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Subramaniam NK, Mann KK. Mechanisms of Metal-Induced Hepatic Inflammation. Curr Environ Health Rep 2024; 11:547-556. [PMID: 39499483 DOI: 10.1007/s40572-024-00463-6] [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] [Accepted: 09/16/2024] [Indexed: 11/07/2024]
Abstract
PURPOSE OF REVIEW Worldwide, there is an increasing prevalence of hepatic diseases. The most common diseases include alcoholic-associated liver disease (ALD), metabolic dysfunction-associated fatty liver disease/ metabolic dysfunction-associated steatohepatitis (MAFLD/MASH) and viral hepatitis. While there are many important mediators of these diseases, there is increasing recognition of the importance of the inflammatory immune response in hepatic disease pathogenesis. RECENT FINDINGS Hepatic inflammation triggers the onset and progression of liver diseases. Chronic and sustained inflammation can lead to fibrosis, then cirrhosis and eventually end-stage cancer, hepatocellular carcinoma. Importantly, growing evidence suggest that metal exposure plays a role in hepatic disease pathogenesis. While in recent years, studies have linked metal exposure and hepatic steatosis, studies emphasizing metal-induced hepatic inflammation are limited. Hepatic inflammation is an important hallmark of fatty liver disease. This review aims to summarize the mechanisms of arsenic (As), cadmium (Cd) and chromium (Cr)-induced hepatic inflammation as they contribute to hepatic toxicity and to identify data gaps for future investigation.
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Affiliation(s)
| | - Koren K Mann
- Division of Experimental Medicine, McGill University, Montréal, Québec, Canada.
- Department of Pharmacology and Therapeutics, McGill University, Montréal, Québec, Canada.
- Lady Davis Institute for Medical Research, Jewish General Hospital, 3755 Cote Ste Catherine Rd. Rm 202.1, Montréal, Québec, H3T 1E2, Canada.
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Urushima H, Matsubara T, Qiongya G, Daikoku A, Takayama M, Kadono C, Nakai H, Ikeya Y, Yuasa H, Ikeda K. AHCC inhibited hepatic stellate cells activation by regulation of cytoglobin induction via TLR2-SAPK/JNK pathway and collagen production via TLR4-NF-κβ pathway. Am J Physiol Gastrointest Liver Physiol 2024; 327:G741-G753. [PMID: 39316687 PMCID: PMC11684891 DOI: 10.1152/ajpgi.00134.2024] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/02/2024] [Revised: 09/10/2024] [Accepted: 09/17/2024] [Indexed: 09/26/2024]
Abstract
Cirrhosis, which represents the end stage of liver fibrosis, remains a life-threatening condition without effective treatment. Therefore, prevention of the progression of liver fibrosis through lifestyle habits such as diet and exercise is crucial. The functional food AHCC, a standardized extract of cultured Lentinula edodes mycelia produced by Amino Up Co., Ltd. (Sapporo, Japan)] has been reported to be effective in improving the pathophysiology of various liver diseases. In this study, the aim was to analyze the influence of AHCC on hepatic stellate cells, which are responsible for liver fibrosis. Eight-week-old male C57BL6/j mice were induced with liver fibrosis by intraperitoneal injection of carbon tetrachloride. Simultaneously, they were orally administered 3% AHCC to investigate its impact on the progression of liver fibrosis. Using the human hepatic stellate cell (HHSteC) line, we analyzed the influence of AHCC on the expression of molecules related to hepatic stellate cell activation. The administration of AHCC resulted in reduced expression of collagen1a, α smooth muscle actin (αSMA), and heat shock protein 47 in the liver. Furthermore, the expression of cytoglobin, a marker for quiescent hepatic stellate cells, was enhanced. In vitro study, it was confirmed that AHCC inhibited αSMA by inducing cytoglobin via upregulating the stress-activated protein kinase/Jun NH2-terminal kinase (SAPK/JNK) pathway through Toll-like receptor (TLR) 2. In addition, AHCC suppressed collagen1a production by hepatic stellate cells through TLR4-NF-κβ pathway. AHCC was suggested to suppress hepatic fibrosis by inhibition of hepatic stellate cells activation. Daily intake of AHCC from mild fibrotic stages may have the potential to prevent the progression of liver fibrosis.NEW & NOTEWORTHY AHCC, a standardized extract of cultured Lentinula edodes mycelia, suppresses liver fibrosis progression by induction of cytoglobin via the Toll-like receptor 2 (TLR2)-stress-activated protein kinase/Jun NH2-terminal kinase (SAPK/JNK) pathway and the inhibition of collagen production via the TLR4-NFκβ pathway in hepatic stellate cells. Daily oral administration of AHCC from the stage of MASLD may have the potential to prevent disease progression to MASH with fibrosis.
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Affiliation(s)
- Hayato Urushima
- Department of Anatomy and Regenerative Biology, Graduate School of Medicine, Osaka Metropolitan University, Osaka, Japan
- Laboratory Animal Facility, Graduate School of Medicine, Osaka Metropolitan University, Osaka, Japan
| | - Tsutomu Matsubara
- Department of Anatomy and Regenerative Biology, Graduate School of Medicine, Osaka Metropolitan University, Osaka, Japan
| | - Gu Qiongya
- Department of Anatomy and Regenerative Biology, Graduate School of Medicine, Osaka Metropolitan University, Osaka, Japan
| | - Atsuko Daikoku
- Department of Anatomy and Regenerative Biology, Graduate School of Medicine, Osaka Metropolitan University, Osaka, Japan
| | - Misako Takayama
- Department of Anatomy and Regenerative Biology, Graduate School of Medicine, Osaka Metropolitan University, Osaka, Japan
| | - Chiho Kadono
- Department of Anatomy and Regenerative Biology, Graduate School of Medicine, Osaka Metropolitan University, Osaka, Japan
| | - Hikaru Nakai
- Department of Anatomy and Regenerative Biology, Graduate School of Medicine, Osaka Metropolitan University, Osaka, Japan
| | - Yukinobu Ikeya
- Faculty of Pharmacy, Daiichi University of Pharmacy, Fukuoka, Japan
| | - Hideto Yuasa
- Department of Anatomy and Regenerative Biology, Graduate School of Medicine, Osaka Metropolitan University, Osaka, Japan
| | - Kazuo Ikeda
- Department of Anatomy and Regenerative Biology, Graduate School of Medicine, Osaka Metropolitan University, Osaka, Japan
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Džepina P, Ćorić M, Kovačić Perica M, Aničić MN, Grizelj R, Vuković J. Expression of activin A in liver tissue and the outcome of patients with biliary atresia. Front Pediatr 2024; 12:1457837. [PMID: 39618695 PMCID: PMC11604446 DOI: 10.3389/fped.2024.1457837] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/01/2024] [Accepted: 10/25/2024] [Indexed: 01/03/2025] Open
Abstract
Biliary atresia (BA) is a rare disease of unknown etiology which leads to cirrhosis and death if left untreated. The standard of care is an early hepatoportoenterostomy (HPE). Long-term follow-up is mandatory, during which most patients will require a liver transplant. Activin A belongs to the transforming growth factor-β (TGF-β) superfamily. TGF-β is a central regulator in chronic liver disease. We have studied the expression of activin A in liver tissue collected intraoperatively during the HPE. We included patients who underwent HPE in a single medical center. Clinical, ultrasonographic, and pathohistological data were collected. Activin A immunostaining was performed. Expression in the bile duct epithelium and hepatocytes was scored as either weakly positive, moderately positive, or strongly positive. Patients were then divided into three groups accordingly. We observed the outcome after the HPE at 3 months, 2 years, and at the end of follow-up. The study encompassed 37 patients. At 3 months after HPE, 92.3% of those with a weakly positive activin A reaction (group A) achieved good jaundice clearance, whereas only 44.4% of those with a moderately (group B) and 40% of those with a strongly positive reaction (group C) achieved good jaundice clearance (p = 0.008). Furthermore, 2 years after the HPE, 92.3% of those in group A survived with native liver (SNL), but only 33.3% of those in group B and 46.7% of those in group C had SNL (p = 0.007). At the end of follow-up, 83.3% of those in group A survived with native liver, as did 33.3% in group B and 40% in group C. Activin A is a valuable pathohistological predictor of the outcome of BA after an HPE.
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Affiliation(s)
- Petra Džepina
- Department of Pediatrics, School of Medicine, University Hospital Centre Zagreb, University of Zagreb, Zagreb, Croatia
| | - Marijana Ćorić
- Department of Pathology and Cytology, School of Medicine, University Hospital Centre Zagreb, University of Zagreb, Zagreb, Croatia
- School of Medicine, University of Zagreb, Zagreb, Croatia
| | - Matea Kovačić Perica
- Department of Pediatrics, School of Medicine, University Hospital Centre Zagreb, University of Zagreb, Zagreb, Croatia
| | - Mirna Natalija Aničić
- Department of Pediatrics, School of Medicine, University Hospital Centre Zagreb, University of Zagreb, Zagreb, Croatia
- School of Medicine, University of Zagreb, Zagreb, Croatia
| | - Ruža Grizelj
- Department of Pediatrics, School of Medicine, University Hospital Centre Zagreb, University of Zagreb, Zagreb, Croatia
- School of Medicine, University of Zagreb, Zagreb, Croatia
| | - Jurica Vuković
- Department of Pediatrics, School of Medicine, University Hospital Centre Zagreb, University of Zagreb, Zagreb, Croatia
- School of Medicine, University of Zagreb, Zagreb, Croatia
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Kamada Y, Ueda Y, Matsuno E, Matsumoto R, Akita M, Takamatsu S, Miyoshi E. Core-fucose-specific Pholiota squarrosa lectin decreased hepatic inflammatory macrophage infiltration in steatohepatitis mice. Glycoconj J 2024; 41:267-278. [PMID: 39249179 DOI: 10.1007/s10719-024-10163-w] [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: 01/06/2024] [Revised: 07/12/2024] [Accepted: 07/29/2024] [Indexed: 09/10/2024]
Abstract
Recent findings in glycobiology revealed direct evidence of the involvement of oligosaccharide changes in human diseases, including liver diseases. Fucosylation describes the attachment of a fucose residue to a glycan or glycolipid. We demonstrated that fucosylated proteins are useful serum biomarkers for nonalcoholic fatty liver disease. Among fucosyltransferases, expression of alpha-1, 6-fucosyltransferase (Fut8), which produces core fucose, is frequently elevated during the progression of human chronic liver diseases. Previously, we discovered core-fucose-specific Pholiota squarrosa lectin (PhoSL) from Japanese mushroom Sugitake. Lectins are bioactive compounds that bind to glycan specifically, and various kinds of lectin have a variety of biological functions. Using high-fat and high-cholesterol (HFHC)-fed steatohepatitic mice, we found that core fucosylation increases in hepatic inflammatory macrophages. Antibody drugs bind to specific antigens and block protein function. We hypothesized that, like antibody drugs, PhoSL could have inhibitory effects on glycoproteins involved in steatohepatitis progression. PhoSL administration dramatically decreased hepatic macrophage infiltration and liver fibrosis-related gene expression. Using mouse macrophage-like cell RAW264.7, we found that PhoSL enhanced core-fucose-mediated activation of macrophage cell death by blocking interferon-γ/signal transducer and activator of transcription 1 (STAT1) signaling. Core-fucose-mediated cell death is a mechanism for the anti-inflammatory effects and anti-fibrotic effects of PhoSL on activated macrophages in steatohepatitic liver. In addition, PhoSL provides an anti-fibrotic effect by blocking transforming growth factor-β/SMAD family member 3 signaling in hepatic stellate cells. In conclusion, we found core-fucose-specific PhoSL administration could suppress steatohepatitis progression by decreasing inflammatory macrophage infiltration and fibrotic signaling in hepatic stellate cells.
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Affiliation(s)
- Yoshihiro Kamada
- Department of Advanced Metabolic Hepatology, Osaka University Graduate School of Medicine, 1-7, Yamada-Oka, Suita, Osaka, 565-0871, Japan.
| | - Yui Ueda
- Department of Molecular Biochemistry and Clinical Investigation, Osaka University Graduate School of Medicine, 1-7, Yamada-Oka, Suita, Osaka, 565-0871, Japan
| | - Eriko Matsuno
- Department of Molecular Biochemistry and Clinical Investigation, Osaka University Graduate School of Medicine, 1-7, Yamada-Oka, Suita, Osaka, 565-0871, Japan
| | - Riku Matsumoto
- Department of Molecular Biochemistry and Clinical Investigation, Osaka University Graduate School of Medicine, 1-7, Yamada-Oka, Suita, Osaka, 565-0871, Japan
| | - Maaya Akita
- Department of Molecular Biochemistry and Clinical Investigation, Osaka University Graduate School of Medicine, 1-7, Yamada-Oka, Suita, Osaka, 565-0871, Japan
| | - Shinji Takamatsu
- Department of Molecular Biochemistry and Clinical Investigation, Osaka University Graduate School of Medicine, 1-7, Yamada-Oka, Suita, Osaka, 565-0871, Japan
| | - Eiji Miyoshi
- Department of Molecular Biochemistry and Clinical Investigation, Osaka University Graduate School of Medicine, 1-7, Yamada-Oka, Suita, Osaka, 565-0871, Japan.
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Li Y, Chen L, Papadopoulos V. The mitochondrial translocator protein (TSPO, 18 kDa): A key multifunctional molecule in liver diseases. Biochimie 2024; 224:91-103. [PMID: 38065288 DOI: 10.1016/j.biochi.2023.11.013] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/18/2023] [Revised: 11/23/2023] [Accepted: 11/29/2023] [Indexed: 08/23/2024]
Abstract
Translocator protein (TSPO, 18 kDa), previously known as peripheral-type benzodiazepine receptor, is an evolutionarily conserved and tryptophan-rich 169-amino-acid protein located on the outer mitochondrial membrane. TSPO plays a crucial role in various fundamental physiological functions and cellular processes. Its expression is altered in pathological conditions, thus rendering TSPO a potential tool for diagnostic imaging and an appealing therapeutic target. The investigation of synthetic TSPO ligands as both agonists and antagonists has provided valuable insights into the regulatory mechanisms and functional properties of TSPO. Recently, accumulating evidence has highlighted the significance of TSPO in liver diseases. However, a comprehensive summary of TSPO function in the normal liver and diverse liver diseases is lacking. This review aims to provide an overview of recent advances in understanding TSPO function in both normal liver cells and various liver diseases, with a particular emphasis on its involvement in liver fibrosis and inflammation and addresses the existing knowledge gaps in the field that require further investigation.
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Affiliation(s)
- Yuchang Li
- Department of Pharmacology and Pharmaceutical Sciences, Alfred E. Mann School of Pharmacy and Pharmaceutical Sciences, University of Southern California, Los Angeles, CA 90089, USA.
| | - Liting Chen
- Department of Pharmacology and Pharmaceutical Sciences, Alfred E. Mann School of Pharmacy and Pharmaceutical Sciences, University of Southern California, Los Angeles, CA 90089, USA
| | - Vassilios Papadopoulos
- Department of Pharmacology and Pharmaceutical Sciences, Alfred E. Mann School of Pharmacy and Pharmaceutical Sciences, University of Southern California, Los Angeles, CA 90089, USA.
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Liu Y, Pierre CJ, Joshi S, Sun L, Li Y, Guan J, Favor JDL, Holmes C. Cell-Specific Impacts of Surface Coating Composition on Extracellular Vesicle Secretion. ACS APPLIED MATERIALS & INTERFACES 2024; 16:29737-29759. [PMID: 38805212 DOI: 10.1021/acsami.4c03213] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/29/2024]
Abstract
Biomaterial properties have recently been shown to modulate extracellular vesicle (EV) secretion and cargo; however, the effects of substrate composition on EV production remain underexplored. This study investigates the impacts of surface coatings composed of collagen I (COLI), fibronectin (FN), and poly l-lysine (PLL) on EV secretion for applications in therapeutic EV production and to further understanding of how changes in the extracellular matrix microenvironment affect EVs. EV secretion from primary bone marrow-derived mesenchymal stromal cells (BMSCs), primary adipose-derived stem cells (ASCs), HEK293 cells, NIH3T3 cells, and RAW264.7 cells was characterized on the different coatings. Expression of EV biogenesis genes and cellular adhesion genes was also analyzed. COLI coatings significantly decreased EV secretion in RAW264.7 cells, with associated decreases in cell viability and changes in EV biogenesis-related and cell adhesion genes at day 4. FN coatings increased EV secretion in NIH3T3 cells, while PLL coatings increased EV secretion in ASCs. Surface coatings had significant effects on the capacity of EVs derived from RAW264.7 and NIH3T3 cells to impact in vitro macrophage proliferation. Overall, surface coatings had different cell-specific effects on EV secretion and in vitro functional capacity, thus highlighting the potential of substrate coatings to further the development of clinical EV production systems.
