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Diao S, Li L, Zhang J, Ji M, Sun L, Shen W, Wu S, Chen Z, Huang C, Li J. Macrophage-derived CCL1 targets CCR8 receptor in hepatic stellate cells to promote liver fibrosis through JAk/STAT pathway. Biochem Pharmacol 2025; 237:116884. [PMID: 40122149 DOI: 10.1016/j.bcp.2025.116884] [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: 06/05/2024] [Revised: 02/18/2025] [Accepted: 03/18/2025] [Indexed: 03/25/2025]
Abstract
Liver fibrosis is caused by liver injury resulting from the wound healing response. According to recent research, the primary factor responsible for liver fibrosis is the activation of hepatic stellate cells (HSCs). C-C motif chemokine ligand 1 (CCL1) is one of several chemokine genes clustered on chromosome 17, which is involved in immune regulation and inflammatory processes. However, the role of CCL1 in liver fibrosis has not been reported. We found that CCL1 secreted by macrophages can target and activate the receptor protein C-C motif chemokine receptor 8 (CCR8) of HSCs, accelerating liver fibrosis progression by activating the Janus kinase (JAK)/signal transducer and activator of transcription (STAT) signalling pathway. This suggested that the CCL1-mediated regulation of CCR8 is an important event in liver fibrosis progression. In conclusion, this study identified a novel signalling axis, the CCL1/CCR8/JAK/STAT pathway, which regulates the activation and apoptosis of HSCs, thus providing a novel therapeutic strategy for liver fibrosis.
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Affiliation(s)
- Shaoxi Diao
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, Hefei 230032, PR China; Institute for Liver Diseases of Anhui Medical University, PR China
| | - Liangyun Li
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, Hefei 230032, PR China; Institute for Liver Diseases of Anhui Medical University, PR China
| | - Jintong Zhang
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, Hefei 230032, PR China; Institute for Liver Diseases of Anhui Medical University, PR China
| | - Minglu Ji
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, Hefei 230032, PR China; Institute for Liver Diseases of Anhui Medical University, PR China
| | - Lijiao Sun
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, Hefei 230032, PR China; Institute for Liver Diseases of Anhui Medical University, PR China
| | - Wenwen Shen
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, Hefei 230032, PR China; Institute for Liver Diseases of Anhui Medical University, PR China
| | - Shuai Wu
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, Hefei 230032, PR China; Institute for Liver Diseases of Anhui Medical University, PR China
| | - Zixiang Chen
- Department of Hepatopancreatobiliary Surgery, The First Affiliated Hospital of Anhui Medical University, Hefei 230022, PR China
| | - Cheng Huang
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, Hefei 230032, PR China; Institute for Liver Diseases of Anhui Medical University, PR China.
| | - Jun Li
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, Hefei 230032, PR China; Institute for Liver Diseases of Anhui Medical University, PR China.
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Jain S. Can Schistosoma japonicum infection cause liver cancer? J Helminthol 2025; 99:e11. [PMID: 39924660 DOI: 10.1017/s0022149x24000762] [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: 02/11/2025]
Abstract
A co-relation between Schistosoma japonicum (Sj) and liver cancer (LC) in humans has been reported in the literature; however, this association is circumstantial. Due to the inconclusive nature of this association, the International Agency for Research on Cancer has placed Sj in Group 2B for LC, signifying it to be a 'possible carcinogen'. Many epidemiological, pathological and clinical studies have identified multiple factors, linked with Sj infection, which can lead to liver carcinogenesis. These factors include chronic inflammation in response to deposited eggs (which leads to fibrosis, cirrhosis and chromosomal instability at cellular level), hepatotoxic effects of egg-antigens, co-infection with hepatitis viruses, and up-regulation of glycolysis linked genes among others which predisposes hepatic tissue towards malignant transformation. The objective of this work is to present the current understanding on the association of Sj infection with LC. Mechanisms and factors linked with Sj infection that can lead to LC are emphasized, along with measures to diagnose and treat it. A comparison of liver carcinogenesis is also provided for cases linked with and independent of Sj infection. It appears that Sj, alone or with another carcinogen, is an important factor in liver carcinogenesis, but further studies are warranted to conclusively label 'infection with Sj alone' as a liver carcinogen.
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Affiliation(s)
- S Jain
- Independent Researcher, Institute for Globally Distributed Open Research and Education (IGDORE), Rewari, Haryana, India
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3
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Jain S. Is Schistosoma mansoni playing a part in liver carcinogenesis? J Helminthol 2024; 98:e61. [PMID: 39469749 DOI: 10.1017/s0022149x24000506] [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: 10/30/2024]
Abstract
The relationship between Schistosoma mansoni (Sm) and hepatocellular carcinoma (HCC) has been evaluated by many studies that point towards a co-relation between schistosomal infection and HCC. While many such studies demonstrated that Sm infection in the presence of another carcinogenic factors leads to HCC, none of these studies could conclusively prove the cancer-inducing ability of Sm in humans, independent of other carcinogenic factors. The aim of this work is to present the current understanding on the association of Sm with HCC. Many epidemiological, pathological, and clinical studies have shown the role of multiple events like chronic inflammation and fibrosis as well as hepato-toxic agents like soluble egg antigens (SEAs), which help in creating a micro-environment which is suitable for HCC development. The role of Sm infection and deposited eggs in causing persistent inflammation, advanced fibrosis, and the role of SEAs, especially IPSE/alpha-1, is emphasised. This work concludes that Sm infection has the potential to induce cancer independently but the same has not been reported in humans to date. Extensive research is required to establish a causal relationship between Sm infection and HCC induction, or a complete lack thereof. However, Sm infection definitely acts along with other carcinogenic factors to induce HCC at a much faster pace and also leads to an aggressive form of liver cancer, which the other carcinogenic factor could not have achieved alone.
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Affiliation(s)
- S Jain
- Institute for Globally Distributed Open Research and Education (IGDORE), India
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4
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Chen S, Zhuang D, Jia Q, Guo B, Hu G. Advances in Noninvasive Molecular Imaging Probes for Liver Fibrosis Diagnosis. Biomater Res 2024; 28:0042. [PMID: 38952717 PMCID: PMC11214848 DOI: 10.34133/bmr.0042] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2024] [Accepted: 05/08/2024] [Indexed: 07/03/2024] Open
Abstract
Liver fibrosis is a wound-healing response to chronic liver injury, which may lead to cirrhosis and cancer. Early-stage fibrosis is reversible, and it is difficult to precisely diagnose with conventional imaging modalities such as magnetic resonance imaging, positron emission tomography, single-photon emission computed tomography, and ultrasound imaging. In contrast, probe-assisted molecular imaging offers a promising noninvasive approach to visualize early fibrosis changes in vivo, thus facilitating early diagnosis and staging liver fibrosis, and even monitoring of the treatment response. Here, the most recent progress in molecular imaging technologies for liver fibrosis is updated. We start by illustrating pathogenesis for liver fibrosis, which includes capillarization of liver sinusoidal endothelial cells, cellular and molecular processes involved in inflammation and fibrogenesis, as well as processes of collagen synthesis, oxidation, and cross-linking. Furthermore, the biological targets used in molecular imaging of liver fibrosis are summarized, which are composed of receptors on hepatic stellate cells, macrophages, and even liver collagen. Notably, the focus is on insights into the advances in imaging modalities developed for liver fibrosis diagnosis and the update in the corresponding contrast agents. In addition, challenges and opportunities for future research and clinical translation of the molecular imaging modalities and the contrast agents are pointed out. We hope that this review would serve as a guide for scientists and students who are interested in liver fibrosis imaging and treatment, and as well expedite the translation of molecular imaging technologies from bench to bedside.
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Affiliation(s)
- Shaofang Chen
- Department of Radiology, Shenzhen People’s Hospital (The Second Clinical Medical College,
Jinan University; The First Affiliated Hospital, Southern University of Science and Technology), Shenzhen 518020, Guangdong, China
| | - Danping Zhuang
- Department of Radiology, Shenzhen People’s Hospital (The Second Clinical Medical College,
Jinan University; The First Affiliated Hospital, Southern University of Science and Technology), Shenzhen 518020, Guangdong, China
| | - Qingyun Jia
- Department of Radiology, Shenzhen People’s Hospital (The Second Clinical Medical College,
Jinan University; The First Affiliated Hospital, Southern University of Science and Technology), Shenzhen 518020, Guangdong, China
| | - Bing Guo
- School of Science, Shenzhen Key Laboratory of Flexible Printed Electronics Technology, Shenzhen Key Laboratory of Advanced Functional Carbon Materials Research and Comprehensive Application,
Harbin Institute of Technology, Shenzhen 518055, China
| | - Genwen Hu
- Department of Radiology, Shenzhen People’s Hospital (The Second Clinical Medical College,
Jinan University; The First Affiliated Hospital, Southern University of Science and Technology), Shenzhen 518020, Guangdong, China
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Zhu M, Wang Y, Han J, Sun Y, Wang S, Yang B, Wang Q, Kuang H. Artesunate Exerts Organ- and Tissue-Protective Effects by Regulating Oxidative Stress, Inflammation, Autophagy, Apoptosis, and Fibrosis: A Review of Evidence and Mechanisms. Antioxidants (Basel) 2024; 13:686. [PMID: 38929125 PMCID: PMC11200509 DOI: 10.3390/antiox13060686] [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: 04/12/2024] [Revised: 05/29/2024] [Accepted: 05/30/2024] [Indexed: 06/28/2024] Open
Abstract
The human body comprises numerous organs and tissues operating in synchrony, it facilitates metabolism, circulation, and overall organismal function. Consequently, the well-being of our organs and tissues significantly influences our overall health. In recent years, research on the protective effects of artesunate (AS) on various organ functions, including the heart, liver, brain, lungs, kidneys, gastrointestinal tract, bones, and others has witnessed significant advancements. Findings from in vivo and in vitro studies suggest that AS may emerge as a newfound guardian against organ damage. Its protective mechanisms primarily entail the inhibition of inflammatory factors and affect anti-fibrotic, anti-aging, immune-enhancing, modulation of stem cells, apoptosis, metabolic homeostasis, and autophagy properties. Moreover, AS is attracting a high level of interest because of its obvious antioxidant activities, including the activation of Nrf2 and HO-1 signaling pathways, inhibiting the release of reactive oxygen species, and interfering with the expression of genes and proteins associated with oxidative stress. This review comprehensively outlines the recent strides made by AS in alleviating organismal injuries stemming from various causes and protecting organs, aiming to serve as a reference for further in-depth research and utilization of AS.
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Affiliation(s)
- Mingtao Zhu
- Key Laboratory of Basic and Application Research of Beiyao (Heilongjiang University of Chinese Medicine), Ministry of Education, Harbin 150040, China; (M.Z.); (Y.W.); (J.H.); (Y.S.); (S.W.); (B.Y.)
| | - Yu Wang
- Key Laboratory of Basic and Application Research of Beiyao (Heilongjiang University of Chinese Medicine), Ministry of Education, Harbin 150040, China; (M.Z.); (Y.W.); (J.H.); (Y.S.); (S.W.); (B.Y.)
| | - Jianwei Han
- Key Laboratory of Basic and Application Research of Beiyao (Heilongjiang University of Chinese Medicine), Ministry of Education, Harbin 150040, China; (M.Z.); (Y.W.); (J.H.); (Y.S.); (S.W.); (B.Y.)
| | - Yanping Sun
- Key Laboratory of Basic and Application Research of Beiyao (Heilongjiang University of Chinese Medicine), Ministry of Education, Harbin 150040, China; (M.Z.); (Y.W.); (J.H.); (Y.S.); (S.W.); (B.Y.)
| | - Shuang Wang
- Key Laboratory of Basic and Application Research of Beiyao (Heilongjiang University of Chinese Medicine), Ministry of Education, Harbin 150040, China; (M.Z.); (Y.W.); (J.H.); (Y.S.); (S.W.); (B.Y.)
| | - Bingyou Yang
- Key Laboratory of Basic and Application Research of Beiyao (Heilongjiang University of Chinese Medicine), Ministry of Education, Harbin 150040, China; (M.Z.); (Y.W.); (J.H.); (Y.S.); (S.W.); (B.Y.)
| | - Qiuhong Wang
- School of Traditional Chinese Medicine, Guangdong Pharmaceutical University, Guangzhou 510024, China
| | - Haixue Kuang
- Key Laboratory of Basic and Application Research of Beiyao (Heilongjiang University of Chinese Medicine), Ministry of Education, Harbin 150040, China; (M.Z.); (Y.W.); (J.H.); (Y.S.); (S.W.); (B.Y.)
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Li Z, Yang H, Li X, She T, Tao Z, Zhong Y, Su T, Feng Y, Shi Q, Li L, Tian R, Wang S, Cheng J, Cai H, Lu X. Platelet-derived growth factor receptor β-targeted positron emission tomography imaging for the noninvasive monitoring of liver fibrosis. Eur J Nucl Med Mol Imaging 2024; 51:1530-1543. [PMID: 38189910 DOI: 10.1007/s00259-023-06577-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2023] [Accepted: 12/15/2023] [Indexed: 01/09/2024]
Abstract
PURPOSE Noninvasive quantifying activated hepatic stellate cells (aHSCs) by molecular imaging is helpful for assessing disease progression and therapeutic responses of liver fibrosis. Our purpose is to develop platelet-derived growth factor receptor β (PDGFRβ)-targeted radioactive tracer for assessing liver fibrosis by positron emission tomography (PET) imaging of aHSCs. METHODS Comparative transcriptomics, immunofluorescence staining and flow cytometry were used to evaluate PDGFRβ as biomarker for human aHSCs and determine the correlation of PDGFRβ with the severity of liver fibrosis. The high affinity affibody for PDGFRβ (ZPDGFRβ) was labeled with gallium-68 (68Ga) for PET imaging of mice with carbon tetrachloride (CCl4)-induced liver fibrosis. Binding of the [68Ga]Ga-labeled ZPDGFRβ ([68Ga]Ga-DOTA-ZPDGFRβ) for aHSCs in human liver tissues was measured by autoradiography. RESULTS PDGFRβ overexpressed in aHSCs was highly correlated with the severity of liver fibrosis in patients and CCl4-treated mice. The 68Ga-labeled ZPDGFRβ affibody ([68Ga]Ga-DOTA-ZPDGFRβ) showed PDGFRβ-dependent binding to aHSCs. According to the PET imaging, hepatic uptake of [68Ga]Ga-DOTA-ZPDGFRβ increased with the accumulation of aHSCs and collagens in the fibrotic livers of mice. In contrast, hepatic uptake of [68Ga]Ga-DOTA-ZPDGFRβ decreased with spontaneous recovery or treatment of liver fibrosis, indicating that the progression and therapeutic responses of liver fibrosis in mice could be visualized by PDGFRβ-targeted PET imaging. [68Ga]Ga-DOTA-ZPDGFRβ also bound human aHSCs and visualized fibrosis in patient-derived liver tissues. CONCLUSIONS PDGFRβ is a reliable biomarker for both human and mouse aHSCs. PDGFRβ-targeted PET imaging could be used for noninvasive monitoring of liver fibrosis in mice and has great potential for clinical translation.
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Affiliation(s)
- Zhao Li
- Department of Nuclear Medicine, NHC Key Lab of Transplant Engineering and Immunology, West China Hospital, Sichuan University, Chengdu, 610041, China
- Department of Nuclear Medicine , West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Hao Yang
- Department of Nuclear Medicine, NHC Key Lab of Transplant Engineering and Immunology, West China Hospital, Sichuan University, Chengdu, 610041, China
- Sichuan Provincial Engineering Laboratory of Pathology in Clinical Application, West China Hospital, Sichuan University, Chengdu, 610041, China
- Institutes for Systems Genetics, Frontiers Science Center for Disease-Related Molecular Network, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Xin Li
- Department of Nuclear Medicine , West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Tianshan She
- Department of Nuclear Medicine, NHC Key Lab of Transplant Engineering and Immunology, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Ze Tao
- Department of Nuclear Medicine, NHC Key Lab of Transplant Engineering and Immunology, West China Hospital, Sichuan University, Chengdu, 610041, China
- Sichuan Provincial Engineering Laboratory of Pathology in Clinical Application, West China Hospital, Sichuan University, Chengdu, 610041, China
- Institutes for Systems Genetics, Frontiers Science Center for Disease-Related Molecular Network, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Yi Zhong
- Laboratory of Clinical Proteomics and Metabolomics, Institutes for Systems Genetics , West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Tao Su
- Laboratory of Clinical Proteomics and Metabolomics, Institutes for Systems Genetics , West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Yanru Feng
- Department of Nuclear Medicine, NHC Key Lab of Transplant Engineering and Immunology, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Qiuxiao Shi
- Department of Nuclear Medicine, NHC Key Lab of Transplant Engineering and Immunology, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Lin Li
- Department of Nuclear Medicine , West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Rong Tian
- Department of Nuclear Medicine , West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Shisheng Wang
- Laboratory of Clinical Proteomics and Metabolomics, Institutes for Systems Genetics , West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Jingqiu Cheng
- Department of Nuclear Medicine, NHC Key Lab of Transplant Engineering and Immunology, West China Hospital, Sichuan University, Chengdu, 610041, China
- Sichuan Provincial Engineering Laboratory of Pathology in Clinical Application, West China Hospital, Sichuan University, Chengdu, 610041, China
- Institutes for Systems Genetics, Frontiers Science Center for Disease-Related Molecular Network, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Huawei Cai
- Department of Nuclear Medicine , West China Hospital, Sichuan University, Chengdu, 610041, China.
| | - Xiaofeng Lu
- Department of Nuclear Medicine, NHC Key Lab of Transplant Engineering and Immunology, West China Hospital, Sichuan University, Chengdu, 610041, China.
