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R LC, P.F. CM, M UE, V.J. BB. Hepatic schistosomiasis as a determining factor in the development of hepatic granulomas and liver fibrosis: a review of the current literature. Pathog Glob Health 2024; 118:529-537. [PMID: 39268619 PMCID: PMC11892069 DOI: 10.1080/20477724.2024.2400033] [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] [Indexed: 09/17/2024] Open
Abstract
Hepatic schistosomiasis is a neglected parasitosis that affects millions of people each year worldwide and leads to high healthcare costs and increased morbidity and mortality in infected humans. It is a disease that has been widely studied in terms of its pathophysiology; therefore, the signaling pathways that lead to liver damage, with the consequent development of liver fibrosis, are now better understood. Research has elucidated the role of soluble egg antigen in the development of hepatic granulomas and liver fibrosis, the signal transducer and activator of transcription 3 and its participation in liver damage, the role of heat shock protein 47 and its involvement in liver fibrosis, the anti-inflammatory effects caused by interleukin-37, and the role of natural killer and natural killer T cells in the development of the disease. Hepatic schistosomiasis can range from simple hepatomegaly to the development of portal hypertension combined with hepatic fibrosis. For diagnostic purposes, a microscopic examination of excreta remains the gold standard; however, abdominal ultrasound has recently taken on an important role in the assessment of liver lesions produced by the parasite. Praziquantel is considered the management drug of choice, and has been associated with a potential preventive antifibrotic effect.
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Affiliation(s)
- Lara-Cano R
- Translational Research Unit, Medica Sur Clinic & Foundation, Mexico City, Mexico
- Benemérita Universidad Autónoma de Puebla, Mexico City, Mexico
| | | | - Uribe-Esquivel M
- Gastroenterology and Obesity Unit, Medica Sur Clinic & Foundation, Mexico City, Mexico
| | - Barbero-Becerra V.J.
- Translational Research Unit, Medica Sur Clinic & Foundation, Mexico City, Mexico
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2
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Khan ES, Däinghaus T. HSP47 in human diseases: Navigating pathophysiology, diagnosis and therapy. Clin Transl Med 2024; 14:e1755. [PMID: 39135385 PMCID: PMC11319607 DOI: 10.1002/ctm2.1755] [Citation(s) in RCA: 6] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2024] [Revised: 06/12/2024] [Accepted: 06/17/2024] [Indexed: 08/16/2024] Open
Abstract
Heat shock protein 47 (HSP47) is a chaperone protein responsible for regulating collagen maturation and transport, directly impacting collagen synthesis levels. Aberrant HSP47 expression or malfunction has been associated with collagen-related disorders, most notably fibrosis. Recent reports have uncovered new functions of HSP47 in various cellular processes. Hsp47 dysregulation in these alternative roles has been linked to various diseases, such as cancer, autoimmune and neurodegenerative disorders, thereby highlighting its potential as both a diagnostic biomarker and a therapeutic target. In this review, we discuss the pathophysiological roles of HSP47 in human diseases, its potential as a diagnostic tool, clinical screening techniques and its role as a target for therapeutic interventions.
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Affiliation(s)
- Essak. S. Khan
- Posttranscriptional Gene RegulationCancer Research and Experimental HemostasisUniversity Medical Center Mainz (UMCM)MainzGermany
- Center for Thrombosis and Hemostasis (CTH)UMCMMainzGermany
- German Consortium for Translational Cancer Research (DKTK)DKFZ Frankfurt‐MainzFrankfurt am MainGermany
| | - Tobias Däinghaus
- Posttranscriptional Gene RegulationCancer Research and Experimental HemostasisUniversity Medical Center Mainz (UMCM)MainzGermany
- Center for Thrombosis and Hemostasis (CTH)UMCMMainzGermany
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3
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Mostafa DK, Eissa MM, Ghareeb DA, Abdulmalek S, Hewedy WA. Resveratrol protects against Schistosoma mansoni-induced liver fibrosis by targeting the Sirt-1/NF-κB axis. Inflammopharmacology 2024; 32:763-775. [PMID: 38041753 PMCID: PMC10907480 DOI: 10.1007/s10787-023-01382-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2023] [Accepted: 10/19/2023] [Indexed: 12/03/2023]
Abstract
Hepatic schistosomiasis is a prevalent form of chronic liver disease that drastically affects human health. Nevertheless, an antifibrotic drug that could suppress the development of hepatic fibrosis does not exist yet. The current study aimed to evaluate the effect of resveratrol, a natural polyphenol with multiple biological activities, on Schistosoma mansoni (S. mansoni)-induced hepatic fibrosis and delineate the underlying molecular mechanism. Swiss male albino mice were randomly assigned into infected and non-infected groups. Hepatic schistosomiasis infection was induced via exposure to S. mansoni cercariae. 6 weeks later, resveratrol was administrated either as 20 mg/kg/day or 100 mg/kg/day for 4 weeks to two infected groups. Another group received vehicle and served as infected control group. At the end of the study, portal hemodynamic, biochemical, and histopathological evaluation of liver tissues were conducted. Remarkably, resveratrol significantly reduced portal pressure, portal and mesenteric flow in a dose-dependent manner. It improved several key features of hepatic injury as evidenced biochemically by a significant reduction of bilirubin and liver enzymes, and histologically by amelioration of the granulomatous and inflammatory reactions. In line, resveratrol reduced the expression of pro-inflammatory markers; TNF-α, IL-1β and MCP-1 mRNA, together with fibrotic markers; collagen-1, TGF-β1 and α-SMA. Moreover, resveratrol restored SIRT1/NF-κB balance in hepatic tissues which is the main switch-off control for all the fibrotic and inflammatory mechanisms. Taken together, it can be inferred that resveratrol possesses a possible anti-fibrotic effect that can halt the progression of hepatic schistosomiasis via targeting SIRT1/ NF-κB signaling.
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Affiliation(s)
- Dalia Kamal Mostafa
- Clinical Pharmacology Department, Faculty of Medicine, Alexandria University, Al-Moassat Medical Campus, Elhadara, Alexandria, 21561, Egypt
| | - Maha M Eissa
- Medical Parasitology Department, Faculty of Medicine, Alexandria University, Alexandria, Egypt
| | - Doaa A Ghareeb
- Biochemistry Department, Faculty of Science, Alexandria University, Alexandria, Egypt
| | - Shaymaa Abdulmalek
- Biochemistry Department, Faculty of Science, Alexandria University, Alexandria, Egypt
| | - Wafaa A Hewedy
- Clinical Pharmacology Department, Faculty of Medicine, Alexandria University, Al-Moassat Medical Campus, Elhadara, Alexandria, 21561, Egypt.
