysis revealed distinct proteomic profiles among the groups, while gene ontology analysis associated the differentially expressed proteins with biological binding activities and metabolic processes. KEGG analysis revealed significant enrichment of immune-related and metabolic pathways, including AMPK, IL-17, and p53 signaling pathways. These findings reveal dynamic alterations in spleen proteins during C. sinensis infection, offering valuable insights into the biomarker candidates for early diagnosis. Future studies are warranted to validate these potential biomarkers and explore their utility for early diagnosis of clonorchiasis.
Collapse
Affiliation(s)
- Su Han
- Department of Public Health and Preventive Medicine, Wuxi School of Medicine, Jiangnan University, Wuxi, China; Department of Parasitology, Harbin Medical University, Harbin, P. R. China.; Affiliated Hospital of Jiangnan University, Wuxi, China
| | - Jie Wan
- Department of Public Health and Preventive Medicine, Wuxi School of Medicine, Jiangnan University, Wuxi, China
| | - Xiaoli Zhang
- Department of Parasitology, Harbin Medical University, Harbin, P. R. China
| | - Jian Ding
- Department of Parasitology, Harbin Medical University, Harbin, P. R. China
| | - Xiang Li
- Department of Parasitology, Harbin Medical University, Harbin, P. R. China
| | - Yang Cheng
- Department of Public Health and Preventive Medicine, Wuxi School of Medicine, Jiangnan University, Wuxi, China
| | - Yifan Sun
- Department of Public Health and Preventive Medicine, Wuxi School of Medicine, Jiangnan University, Wuxi, China
| | - Zhenli Xu
- Department of Public Health and Preventive Medicine, Wuxi School of Medicine, Jiangnan University, Wuxi, China
| | - Jianlin Wu
- Hospital of Guangxi medical university, nanning, China..
| | - Rui Chen
- Affiliated Hospital of Jiangnan University, Wuxi, China.
| |
Collapse
|
|
2
|
Mostafa DK, Eissa MM, Ghareeb DA, Abdulmalek S, Hewedy WA. Resveratrol protects against Schistosoma mansoni-induced liver fibrosis by targeting the Sirt-1/NF-κB axis. Inflammopharmacology 2024; 32:763-775. [PMID: 38041753 PMCID: PMC10907480 DOI: 10.1007/s10787-023-01382-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2023] [Accepted: 10/19/2023] [Indexed: 12/03/2023]
Abstract
Hepatic schistosomiasis is a prevalent form of chronic liver disease that drastically affects human health. Nevertheless, an antifibrotic drug that could suppress the development of hepatic fibrosis does not exist yet. The current study aimed to evaluate the effect of resveratrol, a natural polyphenol with multiple biological activities, on Schistosoma mansoni (S. mansoni)-induced hepatic fibrosis and delineate the underlying molecular mechanism. Swiss male albino mice were randomly assigned into infected and non-infected groups. Hepatic schistosomiasis infection was induced via exposure to S. mansoni cercariae. 6 weeks later, resveratrol was administrated either as 20 mg/kg/day or 100 mg/kg/day for 4 weeks to two infected groups. Another group received vehicle and served as infected control group. At the end of the study, portal hemodynamic, biochemical, and histopathological evaluation of liver tissues were conducted. Remarkably, resveratrol significantly reduced portal pressure, portal and mesenteric flow in a dose-dependent manner. It improved several key features of hepatic injury as evidenced biochemically by a significant reduction of bilirubin and liver enzymes, and histologically by amelioration of the granulomatous and inflammatory reactions. In line, resveratrol reduced the expression of pro-inflammatory markers; TNF-α, IL-1β and MCP-1 mRNA, together with fibrotic markers; collagen-1, TGF-β1 and α-SMA. Moreover, resveratrol restored SIRT1/NF-κB balance in hepatic tissues which is the main switch-off control for all the fibrotic and inflammatory mechanisms. Taken together, it can be inferred that resveratrol possesses a possible anti-fibrotic effect that can halt the progression of hepatic schistosomiasis via targeting SIRT1/ NF-κB signaling.
Collapse
Affiliation(s)
- Dalia Kamal Mostafa
- Clinical Pharmacology Department, Faculty of Medicine, Alexandria University, Al-Moassat Medical Campus, Elhadara, Alexandria, 21561, Egypt
| | - Maha M Eissa
- Medical Parasitology Department, Faculty of Medicine, Alexandria University, Alexandria, Egypt
| | - Doaa A Ghareeb
- Biochemistry Department, Faculty of Science, Alexandria University, Alexandria, Egypt
| | - Shaymaa Abdulmalek
- Biochemistry Department, Faculty of Science, Alexandria University, Alexandria, Egypt
| | - Wafaa A Hewedy
- Clinical Pharmacology Department, Faculty of Medicine, Alexandria University, Al-Moassat Medical Campus, Elhadara, Alexandria, 21561, Egypt.
| |
Collapse
|
|
3
|
Chen Y, Yang S, Liu L, Yang X, Duan Y, Zhang S, Han J. A novel therapy for hepatic cholestasis treatment-the combination of rosiglitazone and fenofibrate. Eur J Pharmacol 2022; 938:175428. [PMID: 36436592 DOI: 10.1016/j.ejphar.2022.175428] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2022] [Revised: 11/22/2022] [Accepted: 11/23/2022] [Indexed: 11/26/2022]
Abstract
Hepatic cholestasis can develop into liver fibrosis and eventually liver failure. Currently, ursodeoxycholic acid (UDCA) or UDCA combined with fenofibrate is used for cholestasis treatment. Rosiglitazone inhibited α-naphthyl isothiocyanate (ANIT)-induced cholestasis in mice. In this study, we compared the effect of rosiglitazone, UDCA, fenofibrate, combined rosiglitazone and fenofibrate or UDCA and fenofibrate on ANIT-induced cholestasis. C57BL/6J mice were induced cholestasis by ANIT while treated with rosiglitazone, UDCA, fenofibrate, combination of rosiglitazone and fenofibrate, or combination of UDCA and fenofibrate. Liver and serum samples were collected to determine liver necrosis and serum biochemical parameters. Rosiglitazone alone or combined with fenofibrate demonstrated better effects than UDCA alone or UDCA combined with fenofibrate in reduction of cholestasis-induced serum biochemical parameters and liver necrosis. Surprisingly, UDCA combined with fenofibrate, but not rosiglitazone combined with fenofibrate, potently increased accumulation of free fatty acids (FFAs) in the liver. Mechanistically, the protection of combination of rosiglitazone and fenofibrate against cholestasis was attributed to activated adiponectin pathway to enhance FXR and mitochondrial functions and reduce apoptosis in the liver. The accumulation of FFAs in the liver by combination of UDCA and fenofibrate was caused by activation of fatty acid biosynthesis and uptake, and triglyceride hydrolysis. Taken together, our study not only demonstrates the adverse effect of combination therapy of UDCA and fenofibrate, but also suggests the combination of rosiglitazone and fenofibrate can be another option for cholestasis treatment.
Collapse
Affiliation(s)
- Yuanli Chen
- Key Laboratory of Metabolism and Regulation for Major Diseases of Anhui Higher Education Institutes, College of Food and Biological Engineering, Hefei University of Technology, Hefei, China
| | - Shu Yang
- Department of Geriatrics, Shenzhen People's Hospital (The Second Clinical Medical College, Jinan University, The First Affiliated Hospital, Southern University of Science and Technology), Shenzhen, China; College of Life Sciences, Key Laboratory of Bioactive Materials of Ministry of Education, State Key Laboratory of Medicinal Chemical Biology, Nankai University, Tianjin, China
| | - Lipei Liu
- College of Life Sciences, Key Laboratory of Bioactive Materials of Ministry of Education, State Key Laboratory of Medicinal Chemical Biology, Nankai University, Tianjin, China
| | - Xiaoxiao Yang
- Key Laboratory of Metabolism and Regulation for Major Diseases of Anhui Higher Education Institutes, College of Food and Biological Engineering, Hefei University of Technology, Hefei, China
| | - Yajun Duan
- Key Laboratory of Metabolism and Regulation for Major Diseases of Anhui Higher Education Institutes, College of Food and Biological Engineering, Hefei University of Technology, Hefei, China
| | - Shuang Zhang
- Key Laboratory of Metabolism and Regulation for Major Diseases of Anhui Higher Education Institutes, College of Food and Biological Engineering, Hefei University of Technology, Hefei, China.
| | - Jihong Han
- Key Laboratory of Metabolism and Regulation for Major Diseases of Anhui Higher Education Institutes, College of Food and Biological Engineering, Hefei University of Technology, Hefei, China; College of Life Sciences, Key Laboratory of Bioactive Materials of Ministry of Education, State Key Laboratory of Medicinal Chemical Biology, Nankai University, Tianjin, China.
| |
Collapse
|
|
4
|
Bakery HH, Allam GA, Abuelsaad ASA, Abdel‐Latif M, Elkenawy AE, Khalil RG. Anti‐inflammatory, antioxidant, anti‐fibrotic, and schistosomicidal properties of plumbagin in murine schistosomiasis. Parasite Immunol 2022; 44:e12945. [DOI: 10.1111/pim.12945] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2022] [Revised: 08/01/2022] [Accepted: 08/08/2022] [Indexed: 11/29/2022]
Affiliation(s)
- Heba H. Bakery
- Immunology Divisions, Zoology Department Faculty of Science, Beni‐Suef University Beni‐Suef Egypt
| | - Gamal A. Allam
- Immunology Divisions, Zoology Department Faculty of Science, Beni‐Suef University Beni‐Suef Egypt
| | | | - Mahmoud Abdel‐Latif
- Immunology Divisions, Zoology Department Faculty of Science, Beni‐Suef University Beni‐Suef Egypt
| | - Ayman E. Elkenawy
- Department of Pathology College of Medicine, Taif University, P.O. Box 11099 Taif Saudi Arabia
- Department of Molecular Biology, GEBRI University of Sadat City Sadat City Egypt
| | - Rehab G. Khalil
- Immunology Divisions, Zoology Department Faculty of Science, Beni‐Suef University Beni‐Suef Egypt
| |
Collapse
|
|
5
|
Liu J, Yao Q, Xie X, Cui Q, Jiang T, Zhao Z, Du X, Lai B, Xiao L, Wang N. Procyanidin B2 Attenuates Nicotine-Induced Hepatocyte Pyroptosis through a PPARγ-Dependent Mechanism. Nutrients 2022; 14:nu14091756. [PMID: 35565726 PMCID: PMC9103831 DOI: 10.3390/nu14091756] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2022] [Revised: 04/20/2022] [Accepted: 04/21/2022] [Indexed: 12/23/2022] Open
Abstract
Procyanidin B2 (PCB2), a natural flavonoid, has been demonstrated to exert anti-oxidation and anti-inflammatory effects on hepatic diseases. Increasing evidence shows the hepatoxicity of nicotine. However, whether PCB2 protects against nicotine-induced hepatoxicity and the underlying mechanisms remains uncharacterized. Here, we reported that nicotine promoted hepatocyte pyroptosis, as evidenced by the elevation of propidium iodide (PI)-positive cells, the activation of Caspase-1 and gasdermin D (GSDMD), the enhanced expression of NOD-like receptor containing pyrin domain 3 (NLRP3) and the increased release of lactate dehydrogenase (LDH), interleukin (IL)-1β and IL-18. The silencing of GSDMD by small interfering RNA (siRNA) efficiently inhibited the release of LDH and the secretion of IL-1β and IL-18. In addition, rosiglitazone (RGZ) prevented hepatocyte pyroptosis induced by nicotine. Furthermore, we showed that PCB2 attenuated nicotine-induced pyroptosis through the activation of peroxisome proliferator-activated receptor-γ (PPARγ) in hepatocytes. Moreover, administration of PCB2 ameliorated liver injury and hepatocyte pyroptosis in nicotine-treated mice. Hence, our findings demonstrated that PCB2 attenuated pyroptosis and liver damage in a PPARγ-dependent manner. Our results suggest a new mechanism by which PCB2 exerts its liver protective effects.