- Sichuan Provincial Engineering Laboratory of Pathology in Clinical Application, West China Hospital, Sichuan University, Chengdu, 610041, China.
- Institutes for Systems Genetics, Frontiers Science Center for Disease-Related Molecular Network, West China Hospital, Sichuan University, Chengdu, 610041, China.
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Yao Z, Du M, Wang Y, Zhu H, Shu L, You X, Wang J. Pharmacodynamic study of chitosan in combination with salvianolic acid B in the treatment of CC1 4 -induced liver fibrosis in mice. Clin Exp Pharmacol Physiol 2024; 51:17-29. [PMID: 37749921 DOI: 10.1111/1440-1681.13828] [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: 07/02/2023] [Revised: 09/01/2023] [Accepted: 09/07/2023] [Indexed: 09/27/2023]
Abstract
Liver fibrosis is a chronic liver lesion caused by excessive deposition of the extracellular matrix after liver damage, resulting in fibrous scarring of liver tissue. The progression of liver fibrosis is partially influenced by the gut microbiota. Chitosan can play a therapeutic role in liver fibrosis by regulating the gut microbiota based on the 'gut-liver axis' theory. Salvianolic acid B can inhibit the development of liver fibrosis by inhibiting the activation of hepatic stellate cells and reducing the production of extracellular matrix. In this study, the therapeutic effect of chitosan in combination with salvianolic acid B on liver fibrosis was investigated in a mouse liver fibrosis model. The results showed that the combination of chitosan and salvianolic acid B was better than the drug alone, improving AST/ALT levels and reducing the expression of α-SAM, COL I, IL-6 and other related genes. It improved the structure of gut microbiota and increased the abundance of beneficial bacteria such as Lactobacillus. The above results could provide new ideas for the clinical treatment of liver fibrosis.
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Affiliation(s)
- Zhongwei Yao
- Affiliated Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing, China
| | - Minshu Du
- Affiliated Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing, China
| | - Yalu Wang
- Affiliated Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing, China
| | - He Zhu
- Affiliated Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing, China
| | - Luan Shu
- Affiliated Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing, China
| | - Xia You
- Nanjing Lishui District Hospital of Traditional Chinese Medicine, Nanjing, China
| | - Jing Wang
- Affiliated Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing, China
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Wegrzyniak O, Zhang B, Rokka J, Rosestedt M, Mitran B, Cheung P, Puuvuori E, Ingvast S, Persson J, Nordström H, Löfblom J, Pontén F, Frejd FY, Korsgren O, Eriksson J, Eriksson O. Imaging of fibrogenesis in the liver by [ 18F]TZ-Z09591, an Affibody molecule targeting platelet derived growth factor receptor β. EJNMMI Radiopharm Chem 2023; 8:23. [PMID: 37733133 PMCID: PMC10513984 DOI: 10.1186/s41181-023-00210-6] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2023] [Accepted: 09/04/2023] [Indexed: 09/22/2023] Open
Abstract
BACKGROUND Platelet-derived growth factor receptor beta (PDGFRβ) is a receptor overexpressed on activated hepatic stellate cells (aHSCs). Positron emission tomography (PET) imaging of PDGFRβ could potentially allow the quantification of fibrogenesis in fibrotic livers. This study aims to evaluate a fluorine-18 radiolabeled Affibody molecule ([18F]TZ-Z09591) as a PET tracer for imaging liver fibrogenesis. RESULTS In vitro specificity studies demonstrated that the trans-Cyclooctenes (TCO) conjugated Z09591 Affibody molecule had a picomolar affinity for human PDGFRβ. Biodistribution performed on healthy rats showed rapid clearance of [18F]TZ-Z09591 through the kidneys and low liver background uptake. Autoradiography (ARG) studies on fibrotic livers from mice or humans correlated with histopathology results. Ex vivo biodistribution and ARG revealed that [18F]TZ-Z09591 binding in the liver was increased in fibrotic livers (p = 0.02) and corresponded to binding in fibrotic scars. CONCLUSIONS Our study highlights [18F]TZ-Z09591 as a specific tracer for fibrogenic cells in the fibrotic liver, thus offering the potential to assess fibrogenesis clearly.
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Affiliation(s)
- Olivia Wegrzyniak
- Science for Life Laboratory, Department of Medicinal Chemistry, Uppsala University, Dag Hammarskjölds Väg 14C, 3tr, 751 83, Uppsala, Sweden
| | - Bo Zhang
- Science for Life Laboratory, Department of Medicinal Chemistry, Uppsala University, Dag Hammarskjölds Väg 14C, 3tr, 751 83, Uppsala, Sweden
| | - Johanna Rokka
- Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden
| | - Maria Rosestedt
- Science for Life Laboratory, Department of Medicinal Chemistry, Uppsala University, Dag Hammarskjölds Väg 14C, 3tr, 751 83, Uppsala, Sweden
| | - Bogdan Mitran
- Science for Life Laboratory, Department of Medicinal Chemistry, Uppsala University, Dag Hammarskjölds Väg 14C, 3tr, 751 83, Uppsala, Sweden
- Antaros Medical AB, Uppsala, Sweden
| | - Pierre Cheung
- Science for Life Laboratory, Department of Medicinal Chemistry, Uppsala University, Dag Hammarskjölds Väg 14C, 3tr, 751 83, Uppsala, Sweden
| | - Emmi Puuvuori
- Science for Life Laboratory, Department of Medicinal Chemistry, Uppsala University, Dag Hammarskjölds Väg 14C, 3tr, 751 83, Uppsala, Sweden
| | - Sofie Ingvast
- Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden
| | - Jonas Persson
- Science for Life Laboratory, Department of Medicinal Chemistry, Uppsala University, Dag Hammarskjölds Väg 14C, 3tr, 751 83, Uppsala, Sweden
- Department of Protein Science, Division of Protein Engineering, KTH Royal Institute of Technology, Stockholm, Sweden
| | - Helena Nordström
- Science for Life Laboratory, Drug Discovery and Development Platform, Department of Chemistry-BMC, Uppsala University, Uppsala, Sweden
| | - John Löfblom
- Department of Protein Science, Division of Protein Engineering, KTH Royal Institute of Technology, Stockholm, Sweden
| | - Fredrik Pontén
- Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden
| | - Fredrik Y Frejd
- Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden
- Affibody AB, Solna, Sweden
| | - Olle Korsgren
- Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden
| | - Jonas Eriksson
- Science for Life Laboratory, Department of Medicinal Chemistry, Uppsala University, Dag Hammarskjölds Väg 14C, 3tr, 751 83, Uppsala, Sweden.
- Uppsala University Hospital PET Center, Entrance 85, Dag Hammarskjölds Väg 21, 752 37, Uppsala, Sweden.
| | - Olof Eriksson
- Science for Life Laboratory, Department of Medicinal Chemistry, Uppsala University, Dag Hammarskjölds Väg 14C, 3tr, 751 83, Uppsala, Sweden.
- Antaros Medical AB, Uppsala, Sweden.
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Li H, Liu T, Yang Y, Cho WC, Flynn RJ, Harandi MF, Song H, Luo X, Zheng Y. Interplays of liver fibrosis-associated microRNAs: Molecular mechanisms and implications in diagnosis and therapy. Genes Dis 2023; 10:1457-1469. [PMID: 37397560 PMCID: PMC10311052 DOI: 10.1016/j.gendis.2022.08.013] [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: 06/15/2022] [Revised: 08/09/2022] [Accepted: 08/20/2022] [Indexed: 11/22/2022] Open
Abstract
microRNAs (miRNAs) are a class of non-coding functional small RNA composed of 21-23 nucleotides, having multiple associations with liver fibrosis. Fibrosis-associated miRNAs are roughly classified into pro-fibrosis or anti-fibrosis types. The former is capable of activating hepatic stellate cells (HSCs) by modulating pro-fibrotic signaling pathways, mainly including TGF-β/SMAD, WNT/β-catenin, and Hedgehog; the latter is responsible for maintenance of the quiescent phenotype of normal HSCs, phenotypic reversion of activated HSCs (aHSCs), inhibition of HSCs proliferation and suppression of the extracellular matrix-associated gene expression. Moreover, several miRNAs are involved in regulation of liver fibrosis via alternative mechanisms, such as interacting between hepatocytes and other liver cells via exosomes and increasing autophagy of aHSCs. Thus, understanding the role of these miRNAs may provide new avenues for the development of novel interventions against hepatic fibrosis.
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Affiliation(s)
- Hong Li
- State Key Laboratory of Veterinary Etiological Biology, Key Laboratory of Veterinary Parasitology of Gansu Province, Lanzhou Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Lanzhou, Gansu 730046, China
| | - Tingli Liu
- State Key Laboratory of Veterinary Etiological Biology, Key Laboratory of Veterinary Parasitology of Gansu Province, Lanzhou Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Lanzhou, Gansu 730046, China
| | - Yongchun Yang
- Key Laboratory of Applied Technology on Green-Eco-Healthy Animal Husbandry of Zhejiang Province, Zhejiang Provincial Engineering Laboratory for Animal Health Inspection & Internet Technology, Zhejiang International Science and Technology Cooperation Base for Veterinary Medicine and Health Management, China-Australia Joint Laboratory for Animal Health Big Data Analytics, College of Animal Science and Technology & College of Veterinary Medicine of Zhejiang A&F University, Hangzhou, Zhejiang 311300, China
| | - William C. Cho
- Department of Clinical Oncology, Queen Elizabeth Hospital, Hong Kong SAR 999077, China
| | - Robin J. Flynn
- Department of Infection Biology, Institute of Infection and Global Health, University of Liverpool, Liverpool L3 5RF, UK
- Graduate Studies Office, Department of Research, Innovation and Graduate Studies, Waterford Institute of Technology, X91 K0EK, Ireland
| | - Majid Fasihi Harandi
- Research Center for Hydatid Disease in Iran, Kerman University of Medical Sciences, Kerman 7616914115, Iran
| | - Houhui Song
- Key Laboratory of Applied Technology on Green-Eco-Healthy Animal Husbandry of Zhejiang Province, Zhejiang Provincial Engineering Laboratory for Animal Health Inspection & Internet Technology, Zhejiang International Science and Technology Cooperation Base for Veterinary Medicine and Health Management, China-Australia Joint Laboratory for Animal Health Big Data Analytics, College of Animal Science and Technology & College of Veterinary Medicine of Zhejiang A&F University, Hangzhou, Zhejiang 311300, China
| | - Xuenong Luo
- State Key Laboratory of Veterinary Etiological Biology, Key Laboratory of Veterinary Parasitology of Gansu Province, Lanzhou Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Lanzhou, Gansu 730046, China
| | - Yadong Zheng
- Key Laboratory of Applied Technology on Green-Eco-Healthy Animal Husbandry of Zhejiang Province, Zhejiang Provincial Engineering Laboratory for Animal Health Inspection & Internet Technology, Zhejiang International Science and Technology Cooperation Base for Veterinary Medicine and Health Management, China-Australia Joint Laboratory for Animal Health Big Data Analytics, College of Animal Science and Technology & College of Veterinary Medicine of Zhejiang A&F University, Hangzhou, Zhejiang 311300, China
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10
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Ma M, Wang X, Liu X, Han Y, Chu Y, Guan Y, Liu H. Engineered fibrotic liver-targeted truncated transforming growth factor β receptor type II variant for superior anti-liver fibrosis therapy. Arch Pharm Res 2023; 46:177-191. [PMID: 36905489 DOI: 10.1007/s12272-023-01435-4] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2022] [Accepted: 02/25/2023] [Indexed: 03/12/2023]
Abstract
Truncated transforming growth factor β receptor type II (tTβRII) is a promising anti-liver fibrotic candidate because it serves as a trap for binding excessive TGF-β1 by means of competing with wild type TβRII (wtTβRII). However, the widespread application of tTβRII for the treatment of liver fibrosis has been limited by its poor fibrotic liver-homing capacity. Herein, we designed a novel tTβRII variant Z-tTβRII by fusing the platelet-derived growth factor β receptor (PDGFβR)-specific affibody ZPDGFβR to the N-terminus of tTβRII. The target protein Z-tTβRII was produced using Escherichia coli expression system. In vitro and in vivo studies showed that Z-tTβRII has a superior specific fibrotic liver-targeting potential via the engagement of PDGFβR-overexpressing activated hepatic stellate cells (aHSCs) in liver fibrosis. Moreover, Z-tTβRII significantly inhibited cell migration and invasion, and downregulated fibrosis- and TGF-β1/Smad pathway-related protein levels in TGF-β1-stimiluated HSC-T6 cells. Furthermore, Z-tTβRII remarkably ameliorated liver histopathology, mitigated the fibrosis responses and blocked TGF-β1/Smad signaling pathway in CCl4-induced liver fibrotic mice. More importantly, Z-tTβRII exhibits a higher fibrotic liver-targeting potential and stronger anti-fibrotic effects than either its parent tTβRII or former variant BiPPB-tTβRII (PDGFβR-binding peptide BiPPB modified tTβRII). In addition, Z-tTβRII shows no significant sign of potential side effects in other vital organs in liver fibrotic mice. Taken together, we conclude that Z-tTβRII with its a high fibrotic liver-homing potential, holds a superior anti-fibrotic activity in liver fibrosis in vitro and in vivo, which may be a potential candidate for targeted therapy for liver fibrosis.
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Affiliation(s)
- Manman Ma
- Heilongjiang Province Key Laboratory for Anti-fibrosis Biotherapy, Mudanjiang Medical University, Mudanjiang, 157011, People's Republic of China
| | - Xiaohua Wang
- Laboratory of Pathogenic Microbiology and Immunology, Mudanjiang Medical University, Mudanjiang, 157011, People's Republic of China
| | - Xiaohui Liu
- Heilongjiang Province Key Laboratory for Anti-fibrosis Biotherapy, Mudanjiang Medical University, Mudanjiang, 157011, People's Republic of China
| | - Yang Han
- The First Clinical College, Mudanjiang Medical University, Mudanjiang, 157011, People's Republic of China
| | - Yanhui Chu
- Heilongjiang Province Key Laboratory for Anti-fibrosis Biotherapy, Mudanjiang Medical University, Mudanjiang, 157011, People's Republic of China
| | - Yanzhong Guan
- Department of Physiology and Neurobiology, Mudanjiang Medical University, Mudanjiang, 157011, People's Republic of China.
| | - Haifeng Liu
- Heilongjiang Province Key Laboratory for Anti-fibrosis Biotherapy, Mudanjiang Medical University, Mudanjiang, 157011, People's Republic of China.
- Laboratory of Pathogenic Microbiology and Immunology, Mudanjiang Medical University, Mudanjiang, 157011, People's Republic of China.
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11
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Research progress of metformin in the treatment of liver fibrosis. Int Immunopharmacol 2023; 116:109738. [PMID: 36696857 DOI: 10.1016/j.intimp.2023.109738] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2022] [Revised: 01/12/2023] [Accepted: 01/12/2023] [Indexed: 01/24/2023]
Abstract
Liver fibrosis is a disease with significant morbidity and mortality. It is a chronic pathological process characterized by an imbalance of extracellular matrix production and degradation in liver tissue. Metformin is a type of hypoglycemic biguanide drug, which can be used in the treatment of liver fibrosis, but its anti-fibrotic effect and mechanism of action are unclear. The purpose of this article is to review the research progress of metformin in the treatment of liver fibrosis and to provide a theoretical basis for its application in the treatment of liver fibrosis.
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12
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Peng H, Zhong L, Cheng L, Chen L, Tong R, Shi J, Bai L. Ganoderma lucidum: Current advancements of characteristic components and experimental progress in anti-liver fibrosis. Front Pharmacol 2023; 13:1094405. [PMID: 36703748 PMCID: PMC9872944 DOI: 10.3389/fphar.2022.1094405] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2022] [Accepted: 12/23/2022] [Indexed: 01/11/2023] Open
Abstract
Ganoderma lucidum (G. lucidum, Lingzhi) is a well-known herbal medicine with a variety of pharmacological effects. Studies have found that G. lucidum has pharmacological effects such as antioxidant, antitumor, anti-aging, anti-liver fibrosis, and immunomodulation. The main active components of G. lucidum include triterpenoids, polysaccharides, sterols, peptides and other bioactive components. Among them, the triterpenoids and polysaccharide components of G. lucidum have a wide range of anti-liver fibrotic effects. Currently, there have been more reviews and studies on the antioxidant, antitumor, and anti-aging properties of G. lucidum. Based on the current trend of increasing number of liver fibrosis patients in the world, we summarized the role of G.lucidum extract in anti-liver fibrosis and the effect of G. lucidum extract on liver fibrosis induced by different pathogenesis, which were discussed and analyzed. Research and development ideas and references are provided for the subsequent application of G. lucidum extracts in anti-liver fibrosis treatment.