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Affiliation(s)
- Yuan Liu
- Department of Chemical & Biomedical Engineering, FAMU-FSU College of Engineering, Florida A&M University, Florida State University, 2525 Pottsdamer Street, Tallahasee, Florida 32310-6046, United States
| | - Clifford J Pierre
- Department of Health, Nutrition, and Food Science, College of Education, Health and Human Sciences, Florida State University, 1114 West Call Street, Tallahasee, Florida 32306, United States
| | - Sailesti Joshi
- Department of Chemical & Biomedical Engineering, FAMU-FSU College of Engineering, Florida A&M University, Florida State University, 2525 Pottsdamer Street, Tallahasee, Florida 32310-6046, United States
| | - Li Sun
- Department of Chemical & Biomedical Engineering, FAMU-FSU College of Engineering, Florida A&M University, Florida State University, 2525 Pottsdamer Street, Tallahasee, Florida 32310-6046, United States
- Department of Biomedical Sciences, College of Medicine, Florida State University, 1115 West Call Street, Tallahasee, Florida 32306-4300, United States
| | - Yan Li
- Department of Chemical & Biomedical Engineering, FAMU-FSU College of Engineering, Florida A&M University, Florida State University, 2525 Pottsdamer Street, Tallahasee, Florida 32310-6046, United States
| | - Jingjiao Guan
- Department of Chemical & Biomedical Engineering, FAMU-FSU College of Engineering, Florida A&M University, Florida State University, 2525 Pottsdamer Street, Tallahasee, Florida 32310-6046, United States
| | - Justin D La Favor
- Department of Health, Nutrition, and Food Science, College of Education, Health and Human Sciences, Florida State University, 1114 West Call Street, Tallahasee, Florida 32306, United States
| | - Christina Holmes
- Department of Chemical & Biomedical Engineering, FAMU-FSU College of Engineering, Florida A&M University, Florida State University, 2525 Pottsdamer Street, Tallahasee, Florida 32310-6046, United States
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Zhang J, Wang W, Cui X, Zhu P, Li S, Yuan S, Peng D, Peng C. Ganoderma lucidum ethanol extracts ameliorate hepatic fibrosis and promote the communication between metabolites and gut microbiota g_Ruminococcus through the NF-κB and TGF-β1/Smads pathways. JOURNAL OF ETHNOPHARMACOLOGY 2024; 322:117656. [PMID: 38154526 DOI: 10.1016/j.jep.2023.117656] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/31/2023] [Revised: 12/10/2023] [Accepted: 12/22/2023] [Indexed: 12/30/2023]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE Ganoderma lucidum, a traditional edible medicinal mushroom, has been widely reported to improve liver diseases as a dietary intervention for people. Ganoderma lucidum extracts, primarily total triterpenoids (GLTTs), are one of the bioactive ingredients that have excellent beneficial effects on hepatic fibrosis. Therefore, its prevention and reversal are particularly critical due to the increasing number of patients with chronic liver diseases worldwide. AIM OF THE STUDY The study aimed to evaluate whether GLTTs had a hepatoprotective effect against hepatic fibrosis through metabolic perturbations and gut microbiota changes and its underlying mechanisms. MATERIALS AND METHODS The compound compositions of GLTTs were quantified, and carbon tetrachloride (CCl4)-induced hepatic fibrosis rats were used to investigate the cause of the improvement in various physiological states with GLTTs treatment, and to determine whether its consequent effect was associated with endogenous metabolites and gut microbiota using UPLC-Q-TOF-MSE metabolomics and 16S rRNA gene sequencing technology. RESULTS GLTTs alleviated physical status, reduced liver pathological indicators, proinflammatory cytokines, and deposition of hepatic collagen fibers via regulating the NF-κB and TGF-β1/Smads pathways. The untargeted metabolomics analysis identified 16 potential metabolites that may be the most relevant metabolites for gut microbiota dysbiosis and the therapeutic effects of GLTTs in hepatic fibrosis. Besides, although GLTTs did not significantly affect the α-diversity indexes, significant changes were observed in the composition of microflora structure. In addition, Spearman analysis revealed strong correlations between endogenous metabolites and gut microbiota g_Ruminococcus with hepatic fibrosis. CONCLUSION GLTTs could provide a potential target for the practical design and application of novel functional food ingredients or drugs in the therapy of hepatic fibrosis.
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Affiliation(s)
- Jing Zhang
- School of Pharmacy, Anhui University of Chinese Medicine, Hefei, 230012, China; Center for Xin'an Medicine and Modernization of Traditional Chinese Medicine of IHM, Anhui University of Chinese Medicine, Hefei, 230012, China
| | - Wen Wang
- School of Pharmacy, Anhui University of Chinese Medicine, Hefei, 230012, China; Anhui Province Key Laboratory of Pharmaceutical Preparation Technology and Application, Hefei, Anhui, 230012, China; Center for Xin'an Medicine and Modernization of Traditional Chinese Medicine of IHM, Anhui University of Chinese Medicine, Hefei, 230012, China
| | - Xinge Cui
- School of Pharmacy, Anhui University of Chinese Medicine, Hefei, 230012, China; Anhui Province Key Laboratory of Pharmaceutical Preparation Technology and Application, Hefei, Anhui, 230012, China; Center for Xin'an Medicine and Modernization of Traditional Chinese Medicine of IHM, Anhui University of Chinese Medicine, Hefei, 230012, China
| | - Pengling Zhu
- School of Pharmacy, Anhui University of Chinese Medicine, Hefei, 230012, China; Anhui Province Key Laboratory of Pharmaceutical Preparation Technology and Application, Hefei, Anhui, 230012, China; Center for Xin'an Medicine and Modernization of Traditional Chinese Medicine of IHM, Anhui University of Chinese Medicine, Hefei, 230012, China
| | - Siyu Li
- School of Pharmacy, Anhui University of Chinese Medicine, Hefei, 230012, China; Anhui Province Key Laboratory of Pharmaceutical Preparation Technology and Application, Hefei, Anhui, 230012, China; Center for Xin'an Medicine and Modernization of Traditional Chinese Medicine of IHM, Anhui University of Chinese Medicine, Hefei, 230012, China
| | - Shujie Yuan
- School of Pharmacy, Anhui University of Chinese Medicine, Hefei, 230012, China; Anhui Province Key Laboratory of Pharmaceutical Preparation Technology and Application, Hefei, Anhui, 230012, China; Center for Xin'an Medicine and Modernization of Traditional Chinese Medicine of IHM, Anhui University of Chinese Medicine, Hefei, 230012, China
| | - Daiyin Peng
- School of Pharmacy, Anhui University of Chinese Medicine, Hefei, 230012, China; Generic Technology Research Center for Anhui TCM Industry, Anhui University of Chinese Medicine, Hefei, 230012, China; MOE-Anhui Joint Collaborative Innovation Center for Quality Improvement of Anhui Genuine Chinese Medicinal Materials, Hefei, 230012, China; Anhui Province Key Laboratory of Pharmaceutical Preparation Technology and Application, Hefei, Anhui, 230012, China; Center for Xin'an Medicine and Modernization of Traditional Chinese Medicine of IHM, Anhui University of Chinese Medicine, Hefei, 230012, China.
| | - Can Peng
- School of Pharmacy, Anhui University of Chinese Medicine, Hefei, 230012, China; Rural Revitalization Collaborative Technical Service Center of Anhui Province, Anhui University of Chinese Medicine, Hefei, 230012, China; MOE-Anhui Joint Collaborative Innovation Center for Quality Improvement of Anhui Genuine Chinese Medicinal Materials, Hefei, 230012, China; Anhui Province Key Laboratory of Pharmaceutical Preparation Technology and Application, Hefei, Anhui, 230012, China; Center for Xin'an Medicine and Modernization of Traditional Chinese Medicine of IHM, Anhui University of Chinese Medicine, Hefei, 230012, China.
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Sato S, Nakaji S, Sawada K, Akimoto N, Tateda T, Kaizuka M, Sasada T, Nomiya H, Igarashi G, Iino C, Chinda D, Mikami T, Sakuraba H, Fukuda S. Association between reactive oxygen species production in neutrophils and liver fibrosis in the general population. J Clin Biochem Nutr 2023; 73:214-220. [PMID: 37970548 PMCID: PMC10636577 DOI: 10.3164/jcbn.23-46] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/19/2023] [Accepted: 07/22/2023] [Indexed: 11/17/2023] Open
Abstract
Fibrosis, induced by reactive oxygen species (ROS) production in neutrophils, has harmful effects on the liver and various other organs. However, little is known about the association between liver fibrosis and ROS levels in neutrophils in the general population. This large-scale epidemiological study aimed to determine the association between liver fibrosis and neutrophil-generated ROS levels according to age and sex in the general population. This cross-sectional study included 1,000 participants from a district health promotion project. Participants were grouped based on sex (male; female) and age (young, <65 years; old, ≥65 years). The four groups were as follows: male, young (n = 289); male, old (n = 100); female, young (n = 425); and female, old (n = 186). Liver fibrosis was assessed using the fibrosis 4 (FIB-4) index, aspartate aminotransferase-to-platelet ratio index (APRI), and non-alcoholic fatty liver disease (NAFLD) fibrosis score (NFS). Basal and stimulated ROS were considered in the analysis. Multiple linear analyses showed (1) significant positive correlations between all liver fibrosis scores and basal ROS in the young groups, and (2) significant negative correlations between NFS and stimulated ROS in females. Preventing liver fibrosis through neutrophil-related immune system enhancement may avert the development of lifestyle-related diseases and infections.
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Affiliation(s)
- Satoshi Sato
- Department of Gastroenterology and Hematology, Hirosaki University Graduate School of Medicine, 5 Zaifu-cho, Hirosaki, Aomori 036-8562, Japan
| | - Shigeyuki Nakaji
- Center of Healthy Aging Innovation, Hirosaki University Graduate School of Medicine, 5 Zaifu-cho, Hirosaki, Aomori 036-8562, Japan
| | - Kaori Sawada
- Center of Healthy Aging Innovation, Hirosaki University Graduate School of Medicine, 5 Zaifu-cho, Hirosaki, Aomori 036-8562, Japan
| | - Naoki Akimoto
- Department of Gastroenterology and Hematology, Hirosaki University Graduate School of Medicine, 5 Zaifu-cho, Hirosaki, Aomori 036-8562, Japan
| | - Tetsuyuki Tateda
- Department of Gastroenterology and Hematology, Hirosaki University Graduate School of Medicine, 5 Zaifu-cho, Hirosaki, Aomori 036-8562, Japan
| | - Masatoshi Kaizuka
- Department of Gastroenterology and Hematology, Hirosaki University Graduate School of Medicine, 5 Zaifu-cho, Hirosaki, Aomori 036-8562, Japan
| | - Takafumi Sasada
- Department of Gastroenterology and Hematology, Hirosaki University Graduate School of Medicine, 5 Zaifu-cho, Hirosaki, Aomori 036-8562, Japan
| | - Hiroki Nomiya
- Department of Gastroenterology and Hematology, Hirosaki University Graduate School of Medicine, 5 Zaifu-cho, Hirosaki, Aomori 036-8562, Japan
| | - Go Igarashi
- Department of Gastroenterology and Hematology, Hirosaki University Graduate School of Medicine, 5 Zaifu-cho, Hirosaki, Aomori 036-8562, Japan
| | - Chikara Iino
- Department of Gastroenterology and Hematology, Hirosaki University Graduate School of Medicine, 5 Zaifu-cho, Hirosaki, Aomori 036-8562, Japan
| | - Daisuke Chinda
- Department of Gastroenterology and Hematology, Hirosaki University Graduate School of Medicine, 5 Zaifu-cho, Hirosaki, Aomori 036-8562, Japan
| | - Tatsuya Mikami
- Center of Healthy Aging Innovation, Hirosaki University Graduate School of Medicine, 5 Zaifu-cho, Hirosaki, Aomori 036-8562, Japan
| | - Hirotake Sakuraba
- Department of Gastroenterology and Hematology, Hirosaki University Graduate School of Medicine, 5 Zaifu-cho, Hirosaki, Aomori 036-8562, Japan
| | - Shinsaku Fukuda
- Department of Gastroenterology and Hematology, Hirosaki University Graduate School of Medicine, 5 Zaifu-cho, Hirosaki, Aomori 036-8562, Japan
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Lee JH, Kim KM, Jung EH, Lee HR, Yang JH, Cho SS, Ki SH. Parkin-Mediated Mitophagy by TGF-β Is Connected with Hepatic Stellate Cell Activation. Int J Mol Sci 2023; 24:14826. [PMID: 37834275 PMCID: PMC10573240 DOI: 10.3390/ijms241914826] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2023] [Revised: 09/27/2023] [Accepted: 09/28/2023] [Indexed: 10/15/2023] Open
Abstract
Hepatic stellate cells (HSCs) are the main contributors to the development and progression of liver fibrosis. Parkin is an E3 ligase involved in mitophagy mediated by lysosomes that maintains mitochondrial homeostasis. Unfortunately, there is little information regarding the regulation of parkin by transforming growth factor-β (TGF-β) and its association with HSC trans-differentiation. This study showed that parkin is upregulated in fibrotic conditions and elucidated the underlying mechanism. Parkin was observed in the cirrhotic region of the patient liver tissues and visualized using immunostaining and immunoblotting of mouse fibrotic liver samples and primary HSCs. The role of parkin-mediated mitophagy in hepatic fibrogenesis was examined using TGF-β-treated LX-2 cells with mitophagy inhibitor, mitochondrial division inhibitor 1. Parkin overexpression and its colocalization with desmin in human tissues were found. Increased parkin in fibrotic liver homogenates of mice was observed. Parkin was expressed more abundantly in HSCs than in hepatocytes and was upregulated under TGF-β. TGF-β-induced parkin was due to Smad3. TGF-β facilitated mitochondrial translocation, leading to mitophagy activation, reversed by mitophagy inhibitor. However, TGF-β did not change mitochondrial function. Mitophagy inhibitor suppressed profibrotic genes and HSC migration mediated by TGF-β. Collectively, parkin-involved mitophagy by TGF-β facilitates HSC activation, suggesting mitophagy may utilize targets for liver fibrosis.
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Affiliation(s)
- Ji Hyun Lee
- College of Pharmacy, Chosun University, Gwangju 61452, Republic of Korea (E.H.J.); (H.R.L.); (S.S.C.)
| | - Kyu Min Kim
- College of Pharmacy, Chosun University, Gwangju 61452, Republic of Korea (E.H.J.); (H.R.L.); (S.S.C.)
- Department of Biomedical Science, College of Natural Science, Chosun University, Gwangju 61452, Republic of Korea
| | - Eun Hee Jung
- College of Pharmacy, Chosun University, Gwangju 61452, Republic of Korea (E.H.J.); (H.R.L.); (S.S.C.)
| | - Hye Rim Lee
- College of Pharmacy, Chosun University, Gwangju 61452, Republic of Korea (E.H.J.); (H.R.L.); (S.S.C.)
| | - Ji Hye Yang
- College of Korean Medicine, Dongshin University, Naju 58245, Republic of Korea;
| | - Sam Seok Cho
- College of Pharmacy, Chosun University, Gwangju 61452, Republic of Korea (E.H.J.); (H.R.L.); (S.S.C.)
| | - Sung Hwan Ki
- College of Pharmacy, Chosun University, Gwangju 61452, Republic of Korea (E.H.J.); (H.R.L.); (S.S.C.)
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10
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Abstract
Chronic liver diseases such as nonalcoholic fatty liver disease (NAFLD) or viral hepatitis are characterized by persistent inflammation and subsequent liver fibrosis. Liver fibrosis critically determines long-term morbidity (for example, cirrhosis or liver cancer) and mortality in NAFLD and nonalcoholic steatohepatitis (NASH). Inflammation represents the concerted response of various hepatic cell types to hepatocellular death and inflammatory signals, which are related to intrahepatic injury pathways or extrahepatic mediators from the gut-liver axis and the circulation. Single-cell technologies have revealed the heterogeneity of immune cell activation concerning disease states and the spatial organization within the liver, including resident and recruited macrophages, neutrophils as mediators of tissue repair, auto-aggressive features of T cells as well as various innate lymphoid cell and unconventional T cell populations. Inflammatory responses drive the activation of hepatic stellate cells (HSCs), and HSC subsets, in turn, modulate immune mechanisms via chemokines and cytokines or transdifferentiate into matrix-producing myofibroblasts. Current advances in understanding the pathogenesis of inflammation and fibrosis in the liver, mainly focused on NAFLD or NASH owing to the high unmet medical need, have led to the identification of several therapeutic targets. In this Review, we summarize the inflammatory mediators and cells in the diseased liver, fibrogenic pathways and their therapeutic implications.
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Affiliation(s)
- Linda Hammerich
- Department of Hepatology and Gastroenterology, Campus Virchow-Klinikum and Campus Charité Mitte, Charité - Universitätsmedizin Berlin, Berlin, Germany
| | - Frank Tacke
- Department of Hepatology and Gastroenterology, Campus Virchow-Klinikum and Campus Charité Mitte, Charité - Universitätsmedizin Berlin, Berlin, Germany.
