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Chatterjee N, Sharma R, Kale PR, Trehanpati N, Ramakrishna G. Is the liver resilient to the process of ageing? Ann Hepatol 2024; 30:101580. [PMID: 39276981 DOI: 10.1016/j.aohep.2024.101580] [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: 05/25/2024] [Revised: 08/15/2024] [Accepted: 08/21/2024] [Indexed: 09/17/2024]
Abstract
The liver's unique regenerative capacity, immunotolerant feature, and polyploidy status distinguish it as a metabolic organ unlike any other in the body. Despite aging, the liver generally exhibits fewer pathological abnormalities than other organs (such as the kidney), maintaining its functions near-normal balanced manner. Subtle changes in the liver, including reduced blood flow, detoxification alterations, pseudo-capillarization, and lipofuscin deposition, may occur with chronological age. Research indicates that carefully selected liver grafts from octogenarian donors can perform well post-transplant, emphasizing instances where age doesn't necessarily compromise liver function. Notably, a recent report suggests that the liver is a youthful organ, with hepatocytes averaging an age of only 3 years. Despite the liver's impressive regenerative capabilities and cellular reserve, a lingering question persists: how does the liver maintain its youthful characteristic amidst the chronological aging of the entire organism? The various adaptive mechanism possibly include:(a) cellular hypertrophy to maintain physiological capacity even before proliferation initiates, (b) the "ploidy conveyor" as a genetic adaptation to endure aging-related stress, (c) sustained telomere length indicative of youthfulness (d) active extracellular matrix remodelling for normal cellular functioning, (e) Mitochondria-Endoplasmic Reticulum based metabolic adaptation and (c) cellular plasticity as fitness mechanisms for healthy aging. However, it is crucial to note that aged livers may have compromised regenerative capacity and chronic liver disease is often associated with declining function due to premature hepatocyte senescence. This review delves into varied cellular adaptations sustaining liver homeostasis with chronological aging and briefly explores the role of accelerated hepatocyte aging as a precursor to chronic liver disease.
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Affiliation(s)
- Nirupama Chatterjee
- Artemis Education and Research Foundation, Artemis Health Institute, Sector 51 Gurugram, India
| | - Rishabh Sharma
- Amity Stem Cell Institute, Amity Medical School, Amity University Haryana Amity Education Valley, Panchgaon, Manesar Gurugram, HR 122413, India
| | - Pratibha R Kale
- Department of Clinical Microbiology, Molecular and Cellular Medicine, Institute of Liver and Biliary Sciences, India
| | - Nirupma Trehanpati
- Department of Molecular and Cellular Medicine, Institute of Liver and Biliary Sciences, India
| | - Gayatri Ramakrishna
- Department of Molecular and Cellular Medicine, Institute of Liver and Biliary Sciences, India.
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2
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Tarchi SM, Salvatore M, Lichtenstein P, Sekar T, Capaccione K, Luk L, Shaish H, Makkar J, Desperito E, Leb J, Navot B, Goldstein J, Laifer S, Beylergil V, Ma H, Jambawalikar S, Aberle D, D'Souza B, Bentley-Hibbert S, Marin MP. Radiology of fibrosis part II: abdominal organs. J Transl Med 2024; 22:610. [PMID: 38956593 PMCID: PMC11218138 DOI: 10.1186/s12967-024-05346-w] [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: 02/12/2024] [Accepted: 05/25/2024] [Indexed: 07/04/2024] Open
Abstract
Fibrosis is the aberrant process of connective tissue deposition from abnormal tissue repair in response to sustained tissue injury caused by hypoxia, infection, or physical damage. It can affect almost all organs in the body causing dysfunction and ultimate organ failure. Tissue fibrosis also plays a vital role in carcinogenesis and cancer progression. The early and accurate diagnosis of organ fibrosis along with adequate surveillance are helpful to implement early disease-modifying interventions, important to reduce mortality and improve quality of life. While extensive research has already been carried out on the topic, a thorough understanding of how this relationship reveals itself using modern imaging techniques has yet to be established. This work outlines the ways in which fibrosis shows up in abdominal organs and has listed the most relevant imaging technologies employed for its detection. New imaging technologies and developments are discussed along with their promising applications in the early detection of organ fibrosis.
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Affiliation(s)
- Sofia Maria Tarchi
- Department of Biomedical Sciences, Humanitas University, Milan, Italy.
- Department of Radiology, Columbia University Irving Medical Center, New York, NY, USA.
| | - Mary Salvatore
- Department of Radiology, Columbia University Irving Medical Center, New York, NY, USA
| | - Philip Lichtenstein
- Department of Radiology, Columbia University Irving Medical Center, New York, NY, USA
| | - Thillai Sekar
- Department of Radiology, Columbia University Irving Medical Center, New York, NY, USA
| | - Kathleen Capaccione
- Department of Radiology, Columbia University Irving Medical Center, New York, NY, USA
| | - Lyndon Luk
- Department of Radiology, Columbia University Irving Medical Center, New York, NY, USA
| | - Hiram Shaish
- Department of Radiology, Columbia University Irving Medical Center, New York, NY, USA
| | - Jasnit Makkar
- Department of Radiology, Columbia University Irving Medical Center, New York, NY, USA
| | - Elise Desperito
- Department of Radiology, Columbia University Irving Medical Center, New York, NY, USA
| | - Jay Leb
- Department of Radiology, Columbia University Irving Medical Center, New York, NY, USA
| | - Benjamin Navot
- Department of Radiology, Columbia University Irving Medical Center, New York, NY, USA
| | - Jonathan Goldstein
- Department of Radiology, Columbia University Irving Medical Center, New York, NY, USA
| | - Sherelle Laifer
- Department of Radiology, Columbia University Irving Medical Center, New York, NY, USA
| | - Volkan Beylergil
- Department of Radiology, Columbia University Irving Medical Center, New York, NY, USA
| | - Hong Ma
- Department of Radiology, Columbia University Irving Medical Center, New York, NY, USA
| | - Sachin Jambawalikar
- Department of Radiology, Columbia University Irving Medical Center, New York, NY, USA
| | - Dwight Aberle
- Department of Radiology, Columbia University Irving Medical Center, New York, NY, USA
| | - Belinda D'Souza
- Department of Radiology, Columbia University Irving Medical Center, New York, NY, USA
| | | | - Monica Pernia Marin
- Department of Radiology, Columbia University Irving Medical Center, New York, NY, USA
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3
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Chu R, Wang Y, Kong J, Pan T, Yang Y, He J. Lipid nanoparticles as the drug carrier for targeted therapy of hepatic disorders. J Mater Chem B 2024; 12:4759-4784. [PMID: 38682294 DOI: 10.1039/d3tb02766j] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 05/01/2024]
Abstract
The liver, a complex and vital organ in the human body, is susceptible to various diseases, including metabolic disorders, acute hepatitis, cirrhosis, and hepatocellular carcinoma. In recent decades, these diseases have significantly contributed to global morbidity and mortality. Currently, liver transplantation remains the most effective treatment for hepatic disorders. Nucleic acid therapeutics offer a selective approach to disease treatment through diverse mechanisms, enabling the regulation of relevant genes and providing a novel therapeutic avenue for hepatic disorders. It is expected that nucleic acid drugs will emerge as the third generation of pharmaceuticals, succeeding small molecule drugs and antibody drugs. Lipid nanoparticles (LNPs) represent a crucial technology in the field of drug delivery and constitute a significant advancement in gene therapies. Nucleic acids encapsulated in LNPs are shielded from the degradation of enzymes and effectively delivered to cells, where they are released and regulate specific genes. This paper provides a comprehensive review of the structure, composition, and applications of LNPs in the treatment of hepatic disorders and offers insights into prospects and challenges in the future development of LNPs.
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Affiliation(s)
- Runxuan Chu
- National Advanced Medical Engineering Research Center, China State Institute of Pharmaceutical Industry, 285 Gebaini Road, Shanghai 201203, P. R. China.
| | - Yi Wang
- Department of Chemistry, Hong Kong Baptist University, Kowloon Tung, Hong Kong SAR, P. R. China.
| | - Jianglong Kong
- Department of Chemistry, Hong Kong Baptist University, Kowloon Tung, Hong Kong SAR, P. R. China.
| | - Ting Pan
- National Advanced Medical Engineering Research Center, China State Institute of Pharmaceutical Industry, 285 Gebaini Road, Shanghai 201203, P. R. China.
- Department of Pharmaceutics School of Pharmacy, China Pharmaceutical University, Nanjing 210009, P. R. China
| | - Yani Yang
- National Advanced Medical Engineering Research Center, China State Institute of Pharmaceutical Industry, 285 Gebaini Road, Shanghai 201203, P. R. China.
| | - Jun He
- National Advanced Medical Engineering Research Center, China State Institute of Pharmaceutical Industry, 285 Gebaini Road, Shanghai 201203, P. R. China.
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Caon E, Forlano R, Mullish BH, Manousou P, Rombouts K. Liver sinusoidal cells in the diagnosis and treatment of liver diseases: Role of hepatic stellate cells. SINUSOIDAL CELLS IN LIVER DISEASES 2024:513-532. [DOI: 10.1016/b978-0-323-95262-0.00025-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
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Nauser S, Steinkohl E, Olesen SS, Drewes AM, Frøkjær JB. Co-existence of hepatic and pancreatic fibrosis in chronic pancreatitis patients including associated risk factors: a magnetic resonance elastography study. Scand J Gastroenterol 2024; 59:100-107. [PMID: 37615331 DOI: 10.1080/00365521.2023.2250496] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/31/2023] [Accepted: 08/15/2023] [Indexed: 08/25/2023]
Abstract
OBJECTIVES To investigate the co-existence of hepatic and pancreatic fibrosis using magnetic resonance elastography (MRE) in chronic pancreatitis (CP), including the association between hepatic and pancreatic MRE-derived stiffness and exploration of potential etiological risk factors. MATERIALS AND METHODS Fifty-four CP patients and 35 healthy controls underwent hepatic and pancreatic MRE with measurements of tissue stiffness. Clinical parameters including stage (probable or definite CP), etiology of CP, the presence of diabetes or exocrine insufficiency, and previous history of common bile duct stenosis were assessed. Uni- and multivariate regression models were used to investigate risk factors associated with hepatic fibrosis/stiffness in CP patients. RESULTS Fifteen percent of CP patients and none of the controls had abnormal liver stiffness (>2.5 kPa), p = 0.02. 5.6% of CP patients had liver stiffness indicating F1 fibrosis (>2.93 kPa). However, hepatic stiffness was not higher in patients than in healthy controls (2.20 ± 0.41 vs 2.08 ± 0.21 kPa, p = 0.10). In patients, a positive association was seen between hepatic and pancreatic stiffness (r = 0.270, p = 0.048). In the multivariate analysis (adjusted for age, gender and BMI), liver stiffness was significantly associated with alcoholic etiology of CP (p = 0.029). In contrast, stage of CP, history of common bile duct stenosis, and the presence of diabetes or exocrine insufficiency were not associated with liver stiffness (all p > 0.14). CONCLUSIONS Only a modest co-existence of hepatic and pancreatic fibrosis was observed in CP. However, the positive association between hepatic and pancreatic stiffness indicates some level of common pathophysiology. Especially, alcoholic etiology of CP was related to increased hepatic stiffness.
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Affiliation(s)
- Serena Nauser
- Department of Clinical Medicine, Aalborg University, Aalborg, Denmark
| | - Emily Steinkohl
- Department of Clinical Medicine, Aalborg University, Aalborg, Denmark
- Department of Radiology, Aalborg University Hospital, Aalborg, Denmark
- Centre for Pancreatic Diseases, Department of Gastroenterology & Hepatology, Aalborg University Hospital, Aalborg, Denmark
| | - Søren Schou Olesen
- Department of Clinical Medicine, Aalborg University, Aalborg, Denmark
- Centre for Pancreatic Diseases, Department of Gastroenterology & Hepatology, Aalborg University Hospital, Aalborg, Denmark
| | - Asbjørn Mohr Drewes
- Department of Clinical Medicine, Aalborg University, Aalborg, Denmark
- Centre for Pancreatic Diseases, Department of Gastroenterology & Hepatology, Aalborg University Hospital, Aalborg, Denmark
| | - Jens Brøndum Frøkjær
- Department of Clinical Medicine, Aalborg University, Aalborg, Denmark
- Department of Radiology, Aalborg University Hospital, Aalborg, Denmark
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Shu Y, He Y, Ye G, Liu X, Huang J, Zhang Q, Tian D, Wang T, Shu J. Curcumin inhibits the activity and induces apoptosis of activated hepatic stellate cell by suppressing autophagy. J Cell Biochem 2023; 124:1764-1778. [PMID: 37909649 DOI: 10.1002/jcb.30487] [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: 02/01/2023] [Revised: 09/09/2023] [Accepted: 09/25/2023] [Indexed: 11/03/2023]
Abstract
Curcumin, a kind of natural compound, has been previously proven to inhibit the autophagy in hepatic stellate cells (HSCs) and induce their apoptosis. However, it is not clear whether the enhanced apoptosis of activated HSCs (aHSCs) caused by curcumin depends on autophagy inhibition. We aim to verify this hypothesis and explore the potential mechanisms in this study. Immortalized human HSC line LX-2 was used as an experimental specimen and pretreated with transforming growth factor β1(TGF-β1) for 24 h to activate it before drug application. The levels of autophagy, apoptosis, cell activity, lipid metabolism, and the activity of the PI3K/Akt/mTOR signal pathway were evaluated by multiple methods, such as Western blotting, mcherry-EGFP-LC3B adenoviruses transfection, immunofluorescence, Nile Red staining, flow cytometry among others. Our results showed that rapamycin, an autophagy activator, could partly offset the effects of curcumin on autophagy and apoptosis of LX-2 cells, while 3-Methyladenine (3-MA), an autophagy inhibitor, could enhance these effects. Furthermore, curcumin could promote the activity of the PI3K/Akt/mTOR signal pathway in LX-2 cells, while PI3K inhibitor could partly offset this effect and increase the autophagy level. Overall, we demonstrated that curcumin could inhibit the activity and promote LX-2 cells apoptosis by suppressing autophagy by activating the PI3K/Akt/mTOR signal pathway. In addition, lipid recovery and energy deprivation due to autophagy inhibition may be the exact mechanism by which curcumin attenuates the pro-fibrotic activity of LX-2.