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Affiliation(s)
- Haoyuan Peng
- The State Key Laboratory of Southwestern Chinese Medicine Resources, Department of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Lei Zhong
- Department of Pharmacy, Personalized Drug Therapy Key Laboratory of Sichuan Province, Sichuan Provincial People's Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, China
| | - Lin Cheng
- College of Medicine, Southwest Jiaotong University, Chengdu, Sichuan, China
| | - Lu Chen
- Department of Pharmacy, Personalized Drug Therapy Key Laboratory of Sichuan Province, Sichuan Provincial People's Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, China
| | - Rongsheng Tong
- The State Key Laboratory of Southwestern Chinese Medicine Resources, Department of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, China,Department of Pharmacy, Personalized Drug Therapy Key Laboratory of Sichuan Province, Sichuan Provincial People's Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, China
| | - Jianyou Shi
- The State Key Laboratory of Southwestern Chinese Medicine Resources, Department of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, China,Department of Pharmacy, Personalized Drug Therapy Key Laboratory of Sichuan Province, Sichuan Provincial People's Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, China,*Correspondence: Jianyou Shi, ; Lan Bai,
| | - Lan Bai
- The State Key Laboratory of Southwestern Chinese Medicine Resources, Department of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, China,Department of Pharmacy, Personalized Drug Therapy Key Laboratory of Sichuan Province, Sichuan Provincial People's Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, China,*Correspondence: Jianyou Shi, ; Lan Bai,
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13
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Self-homing nanocarriers for mRNA delivery to the activated hepatic stellate cells in liver fibrosis. J Control Release 2023; 353:685-698. [PMID: 36521688 DOI: 10.1016/j.jconrel.2022.12.020] [Citation(s) in RCA: 20] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2022] [Revised: 11/17/2022] [Accepted: 12/09/2022] [Indexed: 12/23/2022]
Abstract
Herein, we report on the development of a platform for the selective delivery of mRNA to the hard-to-transfect Activated Hepatic Stellate Cells (aHSCs), the fundamental player in the progression of liver fibrosis. Using a microfluidic device (iLiNP), we prepared a series of lipid nanoparticles (LNPs) based on a diverse library of pH-sensitive lipids. After an in-depth in vivo optimization of the LNPs, their mRNA delivery efficiency, selectivity, potency, robustness, and biosafety were confirmed. Furthermore, some mechanistic aspects of their selective delivery to aHSCs were investigated. We identified a promising lipid candidate, CL15A6, that has a high affinity to aHSCs. Tweaking the composition and physico-chemical properties of the LNPs enabled the robust and ligand-free mRNA delivery to aHSCs in vivo post intravenous administration, with a high biosafety at mRNA doses of up to 2 mg/Kg, upon either acute or chronic administrations. The mechanistic investigation suggested that CL15A6 LNPs were taken up by aHSCs via Clathrin-mediated endocytosis through the Platelet-derived growth factor receptor beta (PDGFRβ) and showed a pKa-dependent cellular uptake. The novel and scalable platform reported in this study is highly promising for clinical applications.
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14
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Dong H, Zhao L, Sun H, Shang M, Lv G, Yu X, Hu B, Huang Y. Coinfection of Clonorchis sinensis and hepatitis B virus: clinical liver indices and interaction in hepatic cell models. Parasit Vectors 2022; 15:460. [PMID: 36510325 PMCID: PMC9746095 DOI: 10.1186/s13071-022-05548-5] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2022] [Accepted: 10/19/2022] [Indexed: 12/14/2022] Open
Abstract
BACKGROUND In China, people infected with hepatitis B virus (HBV) are commonly found in areas with a high prevalence of Clonorchis sinensis, a trematode worm. Published studies have reported that the progression of hepatitis B is affected by coinfection C. sinensis. METHODS Clinical data from a total of 72 patients with C. sinensis and HBV (as sole infection or with coinfections) and 29 healthy individuals were analysed. We also incubated the hepatic stellate cell line LX-2 with total proteins from C. sinensis adult worms (CsTPs) and HBV-positive sera. In addition, the human hepatoblastoma cell line HepG2.2.15 was treated with the antiviral drug entecavir (ETV), CsTPs and the anti-C. sinensis drug praziquantel (PZQ). RESULTS Our clinical data indicated that the levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), total bilirubin (TB) and hyaluronic acid (HA) were significantly higher in patients with coinfection than in those infected with HBV only. In cell models, compared with the model in which LX-2 cells were incubated with HBV-positive sera (HBV group), transcripts of alpha-smooth muscle actin and types I and III collagen were significantly elevated in the models of LX-2 cells treated with CsTPs and HBV-positive sera (CsTP+HBV group), while the messenger RNA levels of tumour necrosis factor-α, interleukin (IL)-1β and IL-6 in the CsTP+HBV group were clearly lower. The HBV surface antigen and hepatitis B e-antigen levels were higher in the HepG2.2.15 cells treated with ETV and CsTPs than in those in the ETV group and in the cells administered a mixture of ETV, CsTPs and PZQ. CONCLUSIONS These results confirmed that C. sinensis and HBV coinfection could aggravate the progression of liver fibrosis. CsTPs might promote chronic inflammation of the liver in individuals with HBV infection, resulting in the development of hepatic fibrosis.
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Affiliation(s)
- Huimin Dong
- grid.412558.f0000 0004 1762 1794Department of Laboratory Medicine, The Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, Guangdong People’s Republic of China ,grid.12981.330000 0001 2360 039XDepartment of Parasitology, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, Guangdong People’s Republic of China ,grid.12981.330000 0001 2360 039XKey Laboratory for Tropical Diseases Control of Ministry of Education, Sun Yat-Sen University, Guangzhou, Guangdong People’s Republic of China ,Provincial Engineering Technology Research Center for Biological Vector Control, Guangzhou, Guangdong People’s Republic of China
| | - Lu Zhao
- grid.12981.330000 0001 2360 039XDepartment of Parasitology, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, Guangdong People’s Republic of China ,grid.12981.330000 0001 2360 039XKey Laboratory for Tropical Diseases Control of Ministry of Education, Sun Yat-Sen University, Guangzhou, Guangdong People’s Republic of China ,Provincial Engineering Technology Research Center for Biological Vector Control, Guangzhou, Guangdong People’s Republic of China ,grid.488525.6Department of Clinical Laboratory, The Sixth Affiliated Hospital of Sun Yat-Sen University, Guangzhou, Guangdong People’s Republic of China
| | - Hengchang Sun
- grid.412558.f0000 0004 1762 1794Department of Laboratory Medicine, The Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, Guangdong People’s Republic of China ,grid.12981.330000 0001 2360 039XDepartment of Parasitology, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, Guangdong People’s Republic of China ,grid.12981.330000 0001 2360 039XKey Laboratory for Tropical Diseases Control of Ministry of Education, Sun Yat-Sen University, Guangzhou, Guangdong People’s Republic of China ,Provincial Engineering Technology Research Center for Biological Vector Control, Guangzhou, Guangdong People’s Republic of China
| | - Mei Shang
- grid.412558.f0000 0004 1762 1794Department of Laboratory Medicine, The Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, Guangdong People’s Republic of China ,grid.12981.330000 0001 2360 039XDepartment of Parasitology, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, Guangdong People’s Republic of China ,grid.12981.330000 0001 2360 039XKey Laboratory for Tropical Diseases Control of Ministry of Education, Sun Yat-Sen University, Guangzhou, Guangdong People’s Republic of China ,Provincial Engineering Technology Research Center for Biological Vector Control, Guangzhou, Guangdong People’s Republic of China
| | - Gang Lv
- grid.443397.e0000 0004 0368 7493Key Laboratory of Tropical Translational Medicine of Ministry of Education, Hainan Medical University, Haikou, Hainan People’s Republic of China
| | - Xinbing Yu
- grid.12981.330000 0001 2360 039XDepartment of Parasitology, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, Guangdong People’s Republic of China ,grid.12981.330000 0001 2360 039XKey Laboratory for Tropical Diseases Control of Ministry of Education, Sun Yat-Sen University, Guangzhou, Guangdong People’s Republic of China ,Provincial Engineering Technology Research Center for Biological Vector Control, Guangzhou, Guangdong People’s Republic of China
| | - Bo Hu
- grid.412558.f0000 0004 1762 1794Department of Laboratory Medicine, The Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, Guangdong People’s Republic of China
| | - Yan Huang
- grid.12981.330000 0001 2360 039XDepartment of Parasitology, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, Guangdong People’s Republic of China ,grid.12981.330000 0001 2360 039XKey Laboratory for Tropical Diseases Control of Ministry of Education, Sun Yat-Sen University, Guangzhou, Guangdong People’s Republic of China ,Provincial Engineering Technology Research Center for Biological Vector Control, Guangzhou, Guangdong People’s Republic of China
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Sen S, Spasic A, Sinha A, Wang J, Bush M, Li J, Nešić D, Zhou Y, Angiulli G, Morgan P, Salas-Estrada L, Takagi J, Walz T, Coller BS, Filizola M. Structure-Based Discovery of a Novel Class of Small-Molecule Pure Antagonists of Integrin αVβ3. J Chem Inf Model 2022; 62:5607-5621. [PMID: 36279366 PMCID: PMC9767310 DOI: 10.1021/acs.jcim.2c00999] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Inhibitors of integrin αVβ3 have therapeutic promise for a variety of diseases. Most αVβ3-targeting small molecules patterned after the RGD motif are partial agonists because they induce a high-affinity, ligand-binding conformation and prime the receptor to bind the ligand without an activating stimulus, in part via a charge-charge interaction between their aspartic acid carboxyl group and the metal ion in the metal-ion-dependent adhesion site (MIDAS). Building upon our previous studies on the related integrin αIIbβ3, we searched for pure αVβ3 antagonists that lack this typical aspartic acid carboxyl group and instead engage through direct binding to one of the coordinating residues of the MIDAS metal ion, specifically β3 E220. By in silico screening of two large chemical libraries for compounds interacting with β3 E220, we indeed discovered a novel molecule that does not contain an acidic carboxyl group and does not induce the high-affinity, ligand-binding state of the receptor. Functional and structural characterization of a chemically optimized version of this compound led to the discovery of a novel small-molecule pure αVβ3 antagonist that (i) does not prime the receptor to bind the ligand and does not induce hybrid domain swing-out or receptor extension as judged by antibody binding and negative-stain electron microscopy, (ii) binds at the RGD-binding site as predicted by metadynamics rescoring of induced-fit docking poses and confirmed by a cryo-electron microscopy structure of the compound-bound integrin, and (iii) coordinates the MIDAS metal ion via a quinoline moiety instead of an acidic carboxyl group.
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Affiliation(s)
- Soumyo Sen
- Department of Pharmacological Sciences, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, Box 1677, New York, New York10029, United States
| | - Aleksandar Spasic
- Department of Pharmacological Sciences, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, Box 1677, New York, New York10029, United States
| | - Anjana Sinha
- Allen and Frances Adler Laboratory of Blood and Vascular Biology, The Rockefeller University, 1230 York Avenue, P.O. Box 309, New York, New York10065, United States
| | - Jialing Wang
- Laboratory of Molecular Electron Microscopy, The Rockefeller University, 1230 York Avenue, P.O. Box 219, New York, New York10065, United States
| | - Martin Bush
- Laboratory of Molecular Electron Microscopy, The Rockefeller University, 1230 York Avenue, P.O. Box 219, New York, New York10065, United States
| | - Jihong Li
- Allen and Frances Adler Laboratory of Blood and Vascular Biology, The Rockefeller University, 1230 York Avenue, P.O. Box 309, New York, New York10065, United States
| | - Dragana Nešić
- Allen and Frances Adler Laboratory of Blood and Vascular Biology, The Rockefeller University, 1230 York Avenue, P.O. Box 309, New York, New York10065, United States
| | - Yuchen Zhou
- Department of Pharmacological Sciences, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, Box 1677, New York, New York10029, United States
| | - Gabriella Angiulli
- Laboratory of Molecular Electron Microscopy, The Rockefeller University, 1230 York Avenue, P.O. Box 219, New York, New York10065, United States
| | - Paul Morgan
- Department of Pharmacological Sciences, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, Box 1677, New York, New York10029, United States
| | - Leslie Salas-Estrada
- Department of Pharmacological Sciences, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, Box 1677, New York, New York10029, United States
| | - Junichi Takagi
- Laboratory of Protein Synthesis and Expression, Institute for Protein Research, Osaka University, 3-2 Yamadaoka, Suita, Osaka565-0871, Japan
| | - Thomas Walz
- Laboratory of Molecular Electron Microscopy, The Rockefeller University, 1230 York Avenue, P.O. Box 219, New York, New York10065, United States
| | - Barry S Coller
- Allen and Frances Adler Laboratory of Blood and Vascular Biology, The Rockefeller University, 1230 York Avenue, P.O. Box 309, New York, New York10065, United States
| | - Marta Filizola
- Department of Pharmacological Sciences, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, Box 1677, New York, New York10029, United States
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16
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Zhao H, Wu L, Zhang Y, Feng S, Ding Y, Deng X, Feng R, Li J, Ma T, Huang C. Betulinic acid prevents liver fibrosis by binding Lck and suppressing Lck in HSC activation and proliferation. JOURNAL OF ETHNOPHARMACOLOGY 2022; 296:115459. [PMID: 35714879 DOI: 10.1016/j.jep.2022.115459] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/20/2022] [Revised: 06/07/2022] [Accepted: 06/10/2022] [Indexed: 06/15/2023]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE Hypericum japonicum Thunb. ex Murray (Hypericaceae), named 'Tianjihuang' is a traditional Chinese medicine with hepatoprotective, antibacterial, and antitumour effects. Betulinic acid (BA) is its active constituent and has been found to have a number of biological effects, including antiviral, anti-inflammatory, and anti-malarial therapeutic properties. Non-alcoholic fatty liver disease and acute alcoholic liver injury have both been proven to benefit from BA. BA's effects and mechanism on liver fibrosis are still unknown. AIM OF THE STUDY The purpose of this study was to explore the influence of BA on lymphocyte-specific protein tyrosine kinase (Lck), a non-receptor Src family kinase, that reduces liver fibrosis by inhibiting the phosphorylation of the Janus kinase (JAK)/signal transducer and activator of transcription (STAT) pathways through the interaction of Lck and SOCS1. MATERIALS AND METHODS A liver fibrosis model was established in vivo with CCl4 using haematoxylin and eosin (HE) staining, Masson staining, immunohistochemical staining, and immunofluorescence staining. Hepatic stellate cells were induced with transforming growth factor (TGF)-β1 in vitro, using Western blotting, immunofluorescence staining, and a cell scratch assay. RESULTS In a CCl4-induced mouse hepatic fibrosis model and in TGF-β1-activated HSC-T6 cells, BA markedly reduced fibrosis, as demonstrated by the dramatic downregulation of α-smooth muscle actin (α-SMA) and type I collagen alpha-1 (Col1α1) protein levels in vivo and in vitro. BA significantly suppressed the activity and expression of Lck in vitro. Overexpression of Lck may diminish the effect of BA on liver fibrosis. In vitro, BA also greatly increased the expression of suppressor of cytokine signalling 1 (SOCS1) while it considerably inhibited the expression of p-JAK and p-STAT1. CONCLUSIONS These findings suggest that BA promotes the expression of SOCS1 by the inhibiting the interaction between Lck and SOCS1, followed by the inhibition of JAK/STAT phosphorylation to prevent the progression of liver fibrosis. Therefore, BA could be used as a promising natural supplement for the treatment of liver fibrosis.
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Affiliation(s)
- Huizi Zhao
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, Hefei, 230032, China
| | - Lin Wu
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, Hefei, 230032, China
| | - Yuan Zhang
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, Hefei, 230032, China
| | - Shiqi Feng
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, Hefei, 230032, China
| | - Yuhao Ding
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, Hefei, 230032, China
| | - Xin Deng
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, Hefei, 230032, China
| | - Rui Feng
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, Hefei, 230032, China
| | - Jun Li
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, Hefei, 230032, China
| | - Taotao Ma
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, Hefei, 230032, China.
| | - Cheng Huang
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, Hefei, 230032, China.
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Tang X, Li X, Li M, Zhong X, Fu W, Ao M, Xuan J. Enhanced US/CT/MR imaging of integrin αvβ3 for liver fibrosis staging in rat. Front Chem 2022; 10:996116. [PMID: 36262337 PMCID: PMC9574014 DOI: 10.3389/fchem.2022.996116] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2022] [Accepted: 09/08/2022] [Indexed: 11/13/2022] Open
Abstract
Liver fibrosis is a global health challenge with high morbidity and mortality rates, and diagnostic sensitivity of liver fibrosis tests can be increased using multimodal molecular agents. We designed cyclic arginine-glycine-aspartic acid (cRGD)-modified nanoparticles (NPs) using ultrasound (US)/computed tomography (CT)/magnetic resonance (MR) triple-modality imaging to evaluate liver fibrosis stages. In vitro and in vivo studies were conducted using primary hepatic stellate cells (HSCs) and a rat model of liver fibrosis induced by carbon tetrachloride (CCl4). Our results showed cRGD-poly(lactic-co-glycolic acid)-Fe3O4-perfluorocarbon bromide (cRGD-PLGA-Fe3O4-PFOB) NPs were preferentially internalised by activated HSCs (aHSCs). The main cell types expressing integrin αvβ3 during liver fibrogenesis were the aHSCs. The protein levels of αv and β3 expressed on aHSCs increased with the progression of liver fibrosis. After intravenous injection of cRGD-PLGA-Fe3O4-PFOB NPs, the echo intensity (EI) values, CT values, and T2 values of liver parenchyma correlated well with liver fibrosis severity. cRGD-PLGA-Fe3O4-PFOB NPs as multifunction contrast agents showed great potential to reflect the degree of HSC activation and distinguish among different liver fibrotic stages. The ligand-directed and integrin αvβ3-mediated accumulation provides active and passive targeting capabilities, permitting the targeted multimodal imaging of cRGD-PLGA-Fe3O4-PFOB NPs, which delivers accurate non-invasive diagnosis and real-time monitoring of liver fibrosis development.