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11
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Kim KM, Shin EJ, Yang JH, Ki SH. Integrative roles of sphingosine kinase in liver pathophysiology. Toxicol Res 2023; 39:549-564. [PMID: 37779595 PMCID: PMC10541397 DOI: 10.1007/s43188-023-00193-1] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2023] [Revised: 05/17/2023] [Accepted: 05/24/2023] [Indexed: 10/03/2023] Open
Abstract
Bioactive sphingolipids and enzymes that metabolize sphingolipid-related substances have been considered as critical messengers in various signaling pathways. One such enzyme is the crucial lipid kinase, sphingosine kinase (SphK), which mediates the conversion of sphingosine to the potent signaling substance, sphingosine-1-phosphate. Several studies have demonstrated that SphK metabolism is strictly regulated to maintain the homeostatic balance of cells. Here, we summarize the role of SphK in the course of liver disease and illustrate its effects on both physiological and pathological conditions of the liver. SphK has been implicated in a variety of liver diseases, such as steatosis, liver fibrosis, hepatocellular carcinoma, and hepatic failure. This study may advance the understanding of the cellular and molecular foundations of liver disease and establish therapeutic approaches via SphK modulation.
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Affiliation(s)
- Kyu Min Kim
- Department of Biomedical Science, College of Natural Science, Chosun University, Gwangju, 61452 Republic of Korea
| | - Eun Jin Shin
- Department of Biomedical Science, College of Natural Science, Chosun University, Gwangju, 61452 Republic of Korea
| | - Ji Hye Yang
- College of Korean Medicine, Dongshin University, Naju, Jeollanam-Do 58245 Republic of Korea
| | - Sung Hwan Ki
- College of Pharmacy, Chosun University, 309 Pilmun-Daero, Dong-Gu, Gwangju, 61452 Republic of Korea
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12
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Sato S, Iino C, Chinda D, Sasada T, Tateda T, Kaizuka M, Nomiya H, Igarashi G, Sawada K, Mikami T, Nakaji S, Sakuraba H, Fukuda S. Effect of Liver Fibrosis on Oral and Gut Microbiota in the Japanese General Population Determined by Evaluating the FibroScan-Aspartate Aminotransferase Score. Int J Mol Sci 2023; 24:13470. [PMID: 37686272 PMCID: PMC10487682 DOI: 10.3390/ijms241713470] [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: 07/26/2023] [Revised: 08/18/2023] [Accepted: 08/28/2023] [Indexed: 09/10/2023] Open
Abstract
The association between liver fibrosis and oral or gut microbiota has been studied before. However, epidemiological studies in the general population are limited owing to the difficulty of noninvasive liver-fibrosis assessment. FibroScan-asparate aminotransferase (FAST) scores can be used to accurately and non-invasively evaluate liver fibrosis. This study aimed to determine the association between liver fibrosis and oral or gut microbiota using the FAST score in the general population. After propensity score matching of 1059 participants based on sex, age, body mass index, homeostasis model assessment of insulin resistance, and triglyceride levels, 125 (non-liver-fibrosis group, 100; liver fibrosis group, 25) were included. The diversity of gut microbiota differed significantly between the two groups; however, no significant differences were noted in their oral microbiota. The liver fibrosis group showed an increase in the relative abundance of Fusobacteria strains and a decrease in the relative abundance of Faecalibacterium, with the presence of Fusicatenibacter in the gut microbiota. Feacalibacterium was not identified as an independent factor of liver fibrosis in adjusting the fatty liver index. In the general population, gut microbiota may be more involved in liver fibrosis than oral microbiota.
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Affiliation(s)
- Satoshi Sato
- Department of Gastroenterology and Hematology, Hirosaki University Graduate School of Medicine, Hirosaki 036-8562, Japan; (S.S.); (T.S.); (T.T.); (M.K.); (H.N.); (G.I.); (H.S.); (S.F.)
| | - Chikara Iino
- Department of Gastroenterology and Hematology, Hirosaki University Graduate School of Medicine, Hirosaki 036-8562, Japan; (S.S.); (T.S.); (T.T.); (M.K.); (H.N.); (G.I.); (H.S.); (S.F.)
| | - Daisuke Chinda
- Division of Endoscopy, Hirosaki University Graduate School of Medicine, Hirosaki 036-8562, Japan
| | - Takafumi Sasada
- Department of Gastroenterology and Hematology, Hirosaki University Graduate School of Medicine, Hirosaki 036-8562, Japan; (S.S.); (T.S.); (T.T.); (M.K.); (H.N.); (G.I.); (H.S.); (S.F.)
| | - Tetsuyuki Tateda
- Department of Gastroenterology and Hematology, Hirosaki University Graduate School of Medicine, Hirosaki 036-8562, Japan; (S.S.); (T.S.); (T.T.); (M.K.); (H.N.); (G.I.); (H.S.); (S.F.)
| | - Masatoshi Kaizuka
- Department of Gastroenterology and Hematology, Hirosaki University Graduate School of Medicine, Hirosaki 036-8562, Japan; (S.S.); (T.S.); (T.T.); (M.K.); (H.N.); (G.I.); (H.S.); (S.F.)
| | - Hiroki Nomiya
- Department of Gastroenterology and Hematology, Hirosaki University Graduate School of Medicine, Hirosaki 036-8562, Japan; (S.S.); (T.S.); (T.T.); (M.K.); (H.N.); (G.I.); (H.S.); (S.F.)
| | - Go Igarashi
- Department of Gastroenterology and Hematology, Hirosaki University Graduate School of Medicine, Hirosaki 036-8562, Japan; (S.S.); (T.S.); (T.T.); (M.K.); (H.N.); (G.I.); (H.S.); (S.F.)
| | - Kaori Sawada
- Department of Preemptive Medicine, Hirosaki University Graduate School of Medicine, Hirosaki 036-8562, Japan; (K.S.); (T.M.)
| | - Tatsuya Mikami
- Department of Preemptive Medicine, Hirosaki University Graduate School of Medicine, Hirosaki 036-8562, Japan; (K.S.); (T.M.)
| | - Shigeyuki Nakaji
- Center of Healthy Aging Innovation, Hirosaki University Graduate School of Medicine, Hirosaki 036-8562, Japan;
| | - Hirotake Sakuraba
- Department of Gastroenterology and Hematology, Hirosaki University Graduate School of Medicine, Hirosaki 036-8562, Japan; (S.S.); (T.S.); (T.T.); (M.K.); (H.N.); (G.I.); (H.S.); (S.F.)
| | - Shinsaku Fukuda
- Department of Gastroenterology and Hematology, Hirosaki University Graduate School of Medicine, Hirosaki 036-8562, Japan; (S.S.); (T.S.); (T.T.); (M.K.); (H.N.); (G.I.); (H.S.); (S.F.)
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13
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Lingas EC. Hematological Abnormalities in Cirrhosis: A Narrative Review. Cureus 2023; 15:e39239. [PMID: 37337504 PMCID: PMC10277171 DOI: 10.7759/cureus.39239] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 05/18/2023] [Indexed: 06/21/2023] Open
Abstract
Liver cirrhosis remains a major public health issue. Liver fibrosis leading to cirrhosis is the terminal stage of various chronic liver diseases. Inflammatory cytokines are involved in the pathogenesis. Patients with cirrhosis often have hematological abnormalities, such as anemia and thrombocytopenia, which have multifactorial etiologies. Anemia in cirrhosis could be related to bleeding leading to iron deficiency anemia or other nutritional anemia such as vitamin B12 and folate deficiency. The pathophysiology of thrombocytopenia in liver cirrhosis has been postulated to range from splenic sequestration to bone marrow suppression from toxic agents, such as alcohol. It often complicates management due to the risk of bleeding with severely low platelets. This review aimed to highlight pathogenesis of liver cirrhosis, hematological abnormalities in liver cirrhosis, and their clinical significance.
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14
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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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15
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Wang H, Wu J, Ma L, Bai Y, Liu J. Theroleofinterleukin-1familyinfibroticdiseases. Cytokine 2023; 165:156161. [PMID: 36921509 DOI: 10.1016/j.cyto.2023.156161] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/27/2022] [Accepted: 02/02/2023] [Indexed: 03/17/2023]
Abstract
Fibrosis refers to the phenomenon that fibrous connective tissues are increased and parenchymal cells are decreased in organs or tissues such as lung, heart, liver, kidney, skin and so on. It usually occurs at the late stage of repair of chronic or recurrent tissue damage. Fibrotic disease is the main factor for the morbidity and mortality of all tissues and organ systems. Long-term fibrosis can lead to organ and tissue dysfunction and even failure. Interleukin -1 family cytokines are a series of classical inflammatory factors and involved in the occurrence and development process of multiple fibrotic diseases, its biological function, relationship with diseases and application are more and more favored by scientists from various countries. So far, 11 cytokines and 10 receptors of IL-1 family have been identified. In this paper, the cytokines, receptors, signaling pathways and biological functions of IL-1 family are summarized, and the correlation with fibrosis diseases is analyzed.
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Affiliation(s)
- Haoran Wang
- Department of Orthopedics, The Second Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu 210011, China.
| | - Ji Wu
- Department of Orthopaedics, Sir Run Run Hospital of Nanjing Medical University, Nanjing, China.
| | - Li Ma
- Cancer Medical Center, The Second Affiliated Hospital of Nanjing Medical University, Nanjing, 210011 Jiangsu, China.
| | - Yunfeng Bai
- Department of Orthopedics, The Second Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu 210011, China.
| | - Jun Liu
- Department of Orthopedics, The Second Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu 210011, China.
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16
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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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17
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Wilczynski E, Sasson E, Eliav U, Navon G, Nevo U. Quantitative Magnetization EXchange MRI Measurement of Liver Fibrosis Model in Rodents. J Magn Reson Imaging 2023; 57:285-295. [PMID: 35521943 PMCID: PMC10084184 DOI: 10.1002/jmri.28228] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2022] [Revised: 04/26/2022] [Accepted: 04/26/2022] [Indexed: 02/04/2023] Open
Abstract
BACKGROUND Quantitative MRI can elucidate the complex microstructural changes in liver disease. The Magnetization EXchange (MEX) method estimates macromolecular fraction, such as collagen, and can potentially aid in this task. HYPOTHESIS MEX sequence, and its derived quantitative macromolecular fraction, should correlate with collagen deposition in rodents liver fibrosis model. STUDY TYPE Prospective. ANIMAL MODEL Sixteen adults Sprague-Dawley rats and 13 adults C57BL/6 strain mice given carbon tetrachloride (CCl4 ) twice weekly for 6 or 8 weeks. FIELD STRENGTH/SEQUENCE A 7 T scanner. MEX sequence (selective suppression and magnetization exchange), spin-echo and gradient-echo scans. ASSESSMENT Macromolecular fraction (F) and T1 were extracted for each voxel and for livers' regions of interest, additional to calculating the percentage of F > 0.1 pixels in F maps (high-F). Histology included staining with hematoxylin and eosin, picrosirius red and Masson trichrome, and inflammation scoring. Quantitative collagen percentage calculated using automatic spectral-segmentation of the staining. STATISTICAL TESTS Comparing CCl4 -treated groups and controls using Welch's t-test and paired t-test between different time points. Pearson's correlation used between ROI MEX parameters or high-F fraction, and quantitative histology. F or T1 , and inflammation scores were tested with one-sided t-test. P < 0.05 was deemed significant. RESULTS Rats: F values were significantly different after 6 weeks of treatment (0.10 ± 0.02) compared to controls (0.080 ± 0.003). After 8 weeks, F significantly increased (0.11 ± 0.02) in treated animals, while controls are not significant (0.0814 ± 0.0008, P = 0.079). F correlated with quantitative histology (R = 0.87), and T1 was significantly different between inflammation scores (1: 1332 ± 224 msec, 2: 2007 ± 464 msec). Mice: F was significantly higher (0.062 ± 0.006) in treatment group compared to controls (0.042 ± 0.006). F and high-F fraction correlated with quantitative histology (R = 0.88; R = 0.84). T1 was significantly different between inflammation scores (1:1366 ± 99 msec; 2:1648 ± 45 msec). DATA CONCLUSION MEX extracted parameters are sensitive to collagen deposition and inflammation and are correlated with histology results of mouse and rat liver fibrosis model. EVIDENCE LEVEL 1 TECHNICAL EFFICACY: Stage 3.
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Affiliation(s)
- Ella Wilczynski
- Department of Biomedical Engineering, Faculty of Engineering, Tel Aviv University, Tel Aviv, Israel
| | - Efrat Sasson
- School of Chemistry, Faculty of Exact Sciences, Tel Aviv University, Tel Aviv, Israel
| | - Uzi Eliav
- School of Chemistry, Faculty of Exact Sciences, Tel Aviv University, Tel Aviv, Israel
| | - Gil Navon
- School of Chemistry, Faculty of Exact Sciences, Tel Aviv University, Tel Aviv, Israel
| | - Uri Nevo
- Department of Biomedical Engineering, Faculty of Engineering, Tel Aviv University, Tel Aviv, Israel.,Sagol School of Neuroscience, Faculty of Life Sciences, Tel Aviv University, Tel Aviv, Israel
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18
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PRDX6 inhibits hepatic stellate cells activation and fibrosis via promoting MANF secretion. Biomed Pharmacother 2022; 156:113931. [DOI: 10.1016/j.biopha.2022.113931] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2022] [Revised: 10/15/2022] [Accepted: 10/26/2022] [Indexed: 11/23/2022] Open
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19
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Park HJ, Seo KI, Lee SU, Han BH, Yun BC, Park ET, Lee J, Hwang H, Yoon M. Clinical usefulness of Mac-2 binding protein glycosylation isomer for diagnosing liver cirrhosis and significant fibrosis in patients with chronic liver disease: A retrospective single-center study. Medicine (Baltimore) 2022; 101:e30489. [PMID: 36221351 PMCID: PMC9542736 DOI: 10.1097/md.0000000000030489] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/22/2022] Open
Abstract
Accurate diagnosis of liver cirrhosis (LC) and significant fibrosis in patients with chronic liver disease (CLD) is important. The Mac-2 binding protein glycosylation isomer (M2BPGi) has emerged as a novel serum biomarker for liver fibrosis; however, insufficient clinical data of M2BPGi are available in patients with CLD. Therefore, we performed a retrospective cohort study to investigate the clinical usefulness of serum M2BPGi for assessing LC and significant fibrosis in CLD patients. We retrospectively reviewed the CLD patients with measured serum M2BPGi at Kosin University Gospel Hospital between January 2016 and December 2019. Multivariate logistic regression analyses were conducted to identify the independent factors associated with LC. The diagnostic power of serum M2BPGi for LC and significant fibrosis (≥F2) was evaluated and compared to that of other serum biomarkers using receiver operating characteristic curve and area under the curve (AUC). A total of 454 patients enrolled in this study. M2BPGi (adjusted odds ratio [aOR], 1.77; 95% confidence interval [CI], 1.52-2.07) and fibrosis index based on four factors (aOR, 1.23; 95% CI, 1.11-1.37) were identified as significant independent factors for LC. The AUC of M2BPGi for LC (0.866) and significant fibrosis (0.816) were comparable to those of fibrosis index based on four factors (0.860, 0.773), aspartate aminotransferase-to-platelet ratio index (0.806, 0.752), and gamma-glutamyl transpeptidase-to-platelet ratio (0.759, 0.710). The optimal cut-off values for M2BPGi for LC and significant fibrosis were 1.37 and 0.89, respectively. Serum M2BPGi levels were significantly correlated with liver stiffness measurements (ρ = 0.778). Serum M2BPGi is a reliable noninvasive method for the assessment of LC and significant fibrosis in patients with CLD.