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Boo YC. Therapeutic Potential and Mechanisms of Rosmarinic Acid and the Extracts of Lamiaceae Plants for the Treatment of Fibrosis of Various Organs. Antioxidants (Basel) 2024; 13:146. [PMID: 38397744 PMCID: PMC10886237 DOI: 10.3390/antiox13020146] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2023] [Revised: 01/22/2024] [Accepted: 01/23/2024] [Indexed: 02/25/2024] Open
Abstract
Fibrosis, which causes structural hardening and functional degeneration in various organs, is characterized by the excessive production and accumulation of connective tissue containing collagen, alpha-smooth muscle actin (α-SMA), etc. In traditional medicine, extracts of medicinal plants or herbal prescriptions have been used to treat various fibrotic diseases. The purpose of this narrative review is to discuss the antifibrotic effects of rosmarinic acid (RA) and plant extracts that contain RA, as observed in various experimental models. RA, as well as the extracts of Glechoma hederacea, Melissa officinalis, Elsholtzia ciliata, Lycopus lucidus, Ocimum basilicum, Prunella vulgaris, Salvia rosmarinus (Rosmarinus officinalis), Salvia miltiorrhiza, and Perilla frutescens, have been shown to attenuate fibrosis of the liver, kidneys, heart, lungs, and abdomen in experimental animal models. Their antifibrotic effects were associated with the attenuation of oxidative stress, inflammation, cell activation, epithelial-mesenchymal transition, and fibrogenic gene expression. RA treatment activated peroxisomal proliferator-activated receptor gamma (PPARγ), 5' AMP-activated protein kinase (AMPK), and nuclear factor erythroid 2-related factor 2 (NRF2) while suppressing the transforming growth factor beta (TGF-β) and Wnt signaling pathways. Interestingly, most plants that are reported to contain RA and exhibit antifibrotic activity belong to the family Lamiaceae. This suggests that RA is an active ingredient for the antifibrotic effect of Lamiaceae plants and that these plants are a useful source of RA. In conclusion, accumulating scientific evidence supports the effectiveness of RA and Lamiaceae plant extracts in alleviating fibrosis and maintaining the structural architecture and normal functions of various organs under pathological conditions.
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Affiliation(s)
- Yong Chool Boo
- Department of Molecular Medicine, School of Medicine, Kyungpook National University, 680 Gukchaebosang-ro, Jung-gu, Daegu 41944, Republic of Korea;
- BK21 Plus KNU Biomedical Convergence Program, Department of Biomedical Science, The Graduate School, Kyungpook National University, 680 Gukchaebosang-ro, Jung-gu, Daegu 41944, Republic of Korea
- Cell and Matrix Research Institute, Kyungpook National University, 680 Gukchaebosang-ro, Jung-gu, Daegu 41944, Republic of Korea
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Luangmonkong T, Parichatikanond W, Olinga P. Targeting collagen homeostasis for the treatment of liver fibrosis: Opportunities and challenges. Biochem Pharmacol 2023; 215:115740. [PMID: 37567319 DOI: 10.1016/j.bcp.2023.115740] [Citation(s) in RCA: 15] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/25/2023] [Revised: 07/24/2023] [Accepted: 08/08/2023] [Indexed: 08/13/2023]
Abstract
Liver fibrosis is an excessive production, aberrant deposition, and deficit degradation of extracellular matrix (ECM). Patients with unresolved fibrosis ultimately undergo end-stage liver diseases. To date, the effective and safe strategy to cease fibrosis progression remains an unmet clinical need. Since collagens are the most abundant ECM protein which play an essential role in fibrogenesis, the suitable regulation of collagen homeostasis could be an effective strategy for the treatment of liver fibrosis. Therefore, this review provides a brief overview on the dysregulation of ECM homeostasis, focusing on collagens, in the pathogenesis of liver fibrosis. Most importantly, promising therapeutic mechanisms related to biosynthesis, deposition and extracellular interactions, and degradation of collagens, together with preclinical and clinical antifibrotic evidence of drugs affecting each target are orderly criticized. In addition, challenges for targeting collagen homeostasis in the treatment of liver fibrosis are discussed.
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Affiliation(s)
- Theerut Luangmonkong
- Department of Pharmacology, Faculty of Pharmacy, Mahidol University, Thailand; Centre of Biopharmaceutical Science for Healthy Ageing (BSHA), Faculty of Pharmacy, Mahidol University, Bangkok, Thailand.
| | - Warisara Parichatikanond
- Department of Pharmacology, Faculty of Pharmacy, Mahidol University, Thailand; Centre of Biopharmaceutical Science for Healthy Ageing (BSHA), Faculty of Pharmacy, Mahidol University, Bangkok, Thailand
| | - Peter Olinga
- Department of Pharmaceutical Technology and Biopharmacy, University of Groningen, The Netherlands
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Guo T, Wantono C, Tan Y, Deng F, Duan T, Liu D. Regulators, functions, and mechanotransduction pathways of matrix stiffness in hepatic disease. Front Physiol 2023; 14:1098129. [PMID: 36711017 PMCID: PMC9878334 DOI: 10.3389/fphys.2023.1098129] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2022] [Accepted: 01/06/2023] [Indexed: 01/15/2023] Open
Abstract
The extracellular matrix (ECM) provides physical support and imparts significant biochemical and mechanical cues to cells. Matrix stiffening is a hallmark of liver fibrosis and is associated with many hepatic diseases, especially liver cirrhosis and carcinoma. Increased matrix stiffness is not only a consequence of liver fibrosis but is also recognized as an active driver in the progression of fibrotic hepatic disease. In this article, we provide a comprehensive view of the role of matrix stiffness in the pathological progression of hepatic disease. The regulators that modulate matrix stiffness including ECM components, MMPs, and crosslinking modifications are discussed. The latest advances of the research on the matrix mechanics in regulating intercellular signaling and cell phenotype are classified, especially for hepatic stellate cells, hepatocytes, and immunocytes. The molecular mechanism that sensing and transducing mechanical signaling is highlighted. The current progress of ECM stiffness's role in hepatic cirrhosis and liver cancer is introduced and summarized. Finally, the recent trials targeting ECM stiffness for the treatment of liver disease are detailed.
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Affiliation(s)
- Ting Guo
- Department of Gastroenterology, The Second Xiangya Hospital of Central South University, Changsha, China
- Research Center of Digestive Disease, Central South University, Changsha, China
| | - Cindy Wantono
- Department of Gastroenterology, The Second Xiangya Hospital of Central South University, Changsha, China
- Research Center of Digestive Disease, Central South University, Changsha, China
| | - Yuyong Tan
- Department of Gastroenterology, The Second Xiangya Hospital of Central South University, Changsha, China
- Research Center of Digestive Disease, Central South University, Changsha, China
| | - Feihong Deng
- Department of Gastroenterology, The Second Xiangya Hospital of Central South University, Changsha, China
- Research Center of Digestive Disease, Central South University, Changsha, China
| | - Tianying Duan
- Department of Gastroenterology, The Second Xiangya Hospital of Central South University, Changsha, China
- Research Center of Digestive Disease, Central South University, Changsha, China
| | - Deliang Liu
- Department of Gastroenterology, The Second Xiangya Hospital of Central South University, Changsha, China
- Research Center of Digestive Disease, Central South University, Changsha, China
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Abd El-Fattah EE, Zakaria AY. Targeting HSP47 and HSP70: promising therapeutic approaches in liver fibrosis management. J Transl Med 2022; 20:544. [DOI: 10.1186/s12967-022-03759-z] [Citation(s) in RCA: 20] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2022] [Accepted: 11/06/2022] [Indexed: 11/28/2022] Open
Abstract
AbstractLiver fibrosis is a liver disease in which there is an excessive buildup of extracellular matrix proteins, including collagen. By regulating cytokine production and the inflammatory response, heat shock proteins (HSPs) contribute significantly to a wider spectrum of fibrotic illnesses, such as lung, liver, and idiopathic pulmonary fibrosis by aiding in the folding and assembly of freshly synthesized proteins, HSPs serve as chaperones. HSP70 is one of the key HSPs in avoiding protein aggregation which induces its action by sending unfolded and/or misfolded proteins to the ubiquitin–proteasome degradation pathway and antagonizing influence on epithelial-mesenchymal transition. HSP47, on the other hand, is crucial for boosting collagen synthesis, and deposition, and fostering the emergence of fibrotic disorders. The current review aims to provide light on how HSP70 and HSP47 affect hepatic fibrogenesis. Additionally, our review looks into new therapeutic approaches that target HSP70 and HSP47 and could potentially be used as drug candidates to treat liver fibrosis, especially in cases of comorbidities.