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Affiliation(s)
- Xueyao Tang
- Department of Ultrasound, The Affiliated Hospital of Southwest Medical University, Luzhou, China
- Department of Ultrasound, The Third People’s Hospital of Chengdu, Clinical College of Southwest Jiao Tong University, The Second Affiliated Chengdu Hospital of Chongqing Medical University, Chengdu, China
| | - Xuan Li
- Department of Ultrasound, The Affiliated Hospital of Southwest Medical University, Luzhou, China
- Department of Ultrasound, Sichuan Provincial People’s Hospital, Chengdu, China
| | - Mingxing Li
- Department of Ultrasound, The Affiliated Hospital of Southwest Medical University, Luzhou, China
| | - Xiaoling Zhong
- Department of Gastroenterology, The Affiliated Hospital of Southwest Medical University, Luzhou, China
| | - Wenguang Fu
- Academician (Expert) Workstation of Sichuan Province, The Affiliated Hospital of Southwest Medical University, Luzhou, China
- Department of Hepatobiliary Surgery, The Affiliated Hospital of Southwest Medical University, Luzhou, China
| | - Meng Ao
- Department of Ultrasound, The Second Affiliated Hospital of Chongqing Medical University & Chongqing Key Laboratory of Ultrasound Molecular Imaging, Chongqing, China
- *Correspondence: Jiqing Xuan, ; Meng Ao,
| | - Jiqing Xuan
- Department of Ultrasound, The Affiliated Hospital of Southwest Medical University, Luzhou, China
- *Correspondence: Jiqing Xuan, ; Meng Ao,
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18
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Subramanian R, Tang R, Zhang Z, Joshi V, Miner JN, Lo YH. Multimodal NASH prognosis using 3D imaging flow cytometry and artificial intelligence to characterize liver cells. Sci Rep 2022; 12:11180. [PMID: 35778474 PMCID: PMC9249889 DOI: 10.1038/s41598-022-15364-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2022] [Accepted: 06/17/2022] [Indexed: 11/17/2022] Open
Abstract
To improve the understanding of the complex biological process underlying the development of non-alcoholic steatohepatitis (NASH), 3D imaging flow cytometry (3D-IFC) with transmission and side-scattered images were used to characterize hepatic stellate cell (HSC) and liver endothelial cell (LEC) morphology at single-cell resolution. In this study, HSC and LEC were obtained from biopsy-proven NASH subjects with early-stage NASH (F2-F3) and healthy controls. Here, we applied single-cell imaging and 3D digital reconstructions of healthy and diseased cells to analyze a spatially resolved set of morphometric cellular and texture parameters that showed regression with disease progression. By developing a customized autoencoder convolutional neural network (CNN) based on label-free cell transmission and side scattering images obtained from a 3D imaging flow cytometer, we demonstrated key regulated cell types involved in the development of NASH and cell classification performance superior to conventional machine learning methods.
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Affiliation(s)
- Ramkumar Subramanian
- Department of Electrical and Computer Engineering, University of California San Diego, La Jolla, CA, 92093, USA
| | - Rui Tang
- Department of Electrical and Computer Engineering, University of California San Diego, La Jolla, CA, 92093, USA
| | - Zunming Zhang
- Department of Electrical and Computer Engineering, University of California San Diego, La Jolla, CA, 92093, USA
| | | | | | - Yu-Hwa Lo
- Department of Electrical and Computer Engineering, University of California San Diego, La Jolla, CA, 92093, USA.
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19
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Friedman SL, Pinzani M. Hepatic fibrosis 2022: Unmet needs and a blueprint for the future. Hepatology 2022; 75:473-488. [PMID: 34923653 DOI: 10.1002/hep.32285] [Citation(s) in RCA: 246] [Impact Index Per Article: 82.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/11/2021] [Revised: 11/12/2021] [Accepted: 11/15/2021] [Indexed: 12/12/2022]
Abstract
Steady progress over four decades toward understanding the pathogenesis and clinical consequences of hepatic fibrosis has led to the expectation of effective antifibrotic drugs, yet none has been approved. Thus, an assessment of the field is timely, to clarify priorities and accelerate progress. Here, we highlight the successes to date but, more importantly, identify gaps and unmet needs, both experimentally and clinically. These include the need to better define cell-cell interactions and etiology-specific elements of fibrogenesis and their link to disease-specific drivers of portal hypertension. Success in treating viral hepatitis has revealed the remarkable capacity of the liver to degrade scar in reversing fibrosis, yet we know little of the mechanisms underlying this response. Thus, there is an exigent need to clarify the cellular and molecular mechanisms of fibrosis regression in order for therapeutics to mimic the liver's endogenous capacity. Better refined and more predictive in vitro and animal models will hasten drug development. From a clinical perspective, current diagnostics are improving but not always biologically plausible or sufficiently accurate to supplant biopsy. More urgently, digital pathology methods that leverage machine learning and artificial intelligence must be validated in order to capture more prognostic information from liver biopsies and better quantify the response to therapies. For more refined treatment of NASH, orthogonal approaches that integrate genetic, clinical, and pathological data sets may yield treatments for specific subphenotypes of the disease. Collectively, these and other advances will strengthen and streamline clinical trials and better link histologic responses to clinical outcomes.
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Affiliation(s)
- Scott L Friedman
- Division of Liver DiseasesIcahn School of Medicine at Mount SinaiNew YorkNew YorkUSA
| | - Massimo Pinzani
- Institute for Liver and Digestive HealthUniversity College LondonLondonUK
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20
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Tao S, Duan R, Xu T, Hong J, Gu W, Lin A, Lian L, Huang H, Lu J, Li T. Salvianolic acid B inhibits the progression of liver fibrosis in rats via modulation of the Hedgehog signaling pathway. Exp Ther Med 2022; 23:116. [PMID: 34970339 PMCID: PMC8713182 DOI: 10.3892/etm.2021.11039] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2021] [Accepted: 11/16/2021] [Indexed: 11/09/2022] Open
Abstract
Salvianolic acid B (Sal B) has previously reported anti-hepatic fibrosis effects, though it is not clear if it can inhibit hepatic fibrosis by regulating the hedgehog (Hh) signaling pathway. The aim of the present study was to explore the roles and mechanism of Sal B in preventing and treating liver fibrosis in rats. The study also aimed to determine the role of the Hh signaling pathway in this process. A rat model of liver fibrosis was induced through the subcutaneous injection of 50% carbon tetrachloride, followed by treatment with Sal B. After gavage, blood was collected to detect serum markers of liver injury. The degree of liver fibrosis and tissue damage was assessed using histopathological analysis. Western blotting and reverse transcription-quantitative PCR were used to detect the expression levels of TGF-β1 and Hh signaling pathway-related genes, including Sonic hedgehog (Shh) protein, membrane protein receptor protein patched homolog 1 (Ptch1), membrane protein receptor Smoothened (Smo) and transcription factor glioma-associated oncogene homolog 1 (Gli1). Serum alanine aminotransferase, aspartate aminotransferase and total bilirubin levels were decreased, whilst levels of albumin were increased in rats with liver fibrosis that were treated with Sal B (P<0.05). Additionally, significant increases in TGF-β1, Shh, Ptch1, Smo, Gli1 and α-smooth muscle actin expression levels were observed in the liver tissues of rats with hepatic fibrosis (P<0.05). However, Sal B treatment significantly reduced the expression levels of these proteins (P<0.05). In conclusion, the results of the present study suggested that the Hh signaling pathway may be activated during the process of rat liver fibrosis. Thus, Sal B may exert its anti-hepatic fibrosis effects, at least in part, by inhibiting the activation of the Hh signaling pathway.
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Affiliation(s)
- Shanjun Tao
- Department of Medical Biology, School of Preclinical Medicine, Wannan Medical College, Wuhu, Anhui 241000, P.R. China.,Department of Clinical Biochemistry, School of Laboratory Medicine, Wannan Medical College, Wuhu, Anhui 241000, P.R. China
| | - Renjie Duan
- Department of Medical Biology, School of Preclinical Medicine, Wannan Medical College, Wuhu, Anhui 241000, P.R. China
| | - Tong Xu
- Department of Medical Biology, School of Preclinical Medicine, Wannan Medical College, Wuhu, Anhui 241000, P.R. China
| | - Jiao Hong
- Department of Medical Biology, School of Preclinical Medicine, Wannan Medical College, Wuhu, Anhui 241000, P.R. China
| | - Wenjie Gu
- Department of Medical Biology, School of Preclinical Medicine, Wannan Medical College, Wuhu, Anhui 241000, P.R. China
| | - Aiqin Lin
- Department of Medical Biology, School of Preclinical Medicine, Wannan Medical College, Wuhu, Anhui 241000, P.R. China
| | - Likai Lian
- Department of Medical Biology, School of Preclinical Medicine, Wannan Medical College, Wuhu, Anhui 241000, P.R. China
| | - Haoyu Huang
- Department of Clinical Biochemistry, School of Laboratory Medicine, Wannan Medical College, Wuhu, Anhui 241000, P.R. China
| | - Jiangtao Lu
- Department of Clinical Biochemistry, School of Laboratory Medicine, Wannan Medical College, Wuhu, Anhui 241000, P.R. China
| | - Tiechen Li
- Department of Medical Biology, School of Preclinical Medicine, Wannan Medical College, Wuhu, Anhui 241000, P.R. China
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21
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Ghufran H, Azam M, Mehmood A, Butt H, Riazuddin S. Standardization of diethylnitrosamine-induced hepatocellular carcinoma rat model with time based molecular assessment. Exp Mol Pathol 2021; 123:104715. [PMID: 34699901 DOI: 10.1016/j.yexmp.2021.104715] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2020] [Revised: 10/16/2021] [Accepted: 10/20/2021] [Indexed: 02/06/2023]
Abstract
This study was intended (1) to develop a robust animal model for hepatocellular carcinoma (HCC) research, in which HCC tumors develop in a background of fibrosis or cirrhosis; and (2) to explore time-dependent regulatory changes in key molecular markers during disease advancement and HCC development. With the aim of establishing such HCC model, male Sprague-Dawley rats were injected with diethylnitrosamine (DEN) at a dose of 30 mg/kg twice a week for 10 weeks then once a week from 12th to 16th weeks. The rats were kept under observation until 18th week. At defined time intervals (2nd, 4th, 12th, and 18th week), serum biomarkers and microscopic components of tissue samples were used to investigate the chronic progression of liver disease, while gene and protein analysis was used to monitor expression patterns during HCC development. DEN-intoxicated rats manifested inflammation at week 4, fibrosis at week 12 and cirrhosis with early HCC tumors at week 18. Molecular analysis revealed that key markers of inflammation (Il-1β, Il-6, and Tnf-α), fibrosis (Tgf-β1, Col1α1, Col3α1, and Timp-1), and angiogenesis (Hif1-α and Vegf) were promptly (P ≤ 0.001) up-regulated at week 4, week 12 and week 18, respectively. Oxidative stress (iNos, Cyp2e1, and Sod1) and pro-apoptotic (Bax) markers showed significant upregulation from week 4 to week 12. However, Sod1 and Bax expressions dropped after week 12 and reached a minimum at 18th week. Strikingly, expressions of anti-apoptotic (Bcl-2) and cell proliferation (Pcna, Hgf, and Afp) markers were abruptly increased at week 18. Collectively, we describe an 18-week HCC model in DEN-intoxicated rats that exhibit chronic inflammation, oxidative imbalance, advance fibrosis/cirrhosis, halted apoptosis, and angiogenic sprouting, progressively.
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Affiliation(s)
- Hafiz Ghufran
- National Centre of Excellence in Molecular Biology, 87-West Canal Bank Road, University of the Punjab, Lahore, Pakistan
| | - Maryam Azam
- National Centre of Excellence in Molecular Biology, 87-West Canal Bank Road, University of the Punjab, Lahore, Pakistan
| | - Azra Mehmood
- National Centre of Excellence in Molecular Biology, 87-West Canal Bank Road, University of the Punjab, Lahore, Pakistan
| | - Hira Butt
- National Centre of Excellence in Molecular Biology, 87-West Canal Bank Road, University of the Punjab, Lahore, Pakistan
| | - Sheikh Riazuddin
- National Centre of Excellence in Molecular Biology, 87-West Canal Bank Road, University of the Punjab, Lahore, Pakistan; Allama Iqbal Medical Research Centre, Jinnah Burn and Reconstructive Surgery Centre, Lahore, Pakistan.
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22
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Wu M, Miao H, Fu R, Zhang J, Zheng W. Hepatic Stellate Cell: A Potential Target for Hepatocellular Carcinoma. Curr Mol Pharmacol 2021; 13:261-272. [PMID: 32091349 DOI: 10.2174/1874467213666200224102820] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/23/2019] [Revised: 01/11/2020] [Accepted: 01/16/2020] [Indexed: 12/24/2022]
Abstract
Liver cancer is a leading cause of cancer-related death worldwide, in which hepatocellular carcinoma (HCC) accounts for the majority. Despite the progression in treatment, the prognosis remains extremely poor for HCC patients. The mechanisms of hepatocarcinogenesis are complex, of which fibrosis is acknowledged as the pre-cancerous stage of HCC. Approximately, 80-90% of HCC develops in the fibrotic or cirrhotic livers. Hepatic stellate cells (HSCs), the main effector cells of liver fibrosis, could secret various biological contents to maintain the liver inflammation. By decades, HSCs are increasingly correlated with HCC in the tumor microenvironment. In this review, we summarized the underlying mechanisms that HSCs participated in the genesis and progression of HCC. HSCs secrete various bioactive contents and regulate tumor-related pathways, subsequently contribute to metastasis, angiogenesis, immunosuppression, chemoresistance and cancer stemness. The study indicates that HSC plays vital roles in HCC progression, suggesting it as a promising therapeutic target for HCC treatment.
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Affiliation(s)
- Mengna Wu
- Research Center of Clinical Medicine, Affiliated Hospital of Nantong University, 20 Xisi Road, 226001 Nantong, Jiangsu, China
| | - Huajie Miao
- Research Center of Clinical Medicine, Affiliated Hospital of Nantong University, 20 Xisi Road, 226001 Nantong, Jiangsu, China
| | - Rong Fu
- Department of Pathology, Affiliated Haian Hospital of Nantong University, 17 Zhongba Road, 226600, Haian, Jiangsu, China
| | - Jie Zhang
- Department of Chemotherapy, Affiliated Hospital of Nantong University, 20 Xisi Road, 226001 Nantong, Jiangsu, China
| | - Wenjie Zheng
- Research Center of Clinical Medicine, Affiliated Hospital of Nantong University, 20 Xisi Road, 226001 Nantong, Jiangsu, China
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23
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Abstract
Early diagnosis of hepatic fibrosis (HF) is pivotal for management to cease progression to cirrhosis and hepatocellular carcinoma. HF is the telltale sign of chronic liver disease, and confirmed by liver biopsy, which is an invasive technique and inclined to sampling errors. The morphologic parameters of cirrhosis are assessed on conventional imaging such as on ultrasound (US), computed tomography (CT) and magnetic resonance imaging (MRI). Newer imaging modalities such as magnetic resonance elastography and US elastography are reliable and accurate. More research studies on novel imaging modalities such as MRI with diffusion weighted imaging, enhancement by hepatobiliary contrast agents, and CT using perfusion are essential for earlier diagnosis, surveillance and accurate management. The purpose of this article is to discuss non-invasive CT, MRI, and US imaging modalities for diagnosis and stratify HF.
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Affiliation(s)
- Mayur Virarkar
- Department of Neuroradiology, The University of Texas Health Science Center, Houston, TX.
| | - Ajaykumar C Morani
- Department of Abdominal Radiology, The University of Texas MD Anderson Cancer Center, Houston, TX
| | - Melissa W Taggart
- Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX
| | - Priya Bhosale
- Department of Abdominal Radiology, The University of Texas MD Anderson Cancer Center, Houston, TX
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24
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Wegrzyniak O, Rosestedt M, Eriksson O. Recent Progress in the Molecular Imaging of Nonalcoholic Fatty Liver Disease. Int J Mol Sci 2021; 22:7348. [PMID: 34298967 PMCID: PMC8306605 DOI: 10.3390/ijms22147348] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2021] [Revised: 06/30/2021] [Accepted: 07/06/2021] [Indexed: 12/12/2022] Open
Abstract
Pathological fibrosis of the liver is a landmark feature in chronic liver diseases, including nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH). Diagnosis and assessment of progress or treatment efficacy today requires biopsy of the liver, which is a challenge in, e.g., longitudinal interventional studies. Molecular imaging techniques such as positron emission tomography (PET) have the potential to enable minimally invasive assessment of liver fibrosis. This review will summarize and discuss the current status of the development of innovative imaging markers for processes relevant for fibrogenesis in liver, e.g., certain immune cells, activated fibroblasts, and collagen depositions.