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Affiliation(s)
- Yongxiang Shu
- Department of Gastroenterology, Guangzhou Red Cross Hospital of Jinan University, Guangzhou, China
| | - Yajun He
- Department of Clinical laboratory, Guangzhou Red Cross Hospital of Jinan University, Guangzhou, China
| | - Guorong Ye
- Department of Gastroenterology, Guangzhou Red Cross Hospital of Jinan University, Guangzhou, China
| | - Xuyou Liu
- Department of Gastroenterology, Guangzhou Red Cross Hospital of Jinan University, Guangzhou, China
| | - Jiahuang Huang
- Department of Gastroenterology, Guangzhou Red Cross Hospital of Jinan University, Guangzhou, China
| | - Qinghui Zhang
- Department of Gastroenterology, Guangzhou Red Cross Hospital of Jinan University, Guangzhou, China
| | - Da Tian
- Department of Gastroenterology, Guangzhou Red Cross Hospital of Jinan University, Guangzhou, China
| | - Tengyan Wang
- Department of Gastroenterology, Guangzhou Red Cross Hospital of Jinan University, Guangzhou, China
| | - Jianchang Shu
- Department of Gastroenterology, Guangzhou Red Cross Hospital of Jinan University, Guangzhou, China
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Solitano V, Dal Buono A, Gabbiadini R, Wozny M, Repici A, Spinelli A, Vetrano S, Armuzzi A. Fibro-Stenosing Crohn's Disease: What Is New and What Is Next? J Clin Med 2023; 12:jcm12093052. [PMID: 37176493 PMCID: PMC10179180 DOI: 10.3390/jcm12093052] [Citation(s) in RCA: 20] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2023] [Revised: 04/03/2023] [Accepted: 04/19/2023] [Indexed: 05/15/2023] Open
Abstract
Fibro-stenosing Crohn's disease (CD) is a common disease presentation that leads to impaired quality of life and often requires endoscopic treatments or surgery. From a pathobiology perspective, the conventional view that intestinal fibro-stenosis is an irreversible condition has been disproved. Currently, there are no existing imaging techniques that can accurately quantify the amount of fibrosis within a stricture, and managing patients is challenging, requiring a multidisciplinary team. Novel therapies targeting different molecular components of the fibrotic pathways are increasing regarding other diseases outside the gut. However, a large gap between clinical need and the lack of anti-fibrotic agents in CD remains. This paper reviews the current state of pathobiology behind fibro-stenosing CD, provides an updated diagnostic and therapeutic approach, and finally, focuses on clinical trial endpoints and possible targets of anti-fibrotic therapies.
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Affiliation(s)
- Virginia Solitano
- Department of Biomedical Sciences, Humanitas University, Pieve Emanuele, 20090 Milan, Italy
- Division of Gastroenterology, Department of Medicine, Western University, London, ON N6A 4V2, Canada
| | - Arianna Dal Buono
- IBD Center, IRCCS Humanitas Research Hospital, Rozzano, 20089 Milan, Italy
| | - Roberto Gabbiadini
- IBD Center, IRCCS Humanitas Research Hospital, Rozzano, 20089 Milan, Italy
| | - Marek Wozny
- Department of Biomedical Sciences, Humanitas University, Pieve Emanuele, 20090 Milan, Italy
| | - Alessandro Repici
- Department of Biomedical Sciences, Humanitas University, Pieve Emanuele, 20090 Milan, Italy
- Department of Endoscopy, IRCCS Humanitas Research Hospital, Rozzano, 20089 Milan, Italy
| | - Antonino Spinelli
- Department of Biomedical Sciences, Humanitas University, Pieve Emanuele, 20090 Milan, Italy
- Division of Colon and Rectal Surgery, IRCCS Humanitas Research Hospital, Rozzano, 20089 Milan, Italy
| | - Stefania Vetrano
- Department of Biomedical Sciences, Humanitas University, Pieve Emanuele, 20090 Milan, Italy
- IBD Center, IRCCS Humanitas Research Hospital, Rozzano, 20089 Milan, Italy
| | - Alessandro Armuzzi
- Department of Biomedical Sciences, Humanitas University, Pieve Emanuele, 20090 Milan, Italy
- IBD Center, IRCCS Humanitas Research Hospital, Rozzano, 20089 Milan, Italy
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8
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Niu W, Zhu M, Wang M, Zhang G, Zheng C, Bao Y, Li Y, Zhang N, Wang J, He H, Wang Y. Discovery and development of benzene sulfonamide derivatives as anti-hepatic fibrosis agents. Bioorg Med Chem Lett 2023; 88:129290. [PMID: 37080476 DOI: 10.1016/j.bmcl.2023.129290] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2023] [Revised: 04/14/2023] [Accepted: 04/15/2023] [Indexed: 04/22/2023]
Abstract
A novel benzene sulfonamide compound named IMB16-4 exhibits excellent anti-hepatic fibrosis activity in a recent study. To develop potential anti-hepatic fibrosis agents, a series of benzene sulfonamide derivatives were designed and synthesized based on the scaffold of the lead compound IMB16-4. As it turned out, most of the derivatives displayed potential anti-hepatic fibrosis activity, among which, compounds 11a, 11b, 11d, 13a, 36b, and 47b exhibited inhibition rates of 42.3%, 48.7%, 42.4%, 40.0%, 39.4%, and 49.3%, respectively, which were equivalent to the control IMB16-4 with an inhibition rate of 35.9%, Costunolide with an inhibition rate of 45.4%, and much more potent than that of Epigallocatechin gallate (EGCG) with an inhibition rate of 25.3%. Especially, compounds 46a, 46b, and 46c exhibited excellent anti-hepatic fibrosis activity with inhibition rates of 61.7%, 54.8%, and 60.7%, which were almost 1.5-fold inhibition rates of IMB16-4. In addition, compounds 46a, 46b, and 46c exhibited remarkable inhibitory activity in the gene expression of COL1A1, MMP-2, and the protein expression of COL1A1, FN, α-SMA, and TIMP-1 by inhibiting the JAK1-STAT1/3 pathway. These findings furnished valuable inspiration for the further development of anti-hepatic fibrosis agents.
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Affiliation(s)
- Weiping Niu
- Institute of Medicinal Biotechnology, Chinese Academy of Medical Science and Peking Union Medical College, Beijing 100050, China
| | - Mei Zhu
- Institute of Medicinal Biotechnology, Chinese Academy of Medical Science and Peking Union Medical College, Beijing 100050, China
| | - Minghua Wang
- Institute of Medicinal Biotechnology, Chinese Academy of Medical Science and Peking Union Medical College, Beijing 100050, China
| | - Guoning Zhang
- Institute of Medicinal Biotechnology, Chinese Academy of Medical Science and Peking Union Medical College, Beijing 100050, China
| | - Chenghong Zheng
- Institute of Medicinal Biotechnology, Chinese Academy of Medical Science and Peking Union Medical College, Beijing 100050, China
| | - Yunyang Bao
- Institute of Medicinal Biotechnology, Chinese Academy of Medical Science and Peking Union Medical College, Beijing 100050, China
| | - Yiming Li
- Institute of Medicinal Biotechnology, Chinese Academy of Medical Science and Peking Union Medical College, Beijing 100050, China
| | - Na Zhang
- Institute of Medicinal Biotechnology, Chinese Academy of Medical Science and Peking Union Medical College, Beijing 100050, China
| | - Juxian Wang
- Institute of Medicinal Biotechnology, Chinese Academy of Medical Science and Peking Union Medical College, Beijing 100050, China
| | - Hongwei He
- Institute of Medicinal Biotechnology, Chinese Academy of Medical Science and Peking Union Medical College, Beijing 100050, China
| | - Yucheng Wang
- Institute of Medicinal Biotechnology, Chinese Academy of Medical Science and Peking Union Medical College, Beijing 100050, China.
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Zhang J, Zao X, Zhang J, Guo Z, Jin Q, Chen G, Gan D, Du H, Ye Y. Is it possible to intervene early cirrhosis by targeting toll-like receptors to rebalance the intestinal microbiome? Int Immunopharmacol 2023; 115:109627. [PMID: 36577151 DOI: 10.1016/j.intimp.2022.109627] [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: 11/01/2022] [Revised: 12/13/2022] [Accepted: 12/19/2022] [Indexed: 12/27/2022]
Abstract
Cirrhosis is a progressive chronic liver disease caused by one or more causes and characterized by diffuse fibrosis, pseudolobules, and regenerated nodules. Once progression to hepatic decompensation, the function of the liver and other organs is impaired and almost impossible to reverse and recover, which often results in hospitalization, impaired quality of life, and high mortality. However, in the early stage of cirrhosis, there seems to be a possibility of cirrhosis reversal. The development of cirrhosis is related to the intestinal microbiota and activation of toll-like receptors (TLRs) pathways, which could regulate cell proliferation, apoptosis, expression of the hepatomitogen epiregulin, and liver inflammation. Targeting regulation of intestinal microbiota and TLRs pathways could affect the occurrence and development of cirrhosis and its complications. In this paper, we first reviewed the dynamic change of intestinal microbiota and TLRs during cirrhosis progression. And further discussed the interaction between them and potential therapeutic targets to reverse early staged cirrhosis.
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Affiliation(s)
- Jiaxin Zhang
- Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing, China; Institute of Liver Diseases, Beijing University of Chinese Medicine, Beijing, China
| | - Xiaobin Zao
- Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing, China; Institute of Liver Diseases, Beijing University of Chinese Medicine, Beijing, China
| | - Jiaying Zhang
- School of Mechanical Engineering and Automation, Beihang University, Beijing, China
| | - Ziwei Guo
- Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing, China
| | - Qian Jin
- Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing, China
| | - Guang Chen
- Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing, China; Institute of Liver Diseases, Beijing University of Chinese Medicine, Beijing, China
| | - Da'nan Gan
- Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing, China; Institute of Liver Diseases, Beijing University of Chinese Medicine, Beijing, China
| | - Hongbo Du
- Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing, China; Institute of Liver Diseases, Beijing University of Chinese Medicine, Beijing, China
| | - Yong'an Ye
- Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing, China; Institute of Liver Diseases, Beijing University of Chinese Medicine, Beijing, China.
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10
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Wu ZC, Liu XY, Liu JY, Piao JS, Piao MG. Preparation of Betulinic Acid Galactosylated Chitosan Nanoparticles and Their Effect on Liver Fibrosis. Int J Nanomedicine 2022; 17:4195-4210. [PMID: 36134203 PMCID: PMC9484277 DOI: 10.2147/ijn.s373430] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2022] [Accepted: 08/31/2022] [Indexed: 11/23/2022] Open
Abstract
Aim Liver fibrosis is mainly characterized by the formation of fibrous scars. Galactosylated chitosan (GC) has gained increasing attention as a liver-targeted drug carrier in recent years. The present study aimed to investigate the availability of betulinic acid-loaded GC nanoparticles (BA-GC-NPs) for liver protection. Covalently-conjugated galactose, recognized by asialoglycoprotein receptors exclusively expressed in hepatocytes, was employed to target the liver. Materials and Methods Galactose was coupled to chitosan by chemical covalent binding. BA-GC-NPs were synthesized by wrapping BA into NPs via ion-crosslinking method. The potential advantage of BA-GC-NP as a liver-targeting agent in the treatment of liver fibrosis has been demonstrated in vivo and in vitro. Results BA-GC-NPs with diameters <200 nm were manufactured in a virtually spherical core-shell arrangement, and BA was released consistently and continuously for 96 h, as assessed by an in vitro release assay. According to the safety evaluation, BA-GC-NPs demonstrated good biocompatibility at the cellular level and did not generate any inflammatory reaction in mice. Importantly, BA-GC-NPs showed an inherent liver-targeting potential in the uptake behavioral studies in cells and bioimaging tests in vivo. Efficacy tests revealed that administering BA-GC-NPs in a mouse model of liver fibrosis reduced the degree of liver injury in mice. Conclusion The findings showed that BA-GC-NPs form a safe and effective anti-hepatic fibrosis medication delivery strategy.
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Affiliation(s)
- Zi Chao Wu
- School of Pharmacy, Yanbian University, Yanji, 133002, People's Republic of China.,Research Institute, Shijiazhuang Yiling Pharmaceutical Co., Ltd, Shijiazhuang, 050035, People's Republic of China
| | - Xin Yu Liu
- School of Pharmacy, Yanbian University, Yanji, 133002, People's Republic of China
| | - Jia Yan Liu
- School of Pharmacy, Yanbian University, Yanji, 133002, People's Republic of China
| | - Jing Shu Piao
- School of Pharmacy, Yanbian University, Yanji, 133002, People's Republic of China
| | - Ming Guan Piao
- School of Pharmacy, Yanbian University, Yanji, 133002, People's Republic of China.,Key Laboratory of Natural Medicines of the Changbai Mountain, Ministry of Education, Yanbian University, Yanji, 133002, People's Republic of China
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11
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Zhang R, Li P, Zhou J, Guo P, Liu Y, Shi S. A novel, simple and reliable method for the determination of hydronidone and its metabolites M3 and M4 in human plasma and urine by HPLC-MS/MS and its application to a pharmacokinetic study in health Chinese subjects. Anal Biochem 2022; 655:114842. [DOI: 10.1016/j.ab.2022.114842] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2022] [Revised: 07/26/2022] [Accepted: 07/31/2022] [Indexed: 12/01/2022]
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12
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Han SK, Kim MY, Kang SH, Baik SK. Application of ultrasound for the diagnosis of cirrhosis/portal hypertension. J Med Ultrason (2001) 2022; 49:321-331. [PMID: 35179669 DOI: 10.1007/s10396-022-01191-w] [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: 10/29/2021] [Accepted: 12/03/2021] [Indexed: 11/28/2022]
Abstract
With advances in technologic approaches in patients with cirrhosis, including the improvement of management, a simple, one-step approach for advanced fibrotic state of the liver is clinically useful. Although refining the diagnosis of cirrhosis to reflect disease heterogeneity is essential, current diagnostic tests have not kept pace with the progression of this new paradigm. There are unmet needs in primary care centers with respect to patients with cirrhosis. Liver biopsy and measurement of hepatic venous pressure gradient in patients with cirrhosis are the gold standards for the estimation of hepatic fibrosis, and they have diagnostic and prognostic value. However, both approaches are invasive and cannot be used repeatedly in clinical practice. Ultrasonography (US) is safe, easy to perform, inexpensive, and yields numerical and accurate results. Conventionally, the size of the liver and spleen, bluntness of the liver edge, nodularity of the liver surface, and coarseness of the liver parenchyma have been known as useful parameters for hepatic fibrosis or portal hypertension (PHT) in chronic liver disease. Additionally, some functional US indices including Doppler and CEUS-based examination have been suggested as promising markers for diagnosing cirrhosis and PHT. Identification of the reproducibility and long-term prognostic value through further investigations can demonstrate the clinical usefulness of functional US indices, which are characterized as quantitative parameters for hepatic fibrosis and PHT.
