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Zhang K, Ren L, Zhai Y. Effect and mechanism of Nintedanib on acute and chronic radiation-induced lung injury in mice. PLoS One 2025; 20:e0324339. [PMID: 40408456 PMCID: PMC12101626 DOI: 10.1371/journal.pone.0324339] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2024] [Accepted: 04/23/2025] [Indexed: 05/25/2025] Open
Abstract
OBJECTIVE To investigate the efficacy of Nintedanib in treating acute and chronic radiation-induced lung injury and its mechanism of action. METHODS A radiation-induced lung injury model was established in mice using 6MV X-rays at 18Gy to irradiate the lungs. The mice were randomly divided into four groups: control group, radiation therapy group, low-dosage Nintedanib + radiation therapy group, and high dosage Nintedanib + radiation therapy group. The mice were euthanized on day 14 and 3 months post-radiation to observe changes in acute and chronic inflammation and the expression of related proteins. RESULTS Compared to the radiation therapy group, the low and high-dosage Nintedanib groups showed varying degrees of improvement in mental state, responsiveness, food and water intake, and fur condition. During the acute inflammatory phase, HE staining revealed inflammatory changes in the lung tissues of both Nintedanib groups, but the pathology was less severe than in the radiation group, with the high-dosage group showing more significant reduction. Serum levels of IL-6, TNF-α and TGF-β1 were significantly reduced (P < 0.05), suggesting that Nintedanib can decrease the expression of serum inflammatory factors. The percentage of Smad2-positive area in the low and high-dosage Nintedanib groups was (7.395 ± 0.90)% and (5.577 ± 1.56)%, respectively, both significantly lower than the radiation group (P < 0.05). At 3 months post-radiation, Masson's trichrome staining showed that the Ashcroft score in the Nintedanib groups was significantly lower than in the radiation group (P < 0.05). There were statistically significant differences between the low and high-dosage groups in the percentage of Smad2 and αSMA-positive areas and the levels of serum TGF-β1 (all P < 0.05), and both were significantly lower compared to the radiation group (P < 0.05). CONCLUSION (1) Nintedanib can improve the general condition of mice with acute and chronic radiation-induced lung injury and reduce pathological damage to lung tissue. (2) Nintedanib may exert a protective effect on mice with acute and chronic radiation-induced lung injury by downregulating the TGF-β1/Smad2 signaling pathway, thereby inhibiting inflammatory and fibrotic responses.
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Affiliation(s)
- Kun Zhang
- Department of Oncology, Binzhou Medical University Hospital, Binzhou, Shandong, P.R.China
- Department of Oncology, Jieshou City People’s Hospital, Jieshou Hospital Affiliated to Anhui Medical College, Jieshou, Anhui, P.R.China
| | - Lu Ren
- Department of Hematology, Jieshou City People’s Hospital, Jieshou Hospital Affiliated to Anhui Medical College, Jieshou, Anhui, P.R.China
| | - Yujie Zhai
- Department of Oncology, Binzhou Medical University Hospital, Binzhou, Shandong, P.R.China
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Atif M, Malik MNH, Alsahli TG, Ali M, Younis W, Alharbi KS, Alzare SI, Alsuwayt B, Maqbool T, Anjum I, Jahan S, Alanzi AR, Solre GFB, Bilal HM. p-Cymene inhibits pro-fibrotic and inflammatory mediators to prevent hepatic dysfunction. Open Life Sci 2025; 20:20221054. [PMID: 40291773 PMCID: PMC12032992 DOI: 10.1515/biol-2022-1054] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2024] [Revised: 12/16/2024] [Accepted: 12/31/2024] [Indexed: 04/30/2025] Open
Abstract
This study evaluated the hepatoprotective potential of p-cymene (p-CYM) against two models of liver damage: ethanol (EtOH)-induced hepatocellular injury and diethylnitrosamine-carbon tetrachloride (DEN-CCl4)-induced liver fibrosis (LF). HepG2 cells were treated with p-CYM or silymarin (SIL) before exposure to 10% EtOH in order to induce cellular injury. LF was induced in Sprague-Dawley rats using a single dose of DEN followed by increasing doses of CCl4 over 60 days. Rats were treated twice weekly with p-CYM or SIL from day 21 to day 60. Results showed that p-CYM effectively mitigated EtOH-induced cell death in HepG2 cells by enhancing the activity of superoxide dismutase and glutathione reductase. In vivo findings revealed that p-CYM attenuated DEN- CCl4-induced liver damage by preventing weight loss, improving serum biomarkers (e.g., aspartate transaminase, alanine aminotransferase, alkaline phosphatase, and bilirubin), and reducing liver fibrotic changes. It also decreased the expression of pro-inflammatory and pro-fibrotic markers such as TNF-α, IL-1β, IL-6, TGF-β1, COL1A1, and TIMP-1. Molecular docking further supported the experimental findings, showing strong interactions between p-CYM and the target proteins. These results indicate that the hepatoprotective effects of p-CYM are likely due to its combined antioxidant, anti-inflammatory, and anti-fibrotic properties.