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Affiliation(s)
- Hyun Joon Park
- Department of Internal Medicine, Kosin University College of Medicine, Busan, South Korea
- Chang Kee-Ryo Memorial Liver Institute, Kosin University College of Medicine, Busan, South Korea
| | - Kwang Il Seo
- Department of Internal Medicine, Kosin University College of Medicine, Busan, South Korea
- Chang Kee-Ryo Memorial Liver Institute, Kosin University College of Medicine, Busan, South Korea
- *Correspondence: Kwang Il Seo, MD, PhD, Department of Internal Medicine, Kosin University College of Medicine, 262 Gamcheon-ro, Seo-gu, Busan, 49267, South Korea. (e-mail: )
| | - Sang Uk Lee
- Department of Internal Medicine, Kosin University College of Medicine, Busan, South Korea
- Chang Kee-Ryo Memorial Liver Institute, Kosin University College of Medicine, Busan, South Korea
| | - Byung Hoon Han
- Department of Internal Medicine, Kosin University College of Medicine, Busan, South Korea
- Chang Kee-Ryo Memorial Liver Institute, Kosin University College of Medicine, Busan, South Korea
| | - Byung Cheol Yun
- Department of Internal Medicine, Kosin University College of Medicine, Busan, South Korea
- Chang Kee-Ryo Memorial Liver Institute, Kosin University College of Medicine, Busan, South Korea
| | - Eun Taek Park
- Department of Internal Medicine, Kosin University College of Medicine, Busan, South Korea
- Chang Kee-Ryo Memorial Liver Institute, Kosin University College of Medicine, Busan, South Korea
| | - Jinwook Lee
- Department of Internal Medicine, Kosin University College of Medicine, Busan, South Korea
- Chang Kee-Ryo Memorial Liver Institute, Kosin University College of Medicine, Busan, South Korea
| | - Hyunyong Hwang
- Department of Laboratory Medicine, Kosin University College of Medicine, Busan, South Korea
| | - Myunghee Yoon
- Division of Hepatobiliary and Pancreas Surgery, Department of Surgery Biomedical Research Institute, Pusan National University, College of Medicine, Busan, South Korea
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Hirano R, Rogalla P, Farrell C, Hoppel B, Fujisawa Y, Ohyu S, Hattori C, Sakaguchi T. Development of a classification method for mild liver fibrosis using non-contrast CT image. Int J Comput Assist Radiol Surg 2022; 17:2041-2049. [PMID: 35930131 DOI: 10.1007/s11548-022-02724-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/07/2022] [Accepted: 07/19/2022] [Indexed: 11/24/2022]
Abstract
PURPOSE Detection of early-stage liver fibrosis has direct clinical implications on patient management and treatment. The aim of this paper is to develop a non-invasive, cost-effective method for classifying liver disease between "non-fibrosis" (F0) and "fibrosis" (F1-F4), and to evaluate the classification performance quantitatively. METHODS Image data from 75 patients who underwent a simultaneous liver biopsy and non-contrast CT examination were used for this study. Non-contrast CT image texture features such as wavelet-based features, standard deviation of variance filter, and mean CT number were calculated in volumes of interest (VOIs) positioned within the liver parenchyma. In addition, a combined feature was calculated using logistic regression with L2-norm regularization to further improve fibrosis detection. Based on the final pathology from the liver biopsy, the patients were labelled either as "non-fibrosis" or "fibrosis". Receiver-operating characteristic (ROC) curve, area under the ROC curve (AUROC), specificity, sensitivity, and accuracy were determined for the algorithm to differentiate between "non-fibrosis" and "fibrosis". RESULTS The combined feature showed the highest classification performance with an AUROC of 0.86, compared to the wavelet-based feature (AUROC, 0.76), the standard deviation of variance filter (AUROC, 0.65), and mean CT number (AUROC, 0.84). The combined feature's specificity, sensitivity, and accuracy were 0.66, 0.88, and 0.76, respectively, showing the most promising results. CONCLUSION A new non-invasive and cost-effective method was developed to classify liver diseases between "non-fibrosis" (F0) and "fibrosis" (F1-F4). The proposed method makes it possible to detect liver fibrosis in asymptomatic patients using non-contrast CT images for better patient management and treatment.
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Affiliation(s)
- Ryo Hirano
- Research and Development Center, Canon Medical Systems Corporation, Otawara, Japan.
| | - Patrik Rogalla
- Joint Department of Medical Imaging, University of Toronto, Toronto, Canada
| | | | | | - Yasuko Fujisawa
- Research and Development Center, Canon Medical Systems Corporation, Otawara, Japan
| | - Shigeharu Ohyu
- Research and Development Center, Canon Medical Systems Corporation, Otawara, Japan
| | - Chihiro Hattori
- Research and Development Center, Canon Medical Systems Corporation, Otawara, Japan
| | - Takuya Sakaguchi
- Research and Development Center, Canon Medical Systems Corporation, Otawara, Japan
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21
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Raissa R, Riawan W, Safitri A, Masruri M, Beltran MAG, Aulanniam A. In vitro and in vivo study: Ethanolic extract leaves of Azadirachta indica Juss. variant of Indonesia and Philippines suppresses tumor growth of hepatocellular carcinoma by inhibiting IL-6/STAT3 signaling. F1000Res 2022; 11:477. [PMID: 37829248 PMCID: PMC10565427 DOI: 10.12688/f1000research.109557.1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 03/30/2022] [Indexed: 10/14/2023] Open
Abstract
Background: Azadirachta indica Juss. has been shown to suppress cancer progression through a variety of mechanisms. In order to treat cancer progression, cancer immunotherapy is used to stimulate the immune system where immunosuppression is present in tumor microenvironments. Many cancer cells produce a lot of interleukin-6 (IL-6) and signal transducer activator of transcription 3 (STAT3). STAT3 plays a key role in suppressing the expression of critical immune activation regulators. IL-6-mediated STAT3 activation is common in the tumor microenvironment. Inhibiting the IL-6/STAT3 signaling pathway has become a therapeutic option for cancer progression. As vimentin is also expressed in hepatic stellate cells boosting cancer survival. We focused on the precise effect of extract from leaves of Azadirachta indica Juss, on inhibiting the IL-6/STAT3 signaling cascade on hepatocellular carcinoma by in vitro and in vivo study. Methods: In the in vitro study, the effect of Azadirachta indica Juss. variant Indonesia and Philippines against the expression of IL-6 and STAT3 was examined in liver cancer cell line. In the in vivo study, 24 male rats ( Rattus norvegicus) strain Wistar were induced by diethylnitrosamine and carbon tetrachloride (CCl 4). Based on the therapy given, the groups were divided into negative control, positive control, Indonesia extract, and Philippine extract. Expression of IL-6, STAT3, and vimentin were tested using immunohistochemistry staining. The data were analyzed using analysis of variance, which was then followed by the Tukey test. Results: Statistically significant difference in IL-6 and STAT3 was observed between the treatment groups and positive control group by in vitro study and in vivo study. Generally, there is no significant difference between treatment using Indonesian and Philippine leaves. Conclusion: Both therapy doses of Azadirachta indica variant in Indonesia and Philippines were able to reduce IL-6, STAT3 and vimentin expression of hepatocellular carcinoma cell by in vitro and in vivo experiment.
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Affiliation(s)
- Ricadonna Raissa
- Doctoral Program of Chemistry, Faculty of Mathematics and Natural Science, Universitas Brawijaya, Malang, East Java, Indonesia
| | - Wibi Riawan
- Department of Biochemistry, Faculty of Medicine, Universitas Brawijaya, Malang, East Java, Indonesia
| | - Anna Safitri
- Department of Chemistry, Faculty of Mathematics and Natural Science, Universitas Brawijaya, Malang, East Java, Indonesia
- Research Center for Smart Molecules of Natural Genetic Resources (SMONAGENES), Universitas Brawijaya, Malang, East Java, Indonesia
| | - Masruri Masruri
- Department of Chemistry, Faculty of Mathematics and Natural Science, Universitas Brawijaya, Malang, East Java, Indonesia
| | | | - Aulanniam Aulanniam
- Department of Chemistry, Faculty of Mathematics and Natural Science, Universitas Brawijaya, Malang, East Java, Indonesia
- Department of Biochemistry, Faculty of Veterinary Medicine, Universitas Brawijaya, Malang, East Java, Indonesia
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22
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Sun Y, Liu B, Xie J, Jiang X, Xiao B, Hu X, Xiang J. Aspirin attenuates liver fibrosis by suppressing TGF‑β1/Smad signaling. Mol Med Rep 2022; 25:181. [PMID: 35322863 PMCID: PMC8972277 DOI: 10.3892/mmr.2022.12697] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2021] [Accepted: 02/28/2022] [Indexed: 12/13/2022] Open
Abstract
Aspirin reduces the liver fibrosis index and inflammation in patients and rats. However, the specific mechanism underlying the effects of aspirin are yet to be elucidated. The present study aimed to investigate the effects of aspirin on thioacetamide (TAA)-induced liver fibrosis in rats and hepatic stellate cells (HSCs) via the TGF-β1/Smad signaling pathway. Liver fibrosis was induced in Sprague Dawley rats by intraperitoneal injection of 200 mg/kg TAA twice weekly for 8 weeks. Aspirin (30 mg/kg) was administered to rats by gavage once every morning over a period of 8 weeks. Masson's trichrome and H&E staining were used to detect and analyze the pathological changes in liver tissues. Western blot analysis and immunohistochemistry were applied to determine the protein expression levels of α-smooth muscle actin (α-SMA), collagen I, TGF-β1, phosphorylated (p)-Smad2 and p-Smad3. In addition, reverse transcription-quantitative PCR was performed to detect the mRNA expression levels of α-SMA, collagen type I α 1 chain (COL1A1) and TGF-β1. The results demonstrated that treatment with aspirin significantly reduced the serum levels of alanine aminotransferase, aspartate aminotransferase and hydroxyproline in the TAA + aspirin compared with that in the TAA group. In the rat liver fibrosis model, pathological changes in liver tissues were improved following treatment with aspirin. Similarly, a marked decrease was observed in protein expression levels of α-SMA, collagen I, TGF-β1, p-Smad2 and p-Smad3. Furthermore, aspirin administration decreased the mRNA levels of α-SMA, COL1A1 and TGF-β1. In addition, HSCs were treated with different concentrations of aspirin (10, 20 and 40 mmol/l), and the protein expression levels of α-SMA, collagen I, TGF-β1, p-Smad2 and p-Smad3 were reduced in a dose-dependent manner. Overall, the present study showed that aspirin attenuated liver fibrosis and reduced collagen production by suppressing the TGF-β1/Smad signaling pathway, thus revealing a potential mechanism of aspirin in the treatment of liver fibrosis.
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Affiliation(s)
- Yimin Sun
- Department of Gastrointestinal Surgery, The First Affiliated Hospital of Yangtze University, Jingzhou, Hubei 434000, P.R. China
| | - Bingyan Liu
- Department of Neurology, The First Affiliated Hospital of Yangtze University, Jingzhou, Hubei 434000, P.R. China
| | - Jianping Xie
- Department of Gastrointestinal Surgery, The First Affiliated Hospital of Yangtze University, Jingzhou, Hubei 434000, P.R. China
| | - Xuefeng Jiang
- Department of Gastrointestinal Surgery, The First Affiliated Hospital of Yangtze University, Jingzhou, Hubei 434000, P.R. China
| | - Baolai Xiao
- Department of Gastrointestinal Surgery, The First Affiliated Hospital of Yangtze University, Jingzhou, Hubei 434000, P.R. China
| | - Xiaomiao Hu
- Department of Gastrointestinal Surgery, The First Affiliated Hospital of Yangtze University, Jingzhou, Hubei 434000, P.R. China
| | - Jinjian Xiang
- Department of Gastrointestinal Surgery, The First Affiliated Hospital of Yangtze University, Jingzhou, Hubei 434000, P.R. China
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Ding Z, Cheng R, Liu J, Zhao Y, Ge W, Yang Y, Xu X, Wang S, Zhang J. The suppression of pancreatic lipase-related protein 2 ameliorates experimental hepatic fibrosis in mice. Biochim Biophys Acta Mol Cell Biol Lipids 2022; 1867:159102. [PMID: 34995790 DOI: 10.1016/j.bbalip.2021.159102] [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: 06/05/2021] [Revised: 11/20/2021] [Accepted: 12/15/2021] [Indexed: 11/24/2022]
Abstract
Quiescent hepatic stellate cells (HSCs) store vitamin A as lipid droplets in the cytoplasm. When activated, these cells lose vitamin A and exhibit an increased capacity for proliferation, mobility, contractility, and the synthesis of collagen and other components of the extracellular matrix. Our previous work demonstrated that the lipid hydrolytic gene pancreatic lipase-related protein 2 (mPlrp2) is involved in the hydrolysis of retinyl esters (REs) in the liver. Here, we showed that bile duct ligation (BDL)-induced liver injury triggered the conditional expression of mPlrp2 in livers and describe evidence of a strong relationship between the expression of mPlrp2 and Acta-2, a marker for activated HSCs. RNA interference targeting mPlrp2 inhibited HSC activation and ameliorated hepatic fibrosis induced by BDL in mice. Liver BDL markedly reduced the adenosine level and increased the ratio between S-adenosyl-L-methionine (SAM) and S-adenosyl-L-homocysteine (SAH). Chromatin immunoprecipitation (ChIP) analysis demonstrated an increase in trimethylated histone H3K4 at the mPlrp2 promoter in BDL mice, which was associated with the conditional expression of mPlrp2 in the liver. SAM, a well-known hepatoprotective substance, inhibited mPlrp2 expression and reduced RE hydrolysis in mice with hepatic fibrosis induced by chronic CCl4 treatment. Liver fibrosis induced by CCl4 or BDL was improved in Plrp2-/- mice. Our results reveal that mPlrp2 suppression is a potential approach for treating hepatic fibrosis.
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Affiliation(s)
- Zhao Ding
- Center for Molecular Metabolism, Nanjing University of Science & Technology, Nanjing, China
| | - Rui Cheng
- Center for Molecular Metabolism, Nanjing University of Science & Technology, Nanjing, China
| | - Junhao Liu
- Center for Molecular Metabolism, Nanjing University of Science & Technology, Nanjing, China
| | - Yang Zhao
- Center for Molecular Metabolism, Nanjing University of Science & Technology, Nanjing, China
| | - Wenhao Ge
- Center for Molecular Metabolism, Nanjing University of Science & Technology, Nanjing, China
| | - Yunxia Yang
- Center for Molecular Metabolism, Nanjing University of Science & Technology, Nanjing, China
| | - Xi Xu
- Center for Molecular Metabolism, Nanjing University of Science & Technology, Nanjing, China
| | - Shiming Wang
- Center for Molecular Metabolism, Nanjing University of Science & Technology, Nanjing, China
| | - Jianfa Zhang
- Center for Molecular Metabolism, Nanjing University of Science & Technology, Nanjing, China.
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24
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Yan Z, Da Q, Li Z, Lin Q, Yi J, Su Y, Yu G, Ren Q, Liu X, Lin Z, Qu J, Yin W, Liu J. Inhibition of NEK7 Suppressed Hepatocellular Carcinoma Progression by Mediating Cancer Cell Pyroptosis. Front Oncol 2022; 12:812655. [PMID: 35223495 PMCID: PMC8866693 DOI: 10.3389/fonc.2022.812655] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2021] [Accepted: 01/07/2022] [Indexed: 02/05/2023] Open
Abstract
NIMA-related kinase 7 (NEK7) is a serine/threonine kinase involved in cell cycle progression via mitotic spindle formation and cytokinesis. It has been related to multiple cancers, including breast cancer, hepatocellular cancer, lung cancer, and colorectal cancer. Moreover, NEK7 regulated the NLRP3 inflammasome to activate Caspase-1, resulting in cell pyroptosis. In the present study, we investigated whether NEK7 is involved in cell pyroptosis of hepatocellular carcinoma (HCC). Interestingly, we found that NEK7 was significantly related to expression of pyroptosis marker GSDMD in HCC. We found that NEK7 expression was significantly correlated with GSDMD expression in bioinformatics analysis, and NEK7 expression was significantly co-expressed with GSDMD in our HCC specimens. Cell viability, migration, and invasion capacity of HCC cell lines were inhibited, and the tumor growth in the xenograft mouse model was also suppressed following knockdown of NEK7 expression. Mechanistic studies revealed that knockdown of NEK7 in HCC cells significantly upregulated the expression of pyroptosis markers such as NLRP3, Caspase-1, and GSDMD. Coculture of HCC cells stimulated hepatic stellate cell activation by increasing p-ERK1/2 and α-SMA. Knockdown of NEK7 impaired the stimulation of HCC cells. Therefore, downregulation of NEK7 inhibited cancer–stromal interaction by triggering cancer cell pyroptosis. Taken together, this study highlights the functional role of NEK7-regulated pyroptosis in tumor progression and cancer–stromal interaction of HCC, suggesting NEK7 as a potential target for a new therapeutic strategy of HCC treatment.
