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Park HJ, Choi J, Kim H, Yang DY, An TH, Lee EW, Han BS, Lee SC, Kim WK, Bae KH, Oh KJ. Cellular heterogeneity and plasticity during NAFLD progression. Front Mol Biosci 2023; 10:1221669. [PMID: 37635938 PMCID: PMC10450943 DOI: 10.3389/fmolb.2023.1221669] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2023] [Accepted: 07/18/2023] [Indexed: 08/29/2023] Open
Abstract
Nonalcoholic fatty liver disease (NAFLD) is a progressive liver disease that can progress to nonalcoholic steatohepatitis (NASH), NASH-related cirrhosis, and hepatocellular carcinoma (HCC). NAFLD ranges from simple steatosis (or nonalcoholic fatty liver [NAFL]) to NASH as a progressive form of NAFL, which is characterized by steatosis, lobular inflammation, and hepatocellular ballooning with or without fibrosis. Because of the complex pathophysiological mechanism and the heterogeneity of NAFLD, including its wide spectrum of clinical and histological characteristics, no specific therapeutic drugs have been approved for NAFLD. The heterogeneity of NAFLD is closely associated with cellular plasticity, which describes the ability of cells to acquire new identities or change their phenotypes in response to environmental stimuli. The liver consists of parenchymal cells including hepatocytes and cholangiocytes and nonparenchymal cells including Kupffer cells, hepatic stellate cells, and endothelial cells, all of which have specialized functions. This heterogeneous cell population has cellular plasticity to adapt to environmental changes. During NAFLD progression, these cells can exert diverse and complex responses at multiple levels following exposure to a variety of stimuli, including fatty acids, inflammation, and oxidative stress. Therefore, this review provides insights into NAFLD heterogeneity by addressing the cellular plasticity and metabolic adaptation of hepatocytes, cholangiocytes, hepatic stellate cells, and Kupffer cells during NAFLD progression.
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Affiliation(s)
- Hyun-Ju Park
- Metabolic Regulation Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon, Republic of Korea
- Department of Functional Genomics, KRIBB School of Bioscience, University of Science and Technology (UST), Daejeon, Republic of Korea
| | - Juyong Choi
- Metabolic Regulation Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon, Republic of Korea
- Department of Functional Genomics, KRIBB School of Bioscience, University of Science and Technology (UST), Daejeon, Republic of Korea
| | - Hyunmi Kim
- Metabolic Regulation Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon, Republic of Korea
- Department of Functional Genomics, KRIBB School of Bioscience, University of Science and Technology (UST), Daejeon, Republic of Korea
| | - Da-Yeon Yang
- Metabolic Regulation Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon, Republic of Korea
- Department of Functional Genomics, KRIBB School of Bioscience, University of Science and Technology (UST), Daejeon, Republic of Korea
| | - Tae Hyeon An
- Metabolic Regulation Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon, Republic of Korea
- Department of Functional Genomics, KRIBB School of Bioscience, University of Science and Technology (UST), Daejeon, Republic of Korea
| | - Eun-Woo Lee
- Metabolic Regulation Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon, Republic of Korea
- Department of Functional Genomics, KRIBB School of Bioscience, University of Science and Technology (UST), Daejeon, Republic of Korea
| | - Baek-Soo Han
- Department of Functional Genomics, KRIBB School of Bioscience, University of Science and Technology (UST), Daejeon, Republic of Korea
- Biodefense Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon, Republic of Korea
| | - Sang Chul Lee
- Metabolic Regulation Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon, Republic of Korea
- Department of Functional Genomics, KRIBB School of Bioscience, University of Science and Technology (UST), Daejeon, Republic of Korea
| | - Won Kon Kim
- Metabolic Regulation Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon, Republic of Korea
- Department of Functional Genomics, KRIBB School of Bioscience, University of Science and Technology (UST), Daejeon, Republic of Korea
| | - Kwang-Hee Bae
- Metabolic Regulation Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon, Republic of Korea
- Department of Functional Genomics, KRIBB School of Bioscience, University of Science and Technology (UST), Daejeon, Republic of Korea
| | - Kyoung-Jin Oh
- Metabolic Regulation Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon, Republic of Korea
- Department of Functional Genomics, KRIBB School of Bioscience, University of Science and Technology (UST), Daejeon, Republic of Korea