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Zhou L, Li Y, Liang Q, Liu J, Liu Y. Combination therapy based on targeted nano drug co-delivery systems for liver fibrosis treatment: A review. J Drug Target 2022; 30:577-588. [PMID: 35179094 DOI: 10.1080/1061186x.2022.2044485] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
Liver fibrosis is the hallmark of liver disease and occurs prior to the stages of cirrhosis and hepatocellular carcinoma. Any type of liver damage or inflammation can result in fibrosis. Fibrosis does not develop overnight, but rather as a result of the long-term action of injury factors. At present, however, there are no good treatment methods or specific drugs other than removing the pathogenic factors. Drug application is still limited, which means that drugs with good performance in vitro cannot achieve good therapeutic effects in vivo, owing to various factors such as poor drug targeting, large side effects, and strong hydrophobicity. Hepatic stellate cells (HSC) are the primary effector cells in liver fibrosis. The nano-drug delivery system is a new and safe drug delivery system that has many advantages which are widely used in the field of liver fibrosis. Drug resistance and side effects can be reduced when two or more drugs are used in combination drug delivery. Combination therapy of drugs with different targets has emerged as a novel approach to treating liver fibrosis, and the nano co-delivery system enhances the benefits of combination therapy. While nano co-delivery systems can maximize benefits while avoiding drug side effects, this is precisely the advantage of the nano co-delivery system. This review briefly described the pathogenesis and current treatment strategies, the different co-delivery systems of combination drugs in the nano delivery system, and targeting strategies for nano delivery systems on liver fibrosis therapy. Because of their superior performance, nano delivery systems and targeting drug delivery systems have received a lot of attention in the new drug delivery system. The new delivery systems offer a new pathway in the treatment of liver fibrosis, and it is believed that it can be a new treatment for fibrosis in the future. Nano co-delivery system of combination drugs and targeting strategies has proven the effectiveness of anti-fibrosis at the experimental level.
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Affiliation(s)
- Liyue Zhou
- Department of Pharmaceutics, School of Pharmacy, Ningxia Medical University, Yinchuan, China
| | - Yifan Li
- Department of Pharmaceutics, School of Pharmacy, Ningxia Medical University, Yinchuan, China
| | - Qiangwei Liang
- Department of Pharmaceutics, School of Pharmacy, Ningxia Medical University, Yinchuan, China
| | - Jinxia Liu
- Department of Pharmaceutics, School of Pharmacy, Ningxia Medical University, Yinchuan, China
| | - Yanhua Liu
- Department of Pharmaceutics, School of Pharmacy, Ningxia Medical University, Yinchuan, China.,Key Laboratory of Hui Ethnic Medicine Modernization, Ministry of Education, Ningxia Medical University, Yinchuan, China
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Lønsmann I, Gudmann NS, Manon-Jensen T, Thiele M, Moreno YM, Langholm LL, Nielsen MJ, Detlefsen S, Karsdal MA, Krag AA, Leeming DJ. Serologically assessed heat shock protein 47 is related to fibrosis stage in early compensated alcohol-related liver disease. Clin Biochem 2021; 104:36-43. [DOI: 10.1016/j.clinbiochem.2021.12.008] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2021] [Revised: 11/27/2021] [Accepted: 12/14/2021] [Indexed: 12/31/2022]
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10
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Zheng L, Wang L, Hu Y, Yi J, Wan L, Shen Y, Liu S, Zhou X, Cao J. Higher frequency of circulating Vδ1 γδT cells in patients with advanced schistosomiasis. Parasite Immunol 2021; 43:e12871. [PMID: 34037255 PMCID: PMC9285544 DOI: 10.1111/pim.12871] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2021] [Revised: 05/08/2021] [Accepted: 05/21/2021] [Indexed: 11/29/2022]
Abstract
Gamma‐delta (γδ) T cells are the bridge between natural and adaptive immunity. In the present study, peripheral blood was collected from 13 patients with advanced schistosomiasis (schistosomiasis group) and 13 uninfected people (control group) to investigate the γδ T cells and their subtypes in human schistosomiasis. Compared with the control group, the proportion of Vδ1 cells and CD27+Vδ1+ cells in the schistosomiasis group increased significantly, while CD27− cells and CD27−Vδ1− cells decreased. Only the level of IL‐17A differed between the groups, being significantly decreased in the schistosomiasis group. In the schistosomiasis group, there were no correlations between the liver fibrosis and subsets of γδ T cells, or the level of cytokines. Additionally, the level of IL‐17A correlated positively with the proportion of CD27− Vδ1− cells. Thus, there was a higher frequency of circulating Vδ1 γδT cells in patients with advanced schistosomiasis. The decreased IL‐17A might be related to the reduction in CD27−Vδ1− cell.
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Affiliation(s)
- Li Zheng
- Department of Immunology, Key Laboratory of Tropical Translational Medicine of Ministry of Education, Hainan Medical University-The University of Hong Kong Joint Laboratory of Tropical Infectious Diseases, Hainan Medical University, Haikou, China
| | - Lixia Wang
- Hubei Provincial Academy of Preventive Medicine, Hubei Provincial Key Laboratory for Applied Toxicology, Hubei Provincial Center for Disease Control and Prevention, Wuhan, China
| | - Yuan Hu
- National Institute of Parasitic Diseases, Chinese Center for Disease Control and Prevention (Chinese Center for Tropical Diseases Research), Key Laboratory of Parasite and Vector Biology, National Health Commission of People's Republic of China, WHO Collaborating Center for Tropical Diseases, Shanghai, China.,The School of Global Health, Chinese Center for Tropical Diseases Research, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Jia Yi
- Hubei Provincial Academy of Preventive Medicine, Hubei Provincial Key Laboratory for Applied Toxicology, Hubei Provincial Center for Disease Control and Prevention, Wuhan, China
| | - Lun Wan
- Hubei Provincial Academy of Preventive Medicine, Hubei Provincial Key Laboratory for Applied Toxicology, Hubei Provincial Center for Disease Control and Prevention, Wuhan, China
| | - Yujuan Shen
- National Institute of Parasitic Diseases, Chinese Center for Disease Control and Prevention (Chinese Center for Tropical Diseases Research), Key Laboratory of Parasite and Vector Biology, National Health Commission of People's Republic of China, WHO Collaborating Center for Tropical Diseases, Shanghai, China.,The School of Global Health, Chinese Center for Tropical Diseases Research, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Si Liu
- Hubei Provincial Academy of Preventive Medicine, Hubei Provincial Key Laboratory for Applied Toxicology, Hubei Provincial Center for Disease Control and Prevention, Wuhan, China
| | - Xiaorong Zhou
- Hubei Provincial Academy of Preventive Medicine, Hubei Provincial Key Laboratory for Applied Toxicology, Hubei Provincial Center for Disease Control and Prevention, Wuhan, China