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Affiliation(s)
- Seul Ki Han
- Department of Internal Medicine, Wonju Severance Christian Hospital, Yonsei University Wonju College of Medicine, 20 Ilsanro, Wonju, 220-701, Republic of Korea
| | - Moon Young Kim
- Department of Internal Medicine, Wonju Severance Christian Hospital, Yonsei University Wonju College of Medicine, 20 Ilsanro, Wonju, 220-701, Republic of Korea.,Regeneration Medicine Research Center, Yonsei University Wonju College of Medicine, Wonju, Republic of Korea.,Cell Therapy and Tissue Engineering Center, Yonsei University Wonju College of Medicine, Wonju, Republic of Korea
| | - Seong Hee Kang
- Department of Internal Medicine, Wonju Severance Christian Hospital, Yonsei University Wonju College of Medicine, 20 Ilsanro, Wonju, 220-701, Republic of Korea.,Regeneration Medicine Research Center, Yonsei University Wonju College of Medicine, Wonju, Republic of Korea
| | - Soon Koo Baik
- Department of Internal Medicine, Wonju Severance Christian Hospital, Yonsei University Wonju College of Medicine, 20 Ilsanro, Wonju, 220-701, Republic of Korea. .,Regeneration Medicine Research Center, Yonsei University Wonju College of Medicine, Wonju, Republic of Korea. .,Cell Therapy and Tissue Engineering Center, Yonsei University Wonju College of Medicine, Wonju, Republic of Korea.
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13
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Friedman SL, Pinzani M. Hepatic fibrosis 2022: Unmet needs and a blueprint for the future. Hepatology 2022; 75:473-488. [PMID: 34923653 DOI: 10.1002/hep.32285] [Citation(s) in RCA: 246] [Impact Index Per Article: 82.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/11/2021] [Revised: 11/12/2021] [Accepted: 11/15/2021] [Indexed: 12/12/2022]
Abstract
Steady progress over four decades toward understanding the pathogenesis and clinical consequences of hepatic fibrosis has led to the expectation of effective antifibrotic drugs, yet none has been approved. Thus, an assessment of the field is timely, to clarify priorities and accelerate progress. Here, we highlight the successes to date but, more importantly, identify gaps and unmet needs, both experimentally and clinically. These include the need to better define cell-cell interactions and etiology-specific elements of fibrogenesis and their link to disease-specific drivers of portal hypertension. Success in treating viral hepatitis has revealed the remarkable capacity of the liver to degrade scar in reversing fibrosis, yet we know little of the mechanisms underlying this response. Thus, there is an exigent need to clarify the cellular and molecular mechanisms of fibrosis regression in order for therapeutics to mimic the liver's endogenous capacity. Better refined and more predictive in vitro and animal models will hasten drug development. From a clinical perspective, current diagnostics are improving but not always biologically plausible or sufficiently accurate to supplant biopsy. More urgently, digital pathology methods that leverage machine learning and artificial intelligence must be validated in order to capture more prognostic information from liver biopsies and better quantify the response to therapies. For more refined treatment of NASH, orthogonal approaches that integrate genetic, clinical, and pathological data sets may yield treatments for specific subphenotypes of the disease. Collectively, these and other advances will strengthen and streamline clinical trials and better link histologic responses to clinical outcomes.
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Affiliation(s)
- Scott L Friedman
- Division of Liver DiseasesIcahn School of Medicine at Mount SinaiNew YorkNew YorkUSA
| | - Massimo Pinzani
- Institute for Liver and Digestive HealthUniversity College LondonLondonUK
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14
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Zuñiga-Aguilar E, Ramírez-Fernández O. Fibrosis and hepatic regeneration mechanism. Transl Gastroenterol Hepatol 2022; 7:9. [PMID: 35243118 PMCID: PMC8826211 DOI: 10.21037/tgh.2020.02.21] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/12/2019] [Accepted: 02/10/2020] [Indexed: 11/26/2023] Open
Abstract
Liver cirrhosis is the final stage of continuous hepatic inflammatory activity derived by viral, metabolic or autoimmune origin. In the last years, cirrhosis was considered a unique and static condition; recently was accepted some patients subgroups with different liver injury degrees that coexist under the same diagnosis, with implications about the natural disease history. The liver growth factor (LGF) is a potent in vivo and in vitro mitogenic agent and an inducer of hepatic regeneration (HR) through the hepatocytes DNA synthesis. The clinical implications of the LGF levels in cirrhosis, are not clear and even with having a fundamental role in the liver regeneration processes, the studies suggest that it could be a cirrhosis severity marker, in acute liver failure and in chronic hepatitis. Its role as predictor of mortality in fulminant hepatic insufficiency patients has been suggested. HR is one of the most enigmatic and fascinating biological phenomena. The rapid volume and liver function restoration after a major hepatectomy (>70%) or severe hepatocellular damage and its strict regulation of tissue damage response after the cessation, is an exclusive property of the liver. HR is the clinical applications fundament, such as extensive hepatic resections (>70% of the liver parenchyma), segmental transplantation or living donor transplantation, sequential hepatectomies, isolated portal embolization or associated with in situ hepatic transection, temporary artificial support in acute liver failure and the possible cell therapy clinical applications.
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Affiliation(s)
- Esmeralda Zuñiga-Aguilar
- Universidad Autonoma de Ciudad Juárez, Depto de Ingeniería Eléctrica y Computación, Ciudad Juárez, Chih., México
| | - Odin Ramírez-Fernández
- Tecnologico Nacional de Mexico, Depto. De Ciencias Basicas, Tlalnepantla de Baz, Mexico
- Facultad de Medicina, HIPAM, Universidad Nacional Autonoma de Mexico, Ciudad de México, Mexico
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15
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MicroRNA-494-3p prevents liver fibrosis and attenuates hepatic stellate cell activation by inhibiting proliferation and inducing apoptosis through targeting TRAF3. Ann Hepatol 2022; 23:100305. [PMID: 33434689 DOI: 10.1016/j.aohep.2021.100305] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/08/2020] [Revised: 12/03/2020] [Accepted: 12/03/2020] [Indexed: 02/07/2023]
Abstract
INTRODUCTION AND OBJECTIVES Alcoholic hepatitis (AH) is characterized by high morbidity and mortality. MicroRNA-494-3p is possibly involved in the regulation of cancers, but its role in AH has been rarely studied. MATERIALS AND METHODS AH mice model and primarily cultured mice hepatic stellate cells (HSCs) model were constructed. Levels of aspartate aminotransferase (AST) and alanine aminotransferase (ALT) were analyzed by ELISA. Expressions of miRNAs, HSC activation-related proteins and fibrosis-related protein were analyzed by qRT-PCR and Western blot. Cell counting kit, colony formation and flow cytometry assays were used to detect cell viability, proliferation and apoptosis, respectively. The relationship between TNF receptor-associated factor 3 (TRAF3) and miR-494-3p was predicted and verified by TargetScan and dual-luciferase assay, respectively. Results of the above experiments were verified by rescue experiments using TRAF3. RESULTS Liver damage and miRNA expression were observed in AH mice, and AST and ALT levels were increased in serum of AH mice. MiR-494-3p was reduced in AH liver tissues, and it decreased the levels of α-SMA and fibrosis-related proteins. HSCs were isolated, and activating HSCs or upregulating miR-494-3p had a regulatory effect on the levels of miR-494-3p, HSC activation-related proteins and fibrosis-related proteins as well as cell viability, proliferation and apoptosis. In addition, miR-494-3p targeted TRAF3 and inhibited TRAF3 expression, while overexpressed TRAF3 promoted TRAF3 expression and rescued the regulatory effect of miR-494-3p on the levels of related proteins as well as cell viability, proliferation and apoptosis. CONCLUSIONS This study provided a novel mechanistic comprehension of the anti-fibrotic effect of miR-494-3p.
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16
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Li Z, Lu B, Lin J, He S, Huang L, Wang Y, Meng J, Li Z, Feng ST, Lin S, Mao R, Li XH. A Type I Collagen-Targeted MR Imaging Probe for Staging Fibrosis in Crohn's Disease. Front Mol Biosci 2021; 8:762355. [PMID: 34859052 PMCID: PMC8631902 DOI: 10.3389/fmolb.2021.762355] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2021] [Accepted: 10/20/2021] [Indexed: 02/01/2023] Open
Abstract
Fibrostenosis is a serious complication of Crohn's disease (CD), affecting approximately one-half of all patients. Surgical resection is the typical clinical end due to ineffective antifibrotic therapy mainly through anti-inflammatory treatment and fibrosis can be reverted only at early stages. Mover, human fibrotic disorders is known to be associated with aging process. Thus, accurate monitoring of the progression of fibrosis is crucial for CD management as well as can be benefit to aging related fibrosis. The excessive deposition of type I collagen (ColI) is the core point in major complications of fibrosis, including that in patients with CD and aging related fibrosis. Therefore, a MR imaging probe (EP-3533) targeted ColI was employed to stage bowel fibrosis in CD using a rat model and to compare its efficiency with the common MR imaging contrast medium gadopentetatedimeglumine (Gd-DTPA). The bowel fibrotic rat model was established with different degrees of bowel fibrosis, were scanned using a 3.0-T MRI scanner with a specialized animal coil. MRI sequence including T 1 mapping and T1-weighed imaging were performed before and after injecting the MRI probe (EP-3533 or Gd-DTPA). The T 1 relaxation time (T 1 value) and change in the contrast-to-noise ratio (ΔCNR) were measured to evaluate bowel fibrosis. Masson's trichrome staining was performed to determine the severity of fibrosis. EP-3533 offered a better longitudinal relaxivity (r1) with 67.537 L/mmol·s, which was approximately 13 times that of Gd-DTPA. The T 1 value on bowel segments was reduced in the images from EP-3533 compared to that from Gd-DTPA (F = 16.478; p < 0.001). Additionally, a better correlation between ΔCNR calculated from EP-3533 imaging and bowel fibrosis (AUC = 0.846) was determined 10 min after enhanced media administration than with Gd-DTPA (AUC = 0.532). The 10th-minute ΔCNR performed using the ColI probe showed the best correlation with the severity of bowel fibrosis (r = 0.538; p = 0.021). Our results demonstrates that targeted MRI probe (EP-3533) supplies a better enhanced effect compared to Gd-DTPA and could be a promising method to evaluate the progression and monitor the therapeutic response of bowel fibrosis.
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Affiliation(s)
- Zhoulei Li
- Department of Radiology, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, China
| | - Baolan Lu
- Department of Radiology, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, China
| | - Jinjiang Lin
- Department of Radiology, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, China
| | - Shaofu He
- Department of Radiology, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, China
| | - Li Huang
- Department of Radiology, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, China
| | - Yangdi Wang
- Department of Radiology, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, China
| | - Jixin Meng
- Department of Radiology, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, China
| | - Ziping Li
- Department of Radiology, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, China
| | - Shi-Ting Feng
- Department of Radiology, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, China
| | - Shaochun Lin
- Department of Radiology, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, China
| | - Ren Mao
- Department of Gastroenterology, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, China
| | - Xue-Hua Li
- Department of Radiology, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, China
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17
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Obrzut M, Atamaniuk V, Chen J, Obrzut B, Ehman RL, Cholewa M, Palusińska A, Gutkowski K. Postprandial hepatic stiffness changes on magnetic resonance elastography in healthy volunteers. Sci Rep 2021; 11:19786. [PMID: 34611231 PMCID: PMC8492759 DOI: 10.1038/s41598-021-99243-7] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2021] [Accepted: 09/14/2021] [Indexed: 11/23/2022] Open
Abstract
Magnetic resonance elastography (MRE) is a reliable noninvasive method for assessment of hepatic stiffness. Liver stiffness is known to be affected by elevated postprandial portal blood flow in patients with chronic liver disease. The goal of this study was to determine whether food intake affects liver stiffness in the absence of known liver disease. We evaluated 100 volunteers (35 men and 65 women) who met inclusion criteria. The subjects had two MRE examinations, first while fasting and then 30 min after a test meal. Fourteen subjects also had two additional MRE exams 1 h 30 min and 2 h 30 min after the meal. Liver stiffness was measured by placing the largest possible polygon ROIs on the four widest liver slices and calculated as a mean of stiffness values from each slice. The correlation of liver stiffness values before and after the meal was assessed using a paired t-test. To evaluate the relationship between the change in postprandial liver stiffness and fasting liver stiffness values, linear regression was performed. The liver stiffness values in the fasting state ranged from 1.84 to 2.82 kPa, with a mean of 2.30 ± 0.23 kPa (95% CI 2.25–2.34). At 30 min after the meal, liver stiffness values ranged from 2.12 to 3.50 kPa, with a mean of 2.70 ± 0.28 kPa (95% CI 2.64–2.75), demonstrating a systematic postprandial increase by 0.40 ± 0.23 kPa (17.7 ± 3.5%). Meal intake significantly increases liver stiffness in healthy individuals, which persists for at least 2 h 30 min. Patients should fast for 3–4 h before MRE examinations to avoid fibrosis overstaging due to postprandial liver stiffness augmentation.
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Affiliation(s)
- Marzanna Obrzut
- Institute of Health Sciences, Medical College, University of Rzeszow, Rzeszow, Poland
| | - Vitaliy Atamaniuk
- Department of Biophysics, College of Natural Sciences, Institute of Physics, University of Rzeszow, aleja Tadeusza Rejtana 16C, 35-959, Rzeszow, Poland.
| | - Jun Chen
- Department of Radiology, Mayo Clinic, Rochester, MN, USA
| | - Bogdan Obrzut
- Department of Obstetrics and Gynecology, Institute of Medical Sciences, Medical College, University of Rzeszow, Rzeszow, Poland
| | | | - Marian Cholewa
- Department of Biophysics, College of Natural Sciences, Institute of Physics, University of Rzeszow, aleja Tadeusza Rejtana 16C, 35-959, Rzeszow, Poland
| | - Agnieszka Palusińska
- Department of Internal Medicine and Nephrodiabetology, Medical University of Lodz, Lodz, Poland
| | - Krzysztof Gutkowski
- Institute of Medical Sciences, Medical College, University of Rzeszow, Rzeszow, Poland
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18
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Yoshino K, Taura K, Iwaisako K, Masano Y, Uemoto Y, Kimura Y, Nam NH, Nishino H, Ikeno Y, Okuda Y, Nishio T, Yamamoto G, Seo S, Uemoto S. Novel mouse model for cholestasis-induced liver fibrosis resolution by cholecystojejunostomy. J Gastroenterol Hepatol 2021; 36:2493-2500. [PMID: 33448457 DOI: 10.1111/jgh.15406] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/09/2020] [Revised: 01/04/2021] [Accepted: 01/09/2021] [Indexed: 01/18/2023]
Abstract
BACKGROUND AND AIM Studies on the resolution of liver fibrosis are becoming more important in this era of etiologic eradication. In contrast to the extensive research on the recovery of liver fibrosis induced by hepatotoxic injuries, regression of cholestatic liver fibrosis has been insufficiently examined owing to the limited availability of animal models. METHODS We examined our novel recanalization mice model of biliary obstruction, involving anastomosis between the gallbladder and jejunum (G-J anastomosis) by invagination. Transgenic mice expressing green fluorescent protein (GFP) under the collagen 1(α)1 promoter underwent G-J anastomosis 14 days after bile duct ligation (BDL) and were sacrificed 14 days later. RESULTS Transaminase and total bilirubin levels decreased to almost normal values on day 14 after G-J anastomosis. G-J anastomosis resulted in dramatic reversal of liver fibrosis induced by BDL. Activated portal fibroblasts (PFs) double-positive for GFP and Thy-1 on immunofluorescence in the liver of BDL-injured mice became less noticeable following G-J anastomosis. Messenger RNA expression of markers for activated PFs in the liver was downregulated after anastomosis. Matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs) were induced by BDL. After anastomosis, expressions of MMP-3, 8 as well as hepatocyte growth factor were further upregulated, whereas those of TIMP-1 and TIMP-3 were markedly downregulated. CONCLUSIONS Our established G-J anastomosis model is associated with fibrosis resolution and reduced PF activation through reopening of bile duct obstruction and will be valuable for studying the recovery process of cholestatic liver fibrosis.