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Affiliation(s)
- Olivia Wegrzyniak
- Science for Life Laboratory, Department of Medicinal Chemistry, Uppsala University, SE-751 83 Uppsala, Sweden; (O.W.); (M.R.)
| | - Maria Rosestedt
- Science for Life Laboratory, Department of Medicinal Chemistry, Uppsala University, SE-751 83 Uppsala, Sweden; (O.W.); (M.R.)
| | - Olof Eriksson
- Science for Life Laboratory, Department of Medicinal Chemistry, Uppsala University, SE-751 83 Uppsala, Sweden; (O.W.); (M.R.)
- Antaros Medical AB, SE-431 83 Mölndal, Sweden
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25
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Dai X, Zeng Y, Zhang H, Gu Z, Gong Q, Luo K. Advances on Nanomedicines for Diagnosis and Theranostics of Hepatic Fibrosis. ADVANCED NANOBIOMED RESEARCH 2021. [DOI: 10.1002/anbr.202000091] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/05/2023] Open
Affiliation(s)
- Xinghang Dai
- Huaxi MR Research Center (HMRRC) Department of Radiology Functional and molecular imaging Key Laboratory of Sichuan Province West China Hospital Sichuan University Chengdu 610041 China
- West China School of Medicine Sichuan University Chengdu 610041 China
| | - Yujun Zeng
- Huaxi MR Research Center (HMRRC) Department of Radiology Functional and molecular imaging Key Laboratory of Sichuan Province West China Hospital Sichuan University Chengdu 610041 China
| | - Hu Zhang
- Huaxi MR Research Center (HMRRC) Department of Radiology Functional and molecular imaging Key Laboratory of Sichuan Province West China Hospital Sichuan University Chengdu 610041 China
- Amgen Bioprocessing Centre Keck Graduate Institute CA 91711 USA
| | - Zhongwei Gu
- Research Unit of Psychoradiology Chinese Academy of Medical Sciences Chengdu 610041 China
| | - Qiyong Gong
- Huaxi MR Research Center (HMRRC) Department of Radiology Functional and molecular imaging Key Laboratory of Sichuan Province West China Hospital Sichuan University Chengdu 610041 China
- Research Unit of Psychoradiology Chinese Academy of Medical Sciences Chengdu 610041 China
| | - Kui Luo
- Huaxi MR Research Center (HMRRC) Department of Radiology Functional and molecular imaging Key Laboratory of Sichuan Province West China Hospital Sichuan University Chengdu 610041 China
- Research Unit of Psychoradiology Chinese Academy of Medical Sciences Chengdu 610041 China
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26
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Eftekhari A, Arjmand A, Asheghvatan A, Švajdlenková H, Šauša O, Abiyev H, Ahmadian E, Smutok O, Khalilov R, Kavetskyy T, Cucchiarini M. The Potential Application of Magnetic Nanoparticles for Liver Fibrosis Theranostics. Front Chem 2021; 9:674786. [PMID: 34055744 PMCID: PMC8161198 DOI: 10.3389/fchem.2021.674786] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2021] [Accepted: 05/03/2021] [Indexed: 12/11/2022] Open
Abstract
Liver fibrosis is a major cause of morbidity and mortality worldwide due to chronic liver damage and leading to cirrhosis, liver cancer, and liver failure. To date, there is no effective and specific therapy for patients with hepatic fibrosis. As a result of their various advantages such as biocompatibility, imaging contrast ability, improved tissue penetration, and superparamagnetic properties, magnetic nanoparticles have a great potential for diagnosis and therapy in various liver diseases including fibrosis. In this review, we focus on the molecular mechanisms and important factors for hepatic fibrosis and on potential magnetic nanoparticles-based therapeutics. New strategies for the diagnosis of liver fibrosis are also discussed, with a summary of the challenges and perspectives in the translational application of magnetic nanoparticles from bench to bedside.
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Affiliation(s)
- Aziz Eftekhari
- Maragheh University of Medical Sciences, Maragheh, Iran
- Polymer Institute, Slovak Academy of Sciences, Bratislava, Slovakia
- Russian Institute for Advanced Study, Moscow State Pedagogical University, Moscow, Russian Federation
- Department of Surface Engineering, The John Paul II Catholic University of Lublin, Lublin, Poland
| | | | | | | | - Ondrej Šauša
- Institute of Physics, Slovak Academy of Sciences, Bratislava, Slovakia
- Department of Nuclear Chemistry, Faculty of Natural Sciences, Comenius University in Bratislava, Bratislava, Slovakia
| | - Huseyn Abiyev
- Department of Biochemistry, Azerbaijan Medical University, Baku, Azerbaijan
| | - Elham Ahmadian
- Kidney Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Oleh Smutok
- Department of Chemistry and Biomolecular Science, Clarkson University, Potsdam, NY, United States
- Institute of Cell Biology, National Academy of Sciences of Ukraine, Lviv, Ukraine
| | - Rovshan Khalilov
- Russian Institute for Advanced Study, Moscow State Pedagogical University, Moscow, Russian Federation
- Department of Biophysics and Biochemistry, Baku State University, Baku, Azerbaijan
- Institute of Radiation Problems, National Academy of Sciences of Azerbaijan, Baku, Azerbaijan
| | - Taras Kavetskyy
- Department of Surface Engineering, The John Paul II Catholic University of Lublin, Lublin, Poland
- Institute of Physics, Slovak Academy of Sciences, Bratislava, Slovakia
- Department of Biology and Chemistry, Drohobych Ivan Franko State Pedagogical University, Drohobych, Ukraine
| | - Magali Cucchiarini
- Center of Experimental Orthopaedics, Saarland University Medical Center, Homburg, Germany
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27
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Zhu Y, Zhang C, Huang M, Lin J, Fan X, Ni T. TRIM26 Induces Ferroptosis to Inhibit Hepatic Stellate Cell Activation and Mitigate Liver Fibrosis Through Mediating SLC7A11 Ubiquitination. Front Cell Dev Biol 2021; 9:644901. [PMID: 33869196 PMCID: PMC8044755 DOI: 10.3389/fcell.2021.644901] [Citation(s) in RCA: 48] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2020] [Accepted: 02/16/2021] [Indexed: 12/12/2022] Open
Abstract
Hepatic stellate cells (HSCs) are activated by inflammatory mediators to secrete extracellular matrix for collagen deposition, leading to liver fibrosis. Ferroptosis is iron- and lipid hydroperoxide-dependent programmed cell death, which has recently been targeted for inhibiting liver fibrogenic processes. Tripartite motif-containing protein 26 (TRIM26) is an E3 ubiquitin ligase that functions as a tumor suppressor in hepatocellular carcinoma, while little is known about its function in liver fibrosis. In the present study, the differential expression of TRIM26 in normal and fibrotic liver tissues was examined based on both online databases and specimens collected from patient cohort. The effects of TRIM26 on HSCs ferroptosis were examined in vitro through evaluating cell proliferation, lipid peroxidation, and expression of key ferroptosis-related factors. In vivo function of TRIM26 in liver fibrosis was examined based on CCl4-induced mice model. We found that TRIM26 was downregulated in fibrotic liver tissues. The overexpression of TRIM26 inhibited HSCs proliferation, promoted lipid peroxidation, manipulated ferroptosis-related factor expressions, and counteracted the effect of iron inhibitor deferoxamine. Moreover, TRIM26 physically interacted with solute carrier family-7 member-11 (SLC7A11), a critical protein for lipid reactive oxygen species (ROS) scavenging, and mediated its ubiquitination. In addition, TRIM26 overexpression induced HSCs ferroptosis and mitigated CCl4-induced liver fibrosis in mice. In conclusion, TRIM26 promotes HSCs ferroptosis to suppress liver fibrosis through mediating the ubiquitination of SLC7A11. The TRIM26-targeted SLC7A11 suppression can be a novel therapeutic strategy for liver fibrosis.
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Affiliation(s)
- Yiming Zhu
- Department of General Surgery, Shanghai Ninth People's Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Chihao Zhang
- Department of General Surgery, Shanghai Ninth People's Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Mingzhe Huang
- Department of General Surgery, Shanghai Ninth People's Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Jiayun Lin
- Department of General Surgery, Shanghai Ninth People's Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Xiao Fan
- Department of General Surgery, Shanghai Ninth People's Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Tao Ni
- Department of Plastic and Reconstructive Surgery, Shanghai Ninth People's Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
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28
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He C, Shu B, Zhou Y, Zhang R, Yang X. The miR-139-5p/peripheral myelin protein 22 axis modulates TGF-β-induced hepatic stellate cell activation and CCl 4-induced hepatic fibrosis in mice. Life Sci 2021; 276:119294. [PMID: 33675896 DOI: 10.1016/j.lfs.2021.119294] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2020] [Revised: 02/19/2021] [Accepted: 02/20/2021] [Indexed: 12/12/2022]
Abstract
Hepatic stellate cells (HSCs) are the major source of extracellular matrix (ECM)-producing myofibroblasts. When activated by multiple injuries, HSCs become proliferative, contractile, inflammatory and chemotactic and are characterized by enhanced ECM production, which plays a central role in hepatic fibrosis initiation and progression. In the present study, through bioinformatics analysis, we identified the abnormal upregulation of Peripheral Myelin Protein 22 (PMP22) in fibrotic murine liver. In CCl4-induced hepatic fibrosis model in mice and TGF-β-activated hHSCs, PMP22 was observed remarkably upregulated. In TGF-β-stimulated hHSCs, PMP22 silencing hindered, whereas PMP22 overexpression aggravated TGF-β-induced hHSC activation. In CCl4-induced hepatic fibrosis model in mice, PMP22 silencing improved CCl4-caused liver damage and fibrotic changes. Through online tools prediction and experimental validation, miR-139-5p was found to bind to the 3'UTR of PMP22 and negatively regulate the expression of PMP22. In contrast to PMP22 silencing, miR-139-5p inhibition enhanced TGF-β-induced hHSC activation; the effects of miR-139-5p inhibition on TGF-β-induced hHSC activation were partially reversed by PMP22 silencing. In conclusion, we identify the abnormal upregulation of PMP22 in TGF-β-activated HSCs and CCl4-induced hepatic fibrosis model in mice, as well as the pro-fibrotic role of PMP22 through aggravating TGF-β-induced HSCs activation. miR-139-5p targets the 3'UTR of PMP22 and inhibits PMP22 expression; miR-139-5p hinders TGF-β-induced HSCs activation through targeting PMP22.
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Affiliation(s)
- Chao He
- Department of General Surgery, The Second Xiangya Hospital, Central South University, Changsha, Hunan 410011, China
| | - Bo Shu
- Department of General Surgery, The Second Xiangya Hospital, Central South University, Changsha, Hunan 410011, China
| | - Yingxia Zhou
- Department of Surgical Operation, The Second Xiangya Hospital, Central South University, Changsha, Hunan 410011, China
| | - Ruizhi Zhang
- Department of General Surgery, The Second Xiangya Hospital, Central South University, Changsha, Hunan 410011, China
| | - Xin Yang
- Department of General Surgery, The Second Xiangya Hospital, Central South University, Changsha, Hunan 410011, China.
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29
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Adhikari A, Singh P, Mahar KS, Adhikari M, Adhikari B, Zhang MR, Tiwari AK. Mapping of Translocator Protein (18 kDa) in Peripheral Sterile Inflammatory Disease and Cancer through PET Imaging. Mol Pharm 2021; 18:1507-1529. [PMID: 33645995 DOI: 10.1021/acs.molpharmaceut.1c00002] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2022]
Abstract
Positron emission tomography (PET) imaging of the translocator 18 kDa protein (TSPO) with radioligands has become an effective means of research in peripheral inflammatory conditions that occur in many diseases and cancers. The peripheral sterile inflammatory diseases (PSIDs) are associated with a diverse group of disorders that comprises numerous enduring insults including the cardiovascular, respiratory, gastrointestinal, or musculoskeletal system. TSPO has recently been introduced as a potential biomarker for peripheral sterile inflammatory diseases (PSIDs). The major critical issue related to PSIDs is its timely characterization and localization of inflammatory foci for proper therapy of patients. As an alternative to metabolic imaging, protein imaging expressed on immune cells after activation is of great importance. The five transmembrane domain translocator protein-18 kDa (TSPO) is upregulated on the mitochondrial cell surface of macrophages during inflammation, serving as a potential ligand for PET tracers. Additionally, the overexpressed TSPO protein has been positively correlated with various tumor malignancies. In view of the association of escalated TSPO expression in both disease conditions, it is an immensely important biomarker for PET imaging in oncology and PSIDs. In this review, we summarize the most outstanding advances on TSPO-targeted PSIDs and cancer in the development of TSPO ligands as a potential diagnostic tool, specifically discussing the last five years.
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Affiliation(s)
- Anupriya Adhikari
- Department of Chemistry, Babasaheb Bhimrao Ambedkar University, (A Central University), Lucknow, Uttar Pradesh 226025, India
| | - Priya Singh
- Department of Chemistry, Babasaheb Bhimrao Ambedkar University, A Central University, Lucknow, Uttar Pradesh 226025, India
| | - Kamalesh S Mahar
- Birbal Sahni Institute of Palaeosciences, Lucknow, Uttar Pradesh 226007, India
| | - Manish Adhikari
- The George Washington University, Washington, D.C. 20052, United States
| | - Bhawana Adhikari
- Plasma Bio-science Research Center, Kwangwoon University, Seoul 01897, South Korea
| | - Ming-Rong Zhang
- Department of Advanced Nuclear Medicine Sciences, National Institute of Radiological Sciences, National Institutes for Quantum and Radiological Science and Technology, Chiba 263-8555, Japan
| | - Anjani Kumar Tiwari
- Department of Chemistry, Babasaheb Bhimrao Ambedkar University, (A Central University), Lucknow, Uttar Pradesh 226025, India
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30
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Zhang Y, Li Y, Mu T, Tong N, Cheng P. Hepatic stellate cells specific liposomes with the Toll-like receptor 4 shRNA attenuates liver fibrosis. J Cell Mol Med 2021; 25:1299-1313. [PMID: 33336563 PMCID: PMC7812270 DOI: 10.1111/jcmm.16209] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2020] [Revised: 11/04/2020] [Accepted: 12/04/2020] [Indexed: 02/05/2023] Open
Abstract
The hepatic stellate cells (HSCs) play a significant role in the onset of liver fibrosis, which can be treated by the inhibition and reversal of HSC activation. The RNA interference-mediated TLR4 gene silencing might be a potential therapeutic approach for liver fibrosis. The crucial challenge in this method is the absence of an efficient delivery system for the RNAi introduction in the target cells. HSCs have an enhanced capacity of vitamin A intake as they contain retinoic acid receptors (RARs). In the current study, we developed cationic liposomes modified with vitamin A to improve the specificity of delivery vehicles for HSCs. The outcome of this study revealed that the VitA-coupled cationic liposomes delivered the TLR4 shRNA to aHSCs more efficiently, as compared to the uncoupled cationic liposomes, both in the in vitro and in vivo conditions. Besides, as evident from the outcome of this study, the TLR4 gene silencing inhibited the HSCs activation and attenuated the liver fibrosis via the NF-κB transcriptional inactivation, pro-inflammatory cytokines secretion and reactive oxygen species (ROS) synthesis. Thus, the VitA-coupled liposomes encapsulated with the TLR4-shRNA might prove as an efficient therapeutic agent for liver fibrosis.
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Affiliation(s)
- Yuwei Zhang
- Division of Endocrinology and MetabolismState Key Laboratory of BiotherapyWest China HospitalSichuan University, and Collaborative Innovation Center for BiotherapyChengduChina
| | - Yang Li
- Division of Endocrinology and MetabolismState Key Laboratory of BiotherapyWest China HospitalSichuan University, and Collaborative Innovation Center for BiotherapyChengduChina
| | - Tong Mu
- Division of Endocrinology and MetabolismState Key Laboratory of BiotherapyWest China HospitalSichuan University, and Collaborative Innovation Center for BiotherapyChengduChina
| | - Nanwei Tong
- Division of Endocrinology and MetabolismState Key Laboratory of BiotherapyWest China HospitalSichuan University, and Collaborative Innovation Center for BiotherapyChengduChina
| | - Ping Cheng
- State Key Laboratory of Biotherapy and Cancer CenterWest China HospitalSichuan University, and Collaborative Innovation Center for BiotherapyChengduChina
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Peroxisome proliferator-activated receptors in the pathogenesis and therapies of liver fibrosis. Pharmacol Ther 2020; 222:107791. [PMID: 33321113 DOI: 10.1016/j.pharmthera.2020.107791] [Citation(s) in RCA: 45] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2020] [Accepted: 12/04/2020] [Indexed: 12/12/2022]
Abstract
Liver fibrosis is a dynamic wound-healing process associated with the deposition of extracellular matrix produced by myofibroblasts. HSCs activation, inflammation, oxidative stress, steatosis and aging play critical roles in the progression of liver fibrosis, which is correlated with the regulation of the peroxisome proliferator-activated receptor (PPAR) pathway. As nuclear receptors, PPARs reduce inflammatory response, regulate lipid metabolism, and inhibit fibrogenesis in the liver associated with aging. Thus, PPAR ligands have been investigated as possible therapeutic agents. Mounting evidence indicated that some PPAR agonists could reverse steatohepatitis and liver fibrosis. Consequently, targeting PPARs might be a promising and novel therapeutic option against liver fibrosis. This review summarizes recent studies on the role of PPARs on the pathogenesis and treatment of liver fibrosis.