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Affiliation(s)
- Zilong Yan
- Department of Hepatobiliary Surgery, Peking University Shenzhen Hospital, Shenzhen-Peking University-Hong Kong University of Science and Technology Medical Center, Shenzhen, China.,Department of Hepatobiliary Surgery, Peking University Shenzhen Hospital, Shenzhen, China
| | - Qingen Da
- Department of Hepatobiliary Surgery, Peking University Shenzhen Hospital, Shenzhen-Peking University-Hong Kong University of Science and Technology Medical Center, Shenzhen, China.,Department of Cardiovascular Surgery, Peking University Shenzhen Hospital, Shenzhen-Peking University-Hong Kong University of Science and Technology Medical Center, Shenzhen, China
| | - Zhangfu Li
- Department of Hepatobiliary Surgery, Peking University Shenzhen Hospital, Shenzhen-Peking University-Hong Kong University of Science and Technology Medical Center, Shenzhen, China.,Department of Hepatobiliary Surgery, Peking University Shenzhen Hospital, Shenzhen, China
| | - Qirui Lin
- Department of Hepatobiliary Surgery, Peking University Shenzhen Hospital, Shenzhen, China
| | - Jing Yi
- Department of Hepatobiliary Surgery, Peking University Shenzhen Hospital, Shenzhen, China
| | - Yanze Su
- Department of Hepatobiliary Surgery, Peking University Shenzhen Hospital, Shenzhen, China
| | - Guanyin Yu
- Department of Pathology, Peking University Shenzhen Hospital, Shenzhen, China
| | - Qingqi Ren
- Department of Hepatobiliary Surgery, Peking University Shenzhen Hospital, Shenzhen, China
| | - Xu Liu
- Department of Hepatobiliary Surgery, Peking University Shenzhen Hospital, Shenzhen, China
| | - Zewei Lin
- Department of Hepatobiliary Surgery, Peking University Shenzhen Hospital, Shenzhen, China
| | - Jianhua Qu
- Department of Hepatobiliary Surgery, Peking University Shenzhen Hospital, Shenzhen, China
| | - Weihua Yin
- Department of Pathology, Peking University Shenzhen Hospital, Shenzhen, China
| | - Jikui Liu
- Department of Hepatobiliary Surgery, Peking University Shenzhen Hospital, Shenzhen, China
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25
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XSSJS inhibits hepatic fibrosis by promoting the mir29b-3p/VEGFA axis in vitro and in vivo. Biosci Rep 2022; 42:230729. [PMID: 35118493 PMCID: PMC8881647 DOI: 10.1042/bsr20212241] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/24/2021] [Revised: 01/21/2022] [Accepted: 02/02/2022] [Indexed: 11/22/2022] Open
Abstract
Hepatic pathological angiogenesis (HPA) is the key event of hepatic fibrosis (HF). Xueshisanjia powder (XSSJS), a Chinese herbal compound, is beneficial for alleviating pathological angiogenesis of hepatic tissue. The present study attempts to reveal the effect and mechanism of XSSJS via regulating miR-29b-3p/VEGFA axis against pathological angiogenesis in HF. In in vitro model, human embryonic kidney 293T cells were transfected with miR-29b-3p mimics, whereby the expression of miR-29b-3p was tested by real-time quantitative polymerase chain reaction (RT-qPCR), ensued by Luciferase assay determining the relationship between miR-29b-3p and vascular endothelial cell growth factor A (VEGFA). In addition, miR-29b-3p mimic transfected into the activated hepatic stellate cell T6 (HSC-T6). The Cell-Counting-Kit 8 (CCK8) and 5-Bromodeoxyuridine (BrdU) staining were first utilized to detect the antiproliferative efficiency of XSSJS following the XSSJS compound serum intervention, and then used to observe the expression of transforming growth factor-β (TGF-β), VEGFA, platelet-derived growth factor (PDGF) via RT-PCR, Western blot (WB), and Immunofluorescence (IF) methods. During the in vivo model, XSSJS with boil-free granules were fed to Wistar rats with liver fibrosis caused by intraperitoneal injection of pig serum followed by the transfection of miR-29b-3p adeno-associated virus (AAV). Hematoxylin–Eosin (HE) staining was used for histopathology assessment. The expression of miR-29b-3p, VEGFA, PDGF, TGF-β have been investigated in liver tissue using RT-PCR, WB, IF. The results verified that XSSJS could up-regulate miR-29b-3p and suppress the expression of VEGFA, PDGA, and TGF-β. In mechanism, miR-29b-3p primarily targeted the 3′UTR of VEGFA. In conclusion, XSSJS could modulate miR-29b-3p/VEGFA axis to inhibit the pathological angiogenesis of HF.
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26
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Brougham-Cook A, Jain I, Kukla DA, Masood F, Kimmel H, Ryoo H, Khetani SR, Underhill GH. High throughput interrogation of human liver stellate cells reveals microenvironmental regulation of phenotype. Acta Biomater 2022; 138:240-253. [PMID: 34800715 PMCID: PMC8738161 DOI: 10.1016/j.actbio.2021.11.015] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2021] [Revised: 11/10/2021] [Accepted: 11/11/2021] [Indexed: 01/17/2023]
Abstract
Liver fibrosis is a common feature of progressive liver disease and is manifested as a dynamic series of alterations in both the biochemical and biophysical properties of the liver. Hepatic stellate cells (HSCs) reside within the perisinusoidal space of the liver sinusoid and are one of the main drivers of liver fibrosis, yet it remains unclear how changes to the sinusoidal microenvironment impact HSC phenotype in the context of liver fibrosis. Cellular microarrays were used to examine and deconstruct the impacts of bio-chemo-mechanical changes on activated HSCs in vitro. Extracellular matrix (ECM) composition and stiffness were found to act individually and in combination to regulate HSC fibrogenic phenotype and proliferation. Hyaluronic acid and collagen III promoted elevated collagen I expression while collagen IV mediated a decrease. Previously activated HSCs exhibited reduced lysyl oxidase (Lox) expression as array substrate stiffness increased, with less dependence on ECM composition. Collagens III and IV increased HSC proliferation, whereas hyaluronic acid had the opposite effect. Meta-analysis performed on these data revealed distinct phenotypic clusters (e.g. low fibrogenesis/high proliferation) as a direct function of their microenvironmental composition. Notably, soft microenvironments mimicking healthy tissue (1 kPa), promoted higher levels of intracellular collagen I and Lox expression in activated HSCs, compared to stiff microenvironments mimicking fibrotic tissue (25 kPa). Collectively, these data suggest potential HSC functional adaptations in response to specific bio-chemo-mechanical changes relevant towards the development of therapeutic interventions. These findings also underscore the importance of the microenvironment when interrogating HSC behavior in healthy, disease, and treatment settings. STATEMENT OF SIGNIFICANCE: In this work we utilized high-throughput cellular microarray technology to systematically interrogate the complex interactions between HSCs and their microenvironment in the context of liver fibrosis. We observed that HSC phenotype is regulated by ECM composition and stiffness, and that these phenotypes can be classified into distinct clusters based on their microenvironmental context. Moreover, the range of these phenotypic responses to microenvironmental stimuli is substantial and a direct consequence of the combinatorial pairing of ECM protein and stiffness signals. We also observed a novel role for microenvironmental context in affecting HSC responses to potential fibrosis therapeutics.
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Affiliation(s)
- Aidan Brougham-Cook
- University of Illinois at Urbana-Champaign, Department of Bioengineering, 1406W Green St, Urbana, IL 61801, United States.
| | - Ishita Jain
- University of Illinois at Urbana-Champaign, Department of Bioengineering, 1406W Green St, Urbana, IL 61801, United States.
| | - David A Kukla
- University of Illinois Chicago, Department of Bioengineering, United States.
| | - Faisal Masood
- University of Illinois at Urbana-Champaign, Department of Bioengineering, 1406W Green St, Urbana, IL 61801, United States.
| | - Hannah Kimmel
- University of Illinois at Urbana-Champaign, Department of Bioengineering, 1406W Green St, Urbana, IL 61801, United States.
| | - Hyeon Ryoo
- University of Illinois at Urbana-Champaign, Department of Bioengineering, 1406W Green St, Urbana, IL 61801, United States.
| | - Salman R Khetani
- University of Illinois Chicago, Department of Bioengineering, United States.
| | - Gregory H Underhill
- University of Illinois at Urbana-Champaign, Department of Bioengineering, 1406W Green St, Urbana, IL 61801, United States.
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Lim AR, Ghajar CM. Thorny ground, rocky soil: Tissue-specific mechanisms of tumor dormancy and relapse. Semin Cancer Biol 2022; 78:104-123. [PMID: 33979673 PMCID: PMC9595433 DOI: 10.1016/j.semcancer.2021.05.007] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2021] [Revised: 04/30/2021] [Accepted: 05/04/2021] [Indexed: 02/07/2023]
Abstract
Disseminated tumor cells (DTCs) spread systemically yet distinct patterns of metastasis indicate a range of tissue susceptibility to metastatic colonization. Distinctions between permissive and suppressive tissues are still being elucidated at cellular and molecular levels. Although there is a growing appreciation for the role of the microenvironment in regulating metastatic success, we have a limited understanding of how diverse tissues regulate DTC dormancy, the state of reversible quiescence and subsequent awakening thought to contribute to delayed relapse. Several themes of microenvironmental regulation of dormancy are beginning to emerge, including vascular association, co-option of pre-existing niches, metabolic adaptation, and immune evasion, with tissue-specific nuances. Conversely, DTC awakening is often associated with injury or inflammation-induced activation of the stroma, promoting a proliferative environment with DTCs following suit. We review what is known about tissue-specific regulation of tumor dormancy on a tissue-by-tissue basis, profiling major metastatic organs including the bone, lung, brain, liver, and lymph node. An aerial view of the barriers to metastatic growth may reveal common targets and dependencies to inform the therapeutic prevention of relapse.
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Affiliation(s)
- Andrea R Lim
- Public Health Sciences Division/Translational Research Program, Fred Hutchinson Cancer Research Center, Seattle, WA, USA; Graduate Program in Molecular and Cellular Biology, University of Washington/Fred Hutchinson Cancer Research Center, Seattle, WA, USA; Human Biology Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.
| | - Cyrus M Ghajar
- Public Health Sciences Division/Translational Research Program, Fred Hutchinson Cancer Research Center, Seattle, WA, USA; Human Biology Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.
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Fu K, Wang C, Ma C, Zhou H, Li Y. The Potential Application of Chinese Medicine in Liver Diseases: A New Opportunity. Front Pharmacol 2021; 12:771459. [PMID: 34803712 PMCID: PMC8600187 DOI: 10.3389/fphar.2021.771459] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2021] [Accepted: 10/19/2021] [Indexed: 12/12/2022] Open
Abstract
Liver diseases have been a common challenge for people all over the world, which threatens the quality of life and safety of hundreds of millions of patients. China is a major country with liver diseases. Metabolic associated fatty liver disease, hepatitis B virus and alcoholic liver disease are the three most common liver diseases in our country, and the number of patients with liver cancer is increasing. Therefore, finding effective drugs to treat liver disease has become an urgent task. Chinese medicine (CM) has the advantages of low cost, high safety, and various biological activities, which is an important factor for the prevention and treatment of liver diseases. This review systematically summarizes the potential of CM in the treatment of liver diseases, showing that CM can alleviate liver diseases by regulating lipid metabolism, bile acid metabolism, immune function, and gut microbiota, as well as exerting anti-liver injury, anti-oxidation, and anti-hepatitis virus effects. Among them, Keap1/Nrf2, TGF-β/SMADS, p38 MAPK, NF-κB/IκBα, NF-κB-NLRP3, PI3K/Akt, TLR4-MyD88-NF-κB and IL-6/STAT3 signaling pathways are mainly involved. In conclusion, CM is very likely to be a potential candidate for liver disease treatment based on modern phytochemistry, pharmacology, and genomeproteomics, which needs more clinical trials to further clarify its importance in the treatment of liver diseases.
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Affiliation(s)
| | | | | | | | - Yunxia Li
- State Key Laboratory of Southwestern Chinese Medicine Resources, Key Laboratory of Standardization for Chinese Herbal Medicine, Ministry of Education, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, China
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Kong W, Lyu C, Liao H, Du Y. Collagen crosslinking: effect on structure, mechanics and fibrosis progression. Biomed Mater 2021; 16. [PMID: 34587604 DOI: 10.1088/1748-605x/ac2b79] [Citation(s) in RCA: 27] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2021] [Accepted: 09/29/2021] [Indexed: 02/07/2023]
Abstract
Biophysical properties of extracellular matrix (ECM), such as matrix stiffness, viscoelasticity and matrix fibrous structure, are emerging as important factors that regulate progression of fibrosis and other chronic diseases. The biophysical properties of the ECM can be rapidly and profoundly regulated by crosslinking reactions in enzymatic or non-enzymatic manners, which further alter the cellular responses and drive disease progression. In-depth understandings of crosslinking reactions will be helpful to reveal the underlying mechanisms of fibrosis progression and put forward new therapeutic targets, whereas related reviews are still devoid. Here, we focus on the main crosslinking mechanisms that commonly exist in a plethora of chronic diseases (e.g. fibrosis, cancer, osteoarthritis) and summarize current understandings including the biochemical reaction, the effect on ECM properties, the influence on cellular behaviors, and related studies in disease model establishment. Potential pharmaceutical interventions targeting the crosslinking process and relevant clinical studies are also introduced. Limitations of pharmaceutical development may be due to the lack of systemic investigations related to the influence on crosslinking mechanism from micro to macro level, which are discussed in the last section. We also propose the unclarified questions regarding crosslinking mechanisms and potential challenges in crosslinking-targeted therapeutics development.
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Affiliation(s)
- Wenyu Kong
- Department of Biomedical Engineering, School of Medicine, Tsinghua-Peking Center for Life Sciences, Tsinghua University, Beijing 100084, People's Republic of China
| | - Cheng Lyu
- Department of Biomedical Engineering, School of Medicine, Tsinghua-Peking Center for Life Sciences, Tsinghua University, Beijing 100084, People's Republic of China
| | - Hongen Liao
- Department of Biomedical Engineering, School of Medicine, Tsinghua University, Beijing 100084, People's Republic of China
| | - Yanan Du
- Department of Biomedical Engineering, School of Medicine, Tsinghua-Peking Center for Life Sciences, Tsinghua University, Beijing 100084, People's Republic of China
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Zhao J, Miao J, Wei X, Guo L, Li P, Lei J, Wang J, Zhu B, Wang L, Jia J. Traditional Chinese Medicine Ganshuang Granules Attenuate CCl 4 -Induced Hepatic Fibrosis by Modulating Gut Microbiota. Chem Biodivers 2021; 18:e2100520. [PMID: 34585845 DOI: 10.1002/cbdv.202100520] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2021] [Accepted: 08/30/2021] [Indexed: 12/17/2022]
Abstract
Gut dysbiosis contributes to hepatic fibrosis. Emerging evidence revealed the major role of traditional Chinese medicine (TCM) in gut microbiota homeostasis. Here, we aimed to investigate the anti-fibrotic activity and underlying mechanism of ganshuang granules (GS), particularly regarding gut microbiota homeostasis. CCl4 -induced hepatic fibrosis models were allocated into 4 groups receiving normal saline (model), 1.0, 2.0, or 4.0 g/kg GS for 5 weeks. As result, GS treatment alleviated liver injury in CCl4 -induced hepatic fibrosis, presenting as decreases of the liver index, alanine aminotransferase, and aspartate transaminase. Histological staining and expression revealed that the enhanced oxidative stress, inflammatory and hepatic fibrosis in CCl4 -induced models were attenuated by GS. Immunohistochemical staining showed that tight junction-associated proteins in intestinal mucosa were up-regulated by GS. 16S rRNA sequencing showed that GS rebalanced the gut dysbiosis manifested as improving alpha and beta diversity of gut microbiota, reducing the ratio of Firmicutes to Bacteroidetes, and regulating the relative abundance of various bacteria. In summary, GS decreased the intestinal permeability and rebalanced the gut microbiota to reduce the oxidative stress and inflammation, eventually attenuating CCl4 -induced hepatic fibrosis.
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Affiliation(s)
- Jie Zhao
- Department of Integrated Traditional Chinese and Western Medicine, Tianjin Second People's Hospital, No.7, Sudi Nan Road, Naikai District, Tianjin, 300192, China
| | - Jing Miao
- Department of Integrated Traditional Chinese and Western Medicine, Tianjin Second People's Hospital, No.7, Sudi Nan Road, Naikai District, Tianjin, 300192, China
| | - Xin Wei
- Graduate School, Tianjin University of Traditional Chinese Medicine, No. 10, Poyanghu Road, Town West Area, Jinghai District, Tianjin, 301617, China
| | - Liying Guo
- Department of Integrated Traditional Chinese and Western Medicine, Tianjin Second People's Hospital, No.7, Sudi Nan Road, Naikai District, Tianjin, 300192, China
| | - Peng Li
- Department of Integrated Traditional Chinese and Western Medicine, Tianjin Second People's Hospital, No.7, Sudi Nan Road, Naikai District, Tianjin, 300192, China
| | - Jinyan Lei
- Department of Integrated Traditional Chinese and Western Medicine, Tianjin Second People's Hospital, No.7, Sudi Nan Road, Naikai District, Tianjin, 300192, China
| | - Jing Wang
- Department of Integrated Traditional Chinese and Western Medicine, Tianjin Second People's Hospital, No.7, Sudi Nan Road, Naikai District, Tianjin, 300192, China
| | - Bo Zhu
- Department of Integrated Traditional Chinese and Western Medicine, Tianjin Second People's Hospital, No.7, Sudi Nan Road, Naikai District, Tianjin, 300192, China
| | - Li Wang
- Department of Pharmacy, Tianjin Second People's Hospital, No. 7, Sudi Nan Road, Naikai District, Tianjin, 300192, China
| | - Jianwei Jia
- Department of Integrated Traditional Chinese and Western Medicine, Tianjin Second People's Hospital, No.7, Sudi Nan Road, Naikai District, Tianjin, 300192, China
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Li X, Ramadori P, Pfister D, Seehawer M, Zender L, Heikenwalder M. The immunological and metabolic landscape in primary and metastatic liver cancer. Nat Rev Cancer 2021; 21:541-557. [PMID: 34326518 DOI: 10.1038/s41568-021-00383-9] [Citation(s) in RCA: 275] [Impact Index Per Article: 68.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 06/18/2021] [Indexed: 02/07/2023]
Abstract
The liver is the sixth most common site of primary cancer in humans, and generally arises in a background of cirrhosis and inflammation. Moreover, the liver is frequently colonized by metastases from cancers of other organs (particularly the colon) because of its anatomical location and organization, as well as its unique metabolic and immunosuppressive environment. In this Review, we discuss how the hepatic microenvironment adapts to pathologies characterized by chronic inflammation and metabolic alterations. We illustrate how these immunological or metabolic changes alter immunosurveillance and thus hinder or promote the development of primary liver cancer. In addition, we describe how inflammatory and metabolic niches affect the spreading of cancer metastases into or within the liver. Finally, we review the current therapeutic options in this context and the resulting challenges that must be surmounted.