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Affiliation(s)
- Kenji Yoshino
- Division of Hepato-Biliary-Pancreatic Surgery and Transplantation, Department of Surgery, Kyoto University Graduate School of Medicine, Kyoto, Japan
| | - Kojiro Taura
- Division of Hepato-Biliary-Pancreatic Surgery and Transplantation, Department of Surgery, Kyoto University Graduate School of Medicine, Kyoto, Japan
| | - Keiko Iwaisako
- Faculity of Life and Medical Sciences, Department of Medical Life Systems, Doshisha University, Kyoto, Japan
| | - Yuki Masano
- Division of Hepato-Biliary-Pancreatic Surgery and Transplantation, Department of Surgery, Kyoto University Graduate School of Medicine, Kyoto, Japan
| | - Yusuke Uemoto
- Division of Hepato-Biliary-Pancreatic Surgery and Transplantation, Department of Surgery, Kyoto University Graduate School of Medicine, Kyoto, Japan
| | - Yusuke Kimura
- Division of Hepato-Biliary-Pancreatic Surgery and Transplantation, Department of Surgery, Kyoto University Graduate School of Medicine, Kyoto, Japan
| | - Nguyen Hai Nam
- Division of Hepato-Biliary-Pancreatic Surgery and Transplantation, Department of Surgery, Kyoto University Graduate School of Medicine, Kyoto, Japan
| | - Hiroto Nishino
- Division of Hepato-Biliary-Pancreatic Surgery and Transplantation, Department of Surgery, Kyoto University Graduate School of Medicine, Kyoto, Japan
| | - Yoshinobu Ikeno
- Division of Hepato-Biliary-Pancreatic Surgery and Transplantation, Department of Surgery, Kyoto University Graduate School of Medicine, Kyoto, Japan
| | - Yukihiro Okuda
- Division of Hepato-Biliary-Pancreatic Surgery and Transplantation, Department of Surgery, Kyoto University Graduate School of Medicine, Kyoto, Japan
| | - Takahiro Nishio
- Division of Hepato-Biliary-Pancreatic Surgery and Transplantation, Department of Surgery, Kyoto University Graduate School of Medicine, Kyoto, Japan
| | - Gen Yamamoto
- Division of Hepato-Biliary-Pancreatic Surgery and Transplantation, Department of Surgery, Kyoto University Graduate School of Medicine, Kyoto, Japan
| | - Satoru Seo
- Division of Hepato-Biliary-Pancreatic Surgery and Transplantation, Department of Surgery, Kyoto University Graduate School of Medicine, Kyoto, Japan
| | - Shinji Uemoto
- Division of Hepato-Biliary-Pancreatic Surgery and Transplantation, Department of Surgery, Kyoto University Graduate School of Medicine, Kyoto, Japan
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19
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Cross-talk between hepatic stellate cells and T lymphocytes in liver fibrosis. Hepatobiliary Pancreat Dis Int 2021; 20:207-214. [PMID: 33972160 DOI: 10.1016/j.hbpd.2021.04.007] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/07/2020] [Accepted: 04/21/2021] [Indexed: 02/07/2023]
Abstract
BACKGROUND Fibrosis results from inflammation and healing following injury. The imbalance between extracellular matrix (ECM) secretion and degradation leads to the ECM accumulation and liver fibrosis. This process is regulated by immune cells. T lymphocytes, including alpha beta (αβ) T cells, which have adaptive immune functions, and gamma delta (γδ) T cells, which have innate immune functions, are considered regulators of liver fibrosis. This review aimed to present the current understanding of the cross-talk between T lymphocytes and hepatic stellate cells (HSCs), which are the key cells in liver fibrosis. DATA SOURCES The keywords "liver fibrosis", "immune", and "T cells" were used to retrieve articles published in PubMed database before January 31, 2020. RESULTS The ratio of CD8+ (suppressor) T cells to CD4+ (helper) T cells is significantly higher in the liver than in the peripheral blood. T cells secrete a series of cytokines and chemokines to regulate the inflammation in the liver and the activation of HSCs to influence the course of liver fibrosis. In addition, HSCs also regulate the differentiation and proliferation of T cells. CONCLUSIONS The cross-talk between T cells and HSCs regulates liver fibrosis progression. The elucidation of this communication process will help us to understand the pathological process of liver fibrosis.
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20
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Dong BT, Huang S, Lyu GR, Qin R, Gu JH. Assessment of liver fibrosis with liver and spleen stiffness measured by sound touch elastography, serum fibrosis markers in patients with chronic hepatitis B. J Dig Dis 2021; 22:342-350. [PMID: 33851510 DOI: 10.1111/1751-2980.12991] [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: 12/13/2020] [Revised: 04/07/2021] [Accepted: 04/11/2021] [Indexed: 12/11/2022]
Abstract
OBJECTIVES To evaluate the performance of liver stiffness (LS) and spleen stiffness (SS) by using the sound touch elastography (STE) technique and compare with those of the splenic index, aspartate transaminase-to-platelet ratio index (APRI), fibrosis-4 (FIB-4) index, King's score and combined models for diagnosing and staging fibrosis in chronic hepatitis B (CHB). METHODS One hundred patients with CHB underwent STE and serological tests. LS and SS values were measured with STE technique, and splenic index was calculated. Staging of fibrosis was determined with liver biopsy. Correlations between the individual parameters and the stage of fibrosis were evaluated with the Spearman correlation analysis. The area under the receiver operating characteristic curve (AUROC) was calculated to analyze the performance of all methods. RESULTS Among all individual parameters, LS showed the highest AUROC for diagnosing fibrosis of ≥S2, ≥S3, and S4 stages (AUROC: 0.70, 0.86, and 0.96, respectively; all P < 0.05). The AUROC of combined model 1 (LS and SS) and 2 (LS, SS, APRI, FIB-4 index, King's score) for diagnosing ≥S2, ≥S3, and S4 fibrosis were 0.70, 0.86, 0.97, and 0.70, 0.86, 0.96, respectively, which were higher than those of APRI, FIB-4 index and the King's score (P < 0.05). No significant differences were found between two combined models and LS for staging fibrosis (P > 0.05). CONCLUSIONS LS measurement is reliable for diagnosing and staging fibrosis in CHB, with a better performance than SS, splenic index and serum biomarkers. It is also comparable with the performance of combined models.
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Affiliation(s)
- Bing Tian Dong
- Department of Ultrasound, The Second Affiliated Hospital of Fujian Medical University, Quanzhou, Fujian Province, China
| | - Shu Huang
- Department of Ultrasound, Chenggong Hospital Affiliated to Xiamen University, Xiamen, Fujian Province, China
| | - Guo Rong Lyu
- Department of Ultrasound, The Second Affiliated Hospital of Fujian Medical University, Quanzhou, Fujian Province, China
| | - Ran Qin
- Department of Ultrasound, Chenggong Hospital Affiliated to Xiamen University, Xiamen, Fujian Province, China
| | - Jiong Hui Gu
- Department of Ultrasound, First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang Province, China
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21
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Jain D, Torres R, Celli R, Koelmel J, Charkoftaki G, Vasiliou V. Evolution of the liver biopsy and its future. Transl Gastroenterol Hepatol 2021; 6:20. [PMID: 33824924 PMCID: PMC7829074 DOI: 10.21037/tgh.2020.04.01] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/12/2020] [Accepted: 03/19/2020] [Indexed: 12/12/2022] Open
Abstract
Liver biopsies are commonly used to evaluate a wide variety of medical disorders, including neoplasms and post-transplant complications. However, its use is being impacted by improved clinical diagnosis of disorders, and non-invasive methods for evaluating liver tissue and as a result the indications of a liver biopsy have undergone major changes in the last decade. The evolution of highly effective treatments for some of the common indications for liver biopsy in the last decade (e.g., viral hepatitis B and C) has led to a decline in the number of liver biopsies in recent years. At the same time, the emergence of better technologies for histologic evaluation, tissue content analysis and genomics are among the many new and exciting developments in the field that hold great promise for the future and are going to shape the indications for a liver biopsy in the future. Recent advances in slide scanners now allow creation of "digital/virtual" slides that have image of the entire tissue section present in a slide [whole slide imaging (WSI)]. WSI can now be done very rapidly and at very high resolution, allowing its use in routine clinical practice. In addition, a variety of technologies have been developed in recent years that use different light sources and/or microscopes allowing visualization of tissues in a completely different way. One such technique that is applicable to liver specimens combines multiphoton microscopy (MPM) with advanced clearing and fluorescent stains known as Clearing Histology with MultiPhoton Microscopy (CHiMP). Although it has not yet been extensively validated, the technique has the potential to decrease inefficiency, reduce artifacts, and increase data while being readily integrable into clinical workflows. Another technology that can provide rapid and in-depth characterization of thousands of molecules in a tissue sample, including liver tissues, is matrix assisted laser desorption/ionization (MALDI) mass spectrometry. MALDI has already been applied in a clinical research setting with promising diagnostic and prognostic capabilities, as well as being able to elucidate mechanisms of liver diseases that may be targeted for the development of new therapies. The logical next step in huge data sets obtained from such advanced analysis of liver tissues is the application of machine learning (ML) algorithms and application of artificial intelligence (AI), for automated generation of diagnoses and prognoses. This review discusses the evolving role of liver biopsies in clinical practice over the decades, and describes newer technologies that are likely to have a significant impact on how they will be used in the future.
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Affiliation(s)
- Dhanpat Jain
- Department of Anatomic Pathology, Yale University School of Medicine, New Haven, CT, USA
| | - Richard Torres
- Department of Laboratory Medicine, Yale University School of Medicine, New Haven, CT, USA
| | - Romulo Celli
- Department of Anatomic Pathology, Yale University School of Medicine, New Haven, CT, USA
| | - Jeremy Koelmel
- Department of Environmental Health Sciences, Yale School of Public Health, New Haven, CT, USA
| | - Georgia Charkoftaki
- Department of Environmental Health Sciences, Yale School of Public Health, New Haven, CT, USA
| | - Vasilis Vasiliou
- Department of Environmental Health Sciences, Yale School of Public Health, New Haven, CT, USA
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22
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Lemmer P, Pospiech JC, Canbay A. Liver failure-future challenges and remaining questions. ANNALS OF TRANSLATIONAL MEDICINE 2021; 9:734. [PMID: 33987432 PMCID: PMC8106069 DOI: 10.21037/atm-20-4968] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 12/25/2022]
Abstract
This review compiles the current state of controversial aspects of liver failure and outlines future challenges. The definition of acute liver failure (ALF) is widely accepted and implies no previous liver injury whereas the term "acute-on-chronic liver failure" remains contested. We will promote a concept, in which we differentiate three types of liver failure: ALF, acute-on-chronic liver failure (AOCLF) and acute-on-liver-cirrhosis (AOCi). The mechanistical insights into the coagulation system in patients with hepatic insufficiency have increased fundamentally in the past 10 years. Therefore, we follow now the concept of the so-called rebalanced hemostasis. This lower-level equilibrium arises from the fact that most coagulation factors and inhibitors are synthesized within the liver. We will demonstrate the advantage of viscoelastic test methods, which can assess the coagulation situation in patients with liver insufficiency much more precisely than conventional global coagulation tests. The therapeutic option of emergency liver transplantation (ELT) has significantly improved the prognosis of patients with ALF. However, limiting factors such as shortage of organs increase more and more the need for reliable prognostic markers. Due to a better understanding of the regenerative process during ALF new survival markers and prognostic tools have been emerging on the horizon in the last decade. Therefore, we will describe the current state of research in this field.
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Affiliation(s)
- Peter Lemmer
- Department of Medicine, Ruhr University Bochum, University Hospital Knappschaftskrankenhaus Bochum, Bochum, Germany
| | - Josef Christian Pospiech
- Department of Medicine, Ruhr University Bochum, University Hospital Knappschaftskrankenhaus Bochum, Bochum, Germany
| | - Ali Canbay
- Department of Medicine, Ruhr University Bochum, University Hospital Knappschaftskrankenhaus Bochum, Bochum, Germany
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Zhu Y, Zhang C, Huang M, Lin J, Fan X, Ni T. TRIM26 Induces Ferroptosis to Inhibit Hepatic Stellate Cell Activation and Mitigate Liver Fibrosis Through Mediating SLC7A11 Ubiquitination. Front Cell Dev Biol 2021; 9:644901. [PMID: 33869196 PMCID: PMC8044755 DOI: 10.3389/fcell.2021.644901] [Citation(s) in RCA: 48] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2020] [Accepted: 02/16/2021] [Indexed: 12/12/2022] Open
Abstract
Hepatic stellate cells (HSCs) are activated by inflammatory mediators to secrete extracellular matrix for collagen deposition, leading to liver fibrosis. Ferroptosis is iron- and lipid hydroperoxide-dependent programmed cell death, which has recently been targeted for inhibiting liver fibrogenic processes. Tripartite motif-containing protein 26 (TRIM26) is an E3 ubiquitin ligase that functions as a tumor suppressor in hepatocellular carcinoma, while little is known about its function in liver fibrosis. In the present study, the differential expression of TRIM26 in normal and fibrotic liver tissues was examined based on both online databases and specimens collected from patient cohort. The effects of TRIM26 on HSCs ferroptosis were examined in vitro through evaluating cell proliferation, lipid peroxidation, and expression of key ferroptosis-related factors. In vivo function of TRIM26 in liver fibrosis was examined based on CCl4-induced mice model. We found that TRIM26 was downregulated in fibrotic liver tissues. The overexpression of TRIM26 inhibited HSCs proliferation, promoted lipid peroxidation, manipulated ferroptosis-related factor expressions, and counteracted the effect of iron inhibitor deferoxamine. Moreover, TRIM26 physically interacted with solute carrier family-7 member-11 (SLC7A11), a critical protein for lipid reactive oxygen species (ROS) scavenging, and mediated its ubiquitination. In addition, TRIM26 overexpression induced HSCs ferroptosis and mitigated CCl4-induced liver fibrosis in mice. In conclusion, TRIM26 promotes HSCs ferroptosis to suppress liver fibrosis through mediating the ubiquitination of SLC7A11. The TRIM26-targeted SLC7A11 suppression can be a novel therapeutic strategy for liver fibrosis.