| | - Jianping Cao
- National Institute of Parasitic Diseases, Chinese Center for Disease Control and Prevention (Chinese Center for Tropical Diseases Research), Key Laboratory of Parasite and Vector Biology, National Health Commission of People's Republic of China, WHO Collaborating Center for Tropical Diseases, Shanghai, China.,The School of Global Health, Chinese Center for Tropical Diseases Research, Shanghai Jiao Tong University School of Medicine, Shanghai, China
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Santana JB, de Almeida TVVS, Lopes DM, Page B, Oliveira SC, Souza I, Ribeiro LEVS, Gutiérrez NAG, Carvalho EM, Cardoso LS. Phenotypic Characterization of CD4 + T Lymphocytes in Periportal Fibrosis Secondary to Schistosomiasis. Front Immunol 2021; 12:605235. [PMID: 33692784 PMCID: PMC7937650 DOI: 10.3389/fimmu.2021.605235] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2020] [Accepted: 01/04/2021] [Indexed: 01/13/2023] Open
Abstract
Schistosomiasis is a parasitic disease that affects about 166 million people around the world. It is estimated that 5%-10% of individuals with schistosomiasis develop severe forms of the disease, which are characterized by pulmonary hypertension, ascites, periportal fibrosis, and other significant complications. The chronic phase of the disease is associated with a Th2 type immune response, but evidence also suggests there are roles for Th1 and Th17 in the development of severe disease. The aim of this study was to evaluate the CD4+ T lymphocyte profile of patients with different degrees of periportal fibrosis secondary to schistosomiasis. These individuals had been treated for schistosomiasis, but since they live in a S. mansoni endemic area, they are at risk of reinfection. They were evaluated in relation to the degree of periportal fibrosis and classified into three groups: without fibrosis or with incipient fibrosis (WF/IFNE), n=12, possible periportal fibrosis/periportal fibrosis, n=13, and advanced periportal fibrosis/advanced periportal fibrosis with portal hypertension, n=4. We observed in the group without fibrosis a balance between the low expression of Th2 cytokines and high expression of T reg cells. As has already been described in the literature, we found an increase of the Th2 cytokines IL-4, IL-5, and IL-13 in the group with periportal fibrosis. In addition, this group showed higher expression of IL-17 and IL-10 but lower IL-10/IL-13 ratio than patients in the WF/IFNE group. Cells from individuals who present any level of fibrosis expressed more TGF-β compared to the WF/IFNE group and a positive correlation with left lobe enlargement and portal vein wall thickness. There was a negative correlation between IL-17 and the thickness of the portal vein wall, but more studies are necessary in order to explore the possible protective role of this cytokine. Despite the fibrosis group having presented a higher expression of pro-fibrotic molecules compared to WF/IFNE patients, it seems there is a regulation through IL-10 and T reg cells that is able to maintain the low morbidity of this group.
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Affiliation(s)
- Jordana Batista Santana
- Serviço de Imunologia, Hospital Universitário Professor Edgard Santos, Universidade Federal da Bahia, Salvador, Brazil
| | | | - Diego Mota Lopes
- Serviço de Imunologia, Hospital Universitário Professor Edgard Santos, Universidade Federal da Bahia, Salvador, Brazil
| | - Brady Page
- Massachusetts General Hospital, Boston, MA, United States
| | - Sergio Costa Oliveira
- Departamento de Bioquímica e Imunologia, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil
- Instituto Nacional de Ciência e Tecnologia em Doenças Tropicais (INCT–DT/CNPq), Salvador, Brazil
| | | | | | | | - Edgar M. Carvalho
- Serviço de Imunologia, Hospital Universitário Professor Edgard Santos, Universidade Federal da Bahia, Salvador, Brazil
- Instituto Nacional de Ciência e Tecnologia em Doenças Tropicais (INCT–DT/CNPq), Salvador, Brazil
- Laboratório de Pesquisas Clínicas, Instituto Gonçalo Moniz, Fundação Oswaldo Cruz (FIOCRUZ), Salvador, Brazil
| | - Luciana Santos Cardoso
- Serviço de Imunologia, Hospital Universitário Professor Edgard Santos, Universidade Federal da Bahia, Salvador, Brazil
- Instituto Nacional de Ciência e Tecnologia em Doenças Tropicais (INCT–DT/CNPq), Salvador, Brazil
- Departamento de Análises Clínicas e Toxicológicas, Faculdade de Farmácia, Universidade Federal da Bahia (UFBA), Salvador, Brazil
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12
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Zhang X, Zhang X, Huang W, Ge X. The role of heat shock proteins in the regulation of fibrotic diseases. Biomed Pharmacother 2020; 135:111067. [PMID: 33383375 DOI: 10.1016/j.biopha.2020.111067] [Citation(s) in RCA: 21] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/18/2020] [Revised: 11/08/2020] [Accepted: 11/20/2020] [Indexed: 12/29/2022] Open
Abstract
Heat shock proteins (HSPs) are key players to restore cell homeostasis and act as chaperones by assisting the folding and assembly of newly synthesized proteins and preventing protein aggregation. Recently, evidence has been accumulating that HSPs have been proven to have other functions except for the classical molecular chaperoning in that they play an important role in a wider range of fibrotic diseases via modulating cytokine induction and inflammation response, including lung fibrosis, liver fibrosis, and idiopathic pulmonary fibrosis. The recruitment of inflammatory cells, a large number of secretion of pro-fibrotic cytokines such as transforming growth factor-β1 (TGF-β1) and increased apoptosis, oxidative stress, and proteasomal system degradation are all events occurring during fibrogenesis, which might be associated with HSPs. However, their role on fibrotic process is not yet fully understood. In this review, we discuss new discoveries regarding the involvement of HSPs in the regulation of organ and tissue fibrosis, and note recent findings suggesting that HSPs may be a promising therapeutic target for improving the current frustrating outcome of fibrotic disorders.
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Affiliation(s)
- Xiaoling Zhang
- Institute of Translational Medicine, Medical College, Yangzhou University, Yangzhou, 225001, PR China; School of Pharmacy, Nantong University, 19 Qixiu Road, Nantong, 226019, PR China.
| | - Xiaoyan Zhang
- Institute of Translational Medicine, Medical College, Yangzhou University, Yangzhou, 225001, PR China
| | - Wenmin Huang
- Institute of Translational Medicine, Medical College, Yangzhou University, Yangzhou, 225001, PR China
| | - Xiaoqun Ge
- Institute of Translational Medicine, Medical College, Yangzhou University, Yangzhou, 225001, PR China; Jiangsu Key Laboratory of Integrated Traditional Chinese and Western Medicine for Prevention and Treatment of Senile Diseases, Yangzhou University, Yangzhou, 225001, PR China; Jiangsu Co-Innovation Center for the Prevention and Control of Important Animal Infectious Diseases and Zoonoses, College of Veterinary Medicine, Yangzhou University, Yangzhou, 225009, PR China.
