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Periferakis A, Periferakis AT, Troumpata L, Periferakis K, Georgatos-Garcia S, Touriki G, Dragosloveanu CDM, Caruntu A, Savulescu-Fiedler I, Dragosloveanu S, Scheau AE, Badarau IA, Caruntu C, Scheau C. Pinosylvin: A Multifunctional Stilbenoid with Antimicrobial, Antioxidant, and Anti-Inflammatory Potential. Curr Issues Mol Biol 2025; 47:204. [PMID: 40136458 PMCID: PMC11941527 DOI: 10.3390/cimb47030204] [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: 02/14/2025] [Revised: 03/13/2025] [Accepted: 03/15/2025] [Indexed: 03/27/2025] Open
Abstract
Stilbenoids are a category of plant compounds exhibiting notable health-related benefits. After resveratrol, perhaps the most well-known stilbenoid is pinosylvin, a major phytochemical constituent of most plants characterised by the pine spines among others. Pinosylvin and its derivatives have been found to exert potent antibacterial and antifungal effects, while their antiparasitic and antiviral properties are still a subject of ongoing research. The antioxidant properties of pinosylvin are mostly based on its scavenging of free radicals, inhibition of iNOS and protein kinase C, and promotion of HO-1 expression. Its anti-inflammatory properties are based on a variety of mechanisms, such as COX-2 inhibition, NF-κB and TRPA1 activation inhibition, and reduction in IL-6 levels. Its anticancer properties are partly associated with its antioxidant and anti-inflammatory potential, although a number of other mechanisms are described, such as apoptosis induction and matrix metalloproteinase inhibition. A couple of experiments have also suggested a neuroprotective potential. A multitude of ethnomedical and ethnobotanical effects of pinosylvin-containing plants are reported, like antimicrobial, antioxidant, anti-inflammatory, hepatoprotective, and prokinetic actions; many of these are corroborated by recent research. The advent of novel methods of artificial pinosylvin synthesis may facilitate its mass production and adoption as a medical compound. Finally, pinosylvin may be a tool in promoting environmentally friendly pesticide and insecticide policies and be used in land remediation schemes.
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Affiliation(s)
- Argyrios Periferakis
- Department of Physiology, The “Carol Davila” University of Medicine and Pharmacy, 050474 Bucharest, Romania
- Akadimia of Ancient Greek and Traditional Chinese Medicine, 16675 Athens, Greece
- Elkyda, Research & Education Centre of Charismatheia, 17675 Athens, Greece
| | - Aristodemos-Theodoros Periferakis
- Department of Physiology, The “Carol Davila” University of Medicine and Pharmacy, 050474 Bucharest, Romania
- Elkyda, Research & Education Centre of Charismatheia, 17675 Athens, Greece
| | - Lamprini Troumpata
- Department of Physiology, The “Carol Davila” University of Medicine and Pharmacy, 050474 Bucharest, Romania
| | - Konstantinos Periferakis
- Akadimia of Ancient Greek and Traditional Chinese Medicine, 16675 Athens, Greece
- Pan-Hellenic Organization of Educational Programs (P.O.E.P.), 17236 Athens, Greece
| | - Spyrangelos Georgatos-Garcia
- Tilburg Institute for Law, Technology, and Society (TILT), Tilburg University, 5037 DE Tilburg, The Netherlands
- Corvers Greece IKE, 15124 Athens, Greece
| | - Georgia Touriki
- Faculty of Law, Democritus University of Thrace, 69100 Komotini, Greece
| | - Christiana Diana Maria Dragosloveanu
- Department of Ophthalmology, Faculty of Dentistry, The “Carol Davila” University of Medicine and Pharmacy, 020021 Bucharest, Romania
- Department of Ophthalmology, Clinical Hospital for Ophthalmological Emergencies, 010464 Bucharest, Romania
| | - Ana Caruntu
- Department of Oral and Maxillofacial Surgery, “Carol Davila” Central Military Emergency Hospital, 010825 Bucharest, Romania
- Department of Oral and Maxillofacial Surgery, Faculty of Dental Medicine, Titu Maiorescu University, 031593 Bucharest, Romania
| | - Ilinca Savulescu-Fiedler
- Department of Internal Medicine, The “Carol Davila” University of Medicine and Pharmacy, 050474 Bucharest, Romania
- Department of Internal Medicine and Cardiology, Coltea Clinical Hospital, 030167 Bucharest, Romania
| | - Serban Dragosloveanu
- Department of Orthopaedics and Traumatology, The “Carol Davila” University of Medicine and Pharmacy, 050474 Bucharest, Romania
- Department of Orthopaedics, “Foisor” Clinical Hospital of Orthopaedics, Traumatology and Osteoarticular TB, 021382 Bucharest, Romania
| | - Andreea-Elena Scheau
- Department of Radiology and Medical Imaging, “Foisor” Clinical Hospital of Orthopaedics, Traumatology and Osteoarticular TB, 021382 Bucharest, Romania
| | - Ioana Anca Badarau
- Department of Physiology, The “Carol Davila” University of Medicine and Pharmacy, 050474 Bucharest, Romania
| | - Constantin Caruntu
- Department of Physiology, The “Carol Davila” University of Medicine and Pharmacy, 050474 Bucharest, Romania
- Department of Dermatology, “Prof. N.C. Paulescu” National Institute of Diabetes, Nutrition and Metabolic Diseases, 011233 Bucharest, Romania
| | - Cristian Scheau
- Department of Physiology, The “Carol Davila” University of Medicine and Pharmacy, 050474 Bucharest, Romania
- Department of Radiology and Medical Imaging, “Foisor” Clinical Hospital of Orthopaedics, Traumatology and Osteoarticular TB, 021382 Bucharest, Romania
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Zeng Y, Liu X, Wang Z, Gao W, Zhang S, Wang Y, Liu Y, Yu H. Multidepth quantitative analysis of liver cell viscoelastic properties: Fusion of nanoindentation and finite element modeling techniques. Microsc Res Tech 2025; 88:202-212. [PMID: 39254440 DOI: 10.1002/jemt.24697] [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: 03/20/2024] [Revised: 06/11/2024] [Accepted: 08/27/2024] [Indexed: 09/11/2024]
Abstract
Liver cells are the basic functional unit of the liver. However, repeated or sustained injury leads to structural disorders of liver lobules, proliferation of fibrous tissue and changes in structure, thus increasing scar tissue. Cellular fibrosis affects tissue stiffness, shear force, and other cellular mechanical forces. Mechanical force characteristics can serve as important indicators of cell damage and cirrhosis. Atomic force microscopy (AFM) has been widely used to study cell surface mechanics. However, characterization of the deep mechanical properties inside liver cells remains an underdeveloped field. In this work, cell nanoindentation was combined with finite element analysis to simulate and analyze the mechanical responses of liver cells at different depths in vitro and their internal responses and stress diffusion distributions after being subjected to normal stress. The sensitivities of the visco-hyperelastic parameters of the finite element model to the effects of the peak force and equilibrium force were compared. The force curves of alcohol-damaged liver cells at different depths were measured and compared with those of undamaged liver cells. The inverse analysis method was used to simulate the finite element model in vitro. Changes in the parameters of the cell model after injury were explored and analyzed, and their potential for characterizing hepatocellular injury and related treatments was evaluated. RESEARCH HIGHLIGHTS: This study aims to establish an in vitro hyperelastic model of liver cells and analyze the mechanical changes of cells in vitro. An analysis method combining finite element analysis model and nanoindentation was used to obtain the key parameters of the model. The multi-depth mechanical differences and internal structural changes of injured liver cells were analyzed.
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Affiliation(s)
- Yi Zeng
- International Research Centre for Nano Handling and Manufacturing of China, Changchun University of Science and Technology, Changchun, China
- Ministry of Education Key Laboratory for Cross-Scale Micro and Nano Manufacturing, Changchun University of Science and Technology, Changchun, China
- School of Electronic Information Engineering, Changchun University, Changchun, China
| | - Xianping Liu
- School of Engineering, University of Warwick, Coventry, UK
| | - Zuobin Wang
- International Research Centre for Nano Handling and Manufacturing of China, Changchun University of Science and Technology, Changchun, China
- Ministry of Education Key Laboratory for Cross-Scale Micro and Nano Manufacturing, Changchun University of Science and Technology, Changchun, China
- JR3CN & IRAC, University of Bedfordshire, Luton, UK
| | - Wei Gao
- School of Electronic Information Engineering, Changchun University, Changchun, China
- School of Electronic Information Engineering, Changchun University of Science and Technology, Changchun, China
| | - Shengli Zhang
- International Research Centre for Nano Handling and Manufacturing of China, Changchun University of Science and Technology, Changchun, China
- Ministry of Education Key Laboratory for Cross-Scale Micro and Nano Manufacturing, Changchun University of Science and Technology, Changchun, China
| | - Ying Wang
- International Research Centre for Nano Handling and Manufacturing of China, Changchun University of Science and Technology, Changchun, China
- Ministry of Education Key Laboratory for Cross-Scale Micro and Nano Manufacturing, Changchun University of Science and Technology, Changchun, China
| | - Yunqing Liu
- School of Electronic Information Engineering, Changchun University of Science and Technology, Changchun, China
| | - Haiyue Yu
- International Research Centre for Nano Handling and Manufacturing of China, Changchun University of Science and Technology, Changchun, China
- Ministry of Education Key Laboratory for Cross-Scale Micro and Nano Manufacturing, Changchun University of Science and Technology, Changchun, China
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Guan Y, Fang Z, Hu A, Roberts S, Wang M, Ren W, Johansson PK, Heilshorn SC, Enejder A, Peltz G. Live-cell imaging of human liver fibrosis using hepatic micro-organoids. JCI Insight 2024; 10:e187099. [PMID: 39656528 PMCID: PMC11790020 DOI: 10.1172/jci.insight.187099] [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: 09/18/2024] [Accepted: 12/03/2024] [Indexed: 01/24/2025] Open
Abstract
Due to the limitations of available in vitro systems and animal models, we lack a detailed understanding of the pathogenetic mechanisms of and have minimal treatment options for liver fibrosis. Therefore, we engineered a live-cell imaging system that assessed fibrosis in a human multilineage hepatic organoid in a microwell (i.e., microHOs). Transcriptomic analysis revealed that TGFB converted mesenchymal cells in microHOs into myofibroblast-like cells resembling those in fibrotic human liver tissue. When pro-fibrotic intracellular signaling pathways were examined, the antifibrotic effect of receptor-specific tyrosine kinase inhibitors was limited to the fibrosis induced by the corresponding growth factor, which indicates their antifibrotic efficacy would be limited to fibrotic diseases solely mediated by that growth factor. Based upon transcriptomic and transcription factor activation analyses in microHOs, glycogen synthase kinase 3β and p38 MAPK inhibitors were identified as potential new broad-spectrum therapies for liver fibrosis. Other new therapies could subsequently be identified using the microHO system.
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Affiliation(s)
- Yuan Guan
- Department of Anesthesia, Pain and Perioperative Medicine, Stanford University School of Medicine, Stanford, California, USA
| | - Zhuoqing Fang
- Department of Anesthesia, Pain and Perioperative Medicine, Stanford University School of Medicine, Stanford, California, USA
| | - Angelina Hu
- Department of Anesthesia, Pain and Perioperative Medicine, Stanford University School of Medicine, Stanford, California, USA
| | - Sarah Roberts
- Department of Anesthesia, Pain and Perioperative Medicine, Stanford University School of Medicine, Stanford, California, USA
| | - Meiyue Wang
- Department of Anesthesia, Pain and Perioperative Medicine, Stanford University School of Medicine, Stanford, California, USA
| | - Wenlong Ren
- Department of Anesthesia, Pain and Perioperative Medicine, Stanford University School of Medicine, Stanford, California, USA
| | - Patrik K. Johansson
- Department of Materials Science and Engineering, Stanford University, Stanford, California, USA
| | - Sarah C. Heilshorn
- Department of Materials Science and Engineering, Stanford University, Stanford, California, USA
| | - Annika Enejder
- Department of Materials Science and Engineering, Stanford University, Stanford, California, USA
| | - Gary Peltz
- Department of Anesthesia, Pain and Perioperative Medicine, Stanford University School of Medicine, Stanford, California, USA
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AbouSamra MM. Liposomal nano-carriers mediated targeting of liver disorders: mechanisms and applications. J Liposome Res 2024; 34:728-743. [PMID: 38988127 DOI: 10.1080/08982104.2024.2377085] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/18/2024] [Revised: 06/12/2024] [Accepted: 07/02/2024] [Indexed: 07/12/2024]
Abstract
Liver disorders present a significant global health challenge, necessitating the exploration of innovative treatment modalities. Liposomal nanocarriers have emerged as promising candidates for targeted drug delivery to the liver. This review offers a comprehensive examination of the mechanisms and applications of liposomal nanocarriers in addressing various liver disorders. Firstly discussing the liver disorders and the conventional treatment approaches, the review delves into the liposomal structure and composition. Moreover, it tackles the different mechanisms of liposomal targeting including both passive and active strategies. After that, the review moves on to explore the therapeutic potentials of liposomal nanocarriers in treating liver cirrhosis, fibrosis, viral hepatitis, and hepatocellular carcinoma. Through discussing recent advancements and envisioning future perspectives, this review highlights the role of liposomal nanocarriers in enhancing the effectiveness and the safety of liver disorders and consequently improving patient outcomes and enhances life quality.
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Affiliation(s)
- Mona M AbouSamra
- Pharmaceutical Technology Department, National Research Centre, Giza, Egypt
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Schönke M, Rensen PC. Mouse Models for the Study of Liver Fibrosis Regression In Vivo and Ex Vivo. J Clin Transl Hepatol 2024; 12:930-938. [PMID: 39544245 PMCID: PMC11557367 DOI: 10.14218/jcth.2024.00212] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/26/2024] [Revised: 09/10/2024] [Accepted: 09/29/2024] [Indexed: 11/17/2024] Open
Abstract
This review discussed experimental mouse models used in the pre-clinical study of liver fibrosis regression, a pivotal process in preventing the progression of metabolic dysfunction-associated steatohepatitis to irreversible liver cirrhosis. These models provide a valuable resource for understanding the cellular and molecular processes underlying fibrosis regression in different contexts. The primary focus of this review is on the most commonly used models with diet- or hepatotoxin-induced fibrosis, but it also touches upon genetic models and mouse models with biliary atresia or parasite-induced fibrosis. In addition to emphasizing in vivo models, we briefly summarized current in vitro approaches designed for studying fibrosis regression and provided an outlook on evolving methodologies that aim to refine and reduce the number of experimental animals needed for these studies. Together, these models contribute significantly to unraveling the underlying mechanisms of liver fibrosis regression and offer insights into potential therapeutic interventions. By presenting a comprehensive overview of these models and highlighting their respective advantages and limitations, this review serves as a roadmap for future research.
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Affiliation(s)
- Milena Schönke
- Division of Endocrinology, Department of Medicine, Leiden University Medical Center, Leiden, The Netherlands
- Einthoven Laboratory for Experimental Vascular Medicine, Leiden University Medical Center, Leiden, The Netherlands
| | - Patrick C.N. Rensen
- Division of Endocrinology, Department of Medicine, Leiden University Medical Center, Leiden, The Netherlands
- Einthoven Laboratory for Experimental Vascular Medicine, Leiden University Medical Center, Leiden, The Netherlands
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Wang P, Li J, Ji M, Pan J, Cao Y, Kong Y, Zhu L, Li J, Li B, Chang L, Zhang Z. Vitamin D receptor attenuates carbon tetrachloride-induced liver fibrosis via downregulation of YAP. JOURNAL OF HAZARDOUS MATERIALS 2024; 478:135480. [PMID: 39146589 DOI: 10.1016/j.jhazmat.2024.135480] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/13/2024] [Revised: 08/02/2024] [Accepted: 08/08/2024] [Indexed: 08/17/2024]
Abstract
Liver fibrosis is characterized by the excessive accumulation of extracellular matrix proteins, which can lead to cirrhosis and liver cancer. Metabolic dysfunction-associated steatosis liver diseases are common causes of liver fibrosis, sharing a similar pathogenesis with carbon tetrachloride (CCl₄) exposure. This process involves the activation of hepatic stellate cells (HSCs) into myofibroblasts. However, the detailed mechanism and effective treatment strategies require further investigation. In this study, we uncovered a negative correlation between VDR expression and YAP within HSCs. Subsequently, we demonstrated that VDR exerted a downregulatory influence on YAP transcriptional activity in HSCs. Intriguingly, activation VDR effectively inhibited the culture induced activation of primary HSCs by suppressing the transcriptional activity of early YAP. Furthermore, in vivo results manifested that hepatic-specific deletion of YAP/TAZ ameliorates CCl4-induced liver fibrosis, and nullified the antifibrotic efficacy of VDR. Importantly, a YAP inhibitor rescued the exacerbation of liver fibrosis induced by hepatic-specific VDR knockout. Moreover, the combined pharmacological of VDR agonist and YAP inhibitor demonstrated a synergistic effect in diminishing CCl4-induced liver fibrosis, primary HSCs activation and hepatic injury in vivo. These effects were underpinned by their collective ability to inhibit HSC activation through AMPK activation, consequently curbing ATP synthesis and HSCs proliferation. In conclusion, our results not only revealed the inhibition of VDR on YAP-activated liver stellate cells but also identified a synergistic effect of VDR agonist and YAP inhibitor in an AMPKα-dependent manner, providing a practical foundation for integration of multi-targeted drugs in the therapy of CCl4-induced hepatic fibrosis.