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Affiliation(s)
- Yiming Zhu
- Department of General Surgery, Shanghai Ninth People's Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Chihao Zhang
- Department of General Surgery, Shanghai Ninth People's Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Mingzhe Huang
- Department of General Surgery, Shanghai Ninth People's Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Jiayun Lin
- Department of General Surgery, Shanghai Ninth People's Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Xiao Fan
- Department of General Surgery, Shanghai Ninth People's Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Tao Ni
- Department of Plastic and Reconstructive Surgery, Shanghai Ninth People's Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
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Stefanovic B, Michaels HA, Nefzi A. Discovery of a Lead Compound for Specific Inhibition of Type I Collagen Production in Fibrosis. ACS Med Chem Lett 2021; 12:477-484. [PMID: 33738075 DOI: 10.1021/acsmedchemlett.1c00006] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2021] [Accepted: 02/23/2021] [Indexed: 02/06/2023] Open
Abstract
Fibrosis is a major medical problem caused by excessive synthesis of the extracellular matrix, composed predominantly of type I collagen, in various tissues. There are no approved antifibrotic drugs, and the major obstacle in finding clinically relevant compounds is the lack of specificity of current experimental drugs for type I collagen. Here we describe the discovery of a lead compound that specifically inhibited secretion of type I collagen by fibroblasts in culture at IC50 = 4.5 μM. The inhibition was specific for type I collagen, because secretion of fibronectin was not affected. In vitro, the compound inhibited binding of LARP6, the master regulator of translation of type I collagen mRNAs, to the 5' stem-loop sequence element which regulates their translation. Because binding of LARP6 to collagen mRNAs is crucial for the development of fibrosis, this inhibitor represents a promising lead for optimization into specific antifibrotic drugs.
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Affiliation(s)
- Branko Stefanovic
- Florida State University, 1115 West Call Street, Tallahassee, Florida 32306, United States
| | | | - Adel Nefzi
- Florida International University, Port Saint Lucie, Florida 34987, United States
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Shu Y, Liu X, Huang H, Wen Q, Shu J. Research progress of natural compounds in anti-liver fibrosis by affecting autophagy of hepatic stellate cells. Mol Biol Rep 2021; 48:1915-1924. [PMID: 33609264 PMCID: PMC7925445 DOI: 10.1007/s11033-021-06171-w] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/02/2020] [Accepted: 01/19/2021] [Indexed: 12/11/2022]
Abstract
Chronic liver diseases caused by various pathogenesis are marked by inflammatory infiltration and wound healing reaction, while their normal regeneration ability is impaired. The unbalance between the generation and the degradation of extracellular matrix (ECM) leads to collagen accumulation and develops into liver fibrosis. Inflammation, oxidative stress, and autophagy interact closely in the pathogenesis of hepatic fibrosis. Reactive Oxygen Species (ROS) can not only stimulate Kupffer cells to release massive inflammatory factors, but induce autophagy. However, the latter may suppress inflammatory reaction by inhibiting proinflammatory complex formation directly, and removing damaged organelles or pathogenic microorganism indirectly. At present, effective anti-fibrosis drugs are still lacking. Previous studies have found various natural compounds enabled liver protection through anti-inflammatory, antioxidant, and other mechanisms. In recent years, autophagy, a vital life activity, has been found to be involved in the mechanism of liver fibrosis. As a new target, developing anti-liver fibrosis drugs that regulate the activity of autophagy is very promising. In this review, we summarize the latest studies about natural compounds in the treatment of liver fibrosis by regulating autophagy.
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Affiliation(s)
- Yongxiang Shu
- Department of Gastroenterology, GuangZhou Red Cross Hospital, Jinan University, Guangzhou, 510220 China
| | - Xuyou Liu
- Department of Gastroenterology, GuangZhou Red Cross Hospital, Jinan University, Guangzhou, 510220 China
| | - Haifeng Huang
- Department of Gastroenterology, GuangZhou Red Cross Hospital, Jinan University, Guangzhou, 510220 China
| | - Qi Wen
- Department of Gastroenterology, GuangZhou Red Cross Hospital, Jinan University, Guangzhou, 510220 China
| | - Jianchang Shu
- Department of Gastroenterology, GuangZhou Red Cross Hospital, Jinan University, Guangzhou, 510220 China
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Yang G, Zhan J, Yang Y, Yuan L, Wang P, Ho CT, Li S. Inhibitory effects of oxyresveratrol on ERK and Smad1/2 phosphorylation and HSC activation in preventing carbon tetrachloride-induced rat liver fibrosis. FOOD SCIENCE AND HUMAN WELLNESS 2021. [DOI: 10.1016/j.fshw.2020.08.007] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
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Jiang C, Iwaisako K, Cong M, Diggle K, Hassanein T, Brenner DA, Kisseleva T. Traditional Chinese Medicine Fuzheng Huayu Prevents Development of Liver Fibrosis in Mice. ACTA ACUST UNITED AC 2020; 4:561-580. [PMID: 33210080 PMCID: PMC7671588 DOI: 10.26502/acbr.50170125] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/06/2023]
Abstract
Aim: To investigate the therapeutic effect of FZHY on hepatic fibrosis in mice and to determine the mechanism of its action. Methods: Wild type mice were subjected to toxic (carbon tetrachloride, CCl4) or cholestatic (bile duct ligation, BDL). Upon induction of liver fibrosis, mice were treated with FZHY (4.0g/kg, 2w, oral gavage) or vehicle (PBS). Livers were analyzed by Sirius Red staining, immunostaining and RT-PCR for profibrogenic and pro-inflammatory genes. The effect of FZHY on hepatocytes, inflammatory responses, activation of fibrogenic myofibroblasts, and ROS production was assessed. Results: FZHY strongly inhibited the development of CCl4- and BDL-induced liver fibrosis in mice. Liver fibrosis was significantly improved in FZHY-treated mice, as demonstrated by reduced content of hepatic hydroxyproline and Sirius Red positive area. Moreover, the number of SMA +and Desmin+ myofibroblasts was significantly reduced in the livers of FZHY-treated mice, and correlated with downregulation of the mRNA levels of α-SMA, collagen-α1(I), tissue inhibitor of matrix metalloproteinase-1 (TIMP-1), TGF-β1 and its receptor TGF-βRI, and platelet-derived growth factor-β (PDGF-β), suggesting that FZHY inhibits activation of fibrogenic myofibroblasts. Furthermore, administration of FZHY markedly decreased recruitment of F4/80+ inflammatory macrophages to the livers of CCl4- and BDL-injured mice, and this effect was associated with downregulation of monocyte chemoattractant protein-1(MCP-1) and macrophage inflammatory protein-1 (MIP-1) mRNA. In addition, the lipid peroxidation products 4-hydroxynonenal (4-HNE) and malondialdehyde (MDA) were reduced, demonstrating that treatment with FZHY can effectively block ROS production in livers of CCl4- and BDL-injured mice. Conclusions: Traditional Chinese Medicine FZHY has a variety of anti-fibrotic effects, including strong anti-oxidant, anti-inflammatory and anti-fibrotic effects on myeloid cells and hepatocytes. Although FZHY compound does not seem to directly affect HSCs, it regulates HSC activation via inhibition of macrophage recruitment to fibrotic liver.
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Affiliation(s)
- Chunyan Jiang
- Beijing Friendship Hospital, Capital Medical University, Beijing, China
- Department of Medicine, University of California, San Diego, La Jolla, CA, USA
| | - Keiko Iwaisako
- Department of Medical Life Systems, Faculty of Life and Medical Sciences, Doshisha University, Kyotanabe, Japan
- Department of Medicine, University of California, San Diego, La Jolla, CA, USA
| | - Min Cong
- Beijing Friendship Hospital, Capital Medical University, Beijing, China
- Department of Medicine, University of California, San Diego, La Jolla, CA, USA
| | - Karin Diggle
- Department of Medicine, University of California, San Diego, La Jolla, CA, USA
| | | | - David A Brenner
- Department of Medicine, University of California, San Diego, La Jolla, CA, USA
| | - Tatiana Kisseleva
- Department of Surgery, University of California, San Diego, La Jolla, CA, USA
- Corresponding author: Tatiana Kisseleva, MD, Department of Surgery, University of California, San Diego, La Jolla, CA 92093, USA,
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Rosique-Oramas D, Martínez-Castillo M, Raya A, Medina-Ávila Z, Aragón F, Limón-Castillo J, Hernández-Barragán A, Santoyo A, Montalvo-Javé E, Pérez-Hernández J, Higuera-de la Tijera F, Torre A, Kershenobich D, Gutiérrez-Reyes G. Production of insulin-like growth factor-binding proteins during the development of hepatic fibrosis due to chronic hepatitis C. REVISTA DE GASTROENTEROLOGÍA DE MÉXICO (ENGLISH EDITION) 2020. [DOI: 10.1016/j.rgmxen.2019.08.002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
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Rosique-Oramas D, Martínez-Castillo M, Raya A, Medina-Ávila Z, Aragón F, Limón-Castillo J, Hernández-Barragán A, Santoyo A, Montalvo-Javé E, Pérez-Hernández JL, Higuera-de la Tijera F, Torre A, Kershenobich D, Gutiérrez-Reyes G. Production of insulin-like growth factor-binding proteins during the development of hepatic fibrosis due to chronic hepatitis C. REVISTA DE GASTROENTEROLOGIA DE MEXICO (ENGLISH) 2020; 85:390-398. [PMID: 31740166 DOI: 10.1016/j.rgmx.2019.08.006] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/13/2019] [Accepted: 08/10/2019] [Indexed: 02/05/2023]
Abstract
INTRODUCTION AND AIMS Insulin-like growth factor 1 is modulated by the insulin-like growth factor-binding proteins (IGFBPs) that are synthesized in the liver. The aim of the present study was to evaluate the concentrations of IGFBPs 1-7 in patients with chronic hepatitis C and study their association with fibrosis stage. PATIENTS AND METHODS A prospective, cross-sectional study was conducted that included patients with chronic hepatitis C. The stages of fibrosis were determined through FibroTest and FibroScan and the patients were compared with a control group. Serum levels of IGFBPs 1-7 were quantified through multiple suspension arrays. The Kruskal-Wallis test, Mann-Whitney U test, Spearman's correlation, and ROC curves were used for the statistical analysis. RESULTS Upon comparing the patients and controls, the highest concentrations were found in IGFBPs 1, 2, 4, and 7 (p=0.02, p=0.002, p=0.008, and p<0.001, respectively). IGFBP-3 levels had a tendency to be lower in the patients (p=0.066), whereas values were similar between patients and controls for IGFBP-5 and 6 (p=0.786 and p=0.244, respectively). Of the seven IGFBPs, IGFBP-3 concentrations were the highest. There were significant differences between fibrosis stages for IGFBP-5 and IGFBP-7. CONCLUSION IGFBPs play a relevant role in the fibrotic process in liver damage. IGFBP-7, in particular, differentiates fibrosis stages, making it a potential serum biomarker.
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Affiliation(s)
- D Rosique-Oramas
- Laboratorio de Hígado, Páncreas y Motilidad (HIPAM), Unidad de Investigación en Medicina Experimental, Facultad de Medicina, UNAM, Ciudad de México, México
| | - M Martínez-Castillo
- Laboratorio de Hígado, Páncreas y Motilidad (HIPAM), Unidad de Investigación en Medicina Experimental, Facultad de Medicina, UNAM, Ciudad de México, México
| | - A Raya
- Laboratorio de Hígado, Páncreas y Motilidad (HIPAM), Unidad de Investigación en Medicina Experimental, Facultad de Medicina, UNAM, Ciudad de México, México
| | - Z Medina-Ávila
- Laboratorio de Hígado, Páncreas y Motilidad (HIPAM), Unidad de Investigación en Medicina Experimental, Facultad de Medicina, UNAM, Ciudad de México, México
| | - F Aragón
- Laboratorio de Hígado, Páncreas y Motilidad (HIPAM), Unidad de Investigación en Medicina Experimental, Facultad de Medicina, UNAM, Ciudad de México, México
| | - J Limón-Castillo
- Laboratorio de Hígado, Páncreas y Motilidad (HIPAM), Unidad de Investigación en Medicina Experimental, Facultad de Medicina, UNAM, Ciudad de México, México
| | - A Hernández-Barragán
- Laboratorio de Hígado, Páncreas y Motilidad (HIPAM), Unidad de Investigación en Medicina Experimental, Facultad de Medicina, UNAM, Ciudad de México, México
| | - A Santoyo
- Laboratorio de Hígado, Páncreas y Motilidad (HIPAM), Unidad de Investigación en Medicina Experimental, Facultad de Medicina, UNAM, Ciudad de México, México
| | - E Montalvo-Javé
- Clínica Hepato-Pancreato-Biliar, Servicio de Cirugía General, Hospital General de México Dr. Eduardo Liceaga, Departamento de Cirugía, Facultad de Medicina, UNAM, Ciudad de México, México
| | - J L Pérez-Hernández
- Departamento de Gastroenterología, Hospital General de México Dr. Eduardo Liceaga, Ciudad de México, México
| | - F Higuera-de la Tijera
- Departamento de Gastroenterología, Hospital General de México Dr. Eduardo Liceaga, Ciudad de México, México
| | - A Torre
- Unidad de Hepatología, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Ciudad de México, México
| | - D Kershenobich
- Unidad de Hepatología, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Ciudad de México, México
| | - G Gutiérrez-Reyes
- Laboratorio de Hígado, Páncreas y Motilidad (HIPAM), Unidad de Investigación en Medicina Experimental, Facultad de Medicina, UNAM, Ciudad de México, México.
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Ren X, Zhang L, Xia S, Chen Z, Zhou W, Ji R, Zhou J, Lin Y, Zhan W. A New Visual Transient Elastography Technique for Grading Liver Fibrosis in Patients With Chronic Hepatitis B. Ultrasound Q 2020; 37:105-110. [PMID: 32976320 DOI: 10.1097/ruq.0000000000000509] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
ABSTRACT Liver fibrosis is evaluated to assess the prognosis and guide the treatment of chronic hepatitis B (CHB). To compare the efficiency of 2 transient elastography techniques for grading liver fibrosis in CHB: visual transient elastography (ViTE) with real-time image guidance and FibroScan (FS) with no image guidance. All of the CHB patients in this study underwent both FS and ViTE examinations. The final diagnosis was based on the histological findings of a liver biopsy. According to the severity of liver fibrosis (based on the Scheuer criteria), the area under the receiver operating characteristic curve values for diagnostic efficiency were calculated for the 2 elastography techniques. This study enrolled 227 patients (79 [39.1%] women; mean age, 45.8 ± 16.8 years). The ViTE and FS liver elasticity measurements were highly correlated with liver fibrosis stage (r = 0.852 and r = 0.813, respectively). The area under the receiver operating characteristic curve value was larger for ViTE compared with FS, with respect to differentiating liver fibrosis stage, but not significantly (P > 0.05). The ViTE and FS can be used to detect and stage liver fibrosis. ViTE, easier and quicker to perform with superior interoperator reproducibility, is a stable and reliable elastography technique that benefits from real-time visual guidance.