Collapse
Affiliation(s)
- Jia Liu
- Cardiovascular Research Center, School of Basic Medical Sciences, Xi’an Jiaotong University, Xi’an 710061, China; (J.L.); (Q.Y.); (X.X.); (X.D.); (B.L.); (L.X.)
- Key Laboratory of Environment and Genes Related to Diseases, Xi’an Jiaotong University, Ministry of Education of China, Xi’an 710061, China
| | - Qinyu Yao
- Cardiovascular Research Center, School of Basic Medical Sciences, Xi’an Jiaotong University, Xi’an 710061, China; (J.L.); (Q.Y.); (X.X.); (X.D.); (B.L.); (L.X.)
| | - Xinya Xie
- Cardiovascular Research Center, School of Basic Medical Sciences, Xi’an Jiaotong University, Xi’an 710061, China; (J.L.); (Q.Y.); (X.X.); (X.D.); (B.L.); (L.X.)
| | - Qi Cui
- Advanced Institute for Medical Sciences, Dalian Medical University, Dalian 116044, China; (Q.C.); (T.J.); (Z.Z.)
| | - Tingting Jiang
- Advanced Institute for Medical Sciences, Dalian Medical University, Dalian 116044, China; (Q.C.); (T.J.); (Z.Z.)
| | - Ziwei Zhao
- Advanced Institute for Medical Sciences, Dalian Medical University, Dalian 116044, China; (Q.C.); (T.J.); (Z.Z.)
| | - Xiong Du
- Cardiovascular Research Center, School of Basic Medical Sciences, Xi’an Jiaotong University, Xi’an 710061, China; (J.L.); (Q.Y.); (X.X.); (X.D.); (B.L.); (L.X.)
| | - Baochang Lai
- Cardiovascular Research Center, School of Basic Medical Sciences, Xi’an Jiaotong University, Xi’an 710061, China; (J.L.); (Q.Y.); (X.X.); (X.D.); (B.L.); (L.X.)
| | - Lei Xiao
- Cardiovascular Research Center, School of Basic Medical Sciences, Xi’an Jiaotong University, Xi’an 710061, China; (J.L.); (Q.Y.); (X.X.); (X.D.); (B.L.); (L.X.)
- Key Laboratory of Environment and Genes Related to Diseases, Xi’an Jiaotong University, Ministry of Education of China, Xi’an 710061, China
| | - Nanping Wang
- Health Science Center, East China Normal University, Shanghai 200241, China
- Correspondence: ; Tel.: +86-021-62235057
| |
Collapse
|
|
6
|
Li J, Guo C, Wu J. The Agonists of Peroxisome Proliferator-Activated Receptor-γ for Liver Fibrosis. DRUG DESIGN DEVELOPMENT AND THERAPY 2021; 15:2619-2628. [PMID: 34168433 PMCID: PMC8219117 DOI: 10.2147/dddt.s310163] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/09/2021] [Accepted: 06/07/2021] [Indexed: 12/18/2022]
Abstract
Liver fibrosis is a common link in the transformation of acute and chronic liver diseases to cirrhosis. It is of great clinical significance to study the factors associated with the induction of liver fibrosis and elucidate the method of reversal. Peroxisome proliferator-activated receptors (PPARs) are a class of nuclear transcription factors that can be activated by peroxisome proliferators. PPARs play an important role in fibrosis of various organs, especially the liver, by regulating downstream targeted pathways, such as TGF-β, MAPKs, and NF-κB p65. In recent years, the development and screening of PPAR-γ ligands have become a focus of research. The PPAR-γ ligands include synthetic hypolipidemic and antidiabetic drugs. In addition, microRNAs, lncRNAs, circRNAs and nano new drugs have attracted research interest. In this paper, the research progress of PPAR-γ in the pathogenesis and treatment of liver fibrosis was discussed based on the relevant literature in recent years.
Collapse
Affiliation(s)
- Jingjing Li
- Department of Gastroenterology, Putuo People's Hospital, Tongji University, Shanghai, 200060, People's Republic of China.,Department of Gastroenterology, Shanghai Tenth People's Hospital, Tongji University, Shanghai, 200072, People's Republic of China
| | - Chuanyong Guo
- Department of Gastroenterology, Putuo People's Hospital, Tongji University, Shanghai, 200060, People's Republic of China.,Department of Gastroenterology, Shanghai Tenth People's Hospital, Tongji University, Shanghai, 200072, People's Republic of China
| | - Jianye Wu
- Department of Gastroenterology, Putuo People's Hospital, Tongji University, Shanghai, 200060, People's Republic of China
| |
Collapse
|
|
7
|
Su W, Tai Y, Tang SH, Ye YT, Zhao C, Gao JH, Tuo BG, Tang CW. Celecoxib attenuates hepatocyte apoptosis by inhibiting endoplasmic reticulum stress in thioacetamide-induced cirrhotic rats. World J Gastroenterol 2020; 26:4094-4107. [PMID: 32821072 PMCID: PMC7403803 DOI: 10.3748/wjg.v26.i28.4094] [Citation(s) in RCA: 23] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/30/2020] [Revised: 05/21/2020] [Accepted: 06/25/2020] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Endoplasmic reticulum (ER) stress is an important mechanism in the progression of chronic and acute liver diseases, especially in the progression and recovery of liver fibrosis. Excessive and long-term ER stress induces apoptosis. ER stress-induced apoptosis is considered to be an important pathway in the development of liver fibrosis. Cyclooxygenase-2 (COX-2) induction is also closely related to ER stress. In our previous studies, we showed that celecoxib, a COX-2 inhibitor, improves liver fibrosis and portal hypertension. However, the role and mechanism of celecoxib in alleviating liver fibrosis remain unclear.
AIM To investigate whether celecoxib alleviates liver fibrosis by inhibiting hepatocyte apoptosis via the ER stress response.
METHODS Cirrhosis was induced by intraperitoneal injections of thioacetamide (TAA) for 16 wk (injection dose is 200 mg/kg per 3 d for the first 8 wk and 100 mg /kg per 3 d after 8 wk). Thirty-six male Sprague-Dawley rats were randomly divided into three groups, namely, control group, TAA group, and TAA + celecoxib group. In the last 8 wk, TAA-induced cirrhotic rats received celecoxib (20 mg/kg/day) or the vehicle by gastric gavage. After 16 wk, the rats were sacrificed, and serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), and albumin (ALB) were detected. The hepatic fibrosis areas were evaluated by Sirius red staining and the degree of fibrosis was assessed by measuring the level of hydroxyproline. ER stress levels were evaluated by detecting the marker proteins glucose-regulated protein 78 (GRP78), CCAAT/enhancer binding protein homologous protein (CHOP), PKR-like ER protein kinase (PERK), activating transcription factor 6 (ATF6), and inositol-requiring enzyme 1 alpha (IRE1α). Apoptosis levels were evaluated by detecting caspase-12 and caspase-3.
RESULTS The serum ALT and AST levels in the liver were significantly reduced by celecoxib; however, the serum ALB had no significant changes. Celecoxib significantly reduced the degree of liver fibrosis and the levels of hydroxyproline (-38% and -25.7%, respectively, P < 0.01). Celecoxib ameliorated ER stress by reducing the level of GRP78 compared to the TAA group (P < 0.05). Consistently, after celecoxib administration, the upregulation of TAA-induced hepatic apoptosis markers (caspase-12 and caspase-3) and CHOP were significantly inhibited. In addition, after celecoxib treatment, the expression of key molecules associated with ER stress (PERK, ATF6, and IRE1) was decreased (P < 0.05).
CONCLUSION Therapeutic administration of celecoxib effectively reduces hepatic apoptosis in TAA-induced cirrhotic rats. The mechanism of action may be attributed to the suppression of CHOP expression, which subsequently inhibits ER stress.
Collapse
Affiliation(s)
- Wei Su
- Department of Gastroenterology, West China Hospital, Sichuan University, Chengdu 610041, Sichuan Province, China
- Department of Gastroenterology, Affiliated Hospital, Zunyi Medical University, Zunyi 563003, Guizhou Province, China
| | - Yang Tai
- Laboratory of Gastroenterology and Hepatology, West China Hospital, Sichuan University, Chengdu 610041, Sichuan Province, China
| | - Shi-Hang Tang
- Laboratory of Gastroenterology and Hepatology, West China Hospital, Sichuan University, Chengdu 610041, Sichuan Province, China
| | - Yan-Ting Ye
- Laboratory of Gastroenterology and Hepatology, West China Hospital, Sichuan University, Chengdu 610041, Sichuan Province, China
| | - Chong Zhao
- Laboratory of Gastroenterology and Hepatology, West China Hospital, Sichuan University, Chengdu 610041, Sichuan Province, China
| | - Jin-Hang Gao
- Laboratory of Gastroenterology and Hepatology, West China Hospital, Sichuan University, Chengdu 610041, Sichuan Province, China
| | - Bi-Guang Tuo
- Department of Gastroenterology, Affiliated Hospital, Zunyi Medical University, Zunyi 563003, Guizhou Province, China
| | - Cheng-Wei Tang
- Department of Gastroenterology, West China Hospital, Sichuan University, Chengdu 610041, Sichuan Province, China
- Laboratory of Gastroenterology and Hepatology, West China Hospital, Sichuan University, Chengdu 610041, Sichuan Province, China
| |
Collapse
|
|
8
|
Wilson JL, Mayr HK, Weichhart T. Metabolic Programming of Macrophages: Implications in the Pathogenesis of Granulomatous Disease. Front Immunol 2019; 10:2265. [PMID: 31681260 PMCID: PMC6797840 DOI: 10.3389/fimmu.2019.02265] [Citation(s) in RCA: 51] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2019] [Accepted: 09/09/2019] [Indexed: 12/16/2022] Open
Abstract
Metabolic reprogramming is rapidly gaining appreciation in the etiology of immune cell dysfunction in a variety of diseases. Tuberculosis, schistosomiasis, and sarcoidosis represent an important class of diseases characterized by the formation of granulomas, where macrophages are causatively implicated in disease pathogenesis. Recent studies support the incidence of macrophage metabolic reprogramming in granulomas of both infectious and non-infectious origin. These publications identify the mechanistic target of rapamycin (mTOR), as well as the major regulators of lipid metabolism and cellular energy balance, peroxisome proliferator receptor gamma (PPAR-γ) and adenosine monophosphate-activated protein kinase (AMPK), respectively, as key players in the pathological progression of granulomas. In this review, we present a comprehensive breakdown of emerging research on the link between macrophage cell metabolism and granulomas of different etiology, and how parallels can be drawn between different forms of granulomatous disease. In particular, we discuss the role of PPAR-γ signaling and lipid metabolism, which are currently the best-represented metabolic pathways in this context, and we highlight dysregulated lipid metabolism as a common denominator in granulomatous disease progression. This review therefore aims to highlight metabolic mechanisms of granuloma immune cell fate and open up research questions for the identification of potential therapeutic targets in the future.