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Affiliation(s)
- Ping Wang
- Department of Occupational and Environmental Health, School of Public Health, Suzhou Medical College of Soochow University, Suzhou 215123, China
| | - Jie Li
- Department of Nutrition and Food Hygiene, School of Public Health, Suzhou Medical College of Soochow University, Suzhou 215123, China
| | - Mintao Ji
- State Key Laboratory of Radiation Medicine and Protection, Collaborative Innovation Center of Radiation Medicine of Jiangsu Higher Education Institutions, Jiangsu Key Laboratory of Infection and Immunity. The Fourth Affiliated Hospital of Soochow University, School of Radiation Medicine and Protection, Suzhou Medical College of Soochow University, Suzhou 215123, China
| | - Jinjing Pan
- Department of Nutrition and Food Hygiene, School of Public Health, Suzhou Medical College of Soochow University, Suzhou 215123, China
| | - Yanmei Cao
- Department of Infectious Diseases, The Affiliated Infectious Diseases Hospital of Soochow University, Suzhou 215007, China
| | - Yulin Kong
- Department of Infectious Diseases, The Affiliated Infectious Diseases Hospital of Soochow University, Suzhou 215007, China
| | - Li Zhu
- Department of Infectious Diseases, The Affiliated Infectious Diseases Hospital of Soochow University, Suzhou 215007, China
| | - Jiafu Li
- Department of Occupational and Environmental Health, School of Public Health, Suzhou Medical College of Soochow University, Suzhou 215123, China
| | - Bingyan Li
- Department of Nutrition and Food Hygiene, School of Public Health, Suzhou Medical College of Soochow University, Suzhou 215123, China.
| | - Lei Chang
- State Key Laboratory of Radiation Medicine and Protection, Collaborative Innovation Center of Radiation Medicine of Jiangsu Higher Education Institutions, Jiangsu Key Laboratory of Infection and Immunity. The Fourth Affiliated Hospital of Soochow University, School of Radiation Medicine and Protection, Suzhou Medical College of Soochow University, Suzhou 215123, China; Institute of Radiation Medicine, Shanghai Medical College, Fudan University, Shanghai 200433, China.
| | - Zengli Zhang
- Department of Occupational and Environmental Health, School of Public Health, Suzhou Medical College of Soochow University, Suzhou 215123, China.
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Roy S, Chakrabarti M, Mondal T, Das TK, Sarkar T, Datta S, Kundu M, Banerjee M, Kulkarni OP. Effect of an Autotaxin Inhibitor, 2-(4-Chlorophenyl)-7-methyl-8-pentylimidazo[1,2- a] Pyrimidin-5(8 H)-one (CBT-295), on Bile Duct Ligation-Induced Chronic Liver Disease and Associated Hepatic Encephalopathy in Rats. ACS Pharmacol Transl Sci 2024; 7:2662-2676. [PMID: 39296254 PMCID: PMC11406694 DOI: 10.1021/acsptsci.4c00066] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2024] [Revised: 07/24/2024] [Accepted: 07/26/2024] [Indexed: 09/21/2024]
Abstract
The role of autotaxin (ATX)-lysophosphatidic acid (LPA) is yet to be explored in the context of liver cirrhosis and associated encephalopathy. Our objective of this study was to evaluate the role of an ATX inhibitor in biliary cirrhosis and associated hepatic encephalopathy in rats. The preliminary investigation revealed significant impairment in liver function, which eventually led to the development of hepatic encephalopathy. Interestingly, LPA levels were significantly increased in the plasma, liver, and brain of rats following bile duct ligation. Subsequently, we tested the efficacy of an ATX inhibitor, CBT-295, in bile duct-induced biliary cirrhosis and neuropsychiatric symptoms associated with hepatic encephalopathy. CBT-295 showed good oral bioavailability and favorable pharmacokinetic properties. CBT-295 exhibited a significant reduction in inflammatory cytokines like TGF-β, TNF-α, and IL-6 levels, also reduced bile duct proliferation marker CK-19, and lowered liver fibrosis, as evident from reduced collagen deposition. The reversal of liver fibrosis with CBT-295 led to a reduction in blood and brain ammonia levels. Furthermore, CBT-295 also reduced neuroinflammation induced by ammonia, which is characterized by a significant reduction in brain cytokine levels. It improved neuropsychiatric symptoms such as locomotor activities, cognitive impairment, and clinical grading scores associated with hepatic encephalopathy. The improvement in hepatic encephalopathy observed with the ATX inhibitor could be the result of its hepatoprotective action and its ability to attenuate neuroinflammation. Therefore, inhibition of ATX-LPA signaling can be a multifactorial approach for the treatment of chronic liver diseases.
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Affiliation(s)
- Subhasis Roy
- TCG Lifesciences Private Ltd., Sector V, Salt Lake, Kolkata 700091, West Bengal, India
| | - Monali Chakrabarti
- TCG Lifesciences Private Ltd., Sector V, Salt Lake, Kolkata 700091, West Bengal, India
| | - Trisha Mondal
- TCG Lifesciences Private Ltd., Sector V, Salt Lake, Kolkata 700091, West Bengal, India
| | - Tapas Kumar Das
- TCG Lifesciences Private Ltd., Sector V, Salt Lake, Kolkata 700091, West Bengal, India
| | - Tonmoy Sarkar
- TCG Lifesciences Private Ltd., Sector V, Salt Lake, Kolkata 700091, West Bengal, India
| | - Sebak Datta
- TCG Lifesciences Private Ltd., Sector V, Salt Lake, Kolkata 700091, West Bengal, India
| | - Mrinalkanti Kundu
- TCG Lifesciences Private Ltd., Sector V, Salt Lake, Kolkata 700091, West Bengal, India
| | - Manish Banerjee
- TCG Lifesciences Private Ltd., Sector V, Salt Lake, Kolkata 700091, West Bengal, India
| | - Onkar Prakash Kulkarni
- Metabolic Disorders and Neuroscience Research Laboratory, Department of Pharmacy, Birla Institute of Technology and Science, Pilani-Hyderabad Campus, Hyderabad 500078, India
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Cai Y, Liu J, Yang H, Zheng L, Wu D, Xiao E, Dai Y. Utilizing multicompartmental restriction spectrum magnetic resonance imaging for liver fibrosis characterization in a mouse model. Med Phys 2024; 51:4635-4645. [PMID: 38753987 DOI: 10.1002/mp.17126] [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: 10/07/2023] [Revised: 04/01/2024] [Accepted: 04/05/2024] [Indexed: 05/18/2024] Open
Abstract
BACKGROUND Currently, an advanced imaging method may be necessary for magnetic resonance imaging (MRI) to diagnosis and quantify liver fibrosis (LF). PURPOSE To evaluate the feasibility of the multicompartmental restriction spectrum imaging (RSI) model to characterize LF in a mouse model. METHODS Thirty mice with carbon tetrachloride (CCl4)-induced LF and eight control mice were investigated using multi-b-value (ranging from 0 to 2000 s/mm2) diffusion-weighted imaging (DWI) on a 3T scanner. DWI data were processed using RSI model (2-5 compartments) with the Bayesian Information Criterion (BIC) determining the optimal model. Conventional ADC value and signal fraction of each compartment in the optimal RSI model were compared across groups. Receiver operating characteristics (ROC) curve analysis was performed to determine the diagnosis performances of different parameters, while Spearman correlation analysis was employed to investigate the correlation between different tissue compartments and the stage of LF. RESULTS According to BIC results, a 4-compartment RSI model (RSI4) with optimal ADCs of 0.471 × 10-3, 1.653 × 10-3, 9.487 × 10-3, and > 30 × 10-3, was the optimal model to characterize LF. Significant differences in signal contribution fraction of the C1 and C3 compartments were observed between LF and control groups (P = 0.018 and 0.003, respectively). ROC analysis showed that RSI4-C3 was the most effective single diffusion parameter for characterizing LF (AUC = 0.876, P = 0.003). Furthermore, the combination of ADC values and RSI4-C3 value increased the diagnosis performance significantly (AUC = 0.894, P = 0.002). CONCLUSION The 4-compartment RSI model has the potential to distinguish LF from the control group based on diffusion parameters. RSI4-C3 showed the highest diagnostic performance among all the parameters. The combination of ADC and RSI4-C3 values further improved the discrimination performance.
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Affiliation(s)
- Yeyu Cai
- Department of Radiology, The Second Xiangya Hospital, Central South University, Changsha, Hunan Province, China
| | - Jiayi Liu
- Department of Oncology, The Second Xiangya Hospital, Central South University, Changsha, Hunan Province, China
| | - HaiTao Yang
- Department of Radiology, The Second Xiangya Hospital, Central South University, Changsha, Hunan Province, China
| | - Liyun Zheng
- Shanghai Institute of Medical Imaging, Shanghai, China
| | - Dongmei Wu
- Shanghai Key Laboratory of Magnetic Resonance, School of Physics and Electronics Science, East China Normal University, Shanghai, China
| | - Enhua Xiao
- Department of Radiology, The Second Xiangya Hospital, Central South University, Changsha, Hunan Province, China
| | - Yongming Dai
- School of Biomedical Engineering & State Key Laboratory of Advanced Medical Materials and Devices, ShanghaiTech University, Shanghai, China
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Málaga SK, de Souza Balbueno MC, Martins JA, da Costa LD, de Sousa Barbosa ML, Marcili A, de Paula Coelho C. Contribution of ultrasound examination in diagnosing platynosomiasis and correlation with macro and microscopic findings in callitrichids kept under human care. J Med Primatol 2024; 53:e12712. [PMID: 38825748 DOI: 10.1111/jmp.12712] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2023] [Revised: 04/26/2024] [Accepted: 05/19/2024] [Indexed: 06/04/2024]
Abstract
BACKGROUND Platynosomiasis in non-human primates kept under human care causes chronic disease of the bile ducts and liver, which initially presents with nonspecific signs and can culminate in the death of the animal. Diagnosing this disease is a challenge, and an ultrasound examination can be an excellent tool when it is suspected. METHODS This study describes the ultrasound findings from 57 marmosets with suspected infection by Platynosomum sp., the correlated hepatobiliary changes, and the anatomopathological findings that confirmed the occurrence of platynosomiasis. RESULTS In six marmosets (one C. aurita, two C. jacchus, and three Callithrix sp.), Platynosomum infection was confirmed macroscopically (presence of adult trematodes in the gallbladder) and microscopically (adults, larvae, and eggs in histological examinations and eggs in bile and feces). These findings were compatible with the hepatobiliary changes and with images suggestive of parasitic structures in ante-mortem assessments. CONCLUSION Ultrasound examination demonstrated its usefulness within the clinical routine for investigating this parasitosis.
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Guan Y, Peltz G. Hepatic organoids move from adolescence to maturity. Liver Int 2024; 44:1290-1297. [PMID: 38451053 DOI: 10.1111/liv.15893] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/17/2023] [Revised: 02/08/2024] [Accepted: 02/28/2024] [Indexed: 03/08/2024]
Abstract
Since organoids were developed 15 years ago, they are now in their adolescence as a research tool. The ability to generate 'tissue in a dish' has created enormous opportunities for biomedical research. We examine the contributions that hepatic organoids have made to three areas of liver research: as a source of cells and tissue for basic research, for drug discovery and drug safety testing, and for understanding disease pathobiology. We discuss the features that enable hepatic organoids to provide useful models for human liver diseases and identify four types of advances that will enable them to become a mature (i.e., adult) research tool over the next 5 years. During this period, advances in single-cell RNA sequencing and CRISPR technologies coupled with improved hepatic organoid methodology, which enables them to have a wider range of cell types that are present in liver and to be grown in microwells, will generate discoveries that will dramatically advance our understanding of liver development and the pathogenesis of liver diseases. It will generate also new approaches for treating liver fibrosis, which remains a major public health problem with few treatment options.
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Affiliation(s)
- Yuan Guan
- Department of Anesthesia, Pain and Perioperative Medicine, Stanford University School of Medicine, Stanford, California, USA
| | - Gary Peltz
- Department of Anesthesia, Pain and Perioperative Medicine, Stanford University School of Medicine, Stanford, California, USA
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Xiao L, Sunniya H, Li J, Kakar MU, Dai R, Li B. Isolation and purification of polysaccharides from Bupleurum marginatum Wall.ex DC and their anti-liver fibrosis activities. Front Pharmacol 2024; 15:1342638. [PMID: 38576476 PMCID: PMC10991770 DOI: 10.3389/fphar.2024.1342638] [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: 11/22/2023] [Accepted: 01/23/2024] [Indexed: 04/06/2024] Open
Abstract
Bupleurum marginatum Wall.ex DC [Apiaceae] (BM)is widely grown in southwestern China, and the whole plant is used as Traditional Chinese Medicine (TCM). Polysaccharides are main natural products in lots of TCM and have been studied for their effects of reducing oxidative stress, anti-inflammation and immune regulation. Herein, we investigated the extraction techniques of Bupleurum marginatum Wall.ex DC polysaccharides (BMP), the identification of their key components, and their ability to inhibit liver fibrosis in both cellular and animal models. Component identification indicated that monosaccharides in BMP mainly consisted of glucose, galactose, mannose, rhamnose, arabinose, and xylose. In vivo analysis revealed that BMP provided significant protective effects on N-Nitroso dimethylamine (NDMA)-induced liver fibrosis rats through reducing hepatomegaly, reducing tissue inflammation, and reducing collagen deposition. BMP also improved the hepatobiliary system and liver metabolism in accord to reduce the serum levels of ALT, AST, ALP, r-GT, and TBIL. In addition, BMP could reduce the level of inflammation and fibrosis through inhibition of IL-1β and TGF-β1. Cellular studies showed that the BMP could provide therapeutic effects on lipopolysaccharide (LPS)-induced cellular fibrosis model, and could reduce the level of inflammation and fibrosis by decreasing the level of TGF-β1, IL-1β, and TNF-α. Our study demonstrated that BMP may provide a new therapy strategy of liver injury and liver fibrosis.