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Kong H, He J, Guo S, Song Q, Xiang D, Tao R, Yu H, Chen G, Huang Z, Ning Q, Huang J. Endothelin receptors promote schistosomiasis-induced hepatic fibrosis via splenic B cells. PLoS Pathog 2020; 16:e1008947. [PMID: 33075079 PMCID: PMC7595619 DOI: 10.1371/journal.ppat.1008947] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2020] [Revised: 10/29/2020] [Accepted: 08/31/2020] [Indexed: 12/17/2022] Open
Abstract
Endothelin receptors (ETRs) are activated by vasoactive peptide endothelins and involved in the pathogenesis of hepatic fibrosis. However, less is known about the role of ETRs in Schistosoma (S.) japonicum-induced hepatic fibrosis. Here, we show that the expression of ETRs is markedly enhanced in the liver and spleen tissues of patients with schistosome-induced fibrosis, as well as in murine models. Additional analyses have indicated that the expression levels of ETRs in schistosomiasis patients are highly correlated with the portal vein and spleen thickness diameter, both of which represent the severity of fibrosis. Splenomegaly is a characteristic symptom of schistosome infection, and splenic abnormality may promote the progression of hepatic fibrosis. We further demonstrate that elevated levels of ETRs are predominantly expressed on splenic B cells in spleen tissues during infection. Importantly, using a well-studied model of human schistosomiasis, we demonstrate that endothelin receptor antagonists can partially reverse schistosome-induced hepatic fibrosis by suppressing the activation of splenic B cells characterized by interleukin-10 (IL-10) secretion and regulatory T (Treg) cell-inducing capacity. Our study provides insights into the mechanisms by which ETRs regulate schistosomiasis hepatic fibrosis and highlights the potential of endothelin receptor antagonist as a therapeutic intervention for fibrotic diseases. Schistosomiasis is a serious but neglected tropical infectious disease. which can lead to hepatic fibrosis and death. To date, there are still no approved antifibrotic therapies. Hepatic fibrosis results in portal hypertension and variceal bleeding, and it is the primary cause of mortality from schistosomiasis. Splenomegaly and hypersplenism can manifest following the development of portal hypertension. Accumulating evidence suggests that the spleen plays a critical role in the development of hepatic fibrosis. In this study, using Schistosoma (S.) japonicum in both humans and mice, we show that progressive hepatic schistosomiasis caused elevation of endothelin receptors (ETRs) both in liver and spleen tissues, and the endothelin receptor-producing cells are mainly located in splenic B cells. More importantly, we demonstrate that endothelin receptor antagonists can partially reverse schistosome-induced hepatic fibrosis by suppressing the activation of splenic B cells during infection. Thus, our study highlights the potential of endothelin receptor antagonist as a therapeutic intervention for schistosomiasis and other fibrotic diseases.
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Affiliation(s)
- Hongyan Kong
- Department and Institute of Infectious Disease, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Jinan He
- Department and Institute of Infectious Disease, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Shusen Guo
- Department of Pediatrics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Qiqin Song
- Department and Institute of Infectious Disease, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Dandan Xiang
- Department and Institute of Infectious Disease, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Ran Tao
- Department and Institute of Infectious Disease, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Haijing Yu
- Department and Institute of Infectious Disease, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Guang Chen
- Department and Institute of Infectious Disease, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Zhiyong Huang
- Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Qin Ning
- Department and Institute of Infectious Disease, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Jiaquan Huang
- Department and Institute of Infectious Disease, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- * E-mail:
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Da J, Yang Y, Dong R, Shen Y, Zha Y. Therapeutic effect of 1,25(OH)2-VitaminD3 on fibrosis and angiogenesis of peritoneum induced by chlorhexidine. Biomed Pharmacother 2020; 129:110431. [PMID: 32585450 DOI: 10.1016/j.biopha.2020.110431] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2020] [Revised: 05/31/2020] [Accepted: 06/17/2020] [Indexed: 11/18/2022] Open
Abstract
The biological activity of vitamin D, which mediated by the vitamin D receptor, is widespread throughout the body. The present study aimed to define whether 1,25-dihydroxy vitamin D3 (1,25-(OH)2D3) can protect against the progression of peritoneum fibrosis (PF) through its impact on the expression of connective tissue growth factor (CTGF) and heat shock protein 47 (HSP47) in vivo and in vitro. The male Sprague-Dawley (SD) rats of PF were induced by daily intraperitoneally injection of chlorhexidine gluconate (CG) for 4 wks. PF Rats were also treated with calcitriol (i.p. 6 ng/100g*d) from initiation of the CG. In calcitriol rats, the ultrafiltration and the ratio of dialysate urea nitrogen to blood urea nitrogen were improved (P < 0.05), pathological changes and peritoneal thickness were milder than that of the PF group. Calcitriol ameliorated high glucose-induced HSP47 expression in peritoneal mesothelial cells via CTGF down-regulation both at the mRNA level and protein level. Furthermore, calcitriol prevented angiogenic mediators of fibrosis by reduced the expression of CD34 and vascular endothelial growth factor (VEGF). The present study demonstrated that 1,25-(OH)2D3 intervention had a partially protective effect on peritoneum fibrosis, which might inhibit CTGF/HSP47 and CD34/VEGF in the peritoneum tissues.
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Affiliation(s)
- Jingjing Da
- Guizhou University School of medicine, Guiyang, China; Renal Division, Department of Medicine, Guizhou Provincial People's Hospital, China; NHC Key Laboratory of Pulmonary Immunological Disease, Guizhou Provincial People's Hospital, Guiyang, China
| | - Yuqi Yang
- Renal Division, Department of Medicine, Guizhou Provincial People's Hospital, China; NHC Key Laboratory of Pulmonary Immunological Disease, Guizhou Provincial People's Hospital, Guiyang, China
| | - Rong Dong
- Guizhou University School of medicine, Guiyang, China; Renal Division, Department of Medicine, Guizhou Provincial People's Hospital, China; NHC Key Laboratory of Pulmonary Immunological Disease, Guizhou Provincial People's Hospital, Guiyang, China
| | - Yan Shen
- Renal Division, Department of Medicine, Guizhou Provincial People's Hospital, China; NHC Key Laboratory of Pulmonary Immunological Disease, Guizhou Provincial People's Hospital, Guiyang, China
| | - Yan Zha
- Renal Division, Department of Medicine, Guizhou Provincial People's Hospital, China; NHC Key Laboratory of Pulmonary Immunological Disease, Guizhou Provincial People's Hospital, Guiyang, China.
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15
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Gene expression in human liver fibrosis associated with Echinococcus granulosus sensu lato. Parasitol Res 2020; 119:2177-2187. [PMID: 32377911 DOI: 10.1007/s00436-020-06700-9] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2020] [Accepted: 04/28/2020] [Indexed: 12/12/2022]
Abstract
Liver fibrosis is a dynamic process that occurs in response to chronic liver disease resulting from factors such as chronic infections, autoimmune reactions, allergic responses, toxins, radiation, and infectious agents. Among the infectious agents, multicellular parasites cause chronic inflammation and fibrosis. Twenty-five patients with different stages of cystic echinococcosis (CE) were enrolled in the study. The expression of ACTA2, COL3A1, IFN-γ, MMP2, MMP9, TGF-β1, and TNF-α genes was determined by qRT-PCR in healthy and fibrotic liver tissue of the CE patients. TGF-β1 expression was evaluated by immunohistochemistry, and histology was conducted to assess the development of liver fibrosis. Expression of MMP9, ACTA2, COL3A1, and MMP2 was found significantly higher in the fibrotic tissue compared to healthy tissue. We observed a significant correlation between TGF-β1 and TNF-α gene expressions and liver fibrosis. The mRNA level of IFN-γ was lower in the fibrotic than in the healthy hepatic tissue. Immunohistochemistry analysis revealed TGF-β1 upregulation in the fibrotic tissue. Histology showed inflammation and fibrosis to be significantly higher in the fibrotic tissue. The findings of this study suggest that Echinococcus granulosussensu lato can promotes fibrosis through the overexpression of TGF-β1, MMP9, ACTA2, COL3A1, and MMP2. The downregulation of IFN-γ mRNA in fibrotic samples is probably due to the increased production of TGF-β1 and the suppression of potential anti-fibrotic role of IFN-γ during advanced liver injury caused by E. granulosussensu lato.