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Affiliation(s)
- Xinping Ren
- Ultrasound Department, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai
| | - Lu Zhang
- Ultrasound Department, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai
| | - Shujun Xia
- Ultrasound Department, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai
| | - Zhijie Chen
- Shenzhen Mindray Biomedical Electronic Co., Ltd., Shenzhen, China
| | - Wei Zhou
- Ultrasound Department, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai
| | - Ri Ji
- Ultrasound Department, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai
| | - Jianqiao Zhou
- Ultrasound Department, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai
| | - Yanyan Lin
- Ultrasound Department, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai
| | - Weiwei Zhan
- Ultrasound Department, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai
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In Vivo siRNA Delivery to Immunosuppressive Liver Macrophages by α-Mannosyl-Functionalized Cationic Nanohydrogel Particles. Cells 2020; 9:cells9081905. [PMID: 32824208 PMCID: PMC7465192 DOI: 10.3390/cells9081905] [Citation(s) in RCA: 32] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2020] [Revised: 08/08/2020] [Accepted: 08/12/2020] [Indexed: 12/21/2022] Open
Abstract
Macrophages are the front soldiers of the innate immune system and are vital for immune defense, tumor surveillance, and tissue homeostasis. In chronic diseases, including cancer and liver fibrosis, macrophages can be forced into an immunosuppressive and profibrotic M2 phenotype. M2-type macrophages overexpress the mannose receptor CD206. Targeting these cells via CD206 and macrophage repolarization towards an immune stimulating and antifibrotic M1 phenotype through RNA interference represents an appealing therapeutic approach. We designed nanohydrogel particles equipped with mannose residues on the surface (ManNP) that delivered siRNA more efficiently to M2 polarized macrophages compared to their untargeted counterparts (NonNP) in vitro. The ManNP were then assessed for their in vivo targeting potential in mice with experimental liver fibrosis that is characterized by increased profibrotic (and immunosuppressive) M2-type macrophages. Double-labelled siRNA-loaded ManNP carrying two different near infrared labels for siRNA and ManNP showed good biocompatibility and robust uptake in fibrotic livers as assessed by in vivo near infrared imaging. siRNA–ManNP were highly colocalized with CD206+ M2-type macrophages on a cellular level, while untargeted NP (NonNP) showed little colocalization and were non-specifically taken up by other liver cells. ManNP did not induce hepatic inflammation or kidney dysfunction, as demonstrated by serological analysis. In conclusion, α-mannosyl-functionalized ManNP direct NP towards M2-type macrophages in diseased livers and prevent unspecific uptake in non-target cells. ManNP are promising vehicles for siRNA and other drugs for immunomodulatory treatment of liver fibrosis and liver cancer.
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Pan Q, Guo CJ, Xu QY, Wang JZ, Li H, Fang CH. miR-16 integrates signal pathways in myofibroblasts: determinant of cell fate necessary for fibrosis resolution. Cell Death Dis 2020; 11:639. [PMID: 32801294 PMCID: PMC7429878 DOI: 10.1038/s41419-020-02832-z] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2020] [Revised: 07/29/2020] [Accepted: 07/29/2020] [Indexed: 12/14/2022]
Abstract
Liver fibrosis is characterized by the transdifferentiation of hepatic stellate cells (HSCs) to myofibroblasts and poor response to treatment. This can be attributed to the myofibroblast-specific resistance to phenotype reversal. In this study, we complemented miR-16 into miR-16-deficient myofibroblasts and analyzed the global role of miR-16 using transcriptome profiling and generating a pathway-based action model underlying transcriptomic regulation. Phenotypic analysis of myofibroblasts and fibrogenic characterization were used to understand the effect of miR-16 on phenotypic remodeling of myofibroblasts. miR-16 expression altered the transcriptome of myofibroblasts to resemble that of HSCs. Simultaneous targeting of Smad2 and Wnt3a, etc. by miR-16 integrated signaling pathways of TGF-β and Wnt, etc., which underlay the comprehensive regulation of transcriptome. The synergistic effect of miR-16 on the signaling pathways abolished the phenotypic characteristics of myofibroblasts, including collagen production and inhibition of adipogenesis. In vivo, myofibroblast-specific expression of miR-16 not only eliminated mesenchymal cells with myofibroblast characteristics but also restored the phenotype of HSCs in perisinusoidal space. This phenotypic remodeling resolved liver fibrosis induced by chronic wound healing. Therefore, miR-16 may integrate signaling pathways crucial for the fate determination of myofibroblasts. Its global effect induces the reversal of HSC-to-myofibroblast transdifferentiation and, subsequently, the resolution of fibrogenesis. Taken together, these findings highlight the potential of miR-16 as a promising therapeutic target for liver fibrosis.
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Affiliation(s)
- Qin Pan
- Department of Gastroenterology, Xin-Hua Hospital, School of Medicine, Shanghai JiaoTong University, Shanghai, 200092, China.
| | - Can-Jie Guo
- Department of Gastroenterology, Ren-Ji Hospital, School of Medicine, Shanghai JiaoTong University, Shanghai, 200001, China
| | - Qing-Yang Xu
- Department of Gastroenterology, Xin-Hua Hospital, School of Medicine, Shanghai JiaoTong University, Shanghai, 200092, China
| | - Jin-Zhi Wang
- Department of Gastroenterology, Xin-Hua Hospital, School of Medicine, Shanghai JiaoTong University, Shanghai, 200092, China
| | - Han Li
- Department of Gastroenterology, Xin-Hua Hospital, School of Medicine, Shanghai JiaoTong University, Shanghai, 200092, China
| | - Chun-Hua Fang
- School of Electronics and Information Engineering, Tong-Ji University, Shanghai, 201804, China
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Olson MC, Vietti Violi N, Taouli B, Venkatesh SK. Abbreviated Magnetic Resonance Imaging Protocols in the Abdomen and Pelvis. Magn Reson Imaging Clin N Am 2020; 28:381-394. [PMID: 32624156 DOI: 10.1016/j.mric.2020.03.004] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
In recent decades, the clinical applications for which magnetic resonance (MR) imaging is routinely used have expanded exponentially. MR imaging protocols have become increasingly complex, adversely affecting image acquisition and interpretation times. The MR imaging workflow has become a prime target for process improvement initiatives. There has been growing interest in the cultivation of abbreviated MR imaging protocols that evaluate specific clinical questions while reducing cost and increasing access. The overarching goal is to streamline the MR imaging workflow and reduce the time needed to obtain and report examinations by eliminating duplicative or unnecessary sequences without sacrificing diagnostic accuracy.
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Affiliation(s)
- Michael C Olson
- Department of Radiology, Mayo Clinic College of Medicine, Mayo Clinic, 200 First Street Southwest, Rochester, MN 55905, USA
| | - Naïk Vietti Violi
- Department of Diagnostic, Molecular and Interventional Radiology, Icahn School of Medicine at Mount Sinai, One Gustave Levy Place, Box 1234, New York, NY 10029, USA; Department of Radiology, Lausanne University Hospital, Rue du Bugnon 46, Lausanne 1011, Switzerland
| | - Bachir Taouli
- Department of Diagnostic, Molecular and Interventional Radiology, Icahn School of Medicine at Mount Sinai, One Gustave Levy Place, Box 1234, New York, NY 10029, USA; BioMedical Engineering and Imaging Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Sudhakar Kundapur Venkatesh
- Department of Radiology, Mayo Clinic College of Medicine, Mayo Clinic, 200 First Street Southwest, Rochester, MN 55905, USA.
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Xu LM, Liu P. Guidelines for diagnosis and treatment of hepatic fibrosis with integrated traditional Chinese and Western medicine (2019 edition). JOURNAL OF INTEGRATIVE MEDICINE 2020; 18:203-213. [PMID: 32331978 DOI: 10.1016/j.joim.2020.03.001] [Citation(s) in RCA: 23] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/11/2019] [Accepted: 09/25/2019] [Indexed: 12/16/2022]
Abstract
In 2006, the Hepatology Committee of Chinese Association of Integrative Medicine issued the "Guidelines for the Prevention and Treatment of Liver Fibrosis with Integrated Traditional Chinese and Western Medicine." In recent years, the fields of Chinese medicine, Western medicine, and integrative medicine have made rapid advances in basic and clinical research into chronic liver disease, and accumulated new evidence for the prevention and treatment of hepatic fibrosis. Therefore, in order to meet clinical needs, liver disease experts of integrated traditional Chinese and Western medicine were united to revise the previous guidelines in order to help physicians make correct and reasonable decisions in the diagnosis and treatment of hepatic fibrosis.
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Affiliation(s)
- Lie-Ming Xu
- Institute of Liver Diseases, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China.
| | - Ping Liu
- Institute of Liver Diseases, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China.
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35
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Majeed W, Kalra P, Kolipaka A. Simultaneous multislice rapid magnetic resonance elastography of the liver. NMR IN BIOMEDICINE 2020; 33:e4252. [PMID: 31971301 PMCID: PMC7286422 DOI: 10.1002/nbm.4252] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/12/2018] [Revised: 12/09/2019] [Accepted: 12/10/2019] [Indexed: 06/10/2023]
Abstract
To design and validate a rapid Simultaneous Multi-slice (SMS) Magnetic Resonance Elastography technique (MRE), which combines SMS acquisition, in-plane undersampling and an existing rapid Magnetic Resonance Elastography (MREr) scheme to allow accelerated data acquisition in healthy volunteers and comparison against MREr. SMS-MREr sequence was developed by incorporating SMS acquisition scheme into an existing MREr sequence that accelerates MRE acquisition by acquiring data during opposite phases of mechanical vibrations. The MREr sequence accelerated MRE acquisition by acquiring data during opposite phases of mechanical vibrations. Liver MRE was performed on 23 healthy subjects using MREr and SMS-MREr sequences, and mean stiffness values were obtained for manually drawn regions of interest. Linear correlation and agreement between MREr- and SMS-MREr-based stiffness values were investigated. SMS-MREr reduced the scan time by half relative to MREr, and allowed acquisition of four-slice MRE data in a single 17-second breath-hold. Visual comparison suggested agreement between MREr and SMS-MREr elastograms. A Pearson's correlation of 0.93 was observed between stiffness values derived from MREr and SMS-MREr. Bland-Altman analysis demonstrated good agreement, with -0.08 kPa mean bias and narrow limits of agreement (95% CI: 0.23 to -0.39 kPa) between stiffness values obtained using MREr and SMS-MREr. SMS can be combined with other fast MRE approaches to achieve further acceleration. This pushes the limit on the acceleration that can be achieved in MRE acquisition, and makes it possible to conduct liver MRE exams in a single breath-hold.
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Affiliation(s)
- Waqas Majeed
- Department of RadiologyThe Ohio State University Wexner Medical CenterColumbusOhioUSA
| | - Prateek Kalra
- Department of RadiologyThe Ohio State University Wexner Medical CenterColumbusOhioUSA
| | - Arunark Kolipaka
- Department of RadiologyThe Ohio State University Wexner Medical CenterColumbusOhioUSA
- Department of Biomedical EngineeringThe Ohio State UniversityColumbusOhioUSA
- Department of Internal Medicine ‐ Division of CardiologyThe Ohio State University Wexner Medical CenterColumbusOhioUSA
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Ruth ND, Drury NE, Bennett J, Kelly DA. Cardiac and Liver Disease in Children: Implications for Management Before and After Liver Transplantation. Liver Transpl 2020; 26:437-449. [PMID: 31872564 DOI: 10.1002/lt.25666] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/21/2018] [Accepted: 10/16/2019] [Indexed: 02/06/2023]
Abstract
There is close interaction between the functions of the liver and heart affecting the presentation, diagnosis, and outcome of acute and chronic cardiac and liver disease. Conditions affecting both organ systems should be considered when proposing transplantation because the interaction between cardiac disease and liver disease has implications for diagnosis, management, selection for transplantation, and, ultimately, for longterm outcomes after liver transplantation (LT). The combination of cardiac and liver disease is well recognized in adults but is less appreciated in pediatric patients. The focus of this review is to describe conditions affecting both the liver and heart and how they affect selection and management of LT in the pediatric population.
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Affiliation(s)
- Nicola D Ruth
- Liver Unit, Birmingham Women's & Children's Hospital, Birmingham, United Kingdom.,Institute of Infection and Immunity, University of Birmingham, Birmingham, United Kingdom
| | - Nigel E Drury
- Department of Paediatric Cardiac Surgery, Birmingham Women's & Children's Hospital, Birmingham, United Kingdom.,Institute of Cardiovascular Sciences, University of Birmingham, Birmingham, United Kingdom
| | - James Bennett
- Department of Anaesthesia, Birmingham Women's & Children's Hospital, Birmingham, United Kingdom.,Department of Anaesthesia, Queen Elizabeth Hospital Birmingham, Birmingham, United Kingdom
| | - Deirdre A Kelly
- Liver Unit, Birmingham Women's & Children's Hospital, Birmingham, United Kingdom.,Institute of Infection and Immunity, University of Birmingham, Birmingham, United Kingdom
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Shiha G, Soliman R, Mikhail N, Ibrahim A, Serwah A, Khattab M. Changes in hepatic fibrosis stages after achieving SVR following direct‐acting anti‐viral treatment: a prospective study. ACTA ACUST UNITED AC 2020. [DOI: 10.1002/ygh2.384] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Affiliation(s)
- Gamal Shiha
- Egyptian Liver Research Institute and Hospital (ELRIAH) Sherbin, El‐Mansoura Egypt
- Hepatology and Gastroenterology Unit Internal Medicine Department Faculty of Medicine Mansoura University Mansoura Egypt
| | - Reham Soliman
- Egyptian Liver Research Institute and Hospital (ELRIAH) Sherbin, El‐Mansoura Egypt
- 2-Tropical Medicine Department Faculty of Medicine Port Said University Port Said Egypt
| | - Nabiel Mikhail
- Egyptian Liver Research Institute and Hospital (ELRIAH) Sherbin, El‐Mansoura Egypt
- Department of Biostatistics and Cancer Epidemiology South Egypt Cancer InstituteAssiut University Assiut Egypt
| | - Alaa Ibrahim
- Internal Medicine Department Faculty of Medicine Banha University Banha Egypt
| | - Abdel‐Hamid Serwah
- Internal Medicine Department Faculty of Medicine Suez Canal University Egypt
| | - Mahmoud Khattab
- Internal Medicine Department Faculty of Medicine Minya University Minya Egypt
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Zhang T, Yang Y, Wang B, Zheng X, Wang L, Feng X, Li G, Shi J, Cao N. Meta-analysis of influences of Biejiajian Pill combined with entecavir on serum liver fibrosis markers of compensatory period of hepatitis b cirrhosis: Protocol of systematic review and meta-analysis. Medicine (Baltimore) 2019; 98:e18458. [PMID: 31861022 PMCID: PMC6940166 DOI: 10.1097/md.0000000000018458] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/13/2019] [Accepted: 11/18/2019] [Indexed: 01/19/2023] Open
Abstract
BACKGROUND Chronic viral hepatitis b and its related complications have caused serious harm to human health and become a worldwide public health problem. Hepatitis b cirrhosis is one of the most common complications in Asia. Traditional Chinese medicine combined with antiviral therapy has become the first choice for clinical treatment of hepatitis b Cirrhosis. Biejia Pill is an effective prescription of traditional Chinese medicine in treating Compensatory period of cirrhosis, and there are more and more clinical reports about its validity in treating Compensatory period of cirrhosis. Therefore, we designed this study protocol to evaluate the adjuvant role of Biejia Pill in the treatment of Compensatory period of cirrhosis. METHOD Electronic Databases, PubMed, EMBASE database, Cochrane Library, China National Knowledge Infrastructure (CNKI), Wan Fang, Chinese Scientific Journals Database (VIP) and China Biology Medicine disc, (CBM), will be systematically searched from inception to July 2019. Randomized controlled trials (RCTs) on Biejiajian Pill combined with Entecavir and Entecavir alone against Compensatory period of hepatitis b cirrhosis will be included; inclusion and exclusion criteria will be used to screen the trials. liver fibrosis biomarkers including ECM or its metabolites (serum hyaluronic acid (HA), laminin (LN), procollagen type III (PC-III), and type IV collagen (IV-C)) will be measured as primary outcomes. Liver function, including alanine aminotransferase (ALT) and aspartarte aminotransferase (AST), and improvement of related clinical symptoms will be measured as secondary outcomes. RevMan5 software will be used for literature quality evaluation and data synthesis and analysis. RESULT To evaluate the efficacy and safety of Biejiajian Pill in combination therapy by observing the outcomes of serum liver fibrosis markers, adverse reactions and liver function. CONCLUSION This study protocol will be used to evaluate the efficacy and safety of Biejia Pill in combination with entecavir in the treatment of Compensatory period of hepatitis b cirrhosis, as well as the adjuvant treatment of Biejia Pill in combination.PROSPERO registration number: CRD42019135402.