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Affiliation(s)
- Xin Li
- Division of Chronic Inflammation and Cancer, German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Pierluigi Ramadori
- Division of Chronic Inflammation and Cancer, German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Dominik Pfister
- Division of Chronic Inflammation and Cancer, German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Marco Seehawer
- Department of Medical Oncology and Pneumology (Internal Medicine VIII), University Hospital Tuebingen, Tuebingen, Germany
- Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA
| | - Lars Zender
- Department of Medical Oncology and Pneumology (Internal Medicine VIII), University Hospital Tuebingen, Tuebingen, Germany
- Cluster of Excellence iFIT (EXC 2180) "Image-Guided and Functionally Instructed Tumor Therapies", University of Tuebingen, Tuebingen, Germany
- German Cancer Research Consortium (DKTK), Partner Site Tübingen, German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Mathias Heikenwalder
- Division of Chronic Inflammation and Cancer, German Cancer Research Center (DKFZ), Heidelberg, Germany.
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32
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Yang Y, Zhao Y, Zhang L, Zhang F, Li L. The Application of Mesenchymal Stem Cells in the Treatment of Liver Diseases: Mechanism, Efficacy, and Safety Issues. Front Med (Lausanne) 2021; 8:655268. [PMID: 34136500 PMCID: PMC8200416 DOI: 10.3389/fmed.2021.655268] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2021] [Accepted: 04/15/2021] [Indexed: 12/13/2022] Open
Abstract
Mesenchymal stem cell (MSC) transplantation is a novel treatment for liver diseases due to the roles of MSCs in regeneration, fibrosis inhibition and immune regulation. However, the mechanisms are still not completely understood. Despite the significant efficacy of MSC therapy in animal models and preliminary clinical trials, issues remain. The efficacy and safety of MSC-based therapy in the treatment of liver diseases remains a challenging issue that requires more investigation. This article reviews recent studies on the mechanisms of MSCs in liver diseases and the associated challenges and suggests potential future applications.
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Affiliation(s)
- Ya Yang
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China
| | - Yalei Zhao
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China
| | - Lingjian Zhang
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China
| | - Fen Zhang
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China
| | - Lanjuan Li
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China
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33
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Riaz F, Chen Q, Lu K, Osoro EK, Wu L, Feng L, Zhao R, Yang L, Zhou Y, He Y, Zhu L, Du X, Sadiq M, Yang X, Li D. Inhibition of miR-188-5p alleviates hepatic fibrosis by significantly reducing the activation and proliferation of HSCs through PTEN/PI3K/AKT pathway. J Cell Mol Med 2021; 25:4073-4087. [PMID: 33689215 PMCID: PMC8051718 DOI: 10.1111/jcmm.16376] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2020] [Revised: 01/29/2021] [Accepted: 02/03/2021] [Indexed: 02/06/2023] Open
Abstract
Persistent hepatic damage and chronic inflammation in liver activate the quiescent hepatic stellate cells (HSCs) and cause hepatic fibrosis (HF). Several microRNAs regulate the activation and proliferation of HSCs, thereby playing a critical role in HF progression. Previous studies have reported that miR‐188‐5p is dysregulated during the process of HF. However, the role of miR‐188‐5p in HF remains unclear. This study investigated the potential role of miR‐188‐5p in HSCs and HF. Firstly, we validated the miR‐188‐5p expression in primary cells isolated from liver of carbon tetrachloride (CCl4)‐induced mice, TGF‐β1‐induced LX‐2 cells, livers from 6‐month high‐fat diet (HFD)‐induced rat and 4‐month HFD‐induced mice NASH models, and human non‐alcoholic fatty liver disease (NAFLD) patients. Furthermore, we used miR‐188‐5p inhibitors to investigate the therapeutic effects of miR‐188‐5p inhibition in the HFD + CCl4 induced in vivo model and the potential role of miR‐188‐5p in the activation and proliferation of HSCs. This present study reported that miR‐188‐5p expression is significantly increased in the human NAFLD, HSCs isolated from liver of CCl4 induced mice, and in vitro and in vivo models of HF. Mimicking the miR‐188‐5p resulted in the up‐regulation of HSC activation and proliferation by directly targeting the phosphatase and tensin homolog (PTEN). Moreover, inhibition of miR‐188‐5p reduced the activation and proliferation markers of HSCs through PTEN/AKT pathway. Additionally, in vivo inhibition of miR‐188‐5p suppressed the HF parameters, pro‐fibrotic and pro‐inflammatory genes, and fibrosis. Collectively, our results uncover the pro‐fibrotic role of miR‐188‐5p. Furthermore, we demonstrated that miR‐188‐5p inhibition decreases the severity of HF by reducing the activation and proliferation of HSCs through PTEN/AKT pathway.
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Affiliation(s)
- Farooq Riaz
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Xi'an Jiaotong University Health Science Center, Xi'an, China.,Key Laboratory of Environment and Genes Related to Diseases, Ministry of Education, Xi'an, Shaanxi, China
| | - Qian Chen
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Xi'an Jiaotong University Health Science Center, Xi'an, China.,Key Laboratory of Environment and Genes Related to Diseases, Ministry of Education, Xi'an, Shaanxi, China
| | - Kaikai Lu
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Xi'an Jiaotong University Health Science Center, Xi'an, China.,Key Laboratory of Environment and Genes Related to Diseases, Ministry of Education, Xi'an, Shaanxi, China
| | - Ezra Kombo Osoro
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Xi'an Jiaotong University Health Science Center, Xi'an, China.,Key Laboratory of Environment and Genes Related to Diseases, Ministry of Education, Xi'an, Shaanxi, China
| | - Litao Wu
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Xi'an Jiaotong University Health Science Center, Xi'an, China.,Key Laboratory of Environment and Genes Related to Diseases, Ministry of Education, Xi'an, Shaanxi, China
| | - Lina Feng
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Xi'an Jiaotong University Health Science Center, Xi'an, China.,Key Laboratory of Environment and Genes Related to Diseases, Ministry of Education, Xi'an, Shaanxi, China
| | - Rong Zhao
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Xi'an Jiaotong University Health Science Center, Xi'an, China.,Key Laboratory of Environment and Genes Related to Diseases, Ministry of Education, Xi'an, Shaanxi, China
| | - Luyun Yang
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Xi'an Jiaotong University Health Science Center, Xi'an, China.,Key Laboratory of Environment and Genes Related to Diseases, Ministry of Education, Xi'an, Shaanxi, China
| | - Yimeng Zhou
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Xi'an Jiaotong University Health Science Center, Xi'an, China.,Key Laboratory of Environment and Genes Related to Diseases, Ministry of Education, Xi'an, Shaanxi, China
| | - Yingli He
- Department of Infectious Diseases, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
| | - Li Zhu
- Department of Infectious Diseases, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
| | - Xiaojuan Du
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Xi'an Jiaotong University Health Science Center, Xi'an, China.,Key Laboratory of Environment and Genes Related to Diseases, Ministry of Education, Xi'an, Shaanxi, China
| | - Muhammad Sadiq
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Xi'an Jiaotong University Health Science Center, Xi'an, China.,Key Laboratory of Environment and Genes Related to Diseases, Ministry of Education, Xi'an, Shaanxi, China
| | - Xudong Yang
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Xi'an Jiaotong University Health Science Center, Xi'an, China.,Key Laboratory of Environment and Genes Related to Diseases, Ministry of Education, Xi'an, Shaanxi, China
| | - Dongmin Li
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Xi'an Jiaotong University Health Science Center, Xi'an, China.,Key Laboratory of Environment and Genes Related to Diseases, Ministry of Education, Xi'an, Shaanxi, China
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Sayed EA, Badr G, Hassan KAH, Waly H, Ozdemir B, Mahmoud MH, Alamery S. Induction of liver fibrosis by CCl4 mediates pathological alterations in the spleen and lymph nodes: The potential therapeutic role of propolis. Saudi J Biol Sci 2021; 28:1272-1282. [PMID: 33613057 PMCID: PMC7878719 DOI: 10.1016/j.sjbs.2020.11.068] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2020] [Revised: 11/15/2020] [Accepted: 11/16/2020] [Indexed: 12/19/2022] Open
Abstract
In an animal models, carbon tetrachloride (CCl4) is a carcinogenic agent that causes liver fibrosis. The current study aims to investigate whether induction in liver-fibrosis by CCl4 in the mouse model could promote the initiation of fibrosis in lymph node and spleen due to sustained increase of inflammatory signals and also aimed to clarify the protective therapeutic effects of propolis. The male mice (BALB/c) were categorized into three experimental sets and each group involved 15 mice. Control group falls into first group; group-II and group-III were injected with CCl4 to induce liver-fibrosis and oral supplementation with propolis was provided in group-III for 4-weeks. A major improvement with hepatic collagen and α-smooth muscle actin (α-SMA) production was aligned with the activation of liver fibrosis from CCl4. Mice treated with CCl4 exhibited collagen deposition towards liver sections, pathological alterations in spleen and lymph node architectures, and a significantly increase the circulation of both T&B cells in secondary lymphoid organs. Mechanically, the secondary lymphoid organs treated with CCl4 in mice exposed a positive growth in α-SMA and collagen expression, increased in proinflammatory cytokine levels and a significant increase in TGF-β, NO and ROS levels. A manifest intensification in the expression of Nrf2, COX-2, and eNOS and upregulation of ASK1 and P38 phosphorylation. Interestingly, addition of propolis-treated CCl4 mice, substantially suppressed deposition of liver collagen, repealed inflammatory signals and resorted CCl4-mediated alterations in signaling cascades, thereby repairing the architectures of the secondary lymphoid organs. Our findings revealed benefits of propolis against fibrotic complications and enhancing secondary lymphoid organ architecture.
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Affiliation(s)
- Eman A. Sayed
- Zoology Department, Faculty of Science, Assiut University, Assiut, Egypt
- Laboratory of Immunology, Zoology Department, Faculty of Science, Assiut University, Assiut, Egypt
| | - Gamal Badr
- Zoology Department, Faculty of Science, Assiut University, Assiut, Egypt
- Laboratory of Immunology, Zoology Department, Faculty of Science, Assiut University, Assiut, Egypt
| | | | - Hanan Waly
- Zoology Department, Faculty of Science, Assiut University, Assiut, Egypt
| | - Betul Ozdemir
- Department of Cardiology, Faculty Medicine, Niğde Ömer Halisdemir University, Niğde, Turkey
| | - Mohamed H. Mahmoud
- Department of Biochemistry, College of Science, King Saud University, Riyadh, Saudi Arabia
| | - Salman Alamery
- Department of Biochemistry, College of Science, King Saud University, Riyadh, Saudi Arabia
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35
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Optimization of the isolation procedure and culturing conditions for hepatic stellate cells obtained from mouse. Biosci Rep 2021; 41:227415. [PMID: 33350435 PMCID: PMC7823195 DOI: 10.1042/bsr20202514] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2020] [Revised: 11/28/2020] [Accepted: 12/18/2020] [Indexed: 12/28/2022] Open
Abstract
Liver fibrosis (LF) mortality rate is approximately 2 million per year. Irrespective of the etiology of LF, a key element in its development is the transition of hepatic stellate cells (HSCs) from a quiescent phenotype to a myofibroblast-like cell with the production of fibrotic proteins. It is necessary to define optimal isolation and culturing conditions for good HSCs yield and proper phenotype preservation for studying the activation of HSCs in vitro. In the present study, the optimal conditions of HSC isolation and culture were examined to maintain the HSC’s undifferentiated phenotype. HSCs were isolated from Balb/c mice liver using Nycodenz, 8, 9.6, and 11%. The efficiency of the isolation procedure was evaluated by cell counting and purity determination by flow cytometry. Quiescent HSCs were cultured in test media supplemented with different combinations of fetal bovine serum (FBS), glutamine (GLN), vitamin A (vitA), insulin, and glucose. The cells were assessed at days 3 and 7 of culture by evaluating the morphology, proliferation using cell counting kit-8, lipid storage using Oil Red O (ORO) staining, expression of a-smooth muscle actin, collagen I, and lecithin-retinol acyltransferase by qRT-PCR and immunocytochemistry (ICC). The results showed that Nycodenz, at 9.6%, yielded the best purity and quantity of HSCs. Maintenance of HSC undifferentiated phenotype was achieved optimizing culturing conditions (serum-free Dulbecco’s Modified Eagle’s Medium (DMEM) supplemented with glucose (100 mg/dl), GLN (0.5 mM), vitA (100 μM), and insulin (50 ng/ml)) with a certain degree of proliferation allowing their perpetuation in culture. In conclusion, we have defined optimal conditions for HSCs isolation and culture.
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36
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Liao J, Zhang Z, Yuan Q, Liu Q, Kuang J, Fang Y, Hu X. A lncRNA Gpr137b-ps/miR-200a-3p/CXCL14 axis modulates hepatic stellate cell (HSC) activation. Toxicol Lett 2021; 336:21-31. [PMID: 33069761 DOI: 10.1016/j.toxlet.2020.10.001] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2020] [Revised: 08/31/2020] [Accepted: 10/02/2020] [Indexed: 01/08/2023]
Abstract
Hepatic fibrosis is the wound healing response upon the liver tissue damage caused by multiple stimuli. Targeting activated hepatic stellate cells (HSCs), the major extracellular matrix (ECM)-producing cells within the damaged liver, has been regarded as one of the main treatments for hepatic fibrosis. In the present study, we performed preliminary bioinformatics analysis attempting to identify possible factors related to hepatic fibrosis and found that lncRNA G protein-coupled receptor 137B (Gpr137b-ps) and C-X-C motif chemokine ligand 14 (CXCL14) showed to be markedly upregulated within carbon tetrachloride (CCl4)-caused hepatic fibrotic mice tissue samples and activated HSCs. CXCL14 The silencing of lncRNA Gpr137b-ps or CXCL14 alone could significantly improve CCl4-induced fibrotic changes in mice liver in vivo and collagen I and III release by HSCs and HSC proliferation in vitro. miR-200a-3p directly targeted lncRNA Gpr137b-ps and CXCL14, respectively. LncRNA Gpr137b-ps relieved miR-200a-3p-induced inhibition on CXCL14 expression via acting as a ceRNA. In HSCs, the effects of lncRNA Gpr137b-ps silencing on collagen I and III release by HSCs and HSC proliferation were significantly reversed by miR-200a-3p inhibition, and the effects of miR-200a-3p inhibition were reversed by CXCL14 silencing. In conclusion, we demonstrated a lncRNA Gpr137b-ps/miR-200a-3p/CXCL14 axis that modulates HSC activation and might exert an effect on the pathogenesis of liver fibrosis.
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Affiliation(s)
- Jinmao Liao
- Department of Hepatopathy, The Hunan Provincial People's Hospital, The First Affiliated Hospital of Hunan Normal University, Changsha 410005, Hunan, China
| | - Zheng Zhang
- Department of Hepatopathy, The Hunan Provincial People's Hospital, The First Affiliated Hospital of Hunan Normal University, Changsha 410005, Hunan, China
| | - Qi Yuan
- Department of Hepatopathy, The Hunan Provincial People's Hospital, The First Affiliated Hospital of Hunan Normal University, Changsha 410005, Hunan, China
| | - Qiong Liu
- Department of Hepatopathy, The Hunan Provincial People's Hospital, The First Affiliated Hospital of Hunan Normal University, Changsha 410005, Hunan, China
| | - Jia Kuang
- Department of Hepatopathy, The Hunan Provincial People's Hospital, The First Affiliated Hospital of Hunan Normal University, Changsha 410005, Hunan, China
| | - Yuan Fang
- Department of Hepatopathy, The Hunan Provincial People's Hospital, The First Affiliated Hospital of Hunan Normal University, Changsha 410005, Hunan, China
| | - Xiaoxuan Hu
- Department of Hepatopathy, The Hunan Provincial People's Hospital, The First Affiliated Hospital of Hunan Normal University, Changsha 410005, Hunan, China.
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37
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Healing gone wrong: convergence of hemostatic pathways and liver fibrosis? Clin Sci (Lond) 2020; 134:2189-2201. [PMID: 32844997 DOI: 10.1042/cs20191102] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2020] [Revised: 08/16/2020] [Accepted: 08/18/2020] [Indexed: 12/13/2022]
Abstract
Fibrosis results from a disordered wound healing response within the liver with activated hepatic stellate cells laying down dense, collagen-rich extracellular matrix that eventually restricts liver hepatic synthetic function and causes increased sinusoidal resistance. The end result of progressive fibrosis, cirrhosis, is associated with significant morbidity and mortality as well as tremendous economic burden. Fibrosis can be conceptualized as an aberrant wound healing response analogous to a chronic ankle sprain that is driven by chronic liver injury commonly over decades. Two unique aspects of hepatic fibrosis - the chronic nature of insult required and the liver's unique ability to regenerate - give an opportunity for pharmacologic intervention to stop or slow the pace of fibrosis in patients early in the course of their liver disease. Two potential biologic mechanisms link together hemostasis and fibrosis: focal parenchymal extinction and direct stellate cell activation by thrombin and Factor Xa. Available translational research further supports the role of thrombosis in fibrosis. In this review, we will summarize what is known about the convergence of hemostatic changes and hepatic fibrosis in chronic liver disease and present current preclinical and clinical data exploring the relationship between the two. We will also present clinical trial data that underscores the potential use of anticoagulant therapy as an antifibrotic factor in liver disease.