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Affiliation(s)
- Muhammad Atif
- Faculty of Pharmacy, The University of Lahore, Lahore54000, Pakistan
| | | | - Tariq G. Alsahli
- Department of Pharmacology, College of Pharmacy, Jouf University, Sakaka, Aljouf 72341, Saudi Arabia
| | - Muhammad Ali
- Faculty of Pharmacy, The University of Lahore, Lahore54000, Pakistan
| | - Waqas Younis
- Faculty of Pharmacy, The University of Lahore, Lahore54000, Pakistan
| | - Khalid Saad Alharbi
- Department of Pharmacology and Toxicology, College of Pharmacy, Qassim University, Buraydah, Al-Qassim, 51452, Saudi Arabia
| | - Sami I. Alzare
- Department of Pharmacology, College of Pharmacy, Jouf University, Sakaka, Aljouf 72341, Saudi Arabia
| | - Bader Alsuwayt
- Department of Pharmacy Practice, College of Pharmacy, University of Hafr Al-Batin, Hafr Al-Batin31991, Saudi Arabia
| | - Tahir Maqbool
- Institute of Molecular Biology and Biotechnology (IMBB), The University of Lahore, Lahore54000, Pakistan
| | - Irfan Anjum
- Shifa College of Pharmaceutical Sciences, Shifa Tameer-e-Millat University, Islamabad44000, Pakistan
| | - Shah Jahan
- Department of Immunology, University of Health Sciences, Lahore54000, Pakistan
| | - Abdullah R. Alanzi
- Department of Pharmacognosy, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia
| | - Gideon F. B. Solre
- Department of Chemistry, Thomas J. R. Faulkner College of Science and Technology, University of Liberia, Monrovia, Montserrado, Liberia
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Castanho Martins M, Dixon ED, Lupo G, Claudel T, Trauner M, Rombouts K. Role of PNPLA3 in Hepatic Stellate Cells and Hepatic Cellular Crosstalk. Liver Int 2025; 45:e16117. [PMID: 39394864 PMCID: PMC11891384 DOI: 10.1111/liv.16117] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/29/2024] [Revised: 09/16/2024] [Accepted: 09/17/2024] [Indexed: 10/14/2024]
Abstract
AIMS Since its discovery, the patatin-like phospholipase domain containing 3 (PNPLA3) (rs738409 C>G p.I148M) variant has been studied extensively to unravel its molecular function. Although several studies proved a causal relationship between the PNPLA3 I148M variant and MASLD development and particularly fibrosis, the pathological mechanisms promoting this phenotype have not yet been fully clarified. METHODS We summarise the latest data regarding the PNPLA3 I148M variant in hepatic stellate cells (HSCs) activation and macrophage biology or the path to inflammation-induced fibrosis. RESULTS Elegant but contradictory studies have ascribed PNPLA3 a hydrolase or an acyltransferase function. The PNPLA3 I148M results in hepatic lipid accumulation, which predisposes the hepatocyte to lipotoxicity and lipo-apoptosis, producing DAMPs, cytokines and chemokines leading to recruitment and activation of macrophages and HSCs, propagating fibrosis. Recent studies showed that the PNPLA3 I148M variant alters HSCs biology via attenuation of PPARγ, AP-1, LXRα and TGFβ activity and signalling. CONCLUSIONS The advent of refined techniques in isolating HSCs has made PNPLA3's direct role in HSCs for liver fibrosis development more apparent. However, many other mechanisms still need detailed investigations.