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Affiliation(s)
| | - Yu Yang
- Chengdu University of Traditional Chinese Medicine
| | - Baojia Wang
- Chengdu University of Traditional Chinese Medicine
| | - Xiuli Zheng
- Chengdu University of Traditional Chinese Medicine
| | - Long Wang
- Chengdu University of Traditional Chinese Medicine
| | - Xianrong Feng
- Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan
| | - Guiyu Li
- Chengdu University of Traditional Chinese Medicine
| | - Jinyu Shi
- Chengdu University of Traditional Chinese Medicine
| | - Ning Cao
- Shaanxi University of Traditional Chinese Medicine, Xianyang, Shaanxi province, China
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Rezvani Habibabadi R, Khoshpouri P, Ghadimi M, Shaghaghi M, Ameli S, Hazhirkarzar B, Pandey P, Aliyari Ghasabeh M, Pandey A, Kamel IR. Comparison between ROI-based and volumetric measurements in quantifying heterogeneity of liver stiffness using MR elastography. Eur Radiol 2019; 30:1609-1615. [DOI: 10.1007/s00330-019-06478-0] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2019] [Revised: 09/01/2019] [Accepted: 09/27/2019] [Indexed: 12/15/2022]
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Safety of Simultaneous Hepatectomy and Splenectomy in the Treatment of Hepatocellular Carcinoma Complicated with Hypersplenism: A Meta-analysis. Gastroenterol Res Pract 2019; 2019:9065845. [PMID: 31485220 PMCID: PMC6710750 DOI: 10.1155/2019/9065845] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/01/2018] [Revised: 04/04/2019] [Accepted: 06/28/2019] [Indexed: 01/30/2023] Open
Abstract
Background We conducted this meta-analysis to compare the efficacy and safety of simultaneous hepatectomy and splenectomy (HS) with hepatectomy alone (HA) in patients with hepatocellular carcinoma (HCC) and hypersplenism. Materials and Methods A systematic search was conducted in PubMed, Embase, Cochrane Library, and Wanfang Data through March 1, 2018, with no limits. Two investigators independently screened all retrieved studies. The investigators of the original publications were contacted if required information was absent. All the included studies were managed by EndNote X7. Quality assessment of the included studies was performed using a modified Newcastle-Ottawa Scale judgment. Extracted data for each endpoint were analyzed by using STATA 12.0 software. Results Thirteen studies, including a total of 1468 patients, comparing the effects of HS with HA were pooled in this meta-analysis. Outcomes including postoperative complications, perioperative mortality, intraoperative blood transfusion, and albumin (ALB) content at postoperation day (POD) 7 did not differ significantly between the two groups. Simultaneous approaches significantly promoted 1-, 3-, and 5-year disease-free survival (DFS) rates and overall survival (OS) rates, prolonged operation time, aggravated intraoperative blood loss, increased white blood cell (WBC) and platelet (PLT) counts at POD 7, and lowered total bilirubin (T-Bil) contents at POD 1 and 7. Conclusion Compared to HA, HS is safer and more effective in ameliorating liver function and improving survival of HCC patients complicated with hypersplenism. This trial is registered with CRD42018093779.
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Wang L, Yang G, Yuan L, Yang Y, Zhao H, Ho CT, Li S. Green Tea Catechins Effectively Altered Hepatic Fibrogenesis in Rats by Inhibiting ERK and Smad1/2 Phosphorylation. JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY 2019; 67:5437-5445. [PMID: 30424599 DOI: 10.1021/acs.jafc.8b05179] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/09/2023]
Abstract
Polyphenols derived from green tea have been reported to have a wide range of profound functions. Tea catechins, including epicatechin, epigallocatechin (EGC), epicatechin-3- O-gallate (ECG), and epigallocatechin-3- O-gallate (EGCG), are considered as the major bioactive polyphenols in tea. The present study was designed to elucidate the potential antifibrogenic role of three abundant tea catechins (ECG, EGC, and EGCG) in a CCl4-induced fibrotic rat and their underlying molecular mechanisms. Tea catechins, especially groups of ECG, EGC, and EGCG, effectively induced several beneficial alterations of liver injury markers, oxidative status, and liver histology. Furthermore, catechins ameliorated liver fibrosis, as evidenced by the reduced expression of desmin, α-smooth muscle actin, transforming growth factor β (TGF-β), and downstream ERK1/2 and Smad1/2 phosphorylation. The most significant inhibitory effect on those proteins was observed in ECG (300 mg/kg) and EGCG (300 mg/kg) groups. In addition, catechins conferred their protective role by downregulating the proinflammation cytokines TGF-β, tumor necrosis factor α, and interleukin 17. It is postulated that tea catechins, particularly ECG and EGCG, are potential therapeutic candidates in antifibrotic therapy.
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Affiliation(s)
- Liwen Wang
- Hubei Key Laboratory of Economic Forest Germplasm Improvement and Resources , Huanggang Normal University , Huanggang , Hubei 438000 , People's Republic of China
- Tianjin Key Laboratory of Food and Biotechnology, School of Biotechnology and Food Science , Tianjin University of Commerce , Tianjin 300134 , People's Republic of China
| | - Guliang Yang
- Hubei Key Laboratory of Economic Forest Germplasm Improvement and Resources , Huanggang Normal University , Huanggang , Hubei 438000 , People's Republic of China
| | - Li Yuan
- Hubei Key Laboratory of Economic Forest Germplasm Improvement and Resources , Huanggang Normal University , Huanggang , Hubei 438000 , People's Republic of China
| | - Yiwen Yang
- Hubei Key Laboratory of Economic Forest Germplasm Improvement and Resources , Huanggang Normal University , Huanggang , Hubei 438000 , People's Republic of China
| | - Hui Zhao
- Tianjin Key Laboratory of Food and Biotechnology, School of Biotechnology and Food Science , Tianjin University of Commerce , Tianjin 300134 , People's Republic of China
| | - Chi-Tang Ho
- Department of Food Science , Rutgers, The State University of New Jersey , New Brunswick , New Jersey 08901 , United States
| | - Shiming Li
- Hubei Key Laboratory of Economic Forest Germplasm Improvement and Resources , Huanggang Normal University , Huanggang , Hubei 438000 , People's Republic of China
- Department of Food Science , Rutgers, The State University of New Jersey , New Brunswick , New Jersey 08901 , United States
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Peng Y, Li L, Zhang X, Xie M, Yang C, Tu S, Shen H, Hu G, Tao L, Yang H. Fluorofenidone affects hepatic stellate cell activation in hepatic fibrosis by targeting the TGF-β1/Smad and MAPK signaling pathways. Exp Ther Med 2019; 18:41-48. [PMID: 31258636 PMCID: PMC6566051 DOI: 10.3892/etm.2019.7548] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2017] [Accepted: 09/18/2018] [Indexed: 02/06/2023] Open
Abstract
The aim of the present research was to study the therapeutic impacts of fluorofenidone (AKF-PD) on pig serum (PS)-induced liver fibrosis in rats and the complex molecular mechanisms of its effects on hepatic stellate cells (HSCs). Wistar rats were randomly divided into normal control, PS and PS/AKF-PD treatment groups. The activated human HSC LX-2 cell line was also treated with AKF-PD. The expression of collagen I and III, and α-smooth muscle actin (α-SMA) was determined by immunohistochemical staining and reverse transcription-quantitative polymerase chain reaction (RT-qPCR). Western blotting and/or RT-qPCR analyses were used to determine the expression of transforming growth factor (TGF)-β1, α-SMA, collagen I, mothers against decapentaplegic homolog (Smad)-3, extracellular signal-regulated kinase (ERK)1/2, p38 mitogen-activated protein kinase (p38 MAPK) and c-Jun N-terminal kinase (JNK). AKF-PD attenuated the degree of hepatic fibrosis and liver injury in vivo, which was associated with the downregulation of collagen I and III, and α-SMA at the mRNA and protein levels. In vitro, AKF-PD treatment significantly reduced the TGF-β1-induced activation of HSCs, as determined by the reduction in collagen I and α-SMA protein expression. The TGF-β1-induced upregulation of the phosphorylation of Smad 3, ERK1/2, p38 and JNK was attenuated by AKF-PD treatment. These findings suggested that AKF-PD attenuated the progression of hepatic fibrosis by suppressing HSCs activation via the TGF-β1/Smad and MAPK signaling pathways, and therefore that AKF-PD may be suitable for use as a novel therapeutic agent against liver fibrosis.
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Affiliation(s)
- Yu Peng
- Department of Gastroenterology, Xiangya Hospital, Central South University, Changsha, Hunan 410008, P.R. China
| | - Li Li
- Department of Gastroenterology, The First People's Hospital of Changde City, Changde, Hunan 415000, P.R. China
| | - Xin Zhang
- Department of General Practice, The First People's Hospital of Lianyungang, Lianyungang, Jiangsu 222000, P.R. China
| | - Mingyan Xie
- Department of Gastroenterology, The First People's Hospital of Changde City, Changde, Hunan 415000, P.R. China
| | - Congying Yang
- Department of Endoscopy Center, Hunan Cancer Hospital, Changsha, Hunan 410000, P.R. China
| | - Sha Tu
- Department of Gastroenterology, Xiangya Hospital, Central South University, Changsha, Hunan 410008, P.R. China
| | - Hong Shen
- Institute of Medical Sciences, Xiangya Hospital, Central South University, Changsha, Hunan 410000, P.R. China
| | - Gaoyun Hu
- Faculty of Pharmaceutical Sciences, Central South University, Changsha, Hunan 410000, P.R. China
| | - Lijian Tao
- Department of Nephropathy, Xiangya Hospital, Central South University, Changsha, Hunan 410008, P.R. China
| | - Huixiang Yang
- Department of Gastroenterology, Xiangya Hospital, Central South University, Changsha, Hunan 410008, P.R. China
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Konishi T, Schuster RM, Lentsch AB. Liver repair and regeneration after ischemia-reperfusion injury is associated with prolonged fibrosis. Am J Physiol Gastrointest Liver Physiol 2019; 316:G323-G331. [PMID: 30543462 PMCID: PMC6459287 DOI: 10.1152/ajpgi.00154.2018] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
Liver recovery after hepatic ischemia-reperfusion (I/R) injury is characterized by clearance of dead tissue and its replacement with functional liver parenchyma. Previous reports have observed fibrosis after liver I/R. To determine whether liver fibrosis after I/R was a pathologic consequence of the injury response, we assessed the development of liver fibrosis after I/R and its impact on subsequent insult. A murine model of partial I/R was used to induce liver injury and study the reparative response. During liver remodeling after I/R, expression of the profibrotic genes increased in the ischemic liver. Histologically, α-smooth muscle actin (α-SMA)-positive hepatic stellate cells (HSCs)/myofibroblasts increased, and collagen deposition was enhanced along the injured site. Selective staining experiments showed that HSCs, not portal fibroblasts, were the major source of myofibroblasts. During liver repair after I/R, liver fibrosis was readily observed at the interface between necrotic tissue and regenerating liver in association with HSCs/myofibroblasts. The number of HSCs/myofibroblasts decreasing shortly after the full resolution of necrotic injury and restoration are normal liver architecture. However, liver fibrosis persisted for several more weeks before gradually resolving. Resolution of liver fibrosis was accompanied by upregulated expression of matrix metalloproteinase-13. After resolution of fibrosis, the administration of CCl4 did not result in exacerbated liver injury, suggesting that I/R injury does not predispose the liver to future fibrotic insults. The data suggest that liver fibrosis is a component of tissue repair after I/R, is caused by myofibroblasts derived from HSC, and does not increase susceptibility of the liver to subsequent hepatic injury. NEW & NOTEWORTHY This study is the first to assess pathology of liver fibrosis during the reparative process after ischemia-reperfusion (I/R) injury. Here we show that profibrotic gene expression increased in the liver after I/R, and collagen accumulation produced by hepatic stellate cells (HSCs)/myofibroblasts enhanced at the interface between necrotic tissue and regenerating liver. Liver fibrosis gradually resolved concomitant with decreasing activation of HSC and upregulating matrix metalloproteinase-13. After resolution of fibrosis, the liver was not more susceptible to subsequent hepatic injury.