Collapse
Affiliation(s)
- Jayne Louise Wilson
- Center for Pathobiochemistry and Genetics, Institute of Medical Genetics, Medical University of Vienna, Vienna, Austria
| | - Hannah Katharina Mayr
- Center for Pathobiochemistry and Genetics, Institute of Medical Genetics, Medical University of Vienna, Vienna, Austria
| | - Thomas Weichhart
- Center for Pathobiochemistry and Genetics, Institute of Medical Genetics, Medical University of Vienna, Vienna, Austria
| |
Collapse
|
|
9
|
Abstract
Parasitic infections are responsible for significant morbidity and mortality throughout the world. Management strategies rely primarily on antiparasitic drugs that have side effects and risk of drug resistance. Therefore, novel strategies are needed for treatment of parasitic infections. Host-directed therapy (HDT) is a viable alternative, which targets host pathways responsible for parasite invasion/survival/pathogenicity. Recent innovative combinations of genomics, proteomics and computational biology approaches have led to discovery of several host pathways that could be promising targets for HDT for treating parasitic infections. Herein, we review major advances in HDT for parasitic disease with regard to core regulatory pathways and their interactions.
Collapse
|
|
10
|
Abd El-Aal NF, Abdelbary EH. Paeoniflorin in experimental BALB/c mansoniasis: A novel anti-angiogenic therapy. Exp Parasitol 2018; 197:85-92. [PMID: 30414842 DOI: 10.1016/j.exppara.2018.11.002] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2018] [Revised: 10/15/2018] [Accepted: 11/04/2018] [Indexed: 12/14/2022]
Abstract
Chronic hepatic schistosomiasis causes portal hypertension, fibrosis and lethal hepatosplenic complications. Previous studies focused mainly on schistosomicidal drugs and neglected the therapeutic approaches against the vascular complications after portal hypertension. Investigating a novel anti-angiogenic therapy is an urgent. The current study is to evaluate the performance of Paeoniflorin (PAE) as an anti-angiogenic therapy, being a powerful anti-fibrotic, compared to artemether (ART) and praziqantel (PZQ) in schistosomiasis mansoni BALB/c mice. Thirty two laboratory bred male BALB/c Swiss albino mice. The mice were classified into four groups (8 mice each), control infected (CI), PZQ (300 mg/kg/12 h), ART (0.1 ml/mg/d) and PAE (50 mg/kg/d) treated groups for one month. All mice groups were sacrificed 15 weeks post infection for assessment of the drugs' efficacy by parasitological, histopathological and immunohistochemical studies. Our results in PAE group showed marked reduction in the mean egg count/gram stool, worm burden, egg count/gram liver tissue, granuloma diameter and pro-angiogenic factors as vascular endothelial growth factor (VEGF), Proliferating cell nuclear antigen (PCNA), alpha-smooth muscle actin (α-SMA) and CD34; conversely, there was an augmentation of the tissue inhibitor metalloproteinases-2 (TIMP-2) as an anti-angiogenic expression that was exceeded ART and PZQ treated groups compared to CI group (p˂0.001). Conclusively, PAE has an anti-angiogenic impact with no vascular proliferative activity or recanalization, no micro-vessel density (MVD) changes, granuloma resolution and fibrosis regression. PAE is predicted to be a potential therapy for chronic hepatic diseases associated with fibrosis and angiogenesis, hopeful in protecting from advanced serious complications; cancer and metastasis.
Collapse
|
|
11
|
PPAR- γ Agonist Alleviates Liver and Spleen Pathology via Inducing Treg Cells during Schistosoma japonicum Infection. J Immunol Res 2018; 2018:6398078. [PMID: 30116754 PMCID: PMC6079474 DOI: 10.1155/2018/6398078] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2018] [Revised: 06/12/2018] [Accepted: 06/25/2018] [Indexed: 12/31/2022] Open
Abstract
Background Peroxisome proliferator-activated receptor- (PPAR-) γ plays critical roles in human metabolic disorders and has recently been implicated as a regulator of cellular proliferation and inflammatory responses. Regulatory T cells (Tregs), which express high levels of PPAR-γ protein, have the ability to maintain immune tolerance to self-antigens and regulate immune response to Schistosoma infection. However, mechanisms involved in the resolution of these responses are elusive. Methods Liver and spleen tissue samples in Schistosoma japonicum-infected mice after administration of pioglitazone (a PPAR-γ agonist) were collected. The hepatic and splenic pathologies were detected by H&E and Masson staining. The percentages of Th1/2 and Treg cells in the liver and spleen of each mouse were determined using flow cytometry. Levels of gene expression of PPAR-γ and Foxp3 in tissues or cells were determined using real-time PCR (RT-PCR). Macrophages were treated with pioglitazone in vitro or cocultured with normal purified CD4+ T cells for detecting Treg cells by flow cytometry. The interactions of PPAR-γ with Foxp3 in CD4+ T cells were detected by coimmunoprecipitation. Results Administration of pioglitazone resulted in the prevention of the development of hepatic and splenic pathologies. Activation of PPAR-γ by pioglitazone resulted in increased percentages of CD4+CD25+Foxp3+ Treg cells and decreased percentages of CD3+CD4+IFN-γ+ and CD3+CD4+IL-4+ cells in the liver and spleen of Schistosoma japonicum-infected mice. In addition, the PPAR-γ agonist can induce Treg cells in vitro directly or by modulating the macrophage's function indirectly. Furthermore, through interaction with Foxp3 in CD4+ T cells, the PPAR-γ agonist can promote the expression of Foxp3; however, the inhibitor of PPAR-γ weakened the expression of Foxp3 by modifying the coexpression of Foxp3 and PPAR-γ. Conclusions Our study reveals a previously unrecognized role for PPAR-γ/Foxp3 signaling in regulating the immunopathology that occurs during Schistosoma infection through induction of Treg cells.
Collapse
|
|
12
|
Ramos de Carvalho JE, Verwoert MT, Vogels IM, Reits EA, Van Noorden CJ, Klaassen I, Schlingemann RO. Involvement of the ubiquitin-proteasome system in the expression of extracellular matrix genes in retinal pigment epithelial cells. Biochem Biophys Rep 2018; 13:83-92. [PMID: 29387813 PMCID: PMC5789218 DOI: 10.1016/j.bbrep.2018.01.005] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2016] [Revised: 01/08/2018] [Accepted: 01/09/2018] [Indexed: 01/06/2023] Open
Abstract
Emerging evidence suggests that dysfunction of the ubiquitin-proteasome system is involved in the pathogenesis of numerous senile degenerative diseases including retinal disorders. The aim of this study was to assess whether there is a link between proteasome regulation and retinal pigment epithelium (RPE)-mediated expression of extracellular matrix genes. For this purpose, human retinal pigment epithelial cells (ARPE-19) were treated with different concentrations of transforming growth factor-β (TGFβ), connective tissue growth factor (CTGF), interferon-γ (IFNγ) and the irreversible proteasome inhibitor epoxomicin. First, cytotoxicity and proliferation assays were carried out. The expression of proteasome-related genes and proteins was assessed and proteasome activity was determined. Then, expression of fibrosis-associated factors fibronectin (FN), fibronectin EDA domain (FN EDA), metalloproteinase-2 (MMP-2), tissue inhibitor of metalloproteinases-1 (TIMP-1) and peroxisome proliferator-associated receptor-γ (PPARγ) was assessed. The proteasome inhibitor epoxomicin strongly arrested cell cycle progression and down-regulated TGFβ gene expression, which in turn was shown to induce expression of pro-fibrogenic genes in ARPE-19 cells. Furthermore, epoxomicin induced a directional shift in the balance between MMP-2 and TIMP-1 and was associated with down-regulation of transcription of extracellular matrix genes FN and FN-EDA and up-regulation of the anti-fibrogenic factor PPARγ. In addition, both CTGF and TGFβ were shown to affect expression of proteasome-associated mRNA and protein levels. Our results suggest a link between proteasome activity and pro-fibrogenic mechanisms in the RPE, which could imply a role for proteasome-modulating agents in the treatment of retinal disorders characterized by RPE-mediated fibrogenic responses.