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16
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Kamdem SD, Moyou-Somo R, Brombacher F, Nono JK. Host Regulators of Liver Fibrosis During Human Schistosomiasis. Front Immunol 2018; 9:2781. [PMID: 30546364 PMCID: PMC6279936 DOI: 10.3389/fimmu.2018.02781] [Citation(s) in RCA: 82] [Impact Index Per Article: 11.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2018] [Accepted: 11/12/2018] [Indexed: 12/24/2022] Open
Abstract
Liver fibrosis is a wound-healing process purposely aimed at restoring organ integrity after severe injury caused by autoimmune reactions, mechanical stress or infections. The uncontrolled solicitation of this process is pathogenic and a pathognomonic feature of diseases like hepatosplenic schistosomiasis where exacerbated liver fibrosis is centrally positioned among the drivers of the disease morbidity and mortality. Intriguingly, however, liver fibrosis occurs and progresses dissimilarly in schistosomiasis-diseased individuals with the same egg burden and biosocial features including age, duration of residence in the endemic site and gender. This suggests that parasite-independent and currently poorly defined host intrinsic factors might play a defining role in the regulation of liver fibrosis, the hallmark of morbidity, during schistosomiasis. In this review, we therefore provide a comprehensive overview of all known host candidate regulators of liver fibrosis reported in the context of human schistosomiasis.
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Affiliation(s)
- Severin Donald Kamdem
- Cape Town Component, International Centre for Genetic Engineering and Biotechnology, Cape Town, South Africa
- Division of Immunology, Health Science Faculty, University of Cape Town, Cape Town, South Africa
- Immunology of Infectious Diseases Unit, South African Medical Research Center, Cape Town, South Africa
| | - Roger Moyou-Somo
- The Medical Research Centre, Institute of Medical Research and Medicinal Plant Studies, Ministry of Scientific Research and Innovation, Yaoundé, Cameroon
| | - Frank Brombacher
- Cape Town Component, International Centre for Genetic Engineering and Biotechnology, Cape Town, South Africa
- Division of Immunology, Health Science Faculty, University of Cape Town, Cape Town, South Africa
- Immunology of Infectious Diseases Unit, South African Medical Research Center, Cape Town, South Africa
- Faculty of Health Sciences, Wellcome Centre for Infectious Diseases Research in Africa, Institute of Infectious Diseases and Molecular Medicine (IDM), University of Cape Town, Cape Town, South Africa
| | - Justin Komguep Nono
- Cape Town Component, International Centre for Genetic Engineering and Biotechnology, Cape Town, South Africa
- Division of Immunology, Health Science Faculty, University of Cape Town, Cape Town, South Africa
- Immunology of Infectious Diseases Unit, South African Medical Research Center, Cape Town, South Africa
- The Medical Research Centre, Institute of Medical Research and Medicinal Plant Studies, Ministry of Scientific Research and Innovation, Yaoundé, Cameroon
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17
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Almeer RS, El-Khadragy MF, Abdelhabib S, Abdel Moneim AE. Ziziphus spina-christi leaf extract ameliorates schistosomiasis liver granuloma, fibrosis, and oxidative stress through downregulation of fibrinogenic signaling in mice. PLoS One 2018; 13:e0204923. [PMID: 30273397 PMCID: PMC6166951 DOI: 10.1371/journal.pone.0204923] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/02/2018] [Accepted: 09/16/2018] [Indexed: 01/22/2023] Open
Abstract
Schistosomiasis is a widespread parasitic infection that affects humans, as well as wild and domestic animals. It ranks second after malaria, with a significant health and socio-economic impact in the developing countries. The objective of this study was to assess the anti-schistosomal impact of Ziziphus spina-christi leaf extract (ZLE) on Schistosoma mansoni-induced liver fibrosis in CD-1 Swiss male albino mice. S. mansoni infection was achieved by dipping of mouse tails in schistosomal cercariae. ZLE treatment was initiated at 46 days post-infection by administering a dose of the extract on a daily basis for 10 consecutive days. S. mansoni infection resulted in liver granuloma and fibrosis, with a drastic elevation in liver function factors, nitric oxide, and lipid peroxidation, which were associated with a reduction in glutathione content and substantial inhibition of antioxidant enzyme activities compared to those of the control. Induction of hepatic granuloma, oxidative stress, and fibrosis in the liver was controlled by ZLE administration, which also produced inhibition of matrix metalloproteinase-9, alpha-smooth muscle actin, transforming growth factor-β, and tissue inhibitors of metalloproteinases expressions. In addition, the S. mansoni-infected group exhibited an increase in Bax and caspase-3 levels and a decrease in Bcl-2 level. However, treatment with ZLE mainly mitigated apoptosis in the liver. Thus, the findings of this study revealed that Ziziphus spina-christi had anti-apoptotic, anti-fibrotic, antioxidant, and protective effects on S. mansoni-induced liver wounds. The benefits of Ziziphus spina-christi extract on S. mansoni were partly partially mediated by enhancing anti-fibrinogenic and nuclear factor erythroid 2-related factor 2 (Nrf2) pathways.
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Affiliation(s)
- Rafa S. Almeer
- Department of Zoology, College of Science, King Saud University, Riyadh, Saudi Arabia
| | - Manal F. El-Khadragy
- Department of Zoology, College of Science, King Saud University, Riyadh, Saudi Arabia
- Department of Zoology and Entomology, Faculty of Science, Helwan University, Cairo, Egypt
| | - Semlali Abdelhabib
- Genome Research Chair, Department of Biochemistry, College of Science, King Saud University, Riyadh, Saudi Arabia
| | - Ahmed E. Abdel Moneim
- Department of Zoology and Entomology, Faculty of Science, Helwan University, Cairo, Egypt
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18
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Carson JP, Ramm GA, Robinson MW, McManus DP, Gobert GN. Schistosome-Induced Fibrotic Disease: The Role of Hepatic Stellate Cells. Trends Parasitol 2018. [PMID: 29526403 DOI: 10.1016/j.pt.2018.02.005] [Citation(s) in RCA: 71] [Impact Index Per Article: 10.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/28/2022]
Abstract
Hepatic fibrosis is a common pathology in various liver diseases. Hepatic stellate cells (HSCs) are the main cell type responsible for collagen deposition and fibrosis formation in the liver. Schistosomiasis is characterised by granulomatous fibrosis around parasite eggs trapped within the liver and other host tissues. This response is facilitated by the recruitment of immune cells and the activation of HSCs. The interactions between HSCs and schistosome eggs are complex and diverse, and a better understanding of these interactions could lead to improved resolution of fibrotic liver disease, including that associated with schistosomiasis. Here, we discuss recent advances in HSC biology and the role of HSCs in hepatic schistosomiasis.
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Affiliation(s)
- Jack P Carson
- School of Biological Sciences, Queen's University Belfast, Medical Biology Centre, 97 Lisburn Road, Belfast BT9 7BL, UK
| | - Grant A Ramm
- QIMR Berghofer Medical Research Institute, Locked Bag 2000, Royal Brisbane Hospital QLD 4029, Australia; Faculty of Medicine, The University of Queensland, Level 6, Oral Health Centre (Building), Herston Road, Herston, QLD, 4006, Australia
| | - Mark W Robinson
- School of Biological Sciences, Queen's University Belfast, Medical Biology Centre, 97 Lisburn Road, Belfast BT9 7BL, UK
| | - Donald P McManus
- QIMR Berghofer Medical Research Institute, Locked Bag 2000, Royal Brisbane Hospital QLD 4029, Australia
| | - Geoffrey N Gobert
- School of Biological Sciences, Queen's University Belfast, Medical Biology Centre, 97 Lisburn Road, Belfast BT9 7BL, UK.