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Zheng Y, Xie L, Yang D, Luo K, Li X. Small-molecule natural plants for reversing liver fibrosis based on modulation of hepatic stellate cells activation: An update. PHYTOMEDICINE : INTERNATIONAL JOURNAL OF PHYTOTHERAPY AND PHYTOPHARMACOLOGY 2023; 113:154721. [PMID: 36870824 DOI: 10.1016/j.phymed.2023.154721] [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: 11/07/2022] [Revised: 02/07/2023] [Accepted: 02/17/2023] [Indexed: 06/18/2023]
Abstract
BACKGROUND Liver fibrosis (LF) is a trauma repair process carried out by the liver in response to various acute and chronic liver injuries. Its primary pathological characteristics are excessive proliferation and improper dismissal of the extracellular matrix, and if left untreated, it will progress into cirrhosis, liver cancer, and other diseases. Hepatic stellate cells (HSCs) activation is intimately associated to the onset of LF, and it is anticipated that addressing HSCs proliferation can reverse LF. Plant-based small-molecule medications have anti-LF properties, and their mechanisms of action involve suppression of extracellular matrix abnormally accumulating as well as anti-inflammation and anti-oxidative stress. New targeting HSC agents will therefore be needed to provide a potential curative response. PURPOSE The most recent HSC routes and small molecule natural plants that target HSC described domestically and internationally in recent years were examined in this review. METHODS The data was looked up using resources including ScienceDirect, CNKI, Web of Science, and PubMed. Keyword searches for information on hepatic stellate cells included "liver fibrosis", "natural plant", "hepatic stellate cells", "adverse reaction", "toxicity", etc. RESULTS: We discovered that plant monomers can target and control various pathways to prevent the activation and proliferation of HSC and promote the apoptosis of HSC in order to achieve the anti-LF effect in this work by compiling the plant monomers that influence many common pathways of HSC in recent years. It demonstrates the wide-ranging potential of plant monomers targeting different routes to combat LF, with a view to supplying new concepts and new strategies for natural plant therapy of LF as well as research and development of novel pharmaceuticals. The investigation of kaempferol, physalin B, and other plant monomers additionally motivated researchers to focus on the structure-activity link between the main chemicals and LF. CONCLUSION The creation of novel pharmaceuticals can benefit greatly from the use of natural components. They are often harmless for people, non-target creatures, and the environment because they are found in nature, and they can be employed as the starting chemicals for the creation of novel medications. Natural plants are valuable resources for creating new medications with fresh action targets because they feature original and distinctive action mechanisms.
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Affiliation(s)
- Yu Zheng
- State Key Laboratory of Southwestern Chinese Medicine Resources, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China
| | - Long Xie
- State Key Laboratory of Southwestern Chinese Medicine Resources, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China
| | - Dejun Yang
- State Key Laboratory of Southwestern Chinese Medicine Resources, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China
| | - Kaipei Luo
- State Key Laboratory of Southwestern Chinese Medicine Resources, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China
| | - Xiaofang Li
- State Key Laboratory of Southwestern Chinese Medicine Resources, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China.
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Sufleţel RT, Melincovici CS, Gheban BA, Toader Z, Mihu CM. Hepatic stellate cells - from past till present: morphology, human markers, human cell lines, behavior in normal and liver pathology. ROMANIAN JOURNAL OF MORPHOLOGY AND EMBRYOLOGY 2021; 61:615-642. [PMID: 33817704 PMCID: PMC8112759 DOI: 10.47162/rjme.61.3.01] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 01/18/2023]
Abstract
Hepatic stellate cell (HSC), initially analyzed by von Kupffer, in 1876, revealed to be an extraordinary mesenchymal cell, essential for both hepatocellular function and lesions, being the hallmark of hepatic fibrogenesis and carcinogenesis. Apart from their implications in hepatic injury, HSCs play a vital role in liver development and regeneration, xenobiotic response, intermediate metabolism, and regulation of immune response. In this review, we discuss the current state of knowledge regarding HSCs morphology, human HSCs markers and human HSC cell lines. We also summarize the latest findings concerning their roles in normal and liver pathology, focusing on their impact in fibrogenesis, chronic viral hepatitis and liver tumors.