Collapse
Key Words
- AMD, age-related macular degeneration
- ARPE-19, human retinal pigment epithelial cells
- CNV, choroidal neovascularization
- CTGF
- CTGF, connective tissue growth factor
- ECM, extracellular matrix
- EMT, epithelial-mesenchymal transition
- Epoxomicin
- FN EDA, fibronectin EDA domain
- FN, fibronectin
- Fibrosis
- IFNγ, interferon-γ
- MMP-2, matrix metalloproteinase-2
- PPARγ
- PPARγ, peroxisome proliferator-associated receptor-γ
- Proteasome
- RPE
- RPE, retinal pigment epithelium
- Retina
- TGFβ
- TGFβ, transforming growth factor-β
- TIMP-1, tissue inhibitor of metalloproteinases-1
- UPS, ubiquitin-proteasome system
- nAMD, neovascular age-related macular degeneration
Collapse
Affiliation(s)
- J. Emanuel Ramos de Carvalho
- Ocular Angiogenesis Group, Departments of Ophthalmology and Medical Biology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands
| | - Milan T. Verwoert
- Ocular Angiogenesis Group, Departments of Ophthalmology and Medical Biology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands
| | - Ilse M.C. Vogels
- Ocular Angiogenesis Group, Departments of Ophthalmology and Medical Biology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands
| | - Eric A. Reits
- Department of Medical Biology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands
| | - Cornelis J.F. Van Noorden
- Ocular Angiogenesis Group, Departments of Ophthalmology and Medical Biology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands
- Department of Medical Biology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands
| | - Ingeborg Klaassen
- Ocular Angiogenesis Group, Departments of Ophthalmology and Medical Biology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands
| | - Reinier O. Schlingemann
- Ocular Angiogenesis Group, Departments of Ophthalmology and Medical Biology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands
| |
Collapse
|
|
13
|
Alhusseiny SM, El-Beshbishi SN, Hashim MMA, El-nemr HEDE, Handoussa AE. A comparative study on the anti-schistosomal and hepatoprotective effects of vinpocetine and isosorbide-5-mononitrate on Schistosoma mansoni-infected mice. Acta Trop 2017; 176:114-125. [PMID: 28757393 DOI: 10.1016/j.actatropica.2017.07.016] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2016] [Revised: 07/17/2017] [Accepted: 07/18/2017] [Indexed: 12/31/2022]
Abstract
Schistosomiasis is a remarkable public health problem in developing countries. Presently, praziquantel is the optional drug for all human schistosomiasis. Owing to the increased praziquantel resistance, there is an urgent need to develop new alternatives. This study aims at determining the anti-schistosomal and/or the hepatoprotective effects of the anti-inflammatory drug; vinpocetine, and the vasodilator and the nitric oxide donor; isosorbide-5-mononitrate, in comparison to praziquantel. In the present research, the therapeutic efficacies of these drugs were assessed in Swiss albino female mice (CD-I strain) experimentally infected with an Egyptian strain of Schistosoma mansoni, using some general, parasitological, and histopathological parameters. In this work, praziquantel significantly reduced worm burden and hepatic egg load, increased the percentage of dead eggs in the small intestine and decreased granuloma count, but did not reduce granuloma diameter. While, either vinpocetine or isosorbide-5-mononitrate monotherapy did not induce significant reduction in the worm count, hepatic egg load or shift in the oogram pattern, but significantly reduced granuloma count and diameter. Moreover, isosorbide-5-mononitrate significantly reduced hepatic inflammation and necrosis. The best results were obtained in the mice groups treated with isosorbide-5-mononitrate combined with praziquantel or vinpocetine. Our results point to vinpocetine and isosorbide-5-mononitrate as a convenient and promising adjuvant to praziquantel for ameliorating schistosomal liver pathology. Further studies are recommended to reveal the actual pathways responsible for the different activities of vinpocetine and isosorbide-5-mononitrate.
Collapse
|
|
14
|
Abd El-Aal NF, Hamza RS, Harb O. Paeoniflorin targets apoptosis and ameliorates fibrosis in murine schistosomiasis mansoni : A novel insight. Exp Parasitol 2017; 183:23-32. [DOI: 10.1016/j.exppara.2017.10.005] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2017] [Revised: 09/25/2017] [Accepted: 10/12/2017] [Indexed: 01/04/2023]
|
|
15
|
Ahmed SM, Abdelrahman SA, Salama AE. Efficacy of gold nanoparticles against isoproterenol induced acute myocardial infarction in adult male albino rats. Ultrastruct Pathol 2017; 41:168-185. [PMID: 28277146 DOI: 10.1080/01913123.2017.1281367] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/16/2023]
Abstract
This study was undertaken to investigate the role of gold nanoparticles (GNPs) of 50 nm diameter on isoproterenol (ISO) induced acute myocardial infarction in adult male albino rats. Forty five adult Wistar male albino rats were equally divided into three groups. Control (group I) was further subdivided into three subgroups. In group II, the rats received ISO subcutaneously at a dose of 100 mg/kg for three days. In group III, rats received ISO as group II and then GNPs (400 μg/kg/day) intravenously for 14 consecutive days. Echocardiography was performed. Left ventricular specimens were prepared for H&E, van Gieson staining, immunohistochemical analysis for (eNOs and Bcl-2), and Electron microscope examination. Energy dispersive X-ray microanalysis was also performed. Cardiac markers such as creatine Kinase-MB (CK-MB), alanine aminotransferase (ALT), aspartate aminotransferase (AST), and cardiac troponin T (cTnT) were measured. Group II revealed cardiomyocytes with deeply stained acidophilic cytoplasm, small dark nuclei, intracellular vacuolations, wide intercellular spaces, and extravasated red blood cells. Increased collagen fibers were observed. Electron microscope examination showed cardiomyocyte with small and irregular outlined nuclei, mitochondria with irregular cristae and others with ruptured mitochondrial membrane, abnormal alignment of myofibrils, dilated cisternae of smooth endoplasmic reticulum, and disorganized intercalated discs. Group III showed that most cardiomyocytes preserved the normal architecture. Increased expression of eNOs immunoreaction and decreased Bcl-2 immunoreaction were detected in group II as compared to the control and GNP-treated groups. These findings suggested that GNPs of 50 nm diameter improved myocardial injury after ISO-induced myocardial infarction in rats. ABBREVIATIONS Myocardial infarction (MI), Isoproterenol (ISO), Nitric oxide (NO), Neuronal NOS (nNOs), Endothelial NOs (eNOs), Gold nanoparticle (GNPs), Diamiobenzidine (DAB), Serum Creatine Kinase-MB (CK-MB), Alanine aminotransferase (ALT), Cardiac troponin T (cTnT), Electrochemiluminiscence (ECLIA), Cardiomyocytes (CMC), Peroxisomal proliferator activated receptor (PPARs), Reactive oxygen species (ROS).
Collapse
Affiliation(s)
- Samah M Ahmed
- a Histology and Cell Biology Department, Faculty of Human Medicine , Zagazig University , Zagazig , Egypt
| | - Shaimaa Ali Abdelrahman
- a Histology and Cell Biology Department, Faculty of Human Medicine , Zagazig University , Zagazig , Egypt
| | | |
Collapse
|
|
16
|
Curcumin Suppresses Intestinal Fibrosis by Inhibition of PPAR γ-Mediated Epithelial-Mesenchymal Transition. EVIDENCE-BASED COMPLEMENTARY AND ALTERNATIVE MEDICINE 2017; 2017:7876064. [PMID: 28203261 PMCID: PMC5292200 DOI: 10.1155/2017/7876064] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/18/2016] [Revised: 12/04/2016] [Accepted: 12/21/2016] [Indexed: 12/25/2022]
Abstract
Intestinal fibrotic stricture is a major complication of Crohn's disease (CD) and epithelial-to-mesenchymal transition (EMT) is considered as an important contributor to the formation of intestinal fibrosis by increasing extracellular matrix (ECM) proteins. Curcumin, a compound derived from rhizomes of Curcuma, has been demonstrated with a potent antifibrotic effect. However, its effect on intestinal fibrosis and the potential mechanism is not completely understood. Here we found that curcumin pretreatment significantly represses TGF-β1-induced Smad pathway and decreases its downstream α-smooth muscle actin (α-SMA) gene expression in intestinal epithelial cells (IEC-6); in contrast, curcumin increases expression of E-cadherin and peroxisome proliferator-activated receptor γ (PPARγ) in IEC-6. Moreover, curcumin promotes nuclear translocation of PPARγ and the inhibitory effect of curcumin on EMT could be reversed by PPARγ antagonist GW9662. Consistently, in the rat model of intestinal fibrosis induced by 2,4,5-trinitrobenzene sulphonic acid (TNBS), oral curcumin attenuates intestinal fibrosis by increasing the expression of PPARγ and E-cadherin and decreasing the expression of α-SMA, FN, and CTGF in colon tissue. Collectively, these results indicated that curcumin is able to prevent EMT progress in intestinal fibrosis by PPARγ-mediated repression of TGF-β1/Smad pathway.
Collapse
|
|
17
|
Mechanism of action and effect of immune-modulating agents in the treatment of psoriasis. Biomed Pharmacother 2016; 85:141-147. [PMID: 27930978 DOI: 10.1016/j.biopha.2016.11.105] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2016] [Revised: 11/22/2016] [Accepted: 11/27/2016] [Indexed: 12/24/2022] Open
Abstract
OBJECTIVES The aim of this work is to study the possible mechanisms through which different immune-modulating agents can produce their beneficial effects on treatment of psoriasis and to determine whether the supplementation of these agents for psoriasis patients induces regression of psoriasis. SUBJECTS AND METHODS One hundred fifty participants were included in this study. The participants were divided into five groups: 1. Normal control group, 2. Psoriasis patients not taking any treatment, 3. Psoriasis patients treated with anti-psoriatic treatment (including coal tar, vitamin D3 analogues and corticosteroids). 4. Psoriasis patients treated with anti-psoriatic treatment and oral metformin (850mg twice daily) and 5. Psoriasis patients treated with anti-psoriatic treatment and oral pioglitazone (15mg once a day). Demographic characteristics, diabetic index, lipid profile and liver function tests were monitored. The CD4+ Tcells, CD8+ Tcells, CD4+/CD8+ ratio, interleukin-2 (IL-2), C-reactive protein (CRP) and ceruloplasmin (CP) were assayed. RESULTS After treatment of psoriasis patients with a traditional anti-psoriatic drug in combination with metformin and peroxisome proliferator-activated receptor gamma (PPARɤ) agonist (pioglitazone), the CD4+ T cells, IL-2, CRP, CP, ALT and AST levels were statistically significantly decreased compared to psoriasis patients without treatment. Positive and significant correlations between CD4+ % and IL-2, CRP, CP, ALT and AST in psoriasis patients were recorded. CONCLUSIONS The activation of PPAR-γ receptors by pioglitazone results in reduced formation of the proinflammatory cytokines and infiltration by inflammatory cells. Additionally, metformin acts as a modulator of the immune system in psoriasis patients and has a remarkable effect on the early stages of psoriasis. Therefore, either pioglitazone or metformin in combination with traditional anti-psoriatic drugs provides better results in the treatment of psoriasis than does each alone.