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Yin F, Wang WY, Mao LC, Cai QQ, Jiang WH. Effect of Human Umbilical Cord Mesenchymal Stem Cells Transfected with HGF on TGF-β1/Smad Signaling Pathway in Carbon Tetrachloride-Induced Liver Fibrosis Rats. Stem Cells Dev 2020; 29:1395-1406. [DOI: 10.1089/scd.2020.0060] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Affiliation(s)
- Fei Yin
- Department of Histology and Embryology, Basic Medical College of Jilin University, Changchun, China
| | - Wen-Ying Wang
- Department of Histology and Embryology, Basic Medical College of Jilin University, Changchun, China
| | - Li-Cui Mao
- Department of Histology and Embryology, Basic Medical College of Jilin University, Changchun, China
| | - Qi-Qi Cai
- Department of Histology and Embryology, Basic Medical College of Jilin University, Changchun, China
| | - Wen-Hua Jiang
- Department of Histology and Embryology, Basic Medical College of Jilin University, Changchun, China
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Hiroyama S, Rokugawa T, Ito M, Iimori H, Morita I, Maeda H, Fujisawa K, Matsunaga K, Shimosegawa E, Abe K. Quantitative evaluation of hepatic integrin α vβ 3 expression by positron emission tomography imaging using 18F-FPP-RGD 2 in rats with non-alcoholic steatohepatitis. EJNMMI Res 2020; 10:118. [PMID: 33026561 PMCID: PMC7541810 DOI: 10.1186/s13550-020-00704-3] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2020] [Accepted: 09/17/2020] [Indexed: 12/12/2022] Open
Abstract
Background Integrin αvβ3, which are expressed by activated hepatic stellate cells in non-alcoholic steatohepatitis (NASH), play an important role in the fibrosis. Recently, we reported that an RGD peptide positron emission tomography (PET) probe is useful as a predictor of hepatic fibrosis. Kinetic analysis of the RGD PET probe has been performed in tumours, but not in hepatic fibrosis. Therefore, we aimed to quantify hepatic integrin αvβ3 in a model of NASH by kinetic analysis using 18F-FPP-RGD2, an integrin αvβ3 PET probe. Methods 18F-FPP-RGD2 PET/CT scans were performed in control and NASH rats. Tissue kinetic analyses were performed using a one-tissue, two-compartment (1T2C) and a two-tissue, three-compartment (2T3C) model using an image-derived input function (IDIF) for the left ventricle. We then conducted correlation analysis between standard uptake values (SUVs) or volume of distribution (VT), evaluated using compartment kinetic analysis and integrin αv or β3 protein expression. Results Biochemical and histological evaluation confirmed the development of NASH rats. Integrin αvβ3 protein expression and hepatic SUV were higher in NASH- than normal rats. The hepatic activity of 18F-FPP-RGD2 peaked rapidly after administration and then gradually decreased, whereas left ventricular activity rapidly disappeared. The 2T3C model was found to be preferable for 18F-FPP-RGD2 kinetic analysis in the liver. The VT (IDIF) for 18F-FPP-RGD2, calculated using the 2T3C model, was significantly higher in NASH- than normal rats and correlated strongly with hepatic integrin αv and β3 protein expression. The strengths of these correlations were similar to those between SUV60–90 min and hepatic integrin αv or β3 protein expression. Conclusions We have demonstrated that the VT (IDIF) of 18F-FPP-RGD2, calculated using kinetic modelling, positively correlates with integrin αv and β3 protein in the liver of NASH rats. These findings suggest that hepatic VT (IDIF) provides a quantitative assessment of integrin αvβ3 protein in liver.
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Affiliation(s)
- Shuichi Hiroyama
- Translational Research Unit, Biomarker R&D Department, Shionogi & Co., Ltd., 3-1-1 Futaba-cho, Toyonaka, Osaka, 561-0825, Japan.
| | - Takemi Rokugawa
- Translational Research Unit, Biomarker R&D Department, Shionogi & Co., Ltd., 3-1-1 Futaba-cho, Toyonaka, Osaka, 561-0825, Japan
| | - Miwa Ito
- Translational Research Unit, Biomarker R&D Department, Shionogi & Co., Ltd., 3-1-1 Futaba-cho, Toyonaka, Osaka, 561-0825, Japan
| | - Hitoshi Iimori
- Research Laboratory for Development, Shionogi & Co., Ltd., 3-1-1 Futaba-cho, Toyonaka, Osaka, 561-0825, Japan
| | - Ippei Morita
- Laboratory for Advanced Medicine Research, Shionogi & Co., Ltd., 3-1-1 Futaba-cho, Toyonaka, Osaka, 561-0825, Japan
| | - Hiroki Maeda
- Laboratory for Innovative Therapy Research, Shionogi & Co., Ltd., 3-1-1 Futaba-cho, Toyonaka, Osaka, 561-0825, Japan
| | - Kae Fujisawa
- Research Laboratory for Development, Shionogi & Co., Ltd., 3-1-1 Futaba-cho, Toyonaka, Osaka, 561-0825, Japan
| | - Keiko Matsunaga
- Department of Molecular Imaging in Medicine, Graduate School of Medicine, Osaka University, 2-2 Yamadaoka, Suita, Osaka, 565-0871, Japan
| | - Eku Shimosegawa
- Department of Molecular Imaging in Medicine, Graduate School of Medicine, Osaka University, 2-2 Yamadaoka, Suita, Osaka, 565-0871, Japan
| | - Kohji Abe
- Translational Research Unit, Biomarker R&D Department, Shionogi & Co., Ltd., 3-1-1 Futaba-cho, Toyonaka, Osaka, 561-0825, Japan
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Azzam M, El Safy S, Abdelgelil SA, Weiskirchen R, Asimakopoulou A, de Lorenzi F, Lammers T, Mansour S, Tammam S. Targeting Activated Hepatic Stellate Cells Using Collagen-Binding Chitosan Nanoparticles for siRNA Delivery to Fibrotic Livers. Pharmaceutics 2020; 12:E590. [PMID: 32630415 PMCID: PMC7356502 DOI: 10.3390/pharmaceutics12060590] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2020] [Revised: 05/26/2020] [Accepted: 06/04/2020] [Indexed: 12/13/2022] Open
Abstract
Activated hepatic stellate cells (aHSCs) are the main orchestrators of the fibrotic cascade in inflamed livers, with transforming growth factor-beta (TGF-β) being the most potent pro-fibrotic cytokine. Hence, aHSCs serve as interesting therapeutic targets. However, drug delivery to aHSCs is hindered by excessive collagen deposition in the extracellular matrix (ECM) and capillarization of liver sinusoids. Chitosan-nanoparticles (CS-NPs) show intrinsic affinity for collagen, holding potential for drug delivery to fibrotic livers. Here, we employed CS-NPs for anti-TGF-β siRNA delivery, promoting delivery into aHSCs via modification with platelet-derived growth factor receptor-beta binding peptides. In-vitro experiments using aHSCs demonstrated the association of unmodified CS-NPs to the collagen-rich ECM, with reduced intracellular accumulation. Peptide-modified CS-NPs showed a higher propensity to localize intracellularly; however, this was only the case upon ECM-collagen reduction via collagenase treatment. Peptide-modified CS-NPs were more potent than unmodified CS-NPs in reducing TGF-β expression, implying that while collagen binding promotes liver accumulation, it hinders cell-specific siRNA delivery. In-vivo, CS-NPs successfully accumulated in fibrotic livers via collagen binding. Similar to in-vitro findings, when mice were pretreated with collagenase-loaded CS-NPs, the accumulation of peptide-modified NPs increased. Our findings demonstrate the usefulness of NPs modification with targeting ligands and collagenase treatment for aHSCs targeting and highlight the importance of chitosan-collagen binding in drug delivery to fibrotic diseases.
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Affiliation(s)
- Menna Azzam
- Department of Pharmaceutical Technology, Faculty of Pharmacy & Biotechnology, The German University in Cairo (GUC), 11835 Cairo, Egypt; (M.A.); (S.E.S.); (S.A.A.); (S.M.)
| | - Sara El Safy
- Department of Pharmaceutical Technology, Faculty of Pharmacy & Biotechnology, The German University in Cairo (GUC), 11835 Cairo, Egypt; (M.A.); (S.E.S.); (S.A.A.); (S.M.)
| | - Sarah A. Abdelgelil
- Department of Pharmaceutical Technology, Faculty of Pharmacy & Biotechnology, The German University in Cairo (GUC), 11835 Cairo, Egypt; (M.A.); (S.E.S.); (S.A.A.); (S.M.)
| | - Ralf Weiskirchen
- Institute of Molecular Pathobiochemistry, Experimental Gene Therapy and Clinical Chemistry (IFMPEGKC), RWTH University Hospital, D-52074 Aachen, Germany; (R.W.); (A.A.)
| | - Anastasia Asimakopoulou
- Institute of Molecular Pathobiochemistry, Experimental Gene Therapy and Clinical Chemistry (IFMPEGKC), RWTH University Hospital, D-52074 Aachen, Germany; (R.W.); (A.A.)
| | - Federica de Lorenzi
- Department of Nanomedicine and Theranostics, Institute for Experimental Molecular Imaging, RWTH Aachen University Clinic, D-52074 Aachen, Germany; (F.d.L.); (T.L.)
| | - Twan Lammers
- Department of Nanomedicine and Theranostics, Institute for Experimental Molecular Imaging, RWTH Aachen University Clinic, D-52074 Aachen, Germany; (F.d.L.); (T.L.)
| | - Samar Mansour
- Department of Pharmaceutical Technology, Faculty of Pharmacy & Biotechnology, The German University in Cairo (GUC), 11835 Cairo, Egypt; (M.A.); (S.E.S.); (S.A.A.); (S.M.)
| | - Salma Tammam
- Department of Pharmaceutical Technology, Faculty of Pharmacy & Biotechnology, The German University in Cairo (GUC), 11835 Cairo, Egypt; (M.A.); (S.E.S.); (S.A.A.); (S.M.)
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Shao T, Josephson L, Liang SH. PET/SPECT Molecular Probes for the Diagnosis and Staging of Nonalcoholic Fatty Liver Disease. Mol Imaging 2020; 18:1536012119871455. [PMID: 31478458 PMCID: PMC6724487 DOI: 10.1177/1536012119871455] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022] Open
Abstract
Nonalcoholic fatty liver disease (NAFLD) is a significant public health challenge afflicting approximately 1 billion individuals both in the Western world and in the East world. While liver biopsy is considered as gold standard in the diagnosis and staging of liver fibrosis, noninvasive imaging technologies, including ultrasonography, computed tomography, single-photon emission computed tomography (SPECT), magnetic resonance imaging, and positron emission tomography (PET) could offer more sensitive, comprehensive, and quantitative measurement for NAFLD. In this review, we focus on recent development and applications of PET/SPECT molecular probes that enable multispatial/temporal visualization and quantification of physiopathological progress at the molecular level in the NAFLD. We shall also discuss the limitations of current radioligands and future direction for PET/SPECT probe development.
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Affiliation(s)
- Tuo Shao
- 1 Division of Nuclear Medicine and Molecular Imaging, Department of Radiology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA
| | - Lee Josephson
- 1 Division of Nuclear Medicine and Molecular Imaging, Department of Radiology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA
| | - Steven H Liang
- 1 Division of Nuclear Medicine and Molecular Imaging, Department of Radiology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA
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Du QH, Zhang CJ, Li WH, Mu Y, Xu Y, Lowe S, Han L, Yu X, Wang SY, Li Y, Li J. Gan Shen Fu Fang ameliorates liver fibrosis in vitro and in vivo by inhibiting the inflammatory response and extracellular signal-regulated kinase phosphorylation. World J Gastroenterol 2020; 26:2810-2820. [PMID: 32550756 PMCID: PMC7284177 DOI: 10.3748/wjg.v26.i21.2810] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/17/2020] [Revised: 03/26/2020] [Accepted: 04/26/2020] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Liver fibrosis is a common health problem worldwide and there is still a lack of effective medicines. The Chinese herbal medicine, Gan Shen Fu Fang (GSFF) is composed of salvianolic acid B and diammonium glycyrrhizinate. In this study, we observed the effects of GSFF on liver fibrosis in vivo and in vitro in an attempt to provide some hope for the treatment.
AIM To observe the effects of GSFF on liver fibrosis in vivo and in vitro and investigate the mechanism from the perspective of the inflammatory response and extracellular signal-regulated kinase (ERK) phosphorylation.
METHODS Common bile duct-ligated rats were used for in vivo experiments. Hepatic stellate cells-T6 (HSC-T6) cells were used for in vitro experiments. Hematoxylin and eosin staining and Masson staining, biochemical assays, hydroxyproline (Hyp) assays, enzyme-linked immunoasorbent assay and western blotting were performed to evaluate the degree of liver fibrosis, liver function, the inflammatory response and ERK phosphorylation. The CCK8 assay, immunofluorescence and western blotting were applied to test the effect of GSFF on HSC-T6 cell activation and determine whether GSFF had an effect on ERK phosphorylation in HSC-T6 cells.
RESULTS GSFF improved liver function and inhibited liver fibrosis in common bile duct-ligated rats after 3 wk of treatment, as demonstrated by histological changes, hydroxyproline assays and collagen I concentrations. GSFF alleviated inflammatory cell infiltration and reduced the synthesis of pro-inflammatory cytokines [tumor necrosis factor-α (TNF-α) and interlukin-1β] and NF-κB. In addition, GSFF decreased ERK phosphorylation. In vitro, GSFF inhibited the viability of HSC-T6 cells with and without transforming growth factor β1 (TGF-β1) stimulation and decreased the synthesis of collagen I. GSFF had the greatest effect at a concentration of 0.5 μmol/L. GSFF inhibited the expression of α-smooth muscle actin (α-SMA), a marker of HSC activation, in HSC-T6 cells. Consistent with the in vivo results, GSFF also inhibited the phosphorylation of ERK and downregulated the expression of NF-κB.
CONCLUSION GSFF inhibited liver fibrosis progression in vivo and HSC-T6 cell activation in vitro. These effects may be related to an alleviated inflammatory response and downregulated ERK phosphorylation.
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Affiliation(s)
- Qing-Hong Du
- Department of Histology and Embryology, School of Traditional Chinese Medicine, Beijing University of Chinese Medicine, Beijing 102488, China
- Institute of Tibetan Medicine, University of Tibetan Medicine, Lhasa 850000, Tibet Autonomous Region, China
| | - Chu-Jun Zhang
- Department of Histology and Embryology, School of Traditional Chinese Medicine, Beijing University of Chinese Medicine, Beijing 102488, China
| | - Wei-Hong Li
- School of Nursing, Beijing University of Chinese Medicine, Beijing 102488, China
| | - Yan Mu
- Department of Histology and Embryology, School of Traditional Chinese Medicine, Beijing University of Chinese Medicine, Beijing 102488, China
| | - Ya Xu
- Department of Histology and Embryology, School of Traditional Chinese Medicine, Beijing University of Chinese Medicine, Beijing 102488, China
| | - Scott Lowe
- School of Molecular and Cellular Biology, University of Illinois, Urbana-Champaign, IL 61820, United States
| | - Lin Han
- Department of Histology and Embryology, School of Traditional Chinese Medicine, Beijing University of Chinese Medicine, Beijing 102488, China
| | - Xue Yu
- Department of Histology and Embryology, School of Traditional Chinese Medicine, Beijing University of Chinese Medicine, Beijing 102488, China
| | - Shu-Yan Wang
- Department of Histology and Embryology, School of Traditional Chinese Medicine, Beijing University of Chinese Medicine, Beijing 102488, China
| | - Yu Li
- Department of Histology and Embryology, School of Traditional Chinese Medicine, Beijing University of Chinese Medicine, Beijing 102488, China
| | - Jian Li
- Department of Histology and Embryology, School of Traditional Chinese Medicine, Beijing University of Chinese Medicine, Beijing 102488, China
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Neutralizing antibody against osteopontin attenuates non-alcoholic steatohepatitis in mice. J Cell Commun Signal 2020; 14:223-232. [PMID: 32062834 DOI: 10.1007/s12079-020-00554-7] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2019] [Accepted: 02/13/2020] [Indexed: 12/14/2022] Open
Abstract
Previously, we reported that an extracellular matrix protein, osteopontin (OPN), is involved in various autoimmune diseases using a neutralizing polyclonal antibody against OPN generated in rabbits. However, the antibody cannot be used for long-term mouse models of chronic inflammatory disease because of the induction of antibodies against anti-OPN rabbit IgG. In this study, we generated a new antibody, anti-mouse OPN mouse IgG (35B6). 35B6 inhibited the cell adhesion of mouse and human OPN to Chinese Hamster Ovary (CHO) cells or CHO cells expressing α4 or α9 integrin. It was reported that OPN is highly expressed and has an important role in a chronic liver disease, non-alcoholic steatohepatitis (NASH). 35B6 injection twice a week for 8 weeks attenuated liver inflammation and fibrosis in a NASH mouse model, suggesting 35B6 is beneficial for the treatment of NASH. 35B6 was preferable to the rabbit anti-OPN antibody for investigating the in vivo function of OPN in mouse models of long-term disease.