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Affiliation(s)
- Rada Teodora Sufleţel
- Discipline of Histology, Department of Morphological Sciences, Iuliu Haţieganu University of Medicine and Pharmacy, Cluj-Napoca, Romania;
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Hassan S, Zil-e-Rubab, Shah H, Shawana S. Dysregulated epidermal growth factor and tumor growth factor-beta receptor signaling through GFAP-ACTA2 protein interaction in liver fibrosis. Pak J Med Sci 2020; 36:782-787. [PMID: 32494274 PMCID: PMC7260937 DOI: 10.12669/pjms.36.4.1845] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2019] [Revised: 02/11/2020] [Accepted: 02/14/2020] [Indexed: 01/20/2023] Open
Abstract
OBJECTIVE Viral hepatitis is associated with high morbidity and mortality. Identification of biological pathways involved in hepatic fibrosis resulting from chronic hepatitis C are essential for better management of patients. Constructing the HCV-human protein interaction network through bioinformatics may enable us to discover diagnostic biological pathways. We investigated to identify dysregulated pathways and gene enrichment based on actin alpha 2 (ACTA2) and glial fibrillar acidic protein (GFAP) interaction network analysis in hepatic fibrosis. METHODS This is an in-silico study conducted at Ziauddin University from March,2019 to September 2019. Enrichment and protein-protein interaction (PPI) network analysis of the identified proteins: GFAP and ACTA2 along with their mapped gene data sets was performed using FunRich version 3.1.3. RESULTS Biological pathway grouping showed enrichment of proteins (85.7%) in signalling pathway by epidermal growth factor receptor (EGFR) and Tumor growth factor (TGF)-beta Receptor followed by signaling by PDGF, FGFR and NGF (71.4%) (p < 0.001). SRC, PRKACA, PRKCA and PRKCD were enriched in both EGFR and TGF-beta Signalling pathways. CONCLUSION EGFR and TGF-beta signalling pathways were enriched in liver fibrosis. SRC, PRKACA, PRKCA and PRKCD were enriched and differentially expressed in both EGFR and TGF-beta signalling pathways.
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Affiliation(s)
- Sobia Hassan
- Dr. Sobia Hassan, MBBS, M. Phil. Altamash Institute of Dental Medicine, Karachi, Pakistan
| | - Zil-e-Rubab
- Dr. Zil-e-Rubab, MBBS, M. Phil, PhD. Ziauddin University Clifton Campus, Karachi, Pakistan
| | - Hussain Shah
- Mr. Hussain Shah, Department of Chemical & Biomolecular Engineering, University of Melbourne, Australia
| | - Summayya Shawana
- Dr. Summayya Shawana, MBBs, M. Phil. Bahria University Medical & Dental College, Karachi, Pakistan
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Yin W, Zhang W, Zhu Y, Ni H, Gong L, Fu M. miR-219-3p regulates the occurrence of hepatic fibrosis by targeting Smad2. Exp Ther Med 2019; 17:4635-4642. [PMID: 31086594 DOI: 10.3892/etm.2019.7480] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2018] [Accepted: 02/05/2019] [Indexed: 11/09/2022] Open
Abstract
Abnormal expression of microRNA (miR)-219-3p has been widely identified in different tumors. However, whether miR-219-3p is involved in the progression of hepatic fibrosis (HF) has never been explored. The present study showed that compared with healthy controls, the levels of miR-291-3p in peripheral blood were decreased in patients with HF. Furthermore, much lower levels of miR-291-3p were identified in fibrotic liver tissues compared with that of normal liver tissues. Receiver operating characteristic curve analysis showed that the levels of miR-291-3p in peripheral blood may screen patients with HF from healthy controls. Reverse transcription quantitative polymerase chain reaction analysis showed that overexpression of miR-291-3p significantly suppressed the mRNA levels of Snai1, vascular endothelial-specific cadherin (VE-cadherin), Vimentin, transforming growth factor (TGF)-β1, and glial fibrillary acidic protein (GFAP). The protein levels of Snai1, VE-cadherin, Vimentin, TGF-β1, and GFAP were also decreased in hepatic stellate cells transfected with miR-291-3p mimics. Further study indicated that mothers against decapentaplegic homolog 2 (Smad2) was a target gene of miR-291-3p. More importantly, silencing of Smad2 could abolish miR-291-3p inhibition-induced TGF-β1 signaling activation. In summary, reduced peripheral blood miR-291-3p may be involved in the progression of HF via targeting Smad2.