Collapse
|
|
18
|
Adenovirus-mediated expression of orphan nuclear receptor NR4A2 targeting hepatic stellate cell attenuates liver fibrosis in rats. Sci Rep 2016; 6:33593. [PMID: 27646469 PMCID: PMC5028713 DOI: 10.1038/srep33593] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2016] [Accepted: 08/24/2016] [Indexed: 01/20/2023] Open
Abstract
Liver fibrosis is a wound-healing response characterized with the accumulation of extracellular matrix (ECM). And hepatic stellate cells (HSCs) are the principal cell source of ECM. NR4A2 (Nurr1) is a member of orphan nuclear receptor NR4A family and acts as transcription factor. It participates in regulating cell differentiation, proliferation and apoptosis. We previously demonstrated that NR4A2 expression in fibrotic liver reduced significantly compared with normal liver and NR4A2 knockout in HSCs promoted ECM production. In the present study we explored the role of NR4A2 on liver fibrosis. Studies in cultured HSCs demonstrated that NR4A2 over-expression suppressed the activation of HSCs, such as ECM production and invasion ability. Moreover cell cycle was arrested, cell apoptosis was promoted and cell signaling pathway was influenced. Adenovirus-mediated delivery of NR4A2 in rats ameliorated significantly dimethylnitrosamine (DMN) induced liver fibrosis. The In vivo experiments produced results consistent with in vitro experiments. Taken together these results demonstrate NR4A2 enhancement attenuates liver fibrosis via suppressing the activation of HSCs and NR4A2 may be an ideal target for anti-fibrotic therapy.
Collapse
|
|
19
|
Mazidi M, Karimi E, Meydani M, Ghayour-Mobarhan M, Ferns GA. Potential effects of curcumin on peroxisome proliferator-activated receptor-γ in vitro and in vivo. World J Methodol 2016; 6:112-117. [PMID: 27019802 PMCID: PMC4804246 DOI: 10.5662/wjm.v6.i1.112] [Citation(s) in RCA: 36] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/18/2015] [Revised: 01/27/2016] [Accepted: 03/09/2016] [Indexed: 02/06/2023] Open
Abstract
Natural peroxisome proliferator-activated receptor-γ (PPAR-γ) agonists are found in food and may be important for health through their anti-inflammatory properties. Curcumin (Cur) is a bright yellow spice, derived from the rhizome of Curcuma longa Linn. It has been shown to have many biological properties that appear to operate through diverse mechanisms. Some of these potentially beneficial effects of Cur are due to activation of the nuclear transcription factor PPAR-γ. It is reported (using in vitro and in vivo models) that Cur plays a potential role against several diseases. In this review article, we present the current literature on the effects of Cur on the modulation of inflammatory processes that are mediated through PPAR-γ.
Collapse
|
|
20
|
Chen P, Li J, Huo Y, Lu J, Wan L, Li B, Gan R, Guo C. Orphan nuclear receptor NR4A2 inhibits hepatic stellate cell proliferation through MAPK pathway in liver fibrosis. PeerJ 2015; 3:e1518. [PMID: 26713258 PMCID: PMC4690364 DOI: 10.7717/peerj.1518] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/27/2015] [Accepted: 11/28/2015] [Indexed: 02/06/2023] Open
Abstract
Hepatic stellate cells (HSCs) play a crucial role in liver fibrosis, which is a pathological process characterized by extracellular matrix accumulation. NR4A2 is a nuclear receptor belonging to the NR4A subfamily and vital in regulating cell growth, metabolism, inflammation and other biological functions. However, its role in HSCs is unclear. We analyzed NR4A2 expression in fibrotic liver and stimulated HSCs compared with control group and studied the influence on cell proliferation, cell cycle, cell apoptosis and MAPK pathway after NR4A2 knockdown. NR4A2 expression was examined by real-time polymerase chain reaction, Western blotting, immunohistochemistry and immunofluorescence analyses. NR4A2 expression was significantly lower in fibrotic liver tissues and PDGF BB or TGF-β stimulated HSCs compared with control group. After NR4A2 knockdown α-smooth muscle actin and Col1 expression increased. In addition, NR4A2 silencing led to the promotion of cell proliferation, increase of cell percentage in S phase and reduced phosphorylation of ERK1/2, P38 and JNK in HSCs. These results indicate that NR4A2 can inhibit HSC proliferation through MAPK pathway and decrease extracellular matrix in liver fibrogenesis. NR4A2 may be a promising therapeutic target for liver fibrosis.
Collapse
Affiliation(s)
- Pengguo Chen
- Department of Pharmacy, Shanghai Jiao Tong University Affiliated Sixth People's Hospital , Shanghai , China ; Shanghai Jiao Tong University School of Medicine , Shanghai , China
| | - Jie Li
- Department of Pharmacy, Shanghai Jiao Tong University Affiliated Sixth People's Hospital , Shanghai , China
| | - Yan Huo
- Department of Pharmacy, Shanghai Jiao Tong University Affiliated Sixth People's Hospital , Shanghai , China
| | - Jin Lu
- Department of Pharmacy, Shanghai Jiao Tong University Affiliated Sixth People's Hospital , Shanghai , China
| | - Lili Wan
- Department of Pharmacy, Shanghai Jiao Tong University Affiliated Sixth People's Hospital , Shanghai , China
| | - Bin Li
- Department of Pharmacy, Shanghai Jiao Tong University Affiliated Sixth People's Hospital , Shanghai , China
| | - Run Gan
- Department of Pharmacy, Shanghai Jiao Tong University Affiliated Sixth People's Hospital , Shanghai , China
| | - Cheng Guo
- Department of Pharmacy, Shanghai Jiao Tong University Affiliated Sixth People's Hospital , Shanghai , China ; Shanghai Jiao Tong University School of Medicine , Shanghai , China
| |
Collapse
|
|
21
|
Bartneck M, Warzecha KT, Tacke F. Therapeutic targeting of liver inflammation and fibrosis by nanomedicine. Hepatobiliary Surg Nutr 2015; 3:364-76. [PMID: 25568860 DOI: 10.3978/j.issn.2304-3881.2014.11.02] [Citation(s) in RCA: 59] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/16/2014] [Accepted: 10/17/2014] [Indexed: 12/25/2022]
Abstract
Nanomedicine constitutes the emerging field of medical applications for nanotechnology such as nanomaterial-based drug delivery systems. This technology may hold exceptional potential for novel therapeutic approaches to liver diseases. The specific and unspecific targeting of macrophages, hepatic stellate cells (HSC), hepatocytes, and liver sinusoidal endothelial cells (LSEC) using nanomedicine has been developed and tested in preclinical settings. These four major cell types in the liver are crucially involved in the complex sequence of events that occurs during the initiation and maintenance of liver inflammation and fibrosis. Targeting different cell types can be based on their capacity to ingest surrounding material, endocytosis, and specificity for a single cell type can be achieved by targeting characteristic structures such as receptors, sugar moieties or peptide sequences. Macrophages and especially the liver-resident Kupffer cells are in the focus of nanomedicine due to their highly efficient and unspecific uptake of most nanomaterials as well as due to their critical pathogenic functions during inflammation and fibrogenesis. The mannose receptor enables targeting macrophages in liver disease, but macrophages can also become activated by certain nanomaterials, such as peptide-modified gold nanorods (AuNRs) that render them proinflammatory. HSC, the main collagen-producing cells during fibrosis, are currently targeted using nanoconstructs that recognize the mannose 6-phosphate and insulin-like growth factor II, peroxisome proliferator activated receptor 1, platelet-derived growth factor (PDGF) receptor β, or integrins. Targeting of the major liver parenchymal cell, the hepatocyte, has only recently been achieved with high specificity by mimicking apolipoproteins, naturally occurring nanoparticles of the body. LSEC were found to be targeted most efficiently using carboxy-modified micelles and their integrin receptors. This review will summarize important functions of these cell types in healthy and diseased livers and discuss current strategies of cell-specific targeting for liver diseases by nanomedicine.
Collapse
Affiliation(s)
- Matthias Bartneck
- Department of Medicine III, University Hospital Aachen, 52074 Aachen, Germany
| | | | - Frank Tacke
- Department of Medicine III, University Hospital Aachen, 52074 Aachen, Germany
| |
Collapse
|
|
22
|
Mahajan S, Saini A, Kalra R, Gupta P. Frienemies of infection: A chronic case of host nuclear receptors acting as cohorts or combatants of infection. Crit Rev Microbiol 2014; 42:526-34. [PMID: 25358058 DOI: 10.3109/1040841x.2014.970122] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
Macrophages and dendritic cells provide critical effector functions to efficiently resist and promptly eliminate infection. Pattern recognition receptors signaling operative in these cell types is imperative for their innate properties. However, it is now emerging that besides these conventional signaling pathways, nuclear receptors coupled gene regulation and transrepression pathways assemble immune regulatory networks. A couple of these networks associated with members of nuclear receptor superfamily decide heterogeneity in macrophages and dendritic cells population and thereby play decisive role in determining protective immunity against bacteria, viruses, fungi, protozoa and helminths. Pathogens also direct shift in the expression of nuclear receptors and their target genes and this is proclaimed to be a sui generis mechanism whereby microbes disconnect the genomic component from the peripheral immune response. Many endogenous and synthetic nuclear receptor ligands have been tested in various in vitro and in vivo infection models to study their effect on pathogen burden. Here, we discuss current advances in our understanding of the composite interactions between nuclear receptor and pathogens and their implications on the causatum infectious diseases.
Collapse
Affiliation(s)
- Sahil Mahajan
- a Department of Molecular Biology , CSIR Institute of Microbial Technology , Chandigarh , India
| | - Ankita Saini
- a Department of Molecular Biology , CSIR Institute of Microbial Technology , Chandigarh , India
| | - Rashi Kalra
- a Department of Molecular Biology , CSIR Institute of Microbial Technology , Chandigarh , India
| | - Pawan Gupta
- a Department of Molecular Biology , CSIR Institute of Microbial Technology , Chandigarh , India
| |
Collapse
|
|
23
|
Latella G, Vetuschi A, Sferra R, Speca S, Gaudio E. Localization of ανβ6 integrin-TGF-β1/Smad3, mTOR and PPARγ in experimental colorectal fibrosis. Eur J Histochem 2013; 57:e40. [PMID: 24441193 PMCID: PMC3896042 DOI: 10.4081/ejh.2013.e40] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2013] [Revised: 11/26/2013] [Accepted: 11/04/2013] [Indexed: 02/08/2023] Open
Abstract
A simultaneous action of several pro-fibrotic mediators appears relevant in the development of fibrosis. There are evidences that transforming growth factor-β (TGF-β)/Smad3 pathway forms with αvβ6 integrin, mammalian target of Rapamycin (mTOR) and peroxisome proliferator-activated receptor-γ (PPARγ) a complex signalling network with extensive crosstalk and strong effects on fibrosis development. The present study evaluated the expression of TGFβ, Smad3, αvβ6 integrin, mTOR and PPARγ in 2, 4, 6-trinitrobenzenesulphonic acid (TNBS)-induced colorectal fibrosis in Smad3 wild-type (WT) and null mice. Smad3 WT mice treated with TNBS developed a marked colorectal fibrosis and showed a concomitant up-regulation of TGFβ, Smad3, αvβ6 and mTOR and a reduction of PPARγ expression. On the other hand, Smad3 Null mice similarly treated with TNBS did not develop fibrosis and showed a very low or even absent expression of TGFβ, Smad3, αvβ6 and mTOR and a marked over-expression of PPARγ. At the same time the expression of α-smooth muscle actin (a marker of activated myofibroblasts), collagen I-III and connective tissue growth factor (a downstream effector of TGFβ/Smad3-induced extracellular matrix proteins) were up-regulated in Smad3 WT mice treated with TNBS compared to Null TNBS-treated mice. These preliminary results suggest a possible interaction between these pro-fibrotic molecules in the development of intestinal fibrosis.