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Affiliation(s)
- Maria Castanho Martins
- Regenerative Medicine and Fibrosis Group, Institute for Liver and Digestive HealthUniversity College London, Royal Free CampusLondonUK
| | - Emmanuel Dauda Dixon
- Hans Popper Laboratory of Molecular Hepatology, Department of Internal Medicine IIIMedical University of ViennaViennaAustria
| | - Giulia Lupo
- Regenerative Medicine and Fibrosis Group, Institute for Liver and Digestive HealthUniversity College London, Royal Free CampusLondonUK
| | - Thierry Claudel
- Hans Popper Laboratory of Molecular Hepatology, Department of Internal Medicine IIIMedical University of ViennaViennaAustria
| | - Michael Trauner
- Hans Popper Laboratory of Molecular Hepatology, Department of Internal Medicine IIIMedical University of ViennaViennaAustria
| | - Krista Rombouts
- Regenerative Medicine and Fibrosis Group, Institute for Liver and Digestive HealthUniversity College London, Royal Free CampusLondonUK
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Huang G, Cierpicki T, Grembecka J. Thioamides in medicinal chemistry and as small molecule therapeutic agents. Eur J Med Chem 2024; 277:116732. [PMID: 39106658 PMCID: PMC12009601 DOI: 10.1016/j.ejmech.2024.116732] [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: 06/18/2024] [Revised: 07/18/2024] [Accepted: 07/30/2024] [Indexed: 08/09/2024]
Abstract
Thioamides, which are fascinating isosteres of amides, have garnered significant attention in drug discovery and medicinal chemistry programs, spanning peptides and small molecule compounds. This review provides an overview of the various applications of thioamides in small molecule therapeutic agents targeting a range of human diseases, including cancer, microbial infections (e.g., tuberculosis, bacteria, and fungi), viral infections, neurodegenerative conditions, analgesia, and others. Particular focus is given to design strategies of biologically active thioamide-containing compounds and their biological targets, such as kinases and histone methyltransferase ASH1L. Additionally, the review discusses the impact of the thioamide moiety on key properties, including potency, target interactions, physicochemical characteristics, and pharmacokinetics profiles. We hope that this work will offer valuable insights to inspire the future development of novel bioactive thioamide-containing compounds, facilitating their effective use in combating a wide array of human diseases.
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Affiliation(s)
- Guang Huang
- Department of Pathology, University of Michigan, Ann Arbor, MI, 48109, USA.
| | - Tomasz Cierpicki
- Department of Pathology, University of Michigan, Ann Arbor, MI, 48109, USA
| | - Jolanta Grembecka
- Department of Pathology, University of Michigan, Ann Arbor, MI, 48109, USA
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Zhu J, Zhao H, Aierken A, Zhou T, Menggen M, Gao H, He R, Aimulajiang K, Wen H. Ghrelin is involved in regulating the progression of Echinococcus Granulosus-infected liver lesions through suppression of immunoinflammation and fibrosis. PLoS Negl Trop Dis 2024; 18:e0012587. [PMID: 39436864 PMCID: PMC11495594 DOI: 10.1371/journal.pntd.0012587] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2024] [Accepted: 09/30/2024] [Indexed: 10/25/2024] Open
Abstract
BACKGROUND Cystic Echinococcosis (CE) is a zoonotic disease causing fibrosis and necrosis of diseased livers caused by infection with Echinococcus granulosus (E.g). There is evidence that E.g is susceptible to immune escape and tolerance when host expression of immunoinflammation and fibrosis is suppressed, accelerating the progression of CE. Ghrelin has the effect of suppressing immunoinflammation and fibrosis, and whether it is involved in regulating the progression of E.g-infected liver lesions is not clear. METHODS Serum and hepatic Ghrelin levels were observed in E.g-infected mice (4, 12 and 36 weeks) and compared with healthy control groups. Co-localization analysis is performed between protein expression of Ghrelin in and around the hepatic lesions of E.g-infected 12-week