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19
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Sobhy MMK, Mahmoud SS, El-Sayed SH, Rizk EMA, Raafat A, Negm MSI. Impact of treatment with a Protein Tyrosine Kinase Inhibitor (Genistein) on acute and chronic experimental Schistosoma mansoni infection. Exp Parasitol 2018; 185:115-123. [PMID: 29331278 DOI: 10.1016/j.exppara.2018.01.013] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2017] [Revised: 12/12/2017] [Accepted: 01/09/2018] [Indexed: 12/17/2022]
Abstract
Schistosomiasis mansoni is considered one of the most common fibrotic diseases resulting from inflammation and deposition of fibrous tissue around parasitic eggs trapped in the liver, causing morbidity and mortality. Chemotherapy against schistosomiasis is largely dependent on Praziquantel (PZQ). Yet, the huge administration of it in endemic areas and its incompetence towards the immature stages have raised serious alarms against the development of drug resistance. Few drugs are directed to reverse schistosomal liver fibrosis, particularly at the chronic and advanced stages of the disease. Recently, protein tyrosine kinase (PTK) inhibitors have been identified as potent anti-schistosomal and anti-fibrotic drugs against schistosomes, that may suppress and reverse Schistosoma mansoni (S. mansoni) induced liver fibrosis. The present study was designed to assess the anti-schistosomal and antifibrotic activity of Genistein, a PTK inhibitor, in comparison to PZQ, on both acute and chronic S. mansoni-infected mice using different parasitological, histopathological and immunohistochemical studies. Genistein showed a significant reduction (P < .05) in total worm burden, tissue egg load, mean hepatic granulomas diameter and numbers, percentage of collagen and expression of transforming growth factor-beta 1 (TGF-β 1) in the examined hepatocytes with elevation in percentage of degenerated ova, in comparison to the control groups, in both acute and chronic stages of infection. The best results were obtained when Genistein was combined with PZQ. Therefore, it was concluded that Genistein showed a promising anti-schistosomal and anti-fibrotic properties which could make it one of the new potential targets in chemotherapy against schistosomiasis.
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Affiliation(s)
| | | | - Shaimaa Helmy El-Sayed
- Theodor Bilharz Research Institute, Imbaba, Giza, Egypt; Medical Parasitology Department, Faculty of Medicine, Helwan University, Cairo, Egypt.
| | - Enas Mohamed Ali Rizk
- Medical Parasitology Department, Kasr Al-Ainy School of Medicine, Cairo University, Egypt
| | - Amira Raafat
- Medical Parasitology Department, Kasr Al-Ainy School of Medicine, Cairo University, Egypt
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20
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Jia Z, Gong Y, Pi Y, Liu X, Gao L, Kang L, Wang J, Yang F, Tang J, Lu W, Li Q, Zhang W, Yan Z, Yu L. pPB Peptide-Mediated siRNA-Loaded Stable Nucleic Acid Lipid Nanoparticles on Targeting Therapy of Hepatic Fibrosis. Mol Pharm 2017; 15:53-62. [PMID: 29148802 DOI: 10.1021/acs.molpharmaceut.7b00709] [Citation(s) in RCA: 44] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2022]
Abstract
Hepatic fibrosis is a necessary process in the development of liver diseases such as hepatic cirrhosis and its complications, which has become a serious threat to human health. Currently, antifibrotic drug treatment is ineffective, and one reason should be the lack of liver targeting ability. In this report, polypeptide pPB-modified stable nucleic acid lipid nanoparticles (pPB-SNALPs) were prepared to selectively deliver siRNAs against heat shock protein 47 to the liver for targeted therapy of hepatic fibrosis. First, siRNA sequences with high silencing efficiency were screened based on siRNA transfection efficacy. Then, pPB-SNALPs were prepared, which showed a narrow size distribution with a diameter in the range of 110-130 nm and a neutral z-potential of 0 mV. As evidenced by the in vitro and in vivo targeting study, compared with unmodified SNALP, pPB-SNALP showed increased uptake by LX-2 cells and primary hepatic stellate cells (HSC) of mice in vitro and showed increased liver distribution and HSC uptake in vivo. In addition, pPB-SNALP also exhibited an enhanced inhibitory effect on TAA-induced hepatic fibrosis mice with high gp46 mRNA expression in vivo. In summary, our results demonstrated that pPB-SNALP is an effective liver-targeted delivery system. This study could lay a good foundation for the targeted gene therapy of hepatic fibrosis.
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Affiliation(s)
- Zongxiang Jia
- Shanghai Engineering Research Center of Molecular Therapeutics and New Drug Development, School of Chemistry and Molecular Engineering, East China Normal University , Shanghai 200062, P.R. China
| | - Yan Gong
- Department of Geriatrics, Huashan Hospital, Fudan University , Shanghai 200040, P.R. China
| | - Yufang Pi
- Shanghai Engineering Research Center of Molecular Therapeutics and New Drug Development, School of Chemistry and Molecular Engineering, East China Normal University , Shanghai 200062, P.R. China
| | - Xueying Liu
- Shanghai Engineering Research Center of Molecular Therapeutics and New Drug Development, School of Chemistry and Molecular Engineering, East China Normal University , Shanghai 200062, P.R. China
| | - Lipeng Gao
- Shanghai Engineering Research Center of Molecular Therapeutics and New Drug Development, School of Chemistry and Molecular Engineering, East China Normal University , Shanghai 200062, P.R. China
| | - Liqing Kang
- Shanghai Engineering Research Center of Molecular Therapeutics and New Drug Development, School of Chemistry and Molecular Engineering, East China Normal University , Shanghai 200062, P.R. China
| | - Jing Wang
- Shanghai Engineering Research Center of Molecular Therapeutics and New Drug Development, School of Chemistry and Molecular Engineering, East China Normal University , Shanghai 200062, P.R. China
| | - Fan Yang
- Shanghai Engineering Research Center of Molecular Therapeutics and New Drug Development, School of Chemistry and Molecular Engineering, East China Normal University , Shanghai 200062, P.R. China
| | - Jie Tang
- Shanghai Engineering Research Center of Molecular Therapeutics and New Drug Development, School of Chemistry and Molecular Engineering, East China Normal University , Shanghai 200062, P.R. China
| | - Weiyue Lu
- Department of Pharmaceutics, School of Pharmacy, Fudan University & Key Laboratory of Smart Drug Delivery, Fudan University, Ministry of Education , Shanghai 201203, P.R. China
| | - Qinghua Li
- Department of Hepatology and Pancreatology, Shanghai East Hospital, Tongji University , Shanghai 200120, P.R. China
| | - Wei Zhang
- Key Laboratory of Brain Functional Genomics, Ministry of Education, Shanghai Key Laboratory of Brain Functional Genomics, School of Life Science, East China Normal University , Shanghai 200062, P.R. China
| | - Zhiqiang Yan
- Shanghai Engineering Research Center of Molecular Therapeutics and New Drug Development, School of Chemistry and Molecular Engineering, East China Normal University , Shanghai 200062, P.R. China
| | - Lei Yu
- Shanghai Engineering Research Center of Molecular Therapeutics and New Drug Development, School of Chemistry and Molecular Engineering, East China Normal University , Shanghai 200062, P.R. China
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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]