Collapse
|
|
24
|
Kumar V, Mundra V, Mahato RI. Nanomedicines of Hedgehog inhibitor and PPAR-γ agonist for treating liver fibrosis. Pharm Res 2013; 31:1158-69. [PMID: 24249038 DOI: 10.1007/s11095-013-1239-5] [Citation(s) in RCA: 39] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2013] [Accepted: 10/20/2013] [Indexed: 01/01/2023]
Abstract
PURPOSE Hedgehog (Hh) and peroxisome proliferator-activated receptor gamma (PPAR-γ) are major signaling pathways involved in the pathogenesis of liver fibrosis. Since Hh inhibitor, vismodegib (GDC) and PPAR-γ agonist, rosiglitazone (RSG) have poor water solubility, our objective was to formulate biodegradable polymeric nanoparticles encapsulating GDC and RSG for treating liver fibrosis. METHODS Methoxy-polyethylene-glycol-b-poly(carbonate-co-lactide) [mPEG-b-p(CB-co-LA)] was synthesized and characterized using (1)H NMR. Nanoparticles were prepared using this polymer by emulsification/solvent evaporation method to encapsulate GDC and RSG either alone or in combination. Nanoparticles were characterized for particle size, drug loading, drug release, and anti-fibrotic efficacy after tail vein injection into common bile duct ligated (CBDL) fibrotic rats. RESULTS mPEG-b-p(CB-co-LA) copolymer has molecular weight of 30,000 Da as determined by (1)H NMR. Nanoparticles were monodisperse with a mean particle size of 120-130 nm. Drug loading was 5% and 2% w/w for GDC and RSG, respectively. Nanoparticles carrying both GDC and RSG were formulated at half of their individual drug loading. Systemic administration of drug loaded nanoparticles protected liver injury in CBDL rats by suppressing the activation of hepatic stellate cells, and decreasing inflammatory cytokines. CONCLUSION Polymeric nanoparticles for co-delivery of Hh inhibitor and PPAR-γ agonist have the potential to treat liver fibrosis by intervening complex fibrotic cascade.
Collapse
Affiliation(s)
- Virender Kumar
- Department of Pharmaceutical Sciences, University of Tennessee Health Science Center, Memphis, Tennessee, 38163, USA
| | | | | |
Collapse
|
|
25
|
Attia YM, Elalkamy EF, Hammam OA, Mahmoud SS, El-Khatib AS. Telmisartan, an AT1 receptor blocker and a PPAR gamma activator, alleviates liver fibrosis induced experimentally by Schistosoma mansoni infection. Parasit Vectors 2013; 6:199. [PMID: 23829789 PMCID: PMC3733928 DOI: 10.1186/1756-3305-6-199] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2013] [Accepted: 06/17/2013] [Indexed: 12/13/2022] Open
Abstract
Background Hepatic schistosomiasis is considered to be one of the most prevalent forms of chronic liver disease in the world due to its complication of liver fibrosis. The demonstration of the pro-fibrogenic role of angiotensin (Ang) II in chronic liver disease brought up the idea that anti-Ang II agents may be effective in improving hepatic fibrosis by either blocking Ang II type 1 (AT1) receptors or inhibiting the angiotensin converting enzyme. Peroxisome proliferator-activated receptors gamma (PPARγ) activation has been also shown to inhibit hepatic stellate cell activation and progression of fibrosis. The present study has aimed at testing the anti-fibrogenic effects of telmisartan; an AT1 receptor blocker and a PPARγ partial agonist, alone or combined with praziquantel (PZQ) on Schistosoma mansoni-induced liver fibrosis in mice. Methods To achieve the aim of the study, two sets of experiments were performed in which telmisartan was initiated at the 5th (set 1) and the 10th (set 2) weeks post infection to assess drug efficacy in both acute and chronic stages of liver fibrosis, respectively. Schistosoma mansoni-infected mice were randomly divided into the following four groups: infected-control (I), telmisartan-treated (II), PZQ-treated (III), and telmisartan+PZQ-treated (IV). In addition, a normal non-infected group was used for comparison. Parasitological (hepatomesenteric worm load and oogram pattern), histopathological, morphometric, immunohistochemical (hepatic expressions of matrix metalloproteinase-2; MMP-2 and tissue inhibitor of metalloproteinase-2; TIMP-2), and biochemical (serum transforming growth factor beta 1; TGF-β1 and liver function tests) studies were performed. Results Telmisartan failed to improve the parasitological parameters, while it significantly (P<0.05) decreased the mean granuloma diameter, area of fibrosis, and serum TGF-β1. Additionally, telmisartan increased MMP-2 and decreased TIMP-2 hepatic expression. Combined treatment failed to show any additive properties, yet it did not affect the anti-schistosomal activity of PZQ. Conclusions These results suggest potential anti-fibrotic effects of telmisartan, an AT1 receptor blocker and a PPARγ partial agonist, in acute and chronic stages of Schistosoma mansoni–induced liver fibrosis in mice.
Collapse
Affiliation(s)
- Yasmeen M Attia
- Department of Pharmacology and Biochemistry, Faculty of Pharmacy, The British University in Egypt, Suez Desert Road, El Sherouk City, Cairo, Egypt.
| | | | | | | | | |
Collapse
|
|
26
|
Wick G, Grundtman C, Mayerl C, Wimpissinger TF, Feichtinger J, Zelger B, Sgonc R, Wolfram D. The immunology of fibrosis. Annu Rev Immunol 2013; 31:107-35. [PMID: 23516981 DOI: 10.1146/annurev-immunol-032712-095937] [Citation(s) in RCA: 255] [Impact Index Per Article: 21.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
Abstract
Fibrosis is the production of excessive amounts of connective tissue, i.e., scar formation, in the course of reactive and reparative processes. Fibrosis develops as a consequence of various underlying diseases and presents a major diagnostically and therapeutically unsolved problem. In this review, we postulate that fibrosis is always a sequela of inflammatory processes and that the many different causes of fibrosis all channel into the same final stereotypical pathways. During the inflammatory phase, both innate and adaptive immune mechanisms are operative. This concept is exemplified by fibrotic diseases that develop as a consequence of tissue damage, primary inflammatory diseases, fibrotic alterations induced by foreign body implants, "spontaneous" fibrosis, and tumor-associated fibrotic changes.
Collapse
Affiliation(s)
- Georg Wick
- Division of Experimental Pathophysiology and Immunology, 6020 Innsbruck, Austria.
| | | | | | | | | | | | | | | |
Collapse
|
|
27
|
Zhang F, Kong D, Lu Y, Zheng S. Peroxisome proliferator-activated receptor-γ as a therapeutic target for hepatic fibrosis: from bench to bedside. Cell Mol Life Sci 2013; 70:259-76. [PMID: 22699820 PMCID: PMC11113701 DOI: 10.1007/s00018-012-1046-x] [Citation(s) in RCA: 71] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2012] [Revised: 05/18/2012] [Accepted: 05/29/2012] [Indexed: 02/07/2023]
Abstract
Hepatic fibrosis is a dynamic chronic liver disease occurring as a consequence of wound-healing responses to various hepatic injuries. This disorder is one of primary predictors for liver-associated morbidity and mortality worldwide. To date, no pharmacological agent has been approved for hepatic fibrosis or could be recommended for routine use in clinical context. Cellular and molecular understanding of hepatic fibrosis has revealed that peroxisome proliferator-activated receptor-γ (PPARγ), the functioning receptor for antidiabetic thiazolidinediones, plays a pivotal role in the pathobiology of hepatic stellate cells (HSCs), whose activation is the central event in the pathogenesis of hepatic fibrosis. Activation of PPARγ inhibits HSC collagen production and modulates HSC adipogenic phenotype at transcriptional and epigenetic levels. These molecular insights indicate PPARγ as a promising drug target for antifibrotic chemotherapy. Intensive animal studies have demonstrated that stimulation of PPARγ regulatory system through gene therapy approaches and PPARγ ligands has therapeutic promise for hepatic fibrosis induced by a variety of etiologies. At the same time, thiazolidinedione agents have been investigated for their clinical benefits primarily in patients with nonalcoholic steatohepatitis, a common metabolic liver disorder with high potential to progress to fibrosis and liver-related death. Although some studies have shown initial promise, none has established long-term efficacy in well-controlled randomized clinical trials. This comprehensive review covers the 10-year discoveries of the molecular basis for PPARγ regulation of HSC pathophysiology and then focuses on the animal investigations and clinical trials of various therapeutic modalities targeting PPARγ for hepatic fibrosis.
Collapse
Affiliation(s)
- Feng Zhang
- Department of Clinical Pharmacy, College of Pharmacy, Nanjing University of Chinese Medicine, 282 Hanzhong Road, Nanjing, 210029 Jiangsu China
| | - Desong Kong
- Department of Clinical Pharmacy, College of Pharmacy, Nanjing University of Chinese Medicine, 282 Hanzhong Road, Nanjing, 210029 Jiangsu China
| | - Yin Lu
- Department of Clinical Pharmacy, College of Pharmacy, Nanjing University of Chinese Medicine, 282 Hanzhong Road, Nanjing, 210029 Jiangsu China
- Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing, 210046 China
- National First-Class Key Discipline for Traditional Chinese Medicine of Nanjing University of Chinese Medicine, Nanjing, 210046 China
| | - Shizhong Zheng
- Department of Clinical Pharmacy, College of Pharmacy, Nanjing University of Chinese Medicine, 282 Hanzhong Road, Nanjing, 210029 Jiangsu China
- Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing, 210046 China
- National First-Class Key Discipline for Traditional Chinese Medicine of Nanjing University of Chinese Medicine, Nanjing, 210046 China
| |
Collapse
|
|
28
|
Prashantha Kumar B, Baig NR, Sudhir S, Kar K, Kiranmai M, Pankaj M, Joghee NM. Discovery of novel glitazones incorporated with phenylalanine and tyrosine: Synthesis, antidiabetic activity and structure–activity relationships. Bioorg Chem 2012; 45:12-28. [DOI: 10.1016/j.bioorg.2012.08.002] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2012] [Revised: 07/22/2012] [Accepted: 08/03/2012] [Indexed: 10/28/2022]
|
|
29
|
Ahmad A, Ahmad R. Understanding the mechanism of hepatic fibrosis and potential therapeutic approaches. Saudi J Gastroenterol 2012. [PMID: 22626794 DOI: 10.4103/1319-3767.96445]] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Abstract
Hepatic fibrosis (HF) is a progressive condition with serious clinical complications arising from abnormal proliferation and amassing of tough fibrous scar tissue. This defiance of collagen fibers becomes fatal due to ultimate failure of liver functions. Participation of various cell types, interlinked cellular events, and large number of mediator molecules make the fibrotic process enormously complex and dynamic. However, with better appreciation of underlying cellular and molecular mechanisms of fibrosis, the assumption that HF cannot be cured is gradually changing. Recent findings have underlined the therapeutic potential of a number of synthetic compounds as well as plant derivatives for cessation or even the reversal of the processes that transforms the liver into fibrotic tissue. It is expected that future inputs will provide a conceptual framework to develop more specific strategies that would facilitate the assessment of risk factors, shortlist early diagnosis biomarkers, and eventually guide development of effective therapeutic alternatives.