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38
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Gerhard GS, Davis B, Wu X, Hanson A, Wilhelmsen D, Piras IS, Still CD, Chu X, Petrick AT, DiStefano JK. Differentially expressed mRNAs and lncRNAs shared between activated human hepatic stellate cells and nash fibrosis. Biochem Biophys Rep 2020; 22:100753. [PMID: 32258441 PMCID: PMC7109412 DOI: 10.1016/j.bbrep.2020.100753] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2019] [Revised: 03/04/2020] [Accepted: 03/12/2020] [Indexed: 12/12/2022] Open
Abstract
We previously reported dysregulated expression of liver-derived messenger RNA (mRNA) and long noncoding RNA (lncRNA) in patients with advanced fibrosis resulting from nonalcoholic fatty liver disease (NAFLD). Here we sought to identify changes in mRNA and lncRNA levels associated with activation of hepatic stellate cells (HSCs), the predominant source of extracellular matrix production in the liver and key to NAFLD-related fibrogenesis. We performed expression profiling of mRNA and lncRNA from LX-2 cells, an immortalized human HSC cell line, treated to induce phenotypes resembling quiescent and myofibroblastic states. We identified 1964 mRNAs (1377 upregulated and 587 downregulated) and 1460 lncRNAs (665 upregulated and 795 downregulated) showing statistically significant evidence (FDR ≤0.05) for differential expression (fold change ≥|2|) between quiescent and activated states. Pathway analysis of differentially expressed genes showed enrichment for hepatic fibrosis (FDR = 1.35E-16), osteoarthritis (FDR = 1.47E-14), and axonal guidance signaling (FDR = 1.09E-09). We observed 127 lncRNAs/nearby mRNA pairs showing differential expression, the majority of which were dysregulated in the same direction. A comparison of differentially expressed transcripts in LX-2 cells with RNA-sequencing results from NAFLD patients with or without liver fibrosis revealed 1047 mRNAs and 91 lncRNAs shared between the two datasets, suggesting that some of the expression changes occurring during HSC activation can be observed in biopsied human tissue. These results identify lncRNA and mRNA expression patterns associated with activated human HSCs that appear to recapitulate human NAFLD fibrosis.
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Affiliation(s)
- Glenn S. Gerhard
- Lewis Katz School of Medicine, Temple University School of Medicine, Philadelphia, PA, 19140, USA
| | - Bethany Davis
- Diabetes and Fibrotic Disease Unit, Translational Genomics Research Institute, 445 N 5th Street, Phoenix, AZ, 85004, USA
| | - Xiumei Wu
- Diabetes and Fibrotic Disease Unit, Translational Genomics Research Institute, 445 N 5th Street, Phoenix, AZ, 85004, USA
| | - Amanda Hanson
- Diabetes and Fibrotic Disease Unit, Translational Genomics Research Institute, 445 N 5th Street, Phoenix, AZ, 85004, USA
| | - Danielle Wilhelmsen
- Diabetes and Fibrotic Disease Unit, Translational Genomics Research Institute, 445 N 5th Street, Phoenix, AZ, 85004, USA
| | - Ignazio S. Piras
- Diabetes and Fibrotic Disease Unit, Translational Genomics Research Institute, 445 N 5th Street, Phoenix, AZ, 85004, USA
| | | | - Xin Chu
- Geisinger Obesity Institute, Danville, PA, 17822, USA
| | | | - Johanna K. DiStefano
- Diabetes and Fibrotic Disease Unit, Translational Genomics Research Institute, 445 N 5th Street, Phoenix, AZ, 85004, USA
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Targeted delivery of hyaluronic acid nanomicelles to hepatic stellate cells in hepatic fibrosis rats. Acta Pharm Sin B 2020; 10:693-710. [PMID: 32322471 PMCID: PMC7161713 DOI: 10.1016/j.apsb.2019.07.003] [Citation(s) in RCA: 61] [Impact Index Per Article: 12.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2019] [Revised: 07/01/2019] [Accepted: 07/02/2019] [Indexed: 12/21/2022] Open
Abstract
Hepatic fibrosis is one kind of liver diseases with a high mortality rate and incidence. The activation and proliferation of hepatic stellate cells (HSCs) is the most fundamental reason of hepatic fibrosis. There are no specific and effective drug delivery carriers for the treatment of hepatic fibrosis at present. We found that when hepatic fibrosis occurs, the expression of CD44 receptors on the surface of HSCs is significantly increased. Based on this finding, we designed silibinin-loaded hyaluronic acid (SLB-HA) micelles to achieve the treatment of hepatic fibrosis. Meanwhile, we constructed liver fibrosis rat model using Sprague–Dawley rats. We demonstrated that HA micelles had specific uptake to HSCs in vitro while avoiding the distribution in normal liver cells and the phagocytosis of macrophages. Importantly, HA micelles showed a significant liver targeting effect in vivo, especially in fibrotic liver which highly expressed CD44 receptors. In addition, SLB-HA micelles could selectively kill activated HSCs, having an excellent anti-hepatic fibrosis effect in vivo and a significant sustained release effect, and also had a good biological safety and biocompatibility. Overall, HA micelles represented a novel nanomicelle system which showed great potentiality in anti-hepatic fibrosis drugs delivery.
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40
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Ruan Q, Wang H, Burke LJ, Bridle KR, Li X, Zhao CX, Crawford DHG, Roberts MS, Liang X. Therapeutic modulators of hepatic stellate cells for hepatocellular carcinoma. Int J Cancer 2020; 147:1519-1527. [PMID: 32010970 DOI: 10.1002/ijc.32899] [Citation(s) in RCA: 21] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2019] [Revised: 01/14/2020] [Accepted: 01/21/2020] [Indexed: 12/12/2022]
Abstract
Hepatocellular carcinoma (HCC) is the most common type of primary tumor in the liver and is a leading cause of cancer-related death worldwide. Activated hepatic stellate cells (HSCs) are key components of the HCC microenvironment and play an important role in the onset and progression of HCC through the secretion of growth factors and cytokines. Current treatment modalities that include chemotherapy, radiotherapy and ablation are able to activate HSCs and remodel the tumor microenvironment. Growing evidence has demonstrated that the complex interaction between activated HSCs and tumor cells can facilitate cancer chemoresistance and metastasis. Therefore, therapeutic targeting of activated HSCs has emerged as a promising strategy to improve treatment outcomes for HCC. This review summarizes the molecular mechanisms of HSC activation triggered by treatment modalities, the function of activated HSCs in HCC, as well as the crosstalk between tumor cells and activated HSCs. Pathways of activated HSC reduction are discussed, including inhibition, apoptosis, and reversion to the inactivated state. Finally, we outline the progress and challenges of therapeutic approaches targeting activated HSCs in the development of HCC treatment.
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Affiliation(s)
- Qi Ruan
- The University of Queensland Diamantina Institute, The University of Queensland, Woolloongabba, QLD, Australia
| | - Haolu Wang
- The University of Queensland Diamantina Institute, The University of Queensland, Woolloongabba, QLD, Australia.,Gallipoli Medical Research Institute, Greenslopes Private Hospital, Brisbane, QLD, Australia.,Faculty of Medicine, The University of Queensland, Brisbane, QLD, Australia.,Department of Biliary-Pancreatic Surgery, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Leslie J Burke
- The University of Queensland Diamantina Institute, The University of Queensland, Woolloongabba, QLD, Australia.,Gallipoli Medical Research Institute, Greenslopes Private Hospital, Brisbane, QLD, Australia.,Faculty of Medicine, The University of Queensland, Brisbane, QLD, Australia
| | - Kim R Bridle
- Gallipoli Medical Research Institute, Greenslopes Private Hospital, Brisbane, QLD, Australia.,Faculty of Medicine, The University of Queensland, Brisbane, QLD, Australia
| | - Xinxing Li
- Department of General Surgery, Changzheng Hospital, The Second Military Medical University, Shanghai, China
| | - Chun-Xia Zhao
- Australian Institute for Bioengineering and Nanotechnology, The University of Queensland, St Lucia, QLD, Australia
| | - Darrell H G Crawford
- Gallipoli Medical Research Institute, Greenslopes Private Hospital, Brisbane, QLD, Australia.,Faculty of Medicine, The University of Queensland, Brisbane, QLD, Australia
| | - Michael S Roberts
- The University of Queensland Diamantina Institute, The University of Queensland, Woolloongabba, QLD, Australia
| | - Xiaowen Liang
- The University of Queensland Diamantina Institute, The University of Queensland, Woolloongabba, QLD, Australia.,Gallipoli Medical Research Institute, Greenslopes Private Hospital, Brisbane, QLD, Australia.,Faculty of Medicine, The University of Queensland, Brisbane, QLD, Australia
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Li G, Lin J, Peng Y, Qin K, Wen L, Zhao T, Feng Q. Curcumol may reverse early and advanced liver fibrogenesis through downregulating the uPA/uPAR pathway. Phytother Res 2020; 34:1421-1435. [PMID: 31989700 DOI: 10.1002/ptr.6616] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2019] [Revised: 12/10/2019] [Accepted: 01/05/2020] [Indexed: 01/18/2023]
Abstract
Previous studies have suggested strong antifibrotic activity of curcumol in the liver; the underlying mechanisms of which, however, remain largely unknown. Aiming to investigate the role of curcumol in regulating early and advanced liver fibrosis, we designed a rat model with advanced liver fibrosis and cell model with an initial fibrotic stage. Model rats induced by CCl4 and alcohol presented advanced liver fibrosis with complete fibrous septa. The administration of curcumol (25 mg/kg or 50 mg/kg) resulted in reversal of liver fibrosis. Leptin-administrated liver sinusoidal endothelial cells presented defenestration and basement membrane components deposition, including laminin (LN) and type IV collagen (Col IV), the characteristics of capillarization by scanning electron microscopy and immunofluorescence assays. After treatment with curcumol (12.5, 25, or 50 mg/L), defenestration was restored and the levels of LN and Col IV were decreased, consistent with the rat model. Quantitative polymerase chain reaction and Western blot results revealed that increased levels of urokinase plasminogen activator (uPA)/ uPA receptor (uPAR) were observed both in vivo and in vitro, curcumol significantly reduced uPA/uPAR at both the mRNA and protein levels. Reduction of uPA/uPAR may be synergistic with matrix metallopeptidase 13 to reverse liver fibrogenesis. In conclusion, curcumol protects liver from phenotypic changes in the early and advanced fibrogenesis, possibly through uPA/uPAR pathway.
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Affiliation(s)
- Guiyu Li
- School of Basic Medical Sciences, Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan, China.,Department of Physiology, Faculty of Basic Medicine, Guangxi University of Chinese Medicine, Nanning, Guangxi, China
| | - Jiyong Lin
- Traditional Chinese Medicine Department, Shenzhen Center for Chronic Disease Control, Shenzhen, Guangdong, China
| | - Yue Peng
- Department of Physiology, Faculty of Basic Medicine, Guangxi University of Chinese Medicine, Nanning, Guangxi, China
| | - Kefeng Qin
- Department of Neurology, University of Chicago, Chicago, Illinois, USA
| | - Li Wen
- School of Basic Medical Sciences, Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan, China
| | - Tiejian Zhao
- Department of Physiology, Faculty of Basic Medicine, Guangxi University of Chinese Medicine, Nanning, Guangxi, China
| | - Quansheng Feng
- School of Basic Medical Sciences, Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan, China
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42
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Sha M, Gao Y, Deng C, Wan Y, Zhuang Y, Hu X, Wang Y. Therapeutic effects of AdipoRon on liver inflammation and fibrosis induced by CCl 4 in mice. Int Immunopharmacol 2020; 79:106157. [PMID: 31911372 DOI: 10.1016/j.intimp.2019.106157] [Citation(s) in RCA: 22] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2019] [Revised: 12/23/2019] [Accepted: 12/26/2019] [Indexed: 12/12/2022]
Abstract
OBJECTIVE The present work aimed to investigate the effects of AdipoRon against acute hepatitis and liver fibrosis induced by carbon tetrachloride (CCl4) in mice. METHODS C57BL/6 mice were randomly divided into five groups: control, model, AdipoRon groups (three different dosages), CCl4 was administered to induce acute hepatitis or liver fibrosis except for control group. The liver function, inflammatory and fibrotic profiles were evaluated by histology, immunohistochemistry and expression analysis, respectively. RESULTS AdipoRon pretreatment effectively attenuated oxidative stress and hepatocellular damage in acute CCl4 intoxication, demonstrated by marked reduction in peroxidation indexes [hepatic malonaldehyde (MDA), total nitric oxide synthase (tNOS), inducible nitric oxide synthase (iNOS)] and serum transaminases [alanine aminotransferase (ALT), aspartate transaminase (AST)]. Moreover, AdipoRon attenuated the severity of fibrosis induced by sustaining CCl4 challenge, with the alleviation of fibrous deposit and architecture distortion. The levels of canonical fibrosis markers (aminotransferases, hydroxyproline, hyaluronic acid, laminin) were also dose-dependently modulated by AdipoRon. Immunochemistry and expression analysis showed AdipoRon restrained the proinflammatory and profibrotic cytokines (TNF-α, TGF-β1, α-SMA, COL1A1), which somehow, ascribed the anti-fibrotic action to inhibiting hepatic stellate cells (HSCs) activation and quenching specific inflammation-fibrogenesis pathways. CONCLUSIONS AdipoRon demonstrates a remedial capacity against hepatitis and fibrosis induced by CCl4, potentially by inflammation restraint and HSC deactivation, which might pave the way for its therapeutical application in hepatic fibrosis.
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Affiliation(s)
- Min Sha
- School of Life Science and Technology, China Pharmaceutical University, Nanjing 210009, China
| | - Yaru Gao
- School of Life Science and Technology, China Pharmaceutical University, Nanjing 210009, China
| | - Can Deng
- School of Life Science and Technology, China Pharmaceutical University, Nanjing 210009, China
| | - Yuemeng Wan
- School of Life Science and Technology, China Pharmaceutical University, Nanjing 210009, China
| | - Yuan Zhuang
- School of Life Science and Technology, China Pharmaceutical University, Nanjing 210009, China
| | - Xiaochuan Hu
- Department of Occupational Disease, Qingdao Central Hospital, Shandong, China
| | - Ying Wang
- School of Life Science and Technology, China Pharmaceutical University, Nanjing 210009, China.
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43
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Dong X, Zeng Y, Liu Y, You L, Yin X, Fu J, Ni J. Aloe-emodin: A review of its pharmacology, toxicity, and pharmacokinetics. Phytother Res 2019; 34:270-281. [PMID: 31680350 DOI: 10.1002/ptr.6532] [Citation(s) in RCA: 149] [Impact Index Per Article: 24.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2019] [Revised: 09/22/2019] [Accepted: 10/03/2019] [Indexed: 12/12/2022]
Abstract
Aloe-emodin is a naturally anthraquinone derivative and an active ingredient of Chinese herbs, such as Cassia occidentalis, Rheum palmatum L., Aloe vera, and Polygonum multiflorum Thunb. Emerging evidence suggests that aloe-emodin exhibits many pharmacological effects, including anticancer, antivirus, anti-inflammatory, antibacterial, antiparasitic, neuroprotective, and hepatoprotective activities. These pharmacological properties lay the foundation for the treatment of various diseases, including influenza virus, inflammation, sepsis, Alzheimer's disease, glaucoma, malaria, liver fibrosis, psoriasis, Type 2 diabetes, growth disorders, and several types of cancers. However, an increasing number of published studies have reported adverse effects of aloe-emodin. The primary toxicity among these reports is hepatotoxicity and nephrotoxicity, which are of wide concern worldwide. Pharmacokinetic studies have demonstrated that aloe-emodin has a poor intestinal absorption, short elimination half-life, and low bioavailability. This review aims to provide a comprehensive summary of the pharmacology, toxicity, and pharmacokinetics of aloe-emodin reported to date with an emphasis on its biological properties and mechanisms of action.