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Affiliation(s)
- Li Xiao
- Beijing Key Laboratory for Separation and Analysis in Biomedicine and Pharmaceuticals, School of Life Science, Beijing Institute of Technology, Beijing, China
- School of Medical Technology, Beijing Institute of Technology, Beijing, China
| | - Hafsa Sunniya
- Beijing Key Laboratory for Separation and Analysis in Biomedicine and Pharmaceuticals, School of Life Science, Beijing Institute of Technology, Beijing, China
| | - Jingyi Li
- Beijing Key Laboratory for Separation and Analysis in Biomedicine and Pharmaceuticals, School of Life Science, Beijing Institute of Technology, Beijing, China
- School of Life Science, Beijing Institute of Technology, Beijing, China
| | - Mohib Ullah Kakar
- Beijing Key Laboratory for Separation and Analysis in Biomedicine and Pharmaceuticals, School of Life Science, Beijing Institute of Technology, Beijing, China
| | - Rongji Dai
- Beijing Key Laboratory for Separation and Analysis in Biomedicine and Pharmaceuticals, School of Life Science, Beijing Institute of Technology, Beijing, China
- School of Life Science, Beijing Institute of Technology, Beijing, China
| | - Bo Li
- Beijing Key Laboratory for Separation and Analysis in Biomedicine and Pharmaceuticals, School of Life Science, Beijing Institute of Technology, Beijing, China
- Advanced Research Institute of Multidisciplinary Science, Beijing Institute of Technology, Beijing, China
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Calixto-Tlacomulco S, Luna-Reyes I, Delgado-Coello B, Gutiérrez-Vidal R, Reyes-Grajeda JP, Mas-Oliva J. CETP-derived Peptide Seq-1, the Key Component of HB-ATV-8 Vaccine Prevents Stress Responses, and Promotes Downregulation of Pro-Fibrotic Genes in Hepatocytes and Stellate Cells. Arch Med Res 2024; 55:102937. [PMID: 38301446 DOI: 10.1016/j.arcmed.2023.102937] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2023] [Revised: 11/09/2023] [Accepted: 12/14/2023] [Indexed: 02/03/2024]
Abstract
BACKGROUND The nasal vaccine HB-ATV-8 has emerged as a promising approach for NAFLD (non-alcoholic fatty liver disease) and atherosclerosis prevention. HB-ATV-8 contains peptide seq-1 derived from the carboxy-end of the Cholesteryl Ester Transfer Protein (CETP), shown to reduce liver fibrosis, inflammation, and atherosclerotic plaque formation in animal models. Beyond the fact that this vaccine induces B-cell lymphocytes to code for antibodies against the seq-1 sequence, inhibiting CETP's cholesterol transfer activity, we have hypothesized that beyond the modulation of CETP activity carried out by neutralizing antibodies, the observed molecular effects may also correspond to the direct action of peptide seq-1 on diverse cellular systems and molecular features involved in the development of liver fibrosis. METHODS The HepG2 hepatoma-derived cell line was employed to establish an in vitro steatosis model. To obtain a conditioned cell medium to be used with hepatic stellate cell (HSC) cultures, HepG2 cells were exposed to fatty acids or fatty acids plus peptide seq-1, and the culture medium was collected. Gene regulation of COL1A1, ACTA2, TGF-β, and the expression of proteins COL1A1, MMP-2, and TIMP-2 were studied. AIM To establish an in vitro steatosis model employing HepG2 cells that mimics molecular processes observed in vivo during the onset of liver fibrosis. To evaluate the effect of peptide Seq-1 on lipid accumulation and pro-fibrotic responses. To study the effect of Seq-1-treated steatotic HepG2 cell supernatants on lipid accumulation, oxidative stress, and pro-fibrotic responses in HSC. RESULTS AND CONCLUSION Peptide seq-1-treated HepG2 cells show a downregulation of COLIA1, ACTA2, and TGF-β genes, and a decreased expression of proteins such as COL1A1, MMP-2, and TIMP-2, associated with the remodeling of extracellular matrix components. The same results are observed when HSCs are incubated with peptide Seq-1-treated steatotic HepG2 cell supernatants. The present study consolidates the nasal vaccine HB-ATV-8 as a new prospect in the treatment of NASH directly associated with the development of cardiovascular disease.
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Affiliation(s)
| | - Ismael Luna-Reyes
- Cellular Physiology Institute, Universidad Nacional Autónoma de México, Mexico City, Mexico
| | - Blanca Delgado-Coello
- Cellular Physiology Institute, Universidad Nacional Autónoma de México, Mexico City, Mexico
| | - Roxana Gutiérrez-Vidal
- Researchers Program for Mexico CONAHCYT, Mexico City, Mexico; Laboratory of Metabolic Diseases, Cinvestav Unidad Monterey, Apodaca, Nuevo León, Mexico
| | | | - Jaime Mas-Oliva
- Cellular Physiology Institute, Universidad Nacional Autónoma de México, Mexico City, Mexico.
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13
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Zhou Z, Zhang R, Li X, Zhang W, Zhan Y, Lang Z, Tao Q, Yu J, Yu S, Yu Z, Zheng J. Circular RNA cVIM promotes hepatic stellate cell activation in liver fibrosis via miR-122-5p/miR-9-5p-mediated TGF-β signaling cascade. Commun Biol 2024; 7:113. [PMID: 38243118 PMCID: PMC10798957 DOI: 10.1038/s42003-024-05797-3] [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: 04/21/2023] [Accepted: 01/09/2024] [Indexed: 01/21/2024] Open
Abstract
Hepatic stellate cell (HSC) activation is considered as a central driver of liver fibrosis and effective suppression of HSC activation contributes to the treatment of liver fibrosis. Circular RNAs (circRNAs) have been reported to be important in tumor progression. However, the contributions of circRNAs in liver fibrosis remain largely unclear. The liver fibrosis-specific circRNA was explored by a circRNA microarray and cVIM (a circRNA derived from exons 4 to 8 of the vimentin gene mmu_circ_32994) was selected as the research object. Further studies revealed that cVIM, mainly expressed in the cytoplasm, may act as a sponge for miR-122-5p and miR-9-5p to enhance expression of type I TGF-β receptor (TGFBR1) and TGFBR2 and promotes activation of the TGF-β/Smad pathway, thereby accelerating the progression of liver fibrosis. Our results demonstrate a vital role for cVIM in promoting liver fibrosis progression and provide a fresh perspective on circRNAs in liver fibrosis.
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Affiliation(s)
- Zhenxu Zhou
- Department of Hernia and Abdominal Wall Surgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325000, China
| | - Rongrong Zhang
- Key Laboratory of Diagnosis and Treatment of Severe Hepato-Pancreatic Diseases of Zhejiang Province, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325000, China
| | - Xinmiao Li
- Key Laboratory of Diagnosis and Treatment of Severe Hepato-Pancreatic Diseases of Zhejiang Province, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325000, China
| | - Weizhi Zhang
- Key Laboratory of Diagnosis and Treatment of Severe Hepato-Pancreatic Diseases of Zhejiang Province, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325000, China
| | - Yating Zhan
- Key Laboratory of Diagnosis and Treatment of Severe Hepato-Pancreatic Diseases of Zhejiang Province, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325000, China
| | - Zhichao Lang
- Key Laboratory of Diagnosis and Treatment of Severe Hepato-Pancreatic Diseases of Zhejiang Province, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325000, China
| | - Qiqi Tao
- Key Laboratory of Diagnosis and Treatment of Severe Hepato-Pancreatic Diseases of Zhejiang Province, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325000, China
| | - Jinglu Yu
- Key Laboratory of Diagnosis and Treatment of Severe Hepato-Pancreatic Diseases of Zhejiang Province, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325000, China
| | - Suhui Yu
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325000, China
| | - Zhengping Yu
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325000, China
| | - Jianjian Zheng
- Key Laboratory of Clinical Laboratory Diagnosis and Translational Research of Zhejiang Province, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325000, China.
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14
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Zhang L, Zhou Q, Zhang J, Cao K, Fan C, Chen S, Jiang H, Wu F. Liver transcriptomic and proteomic analyses provide new insight into the pathogenesis of liver fibrosis in mice. Genomics 2023; 115:110738. [PMID: 37918454 DOI: 10.1016/j.ygeno.2023.110738] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/17/2023] [Revised: 09/25/2023] [Accepted: 10/30/2023] [Indexed: 11/04/2023]
Abstract
BACKGROUND Liver fibrosis (LF) is a kind of progressive liver injury reaction. The goal of this study was to achieve a more detailed understanding of the molecular changes in response to CCl4-induced LF through the identification of a differentially expressed liver transcriptomic and proteomic. RESULTS A total of 1224 differentially expressed genes (DEGs) and 302 differentially expressed proteins (DEPs) were significantly identified at the transcriptomic and proteomic level, respectively, and 69 genes (hereafter "cor-DEGs-DEPs" genes) were detected at both levels. Pathway enrichment analysis showed that these cor-DEGs-DEPs genes were significantly enriched in 133 pathways. Importantly, among the cor-DEGs-DEPs genes, Gstm1, Gstm3, Ephx1 and Gstp1 were shown to be associated with metabolic pathways, and confirmed by RT-qPCR and parallel reaction monitoring (PRM) verification. CONCLUSIONS Through the combined analysis of transcriptomic and proteomic data, this study provides valuable insights into the potential mechanism of the pathogenesis of LF, and lays a theoretical foundation for the further development of targeted therapy for LF.
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Affiliation(s)
- Lili Zhang
- Experimental Center of Clinical Research, The First Affiliated Hospital of Anhui University of Chinese Medicine, Hefei, China; School of Pharmacy, Anhui University of Chinese Medicine, Hefei, China.
| | - Qiumei Zhou
- Experimental Center of Clinical Research, The First Affiliated Hospital of Anhui University of Chinese Medicine, Hefei, China.
| | - Jiafu Zhang
- Department of Pharmacy, The First Affiliated Hospital of Anhui University of Chinese Medicine, Hefei, China.
| | - Kefeng Cao
- Departments of Laboratory Medicine, Traditional Chinese Medical Hospital of Taihe County, Fuyang, China.
| | - Chang Fan
- Experimental Center of Clinical Research, The First Affiliated Hospital of Anhui University of Chinese Medicine, Hefei, China; School of Pharmacy, Anhui University of Chinese Medicine, Hefei, China.
| | - Sen Chen
- Experimental Center of Clinical Research, The First Affiliated Hospital of Anhui University of Chinese Medicine, Hefei, China; School of Pharmacy, Anhui University of Chinese Medicine, Hefei, China.
| | - Hui Jiang
- Experimental Center of Clinical Research, The First Affiliated Hospital of Anhui University of Chinese Medicine, Hefei, China; School of Pharmacy, Anhui University of Chinese Medicine, Hefei, China.
| | - Furong Wu
- Department of Pharmacy, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China.
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15
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Ye Y, Zhang B, Mai W, Tan Y, Feng Z, Huang Q. Metabolomics study of the hepatoprotective effect of total flavonoids of Mallotus apelta leaf in carbon tetrachloride-induced liver fibrosis in rats. Biomed Chromatogr 2023; 37:e5711. [PMID: 37593807 DOI: 10.1002/bmc.5711] [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: 05/07/2023] [Revised: 06/26/2023] [Accepted: 07/19/2023] [Indexed: 08/19/2023]
Abstract
Mallotus apelta leaf, recorded in the quality standard of Yao Medicinal Material in Guangxi Zhuang autonomous region, is commonly used in the treatment of liver diseases. Total flavonoids of M. apelta leaf (TFM) had good anti-fibrosis activity, but the anti-fibrosis mechanism of TFM is still unclear. Nuclear magnetic resonance technology was used to study the dynamic changes of urine metabolites in CCl4 -induced liver fibrosis before and after TFM treatment. Ingenuity Path Analysis (IPA) was used to find potential target genes for TFM to improve liver fibrosis and verify the expression of target genes by real-time fluorescent quantitative PCR and Western blotting. TFM can significantly reduce serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP) levels, improve liver steatosis and reduce inflammation; in urine metabolomics, a total of seven potential biomarkers were found, mainly involving two metabolic pathways; IPA analysis showed that TNF may be a potential target for TFM to improve liver fibrosis induced by CCl4 in rats. This study found that TNF may be a potential target gene for TFM treatment of liver fibrosis, and shows that the anti-fibrosis mechanism of TFM could improve liver fibrosis by regulating the tricarboxylic acid cycle and subtaurine metabolism.
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Affiliation(s)
- Yong Ye
- Guangxi Key Laboratory of Bioactive Molecules Research and Evaluation, Nanning, China
| | - Bo Zhang
- Scientific Research Center, Guilin Medical University, Guilin, Guangxi, China
| | - Wanting Mai
- Pharmaceutical College, Guangxi Medical University, Nanning, Guangxi, China
| | - Yanjun Tan
- Scientific Research Center, Guilin Medical University, Guilin, Guangxi, China
| | - Zhongwen Feng
- Pharmaceutical College, Guangxi Medical University, Nanning, Guangxi, China
| | - Qiujie Huang
- Pharmaceutical College, Guangxi University of Chinese Medicine, Nanning, Guangxi, China
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16
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Sun Q, Dai H, Wang S, Chen Y, Shi H. Progress in research on the role played by myeloid-derived suppressor cells in liver diseases. Scand J Immunol 2023; 98:e13312. [PMID: 38441348 DOI: 10.1111/sji.13312] [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: 11/18/2022] [Revised: 06/23/2023] [Accepted: 07/02/2023] [Indexed: 03/07/2024]
Abstract
Myeloid-derived suppressor cells (MDSCs) refer to a group of immature myeloid cells with potent immunosuppressive capacity upon activation by pathological conditions. Because of their potent immunosuppressive ability, MDSCs have garnered extensive attention in the past few years in the fields of oncology, infection, chronic inflammation and autoimmune diseases. Research on MDSCs in liver diseases has gradually increased, and their potential therapeutic roles will be further explored. This review presents a summary of the involvement and the role played by MDSCs in liver diseases, thus identifying their potential targets for the treatment of liver diseases and providing new directions for liver disease-related research.
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Affiliation(s)
- Qianqian Sun
- Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, China
| | - Heng Dai
- Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, China
| | - Siliang Wang
- Department of Pharmacy, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, China
| | - Yuanyuan Chen
- Department of Biochemistry and Molecular Biology, Nanjing Medical University, Nanjing, China
| | - Huilian Shi
- Department of Infectious Diseases, Jiangsu Province Hospital of Chinese Medicine, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, China
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17
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Hijazi N, Shi Z, Rockey DC. Paxillin regulates liver fibrosis via actin polymerization and ERK activation in hepatic stellate cells. J Cell Sci 2023; 136:jcs261122. [PMID: 37667902 PMCID: PMC10560551 DOI: 10.1242/jcs.261122] [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: 02/28/2023] [Accepted: 08/15/2023] [Indexed: 09/06/2023] Open
Abstract
Liver injury leads to fibrosis and cirrhosis. The primary mechanism underlying the fibrogenic response is the activation of hepatic stellate cells (HSCs), which are 'quiescent' in normal liver but become 'activated' after injury by transdifferentiating into extracellular matrix (ECM)-secreting myofibroblasts. Given that integrins are important in HSC activation and fibrogenesis, we hypothesized that paxillin, a key downstream effector in integrin signaling, might be critical in the fibrosis pathway. Using a cell-culture-based model of HSC activation and in vivo models of liver injury, we found that paxillin is upregulated in activated HSCs and fibrotic livers. Overexpression of paxillin (both in vitro and in vivo) led to increased ECM protein expression, and depletion of paxillin in a novel conditional mouse injury model reduced fibrosis. The mechanism by which paxillin mediated this effect appeared to be through the actin cytoskeleton, which signals to the ERK pathway and induces ECM protein production. These data highlight a novel role for paxillin in HSC biology and fibrosis.
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Affiliation(s)
- Nour Hijazi
- Digestive Disease Research Center Core, Medical University of South Carolina, Charleston, SC 29425, USA
| | - Zengdun Shi
- Digestive Disease Research Center Core, Medical University of South Carolina, Charleston, SC 29425, USA
| | - Don C. Rockey
- Digestive Disease Research Center Core, Medical University of South Carolina, Charleston, SC 29425, USA
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18
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Li Y, Lu Y, Nian M, Sheng Q, Zhang C, Han C, Dou X, Ding Y. Therapeutic potential and mechanism of Chinese herbal medicines in treating fibrotic liver disease. Chin J Nat Med 2023; 21:643-657. [PMID: 37777315 DOI: 10.1016/s1875-5364(23)60443-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2022] [Indexed: 10/02/2023]
Abstract
Liver fibrosis is a pathological condition characterized by replacement of normal liver tissue with scar tissue, and also the leading cause of liver-related death worldwide. During the treatment of liver fibrosis, in addition to antiviral therapy or removal of inducers, there remains a lack of specific and effective treatment strategies. For thousands of years, Chinese herbal medicines (CHMs) have been widely used to treat liver fibrosis in clinical setting. CHMs are effective for liver fibrosis, though its mechanisms of action are unclear. In recent years, many studies have attempted to determine the possible mechanisms of action of CHMs in treating liver fibrosis. There have been substantial improvements in the experimental investigation of CHMs which have greatly promoted the understanding of anti-liver fibrosis mechanisms. In this review, the role of CHMs in the treatment of liver fibrosis is described, based on studies over the past decade, which has addressed the various mechanisms and signaling pathways that mediate therapeutic efficacy. Among them, inhibition of stellate cell activation is identified as the most common mechanism. This article provides insights into the research direction of CHMs, in order to expand its clinical application range and improve its effectiveness.