mice and protein expression of different hepatic histiocytes by mIHC. HepG2 cells and protoscoleces (PSCs) protein were co-cultured in vitro, as well as PSCs were alone in vitro, followed by exogenously administered of Ghrelin and its receptor blocker, [D-Lys3]-GHRP-6, to assess their regulatory effects on immunoinflammation, fibrosis and survival rate of PSCs. RESULTS Serum Ghrelin levels were increased in E.g-infected 4- and 12-week mice, and reduced in 36-week mice. E.g-infected mice consistently recruited Ghrelin in and around the hepatic lesions, which was extremely strongly co-localized with the protein expression of hepatic stellate cells (HSCs), T cells and the TGF-β1/Smad3 pathway. The secretion of Ghrelin was increased with increasing concentrations of PSCs protein in HepG2 cells culture medium. Moreover, Ghrelin could significantly inhibit the secretion of IL-2, INF-γ and TNF-α, as well as the expression of Myd88/NF-κB and TGF-β1/Smad3 pathway protein, and promoted the secretion of IL-4 and IL-10. Blocking Ghrelin receptor could significantly inhibit PSCs growth in in vitro experiment. CONCLUSION Ghrelin is highly expressed in the early stages of hepatic E.g infection and may be involved in regulating the progression of liver lesions by suppression immunoinflammation and fibrosis.
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Affiliation(s)
- Jiang Zhu
- State Key Laboratory of Pathogenesis, Prevention and Treatment of High Incidence Diseases in Central Asia, Clinical Medicine Institute, The First Affiliated Hospital of Xinjiang Medical University, Xinjiang, China
- Department of Hepatobiliary and Hydatid Disease, Digestive and Vascular Surgery Center Therapy Center, The First Affiliated Hospital of Xinjiang Medical University, Xinjiang, China
| | - Hongqiong Zhao
- College of Veterinary Medicine, Xinjiang Agricultural University, Xinjiang, China
| | - Aili Aierken
- State Key Laboratory of Pathogenesis, Prevention and Treatment of High Incidence Diseases in Central Asia, Clinical Medicine Institute, The First Affiliated Hospital of Xinjiang Medical University, Xinjiang, China
| | - Tanfang Zhou
- State Key Laboratory of Pathogenesis, Prevention and Treatment of High Incidence Diseases in Central Asia, Clinical Medicine Institute, The First Affiliated Hospital of Xinjiang Medical University, Xinjiang, China
- Department of Hepatobiliary and Hydatid Disease, Digestive and Vascular Surgery Center Therapy Center, The First Affiliated Hospital of Xinjiang Medical University, Xinjiang, China
| | - Meng Menggen
- State Key Laboratory of Pathogenesis, Prevention and Treatment of High Incidence Diseases in Central Asia, Clinical Medicine Institute, The First Affiliated Hospital of Xinjiang Medical University, Xinjiang, China
| | - Huijing Gao
- State Key Laboratory of Pathogenesis, Prevention and Treatment of High Incidence Diseases in Central Asia, Clinical Medicine Institute, The First Affiliated Hospital of Xinjiang Medical University, Xinjiang, China
| | - Rongdong He
- State Key Laboratory of Pathogenesis, Prevention and Treatment of High Incidence Diseases in Central Asia, Clinical Medicine Institute, The First Affiliated Hospital of Xinjiang Medical University, Xinjiang, China
- Department of Hepatobiliary and Hydatid Disease, Digestive and Vascular Surgery Center Therapy Center, The First Affiliated Hospital of Xinjiang Medical University, Xinjiang, China
| | - Kalibixiati Aimulajiang
- State Key Laboratory of Pathogenesis, Prevention and Treatment of High Incidence Diseases in Central Asia, Clinical Medicine Institute, The First Affiliated Hospital of Xinjiang Medical University, Xinjiang, China
| | - Hao Wen
- State Key Laboratory of Pathogenesis, Prevention and Treatment of High Incidence Diseases in Central Asia, Clinical Medicine Institute, The First Affiliated Hospital of Xinjiang Medical University, Xinjiang, China
- Department of Hepatobiliary and Hydatid Disease, Digestive and Vascular Surgery Center Therapy Center, The First Affiliated Hospital of Xinjiang Medical University, Xinjiang, China