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Affiliation(s)
- Takanori Konishi
- Department of Surgery, College of Medicine, University of Cincinnati, Cincinnati, Ohio
| | - Rebecca M. Schuster
- Department of Surgery, College of Medicine, University of Cincinnati, Cincinnati, Ohio
| | - Alex B. Lentsch
- Department of Surgery, College of Medicine, University of Cincinnati, Cincinnati, Ohio
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Liu Z, Li C, Kang N, Malhi H, Shah VH, Maiers JL. Transforming growth factor β (TGFβ) cross-talk with the unfolded protein response is critical for hepatic stellate cell activation. J Biol Chem 2019; 294:3137-3151. [PMID: 30610118 PMCID: PMC6398135 DOI: 10.1074/jbc.ra118.005761] [Citation(s) in RCA: 41] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2018] [Revised: 01/02/2019] [Indexed: 12/13/2022] Open
Abstract
Transforming growth factor β (TGFβ) potently activates hepatic stellate cells (HSCs), which promotes production and secretion of extracellular matrix (ECM) proteins and hepatic fibrogenesis. Increased ECM synthesis and secretion in response to TGFβ is associated with endoplasmic reticulum (ER) stress and the unfolded protein response (UPR). TGFβ and UPR signaling pathways are tightly intertwined during HSC activation, but the regulatory mechanism that connects these two pathways is poorly understood. Here, we found that TGFβ treatment of immortalized HSCs (i.e. LX-2 cells) induces phosphorylation of the UPR sensor inositol-requiring enzyme 1α (IRE1α) in a SMAD2/3-procollagen I-dependent manner. We further show that IRE1α mediates HSC activation downstream of TGFβ and that its role depends on activation of a signaling cascade involving apoptosis signaling kinase 1 (ASK1) and c-Jun N-terminal kinase (JNK). ASK1-JNK signaling promoted phosphorylation of the UPR-associated transcription factor CCAAT/enhancer binding protein β (C/EBPβ), which is crucial for TGFβ- or IRE1α-mediated LX-2 activation. Pharmacological inhibition of C/EBPβ expression with the antiviral drug adefovir dipivoxil attenuated TGFβ-mediated activation of LX-2 or primary rat HSCs in vitro and hepatic fibrogenesis in vivo Finally, we identified a critical relationship between C/EBPβ and the transcriptional regulator p300 during HSC activation. p300 knockdown disrupted TGFβ- or UPR-induced HSC activation, and pharmacological inhibition of the C/EBPβ-p300 complex decreased TGFβ-induced HSC activation. These results indicate that TGFβ-induced IRE1α signaling is critical for HSC activation through a C/EBPβ-p300-dependent mechanism and suggest C/EBPβ as a druggable target for managing fibrosis.
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Affiliation(s)
- Zhikui Liu
- From the Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota 55905 and
| | - Chao Li
- From the Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota 55905 and
| | - Ningling Kang
- Tumor Microenvironment and Metastasis, Hormel Institute, University of Minnesota, Austin, Minnesota 55912
| | - Harmeet Malhi
- From the Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota 55905 and
| | - Vijay H Shah
- From the Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota 55905 and
| | - Jessica L Maiers
- From the Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota 55905 and
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Akkaya HE, Erden A, Kuru Öz D, Ünal S, Erden İ. Magnetic resonance elastography: basic principles, technique, and clinical applications in the liver. ACTA ACUST UNITED AC 2019; 24:328-335. [PMID: 30272563 DOI: 10.5152/dir.2018.18186] [Citation(s) in RCA: 28] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
Magnetic resonance elastography (MRE) is a constantly advancing technique for assessment of stiffness of tissues with newer technology and sequences. It is being increasingly used for the assessment of liver fibrosis. In this article, we discuss the advantages of MRE over biopsy and noninvasive methods such as US elastography in the assessment of liver fibrosis. Image acquisition and interpretation of liver MRE is also discussed.
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Affiliation(s)
| | - Ayşe Erden
- Department of Radiology, Ankara University School of Medicine, Ankara, Turkey
| | - Diğdem Kuru Öz
- Department of Radiology, Ankara University School of Medicine, Ankara, Turkey
| | - Sena Ünal
- Department of Radiology, Erzurum Local Training and Research Hospital, Erzurum, Turkey
| | - İlhan Erden
- Department of Radiology, Ankara University School of Medicine, Ankara, Turkey
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Stefanovic B, Manojlovic Z, Vied C, Badger CD, Stefanovic L. Discovery and evaluation of inhibitor of LARP6 as specific antifibrotic compound. Sci Rep 2019; 9:326. [PMID: 30674965 PMCID: PMC6344531 DOI: 10.1038/s41598-018-36841-y] [Citation(s) in RCA: 35] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2018] [Accepted: 11/27/2018] [Indexed: 01/17/2023] Open
Abstract
Fibrosis is characterized by excessive production of type I collagen. Biosynthesis of type I collagen in fibrosis is augmented by binding of protein LARP6 to the 5' stem-loop structure (5'SL), which is found exclusively in type I collagen mRNAs. A high throughput screen was performed to discover inhibitors of LARP6 binding to 5'SL, as potential antifibrotic drugs. The screen yielded one compound (C9) which was able to dissociate LARP6 from 5' SL RNA in vitro and to inactivate the binding of endogenous LARP6 in cells. Treatment of hepatic stellate cells (liver cells responsible for fibrosis) with nM concentrations of C9 reduced secretion of type I collagen. In precision cut liver slices, as an ex vivo model of hepatic fibrosis, C9 attenuated the profibrotic response at 1 μM. In prophylactic and therapeutic animal models of hepatic fibrosis C9 prevented development of fibrosis or hindered the progression of ongoing fibrosis when administered at 1 mg/kg. Toxicogenetics analysis revealed that only 42 liver genes changed expression after administration of C9 for 4 weeks, suggesting minimal off target effects. Based on these results, C9 represents the first LARP6 inhibitor with significant antifibrotic activity.
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Affiliation(s)
- Branko Stefanovic
- Department of Biomedical Sciences, College of Medicine, Florida State University, 1115 West Call Street, Tallahassee, FL, 32306, USA.
| | - Zarko Manojlovic
- Keck School of Medicine of University of Southern California, 1450 Biggy Street, NRT 4510, Los Angeles, CA, 90033, USA
| | - Cynthia Vied
- Translational Science Laboratory, College of Medicine, Florida State University, 1115 West Call Street, Tallahassee, FL, 32306, USA
| | - Crystal-Dawn Badger
- Translational Science Laboratory, College of Medicine, Florida State University, 1115 West Call Street, Tallahassee, FL, 32306, USA
- Proteomics and Metabolomics Facility, Colorado State University, 401 West Pitkin Street, Fort Collins, CO, 80521, USA
| | - Lela Stefanovic
- Department of Biomedical Sciences, College of Medicine, Florida State University, 1115 West Call Street, Tallahassee, FL, 32306, USA
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Abstract
The first clinical application of magnetic resonance elastography (MRE) was in the evaluation of chronic liver disease (CLD) for detection and staging of liver fibrosis. In the past 10 years, MRE has been incorporated seamlessly into a standard magnetic resonance imaging (MRI) liver protocol worldwide. Liver MRE is a robust technique for evaluation of liver stiffness and is currently the most accurate noninvasive imaging technology for evaluation of liver fibrosis. Newer MRE sequences including spin-echo MRE and 3 dimensional MRE have helped in reducing the technical limitations of clinical liver MRE that is performed with 2D gradient recalled echo (GRE) MRE. Advances in MRE technology have led to understanding of newer mechanical parameters such as dispersion, attenuation, and viscoelasticity that may be useful in evaluating pathological processes in CLD and may prove useful in their management.This review article will describe the changes in CLD that cause an increase in stiffness followed by principle and technique of liver MRE. In the later part of the review, we will briefly discuss the advances in liver MRE.
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Liu YM, Shi HB, Liu YR, Shi HL, Ren F, Chen Y, Chen DX, Lou JL, Duan ZP. Protective Effect of Ganshuang Granules () on Liver Cirrhosis by Suppressing Regulatory T Cells in Mouse Model. Chin J Integr Med 2019; 25:51-58. [PMID: 26542309 DOI: 10.1007/s11655-015-2430-9] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 04/10/2015] [Indexed: 12/20/2022]
Abstract
OBJECTIVE To investigate the potential antifibrotic mechanisms of Chinese medicine Ganshuang Granules (, GSG) and to provide clinical therapeutic evidence of its effects. METHODS A cirrhotic mouse model was established by intraperitoneally injecting a mixture of CCl4 (40%) and oil (60%) at 0.2 mL per 100 g of body weight twice a week for 12 weeks. After 12-week modeling, GSG was intragastric administrated to the mice for 2 weeks, and the mice were divided into low-, medium- and high-dose groups at doses of 1, 2 and 4 g/(kg·day), respectively. Liver morphology changes were observed using Masson's trichrome staining and B-ultrasound. The levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST) and hyaluronic acid (HA) in serum were detected using an automatic biochemistry analyzer. The expressions of desmin, smooth muscle actin (SMA) and Foxp3 in liver were detected by immunoflfluorescence. The regulatory T cell (Treg) frequency was determined through flflow cytometry analysis. Collagen-I, SMA, IL-6, tumor necrosis factor α (TNF-α), interleukin (IL)-1β and transforming growth factor β1 (TGF-β1) expression levels were measured using quantitative polymerase chain reaction (qPCR). RESULTS Masson's staining result showed fewer pseudolobule structures and fibrous connective tissue in the GSG-treatment groups than in the spontaneous recovery group. Ultrasonography showed that GSG treatment reduced the number of punctate hyperechoic lesions in mice cirrhotic livers. The serum ALT, AST, HA levels were significantly ameliorated by GSG treatment (ALT: F=8.104, P=0.000; AST: F=7.078, P=0.002; and HA: F=7.621, P=0.001). The expression levels of collagen-I and SMA in the cirrhotic livers were also attenuated by GSG treatment (collagen-I: F=3.938, P=0.011; SMA: F=4.115, P=0.009). Tregs, which were elevated in the fibrotic livers, were suppressed by GSG treatment (F=8.268, P=0.001). The expressions of IL-6, TNF-α and IL-1β increased, and TGF-β levels decreased in the cirrhotic livers after GSG treatment (IL-6: F=5.457, P=0.004; TNF-α: F=6.023, P=0.002; IL-1β: F=6.658, P=0.001; and TGF-β1: F=11.239, P=0.000). CONCLUSIONS GSG promoted the resolution/regression of cirrhosis and restored liver functions in part by suppressing Treg cell differentiation, which may be mediated by hepatic stellate cells.
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Affiliation(s)
- Yan-Min Liu
- Department of Liver Diseases Immunology, Beijing Youan Hospital, Capital Medical University, Beijing, 100069, China
| | - Hong-Bo Shi
- Department of Liver Diseases Immunology, Beijing Youan Hospital, Capital Medical University, Beijing, 100069, China
- Beijing Institute of Hepatology, Beijing Youan Hospital, Capital Medical University, Beijing, 100069, China
| | - Yi-Rong Liu
- Department of Toxic Hepatic Disease, Beijing Youan Hospital, Capital Medical University, Beijing, 100069, China
| | - Hong-Lin Shi
- Department of Liver Diseases Immunology, Beijing Youan Hospital, Capital Medical University, Beijing, 100069, China
- Beijing Institute of Hepatology, Beijing Youan Hospital, Capital Medical University, Beijing, 100069, China
| | - Feng Ren
- Department of Liver Diseases Immunology, Beijing Youan Hospital, Capital Medical University, Beijing, 100069, China
- Beijing Institute of Hepatology, Beijing Youan Hospital, Capital Medical University, Beijing, 100069, China
| | - Yu Chen
- Artifical Liver Center, Beijing Youan Hospital, Capital Medical University, Beijing, 100069, China
| | - De-Xi Chen
- Department of Liver Diseases Immunology, Beijing Youan Hospital, Capital Medical University, Beijing, 100069, China
- Beijing Institute of Hepatology, Beijing Youan Hospital, Capital Medical University, Beijing, 100069, China
| | - Jin-Li Lou
- Clinical Laboratory Center, Beijing Youan Hospital, Capital Medical University, Beijing, 100069, China
| | - Zhong-Ping Duan
- Artifical Liver Center, Beijing Youan Hospital, Capital Medical University, Beijing, 100069, China.
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Gallic Acid Attenuates Dimethylnitrosamine-Induced Liver Fibrosis by Alteration of Smad Phosphoisoform Signaling in Rats. BIOMED RESEARCH INTERNATIONAL 2018; 2018:1682743. [PMID: 30627538 PMCID: PMC6304566 DOI: 10.1155/2018/1682743] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/31/2018] [Revised: 10/31/2018] [Accepted: 11/08/2018] [Indexed: 12/24/2022]
Abstract
Dimethylnitrosamine (DMN) is a potent hepatotoxin, carcinogen, and mutagen. In our previous study, a candidate gallic acid (GA) that widely exists in food and fruit was selected for its capability to alleviate DMN toxicity in vivo. We aimed to investigate the therapeutic potential of GA against DMN-induced liver fibrosis. During the first four weeks, DMN was administered to rats via intraperitoneal injection every other day, except the control group. GA or silymarin was given to rats by gavage once daily from the second to the sixth week. GA significantly reduced liver damage in serum parameters and improved the antioxidant capacity in liver and kidney tissues. Cytokines involved in liver fibrosis were measured at transcriptional and translational levels. These results indicate that GA exhibits robust antioxidant and antifibrosis effects and may be an effective candidate natural medicine for liver fibrosis treatment.
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Udomsinprasert W, Jittikoon J. Vitamin D and liver fibrosis: Molecular mechanisms and clinical studies. Biomed Pharmacother 2018; 109:1351-1360. [PMID: 30551386 DOI: 10.1016/j.biopha.2018.10.140] [Citation(s) in RCA: 54] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2018] [Revised: 10/22/2018] [Accepted: 10/24/2018] [Indexed: 12/21/2022] Open
Abstract
Vitamin D plays a primary role in regulation of bone metabolism and calcium homeostasis. Interestingly, emerging evidence suggests protective effects of vitamin D against liver fibrogenesis. However, the precise mechanisms of this action remain mysterious. Herein, this review aimed to summarize the role of vitamin D in liver fibrosis pathology and to update the current comprehensive knowledge regarding the clinical utility of vitamin D-based treatment in liver fibrosis. In regard to its effect on liver fibrosis, vitamin D possesses an anti-fibrotic effect on hepatic stellate cells via vitamin D receptor-mediated specific signal transduction pathways, which in turn inhibit expression of pro-fibrogenic genes. Furthermore, several studies demonstrated a significant association between low vitamin D levels and an increased risk of liver fibrosis. Additionally, high prevalence of vitamin D deficiency was noted in patients with liver fibrosis, suggesting the use of vitamin D status as a biochemical marker reflecting the progression of liver fibrosis. It is therefore reasonable to postulate that vitamin D supplementation being a cost effective and relative simple procedure may benefit to liver fibrosis. Nevertheless, further research is needed to fully elucidate its regulatory role in inhibiting liver fibrogenesis and to estimate the safety and efficiency of vitamin D supplementation as a relatively inexpensive treatment for liver fibrosis in patients with chronic liver diseases.
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Affiliation(s)
- Wanvisa Udomsinprasert
- Department of Biochemistry, Faculty of Pharmacy, Mahidol University, Bangkok 10400, Thailand.
| | - Jiraphun Jittikoon
- Department of Biochemistry, Faculty of Pharmacy, Mahidol University, Bangkok 10400, Thailand.
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