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Affiliation(s)
- Yanwei Li
- Department of Infectious Diseases, Shengjing Hospital of China Medical University, Shenyang 110000, China
| | - Yunrui Lu
- Liaoning University of Traditional Chinese Medicine, Shenyang 110000, China
| | - Mozuo Nian
- Department of Infectious Diseases, Shengjing Hospital of China Medical University, Shenyang 110000, China
| | - Qiuju Sheng
- Department of Infectious Diseases, Shengjing Hospital of China Medical University, Shenyang 110000, China
| | - Chong Zhang
- Department of Infectious Diseases, Shengjing Hospital of China Medical University, Shenyang 110000, China
| | - Chao Han
- Department of Infectious Diseases, Shengjing Hospital of China Medical University, Shenyang 110000, China
| | - Xiaoguang Dou
- Department of Infectious Diseases, Shengjing Hospital of China Medical University, Shenyang 110000, China
| | - Yang Ding
- Department of Infectious Diseases, Shengjing Hospital of China Medical University, Shenyang 110000, China.
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Melaibari M, Alkreathy HM, Esmat A, Rajeh NA, Shaik RA, Alghamdi AA, Ahmad A. Anti-Fibrotic Efficacy of Apigenin in a Mice Model of Carbon Tetrachloride-Induced Hepatic Fibrosis by Modulation of Oxidative Stress, Inflammation, and Fibrogenesis: A Preclinical Study. Biomedicines 2023; 11:biomedicines11051342. [PMID: 37239014 DOI: 10.3390/biomedicines11051342] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2023] [Revised: 04/27/2023] [Accepted: 04/28/2023] [Indexed: 05/28/2023] Open
Abstract
BACKGROUND Hepatic fibrosis is a major health problem all over the world, and there is no effective treatment to cure it. Hence, the current study sought to assess the anti-fibrotic efficacy of apigenin against CCl4-induced hepatic fibrosis in mice. METHODS Forty-eight mice were put into six groups. G1: Normal Control, G2: CCl4 Control, G3: Silymarin (100 mg/kg), G4 and G5: Apigenin (2 &20 mg/Kg), G6: Apigenin alone (20 mg/Kg). Groups 2, 3, 4, and 5 were given CCl4 (0.5 mL/kg. i.p.) twice/week for six weeks. The level of AST, ALT, TC, TG, and TB in serum and IL-1β, IL-6, and TNF-α in tissue homogenates were assessed. Histological studies by H&E staining and Immunostaining of liver tissues were also performed. RESULTS The CCl4-challenged group showed increased serum AST (4-fold), ALT (6-fold), and TB (5-fold). Both silymarin and apigenin treatments significantly improved these hepatic biomarkers. The CCl4-challenged group showed reduced levels of CAT (89%), GSH (53%), and increased MDA (3-fold). Both silymarin and apigenin treatments significantly altered these oxidative markers in tissue homogenates. The CCl4-treated group showed a two-fold increase in IL-1β, IL-6, and TNF-α levels. Silymarin and apigenin treatment considerably decreased the IL-1β, IL-6, and TNF-α levels. Apigenin treatment inhibited angiogenic activity, as evidenced by a decrease in VEGF (vascular endothelial growth factor) expression in liver tissues, and a decline in vascular endothelial cell antigen expression (CD34). CONCLUSIONS Finally, these data collectively imply that apigenin may have antifibrotic properties, which may be explained by its anti-inflammatory, antioxidant, and antiangiogenic activities.
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Affiliation(s)
- Maryam Melaibari
- Department of Pharmacology, Faculty of Medicine, King Abdulaziz University, Jeddah 21589, Saudi Arabia
| | - Huda M Alkreathy
- Department of Pharmacology, Faculty of Medicine, King Abdulaziz University, Jeddah 21589, Saudi Arabia
| | - Ahmed Esmat
- Department of Pharmacology, Faculty of Medicine, King Abdulaziz University, Jeddah 21589, Saudi Arabia
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Ain Shams University, Cairo 11566, Egypt
| | - Nisreen A Rajeh
- Department of Clinical Anatomy, Faculty of Medicine, King Abdulaziz University, Jeddah 21589, Saudi Arabia
| | - Rasheed A Shaik
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, King Abdulaziz University, Jeddah 21589, Saudi Arabia
| | - Anwar A Alghamdi
- Health Information Technology Department, The Applied College, King Abdulaziz University, Jeddah 21589, Saudi Arabia
- Pharmacovigilance and Medication Safety Unit, Center of Research Excellence for Drug Research and Pharmaceutical Industries, King Abdulaziz University, Jeddah 21589, Saudi Arabia
| | - Aftab Ahmad
- Health Information Technology Department, The Applied College, King Abdulaziz University, Jeddah 21589, Saudi Arabia
- Pharmacovigilance and Medication Safety Unit, Center of Research Excellence for Drug Research and Pharmaceutical Industries, King Abdulaziz University, Jeddah 21589, Saudi Arabia
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Shao M, Wang Y, Dong H, Wang L, Zhang X, Han X, Sang X, Bao Y, Peng M, Cao G. From liver fibrosis to hepatocarcinogenesis: Role of excessive liver H2O2 and targeting nanotherapeutics. Bioact Mater 2023; 23:187-205. [PMID: 36406254 PMCID: PMC9663332 DOI: 10.1016/j.bioactmat.2022.11.001] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/04/2022] [Revised: 10/23/2022] [Accepted: 11/06/2022] [Indexed: 11/13/2022] Open
Abstract
Liver fibrosis and hepatocellular carcinoma (HCC) have been worldwide threats nowadays. Liver fibrosis is reversible in early stages but will develop precancerosis of HCC in cirrhotic stage. In pathological liver, excessive H2O2 is generated and accumulated, which impacts the functionality of hepatocytes, Kupffer cells (KCs) and hepatic stellate cells (HSCs), leading to genesis of fibrosis and HCC. H2O2 accumulation is associated with overproduction of superoxide anion (O2•−) and abolished antioxidant enzyme systems. Plenty of therapeutics focused on H2O2 have shown satisfactory effects against liver fibrosis or HCC in different ways. This review summarized the reasons of liver H2O2 accumulation, and the role of H2O2 in genesis of liver fibrosis and HCC. Additionally, nanotherapeutics targeting H2O2 were summarized for further consideration of antifibrotic or antitumor therapy.
Liver fibrosis and HCC are closely related because ROS induced liver damage and inflammation, especially over-cumulated H2O2. Excess H2O2 diffusion in pathological liver was due to increased metabolic rate and diminished cellular antioxidant systems. Freely diffused H2O2 damaged liver-specific cells, thereby leading to fibrogenesis and hepatocarcinogenesis. Nanotherapeutics targeting H2O2 are summarized for treatment of liver fibrosis and HCC, and also challenges are proposed.
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21
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Ozaki K, Ohtani T, Ishida S, Higuchi S, Ishida T, Takahashi K, Matta Y, KImura H, Gabata T. Extracellular volume fraction obtained by dual-energy CT depicting the etiological differences of liver fibrosis. Abdom Radiol (NY) 2023; 48:1975-1986. [PMID: 36939910 DOI: 10.1007/s00261-023-03873-6] [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: 12/28/2022] [Revised: 02/23/2023] [Accepted: 02/23/2023] [Indexed: 03/21/2023]
Abstract
PURPOSE To assess etiological differences in extracellular volume fraction (ECV) and evaluate its influence on staging performance. METHODS A total of 166 patients with normal liver (n = 14) and chronic liver disease related to viral hepatitis (n = 71), alcohol (n = 44), and nonalcoholic steatohepatitis (NASH) (n = 37) underwent dual-energy CT (DECT) of the liver (5-min equilibrium-phase images) between January 2020 and July 2022. The iodine densities of the parenchyma and aorta were measured and ECV was calculated. Comparisons of ECV between each etiology and METAVIR fibrosis stage were statistically analyzed (p < 0.05). RESULTS ECV in each etiology and all patients significantly increased with higher fibrosis stage (p < 0.001) and showed a strong or moderate correlation with fibrosis stage (Spearman's ρ; all patients, 0.701; viral hepatitis, 0.638; alcoholic, 0.885; NASH, 0.791). In stages F2-F4, ECV in alcoholic liver disease was significantly larger than those for viral hepatitis and NASH (p < 0.05); however, no significant difference in stage F1 was found among the three etiologies. The cutoff values and areas under the receiver operating characteristic curve (AUC-ROCs) for discriminating fibrosis stage (≥ F1- ≥ F4) were higher for alcohol (cutoff values and AUC-ROC; 20.1% and 0.708 for ≥ F1, 23.8% and 0.990 for ≥ F2, 24.3% and 0.968 for ≥ F3, and 26.6% and 0.961 for ≥ F4, respectively) compared with those for the others. CONCLUSION ECV in alcoholic liver disease is higher than that in other etiologies in the advanced stages of fibrosis, and etiological differences in ECV affect the staging performance of fibrosis.
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Affiliation(s)
- Kumi Ozaki
- Department of Radiology, Faculty of Medical Sciences, University of Fukui, 23-3 Matsuoka-Shimoaizuki, Eiheiji, Fukui, 910-1193, Japan. .,Department of Radiology, Hamamatsu University School of Medicine, 1-20-1, Handayama, Higashi-Ku, Hamamatsu, 431-3192, Japan.
| | - Takashi Ohtani
- Radiological Center, University of Fukui Hospital, Eiheiji, Japan
| | - Shota Ishida
- Radiological Center, University of Fukui Hospital, Eiheiji, Japan.,Department of Radiological Technology, Faculty of Medical Science, Kyoto College of Medical Science, Kyoto, Japan
| | - Shohei Higuchi
- Department of Pathology, Faculty of Medical Sciences, University of Fukui, Eiheiji, Japan
| | - Tomokazu Ishida
- Radiological Center, University of Fukui Hospital, Eiheiji, Japan
| | - Kouki Takahashi
- Radiological Center, University of Fukui Hospital, Eiheiji, Japan
| | - Yuki Matta
- Radiological Center, University of Fukui Hospital, Eiheiji, Japan
| | - Hirohiko KImura
- Department of Radiology, Faculty of Medical Sciences, University of Fukui, 23-3 Matsuoka-Shimoaizuki, Eiheiji, Fukui, 910-1193, Japan
| | - Toshifumi Gabata
- Department of Radiology, Graduate School of Medical Sciences, Kanazawa University, Kanazawa, Japan
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22
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Mohammed Mohsen S, Hussein Majeed G. Knowledge and awareness of chronic hepatitis C and liver fibrosis among health care personnel and other domains in Iraq. BIONATURA 2023. [DOI: 10.21931/rb/2023.08.01.35] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/12/2023] Open
Abstract
As a significant public health disease, the Hepatitis C virus (HCV) infects more than 185 million worldwide. Chronic infections are led by 170 million illnesses, resulting in 350,000 because of liver and cirrhosis cancer. Injuring of chronic liver from several insults leads to occur fibrosis. For example, metabolic disease (nonalcoholic fatty liver disease), infections (hepatitis B [HBV] and C viruses [HCV]), and toxins (alcohol). This study evaluates the knowledge and awareness about Of Chronic Hepatitis C and Liver Fibrosis among Health Care Workers and other domains of workers in Iraq. This study was carried out as cross-sectional research in Diyala, Iraq, from February / 2021 to January / 2022. In this work, 350 persons participated; the age range was (18-62) years, with a mean age of (25.9 + 9.79). The participants consisted of 100 males and 250 females. Also, they were divided into two groups: groups I and II. I (health care workers group) consists of 200 students studying in the medical department of Baquba technical institute and workers in Diyala hospitals ). Group II (other domains Workers) includes (100) participants who work in several domains. Similar to previous studies, a questionnaire was adopted to collect this research data. The outcomes demonstrate higher knowledge about HCV, Liver fibrosis, transmission, and a vaccine was noticed with a statistically significant difference among females compared to males. Regarding residency, the ability of HCV and liver fibrosis in Q1, Q2, and Q5 only among Health Care Workers compared to other domains Workers with a statistically significant difference (P<0.05).
Keywords: Chronic Hepatitis C, Liver Fibrosis, Health Care Workers and other domains Workers
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23
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Vyas K, Patel MM. Insights on drug and gene delivery systems in liver fibrosis. Asian J Pharm Sci 2023; 18:100779. [PMID: 36845840 PMCID: PMC9950450 DOI: 10.1016/j.ajps.2023.100779] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2022] [Revised: 01/12/2023] [Accepted: 01/12/2023] [Indexed: 01/30/2023] Open
Abstract
Complications of the liver are amongst the world's worst diseases. Liver fibrosis is the first stage of liver problems, while cirrhosis is the last stage, which can lead to death. The creation of effective anti-fibrotic drug delivery methods appears critical due to the liver's metabolic capacity for drugs and the presence of insurmountable physiological impediments in the way of targeting. Recent breakthroughs in anti-fibrotic agents have substantially assisted in fibrosis; nevertheless, the working mechanism of anti-fibrotic medications is not fully understood, and there is a need to design delivery systems that are well-understood and can aid in cirrhosis. Nanotechnology-based delivery systems are regarded to be effective but they have not been adequately researched for liver delivery. As a result, the capability of nanoparticles in hepatic delivery was explored. Another approach is targeted drug delivery, which can considerably improve efficacy if delivery systems are designed to target hepatic stellate cells (HSCs). We have addressed numerous delivery strategies that target HSCs, which can eventually aid in fibrosis. Recently genetics have proved to be useful, and methods for delivering genetic material to the target place have also been investigated where different techniques are depicted. To summarize, this review paper sheds light on the most recent breakthroughs in drug and gene-based nano and targeted delivery systems that have lately shown useful for the treatment of liver fibrosis and cirrhosis.
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Affiliation(s)
- Kunj Vyas
- Department of Pharmaceutics, Institute of Pharmacy, Nirma University SG Highway, Gujarat 382481, India
| | - Mayur M Patel
- Department of Pharmaceutics, Institute of Pharmacy, Nirma University SG Highway, Gujarat 382481, India
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24
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Łotowska JM, Sobaniec-Łotowska ME, Bobrus-Chociej A, Sobaniec P. The Ultrastructure of Hepatic Stellate Cell-Macrophage Intercellular Crosstalk as a New Morphological Insight into Phenomenon of Fibrogenesis in Pediatric Autoimmune Hepatitis. J Clin Med 2023; 12:jcm12031024. [PMID: 36769672 PMCID: PMC9917971 DOI: 10.3390/jcm12031024] [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: 11/28/2022] [Revised: 01/20/2023] [Accepted: 01/24/2023] [Indexed: 01/31/2023] Open
Abstract
The aim of the study was the pioneering retrospective ultrastructural evaluation of respective forms of hepatic stellate cells (HSCs) and analysis of their crosstalk with other adjacent nonparenchymal cells (NPCs), especially Kupffer cells/macrophages (KCs/MPs), in pediatric autoimmune hepatitis (AIH). METHODS Ultrastructural assessment of the HSC population and NPCs was performed in transmission electron microscopy (TEM) using pretreatment liver biopsies from 25 children (8 boys and 17 girls) aged 4-17 with clinic-pathologically diagnosed untreated AIH. RESULTS Submicroscopic evaluation allowed easy identification of numerous HSCs in the form of transitory cells, i.e., T-HSCs, accompanied by signs of fibrosis. T-HSCs included cells with features of activation initiation (iHSCs) and activation perpetuation (pHSCs), indicating high HSC activation plasticity. The pHSCs were markedly elongated and mainly showed a distinct loss of lipid cytoplasmic material, expanded and dilated channels of granular endoplasmic reticulum, and linear bundles of microfilaments beneath the cell membrane. They were surrounded by usually mature collagen fibers. Frequently activated KCs/MPs adhered directly to T-HSCs. Between them, tight intercellular junctions were formed by means of point desmosomes. CONCLUSIONS Our qualitative TEM observations indicate a key role of T-HSCs in liver fibrogenesis in pediatric AIH, with the essential involvement of activated KCs/MPs that directly adhere to them. Tight intercellular junctions, being the ultrastructural exponent of the specific cellular mechanisms of the crosstalk between NPCs, can play a vital role in hepatic collagen fibroplasia. A better understanding of HSC population morphology at the ultrastructural level in AIH seems important not only to improve the disease morphological diagnostics but to also provide new insights into therapeutic interventions for the phenomenon of liver fibrogenesis.