Collapse
Affiliation(s)
- Areeba Ahmad
- Department of Zoology, Biochemical and Clinical Genetics Research Laboratory, Section of Genetics, Aligarh Muslim University, Aligarh, Uttar Pradesh, India
| | | |
Collapse
|
|
30
|
Role of resident liver cells in the pathogenesis of schistosomiasis. Trends Parasitol 2012; 28:572-9. [PMID: 23099112 DOI: 10.1016/j.pt.2012.09.005] [Citation(s) in RCA: 44] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2012] [Revised: 09/14/2012] [Accepted: 09/21/2012] [Indexed: 12/12/2022]
Abstract
Pathology in schistosomiasis occurs as a result of eggs deposited in the liver by the schistosome parasite. A granulomatous reaction occurs, resulting in portal hypertension and hepatic fibrosis. Resident non-parenchymal cells within the liver take part in this process, including hepatic stellate cells, which are responsible for collagen production, and Kupffer cells, the liver macrophages involved in both host protection and in pathology. Other cells such as liver sinusoidal endothelial cells or portal fibroblasts may also be involved in this process. This review discusses the possible role of these resident liver cells in the pathology associated with schistosomiasis and provides information which may assist our understanding of the mechanisms associated with chronic liver disease in general.
Collapse
|
|
31
|
Speca S, Giusti I, Rieder F, Latella G. Cellular and molecular mechanisms of intestinal fibrosis. World J Gastroenterol 2012; 18:3635-61. [PMID: 22851857 PMCID: PMC3406417 DOI: 10.3748/wjg.v18.i28.3635] [Citation(s) in RCA: 197] [Impact Index Per Article: 15.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/17/2011] [Revised: 03/26/2012] [Accepted: 04/09/2012] [Indexed: 02/06/2023] Open
Abstract
Fibrosis is a chronic and progressive process characterized by an excessive accumulation of extracellular matrix (ECM) leading to stiffening and/or scarring of the involved tissue. Intestinal fibrosis may develop in several different enteropathies, including inflammatory bowel disease. It develops through complex cell, extracellular matrix, cytokine and growth factor interactions. Distinct cell types are involved in intestinal fibrosis, such as resident mesenchymal cells (fibroblasts, myofibroblasts and smooth muscle cells) but also ECM-producing cells derived from epithelial and endothelial cells (through a process termed epithelial- and endothelial-mesenchymal transition), stellate cells, pericytes, local or bone marrow-derived stem cells. The most important soluble factors that regulate the activation of these cells include cytokines, chemokines, growth factors, components of the renin-angiotensin system, angiogenic factors, peroxisome proliferator-activated receptors, mammalian target of rapamycin, and products of oxidative stress. It soon becomes clear that although inflammation is responsible for triggering the onset of the fibrotic process, it only plays a minor role in the progression of this condition, as fibrosis may advance in a self-perpetuating fashion. Definition of the cellular and molecular mechanisms involved in intestinal fibrosis may provide the key to developing new therapeutic approaches.
Collapse
|
|
32
|
Abstract
Hepatic fibrosis (HF) is a progressive condition with serious clinical complications arising from abnormal proliferation and amassing of tough fibrous scar tissue. This defiance of collagen fibers becomes fatal due to ultimate failure of liver functions. Participation of various cell types, interlinked cellular events, and large number of mediator molecules make the fibrotic process enormously complex and dynamic. However, with better appreciation of underlying cellular and molecular mechanisms of fibrosis, the assumption that HF cannot be cured is gradually changing. Recent findings have underlined the therapeutic potential of a number of synthetic compounds as well as plant derivatives for cessation or even the reversal of the processes that transforms the liver into fibrotic tissue. It is expected that future inputs will provide a conceptual framework to develop more specific strategies that would facilitate the assessment of risk factors, shortlist early diagnosis biomarkers, and eventually guide development of effective therapeutic alternatives.
Collapse
Affiliation(s)
- Areeba Ahmad
- Department of Zoology, Biochemical and Clinical Genetics Research Laboratory, Section of Genetics, Aligarh Muslim University, Aligarh, Uttar Pradesh, India
| | - Riaz Ahmad
- Department of Zoology, Biochemical and Clinical Genetics Research Laboratory, Section of Genetics, Aligarh Muslim University, Aligarh, Uttar Pradesh, India,Address for correspondence: Dr. Riaz Ahmad, Department of Zoology, Biochemical and Clinical Genetics Research Laboratory, Section of Genetics, Aligarh Muslim University, Aligarh- 202 002, Uttar Pradesh, India. E-mail:
| |
Collapse
|
|
33
|
The use of pentoxifylline as adjuvant therapy with praziquantel downregulates profibrogenic cytokines, collagen deposition and oxidative stress in experimental schistosomiasis mansoni. Exp Parasitol 2011; 129:152-7. [PMID: 21762692 DOI: 10.1016/j.exppara.2011.06.015] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/04/2010] [Revised: 08/28/2010] [Accepted: 06/28/2011] [Indexed: 02/07/2023]
Abstract
UNLABELLED This study investigates the possible use of pentoxifylline (PTX), with antifibrotic and anti-inflammatory properties, as adjuvant in treatment of schistosomal liver fibrosis through determination of some profibrogenic cytokines, oxidative stress and collagen deposition. Animals were classified into seven groups: normal control (i), Schistosoma mansoni-infected untreated (ii), infected treated with praziquantel (PZQ) curative, 1000mg/kg (iii) or sub curative, 200mg/kg dose (iv), infected treated with PTX alone (10mg/kg/day; 5days/wk) for 8weeks starting from the 2nd to the 10th week post infection (v), or in addition to curative (vi) or sub curative dose of PZQ (vii). Serum transforming growth factor-β1 (TGF-β1), tumor necrosis factor-α (TNF-α), matrix metalloproteinases-2 (MMP-2) and hepatic hydroxyproline (Hyp) content, glutathione related antioxidant enzymes and malondialdehyde (MDA) were determined. Results showed that S. mansoni infection produced remarkable elevations in the serum levels of TGF-β1, TNF-α, MMP-2 and the hepatic contents of Hyp, glutathione reductase (GR), MDA with significant reduction in reduced glutathione (GSH), glutathione peroxidase (GPx), glutathione-S-transferase (GST) and superoxide dismutase (SOD) when compared with their corresponding normal controls. Treatment of infected mice with PTX in addition to PZQ curative rather than its sub curative dose produced the best results evidenced by complete normalization in the previously mentioned serum and hepatic parameters. CONCLUSION PTX could attenuate liver fibrosis in early stages of S. mansoni infection through downregulation of profibrogenic cytokines, oxidative stress and collagen deposition.
Collapse
|
|
34
|
A role for peroxisome proliferator-activated receptors in the immunopathology of schistosomiasis? PPAR Res 2011; 2012:128068. [PMID: 21772837 PMCID: PMC3135066 DOI: 10.1155/2012/128068] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2010] [Accepted: 02/27/2011] [Indexed: 12/27/2022] Open
Abstract
Peroxisome proliferator-activated receptors (PPARs) have been demonstrated to have a role in immune regulation. In general, they are anti-inflammatory and promote Th2 type responses, and they are associated with the alternative activation of macrophages. Interestingly, helminth infections, such as the schistosome blood flukes that cause schistosomiasis, are characterised by a Th2 response and the accumulation of alternative activated macrophages. This would suggest that at some level, PPARs could have a role in the modulation of the immune response in schistosomiasis. This paper discusses possible areas where PPARs could have a role in this disease.
Collapse
|
|
35
|
Wang Z, Xu J, Zheng Y, Chen W, Sun Y, Wu Z, Luo M. Effect of the regulation of retinoid X receptor-α gene expression on rat hepatic fibrosis. Hepatol Res 2011; 41:475-83. [PMID: 21518404 DOI: 10.1111/j.1872-034x.2011.00794.x] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
AIM To study the effect of retinoid X receptor-α (RXR-α) expression on rat hepatic fibrosis. METHODS Rat hepatic fibrosis was induced by CCl(4) , and the rats were randomly divided into an early-phase hepatic fibrosis group (2 weeks) and a sustained hepatic fibrosis group (8 weeks). They were then divided into four groups (normal control, hepatic fibrosis, negative control and RXR-α groups). A recombinant lentiviral expression vector carrying the rat RXR-α gene was injected into the rats to induce RXR-α expression by intraportal infusion, hepatic tissue pathological examination was performed, and hydroxyproline content was detected. Hepatic stellate cells (HSC) were cultured in vitro, an RXR-α lentivirus vector was used to activate HSC, and 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) activation was assayed to detect HSC proliferation. RESULTS In vivo experiments indicated that in the sustained hepatic fibrosis group, there were significant differences in the hydroxyproline content, and expression of RXR-α, α-smooth muscle actin (α-SMA) and type I collagen (P < 0.01). However, in the early-phase hepatic fibrosis group, hydroxyproline content and the protein level of RXR-α showed no significant difference compared with the normal control group (P > 0.05). In vitro studies revealed that expression of RXR-α significantly inhibited expression of α-SMA and type I collagen in activated HSC (P < 0.01), as well as HSC proliferation (P < 0.01). CONCLUSION The increased RXR-α gene expression inhibited HSC activation and proliferation and the degree of hepatic fibrosis.
Collapse
Affiliation(s)
- Zheng Wang
- Department of General Surgery, Renji Hospital Shanghai Jiaotong University School of Medicine, Shanghai, China
| | | | | | | | | | | | | |
Collapse
|
|
36
|
Trauner M, Halilbasic E. Nuclear receptors as new perspective for the management of liver diseases. Gastroenterology 2011; 140:1120-1125.e1-12. [PMID: 21334334 DOI: 10.1053/j.gastro.2011.02.044] [Citation(s) in RCA: 83] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
Nuclear receptors (NRs) are ligand-activated transcription factors that act as sensors for a broad range of natural and synthetic ligands and regulate several key hepatic functions including bile acid homeostasis, bile secretion, lipid and glucose metabolism, as well as drug deposition. Moreover, NRs control hepatic inflammation, regeneration, fibrosis, and tumor formation. Therefore, NRs are key for understanding the pathogenesis and pathophysiology of a wide range of hepatic disorders. Finally, targeting NRs and their alterations offers exciting new perspectives for the treatment of liver diseases.