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Malik MNH, Abid I, Ismail S, Anjum I, Qadir H, Maqbool T, Najam K, Ibenmoussa S, Bourhia M, Salamatullah AM, Wondmie GF. Exploring the hepatoprotective properties of citronellol: In vitro and in silico studies on ethanol-induced damage in HepG2 cells. Open Life Sci 2024; 19:20220950. [PMID: 39290493 PMCID: PMC11406226 DOI: 10.1515/biol-2022-0950] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2024] [Revised: 07/20/2024] [Accepted: 08/07/2024] [Indexed: 09/19/2024] Open
Abstract
Citronellol (CT) is a monoterpene alcohol present in the essential oil of plants of the genus Cymbopogon and exhibits diverse pharmacological activities. The aim of the current study was to investigate the hepatoprotective potential of CT against ethanol-induced toxicity in HepG2 cell lines. Silymarin (SIL) was used as a standard drug. MTT, crystal violet assay, DAPI, and PI staining were carried out to assess the effect of ethanol and CT on cell viability. RT-PCR determined the molecular mechanisms of hepatoprotective action of CT. CT ameliorated cell viability and restricted ethanol-induced cell death. DAPI and PI staining showed distinct differences in cell number and morphology. Less cell viability was observed in the diseased group obviously from strong PI staining when compared to the CT- and SIL-treated group. Moreover, CT showed downregulation of interleukin (IL-6), transforming growth factor-beta 1 (TGF-β1), collagen type 1 A 1 (COL1A1), matrix metalloproteinase-1 (MMP-1), tissue inhibitor of metalloproteinase-1 (TIMP-1) and glutathione peroxidase-7 (GPX-7) levels. Molecular docking studies supported the biochemical findings. It is concluded that the cytoprotective activity of CT against ethanol-induced toxicity might be explained by its anti-inflammatory, immunomodulatory, and collagen-regulating effects.
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Affiliation(s)
| | - Iqra Abid
- Faculty of Pharmacy, The University of Lahore, Lahore, Pakistan
| | - Sana Ismail
- Faculty of Pharmacy, The University of Lahore, Lahore, Pakistan
| | - Irfan Anjum
- Department of Basic Medical Sciences, Shifa College of Pharmaceutical Sciences, Shifa Tameer-e-Millat University, Islamabad, Pakistan
| | - Halima Qadir
- Department of Basic Medical Sciences, Shifa College of Pharmaceutical Sciences, Shifa Tameer-e-Millat University, Islamabad, Pakistan
| | - Tahir Maqbool
- Institute of Molecular Biology and Biotechnology, The University of Lahore, Lahore, Pakistan
| | - Komal Najam
- Faculty of Pharmacy, The University of Lahore, Lahore, Pakistan
| | - Samir Ibenmoussa
- Laboratory of Therapeutic and Organic Chemistry, Faculty of Pharmacy, University of Montpellier, Montpellier, 34000, France
| | - Mohammed Bourhia
- Laboratory of Biotechnology and Natural Resources Valorization, Faculty of Sciences, Ibn Zohr University, 80060, Agadir, Morocco
| | - Ahmad Mohammad Salamatullah
- Department of Food Science & Nutrition, College of Food and Agricultural Sciences, King Saud University, 11 P.O. Box 2460, Riyadh, 11451, Saudi Arabia
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Alzahrani AR, Mohamed DI, Abo Nahas HH, Alaa El-Din Aly El-Waseef D, Altamimi AS, Youssef IH, Ibrahim IAA, Mohamed SMY, Sabry YG, Falemban AH, Elhawary NA, Bamagous GA, Jaremko M, Saied EM. Trimetazidine Alleviates Bleomycin-Induced Pulmonary Fibrosis by Targeting the Long Noncoding RNA CBR3-AS1-Mediated miRNA-29 and Resistin-Like Molecule alpha 1: Deciphering a Novel Trifecta Role of LncRNA CBR3-AS1/miRNA-29/FIZZ1 Axis in Lung Fibrosis. Drug Des Devel Ther 2024; 18:3959-3986. [PMID: 39252766 PMCID: PMC11382803 DOI: 10.2147/dddt.s463626] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2024] [Accepted: 08/28/2024] [Indexed: 09/11/2024] Open
Abstract