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Affiliation(s)
- Xiaoxv Dong
- School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing, China
| | - Yawen Zeng
- School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing, China
| | - Yi Liu
- School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing, China
| | - Longtai You
- School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing, China
| | - Xingbin Yin
- School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing, China
| | - Jing Fu
- Beijing Institute of Traditional Chinese Medicine, Beijing Hospital of Traditional Chinese Medicine, Capital Medical University, Beijing, China
| | - Jian Ni
- Beijing Research Institute of Chinese Medicine, Beijing University of Chinese Medicine, Beijing, China
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44
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Kendall TJ, Duff CM, Boulter L, Wilson DH, Freyer E, Aitken S, Forbes SJ, Iredale JP, Hastie ND. Embryonic mesothelial-derived hepatic lineage of quiescent and heterogenous scar-orchestrating cells defined but suppressed by WT1. Nat Commun 2019; 10:4688. [PMID: 31615982 PMCID: PMC6794268 DOI: 10.1038/s41467-019-12701-9] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2017] [Accepted: 09/11/2019] [Indexed: 12/24/2022] Open
Abstract
Activated hepatic stellate cells (aHSCs) orchestrate scarring during liver injury, with putative quiescent precursor mesodermal derivation. Here we use lineage-tracing from development, through adult homoeostasis, to fibrosis, to define morphologically and transcriptionally discreet subpopulations of aHSCs by expression of WT1, a transcription factor controlling morphological transitions in organogenesis and adult homoeostasis. Two distinct populations of aHSCs express WT1 after injury, and both re-engage a transcriptional signature reflecting embryonic mesothelial origin of their discreet quiescent adult precursor. WT1-deletion enhances fibrogenesis after injury, through upregulated Wnt-signalling and modulation of genes central to matrix persistence in aHSCs, and augmentation of myofibroblastic transition. The mesothelial-derived lineage demonstrates punctuated phenotypic plasticity through bidirectional mesothelial-mesenchymal transitions. Our findings demonstrate functional heterogeneity of adult scar-orchestrating cells that can be whole-life traced back through specific quiescent adult precursors to differential origin in development, and define WT1 as a paradoxical regulator of aHSCs induced by injury but suppressing scarring.
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Affiliation(s)
- Timothy James Kendall
- MRC Human Genetics Unit, MRC Institute of Genetics & Molecular Medicine, The University of Edinburgh, Edinburgh, EH4 2XU, UK.
- University of Edinburgh Centre for Inflammation Research, The University of Edinburgh, Edinburgh, EH4 2XU, UK.
| | - Catherine Mary Duff
- MRC Human Genetics Unit, MRC Institute of Genetics & Molecular Medicine, The University of Edinburgh, Edinburgh, EH4 2XU, UK
- University of Edinburgh Centre for Inflammation Research, The University of Edinburgh, Edinburgh, EH4 2XU, UK
| | - Luke Boulter
- MRC Human Genetics Unit, MRC Institute of Genetics & Molecular Medicine, The University of Edinburgh, Edinburgh, EH4 2XU, UK
| | - David H Wilson
- MRC Human Genetics Unit, MRC Institute of Genetics & Molecular Medicine, The University of Edinburgh, Edinburgh, EH4 2XU, UK
| | - Elisabeth Freyer
- MRC Human Genetics Unit, MRC Institute of Genetics & Molecular Medicine, The University of Edinburgh, Edinburgh, EH4 2XU, UK
| | - Stuart Aitken
- MRC Human Genetics Unit, MRC Institute of Genetics & Molecular Medicine, The University of Edinburgh, Edinburgh, EH4 2XU, UK
| | - Stuart John Forbes
- MRC Centre for Regenerative Medicine, The University of Edinburgh, Edinburgh, EH4 2XU, UK
| | - John Peter Iredale
- University of Edinburgh Centre for Inflammation Research, The University of Edinburgh, Edinburgh, EH4 2XU, UK
- Senate House, University of Bristol, Bristol, BS8 1TH, UK
| | - Nicholas Dixon Hastie
- MRC Human Genetics Unit, MRC Institute of Genetics & Molecular Medicine, The University of Edinburgh, Edinburgh, EH4 2XU, UK
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Hepatic Stellate Cells Enhance Liver Cancer Progression by Inducing Myeloid-Derived Suppressor Cells through Interleukin-6 Signaling. Int J Mol Sci 2019; 20:ijms20205079. [PMID: 31614930 PMCID: PMC6834132 DOI: 10.3390/ijms20205079] [Citation(s) in RCA: 33] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2019] [Revised: 10/05/2019] [Accepted: 10/11/2019] [Indexed: 01/07/2023] Open
Abstract
The tumor microenvironment, which consists of fibroblasts, smooth muscle cells, endothelial cells, immune cells, epithelial cells, and extracellular matrices, plays a crucial role in tumor progression. Hepatic stellate cells (HSCs), a class of unique liver stromal cells, participate in immunomodulatory activities by inducing the apoptosis of effector T-cells, generation of regulatory T-cells, and development of myeloid-derived suppressor cells (MDSCs) to achieve long-term survival of islet allografts. This study provides in vitro and in vivo evidences that HSCs induce the generation of MDSCs to promote hepatocellular carcinoma (HCC) progression through interleukin (IL)-6 secretion. HSC-induced MDSCs highly expressed inducible nitric oxide synthase (iNOS) and arginase 1 mRNA and presented potent inhibitory T-cell immune responses in the tumor environment. Wild-type HSC-induced MDSCs expressed lower levels of CD40, CD86, and MHC II, and a higher level of B7-H1 surface molecules, as well as increased the production of iNOS and arginase I compared with MDSCs induced by IL-6-deficient HSCs in vitro. A murine-transplanted model of the liver tumor showed that HCCs cotransplanted with HSCs could significantly enhance the tumor area and detect more MDSCs compared with HCCs alone or HCCs cotransplanted with HSCs lacking IL-6. In conclusion, the results indicated that MDSCs are induced mainly by HSCs through IL-6 signaling and produce inhibitory enzymes to reduce T-cell immunity and then promote HCC progression within the tumor microenvironment. Therapies targeting the pathway involved in MDSC production or its immune-modulating pathways can serve as an alternative immunotherapy for HCC.
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46
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Ghasemi A, Zadsar M, Shaiegan M, Samiei S, Namvar A, Rasouli M, Moosanejad M. Human platelet antigens polymorphisms; association to the development of liver fibrosis in patients with chronic hepatitis C. J Med Virol 2019; 92:45-52. [PMID: 30729550 DOI: 10.1002/jmv.25423] [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: 11/13/2018] [Revised: 01/20/2019] [Accepted: 02/02/2019] [Indexed: 11/09/2022]
Abstract
Recently, human platelet antigens (HPAs) polymorphisms are found to play a role in susceptibility to hepatitis C virus (HCV) infection and fibrosis progression. The aim of the current study was to evaluate the possible association between the HPAs polymorphisms with liver fibrosis progression in HCV patients. HPAs polymorphisms genotyping was performed in HCV patients (n = 71) by Sequence-specific primers-polymerase chain reaction. Fibrosis progression was evaluated using the Metavir scoring system and liver biopsy, and the patients were assigned to two groups, namely, G1 (n = 35) that included patients with F1 (portal fibrosis without septa) or F2 (few septa) and G2 (n = 36) that comprised patients with F3 (numerous septa) or F4 (cirrhosis). The data analyses were performed using Pearson's χ2 test. The genotype frequency of HPA-3ab was significantly higher in G1 patients than in G2 patients (P = 0.015). No statistically significant differences were found between the patient groups (G1 and G2) regarding the distributions of the allelic and genotypic frequencies of the HPA-1, -2, -4, -5, and -15 systems. Multivariate logistic regression showed an independent association between the genotype HPA-3aa/BB and severe fibrosis (F3-F4), when compared with genotype HPA-3ab, independent of the viral genotype, high alanine transaminase, sex, age, time of infection, diabetes, and high cholesterol as risk factors. The present study suggested that the HPA-3ab genotype could be noticed as a potential protecting factor against hepatic fibrosis. Therefore, the antigenic variation of integrins might be considered as a part of the coordinated inflammatory process involved in the progression of liver fibrosis.
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Affiliation(s)
- Ali Ghasemi
- Department of Hematology, Blood Transfusion Research Center, High Institute for Research & Education in Transfusion Medicine, Tehran, Iran
| | - Maryam Zadsar
- Department of Microbiology, Blood Transfusion Research Center, High Institute for Research & Education in Transfusion Medicine, Tehran, Iran
| | - Mojgan Shaiegan
- Department of Immunohematology, Blood Transfusion Research Center, High Institute for Research & Education in Transfusion Medicine, Tehran, Iran
| | - Shahram Samiei
- Department of Biochemistry, Blood Transfusion Research Center, High Institute for Research & Education in Transfusion Medicine, Tehran, Iran
| | - Ali Namvar
- Department of Genetics, Iranian Comprehensive Hemophilia Care Center, Tehran, Iran
| | - Mahboobeh Rasouli
- Department of Biostatics, School of Public Health, Iran University of Medical Science, Tehran, Iran
| | - Molood Moosanejad
- Department of Clinical Consult, Blood Transfusion Research Center, High Institute for Research & Education in Transfusion Medicine, Tehran, Iran
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Abdel-Rahman N, Sharawy MH, Megahed N, El-Awady MS. Vitamin D3 abates BDL-induced cholestasis and fibrosis in rats via regulating Hedgehog pathway. Toxicol Appl Pharmacol 2019; 380:114697. [DOI: 10.1016/j.taap.2019.114697] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/01/2019] [Revised: 08/01/2019] [Accepted: 08/02/2019] [Indexed: 12/13/2022]
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48
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Shimoda H, Yagi H, Higashi H, Tajima K, Kuroda K, Abe Y, Kitago M, Shinoda M, Kitagawa Y. Decellularized liver scaffolds promote liver regeneration after partial hepatectomy. Sci Rep 2019; 9:12543. [PMID: 31467359 PMCID: PMC6715632 DOI: 10.1038/s41598-019-48948-x] [Citation(s) in RCA: 42] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/12/2019] [Accepted: 08/16/2019] [Indexed: 02/01/2023] Open
Abstract
The resectable liver volume is strictly limited and this reduces the number of patients who may be treated. Recently, “tissue/organ decellularization”, a new approach in bioengineering, has been investigated for its ability to produce a native organ scaffold by removing all the viable cells. Such a scaffold may support the repair of damaged or injured tissue. The purpose of this study was to evaluate the potential contribution of liver scaffolds to hepatic regeneration after hepatectomy. We sutured the partial liver scaffolds onto the surfaces of partially hepatectomized porcine livers and assessed their therapeutic potential by immune histological analysis at various time points. Animals were sacrificed after surgery and the implanted scaffolds were evaluated for the infiltration of various types of cells. Immune histochemical study showed that blood vessel-like structures, covered with CD31 positive endothelial cells and ALB positive cells, were present in all parts of the scaffolds at days 10 and 28. Blood inflow was observed in some of these ductal structures. More interestingly, CK19 and EpCAM positive cells appeared at day 10. These results suggest that the implantation of a decellularized organ scaffold could promote structural reorganization after liver resection.
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Affiliation(s)
- Hirofumi Shimoda
- Department of Surgery, Keio University, School of Medicine, Tokyo, Japan.
| | - Hiroshi Yagi
- Department of Surgery, Keio University, School of Medicine, Tokyo, Japan
| | - Hisanobu Higashi
- Department of Surgery, Keio University, School of Medicine, Tokyo, Japan
| | - Kazuki Tajima
- Department of Surgery, Keio University, School of Medicine, Tokyo, Japan
| | - Kohei Kuroda
- Department of Surgery, Keio University, School of Medicine, Tokyo, Japan
| | - Yuta Abe
- Department of Surgery, Keio University, School of Medicine, Tokyo, Japan
| | - Minoru Kitago
- Department of Surgery, Keio University, School of Medicine, Tokyo, Japan
| | - Masahiro Shinoda
- Department of Surgery, Keio University, School of Medicine, Tokyo, Japan
| | - Yuko Kitagawa
- Department of Surgery, Keio University, School of Medicine, Tokyo, Japan
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Itaba N, Kono Y, Watanabe K, Yokobata T, Oka H, Osaki M, Kakuta H, Morimoto M, Shiota G. Reversal of established liver fibrosis by IC-2-engineered mesenchymal stem cell sheets. Sci Rep 2019; 9:6841. [PMID: 31048740 PMCID: PMC6497888 DOI: 10.1038/s41598-019-43298-0] [Citation(s) in RCA: 15] [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: 10/12/2018] [Accepted: 04/17/2019] [Indexed: 12/17/2022] Open
Abstract
Chronic hepatitis viral infection, alcoholic intoxication, and obesity cause liver fibrosis, which progresses to decompensated liver cirrhosis, a disease for which medical demands cannot be met. Since there are currently no approved anti-fibrotic therapies for established liver fibrosis, the development of novel modalities is required to improve patient prognosis. In this study, we clarified the anti-fibrotic effects of cell sheets produced from human bone marrow-derived mesenchymal stem cells (MSCs) incubated on a temperature-sensitive culture dish with the chemical compound IC-2. Orthotopic transplantation of IC-2-engineered MSC sheets (IC-2 sheets) remarkably reduced liver fibrosis induced by chronic CCl4 administration. Further, the marked production of fibrolytic enzymes such as matrix metalloproteinase (MMP)-1 and MMP-14, as well as thioredoxin, which suppresses hepatic stellate cell activation, was observed in IC-2 sheets. Moreover, the anti-fibrotic effect of IC-2 sheets was much better than that of MSC sheets. Finally, knockdown experiments revealed that MMP-14 was primarily responsible for the reduction of liver fibrosis. Here, we show that IC-2 sheets could be a promising therapeutic option for established liver fibrosis.
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Affiliation(s)
- Noriko Itaba
- Division of Molecular and Genetic Medicine, Graduate School of Medicine, Tottori University, 86 Nishi-cho, Yonago, Tottori, 683-8503, Japan
| | - Yohei Kono
- KanonCure Inc., 86 Nishi-cho, Yonago, Tottori, 683-8503, Japan
| | - Kaori Watanabe
- Division of Molecular and Genetic Medicine, Graduate School of Medicine, Tottori University, 86 Nishi-cho, Yonago, Tottori, 683-8503, Japan
| | - Tsuyoshi Yokobata
- Division of Molecular and Genetic Medicine, Graduate School of Medicine, Tottori University, 86 Nishi-cho, Yonago, Tottori, 683-8503, Japan
| | - Hiroyuki Oka
- Research Initiative Center, Tottori University, 4-101 Koyama, Tottori, 680-8550, Japan
| | - Mitsuhiko Osaki
- Division of Pathological Biochemistry, Department of Biomedical Sciences, Faculty of Medicine, Tottori University, 86 Nishi-cho, Yonago, Tottori, 683-8503, Japan
| | - Hiroki Kakuta
- Division of Pharmaceutical Sciences, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, 1-1-1, Tsushima-naka, Kita-ku, Okayama, 700-8530, Japan
| | - Minoru Morimoto
- Research Initiative Center, Tottori University, 4-101 Koyama, Tottori, 680-8550, Japan
| | - Goshi Shiota
- Division of Molecular and Genetic Medicine, Graduate School of Medicine, Tottori University, 86 Nishi-cho, Yonago, Tottori, 683-8503, Japan.
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50
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Hassan SM, Taha AM, Eldahshan OA, Sayed AA, Salem AM. Modulatory effect of Prosopis juliflora leaves on hepatic fibrogenic and fibrolytic alterations induced in rats by thioacetamide. Biomed Pharmacother 2019; 115:108788. [PMID: 31035010 DOI: 10.1016/j.biopha.2019.108788] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2018] [Revised: 02/23/2019] [Accepted: 03/13/2019] [Indexed: 01/15/2023] Open
Abstract
This study investigated the antifibrotic effect of Prosopis juliflora leaves crude methanolic extract (PJEL) against thioacetamide (TAA)-induced liver fibrosis. The phytochemical analysis of PJEL was performed via HPLC/MS in association with evaluating its free radical scavenging and cytotoxic activities. The antifibrotic activity of PJEL was assessed by dividing Wistar rats into 8 groups: normal control, PJEL1-administered rats (2 mg/ Kg b.w.), PJEL2-administered rats (4 mg/ Kg b.w.), PJEL3-administered rats (8 mg/Kg b.w.), TAA-induced hepatic fibrosis, TTA + PJEL1, TAA + PJEL2, and TAA + PJEL3. Results indicated that PJEL crude methanolic extract is rich in polyphenolic compounds and alkaloids. PJEL exerted free radical scavenging activity with IC50 of 123.5 μg/mL and cytotoxic activity against a well-differentiated hepatocellular cell line (IC50 = 11.1 μg/mL). PJEL at a dose of 4 mg/Kg b.w. ameliorated serum ALT activity and improved serum albumin level and hepatic hydroxyproline content in association with a reduction in the fibrosis stage. PJEL elevated hepatic tumor necrosis factor-α and interleukin-6 contents with less necrosis grade. PJEL post-therapy ameliorated the relative expression of Bcl-2, Col1A1, Mmp-9, and Mmp-2 genes in liver. CONCLUSION: PJEL possesses a good therapeutic activity against TAA-induced liver fibrosis via enhancing extracellular matrix removal and stimulating hepatic regeneration to decrease hepatic necrosis.
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Affiliation(s)
- Salah M Hassan
- Department of Biochemistry, Faculty of Science, Ain Shams University, Cairo, Egypt
| | - AlShaimaa M Taha
- Department of Biochemistry, Faculty of Science, Ain Shams University, Cairo, Egypt.
| | - Omayma A Eldahshan
- Department of Pharmacognosy, Faculty of Pharmacy, Ain Shams University, Cairo, Egypt.
| | - Ahmed A Sayed
- Department of Biochemistry, Faculty of Science, Ain Shams University, Cairo, Egypt; Children's Cancer Hospital, 57357, Egypt
| | - Ahmed M Salem
- Department of Biochemistry, Faculty of Science, Ain Shams University, Cairo, Egypt
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