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Affiliation(s)
- Joanna Maria Łotowska
- Department of Medical Pathomorphology, Faculty of Medicine with the Division of Dentistry and Division of Medical Education in English, Medical University of Bialystok, 15-269 Bialystok, Poland
- Correspondence: (J.M.Ł.); (P.S.)
| | - Maria Elżbieta Sobaniec-Łotowska
- Department of Medical Pathomorphology, Faculty of Medicine with the Division of Dentistry and Division of Medical Education in English, Medical University of Bialystok, 15-269 Bialystok, Poland
| | - Anna Bobrus-Chociej
- Department of Pediatrics, Gastroenterology, Hepatology, Nutrition and Allergology, Faculty of Medicine with the Division of Dentistry and Division of Medical Education in English, Medical University of Bialystok, 15-274 Bialystok, Poland
| | - Piotr Sobaniec
- Department of Pediatric Neurology, Faculty of Medicine with the Division of Dentistry and Division of Medical Education in English, Medical University of Bialystok, 15-274 Bialystok, Poland
- Correspondence: (J.M.Ł.); (P.S.)
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25
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LncRNA CCAT2, involving miR-34a/TGF-β1/Smad4 signaling, regulate hepatic stellate cells proliferation. Sci Rep 2022; 12:21199. [PMID: 36482069 PMCID: PMC9732356 DOI: 10.1038/s41598-022-25738-6] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2022] [Accepted: 12/05/2022] [Indexed: 12/13/2022] Open
Abstract
miR-34a targeting on Smad4 plays important role in TGF-β1 pathway which is a dominant factor for balancing collagen production and degradation in hepatic stellate cells. TGF-β1/Smad4 regulated collagen deposition is a hallmark of hepatic fibrosis. The potential regulation on miR-34a by LncRNAs in hepatic stellate cells (HSCs) is still reserved to be revealed. In current study, it was hypothesized that a miR-34a interactor, lncRNA CCAT2 may regulate TGF-β1 pathway in liver fibrotic remodeling. The interaction between CCAT2 and miR-34a-5p was checked by dual luciferase assay. the effects of CCAT2 and miR-34a-5p on cell proliferation and apoptosis were verified by MTT assay, colony formation assay, and flow cytometry assay. Dual luciferase activity showed CCAT2 are targets of miR-34a-5p. Sh-CCAT2 transfection prohibit HSCs proliferation and induce HSCs apoptosis, also inhibited ECM protein synthesis in HSCs. Decreased miR-34a-5p enhanced HSCs proliferation, blocked HSCs apoptosis and promoted ECM protein production. miR-34a-5p inhibitor undo protective regulation of sh-CCAT2 in liver fibrosis. Furthermore, clinical investigation showed that CCAT2 and Smad4 expression level were significantly induced, while miR-34a-5p was significantly decreased in HBV related liver fibrosis serum. In conclusion, activated HSCs via TGF-β1/Smad4 signaling pathway was successfully alleviated by CCAT2 inhibition through miR-34a-5p elevation.
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26
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Abd El-Fattah EE, Zakaria AY. Targeting HSP47 and HSP70: promising therapeutic approaches in liver fibrosis management. J Transl Med 2022; 20:544. [DOI: 10.1186/s12967-022-03759-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2022] [Accepted: 11/06/2022] [Indexed: 11/28/2022] Open
Abstract
AbstractLiver fibrosis is a liver disease in which there is an excessive buildup of extracellular matrix proteins, including collagen. By regulating cytokine production and the inflammatory response, heat shock proteins (HSPs) contribute significantly to a wider spectrum of fibrotic illnesses, such as lung, liver, and idiopathic pulmonary fibrosis by aiding in the folding and assembly of freshly synthesized proteins, HSPs serve as chaperones. HSP70 is one of the key HSPs in avoiding protein aggregation which induces its action by sending unfolded and/or misfolded proteins to the ubiquitin–proteasome degradation pathway and antagonizing influence on epithelial-mesenchymal transition. HSP47, on the other hand, is crucial for boosting collagen synthesis, and deposition, and fostering the emergence of fibrotic disorders. The current review aims to provide light on how HSP70 and HSP47 affect hepatic fibrogenesis. Additionally, our review looks into new therapeutic approaches that target HSP70 and HSP47 and could potentially be used as drug candidates to treat liver fibrosis, especially in cases of comorbidities.
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27
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Karmacharya MB, Hada B, Park SR, Kim KH, Choi BH. Granulocyte-macrophage colony-stimulating factor (GM-CSF) shows therapeutic effect on dimethylnitrosamine (DMN)-induced liver fibrosis in rats. PLoS One 2022; 17:e0274126. [PMID: 36054162 PMCID: PMC9439244 DOI: 10.1371/journal.pone.0274126] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/20/2022] [Accepted: 08/22/2022] [Indexed: 11/18/2022] Open
Abstract
This study was undertaken to investigate the inhibitory effects of granulocyte-macrophage colony-stimulating factor (GM-CSF) on dimethylnitrosamine (DMN)-induced liver fibrosis in rats. Liver fibrosis was induced in Sprague-Dawley rats by injecting DMN intraperitoneally (at 10 mg/kg of body weight) daily for three consecutive days per week for 4 weeks. To investigate the effect of GM-CSF on disease onset, GM-CSF (50 μg/kg of body weight) was co-treated with DMN for 2 consecutive days per week for 4 weeks (4-week groups). To observe the effect of GM-CSF on the progression of liver fibrosis, GM-CSF was post-treated alone at 5–8 weeks after the 4 weeks of DMN injection (8-week groups). We found that DMN administration for 4 weeks produced molecular and pathological manifestations of liver fibrosis, that is, it increased the expressions of collagen type I, alpha-smooth muscle actin (α-SMA), and transforming growth factor-β1 (TGF-β1), and decreased peroxisome proliferator-activated receptor gamma (PPAR-γ) expression. In addition, elevated serum levels of aspartate aminotransferase (AST), total bilirubin level (TBIL), and decreased albumin level (ALB) were observed. In both the 4-week and 8-week groups, GM-CSF clearly improved the pathological liver conditions in the gross and histological observations, and significantly recovered DMN-induced increases in AST and TBIL and decreases in ALB serum levels to normal. GM-CSF also significantly decreased DMN-induced increases in collagen type I, α-SMA, and TGF-β1 and increased DMN-induced decreases in PPAR-γ expression. In the DMN groups, survival decreased continuously for 8 weeks after DMN treatment for the first 4 weeks. GM-CSF showed a survival benefit when co-treated for the first 4 weeks but a marginal effect when post-treated for 5–8 weeks. In conclusion, co-treatment of GM-CSF showed therapeutic effects on DMN-induced liver fibrosis and survival rates in rats, while post-treatment efficiently blocked liver fibrosis.
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Affiliation(s)
| | - Binika Hada
- Department of Biomedical Sciences, Inha University College of Medicine, Incheon, South Korea
| | - So Ra Park
- Department of Physiology and Biophysics, Inha University College of Medicine, Incheon, South Korea
| | - Kil Hwan Kim
- Veterans Medical Research Institute, Veterans Health Service Medical Center, Seoul, South Korea
- * E-mail: (BHC); (KHK)
| | - Byung Hyune Choi
- Department of Biomedical Sciences, Inha University College of Medicine, Incheon, South Korea
- * E-mail: (BHC); (KHK)
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28
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Kartasheva-Ebertz D, Gaston J, Lair-Mehiri L, Mottez E, Buivan TP, Massault PP, Scatton O, Gaujoux S, Vaillant JC, Pol S, Lagaye S. IL-17A in Human Liver: Significant Source of Inflammation and Trigger of Liver Fibrosis Initiation. Int J Mol Sci 2022; 23:ijms23179773. [PMID: 36077175 PMCID: PMC9456490 DOI: 10.3390/ijms23179773] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2022] [Revised: 08/23/2022] [Accepted: 08/25/2022] [Indexed: 11/16/2022] Open
Abstract
IL-17A is considered to guide liver inflammation and fibrosis. From twenty-two human liver samples of different fibrosis stages (F0 to F4), IL-17A, IL-22, and TGFβ1 protein expression in liver tissue lysates were analyzed. Ten paired samples of liver tissue (F0–F1 stage) and blood from the same patient were used to analyze intrahepatic and blood T-lymphoid IL-17A+ cells by flow cytometry. The analyses have been performed regardless of pathology, considering the stage of fibrosis. Human liver tissue was used for the primary human liver slice cultures, followed by subsequent cytokine stimulation and fibrotic markers’ analysis by ELISA. IL-17A production in human liver tissue was significantly higher in the early fibrotic stage compared with the advanced stage. Th17 T cells and, to a lesser extent, MAIT cells were the main sources of IL-17A in both compartments, the liver and the blood. Moreover, the presence of liver Th17IL-17A+INFγ+ cells was detected in the liver. IL-17A stimulation of human liver slice culture increased the expression of profibrotic and pro-inflammatory markers. IL-17A, secreted by Th17 and MAIT cells in the liver, triggered fibrosis by inducing the expression of IL-6 and profibrotic markers and could be a target for antifibrotic treatment. Further amplitude studies are needed to confirm the current results.
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Affiliation(s)
- Daria Kartasheva-Ebertz
- Institut Pasteur, Immunobiologie des Cellules Dendritiques, INSERM U1223, F-75015 Paris, France
- Université de Paris Cité, F-75005 Paris, France
- Correspondence:
| | - Jesintha Gaston
- Institut Pasteur, Immunobiologie des Cellules Dendritiques, INSERM U1223, F-75015 Paris, France
- Université de Paris Cité, F-75005 Paris, France
| | - Loriane Lair-Mehiri
- Department of Hepatology and Addictology, AP-HP, Groupe Hospitalier Cochin, Université de Paris, F-75014 Paris, France
| | - Estelle Mottez
- Institut Pasteur, Centre de Recherche Translationnelle, F-75015 Paris, France
| | - Tan-Phuc Buivan
- Institut Pasteur, Centre de Recherche Translationnelle, F-75015 Paris, France
| | - Pierre-Philippe Massault
- Department of Digestive Surgery, AP-HP, Groupe Hospitalier Cochin, Université de Paris, F-75014 Paris, France
| | - Olivier Scatton
- Department of Hepato-Biliary and Pancreatic Surgery and Liver Transplantation, AP-HP Pitié-Salpêtrière Hospital, Medecine Sorbonne Université, F-75013 Paris, France
| | - Sebastien Gaujoux
- Department of Hepato-Biliary and Pancreatic Surgery and Liver Transplantation, AP-HP Pitié-Salpêtrière Hospital, Medecine Sorbonne Université, F-75013 Paris, France
| | - Jean-Christophe Vaillant
- Department of Hepato-Biliary and Pancreatic Surgery and Liver Transplantation, AP-HP Pitié-Salpêtrière Hospital, Medecine Sorbonne Université, F-75013 Paris, France
| | - Stanislas Pol
- Institut Pasteur, Immunobiologie des Cellules Dendritiques, INSERM U1223, F-75015 Paris, France
- Université de Paris Cité, F-75005 Paris, France
- Department of Hepatology and Addictology, AP-HP, Groupe Hospitalier Cochin, Université de Paris, F-75014 Paris, France
| | - Sylvie Lagaye
- Institut Pasteur, Immunobiologie des Cellules Dendritiques, INSERM U1223, F-75015 Paris, France
- Centre de Recherche (CDR) Saint-Antoine, INSERM—UMR_S 938/Sorbonne Université, F-75012 Paris, France
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29
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Selim NM, Melk MM, Melek FR, Saleh DO, Sobeh M, El-Hawary SS. Phytochemical profiling and anti-fibrotic activities of Plumbago indica L. and Plumbago auriculata Lam. in thioacetamide-induced liver fibrosis in rats. Sci Rep 2022; 12:9864. [PMID: 35701526 PMCID: PMC9197831 DOI: 10.1038/s41598-022-13718-9] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2022] [Accepted: 05/26/2022] [Indexed: 11/09/2022] Open
Abstract
This study aimed at investigating the chemical composition and the hepatoprotective activities of Plumbago indica L. and P. auriculata Lam. LC-MS/MS analyses for the hydroalcoholic extracts of the aerial parts of the two Plumbago species allowed the tentative identification of thirty and twenty-five compounds from P. indica and P. auriculata, respectively. The biochemical and histopathological alterations associated with thioacetamide (TAA)-induced liver fibrosis in rats were evaluated in vivo where rats received the two extracts at three different dose levels (100, 200 and 400 mg/kg p.o, daily) for 15 consecutive days with induction of hepatotoxicity by TAA (200 mg/kg/day, i.p.) at 14th and 15th days. Results of the present study showed a significant restoration in liver function biomarkers viz. alanine transaminase (ALT), aspartate transaminase (AST), gamma glutamyl transferase and total bilirubin. The liver homogenates exhibited increased levels of antioxidant biomarkers: reduced glutathione (GSH) and catalase (CAT), accompanied with decline in malondialdehyde (MDA). Furthermore, treated groups exhibited a significant suppression in liver inflammatory cytokines: tumor necrosis factor-α (TNF-α) and interlukin-6 (IL-6), and fibrotic biomarker: alpha smooth muscle relaxant. Histopathological examination of the liver showed normality of hepatocytes. Noteworthy, P. indica extract showed better hepatoprotective activity than P. auriculata, particularly at 200 mg/kg. To sum up, all these results indicated the hepatoprotective properties of both extracts, as well as their antifibrotic effect was evidenced by reduction in hepatic collagen deposition. However, additional experiments are required to isolate their individual secondary metabolites, assess the toxicity of the extracts and explore the involved mechanism of action.
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Affiliation(s)
- Nabil Mohamed Selim
- Pharmacognosy Department, Faculty of Pharmacy, Cairo University, Giza, 12613, Egypt.
| | - Mina Michael Melk
- Pharmacognosy Department, Faculty of Pharmacy, Cairo University, Giza, 12613, Egypt
| | - Farouk Rasmy Melek
- Chemistry of Natural Compounds Department, National Research Centre, Giza, 12622, Egypt
| | - Dalia Osama Saleh
- Pharmacology Department, National Research Centre, Giza, 12622, Egypt
| | - Mansour Sobeh
- AgroBioSciences, Mohammed VI Polytechnic University, Lot 660-Hay MoulayRachid, 43150, Benguerir, Morocco
| | - Seham S El-Hawary
- Pharmacognosy Department, Faculty of Pharmacy, Cairo University, Giza, 12613, Egypt
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30
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Zhang K, Lin L, Zhu Y, Zhang N, Zhou M, Li Y. Saikosaponin d Alleviates Liver Fibrosis by Negatively Regulating the ROS/NLRP3 Inflammasome Through Activating the ERβ Pathway. Front Pharmacol 2022; 13:894981. [PMID: 35694250 PMCID: PMC9174603 DOI: 10.3389/fphar.2022.894981] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/12/2022] [Accepted: 05/09/2022] [Indexed: 01/02/2023] Open
Abstract
Background and aims: Saikosaponin d (SSd) has a steroidal structure and significant anti-inflammatory effects. The purpose of this study was to explore the mechanism underlying SSd’s inhibitory effects on liver fibrosis. Methods: Wild-type and estrogen receptor knockout (ERKO) mice were treated with CCl4 to establish liver fibrosis mouse models. The effects of SSd on hepatic fibrogenesis were studied in these mouse models. Hepatic stellate cells (HSCs) were activated by H2O2 to investigate the potential molecular mechanisms. The establishment of the models and the degrees of inflammation and liver tissue fibrosis were evaluated by detecting changes in serum liver enzymes and liver histopathology. The expression of α-SMA and TGF-β1 was determined by immunohistochemistry. The expression and significance of NLRP3 inflammasome proteins were explored by RT-PCR and Western blotting analyses. The mitochondrial ROS-related indexes were evaluated by MitoSOX Red. Results: In wild-type and ERKO mice treated with CCl4, the fluorescence expression of mitochondrial ROS was up-regulated, while the mitochondrial membrane potential and ATP content were decreased, suggesting that the mitochondria were damaged. In addition, the expression of NLRP3 inflammatory bodies and fibrosis markers (α-SMA, TGF-β, TIMP-1, MMP-2, and Vimentin) in liver tissue increased. Furthermore, the above indexes showed the same expression trend in activated HSCs. In addition, the peripheral serum ALT and AST levels increased in CCl4-induced liver injury model mice. And HE staining showed a large number of inflammatory cell infiltration in the liver of model mice. Picric acid-Sirius staining and Masson staining showed that there was significant collagen fibrous tissue deposition in mice liver sections. IHC and WB detection confirmed that the expression of α-SMA and TGF-β1 increased. Liver fibrosis scores were also elevated. Then, after SSd intervention, the expression of ROS in wild-type mice and αERKO mice decreased, mitochondrial membrane potential recovered, ATP level increased, NLRP3 inflammasome and fibrosis indexes decreased, liver enzyme levels decreased, and liver pathology showed liver inflammation. The damage and collagen deposition were significantly relieved, the expression of α-SMA and TGF-β1 was decreased, and the fibrosis score was also decreased. More importantly, the effect of SSd in alleviating liver injury and liver fibrosis had no effect on βERKO mice. Conclusion: SSd alleviated liver fibrosis by negatively regulating the ROS/NLRP3 inflammasome through activating the ERβ pathway. By establishing liver fibrosis models using wild-type and ERKO mice, we demonstrated that SSd could alleviate liver fibrosis by inhibiting the ROS/NLRP3 inflammasome axis through activating the ERβ pathway.