INTRODUCTION Pulmonary fibrosis (PF) and tissue remodeling can greatly impair pulmonary function and often lead to fatal outcomes. METHODOLOGY In the present study, we explored a novel molecular interplay of long noncoding (Lnc) RNA CBR3-AS1/ miRNA-29/ FIZZ1 axis in moderating the inflammatory processes, immunological responses, and oxidative stress pathways in bleomycin (BLM)-induced lung fibrosis. Furthermore, we investigated the pharmacological potential of Trimetazidine (TMZ) in ameliorating lung fibrosis. RESULTS Our results revealed that the BLM-treated group exhibited a significant upregulation in the expression of epigenetic regulators, lncRNA CBR3-AS1 and FIZZ1, compared to the control group (P<0.0001), along with the downregulation of miRNA-29 expression. Furthermore, Correlation analysis showed a significant positive association between lnc CBR3-AS1 and FIZZ1 (R=0.7723, p<0.05) and a significant negative association between miRNA-29 and FIZZ1 (R=-0.7535, p<0.05), suggesting lnc CBR3-AS1 as an epigenetic regulator of FIZZ1 in lung fibrosis. BLM treatment significantly increased the expression of Notch, Jagged1, Smad3, TGFB1, and hydroxyproline. Interestingly, the administration of TMZ demonstrated the ability to attenuate the deterioration effects caused by BLM treatment, as indicated by biochemical and histological analyses. Our investigations revealed that the therapeutic potential of TMZ as an antifibrotic drug could be ascribed to its ability to directly target the epigenetic regulators lncRNA CBR3-AS1/ miRNA-29/ FIZZ1, which in turn resulted in the mitigation of lung fibrosis. Histological and immunohistochemical analyses further validated the potential antifibrotic effects of TMZ by mitigating the structural damage associated with fibrosis. DISCUSSION Taken together, our study showed for the first time the interplay between epigenetic lncRNAs CBR3-AS1 and miRNA-29 in lung fibrosis and demonstrated that FIZZ1 could be a downregulatory gene for lncRNA CBR3-AS1 and miRNA-29. Our key findings demonstrate that TMZ significantly reduces the expression of fibrotic, oxidative stress, immunomodulatory, and inflammatory markers, along with epigenetic regulators associated with lung fibrosis. This validates its potential as an effective antifibrotic agent by targeting the CBR3-AS1/miRNA-29/FIZZ1 axis.
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Affiliation(s)
- Abdullah R Alzahrani
- Department of Pharmacology and Toxicology, Faculty of Medicine, Umm Al-Qura University, Makkah, Saudi Arabia
| | - Doaa I Mohamed
- Department of Clinical Pharmacology and Therapeutics, Faculty of Medicine, Ain Shams University, Cairo, Egypt
| | | | | | - Abdulmalik S Altamimi
- Department of Pharmaceutical Chemistry, College of Pharmacy, Prince Sattam Bin Abdulaziz University, Alkharj, Saudi Arabia
| | - Ibrahim H Youssef
- Department of Chest Diseases, Faculty of Medicine, Al-Azhar University, Cairo, Egypt
| | - Ibrahim Abdel Aziz Ibrahim
- Department of Pharmacology and Toxicology, Faculty of Medicine, Umm Al-Qura University, Makkah, Saudi Arabia
| | - Soha M Y Mohamed
- Physiology Department, Faculty of Medicine, Ain Shams University, Cairo, Egypt
| | - Yasmine Gamal Sabry
- Physiology Department, Faculty of Medicine, Ain Shams University, Cairo, Egypt
| | - Alaa H Falemban
- Department of Pharmacology and Toxicology, Faculty of Medicine, Umm Al-Qura University, Makkah, Saudi Arabia
| | - Nasser Attia Elhawary
- Department of Medical Genetics, College of Medicine, Umm Al-Qura University, Mecca, Saudi Arabia
| | - Ghazi A Bamagous
- Department of Pharmacology and Toxicology, Faculty of Medicine, Umm Al-Qura University, Makkah, Saudi Arabia
| | - Mariusz Jaremko
- Smart-Health Initiative and Red Sea Research Center, Division of Biological and Environmental Sciences and Engineering, King Abdullah University of Science and Technology, Thuwal, Saudi Arabia
| | - Essa M Saied
- Chemistry Department, Faculty of Science, Suez Canal University, Ismailia, Egypt
- Institute for Chemistry, Humboldt Universität Zu Berlin, Berlin, Germany
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Wang XL, Yang M, Wang Y. Roles of transforming growth factor-β signaling in liver disease. World J Hepatol 2024; 16:973-979. [PMID: 39086528 PMCID: PMC11287609 DOI: 10.4254/wjh.v16.i7.973] [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] [Received: 12/28/2023] [Revised: 03/04/2024] [Accepted: 05/24/2024] [Indexed: 07/26/2024] Open
Abstract