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Affiliation(s)
- Weihua Yin
- Department of Infectious Diseases, The First People's Hospital of Kunshan Affiliated with Jiangsu University, Suzhou, Jiangsu 215000, P.R. China
| | - Wei Zhang
- Department of Infectious Diseases, The First People's Hospital of Kunshan Affiliated with Jiangsu University, Suzhou, Jiangsu 215000, P.R. China
| | - Yanfang Zhu
- Department of Infectious Diseases, The First People's Hospital of Kunshan Affiliated with Jiangsu University, Suzhou, Jiangsu 215000, P.R. China
| | - Huihui Ni
- Department of Infectious Diseases, The First People's Hospital of Kunshan Affiliated with Jiangsu University, Suzhou, Jiangsu 215000, P.R. China
| | - Li Gong
- Department of Infectious Diseases, The First People's Hospital of Kunshan Affiliated with Jiangsu University, Suzhou, Jiangsu 215000, P.R. China
| | - Maoying Fu
- Department of Infectious Diseases, The First People's Hospital of Kunshan Affiliated with Jiangsu University, Suzhou, Jiangsu 215000, P.R. China
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Metwally DM, Al-Olayan EM, Alanazi M, Alzahrany SB, Semlali A. Antischistosomal and anti-inflammatory activity of garlic and allicin compared with that of praziquantel in vivo. Altern Ther Health Med 2018; 18:135. [PMID: 29703259 PMCID: PMC5921551 DOI: 10.1186/s12906-018-2191-z] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2017] [Accepted: 03/27/2018] [Indexed: 01/22/2023]
Abstract
Background Schistosomiasis is an acute and chronic zoonotic parasitic disease caused by trematode worms. The host inflammatory response to schistosome eggs leads to perioval granulomata formation, mainly in the liver and intestine. This study investigated the potential antischistosomal and anti-inflammatory activity of both garlic extract and allicin on liver fibrotic markers in BALB/c mice with schistosomiasis (S. mansoni infection) compared with that of the commonly used drug, praziquantel (PZQ). Methods In this study, 140 female BALB/c mice (7-weeks old) were divided into seven groups with 20 mice each. Six groups were infected with S. mansoni cercariae and treated with garlic, allicin, or PZQ. The seventh group was the negative control. Twenty-four hours after the final treatment, the mice were euthanised and perfused for worm recovery. The liver and intestines were harvested for parasitological and histological assessment and to analyse the proinflammatory cytokine mRNA expression. Results Prophylactic administration of garlic and allicin to the infected mice significantly reduced the worm burden. Serum concentrations of liver fibrosis markers and proinflammatory cytokines were also reduced. PZQ was the most efficacious for reduction in the number of worms. These results are similar to those normally obtained using PZQ. Conclusions Crushed garlic homogenate and allicin are potential complementary treatments that may be used with PZQ.
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Zhang C, Tian X, Zhang K, Li GY, Wang HY, Wang JH. Protective effects of Foeniculum vulgare root bark extract against carbon tetrachloride-induced hepatic fibrosis in mice. World J Gastroenterol 2017; 23:5722-5731. [PMID: 28883697 PMCID: PMC5569286 DOI: 10.3748/wjg.v23.i31.5722] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/13/2017] [Revised: 05/14/2017] [Accepted: 06/12/2017] [Indexed: 02/07/2023] Open
Abstract
AIM To investigate the protective effects of Foeniculum vulgare root bark (FVRB), a traditional Uyghur medicine, against carbon tetrachloride (CCl4)-induced hepatic fibrosis in mice.
METHODS Mice were randomly divided into eight groups (n = 20 each). Except for the normal control group, mice in the rest groups were intraperitoneally injected (i.p.) with 0.1% CCl4-olive oil mixture at 10 mL/kg twice a week to induce liver fibrosis. After 4 wk, mice were treated concurrently with the 70% ethanol extract of FVRB (88, 176, 352 and 704 mg/kg, respectively) daily by oral gavage for 4 wk to evaluate its protective effects. Serum aspartate aminotransferase (AST), alanine aminotransferase (ALT), triglyceride (TG), hexadecenoic acid (HA), laminin (LN), glutathione (GSH), superoxide dismutase (SOD), and malondialdehyde (MDA) in liver tissues were measured. Hematoxylin-eosin (H and E) staining and Masson trichrome (MT) staining were performed to assess histopathological changes in the liver. The expression of transforming growth factor β1 (TGF-β1), matrix metalloprotein 9 (MMP-9) and metallopeptidase inhibitor 1 (TIMP-1) was detected by immunohistochemical analysis. Additionally, TGF-β1 and alpha-smooth muscle actin (α-SMA) protein expression was measured by Western blot.
RESULTS A significant reduction in serum levels of AST, ALT, TG, HA and LN was observed in the FVRB-treated groups, suggesting that FVRB displayed hepatoprotective effects. Also, the depletion of GSH, SOD, and MDA accumulation in liver tissues was suppressed by FVRB. The expression of TGF-β1, MMP-9 and TIMP-1 determined by immunohistochemistry was markedly reduced in a dose-dependent manner by FVRB treatment. Furthermore, protective effects of FVRB against CCl4-induced liver injury were confirmed by histopathological studies. Protein expression of TGF-β1 and α-SMA detected by Western blot was decreased by FVRB treatment.