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PDGFRβ-targeted TRAIL specifically induces apoptosis of activated hepatic stellate cells and ameliorates liver fibrosis. Apoptosis 2020; 25:105-119. [DOI: 10.1007/s10495-019-01583-3] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
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Li J, Fukase Y, Shang Y, Zou W, Muñoz-Félix JM, Buitrago L, van Agthoven J, Zhang Y, Hara R, Tanaka Y, Okamoto R, Yasui T, Nakahata T, Imaeda T, Aso K, Zhou Y, Locuson C, Nesic D, Duggan M, Takagi J, Vaughan RD, Walz T, Hodivala-Dilke K, Teitelbaum SL, Arnaout MA, Filizola M, Foley MA, Coller BS. Novel Pure αVβ3 Integrin Antagonists That Do Not Induce Receptor Extension, Prime the Receptor, or Enhance Angiogenesis at Low Concentrations. ACS Pharmacol Transl Sci 2019; 2:387-401. [PMID: 32259072 PMCID: PMC7088984 DOI: 10.1021/acsptsci.9b00041] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2019] [Indexed: 01/12/2023]
Abstract
The integrin αVβ3 receptor has been implicated in several important diseases, but no antagonists are approved for human therapy. One possible limitation of current small-molecule antagonists is their ability to induce a major conformational change in the receptor that induces it to adopt a high-affinity ligand-binding state. In response, we used structural inferences from a pure peptide antagonist to design the small-molecule pure antagonists TDI-4161 and TDI-3761. Both compounds inhibit αVβ3-mediated cell adhesion to αVβ3 ligands, but do not induce the conformational change as judged by antibody binding, electron microscopy, X-ray crystallography, and receptor priming studies. Both compounds demonstrated the favorable property of inhibiting bone resorption in vitro, supporting potential value in treating osteoporosis. Neither, however, had the unfavorable property of the αVβ3 antagonist cilengitide of paradoxically enhancing aortic sprout angiogenesis at concentrations below its IC50, which correlates with cilengitide's enhancement of tumor growth in vivo.
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Affiliation(s)
- Jihong Li
- Allen and
Frances Adler Laboratory of Blood and Vascular Biology, Rockefeller University, 1230 York Avenue, New York, New York 10065, United States
| | - Yoshiyuki Fukase
- Tri-Institutional
Therapeutics Discovery Institute, 413 East 69 Street, New York, New York 10021, United
States
| | - Yi Shang
- Department
of Pharmacological Sciences, Icahn School
of Medicine at Mount Sinai, One Gustave L. Levy Place, Box 1677, New York, New York 10029-6574, United States
| | - Wei Zou
- Washington
University School of Medicine, Campus Box 8118, 660 South Euclid Avenue, St. Louis, Missouri 63110, United States
| | - José M. Muñoz-Félix
- Adhesion
and Angiogenesis Laboratory, Centre for Tumour Biology, Barts Cancer Institute—a CR-UK Centre of Excellence,
Queen Mary University of London, John Vane Science Centre, Charterhouse Square, London, EC1M 6BQ, United Kingdom
| | - Lorena Buitrago
- Allen and
Frances Adler Laboratory of Blood and Vascular Biology, Rockefeller University, 1230 York Avenue, New York, New York 10065, United States
| | - Johannes van Agthoven
- Leukocyte
Biology and Inflammation and Structural Biology Programs, Division
of Nephrology, Massachusetts General Hospital
and Harvard Medical School, 149 13th Street, Charlestown, Massachusetts 02129, United States
| | - Yixiao Zhang
- Laboratory
of Molecular Electron Microscopy, Rockefeller
University, 1230 York Avenue, New York, New York 10065, United
States
| | - Ryoma Hara
- Tri-Institutional
Therapeutics Discovery Institute, 413 East 69 Street, New York, New York 10021, United
States
| | - Yuta Tanaka
- Tri-Institutional
Therapeutics Discovery Institute, 413 East 69 Street, New York, New York 10021, United
States
| | - Rei Okamoto
- Tri-Institutional
Therapeutics Discovery Institute, 413 East 69 Street, New York, New York 10021, United
States
| | - Takeshi Yasui
- Tri-Institutional
Therapeutics Discovery Institute, 413 East 69 Street, New York, New York 10021, United
States
| | - Takashi Nakahata
- Tri-Institutional
Therapeutics Discovery Institute, 413 East 69 Street, New York, New York 10021, United
States
| | - Toshihiro Imaeda
- Tri-Institutional
Therapeutics Discovery Institute, 413 East 69 Street, New York, New York 10021, United
States
| | - Kazuyoshi Aso
- Tri-Institutional
Therapeutics Discovery Institute, 413 East 69 Street, New York, New York 10021, United
States
| | - Yuchen Zhou
- Department
of Pharmacological Sciences, Icahn School
of Medicine at Mount Sinai, One Gustave L. Levy Place, Box 1677, New York, New York 10029-6574, United States
| | - Charles Locuson
- Agios Pharmaceuticals, 88 Sidney Street, Cambridge, Massachusetts 02139-4169, United States
| | - Dragana Nesic
- Allen and
Frances Adler Laboratory of Blood and Vascular Biology, Rockefeller University, 1230 York Avenue, New York, New York 10065, United States
| | - Mark Duggan
- LifeSci
Consulting, LLC, 18243
SE Ridgeview Drive, Tequesta, Florida 33469, United
States
| | - Junichi Takagi
- Laboratory
of Protein Synthesis and Expression, Institute for Protein Research, Osaka University, 3-2 Yamadaoka, Suita, Osaka 565-0871, Japan
| | - Roger D. Vaughan
- Rockefeller
University Center for Clinical and Translational Science, Rockefeller University, 2130 York Avenue, New York, New York 10065, United States
| | - Thomas Walz
- Laboratory
of Molecular Electron Microscopy, Rockefeller
University, 1230 York Avenue, New York, New York 10065, United
States
| | - Kairbaan Hodivala-Dilke
- Adhesion
and Angiogenesis Laboratory, Centre for Tumour Biology, Barts Cancer Institute—a CR-UK Centre of Excellence,
Queen Mary University of London, John Vane Science Centre, Charterhouse Square, London, EC1M 6BQ, United Kingdom
| | - Steven L. Teitelbaum
- Washington
University School of Medicine, Campus Box 8118, 660 South Euclid Avenue, St. Louis, Missouri 63110, United States
| | - M. Amin Arnaout
- Leukocyte
Biology and Inflammation and Structural Biology Programs, Division
of Nephrology, Massachusetts General Hospital
and Harvard Medical School, 149 13th Street, Charlestown, Massachusetts 02129, United States
| | - Marta Filizola
- Department
of Pharmacological Sciences, Icahn School
of Medicine at Mount Sinai, One Gustave L. Levy Place, Box 1677, New York, New York 10029-6574, United States
| | - Michael A. Foley
- Tri-Institutional
Therapeutics Discovery Institute, 413 East 69 Street, New York, New York 10021, United
States
| | - Barry S. Coller
- Allen and
Frances Adler Laboratory of Blood and Vascular Biology, Rockefeller University, 1230 York Avenue, New York, New York 10065, United States
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Imaging Fibrogenesis in a Diet-Induced Model of Nonalcoholic Steatohepatitis (NASH). CONTRAST MEDIA & MOLECULAR IMAGING 2019; 2019:6298128. [PMID: 31866798 PMCID: PMC6914933 DOI: 10.1155/2019/6298128] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/19/2019] [Accepted: 10/26/2019] [Indexed: 02/08/2023]
Abstract
Purpose Liver fibrosis is the hallmark of chronic nonalcoholic steatohepatitis (NASH) and is characterised by the excessive deposition of extracellular matrix proteins. Early detection and accurate staging of liver fibrosis is critically important for patient management. One of the earliest pathological markers in NASH is the activation of hepatic stellate cells (HSCs) which may be exploited as a marker of fibrogenesis. Activated HSCs secreting factors such as integrin αvβ3 propagate fibrosis. The purpose of the current study was to assess the utility of the integrin αvβ3 imaging agent [18F]FtRGD for the early detection of fibrosis in a diet-induced model of NASH longitudinally using PET imaging. Procedures Mice were fed with either standard chow diet (SD), high-fat diet (HFD), or a choline-deficient, L-amino acid-defined high-fat fibrogenic diet (CDAHFD) to mimic the clinical pathology of liver disease and followed longitudinally for 10 weeks to assess the development of liver fibrosis using [18F]FtRGD positron emission tomography (PET) imaging. Standard blood biochemistry, histological measures, and qPCR were used to quantify integrin αvβ3, smooth muscle actin, and collagen types 1 and 6 to assess the extent of NASH pathology and accurately stage liver fibrosis. Results The CDAHFD fibrogenic diet predictably developed hepatic inflammation and steatosis over the 10 weeks studied with little NASH pathology detected in high fat diet-treated animals. Stage 1 fibrosis was detected early by histology at day 21 and progressed to stage 2 by day 35 and stage 3 by day 56 in mice fed with CDAHFD diet only. Noninvasive imaging with [18F]FtRGD correlated well with integrin αvβ3 and was able to distinguish early mild stage 2 fibrosis in CDAHFD animals compared with standard chow diet-fed animals at day 35. When compared with high fat diet-fed animals, [18F]FtRGD was only able to distinguish later moderate stage 2 fibrosis in CDAHFD animals at day 49. Conclusions The diet-induced progression of liver fibrosis was confirmed using histology and correlated well with the mRNA of integrin αvβ3 and extracellular matrix protein expression. [18F]FtRGD showed very good correlation between liver uptake and integrin αvβ3 expression and similar detection sensitivity to the current clinical gold standard modalities for staging of liver fibrosis.
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TGF-β1/Smad7 signaling pathway and cell apoptosis: Two key aspects of Selenium-biofortified soybean peptide attenuating liver fibrosis. J Funct Foods 2019. [DOI: 10.1016/j.jff.2019.103583] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
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Gore E, Bigaeva E, Oldenburger A, Kim YO, Rippmann JF, Schuppan D, Boersema M, Olinga P. PI3K inhibition reduces murine and human liver fibrogenesis in precision-cut liver slices. Biochem Pharmacol 2019; 169:113633. [PMID: 31494146 DOI: 10.1016/j.bcp.2019.113633] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2019] [Accepted: 09/03/2019] [Indexed: 02/08/2023]
Abstract
BACKGROUND Liver fibrosis results from continuous inflammation and injury. Despite its high prevalence worldwide, no approved antifibrotic therapies exist. Omipalisib is a selective inhibitor of the PI3K/mTOR pathway that controls nutrient metabolism, growth and proliferation. It has shown antifibrotic properties in vitro. While clinical trials for idiopathic pulmonary fibrosis have been initiated, an in-depth preclinical evaluation is lacking. We evaluated omipalisib's effects on fibrogenesis using the ex vivo model of murine and human precision-cut tissue slices (PCTS). METHODS Murine and human liver and jejunum PCTS were incubated with omipalisib up to 10 μM for 48 h. PI3K pathway activation was assessed through protein kinase B (Akt) phosphorylation and antifibrotic efficacy was determined via a spectrum of fibrosis markers at the transcriptional and translational level. RESULTS During incubation of PCTS the PI3K pathway was activated and incubation with omipalisib prevented Akt phosphorylation (IC50 = 20 and 1.5 nM for mouse and human, respectively). Viability of mouse and human liver PCTS was compromised only at the high concentration of 10 and 1-5 μM, respectively. However, viability of jejunum PCTS decreased with 0.1 (mouse) and 0.01 μM (human). Spontaneously increased fibrosis related genes and proteins were significantly and similarly suppressed in mouse and in human liver PCTS. CONCLUSIONS Omipalisib has antifibrotic properties in ex vivo mouse and human liver PCTS, but higher concentrations showed toxicity in jejunum PCTS. While the PI3K/mTOR pathway appears to be a promising target for the treatment of liver fibrosis, PCTS revealed likely side effects in the intestine at higher doses.
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Affiliation(s)
- Emilia Gore
- Groningen Research Institute of Pharmacy, Department of Pharmaceutical Technology and Biopharmacy, University of Groningen, Antonius Deusinglaan 1, Groningen 9713AV, The Netherlands
| | - Emilia Bigaeva
- Groningen Research Institute of Pharmacy, Department of Pharmaceutical Technology and Biopharmacy, University of Groningen, Antonius Deusinglaan 1, Groningen 9713AV, The Netherlands
| | - Anouk Oldenburger
- Cardiometabolic Disease Research, Boehringer Ingelheim Pharma GmbH & Co. KG, Birkendorfer Str. 65, Biberach an der Riss 88397, Germany
| | - Yong Ook Kim
- Institute of Translational Immunology and Research Center for Immunotherapy, University Medical Center, Johannes Gutenberg University, Obere Zahlbacherstraße 63, Mainz 55131, Germany
| | - Jörg F Rippmann
- Cardiometabolic Disease Research, Boehringer Ingelheim Pharma GmbH & Co. KG, Birkendorfer Str. 65, Biberach an der Riss 88397, Germany
| | - Detlef Schuppan
- Institute of Translational Immunology and Research Center for Immunotherapy, University Medical Center, Johannes Gutenberg University, Obere Zahlbacherstraße 63, Mainz 55131, Germany; Division of Gastroenterology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, 330 Brookline Avenue, MA 02215, USA
| | - Miriam Boersema
- Groningen Research Institute of Pharmacy, Department of Pharmaceutical Technology and Biopharmacy, University of Groningen, Antonius Deusinglaan 1, Groningen 9713AV, The Netherlands
| | - Peter Olinga
- Groningen Research Institute of Pharmacy, Department of Pharmaceutical Technology and Biopharmacy, University of Groningen, Antonius Deusinglaan 1, Groningen 9713AV, The Netherlands.
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Levada K, Omelyanchik A, Rodionova V, Weiskirchen R, Bartneck M. Magnetic-Assisted Treatment of Liver Fibrosis. Cells 2019; 8:E1279. [PMID: 31635053 PMCID: PMC6830324 DOI: 10.3390/cells8101279] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2019] [Revised: 10/07/2019] [Accepted: 10/15/2019] [Indexed: 12/12/2022] Open
Abstract
Chronic liver injury can be induced by viruses, toxins, cellular activation, and metabolic dysregulation and can lead to liver fibrosis. Hepatic fibrosis still remains a major burden on the global health systems. Nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH) are considered the main cause of liver fibrosis. Hepatic stellate cells are key targets in antifibrotic treatment, but selective engagement of these cells is an unresolved issue. Current strategies for antifibrotic drugs, which are at the critical stage 3 clinical trials, target metabolic regulation, immune cell activation, and cell death. Here, we report on the critical factors for liver fibrosis, and on prospective novel drugs, which might soon enter the market. Apart from the current clinical trials, novel perspectives for anti-fibrotic treatment may arise from magnetic particles and controlled magnetic forces in various different fields. Magnetic-assisted techniques can, for instance, enable cell engineering and cell therapy to fight cancer, might enable to control the shape or orientation of single cells or tissues mechanically. Furthermore, magnetic forces may improve localized drug delivery mediated by magnetism-induced conformational changes, and they may also enhance non-invasive imaging applications.
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Affiliation(s)
- Kateryna Levada
- Institute of Physics, Mathematics and Information Technology, Immanuel Kant Baltic Federal University, 236016 Kaliningrad, Russia.
| | - Alexander Omelyanchik
- Institute of Physics, Mathematics and Information Technology, Immanuel Kant Baltic Federal University, 236016 Kaliningrad, Russia.
| | - Valeria Rodionova
- Institute of Physics, Mathematics and Information Technology, Immanuel Kant Baltic Federal University, 236016 Kaliningrad, Russia.
- National University of Science and Technology "MISiS", 119049 Moscow, Russia.
| | - Ralf Weiskirchen
- Institute of Molecular Pathobiochemistry, Experimental Gene Therapy and Clinical Chemistry, RWTH University Hospital Aachen, D-52074 Aachen, Germany.
| | - Matthias Bartneck
- Department of Medicine III, Medical Faculty, RWTH Aachen, D-52074 Aachen, Germany.