Collapse
Affiliation(s)
- Michael Trauner
- Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Austria.
| | | |
Collapse
|
|
37
|
Wang Z, Xu JP, Zheng YC, Chen W, Sun YW, Wu ZY, Luo M. Peroxisome proliferator-activated receptor gamma inhibits hepatic fibrosis in rats. Hepatobiliary Pancreat Dis Int 2011; 10:64-71. [PMID: 21269937 DOI: 10.1016/s1499-3872(11)60009-x] [Citation(s) in RCA: 40] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/05/2023]
Abstract
BACKGROUND Hepatic fibrosis is a necessary step in the development of hepatic cirrhosis. In this study we used lentiviral vector-mediated transfection technology to evaluate the effect of peroxisome proliferator-activated receptor gamma (PPAR-gamma) on rat hepatic fibrosis. METHODS Hepatic fibrosis in rats was induced by CCl4 for 2 weeks (early fibrosis) and 8 weeks (sustained fibrosis). The rats were randomly divided into four groups: normal control, fibrosis, blank vector, and PPAR-gamma. They were infected with the recombinant lentiviral expression vector carrying the rat PPAR-gamma gene by portal vein injection. The liver of the rats was examined histologically and hydroxyproline was assessed. In vitro primary hepatic stellate cells (HSCs) were infected with the recombinant lentiviral expression vector carrying the rat PPAR-gamma gene. The status of HSC proliferation was measured by the MTT assay. The protein levels of PPAR-gamma, alpha-smooth muscle actin (alpha-SMA) and type I collagen expression were evaluated by the Western blotting method. RESULTS In vitro studies revealed that expression of PPAR-gamma inhibited expression of alpha-SMA and type I collagen in activated HSCs (P<0.01) as well as HSC proliferation (P<0.01). In vivo experiments indicated that in the early hepatic fibrosis group, the hydroxyproline content and the level of collagen I protein in the liver in the PPAR-gamma transfected group were not significantly different compared to the hepatic fibrosis group and the blank vector group; whereas the expressions of PPAR-gamma and alpha-SMA were different compared to the hepatic fibrosis group (P<0.01). In the sustained hepatic fibrosis group, there were significant differences in the hydroxyproline content and the expression of PPAR-gamma, alpha-SMA, and type I collagen between each group. CONCLUSION PPAR-gamma can inhibit HSC proliferation and hepatic fibrosis, and suppress alpha-SMA and type I collagen expression.
Collapse
Affiliation(s)
- Zheng Wang
- Department of General Surgery, Renji Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200127, China
| | | | | | | | | | | | | |
Collapse
|
|
38
|
Anthony B, Allen JT, Li YS, McManus DP. Hepatic stellate cells and parasite-induced liver fibrosis. Parasit Vectors 2010; 3:60. [PMID: 20663176 PMCID: PMC2915969 DOI: 10.1186/1756-3305-3-60] [Citation(s) in RCA: 67] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2010] [Accepted: 07/21/2010] [Indexed: 02/08/2023] Open
Abstract
Fibrogenesis is a common feature of many diseases where there is severe insult to the liver. The hepatic stellate cell trans-differentiation into a myofibroblast has been identified as an important event in liver fibrogenesis and has been well investigated over the last few years in a number of liver diseases. The trans-differentiation process can be monitored in vitro by evaluation of biomarkers that are characteristic of normal quiescent hepatic stellate cells or activated myofibroblasts. Two major parasitic diseases associated with liver injury and fibrosis are schistosomiasis and echinococcosis. Recent studies have highlighted a role for activated hepatic stellate cells in both murine and human schistosomiasis as well as demonstrating that schistosome antigens are able to regulate this trans-differentiation process. Study of the hepatic stellate cell and its interaction with parasite-derived antigens may be pivotal in our understanding of the pathology associated with schistosomiasis and other parasitic diseases, including echinococcosis, as well as revealing new information on the trans-differentiation process in this cell type.
Collapse
Affiliation(s)
- Barrie Anthony
- Queensland Institute of Medical Research, Post Office Royal Brisbane Hospital, Brisbane, Q 4029, Australia.
| | | | | | | |
Collapse
|
|
39
|
Abstract
It is estimated that, combined, 400,000 people are diagnosed with idiopathic pulmonary fibrosis (IPF) or acute lung injury/acute respiratory distress syndrome annually in the United States, and both diseases are associated with an unacceptably high mortality rate. Although these disorders are distinct clinical entities, they share pathogenic mechanisms that may provide overlapping therapeutic targets. One example is fibroblast activation, which occurs concomitant with acute lung injury as well as in the progressive fibrosis of IPF. Both clinical entities are characterized by elevations of the profibrotic cytokine, transforming growth factor (TGF)-beta1. Protein degradation by the ubiquitin-proteasomal system modulates TGF-beta1 expression and signaling. In this review, we highlight the effects of proteasomal inhibition in various animal models of tissue fibrosis and mechanisms by which it may regulate TGF-beta1 expression and signaling. At present, there are no effective therapies for fibroproliferative acute respiratory distress syndrome or IPF, and proteasomal inhibition may provide a novel, attractive target in these devastating diseases.
Collapse
|
|
40
|
Zhang ZF, Zhao G, Zhu Y, Wang LX, Zhu L. Efficacy of metformin in the treatment of adult nonalcoholic fatty liver disease: a meta-analysis. Shijie Huaren Xiaohua Zazhi 2010; 18:1717-1723. [DOI: 10.11569/wcjd.v18.i16.1717] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: To evaluate the efficacy of metformin in the treatment of nonalcoholic fatty liver disease (NAFLD).
METHODS: Randomized controlled clinical trials (RCTs) comparing the efficacy of metformin in combination with dietary control and dietary control alone in the treatment of NAFLD were retrieved by searching Medline, Embase, OVID, Cochrane Library, Cinahl, CESJ, ASP, VIP and National Knowledge Infrastructure. Stata 9.0 and Review Manager 5.0.14 were used for meta-analysis.
RESULTS: Nine RCTs were selected for analysis in accordance with inclusion criteria. Compared with dietary control alone, metformin in combination with dietary control decreased serum ALT, AST and GGT significantly, and the weighted mean differences (WMDs) were -12.12 U/L (95%CI: -22.13, -2.12, P = 0.02), -11.38 U/L (95%CI: -22.86, 0.11, P = 0.05) and -19.91 U/L (95%CI: -37.01, -2.82, P = 0.02), respectively. In addition, metformin in combination with dietary control also decreased the homeostasis model assessment of the insulin resistance (HOMA-IR) significantly when compared with dietary control alone, and the WMD was -0.67 (95%CI: -0.80, -0.55, P < 0.00001). Metformin in combination with dietary control was not superior to dietary control alone in reducing necro-inflammatory score and fibrosis score, and the standardized mean differences (SMDs) were -0.08 (95%CI: -0.51, 0.35, P = 0.71) and -0.32 (95%CI: -0.75, 0.11, P = 0.14), respectively.
CONCLUSION: Metformin is effective in decreasing serum ALT, AST and GGT levels and in reducing HOMA-IR in NAFLD patients. Metformin has no significant impact in improving hepatic histology in NAFLD patients.
Collapse
|
|
41
|
Abstract
Capillaria hepatica (C. hepatica) is a parasitic nematode causing hepatic capillariasis in numerous mammals. Ecologic studies showed that the first hosts of C. hepatica were rodents, among which rats had relatively high infection rates, which explains why C. hepatica spreads globally. Anatomical studies showed that the liver was the principal site of colonization by these parasites and physical damage tended to occur. Although C. hepatica might lead to serious liver disorders, relevant clinical reports were rare, because of the non-specific nature of clinical symptoms, leading to misdiagnosis. This review mainly focuses on the biological characteristics and epidemiology of C. hepatica in China and histopathologic changes in the liver, with expectation of gaining a better understanding of the disease and seeking more effective treatment.
Collapse
|
|
42
|
Peroxisome proliferator-activated receptor (PPAR): balance for survival in parasitic infections. J Biomed Biotechnol 2010; 2010:828951. [PMID: 20169106 PMCID: PMC2821783 DOI: 10.1155/2010/828951] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2009] [Accepted: 11/10/2009] [Indexed: 01/04/2023] Open
Abstract
Parasitic infections induce a magnitude of host responses. At the opposite ends of the spectrum are those that ensure the host's needs to eliminate the invaders and to minimize damage to its own tissues. This review analyzes how parasites would manipulate immunity by activating the immunosuppressive nuclear factor, peroxisome proliferator-activated receptors (PPARs) with type 2 cytokines and free fatty acids from arachidonic acid metabolism. PPARs limit the action of type 1 immunity, in which classically activated macrophages act through the production of proinflammatory signals, to spare the parasites. They also favor the development of alternately activated macrophages which control inflammation so the host would not be destroyed. Possibly, the nuclear factors hold a pivotal role in the establishment of chronic infection by delicately balancing the pro- and anti-inflammatory signaling mechanisms and their ligands may be used as combination therapeutics to limit host pathology.
Collapse
|
|
43
|
Brown M. Parasites as aetiological agents in chronic diseases. Epidemiological associations and potential mechanisms of pathogenesis. Parasite Immunol 2010; 31:653-5. [PMID: 19825104 DOI: 10.1111/j.1365-3024.2009.01153.x] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
Abstract
The aetiological role of parasitic infection has been well established, through epidemiological studies, for many chronic diseases prevalent in the tropics. Examples include Schistosoma mansoni infection leading to portal hypertension, Schistosoma haematobium infection leading to obstructive uropathy and squamous cell carcinoma of the bladder, Clonorchis sinensis leading to cholangiocarcinoma, and Taenia solium infection leading to epilepsy. Our understanding of the pathogenesis of these associations, however, continues to evolve, with new insights from many fertile avenues in chronic disease research. There are also tenuous associations such as schizophrenia with toxoplasmosis, and the findings from observational studies that link malignancy and epilepsy with a range of helminthic infections. Imprecise case definitions, and the lack of good animal models, are limitations to the evidence for a causal role of parasitic infection in these diseases.
Collapse
|
|
44
|
Endocannabinoids anandamide and its cannabinoid receptors in liver fibrosis after murine schistosomiasis. ACTA ACUST UNITED AC 2009; 29:182-6. [DOI: 10.1007/s11596-009-0209-y] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2008] [Indexed: 01/16/2023]
|