In this editorial we expand the discussion on the article by Zhang et al published in the recent issue of the World Journal of Hepatology. We focus on the diagnostic and therapeutic targets identified on the basis of the current understanding of the molecular mechanisms of liver disease. Transforming growth factor-β (TGF-β) belongs to a structurally related cytokine super family. The family members display different time- and tissue-specific expression patterns associated with autoimmunity, inflammation, fibrosis, and tumorigenesis; and, they participate in the pathogenesis of many diseases. TGF-β and its related signaling pathways have been shown to participate in the progression of liver diseases, such as injury, inflammation, fibrosis, cirrhosis, and cancer. The often studied TGF-β/Smad signaling pathway has been shown to promote or inhibit liver fibrosis under different circumstances. Similarly, the early immature TGF-β molecule functions as a tumor suppressor, inducing apoptosis; but, its interaction with the mitogenic molecule epidermal growth factor alters this effect, activating anti-apoptotic signals that promote liver cancer development. Overall, TGF-β signaling displays contradictory effects in different liver disease stages. Therefore, the use of TGF-β and related signaling pathway molecules for diagnosis and treatment of liver diseases remains a challenge and needs further study. In this editorial, we aim to review the evidence for the use of TGF-β signaling pathway molecules as diagnostic or therapeutic targets for different liver disease stages.
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Affiliation(s)
- Xiao-Ling Wang
- Clinical Laboratory, Shanxi Academy of Traditional Chinese Medicine, Taiyuan 030012, Shanxi Province, China.
| | - Meng Yang
- Clinical Laboratory, Shanxi Academy of Traditional Chinese Medicine, Taiyuan 030012, Shanxi Province, China
| | - Ying Wang
- Clinical Laboratory, Shanxi Academy of Traditional Chinese Medicine, Taiyuan 030012, Shanxi Province, China
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Hong W, Xiao T, Lin G, Liu C, Li H, Li Y, Hu H, Wu S, Wang S, Liang Z, Lin T, Liu J, Chen X. Structure-based design and synthesis of anti-fibrotic compounds derived from para-positioned 3,4,5-trisubstituted benzene. Bioorg Chem 2024; 144:107113. [PMID: 38232685 DOI: 10.1016/j.bioorg.2024.107113] [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: 11/17/2023] [Revised: 12/29/2023] [Accepted: 01/08/2024] [Indexed: 01/19/2024]
Abstract
Liver fibrosis is an abnormal wound-healing response to liver injuries. It can lead to liver cirrhosis, and even liver cancer and liver failure. There is a lack of treatment for liver fibrosis and it is of great importance to develop anti-fibrotic drugs. A pivotal event in the process of developing liver fibrosis is the activation of hepatic stellate cells (HSCs), in which the nuclear receptor Nur77 plays a crucial role. This study aimed to develop novel anti-fibrotic agents with Nur77 as the drug target by modifying the structure of THPN, a Nur77-binding and anti-melanoma compound. Specifically, a series of para-positioned 3,4,5-trisubstituted benzene ring compounds with long-chain backbone were generated and tested for anti-fibrotic activity. Among these compounds, compound A8 was with the most potent and Nur77-dependent inhibitory activity against TGF-β1-induced activation of HSCs. In a crystal structure analysis, compound A8 bound Nur77 in a peg-in-hole mode as THPN did but adopted a different conformation that could interfere the Nur77 interaction with AKT, which was previous shown to be important for an anti-fibrotic activity. In a cell-based assay, compound A8 indeed impeded the interaction between Nur77 and AKT leading to the stabilization of Nur77 without the activation of AKT. In a mouse model, compound A8 effectively suppressed the activation of AKT signaling pathway and up-regulated the cellular level of Nur77 to attenuate the HSCs activation and ameliorate liver fibrosis with no significant toxic side effects. Collectively, this work demonstrated that Nur77-targeting compound A8 is a promising anti-fibrotic drug candidate.