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Kong DL, Kong FY, Liu XY, Yan C, Cui J, Tang RX, Zheng KY. Soluble egg antigen of Schistosoma japonicum induces pyroptosis in hepatic stellate cells by modulating ROS production. Parasit Vectors 2019; 12:475. [PMID: 31610797 PMCID: PMC6791022 DOI: 10.1186/s13071-019-3729-8] [Citation(s) in RCA: 26] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2018] [Accepted: 09/23/2019] [Indexed: 02/08/2023] Open
Abstract
BACKGROUND Inflammation-induced dysfunction of hepatic stellate cells (HSCs) is involved in schistosomiasis-associated liver fibrosis, and soluble egg antigen (SEA) is a crucial pathogen-associated molecular pattern associated with liver injury in schistosomiasis. In addition, numerous studies have shown that caspase-1-mediated pyroptosis participates in the development of multiple inflammation-related diseases. However, whether pyroptotic cell death of HSCs is involved in SEA-mediated liver damage is not well understood. METHODS Primary cultured HSCs and Schistosoma japonicum-infected mouse liver tissue were analysed for histological changes and caspase-1 activation, and the role of pyroptosis in the mechanisms underlying SEA-induced HSC death was investigated. Accumulation of reactive oxygen species (ROS) in infected livers and SEA-stimulated HSCs was measured by flow cytometry and immunofluorescence. RESULTS Caspase-1 activity was elevated in both liver tissues and HSCs of S. japonicum-infected mice. Furthermore, SEA stimulation increased the proportion of pyroptotic HSCs, as shown by lactate dehydrogenase (LDH) release assays and by flow cytometric analysis of propidium iodide (PI) and caspase-1 double staining in cells. In addition, ROS generation was elevated in infected liver tissues and SEA-stimulated HSCs, and ROS inhibition downregulated SEA-induced caspase-1 activation and pyroptosis in HSCs. CONCLUSIONS Our present study demonstrates that pyroptotic cell death in HSCs induced by SEA via ROS-mediated caspase-1 activation may serve as a significant mechanism to initiate the inflammatory response and thereby exacerbate liver injury during S. japonicum infection.
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Affiliation(s)
- De-Long Kong
- Jiangsu Key Laboratory of Immunity and Metabolism, Department of Pathogenic Biology and Immunology, Laboratory of Infection and Immunity, Xuzhou Medical University, Xuzhou, 221004, Jiangsu, People's Republic of China
| | - Fan-Yun Kong
- Jiangsu Key Laboratory of Immunity and Metabolism, Department of Pathogenic Biology and Immunology, Laboratory of Infection and Immunity, Xuzhou Medical University, Xuzhou, 221004, Jiangsu, People's Republic of China
| | - Xiang-Ye Liu
- Jiangsu Key Laboratory of Immunity and Metabolism, Department of Pathogenic Biology and Immunology, Laboratory of Infection and Immunity, Xuzhou Medical University, Xuzhou, 221004, Jiangsu, People's Republic of China
| | - Chao Yan
- Jiangsu Key Laboratory of Immunity and Metabolism, Department of Pathogenic Biology and Immunology, Laboratory of Infection and Immunity, Xuzhou Medical University, Xuzhou, 221004, Jiangsu, People's Republic of China
| | - Jie Cui
- Department of Physiology, Xuzhou Medical University, Xuzhou, 221004, Jiangsu, People's Republic of China
| | - Ren-Xian Tang
- Jiangsu Key Laboratory of Immunity and Metabolism, Department of Pathogenic Biology and Immunology, Laboratory of Infection and Immunity, Xuzhou Medical University, Xuzhou, 221004, Jiangsu, People's Republic of China.
| | - Kui-Yang Zheng
- Jiangsu Key Laboratory of Immunity and Metabolism, Department of Pathogenic Biology and Immunology, Laboratory of Infection and Immunity, Xuzhou Medical University, Xuzhou, 221004, Jiangsu, People's Republic of China.
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Chen Z, Jain A, Liu H, Zhao Z, Cheng K. Targeted Drug Delivery to Hepatic Stellate Cells for the Treatment of Liver Fibrosis. J Pharmacol Exp Ther 2019; 370:695-702. [PMID: 30886124 PMCID: PMC6806344 DOI: 10.1124/jpet.118.256156] [Citation(s) in RCA: 72] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/26/2018] [Accepted: 03/04/2019] [Indexed: 12/17/2022] Open
Abstract
Liver fibrosis is caused by excessive accumulation of extracellular matrix during chronic liver injuries. Although clinical evidence suggests that liver fibrosis can be reversed, there is no standard therapy for liver fibrosis. Moreover, there is a lack of diagnostic tools to detect early-stage liver fibrosis. Activation of hepatic stellate cells (HSCs) is the key step during liver fibrogenesis, and its mechanism has been extensively studied by various cell culture and animal models. Targeted delivery of therapeutic agents to activated HSCs is therefore critical for the successful treatment of liver fibrosis. A number of protein markers have been found to be overexpressed in activated HSCs, and their ligands have been used to specifically deliver various antifibrotic agents. In this review, we summarize these HSC-specific protein markers and their ligands for targeted delivery of antifibrotic agents.
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Affiliation(s)
- Zhijin Chen
- Division of Pharmacology and Pharmaceutical Science, School of Pharmacy, University of Missouri-Kansas City, Kansas City, Missouri
| | - Akshay Jain
- Division of Pharmacology and Pharmaceutical Science, School of Pharmacy, University of Missouri-Kansas City, Kansas City, Missouri
| | - Hao Liu
- Division of Pharmacology and Pharmaceutical Science, School of Pharmacy, University of Missouri-Kansas City, Kansas City, Missouri
| | - Zhen Zhao
- Division of Pharmacology and Pharmaceutical Science, School of Pharmacy, University of Missouri-Kansas City, Kansas City, Missouri
| | - Kun Cheng
- Division of Pharmacology and Pharmaceutical Science, School of Pharmacy, University of Missouri-Kansas City, Kansas City, Missouri
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Yin F, Wang WY, Jiang WH. Human umbilical cord mesenchymal stem cells ameliorate liver fibrosis in vitro and in vivo: From biological characteristics to therapeutic mechanisms. World J Stem Cells 2019; 11:548-564. [PMID: 31523373 PMCID: PMC6716089 DOI: 10.4252/wjsc.v11.i8.548] [Citation(s) in RCA: 28] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/18/2019] [Revised: 06/26/2019] [Accepted: 07/17/2019] [Indexed: 02/06/2023] Open
Abstract
Liver fibrosis is a wound-healing response to chronic injuries, characterized by the excessive accumulation of extracellular matrix or scar tissue within the liver; in addition, its formation is associated with multiple cytokines as well as several cell types and a variety of signaling pathways. When liver fibrosis is not well controlled, it can progress to liver cirrhosis, but it is reversible in principle. Thus far, no efficient therapy is available for treatment of liver fibrosis. Although liver transplantation is the preferred strategy, there are many challenges remaining in this approach, such as shortage of donor organs, immunological rejection, and surgical complications. Hence, there is a great need for an alternative therapeutic strategy. Currently, mesenchymal stem cell (MSC) therapy is considered a promising therapeutic strategy for the treatment of liver fibrosis; advantageously, the characteristics of MSCs are continuous self-renewal, proliferation, multipotent differentiation, and immunomodulatory activities. The human umbilical cord-derived (hUC)-MSCs possess not only the common attributes of MSCs but also more stable biological characteristics, relatively easy accessibility, abundant source, and no ethical issues (e.g., bone marrow being the adult source), making hUC-MSCs a good choice for treatment of liver fibrosis. In this review, we summarize the biological characteristics of hUC-MSCs and their paracrine effects, exerted by secretion of various cytokines, which ultimately promote liver repair through several signaling pathways. Additionally, we discuss the capacity of hUC-MSCs to differentiate into hepatocyte-like cells for compensating the function of existing hepatocytes, which may aid in amelioration of liver fibrosis. Finally, we discuss the current status of the research field and its future prospects.
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Affiliation(s)
- Fei Yin
- Department of Histology and Embryology, Basic Medical College of Jilin University, Changchun 130021, Jilin Province, China
| | - Wen-Ying Wang
- Department of Histology and Embryology, Basic Medical College of Jilin University, Changchun 130021, Jilin Province, China
| | - Wen-Hua Jiang
- Department of Histology and Embryology, Basic Medical College of Jilin University, Changchun 130021, Jilin Province, China
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Nagalingam RS, Al-Hattab DS, Czubryt MP. What’s in a name? On fibroblast phenotype and nomenclature. Can J Physiol Pharmacol 2019; 97:493-497. [DOI: 10.1139/cjpp-2018-0555] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
Fibroblasts have long been recognized as important stromal cells, playing key roles in synthesizing and maintaining the extracellular matrix, but historically were treated as a relatively uniform cell type. Studies in recent years have revealed a surprising level of heterogeneity of fibroblasts across tissues, and even within organs such as the skin and heart. This heterogeneity may have functional consequences, including during stress and disease. While the field has moved forward quickly to begin to address the scientific import of this heterogeneity, the descriptive language used for these cells has not kept pace, particularly when considering the phenotype changes that occur as fibroblasts convert to myofibroblasts in response to injury. We discuss here the nature and sources of the heterogeneity of fibroblasts, and review how our understanding of the complexity of the fibroblast to myofibroblast phenotype conversion has changed with increasing scrutiny. We propose that the time is opportune to reevaluate how we name and describe these cells, particularly as they transition to myofibroblasts through discrete stages. A standardized nomenclature is essential to address the confusion that currently exists in the literature as to the usage of terms like myofibroblast and the description of fibroblast phenotype changes in disease.
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Affiliation(s)
- Raghu S. Nagalingam
- Department of Physiology and Pathophysiology, Rady Faculty of Health Sciences, University of Manitoba and Institute of Cardiovascular Sciences, St. Boniface Hospital Albrechtsen Research Centre, Winnipeg, MB R2H 2A6, Canada
| | - Danah S. Al-Hattab
- Department of Physiology and Pathophysiology, Rady Faculty of Health Sciences, University of Manitoba and Institute of Cardiovascular Sciences, St. Boniface Hospital Albrechtsen Research Centre, Winnipeg, MB R2H 2A6, Canada
| | - Michael P. Czubryt
- Department of Physiology and Pathophysiology, Rady Faculty of Health Sciences, University of Manitoba and Institute of Cardiovascular Sciences, St. Boniface Hospital Albrechtsen Research Centre, Winnipeg, MB R2H 2A6, Canada
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Aithal AP, Bairy LK, Seetharam RN, Rao MK. Human bone marrow-derived mesenchymal stromal cells in combination with silymarin regulate hepatocyte growth factor expression and genotoxicity in carbon tetrachloride induced hepatotoxicity in Wistar rats. J Cell Biochem 2019; 120:13026-13036. [PMID: 30873677 DOI: 10.1002/jcb.28573] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2018] [Revised: 01/23/2019] [Accepted: 01/24/2019] [Indexed: 12/31/2022]
Abstract
BACKGROUND To evaluate the antimutagenic potential of combination treatment of human bone marrow-derived mesenchymal stromal cells (BM-MSCs) and silymarin and its effect on hepatocyte growth factor levels in CCl4 induced hepatotoxicity in Wistar rats. METHODS Hepatotoxicity was induced in adult female Wistar rats using carbon tetrachloride (CCl4 ). Thirty-six rats were randomly divided into six groups with six rats in each group: Group 1 (normal control group), Group 2 (received only CCl 4 ), Group 3 (CCl 4 +low dose BM-MSCs), Group 4 (CCl 4 +high dose BM-MSCs), Group 5 (CCl 4 + silymarin), Group 6 (CCl 4 +silymarin+high dose BM-MSCs). Thirty days after the treatment, blood samples were collected for hepatocyte growth factor estimation. The rats were then killed, bone marrow was extracted for chromosomal aberration assay. Liver tissue was processed for evaluating the DNA fragmentation assay, histopathology, and scanning electron microscopy study. RESULTS Combination treatment of silymarin and high dose BM-MSCs significantly (P < 0.05) restored the plasma hepatocyte growth factor levels which were comparable with normal levels and exhibited significant antimutagenic and antiapoptotic activity by decreasing the frequency of structural chromosomal aberrations and suppressing the DNA fragmentation in liver tissue samples. The combination treatment produced significant hepatoprotective effect which was supported by histopathology and scanning electron microscopy study. CONCLUSION Results indicate that the treatment of BM-MSCs in combination with silymarin had a better hepatoprotective and antimutagenic effect and represents a novel strategy for the treatment of hepatotoxicity.
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Affiliation(s)
- Ashwini P Aithal
- Department of Anatomy, Melaka Manipal Medical College (Manipal Campus), Manipal Academy of Higher Education, Manipal, India
| | - Laxminarayana K Bairy
- Department of Pharmacology, RAK College of Medical Sciences, RAK Medical and Health Sciences University, Ras Al Khaimah, UAE
| | | | - Mohandas Kg Rao
- Department of Anatomy, Melaka Manipal Medical College (Manipal Campus), Manipal Academy of Higher Education, Manipal, India
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Montesi SB, Désogère P, Fuchs BC, Caravan P. Molecular imaging of fibrosis: recent advances and future directions. J Clin Invest 2019; 129:24-33. [PMID: 30601139 DOI: 10.1172/jci122132] [Citation(s) in RCA: 95] [Impact Index Per Article: 15.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
Fibrosis, the progressive accumulation of connective tissue that occurs in response to injury, causes irreparable organ damage and may result in organ failure. The few available antifibrotic treatments modify the rate of fibrosis progression, but there are no available treatments to reverse established fibrosis. Thus, more effective therapies are urgently needed. Molecular imaging is a promising biomedical methodology that enables noninvasive visualization of cellular and subcellular processes. It provides a unique means to monitor and quantify dysregulated molecular fibrotic pathways in a noninvasive manner. Molecular imaging could be used for early detection, disease staging, and prognostication, as well as for assessing disease activity and treatment response. As fibrotic diseases are often molecularly heterogeneous, molecular imaging of a specific pathway could be used for patient stratification and cohort enrichment with the goal of improving clinical trial design and feasibility and increasing the ability to detect a definitive outcome for new therapies. Here we review currently available molecular imaging probes for detecting fibrosis and fibrogenesis, the active formation of new fibrous tissue, and their application to models of fibrosis across organ systems and fibrotic processes. We provide our opinion as to the potential roles of molecular imaging in human fibrotic diseases.
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Affiliation(s)
| | - Pauline Désogère
- Department of Radiology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA.,Athinoula A. Martinos Center for Biomedical Imaging and.,Institute for Innovation in Imaging, Massachusetts General Hospital, Boston, Massachusetts, USA
| | - Bryan C Fuchs
- Division of Surgical Oncology, Massachusetts General Hospital Cancer Center and Harvard Medical School, Boston, Massachusetts, USA
| | - Peter Caravan
- Department of Radiology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA.,Athinoula A. Martinos Center for Biomedical Imaging and.,Institute for Innovation in Imaging, Massachusetts General Hospital, Boston, Massachusetts, USA
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Zhang Y, Liu J, Ma Y, Wang J, Zhu J, Liu J, Zhang J. Integration of high‑throughput data of microRNA and mRNA expression profiles reveals novel insights into the mechanism of liver fibrosis. Mol Med Rep 2018; 19:115-124. [PMID: 30431126 PMCID: PMC6297784 DOI: 10.3892/mmr.2018.9641] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2018] [Accepted: 10/09/2018] [Indexed: 12/13/2022] Open
Abstract
Numerous studies have revealed that microRNAs (miRNAs) are functional non-coding RNAs that serve roles in a variety of biological processes. However, the expression patterns and regulatory networks, as well as the miRNAs involved in liver fibrosis remain to be elucidated. In the present study, a mouse model of liver fibrosis was constructed by CCl4 intraperitoneal injection and the total RNAs were extracted from the liver of the mice. The total RNAs were then sequenced on an Illumina HiSeq 2000 platform and an integrated analysis of miRNA and mRNA expression profiles in CCl4-induced liver fibrosis was performed. Compared with normal liver samples, 56 and 15 miRNAs were found to be upregulated and downregulated in fibrotic livers, respectively. To predict the potential functions of these miRNAs, bioinformatics analysis, including Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathway analysis, was used to assess target mRNAs. The results indicated that the mitogen-activated protein kinase, phosphoinositide 3 kinase/protein kinase B and focal adhesion signaling pathways were the most significantly enriched. In addition, a regulatory network containing five dysregulated miRNAs and 22 target mRNAs was constructed based on their inverse correlation. Furthermore, the five dysregulated miRNAs were significantly upregulated and the expression of RELB, RAP1A, PPP3CB, MAP2K4, ARRB1, MAP3K4, FGF1 and PRKCB in the network was significantly decreased in LX-2 cells following TGF-β1 treatment which suggested that they were associated with the activation of human hepatic stellate cells. The miRNA-mRNA regulatory network produced in the present study may provide novel insights into the role of miRNAs in liver fibrosis.
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Affiliation(s)
- Yitong Zhang
- Department of Digestive Diseases, Huashan Hospital, Fudan University, Shanghai 200040, P.R. China
| | - Jing Liu
- State Key Laboratory of Genetic Engineering, Collaborative Innovation Center for Genetics and Development, School of Life Sciences, Fudan University, Shanghai 200438, P.R. China
| | - Yanyun Ma
- Ministry of Education Key Laboratory of Contemporary Anthropology, Department of Anthropology and Human Genetics, School of Life Sciences, Fudan University, Shanghai 200438, P.R. China
| | - Jingjie Wang
- Department of Digestive Diseases, Huashan Hospital, Fudan University, Shanghai 200040, P.R. China
| | - Jie Zhu
- Department of Digestive Diseases, Huashan Hospital, Fudan University, Shanghai 200040, P.R. China
| | - Jie Liu
- Department of Digestive Diseases, Huashan Hospital, Fudan University, Shanghai 200040, P.R. China
| | - Jun Zhang
- Department of Digestive Diseases, Huashan Hospital, Fudan University, Shanghai 200040, P.R. China
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