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31
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Alkreathy HM, Esmat A. Lycorine Ameliorates Thioacetamide-Induced Hepatic Fibrosis in Rats: Emphasis on Antioxidant, Anti-Inflammatory, and STAT3 Inhibition Effects. Pharmaceuticals (Basel) 2022; 15:ph15030369. [PMID: 35337166 PMCID: PMC8955817 DOI: 10.3390/ph15030369] [Citation(s) in RCA: 19] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2022] [Revised: 03/13/2022] [Accepted: 03/17/2022] [Indexed: 02/06/2023] Open
Abstract
Liver fibrosis is a foremost medical concern worldwide. In Saudi Arabia, numerous risk factors contribute to its high rates. Lycorine—a natural alkaloid—has antioxidant, anti-inflammatory, and antitumor activates. It has been reported to inhibit STAT3 in cancer. Therefore, this study aimed at investigating the possible antifibrotic effect of lycorine against thioacetamide (TAA)-induced liver fibrosis in rats and at elucidating the possible mechanisms. Liver fibrosis was induced by TAA (200 mg/kg i.p.), three per week for four weeks. Treatment with lycorine (0.5 and 1 mg/kg/d) amended TAA-induced rise of serum transaminases that was confirmed histopathologically. Moreover, it ameliorated liver fibrosis in a dose-dependent manner, as indicated by hindering the TAA-induced increase of hepatic hydroxyproline content, α-smooth muscle actin (α-SMA) and transforming growth factor (TGF-β1) expressions. TAA-induced oxidative stress was amended by lycorine treatment via restoring reduced glutathione and diminishing lipid peroxidation. Moreover, lycorine ameliorated hepatic inflammation by preventing the rise of inflammatory cytokines. Notably, lycorine inhibited STAT3 activity, as evidenced by the decreased phospho-STAT3 expression, accompanied by the elevation of the hepatic Bax/Bcl-2 ratio. In conclusion, lycorine hinders TAA-induced liver fibrosis in rats, due to—at least partly—its antioxidative and anti-inflammatory properties, along with its ability to inhibit STAT3 signaling.
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Affiliation(s)
- Huda Mohammed Alkreathy
- Department of Pharmacology, Faculty of Medicine, King Abdulaziz University, Jeddah 21589, Saudi Arabia;
| | - Ahmed Esmat
- Department of Pharmacology, Faculty of Medicine, King Abdulaziz University, Jeddah 21589, Saudi Arabia;
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Ain Shams University, Cairo 11566, Egypt
- Correspondence:
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32
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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: 237] [Impact Index Per Article: 79.0] [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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Arwinda R, Liem IK, Fatril AE, Oktorina F, Husna FA, Kodariah R, Wuyung PE. CK19 and OV6 Expressions in the Liver of 2-AAF/CCl4 Rat Model. Open Access Maced J Med Sci 2022. [DOI: 10.3889/oamjms.2022.7923] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/05/2022] Open
Abstract
BACKGROUND: Liver regeneration on a chronic liver injury with rat model research is urgent to study the pathology of human chronic diseases. 2-Acetylaminofluorene (2-AAF) and Carbon Tetrachloride (CCl4) can be applied to study about liver regeneration by liver stem cells, known as oval cells. The use of 2-AAF and CCl4 (2-AAF/CCl4) to induce chronic liver injury can lead severe hepatocyte damages and extensive fibrosis.
AIM: to observed the OV6 and CK19 expression in the liver of 2AAF/CCl4 rat model.
METHODS: In this research, a high dose of 2-AAF (10mg/kg) was applied and combined repeatedly with CCl4 (2ml/kg) for 12 weeks. An immunohistochemistry (IHC) procedure by using OV6 and CK19 antibodies was also applied to examine the regeneration of oval cells. Both antibodies expressions were then examined semi-quantitatively according to the expressions percentage of each sample based on the liver zone. We have observed the OV6 and CK19 expressions in every zone, including in portae hepatis area.
RESULTS: The results showed that OV6 and CK19 with the highest expression in the zone I. A significant difference between OV6 and CK19 expressions was revealed in healthy (control group) and 2-AAF/CCl4 groups (both indicating p=0.045). Moreover, a ductular reaction was also found in Zone I and II of the 2-AAF/CCl4.
CONCLUSIONS: We conclude that 2-AAF/CCl4 induced chronic rat liver injury model, could be utilized to investigate the oval cells with OV6 and CK19 expression.
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Omar ZMM, Ahmed AAN, El-Bakry MH, Ahmed MA, Hasan A. Metformin versus Silymarin as Hepatoprotective Agents in Mice Fibrotic Model Caused by Carbon Tetrachloride. ANNALES PHARMACEUTIQUES FRANÇAISES 2022; 80:659-668. [PMID: 35093389 DOI: 10.1016/j.pharma.2022.01.005] [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: 07/31/2021] [Revised: 12/11/2021] [Accepted: 01/12/2022] [Indexed: 02/07/2023]
Abstract
OBJECTIVES To study metformin hepatoprotective effects compared to silymarin on hepatic fibrosis caused by carbon tetrachloride (CCl4) in mice. MATERIAL AND METHODS liver fibrosis in mice was achieved by intraperitoneal injection of 2 ml/kg of CCl4 dilution in olive oil [1:9 (v/v)] twice a week for 7 weeks followed by oral treatment with metformin (250 mg/kg/day) or silymarin (100 mg/kg/day) (a standard hepatoprotective drug). The changes that follow liver fibrosis were assessed by measurement of hepatic enzymes (ALT, AST and ALP), histopathological examination using hematoxylin and eosin stain, special stains, and α-smooth muscle actin (α-SMA) immunostaining, measuring oxidative stress markers (MDA, GSH, NOx and MnSOD) and transforming growth factor-beta 1 (TGF-β1) in liver. RESULTS liver fibrosis was obviously developed in mice after intraperitoneal injection with CCl4 for 7 weeks. Both silymarin and metformin treatment exhibited a significant decrease in the fibrotic changes and similarly an increase in endogenous antioxidants. Interestingly there is a significant difference between silymarin and metformin regarding both efficacy and potency. CONCLUSION These findings highlight the anti-inflammatory, antioxidant and antifibrotic effects of metformin in CCl4-induced hepatic fibrosis in mice, but silymarin is more beneficial.
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Affiliation(s)
| | | | | | - Mohammed Ahmed Ahmed
- Department of Pathology, Faculty of Medicine, Al- Azhar University, Assiut, Egypt
| | - Abdulkarim Hasan
- Department of Pathology, Faculty of Medicine, Al- Azhar University, Cairo, Egypt.
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Guedes PLR, Carvalho CPF, Carbonel AAF, Simões MJ, Icimoto MY, Aguiar JAK, Kouyoumdjian M, Gazarini ML, Nagaoka MR. Chondroitin Sulfate Protects the Liver in an Experimental Model of Extra-Hepatic Cholestasis Induced by Common Bile Duct Ligation. MOLECULES (BASEL, SWITZERLAND) 2022; 27:molecules27030654. [PMID: 35163920 PMCID: PMC8839946 DOI: 10.3390/molecules27030654] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/13/2021] [Revised: 01/06/2022] [Accepted: 01/12/2022] [Indexed: 12/15/2022]
Abstract
During liver fibrogenesis, there is an imbalance between regeneration and wound healing. The current treatment is the withdrawal of the causing agent; thus, investigation of new and effective treatments is important. Studies have highlighted the action of chondroitin sulfate (CS) in different cells; thus, our aim was to analyze its effect on an experimental model of bile duct ligation (BDL). Adult Wistar rats were subjected to BDL and treated with CS for 7, 14, 21, or 28 days intraperitoneally. We performed histomorphometric analyses on Picrosirius-stained liver sections. Cell death was analyzed according to caspase-3 and cathepsin B activity and using a TUNEL assay. Regeneration was evaluated using PCNA immunohistochemistry. BDL led to increased collagen content with corresponding decreased liver parenchyma. CS treatment reduced total collagen and increased parenchyma content after 21 and 28 days. The treatment also promoted changes in the hepatic collagen type III/I ratio. Furthermore, it was observed that CS treatment reduced caspase-3 activity and the percentage of TUNEL-positive cells after 14 days and cathepsin B activity only after 28 days. The regeneration increased after 14, 21, and 28 days of CS treatment. In conclusion, our study showed a promising hepatoprotective action of CS in fibrogenesis induced by BDL.
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Affiliation(s)
- Pedro L. R. Guedes
- Department of Medicine, Escola Paulista de Medicina, Universidade Federal de São Paulo, São Paulo 04023-062, Brazil;
| | - Carolina P. F. Carvalho
- Department of Biosciences, Instituto Saúde Sociedade, Universidade Federal de São Paulo, Santos 11015-020, Brazil; (C.P.F.C.); (M.L.G.)
| | - Adriana A. F. Carbonel
- Department of Gynecology, Escola Paulista de Medicina, Universidade Federal de São Paulo, São Paulo 04039-001, Brazil;
| | - Manuel J. Simões
- Department of Morphology and Genetic, Escola Paulista de Medicina, Universidade Federal de São Paulo, São Paulo 04023-900, Brazil;
| | - Marcelo Y. Icimoto
- Department of Biophysics, Escola Paulista de Medicina, Universidade Federal de São Paulo, São Paulo 04039-032, Brazil;
| | - Jair A. K. Aguiar
- Department of Biochemistry, Universidade Federal de Juiz de Fora, Juiz de Fora 36036-900, Brazil;
| | - Maria Kouyoumdjian
- Department of Biochemistry, Escola Paulista de Medicina, Universidade Federal de São Paulo, São Paulo 04023-062, Brazil;
| | - Marcos L. Gazarini
- Department of Biosciences, Instituto Saúde Sociedade, Universidade Federal de São Paulo, Santos 11015-020, Brazil; (C.P.F.C.); (M.L.G.)
| | - Marcia R. Nagaoka
- Department of Biosciences, Instituto Saúde Sociedade, Universidade Federal de São Paulo, Santos 11015-020, Brazil; (C.P.F.C.); (M.L.G.)
- Correspondence:
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A human multi-lineage hepatic organoid model for liver fibrosis. Nat Commun 2021; 12:6138. [PMID: 34686668 PMCID: PMC8536785 DOI: 10.1038/s41467-021-26410-9] [Citation(s) in RCA: 67] [Impact Index Per Article: 16.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2021] [Accepted: 09/28/2021] [Indexed: 12/13/2022] Open
Abstract
To investigate the pathogenesis of a congenital form of hepatic fibrosis, human hepatic organoids were engineered to express the most common causative mutation for Autosomal Recessive Polycystic Kidney Disease (ARPKD). Here we show that these hepatic organoids develop the key features of ARPKD liver pathology (abnormal bile ducts and fibrosis) in only 21 days. The ARPKD mutation increases collagen abundance and thick collagen fiber production in hepatic organoids, which mirrors ARPKD liver tissue pathology. Transcriptomic and other analyses indicate that the ARPKD mutation generates cholangiocytes with increased TGFβ pathway activation, which are actively involved stimulating myofibroblasts to form collagen fibers. There is also an expansion of collagen-producing myofibroblasts with markedly increased PDGFRB protein expression and an activated STAT3 signaling pathway. Moreover, the transcriptome of ARPKD organoid myofibroblasts resemble those present in commonly occurring forms of liver fibrosis. PDGFRB pathway involvement was confirmed by the anti-fibrotic effect observed when ARPKD organoids were treated with PDGFRB inhibitors. Besides providing insight into the pathogenesis of congenital (and possibly acquired) forms of liver fibrosis, ARPKD organoids could also be used to test the anti-fibrotic efficacy of potential anti-fibrotic therapies.
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Udomsinprasert W, Sobhonslidsuk A, Jittikoon J, Honsawek S, Chaikledkaew U. Cellular senescence in liver fibrosis: Implications for age-related chronic liver diseases. Expert Opin Ther Targets 2021; 25:799-813. [PMID: 34632912 DOI: 10.1080/14728222.2021.1992385] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/20/2022]
Abstract
INTRODUCTION New insights indicate a causative link between cellular senescence and liver fibrosis. Senescent hepatic stellate cells (HSCs) facilitate fibrosis resolution, while senescence in hepatocytes and cholangiocytes acts as a potent mechanism driving liver fibrogenesis. In many clinical studies, telomeres and mitochondrial DNA contents, which are both aging biomarkers, were reportedly associated with a degree of liver fibrosis in patients with chronic liver diseases (CLDs); this highlights their potential as biomarkers for liver fibrogenesis. A deeper understanding of mechanisms underlying multi-step progression of senescence may yield new therapeutic strategies for age-related chronic liver pathologies. AREAS COVERED This review examines the recent findings from preclinical and clinical studies on mechanisms of senescence in liver fibrogenesis and its involvement in liver fibrosis. A comprehensive literature search in electronic databases consisting of PubMed and Scopus from inception to 31 August 2021 was performed. EXPERT OPINION Cellular senescence has diagnostic, prognostic, and therapeutic potential in progressive liver complications, especially liver fibrosis. Stimulating or reinforcing the immune response against senescent cells may be a promising and forthright biotherapeutic strategy. This approach will need a deeper understanding of the immune system's ability to eliminate senescent cells and the molecular and cellular mechanisms underlying this process.
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Affiliation(s)
| | - Abhasnee Sobhonslidsuk
- Division of Gastroenterology and Hepatology, Department of Medicine, Faculty of Medicine Ramathibodi Hospital, Mahidol University, Bangkok, Thailand
| | - Jiraphun Jittikoon
- Department of Biochemistry, Faculty of Pharmacy, Mahidol University, Bangkok, Thailand
| | - Sittisak Honsawek
- Department of Biochemistry, Osteoarthritis and Musculoskeleton Research Unit, Faculty of Medicine, Chulalongkorn University, King Chulalongkorn Memorial Hospital, Thai Red Cross Society, Bangkok, Thailand
| | - Usa Chaikledkaew
- Social and Administrative Pharmacy Division, Department of Pharmacy, Faculty of Pharmacy, Mahidol University, Bangkok, Thailand.,Mahidol University Health Technology Assessment (MUHTA) Graduate Program, Mahidol University, Bangkok, Thailand
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38
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Chouhan MD, Fitzke HE, Bainbridge A, Atkinson D, Halligan S, Davies N, Lythgoe MF, Mookerjee RP, Menys A, Taylor SA. Cardiac-induced liver deformation as a measure of liver stiffness using dynamic imaging without magnetization tagging-preclinical proof-of-concept, clinical translation, reproducibility and feasibility in patients with cirrhosis. Abdom Radiol (NY) 2021; 46:4660-4670. [PMID: 34148103 DOI: 10.1007/s00261-021-03168-8] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2021] [Revised: 06/03/2021] [Accepted: 06/05/2021] [Indexed: 12/13/2022]
Abstract
PURPOSE MR elastography and magnetization-tagging use liver stiffness (LS) measurements to diagnose fibrosis but require physical drivers, specialist sequences and post-processing. Here we evaluate non-rigid registration of dynamic two-dimensional cine MRI images to measure cardiac-induced liver deformation (LD) as a measure of LS by (i) assessing preclinical proof-of-concept, (ii) clinical reproducibility and inter-reader variability, (iii) the effects of hepatic hemodynamic changes and (iv) feasibility in patients with cirrhosis. METHODS Sprague-Dawley rats (n = 21 bile duct ligated (BDL), n = 17 sham-operated controls) and fasted patients with liver cirrhosis (n = 11) and healthy volunteers (HVs, n = 10) underwent spoiled gradient-echo short-axis cardiac cine MRI studies at 9.4 T (rodents) and 3.0 T (humans). LD measurements were obtained from intrahepatic sub-cardiac regions-of-interest close to the diaphragmatic margin. One-week reproducibility and prandial stress induced hemodynamic changes were assessed in healthy volunteers. RESULTS Normalized LD was higher in BDL (1.304 ± 0.062) compared with sham-operated rats (1.058 ± 0.045, P = 0.0031). HV seven-day reproducibility Bland-Altman (BA) limits-of-agreement (LoAs) were ± 0.028 a.u. and inter-reader variability BA LoAs were ± 0.030 a.u. Post-prandial LD increases were non-significant (+ 0.0083 ± 0.0076 a.u., P = 0.3028) and uncorrelated with PV flow changes (r = 0.42, p = 0.2219). LD measurements successfully obtained from all patients were not significantly higher in cirrhotics (0.102 ± 0.0099 a.u.) compared with HVs (0.080 ± 0.0063 a.u., P = 0.0847). CONCLUSION Cardiac-induced LD is a conceptually reasonable approach from preclinical studies, measurements demonstrate good reproducibility and inter-reader variability, are less likely to be affected by hepatic hemodynamic changes and are feasible in patients with cirrhosis.