CONCLUSION Our results indicate that FVRB may be a promising agent against hepatic fibrosis and its possible mechanisms are inhibiting lipid peroxidation and reducing collagen formation in liver tissue of liver fibrosis mice.
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Affiliation(s)
- Cai Zhang
- School of Pharmacy, Shihezi University, Shihezi 832002, Xinjiang Uygur Autonomous Region, China
| | - Xing Tian
- School of Pharmacy, Shihezi University, Shihezi 832002, Xinjiang Uygur Autonomous Region, China
| | - Ke Zhang
- School of Pharmacy, Shihezi University, Shihezi 832002, Xinjiang Uygur Autonomous Region, China
| | - Guo-Yu Li
- School of Pharmacy, Shihezi University, Shihezi 832002, Xinjiang Uygur Autonomous Region, China
| | - Hang-Yu Wang
- School of Pharmacy, Shihezi University, Shihezi 832002, Xinjiang Uygur Autonomous Region, China
| | - Jin-Hui Wang
- School of Pharmacy, Shihezi University, Shihezi 832002, Xinjiang Uygur Autonomous Region, China
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Yuan J, Liu W, Zhu H, Chen Y, Zhang X, Li L, Chu W, Wen Z, Feng H, Lin J. Curcumin inhibits glial scar formation by suppressing astrocyte-induced inflammation and fibrosis in vitro and in vivo. Brain Res 2016; 1655:90-103. [PMID: 27865778 DOI: 10.1016/j.brainres.2016.11.002] [Citation(s) in RCA: 49] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2016] [Revised: 10/13/2016] [Accepted: 11/04/2016] [Indexed: 12/31/2022]
Abstract
Spinal cord injury (SCI) leads to glial scar formation by astrocytes, which severely hinders neural regeneration. Curcumin (cur) can inhibit glial scar formation, but the underlying mechanism is not fully understood. Using both in vivo and in vitro experiments, the current study investigated the phenotypic transformation of astrocytes following cur and siRNA intervention during the processes of inflammation and fibrosis and determined details of the relationship between cur treatment and the glial scar components GFAP and CSPG. We found that cur and NF-κb p65 siRNA could inhibit astrocyte activation through suppressing NF-κb signaling pathway, which led to down-regulate the expression of chemokines MCP-1, RANTES and CXCL10 released by astrocytes and decreased macrophage and T-cell infiltration, thus reducing the inflammation in the glial scar. In addition, silencing SOX-9 may reduce the deposition of extracellular matrix CSPG; whereas its over-expression could increase the CSPG expression. Cur suppressedSOX-9-inducedCSPG deposition, reduced α-SMA (an important symbol of fibrosis) expression in astrocytes, altered astrocyte phenotype, and inhibited glial scar formation by regulating fibrosis. This study confirmed that cur could regulate both the NF-κb and SOX9 signaling pathways and reduce the expression of intracellular and extracellular glial scar components through dual-target regulating both inflammation and fibrosis after SCI in the rat. This study provides an important hypothesis centered on the dual inhibition of intracellular and extracellular glial scar components as a treatment strategy for SCI.
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Affiliation(s)
- Jichao Yuan
- Department of Neurosurgery, Institute of Neurosurgery, Key Laboratory of Neurotrauma Prevention and Treatment, Southwest Hospital, Third Military Medical University, 29 Gaotanyan Street, Chongqing 400038, China.
| | - Wei Liu
- Department of Neurosurgery, Institute of Neurosurgery, Key Laboratory of Neurotrauma Prevention and Treatment, Southwest Hospital, Third Military Medical University, 29 Gaotanyan Street, Chongqing 400038, China.
| | - Haitao Zhu
- Department of Neurosurgery, Institute of Neurosurgery, Key Laboratory of Neurotrauma Prevention and Treatment, Southwest Hospital, Third Military Medical University, 29 Gaotanyan Street, Chongqing 400038, China.
| | - Yaxing Chen
- Department of Neurosurgery, Institute of Neurosurgery, Key Laboratory of Neurotrauma Prevention and Treatment, Southwest Hospital, Third Military Medical University, 29 Gaotanyan Street, Chongqing 400038, China.
| | - Xuan Zhang
- Department of Neurosurgery, Institute of Neurosurgery, Key Laboratory of Neurotrauma Prevention and Treatment, Southwest Hospital, Third Military Medical University, 29 Gaotanyan Street, Chongqing 400038, China.
| | - Lan Li
- Department of Neurosurgery, Institute of Neurosurgery, Key Laboratory of Neurotrauma Prevention and Treatment, Southwest Hospital, Third Military Medical University, 29 Gaotanyan Street, Chongqing 400038, China.