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Wan C, Jin F, Du Y, Yang K, Yao L, Mei Z, Huang W. Genistein improves schistosomiasis liver granuloma and fibrosis via dampening NF-kB signaling in mice. Parasitol Res 2017; 116:1165-1174. [PMID: 28160073 DOI: 10.1007/s00436-017-5392-3] [Citation(s) in RCA: 30] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2016] [Accepted: 01/19/2017] [Indexed: 02/07/2023]
Abstract
In schistosomiasis, egg deposition in the liver contributes to the formation of hepatic granuloma and fibrosis, which are the most serious clinical pathological features. It has been proposed that activation of the nuclear factor kappa B (NF-κB) signaling pathways is closely associated with the development of hepatic granuloma and fibrosis. Genistein has been shown to inhibit the activity of NF-κB signaling pathways, which might be a potential agent to protect against Schistosoma japonicum egg-induced liver granuloma and fibrosis. In this study, liver granuloma and fibrosis were induced by infecting BALB/c mice with 18 ± 3 cercariae of S. japonicum. At the beginning of egg granuloma formation (early phase genistein treatment from 4 to 6 weeks after infection) or after the formation of liver fibrosis (late phase genistein treatment from 6 to 10 weeks after infection), the infected mice were injected with genistein (25, 50 mg/kg). The results revealed that genistein treatment significantly decreased the extent of hepatic granuloma and fibrosis in infected mice. The activity of NF-κB signaling declined sharply after the treatment with genistein, as evidenced by the inhibition of NF-κB-p65, phospho-NF-κB-p65, and phospo-IκB-α expressions, as well as the expression of IκB-α and the messenger RNA (mRNA) expression of inflammatory cytokines (MCP1, TNFα, IL1β, IL4, IL10) mediated by NF-κB signaling pathways in the early phase of the infection. Moreover, western blot and immunohistochemistry assays demonstrated that the contents of α-smooth muscle actin (α-SMA) and transforming growth factor-β were dramatically reduced in liver tissue under the treatment of genistein in the late phase of the infection. At the same time, the mRNA expression of MCP1, TNFα, and IL10 was inhibited markedly. These results provided evidence that genistein reduces S. japonicum egg-induced liver granuloma and fibrosis, at least partly due to decreased NF-κB signaling, and subsequently decreased MCP1, TNFα, and IL10 expressions. This implies that genistein can be a potential natural agent against schistosomiasis.
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Affiliation(s)
- Chunpeng Wan
- Department of Microbiology and Immunology, Medical College, China Three Gorges University, Yichang, Hubei, 443002, China
- Jiangxi Key Laboratory for Postharvest Technology and Nondestructive Testing of Fruits and Vegetables, College of Agronomy, Jiangxi Agricultural University, Nanchang, Jiangxi, 330045, China
| | - Fen Jin
- Department of Microbiology and Immunology, Medical College, China Three Gorges University, Yichang, Hubei, 443002, China
| | - Youqin Du
- Department of Microbiology and Immunology, Medical College, China Three Gorges University, Yichang, Hubei, 443002, China
| | - Kang Yang
- Department of Microbiology and Immunology, Medical College, China Three Gorges University, Yichang, Hubei, 443002, China
| | - Liangliang Yao
- Affiliated Hospital of Jiangxi University of Traditional Chinese Medicine, Nanchang, Jiangxi, 330006, People's Republic of China
| | - Zhigang Mei
- Department of Microbiology and Immunology, Medical College, China Three Gorges University, Yichang, Hubei, 443002, China.
| | - Weifeng Huang
- Department of Microbiology and Immunology, Medical College, China Three Gorges University, Yichang, Hubei, 443002, China.
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23
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Tissue Transglutaminase-Regulated Transformed Growth Factor-β1 in the Parasite Links Schistosoma japonicum Infection with Liver Fibrosis. Mediators Inflamm 2015. [PMID: 26199461 PMCID: PMC4493306 DOI: 10.1155/2015/659378] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Abstract
Transforming growth factor (TGF-β1) is among the strongest factors of liver fibrogenesis, but its association with Schistosoma-caused liver fibrosis is controversial. Tissue transglutaminase (tTG) is the principal enzyme controlling TGF-β1 maturation and contributes to Sj-infected liver fibrosis. Here we aim to explore the consistency between tTG and TGF-β1 and TGF-β1 source and its correlation with liver fibrosis after Sj-infection. TGF-β1 was upregulated at weeks 6 and 8 upon liver fibrosis induction. During tTG inhibition, TGF-β1 level decreased in sera and liver of infected mice. TGF-β1 showed positive staining in liver containing Sj adult worms and eggs. TGF-β1 was also detected in Sj adult worm sections, soluble egg antigen and Sj adult worm antigen, and adult worms' culture medium. The TGF-β1 mature peptide cDNA sequence and its extended sequence were amplified through RT-PCR and RACE-PCR using adult worms as template, and sequence is analyzed and loaded to NCBI GenBank (number GQ338152.1). TGF-β1 transcript in Sj eggs was higher than in adult worms. In Sj-infected liver, transcriptional level of TGF-β1 from Sj, but not mouse liver, correlated with liver fibrosis extent. This study provides evidence that tTG regulates TGF-β1 and illustrates the importance of targeting tTG in treating Sj infection-induced fibrosis.
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Zhen YZ, Li NR, He HW, Zhao SS, Zhang GL, Hao XF, Shao RG. Protective effect of bicyclol against bile duct ligation-induced hepatic fibrosis in rats. World J Gastroenterol 2015; 21:7155-7164. [PMID: 26109801 PMCID: PMC4476876 DOI: 10.3748/wjg.v21.i23.7155] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/03/2015] [Revised: 02/13/2015] [Accepted: 04/09/2015] [Indexed: 02/06/2023] Open
Abstract
AIM: To evaluate the protective effect of bicyclol against bile duct ligation (BDL)-induced hepatic fibrosis in rats.
METHODS: Sprague-Dawley male rats underwent BDL and sham-operated animals were used as healthy controls. The BDL rats were divided into two groups which received sterilized PBS or bicyclol (100 mg/kg per day) orally for two consecutive weeks. Serum, urine and bile were collected for biochemical determinations. Liver tissues were collected for histological analysis and a whole genome oligonucleotide microarray assay. Reverse transcription-polymerase chain reaction and Western blotting were used to verify the expression of liver fibrosis-related genes.
RESULTS: Treatment with bicyclol significantly reduced liver fibrosis and bile duct proliferation after BDL. The levels of alanine aminotransferase (127.7 ± 72.3 vs 230.4 ± 69.6, P < 0.05) and aspartate aminotransferase (696.8 ± 232.6 vs 1032.6 ± 165.8, P < 0.05) were also decreased by treatment with bicyclol in comparison to PBS. The expression changes of 45 fibrogenic genes and several fibrogenesis-related pathways were reversed by bicyclol in the microarray assay. Bicyclol significantly reduced liver mRNA and/or protein expression levels of collagen 1a1, matrix metalloproteinase 2, tumor necrosis factor, tissue inhibitors of metalloproteinases 2, transforming growth factor-β1 and α-smooth muscle actin.
CONCLUSION: Bicyclol significantly attenuates BDL-induced liver fibrosis by reversing fibrogenic gene expression. These findings suggest that bicyclol might be an effective anti-fibrotic drug for the treatment of cholestatic liver disease.
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