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Affiliation(s)
- Manil D Chouhan
- Division of Medicine, Centre for Medical Imaging, University College London (UCL), London, UK.
| | - Heather E Fitzke
- Division of Medicine, Centre for Medical Imaging, University College London (UCL), London, UK
- Wingate Institute of Neurogastroenterology, Neuroscience and Trauma, Queen Mary University of London (QMUL), London, UK
| | - Alan Bainbridge
- Department of Medical Physics, University College London Hospitals NHS Trust, London, UK
| | - David Atkinson
- Division of Medicine, Centre for Medical Imaging, University College London (UCL), London, UK
| | - Steve Halligan
- Division of Medicine, Centre for Medical Imaging, University College London (UCL), London, UK
| | - Nathan Davies
- Division of Medicine, Institute for Liver and Digestive Health, University College London (UCL), London, UK
| | - Mark F Lythgoe
- Division of Medicine, Centre for Advanced Biomedical Imaging, University College London (UCL), London, UK
| | - Rajeshwar P Mookerjee
- Division of Medicine, Institute for Liver and Digestive Health, University College London (UCL), London, UK
| | - Alex Menys
- Division of Medicine, Centre for Medical Imaging, University College London (UCL), London, UK
- Motilent, London, UK
| | - Stuart A Taylor
- Division of Medicine, Centre for Medical Imaging, University College London (UCL), London, UK
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Mehrabi M, Amini F, Mehrabi S. Kill and Clearance in HCC: An Approach Based on NK Cells and Macrophages. Front Oncol 2021; 11:693076. [PMID: 34557407 PMCID: PMC8453146 DOI: 10.3389/fonc.2021.693076] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2021] [Accepted: 08/23/2021] [Indexed: 11/15/2022] Open
Affiliation(s)
| | | | - Shima Mehrabi
- Internal Medicine, Iran University of Medical Sciences, Tehran, Iran
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40
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Tenório JR, Duarte NT, Andrade NS, Bergamini ML, Mamana AC, Braz-Silva PH, Ortega KL. Assessment of bone metabolism biomarkers in serum and saliva of cirrhotic patients. Clin Oral Investig 2021; 26:1861-1868. [PMID: 34491448 DOI: 10.1007/s00784-021-04161-7] [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: 02/03/2021] [Accepted: 08/24/2021] [Indexed: 10/20/2022]
Abstract
OBJECTIVE To assess the serum and salivary levels of biomarkers related to bone metabolism in cirrhotic patients as well as the evidence of osteoporotic changes on panoramic radiographs. MATERIALS AND METHODS Thirty-eight cirrhotic patients underwent anamnesis and physical examination. Specimens of blood and saliva were collected for evaluation by using Luminex™ xMAP technology to quantify RANKL, OPG, IL-1β, IL-6 and TNF-α. Panoramic radiographs were evaluated based on the mandibular cortical index (MCI) and the resulting data were compared to the expression of biomarkers in serum and saliva. Descriptive data analysis was performed and the Mann-Whitney's test and Spearman's correlation were used. RESULTS Most of the sample consisted of males (68.4%) who had cirrhosis mostly resulting from alcoholism (28.9%). Median concentration values of RANKL (74.44 pg/mL), IL-1 β (45.91 pg/mL), IL-6 (67.69 pg/mL) and TNF-α (5.97 pg/mL) in saliva were higher than those observed in serum. In 72.7% of the panoramic radiographs, MCI was found to be suggestive of osteoporotic changes. No statistically significant correlation was observed between salivary and serum expressions of biomarkers or between biomarkers and MCI. CONCLUSION RANKL, OPG, IL-1β, IL-6 and TNF-α are expressed differently in serum and saliva and the concentration of these biomarkers is not related to MCI. CLINICAL RELEVANCE This study contributes to the study of the mechanisms of osteoporosis in cirrhotic individuals.
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Affiliation(s)
- Jefferson Rocha Tenório
- Department of Stomatology, University of São Paulo School of Dentistry, Av. Prof. Lineu Prestes, 2227-Butantã, São Paulo, SP, 05508-900, Brazil
| | - Nathália Tuany Duarte
- Department of Stomatology, University of São Paulo School of Dentistry, Av. Prof. Lineu Prestes, 2227-Butantã, São Paulo, SP, 05508-900, Brazil
| | - Natália Silva Andrade
- Department of Stomatology, University of São Paulo School of Dentistry, Av. Prof. Lineu Prestes, 2227-Butantã, São Paulo, SP, 05508-900, Brazil.,Department of Dentistry, Federal University of Sergipe, Lagarto, Sergipe, Brazil
| | - Mariana Lobo Bergamini
- Department of Stomatology, University of São Paulo School of Dentistry, Av. Prof. Lineu Prestes, 2227-Butantã, São Paulo, SP, 05508-900, Brazil
| | - Ana Carolina Mamana
- Laboratory of Virology, Institute of Tropical Medicine, University of São Paulo School of Medicine, São Paulo, Brazil
| | - Paulo Henrique Braz-Silva
- Department of Stomatology, University of São Paulo School of Dentistry, Av. Prof. Lineu Prestes, 2227-Butantã, São Paulo, SP, 05508-900, Brazil.,Laboratory of Virology, Institute of Tropical Medicine, University of São Paulo School of Medicine, São Paulo, Brazil
| | - Karem L Ortega
- Department of Stomatology, University of São Paulo School of Dentistry, Av. Prof. Lineu Prestes, 2227-Butantã, São Paulo, SP, 05508-900, Brazil.
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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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Nguyen-Lefebvre AT, Selzner N, Wrana JL, Bhat M. The hippo pathway: A master regulator of liver metabolism, regeneration, and disease. FASEB J 2021; 35:e21570. [PMID: 33831275 DOI: 10.1096/fj.202002284rr] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2020] [Revised: 03/04/2021] [Accepted: 03/18/2021] [Indexed: 12/13/2022]
Abstract
The liver is the only visceral organ in the body with a tremendous capacity to regenerate in response to insults that induce inflammation, cell death, and injury. Liver regeneration is a complicated process involving a well-orchestrated activation of non-parenchymal cells in the injured area and proliferation of undamaged hepatocytes. Furthermore, the liver has a Hepatostat, defined as adjustment of its volume to that required for homeostasis. Understanding the mechanisms that control different steps of liver regeneration is critical to informing therapies for liver repair, to help patients with liver disease. The Hippo signaling pathway is well known for playing an essential role in the control and regulation of liver size, regeneration, stem cell self-renewal, and liver cancer. Thus, the Hippo pathway regulates dynamic cell fates in liver, and in absence of its downstream effectors YAP and TAZ, liver regeneration is severely impaired, and the proliferative expansion of liver cells blocked. We will mainly review upstream mechanisms activating the Hippo signaling pathway following partial hepatectomy in mouse model and patients, its roles during different steps of liver regeneration, metabolism, and cancer. We will also discuss how targeting the Hippo signaling cascade might improve liver regeneration and suppress liver tumorigenesis.
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Affiliation(s)
- Anh Thu Nguyen-Lefebvre
- Department of Medicine, Multi-Organ Transplant Program, Toronto General Hospital, Toronto, ON, Canada.,Lunenfeld-Tanenbaum Research Institute, Toronto, ON, Canada
| | - Nazia Selzner
- Department of Medicine, Multi-Organ Transplant Program, Toronto General Hospital, Toronto, ON, Canada
| | | | - Mamatha Bhat
- Department of Medicine, Multi-Organ Transplant Program, Toronto General Hospital, Toronto, ON, Canada
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Liang J, Yuan H, Xu L, Wang F, Bao X, Yan Y, Wang H, Zhang C, Jin R, Ma L, Zhang J, Huri L, Su X, Xiao R, Ma Y. Study on the effect of Mongolian medicine Qiwei Qinggan Powder on hepatic fibrosis through JAK2/STAT3 pathway. Biosci Biotechnol Biochem 2021; 85:775-785. [PMID: 33686395 DOI: 10.1093/bbb/zbab001] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/27/2020] [Accepted: 12/07/2020] [Indexed: 12/13/2022]
Abstract
This research aimed to evaluate the antihepatic fibrosis effect and explore the mechanism of Qiwei Qinggan Powder (QGS-7) in vivo and in vitro. Carbon tetrachloride (CCl4)-treated rats and hepatic stellate cells (HSCs) were used. QGS-7 treatment significantly improved the liver function of rats as indicated by decreased serum enzymatic activities of alanine aminotransferase, aspartate transaminase, and alkaline phosphatase. Meanwhile, the hydroxyproline of liver was significantly decreased. Histopathological results indicated that QGS-7 alleviated liver damage and reduced the formation of fibrosis septa. Moreover, QGS-7 significantly attenuated expressions of Alpha smooth muscle actin, Collagen I, Janus kinase 2 (JAK2), phosphorylation-JAK2, signal transducer and activator of transcription 3 (STAT3), phosphorylation-STAT3 in the rat hepatic fibrosis model. QGS-7 inhibited HSC proliferation and promoted it apoptosis. QGS-7 may affect hepatic fibrosis through JAK2/STAT3 signaling pathway so as to play an antihepatic fibrosis role.
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Affiliation(s)
- Jie Liang
- Department of Pharmacology, School of Basic Medicine, Inner Mongolia Medical University, Hohhot, China
| | - Hongwei Yuan
- Department of Pathology, School of Basic Medicine, Inner Mongolia Medical University, Hohhot, China
| | - Liping Xu
- Department of Pharmacology, School of Basic Medicine, Inner Mongolia Medical University, Hohhot, China
| | - Feng Wang
- Department of Physiology, School of Basic Medicine, Inner Mongolia Medical University, Hohhot, China
| | - Xiaomei Bao
- Department of Pharmaceutical Engineering, School of Pharmacy, Inner Mongolia Medical University, Hohhot, China
| | - Yuxin Yan
- Department of Pharmacology, School of Basic Medicine, Inner Mongolia Medical University, Hohhot, China
| | - Haisheng Wang
- Department of Biochemistry, School of Basic Medicine, Inner Mongolia Medical University, Hohhot, China
| | - Chunyan Zhang
- Department of Pharmacology, School of Basic Medicine, Inner Mongolia Medical University, Hohhot, China
| | - Rong Jin
- Department of Pharmacology, School of Basic Medicine, Inner Mongolia Medical University, Hohhot, China
| | - Lijie Ma
- Department of Pharmacology, School of Basic Medicine, Inner Mongolia Medical University, Hohhot, China
| | - Jianyu Zhang
- Department of Biochemistry, School of Basic Medicine, Inner Mongolia Medical University, Hohhot, China
| | - Lebagen Huri
- School of Mongolian Medicine and Pharmacy, Inner Mongolia Medical University, Hohhot, China
| | - Xiaoli Su
- Functional Science laboratory, Institute of Basic Medicine, Inner Mongolia Medical University, Hohhot, China
| | - Rui Xiao
- Key Laboratory of Molecular Pathology Inner, Inner Mongolia Medical University, Hohhot City, Inner Mongolia Autonomous Region, China
| | - Yuehong Ma
- Department of Pharmacology, School of Basic Medicine, Inner Mongolia Medical University, Hohhot, China
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Ehsan N, Sweed D, Elsabaawy M. Evaluation of HCV-related liver fibrosis post-successful DAA therapy. EGYPTIAN LIVER JOURNAL 2021. [DOI: 10.1186/s43066-021-00129-0] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022] Open
Abstract
Abstract
Background
The rapidly developing era of direct-acting antiviral regimens (DAAs) for more than one hepatitis C virus (HCV) genotype had certainly alleviated HCV burden all over the world. Liver fibrosis is the major dramatic complication of HCV infection, and its progression leads to cirrhosis, liver failure, and hepatocellular carcinoma. The impact of DAAs on liver fibrosis had been debatably evaluated with undetermined resolution.
Main body
The aim of this review is to accurately revise the effects of DAA regimens on liver fibrosis which can either be regression, progression, or non-significant association. Liver fibrosis regression is a genuine fact assured by many retrospective and prospective clinical studies. Evaluation could be concluded early post-therapy reflecting the dynamic nature of the process.
Conclusions
The ideal application of DAA regimens in treating HCV has to be accomplished with efficient non-invasive markers in differentiating proper fibrosis evaluation from necroinflammation consequences. Liver biopsy is the gold standard that visualizes the dynamic of fibrosis regression.
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Chen Y, Liao W, Zhu Z, Chen J, Yang Q, Zheng Y, Zhang X, Limsila B, Lu M, Fu S, Li R. Essential oil from the raw and vinegar-processed Rhizoma Curcumae ameliorate CCl 4-induced liver fibrosis: integrating network pharmacology and molecular mechanism evaluation. Food Funct 2021; 12:4199-4220. [PMID: 33870974 DOI: 10.1039/d0fo03052j] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/18/2023]
Abstract
Liver fibrosis, caused by multiple chronic liver injuries, is a known contributor to cirrhosis and even liver cancer. As a Traditional Chinese Medicine (TCM), Rhizoma curcumae has been extensively used in the treatment of liver fibrosis with satisfying therapeutic effects; however, its mechanism is unclear. The essential oil is the main bioactive component. The purpose of this study was to investigate the chemical profile and the pharmacological mechanisms of the essential oil of Rhizoma curcumae (EORC) against liver fibrosis by combining network pharmacology and transcriptomic technologies. A total of 37 active compounds were identified using the GC/MS system and literature mining, and the corresponding putative targets were predicted. Then, network pharmacology method was applied to identify the 168 candidate targets of EORC-alleviated liver fibrosis. String database and Cytoscape software were used to build the herb-compound-target network and protein-protein interactions (PPIs) network. Functional and pathway enrichment analysis indicated that EORC significantly influenced TGF-β1/Smads and PI3K/AKT pathways. Experimentally, we verified that EORC attenuated the severity and pathological changes during liver fibrosis progression based on the CCl4-induced liver fibrosis rat model. Transcriptomic technologies demonstrated that EORC ameliorated liver fibrosis partially by regulating the TGF-β1/Smads and PI3K/AKT pathways. In addition, the effect of vinegar-processed EORC was more significant than that of the raw one. Therefore, EORC can alleviate the severity of liver fibrosis through mechanisms predicted by network pharmacology and provide a basis for the further understanding of the application of EORC in the treatment of liver fibrosis.
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Affiliation(s)
- Yi Chen
- State Key Laboratory of Southwestern Chinese Medicine Resources, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, Sichuan, China.
| | - Wan Liao
- State Key Laboratory of Southwestern Chinese Medicine Resources, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, Sichuan, China.
| | - Zongping Zhu
- State Key Laboratory of Southwestern Chinese Medicine Resources, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, Sichuan, China.
| | - Jiao Chen
- State Key Laboratory of Southwestern Chinese Medicine Resources, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, Sichuan, China.
| | - Qingsong Yang
- State Key Laboratory of Southwestern Chinese Medicine Resources, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, Sichuan, China.
| | - Yongfeng Zheng
- State Key Laboratory of Southwestern Chinese Medicine Resources, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, Sichuan, China.
| | - Xinjie Zhang
- State Key Laboratory of Southwestern Chinese Medicine Resources, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, Sichuan, China.
| | - Boonjai Limsila
- Institute of Thai-Chinese Medicine Department of Thai Traditional and Alternative Medicines, Ministry of Public Health, Bangkok 11000, Thailand
| | - Meigui Lu
- Huachiew TCM Hospital, Bangkok 10100, Thailand
| | - Shu Fu
- State Key Laboratory of Southwestern Chinese Medicine Resources, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, Sichuan, China.
| | - Rui Li
- State Key Laboratory of Southwestern Chinese Medicine Resources, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, Sichuan, China.