| | - Weihua Chu
- Department of Neurosurgery, Institute of Neurosurgery, Key Laboratory of Neurotrauma Prevention and Treatment, Southwest Hospital, Third Military Medical University, 29 Gaotanyan Street, Chongqing 400038, China.
| | - Zexian Wen
- Department of Neurosurgery, Institute of Neurosurgery, Key Laboratory of Neurotrauma Prevention and Treatment, Southwest Hospital, Third Military Medical University, 29 Gaotanyan Street, Chongqing 400038, China.
| | - Hua Feng
- Department of Neurosurgery, Institute of Neurosurgery, Key Laboratory of Neurotrauma Prevention and Treatment, Southwest Hospital, Third Military Medical University, 29 Gaotanyan Street, Chongqing 400038, China.
| | - Jiangkai Lin
- Department of Neurosurgery, Institute of Neurosurgery, Key Laboratory of Neurotrauma Prevention and Treatment, Southwest Hospital, Third Military Medical University, 29 Gaotanyan Street, Chongqing 400038, China.
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JIA YUJIE, YUAN LIJUN, XU TINGTING, LI HANSHU, YANG GUANG, JIANG MIAONA, ZHANG CAIHUA, LI CONG. Herbal medicine Gan-fu-kang downregulates Wnt/Ca2+ signaling to attenuate liver fibrogenesis in vitro and in vivo. Mol Med Rep 2016; 13:4705-14. [DOI: 10.3892/mmr.2016.5148] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2015] [Accepted: 01/27/2016] [Indexed: 11/06/2022] Open
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Nutrigenomics analysis reveals that copper deficiency and dietary sucrose up-regulate inflammation, fibrosis and lipogenic pathways in a mature rat model of nonalcoholic fatty liver disease. J Nutr Biochem 2015; 26:996-1006. [PMID: 26033743 DOI: 10.1016/j.jnutbio.2015.04.009] [Citation(s) in RCA: 43] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2014] [Revised: 04/08/2015] [Accepted: 04/13/2015] [Indexed: 12/18/2022]
Abstract
Nonalcoholic fatty liver disease (NAFLD) prevalence is increasing worldwide, with the affected US population estimated near 30%. Diet is a recognized risk factor in the NAFLD spectrum, which includes nonalcoholic steatohepatitis (NASH) and fibrosis. Low hepatic copper (Cu) was recently linked to clinical NAFLD/NASH severity. Simple sugar consumption including sucrose and fructose is implicated in NAFLD, while consumption of these macronutrients also decreases liver Cu levels. Though dietary sugar and low Cu are implicated in NAFLD, transcript-level responses that connect diet and pathology are not established. We have developed a mature rat model of NAFLD induced by dietary Cu deficiency, human-relevant high sucrose intake (30% w/w) or both factors in combination. Compared to the control diet with adequate Cu and 10% (w/w) sucrose, rats fed either high-sucrose or low-Cu diet had increased hepatic expression of genes involved in inflammation and fibrogenesis, including hepatic stellate cell activation, while the combination of diet factors also increased ATP citrate lyase and fatty acid synthase gene transcription (fold change > 2, P < 0.02). Low dietary Cu decreased hepatic and serum Cu (P ≤ 0.05), promoted lipid peroxidation and induced NAFLD-like histopathology, while the combined factors also induced fasting hepatic insulin resistance and liver damage. Neither low Cu nor 30% sucrose in the diet led to enhanced weight gain. Taken together, transcript profiles, histological and biochemical data indicate that low Cu and high sucrose promote hepatic gene expression and physiological responses associated with NAFLD and NASH, even in the absence of obesity or severe steatosis.
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Wang M, Qiu W, Qiu F, Mo Y, Fan W. Tangent function transformation of the Abbreviated Injury Scale improves accuracy and simplifies scoring. Arch Med Sci 2015; 11:130-136. [PMID: 25861299 PMCID: PMC4379373 DOI: 10.5114/aoms.2015.49209] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/03/2013] [Revised: 02/14/2013] [Accepted: 02/20/2013] [Indexed: 11/17/2022] Open
Abstract
INTRODUCTION The Injury Severity Score (ISS) and the New Injury Severity Score (NISS) are widely used for anatomic severity assessments after trauma. We present here the Tangent Injury Severity Score (TISS), which transforms the Abbreviated Injury Scale (AIS) as a predictor of mortality. MATERIAL AND METHODS The TISS is defined as the sum of the tangent function of AIS/6 to the power 3.04 multiplied by 18.67 of a patient's three most severe AIS injuries regardless of body regions. TISS values were calculated for every patient in two large independent data sets: 3,908 and 4,171 patients treated during a 6-year period at level-3 first-class comprehensive hospitals: the Affiliated Hospital of Hangzhou Normal University and Fengtian Hospital Affiliated to Shenyang Medical College, China. The power of TISS to predict mortality was compared with previously calculated NISS values for the same patients in each data set. RESULTS The TISS is more predictive of survival than NISS (Hangzhou: receiver operating characteristic (ROC): NISS = 0.929, TISS = 0.949; p = 0.002; Shenyang: ROC: NISS = 0.924, TISS = 0.942; p = 0.008). Moreover, TISS provides a better fit throughout its entire range of prediction (Hosmer Lemeshow statistic for Hangzhou NISS = 29.71; p < 0.001, TISS = 19.59; p = 0.003; Hosmer Lemeshow statistic for Shenyang NISS = 33.49; p < 0.001, TISS = 21.19; p = 0.002). CONCLUSIONS The TISS shows more accurate prediction of prognosis and a linear relation to mortality. The TISS might be a better injury scoring tool with simple computation.
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Affiliation(s)
- Muding Wang
- Department of Emergency Medicine, Affiliated Hospital of Hangzhou Normal University, Hangzhou, China
| | - Wusi Qiu
- Department of Neurosurgery, Hangzhou Second Hospital, College of Medicine, Hangzhou Normal University, Hangzhou, China
| | - Fang Qiu
- Department of Emergency Medicine, Affiliated Hospital of Hangzhou Normal University, Hangzhou, China
| | - Yinan Mo
- 3 Ward of Hand Surgery, Fengtian Hospital affiliated to Shenyang Medical College, Shenyang, China
| | - Wenhui Fan
- Department of Emergency Medicine, Affiliated Hospital of Hangzhou Normal University, Hangzhou, China
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He H, An ZM. Wnt signaling pathway and liver fibrosis: Recent research status. Shijie Huaren Xiaohua Zazhi 2014; 22:3766-3772. [DOI: 10.11569/wcjd.v22.i25.3766] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Hepatic fibrosis is characterized by the excessive accumulation of extracellular matrix (ECM), and the activiation of hepatic stellate cells (HSCs) is recognized as the core and initial stage. It is reported that the activiation of HSCs is related to the regulation of a series of cell factors and cell signal pathways. The Wnt signaling pathway plays a key role in the physiology and pathology of the liver, and the abnormal activiation of Wnt results in the activiation of HSCs. Therefore, a further understanding of the role of the Wnt signaling pathway in the pathogeneisis of hepatic fibrosis will be valuable in the development of diagnosic and threputic strategies for this disease.
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Hassan S, Syed S, Kehar SI. Glial Fibrillary Acidic Protein (GFAP) as a Mesenchymal marker of Early Hepatic Stellate Cells Activation in Liver Fibrosis in Chronic Hepatitis C Infection. Pak J Med Sci 2014; 30:1027-32. [PMID: 25225520 PMCID: PMC4163226 DOI: 10.12669/pjms.305.5534] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2014] [Revised: 06/06/2014] [Accepted: 06/08/2014] [Indexed: 01/28/2023] Open
Abstract
OBJECTIVE This study aims to determine expression of Glial Fibrillary Acidic Protein and of Alpha Smooth Muscle Actin (α-SMA) in hepatic stellate cells of CHC cases and their association with stage of fibrosis. METHODS The study was conducted at Ziauddin University, Clifton Campus during the year 2010-2012. Sixty Chronic Hepatitis C cases were immmunostained using anti α-SMA antibody and anti-GFAP antibody. Semi quantitative scoring in pericentral, periportal and perisinusoidal area of each case was done to assess immunoexpression of each marker. Results : Immunoexpression of GFAP showed significant association with α-SMA. GFAP expression was inversely correlated with progression of fibrosis. Conclusion : GFAP could represent a useful marker for early hepatic stellate cells activation. Follow up biopsies showing decline in GFAP levels may help identify the target group requiring aggressive therapy.