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Belkahla H, Antunes JC, Lalatonne Y, Sainte Catherine O, Illoul C, Journé C, Jandrot-Perrus M, Coradin T, Gigoux V, Guenin E, Motte L, Helary C. USPIO-PEG nanoparticles functionalized with a highly specific collagen-binding peptide: a step towards MRI diagnosis of fibrosis. J Mater Chem B 2021; 8:5515-5528. [PMID: 32490469 DOI: 10.1039/d0tb00887g] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
Fibrosis is characterized by a pathologic deposition of collagen I, leading to impaired function of organs. Tissue biopsy is the gold standard method for the diagnosis of fibrosis but this is an invasive procedure, subject to sampling errors. Several non-invasive techniques such as magnetic resonance imaging (MRI) using non-specific probes have been developed but they are not fully satisfying as they allow diagnosis at a late stage. In this study, collagelin, a collagen-binding peptide has been covalently linked using click chemistry to pegylated Ultra Small Super Paramagnetic Iron Oxide Nanoparticles (USPIO-PO-PEG-collagelin NPs) with the aim of diagnosing fibrosis at an early stage by MRI. USPIO-PO-PEG-collagelin NPs showed a high affinity for collagen I, two times higher than that of free collagelin whereas not peptide labeled USPIO NPs (USPIO-PO-PEG-yne) did not present any affinity. NPs were not toxic for macrophages and fibroblasts. Diffusion through collagen hydrogels concentrated at 3 and 10 mg mL-1 revealed a large accumulation of USPIO-PO-PEG-collagelin NPs within the collagen network after 72 hours, ca. 3 times larger than that of unlabeled USPIO, thereby evidencing the specific targeting of collagen I. Moreover, the quantity of USPIO-PO-PEG-collagelin NPs accumulated within hydrogels was proportional to the collagen concentration. Subsequently, the NPs diffusion through collagen hydrogels was monitored by MRI. The MRI T2 time relaxation decreased much more significantly with depth for USPIO-PO-PEG-collagelin NPs compared to unlabeled ones. Taken together, these results show that USPIO-PEG-collagelin NPs are promising as effective MRI nanotracers for molecular imaging of fibrosis at an early stage.
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Affiliation(s)
- Hanene Belkahla
- Université Sorbonne Paris Nord, Laboratory for Vascular Translational Science, LVTS, INSERM, UMR 1148, F-93000 Bobigny, Université de Paris, INSERM, UMR 1148, F-75018, Paris, France. and Sorbonne Université, CNRS, Laboratoire de la Chimie de la Matière Condensée (LCMCP), Paris, F-75005, France.
| | - Joana C Antunes
- Université Sorbonne Paris Nord, Laboratory for Vascular Translational Science, LVTS, INSERM, UMR 1148, F-93000 Bobigny, Université de Paris, INSERM, UMR 1148, F-75018, Paris, France.
| | - Yoann Lalatonne
- Université Sorbonne Paris Nord, Laboratory for Vascular Translational Science, LVTS, INSERM, UMR 1148, F-93000 Bobigny, Université de Paris, INSERM, UMR 1148, F-75018, Paris, France. and AP-HP, Hôpital Avicenne, Services de Biochimie et de Medécine Nucléaire Service, F-93009 Bobigny, France
| | - Odile Sainte Catherine
- Université Sorbonne Paris Nord, Laboratory for Vascular Translational Science, LVTS, INSERM, UMR 1148, F-93000 Bobigny, Université de Paris, INSERM, UMR 1148, F-75018, Paris, France.
| | - Corinne Illoul
- Sorbonne Université, CNRS, Laboratoire de la Chimie de la Matière Condensée (LCMCP), Paris, F-75005, France.
| | - Clément Journé
- INSERM, UMR 1148, LVTS, Université de Paris, F-75018, Université Paris Nord, F-93430, Inserm, Plateforme de Recherche FRIM 6-Inserm U1148, Université de Paris, Paris, France
| | - Martine Jandrot-Perrus
- Université Sorbonne Paris Nord, Laboratory for Vascular Translational Science, LVTS, INSERM, UMR 1148, F-93000 Bobigny, Université de Paris, INSERM, UMR 1148, F-75018, Paris, France.
| | - Thibaud Coradin
- Sorbonne Université, CNRS, Laboratoire de la Chimie de la Matière Condensée (LCMCP), Paris, F-75005, France.
| | - Véronique Gigoux
- INSERM ERL1226-Receptology and Therapeutic Targeting of Cancers, Laboratoire de Physique et Chimie des Nano-Objets, CNRS UMR5215-INSA, Université de Toulouse III, F-31432 Toulouse, France
| | - Erwann Guenin
- Université Sorbonne Paris Nord, Laboratory for Vascular Translational Science, LVTS, INSERM, UMR 1148, F-93000 Bobigny, Université de Paris, INSERM, UMR 1148, F-75018, Paris, France. and Sorbonne Universités, Université de Technologie de Compiègne, Integrated Transformations of Renewable Matter Laboratory (EA TIMR 4297 UTC-ESCOM), Compiègne, France
| | - Laurence Motte
- Université Sorbonne Paris Nord, Laboratory for Vascular Translational Science, LVTS, INSERM, UMR 1148, F-93000 Bobigny, Université de Paris, INSERM, UMR 1148, F-75018, Paris, France.
| | - Christophe Helary
- Sorbonne Université, CNRS, Laboratoire de la Chimie de la Matière Condensée (LCMCP), Paris, F-75005, France.
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Park JW, Kim MJ, Kim SE, Kim HJ, Jeon YC, Shin HY, Park SJ, Jang MK, Kim DJ, Park CK, Choi EK. Increased Expression of S100B and RAGE in a Mouse Model of Bile Duct Ligation-induced Liver Fibrosis. J Korean Med Sci 2021; 36:e90. [PMID: 33847081 PMCID: PMC8042478 DOI: 10.3346/jkms.2021.36.e90] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/09/2020] [Accepted: 01/27/2021] [Indexed: 01/07/2023] Open
Abstract
BACKGROUND Liver fibrosis is defined as the accumulation of the extracellular matrix and scar formation. The receptor for advanced glycation end products (RAGE) has been demonstrated to participate in fibrogenesis. S100B is a ligand of RAGE and exerts extracellular functions by inducing a series of signal transduction cascades. However, the involvement of S100B and RAGE in cholestasis-induced liver fibrosis remains unclear. In this study, we investigated S100B and RAGE expression during liver fibrosis in mice that underwent common bile duct ligation (BDL). METHODS BDL was performed in 10-week-old male C57BL/6J mice with sham control (n = 26) and BDL (n = 26) groups. Expression levels of S100B, RAGE and fibrotic markers in the livers from both groups at week 1 and 3 after BDL were examined by western blot and quantitative real-time reverse transcription polymerase chain reaction analysis. Liver fibrotic changes were examined by histological and ultrastructural analysis. RESULTS Histological staining with Sirius Red and the evaluation of the messenger RNA expression of fibrotic markers showed noticeable periportal fibrosis and bile duct proliferation. S100B was mainly present in bile duct epithelial cells, and its expression was upregulated in proportion to the ductular reaction during fibrogenesis by BDL. RAGE expression was also increased, and interestingly, triple immunofluorescence staining and transmission electron microscopy showed that both S100B and RAGE were expressed in proliferating bile duct epithelial cells and activated hepatic stellate cells (HSCs) of the BDL livers. In addition, in rat HSCs (HSC-T6), treatment with recombinant S100B protein significantly increased fibrotic markers in a dose-dependent manner, and RAGE small interfering RNA (siRNA) suppressed S100B-stimulated upregulation of fibrotic markers compared with cells treated with scramble siRNA and S100B. CONCLUSION These findings suggest that the increased expression of S100B and RAGE and the interaction between S100B and RAGE may play an important role in ductular reaction and liver fibrosis induced by BDL.
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Affiliation(s)
- Ji Won Park
- Department of Biomedical Gerontology, Graduate School of Hallym University, Chuncheon, Korea
- Department of Internal Medicine, Hallym University Medical Center, Anyang, Korea
- Institute for Liver and Digestive Diseases, Hallym University, Chuncheon, Korea
| | - Mo Jong Kim
- Department of Biomedical Gerontology, Graduate School of Hallym University, Chuncheon, Korea
- Ilsong Institute of Life Science, Hallym University, Anyang, Korea
| | - Sung Eun Kim
- Department of Internal Medicine, Hallym University Medical Center, Anyang, Korea
- Institute for Liver and Digestive Diseases, Hallym University, Chuncheon, Korea
| | - Hee Jun Kim
- Ilsong Institute of Life Science, Hallym University, Anyang, Korea
| | - Yong Chul Jeon
- Ilsong Institute of Life Science, Hallym University, Anyang, Korea
| | - Hae Young Shin
- Ilsong Institute of Life Science, Hallym University, Anyang, Korea
| | - Se Jin Park
- Ilsong Institute of Life Science, Hallym University, Anyang, Korea
| | - Myoung Kuk Jang
- Institute for Liver and Digestive Diseases, Hallym University, Chuncheon, Korea
- Department of Internal Medicine, Kangdong Sacred Heart Hospital of Hallym University Medical Center, Seoul, Korea
| | - Dong Joon Kim
- Institute for Liver and Digestive Diseases, Hallym University, Chuncheon, Korea
- Department of Internal Medicine, Chuncheon Sacred Heart Hospital of Hallym University Medical Center, Chuncheon, Korea
| | - Choong Kee Park
- Department of Internal Medicine, Hallym University Medical Center, Anyang, Korea
- Institute for Liver and Digestive Diseases, Hallym University, Chuncheon, Korea
| | - Eun Kyoung Choi
- Department of Biomedical Gerontology, Graduate School of Hallym University, Chuncheon, Korea
- Ilsong Institute of Life Science, Hallym University, Anyang, Korea.
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48
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Böttcher K, Longato L, Marrone G, Mazza G, Ghemtio L, Hall A, Luong TV, Caruso S, Viollet B, Zucman-Rossi J, Pinzani M, Rombouts K. AICAR and compound C negatively modulate HCC-induced primary human hepatic stellate cell activation in vitro. Am J Physiol Gastrointest Liver Physiol 2021; 320:G543-G556. [PMID: 33406006 DOI: 10.1152/ajpgi.00262.2020] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
Tumor stroma and microenvironment have been shown to affect hepatocellular carcinoma (HCC) growth, with activated hepatic stellate cells (HSC) as a major contributor in this process. Recent evidence suggests that the energy sensor adenosine monophosphate-activated kinase (AMPK) may mediate a series of essential processes during carcinogenesis and HCC progression. Here, we investigated the effect of different HCC cell lines with known TP53 or CTNBB1 mutations on primary human HSC activation, proliferation, and AMPK activation. We show that conditioned media obtained from multiple HCC cell lines differently modulate human hepatic stellate cell (hHSC) proliferation and hHSC AMPK activity in a paracrine manner. Pharmacological treatment of hHSC with AICAR and Compound C inhibited the HCC-induced proliferation/activation of hHSC through AMPK-dependent and AMPK-independent mechanisms, which was further confirmed using mouse embryonic fibroblasts (MEFs) deficient of both catalytic AMPKα isoforms (AMPKα1/α2-/-) and wild type (wt) MEF. Both compounds induced S-phase cell-cycle arrest and, in addition, AICAR inhibited the mTORC1 pathway by inhibiting phosphorylation of 4E-BP1 and S6 in hHSC and wt MEF. Data mining of the Cancer Genome Atlas (TCGA) and the Liver Cancer (LICA-FR) showed that AMPKα1 (PRKAA1) and AMPKα2 (PRKAA2) expression differed depending on the mutation (TP53 or CTNNB1), tumor grading, and G1-G6 classification, reflecting the heterogeneity in human HCC. Overall, we provide evidence that AMPK modulating pharmacological agents negatively modulate HCC-induced hHSC activation and may therefore provide a novel approach to target the mutual, tumor-promoting interactions between hHSC and HCC.NEW & NOTEWORTHY HCC is marked by genetic heterogeneity and activated hepatic stellate cells (HSC) are considered key players during HCC development. The paracrine effect of different HCC cell lines on the activation of primary hHSC was accompanied by differential AMPK activation depending on the HCC line used. Pharmacological treatment inhibited the HCC-induced hHSC activation through AMPK-dependent and AMPK-independent mechanisms. This heterogenic effect on HCC-induced AMPK activation was confirmed by data mining TCGA and LICA-FR databases.
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Affiliation(s)
- Katrin Böttcher
- Regenerative Medicine and Fibrosis Group, Institute for Liver and Digestive Health, University College London, Royal Free Campus, London, United Kingdom.,Sheila Sherlock Liver Centre, Royal Free Hospital, London, United Kingdom
| | - Lisa Longato
- Regenerative Medicine and Fibrosis Group, Institute for Liver and Digestive Health, University College London, Royal Free Campus, London, United Kingdom
| | - Giusi Marrone
- Regenerative Medicine and Fibrosis Group, Institute for Liver and Digestive Health, University College London, Royal Free Campus, London, United Kingdom
| | - Giuseppe Mazza
- Regenerative Medicine and Fibrosis Group, Institute for Liver and Digestive Health, University College London, Royal Free Campus, London, United Kingdom
| | - Leo Ghemtio
- Drug Research Program, Division of Pharmaceutical Biosciences, Faculty of Pharmacy, University of Helsinki, Helsinki, Finland
| | - Andrew Hall
- Sheila Sherlock Liver Centre, Royal Free Hospital, London, United Kingdom.,Department of Cellular Pathology, Royal Free Hospital, London, United Kingdom
| | - Tu Vinh Luong
- Department of Cellular Pathology, Royal Free Hospital, London, United Kingdom
| | - Stefano Caruso
- Centre de Recherche des Cordeliers, INSERM, Functional Genomics of Solid Tumors Laboratory, Sorbonne Université, Université de Paris, Paris, France
| | - Benoit Viollet
- Université de Paris, Institut Cochin, CNRS, INSERM, Paris, France
| | - Jessica Zucman-Rossi
- Centre de Recherche des Cordeliers, INSERM, Functional Genomics of Solid Tumors Laboratory, Sorbonne Université, Université de Paris, Paris, France.,Hôpital Européen Georges Pompidou, Assistance Publique-Hôpitaux de Paris, Paris, France
| | - Massimo Pinzani
- Regenerative Medicine and Fibrosis Group, Institute for Liver and Digestive Health, University College London, Royal Free Campus, London, United Kingdom.,Sheila Sherlock Liver Centre, Royal Free Hospital, London, United Kingdom
| | - Krista Rombouts
- Regenerative Medicine and Fibrosis Group, Institute for Liver and Digestive Health, University College London, Royal Free Campus, London, United Kingdom
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Imaging Biomarkers of Hepatic Fibrosis: Reliability and Accuracy of Hepatic Periportal Space Widening and Other Morphologic Features on MRI. AJR Am J Roentgenol 2021; 216:1229-1239. [PMID: 33729883 DOI: 10.2214/ajr.20.23099] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
OBJECTIVE. The purpose of this article was to assess the reliability and accuracy of hepatic periportal space widening and other qualitative imaging features for the prediction of hepatic fibrosis. MATERIALS AND METHODS. This single-center retrospective study identified consecutive patients who had undergone liver MR elastography. Two abdominal radiologists independently reviewed anatomic images, assessing multiple qualitative features of chronic liver disease (CLD) including periportal space widening. Each reader also measured the periportal space at the main portal vein (MPV) and right portal vein (RPV). Interrater reliability analysis was then performed. Sensitivity and specificity were determined for the detection of any hepatic fibrosis (stage I or higher) and of advanced fibrosis (stage III or higher) using stiffness on MR elastography as the reference standard. RESULTS. Of 229 subjects, 157 (69%) had fibrosis and 78 (34%) had advanced fibrosis. Agreement for periportal space widening was moderate (κ = 0.47), and agreement for remaining features was moderate to substantial (κ = 0.42-0.80). Agreement for the periportal space at the MPV was moderate (ICC, 0.55), and agreement for the periportal space at the RPV was near perfect (ICC, 0.83). Periportal space widening had the highest sensitivity (83.0%) for any fibrosis, with limited specificity (61.3%). Surface nodularity had the highest specificity (94.4%) for any fibrosis, with limited sensitivity (51.6%). Periportal space widening plus one or more additional imaging feature of CLD or the presence of surface nodularity alone had sensitivity of 72.6% and specificity of 76.1%. A periportal space at the MPV greater than 9.5 mm had substantial agreement with qualitative periportal space widening (κ = 0.74). CONCLUSION. Periportal space widening has a high sensitivity for hepatic fibrosis, with moderate specificity when combined with additional anatomic features of CLD.
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50
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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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