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Affiliation(s)
- Sobia Hassan
- Dr. Sobia Hassan, Lecturer, Pathology Department, Ziauddin University Clifton Campus, Karachi, Pakistan
| | - Serajuddaula Syed
- Prof. Serajuddaula Syed, Head of Pathology Department, Ziauddin University Clifton Campus, Karachi, Pakistan
| | - Shahnaz Imdad Kehar
- Dr. Shahnaz Imdad Kehar, Associate Professor, Pathology Department, BMSI – JPMC, Karachi, Pakistan
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Miao CG, Yang YY, He X, Huang C, Huang Y, Zhang L, Lv XW, Jin Y, Li J. Wnt signaling in liver fibrosis: progress, challenges and potential directions. Biochimie 2013; 95:2326-35. [PMID: 24036368 DOI: 10.1016/j.biochi.2013.09.003] [Citation(s) in RCA: 108] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2013] [Accepted: 09/02/2013] [Indexed: 12/25/2022]
Abstract
Liver fibrosis is a common wound-healing response to chronic liver injuries, including alcoholic or drug toxicity, persistent viral infection, and genetic factors. Myofibroblastic transdifferentiation (MTD) is the pivotal event during liver fibrogenesis, and research in the past few years has identified key mediators and molecular mechanisms responsible for MTD of hepatic stellate cells (HSCs). HSCs are undifferentiated cells which play an important role in liver regeneration. Recent evidence demonstrates that HSCs derive from mesoderm and at least in part via septum transversum and mesothelium, and HSCs express markers for different cell types which derive from multipotent mesenchymal progenitors. There is a regulatory commonality between differentiation of adipocytes and that of HSC, and the shift from adipogenic to myogenic or neuronal phenotype characterizes HSC MTD. Central of this shift is a loss of expression of the master adipogenic regulator peroxisome proliferator activated receptor γ (PPARγ). Restored expression of PPARγ and/or other adipogenic transcription genes can reverse myofibroblastic HSCs to differentiated cells. Vertebrate Wnt and Drosophila wingless are homologous genes, and their translated proteins have been shown to participate in the regulation of cell proliferation, cell polarity, cell differentiation, and other biological roles. More recently, Wnt signaling is implicated in human fibrosing diseases, such as pulmonary fibrosis, renal fibrosis, and liver fibrosis. Blocking the canonical Wnt signal pathway with the co-receptor antagonist Dickkopf-1 (DKK1) abrogates these epigenetic repressions and restores the gene PPARγ expression and HSC differentiation. The identified morphogen mediated epigenetic regulation of PPARγ and HSC differentiation also serves as novel therapeutic targets for liver fibrosis and liver regeneration. In conclusion, the Wnt signaling promotes liver fibrosis by enhancing HSC activation and survival, and we herein discuss what we currently know and what we expect will come in this field in the next future.
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Affiliation(s)
- Cheng-gui Miao
- School of Pharmacy, Institute for Liver Diseases of Anhui Medical University, Anhui Key Laboratory of Bioactivity of Natural Products, Anhui Medical University, Mei Shan Road, Hefei 230032, Anhui Province, China; School of Food and Drug, Anhui Science and Technology University, Bengbu 233100, China
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Paulo JA, Kadiyala V, Banks PA, Conwell DL, Steen H. Mass spectrometry-based quantitative proteomic profiling of human pancreatic and hepatic stellate cell lines. GENOMICS PROTEOMICS & BIOINFORMATICS 2013; 11:105-13. [PMID: 23528454 PMCID: PMC4123426 DOI: 10.1016/j.gpb.2013.01.009] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/31/2012] [Revised: 01/05/2013] [Accepted: 01/15/2013] [Indexed: 02/06/2023]
Abstract
The functions of the liver and the pancreas differ; however, chronic inflammation in both organs is associated with fibrosis. Evidence suggests that fibrosis in both organs is partially regulated by organ-specific stellate cells. We explore the proteome of human hepatic stellate cells (hHSC) and human pancreatic stellate cells (hPaSC) using mass spectrometry (MS)-based quantitative proteomics to investigate pathophysiologic mechanisms. Proteins were isolated from whole cell lysates of immortalized hHSC and hPaSC. These proteins were tryptically digested, labeled with tandem mass tags (TMT), fractionated by OFFGEL, and subjected to MS. Proteins significantly different in abundance (P < 0.05) were classified via gene ontology (GO) analysis. We identified 1223 proteins and among them, 1222 proteins were quantifiable. Statistical analysis determined that 177 proteins were of higher abundance in hHSC, while 157 were of higher abundance in hPaSC. GO classification revealed that proteins of relatively higher abundance in hHSC were associated with protein production, while those of relatively higher abundance in hPaSC were involved in cell structure. Future studies using the methodologies established herein, but with further upstream fractionation and/or use of enhanced MS instrumentation will allow greater proteome coverage, achieving a comprehensive proteomic analysis of hHSC and hPaSC.
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Affiliation(s)
- Joao A Paulo
- Department of Pathology, Boston Children's Hospital, Boston, MA 02115, USA.
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