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Affiliation(s)
- Wenbin Hong
- State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network, State-province Joint Engineering Laboratory of Targeted Drugs from Natural Products, School of Life Sciences, Xiamen University, Xiamen, China; Cancer Research Center of Xiamen University, Xiamen, China; Xiamen Key Laboratory of Clinical Efficacy and Evidence Studies of Traditional Chinese Medicine, The First Affiliated Hospital of Xiamen University, Xiamen, China; The First Affiliated Hospital of Xiamen University, Xiamen, China
| | - Tianyichen Xiao
- State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network, State-province Joint Engineering Laboratory of Targeted Drugs from Natural Products, School of Life Sciences, Xiamen University, Xiamen, China; Cancer Research Center of Xiamen University, Xiamen, China
| | - Gang Lin
- State Key Laboratory of Cellular Stress Biology, Fujian Provincial Key Laboratory of Innovative Drug Target Research, School of Pharmaceutical Sciences, Faculty of Medicine and Life Sciences, Xiamen University, Xiamen 361102, China
| | - Changqin Liu
- Xiamen Key Laboratory of Clinical Efficacy and Evidence Studies of Traditional Chinese Medicine, The First Affiliated Hospital of Xiamen University, Xiamen, China; The First Affiliated Hospital of Xiamen University, Xiamen, China
| | - Hailong Li
- The State Key Laboratory of Medicinal Chemical Biology, College of Pharmacy and Key Laboratory of Molecular Drug Research, Nankai University, Tianjin 300350, China
| | - Yunlong Li
- State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network, State-province Joint Engineering Laboratory of Targeted Drugs from Natural Products, School of Life Sciences, Xiamen University, Xiamen, China; Cancer Research Center of Xiamen University, Xiamen, China
| | - Hongyu Hu
- Xingzhi College, Zhejiang Normal University, Lanxi 321004, China
| | - Siqi Wu
- State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network, State-province Joint Engineering Laboratory of Targeted Drugs from Natural Products, School of Life Sciences, Xiamen University, Xiamen, China; Cancer Research Center of Xiamen University, Xiamen, China
| | - Songqing Wang
- State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network, State-province Joint Engineering Laboratory of Targeted Drugs from Natural Products, School of Life Sciences, Xiamen University, Xiamen, China; Cancer Research Center of Xiamen University, Xiamen, China
| | - Zhijian Liang
- State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network, State-province Joint Engineering Laboratory of Targeted Drugs from Natural Products, School of Life Sciences, Xiamen University, Xiamen, China; Cancer Research Center of Xiamen University, Xiamen, China
| | - Tianwei Lin
- State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network, State-province Joint Engineering Laboratory of Targeted Drugs from Natural Products, School of Life Sciences, Xiamen University, Xiamen, China; Cancer Research Center of Xiamen University, Xiamen, China.
| | - Jie Liu
- State Key Laboratory of Cellular Stress Biology, Fujian Provincial Key Laboratory of Innovative Drug Target Research, School of Pharmaceutical Sciences, Faculty of Medicine and Life Sciences, Xiamen University, Xiamen 361102, China.
| | - Xueqin Chen
- Xiamen Key Laboratory of Clinical Efficacy and Evidence Studies of Traditional Chinese Medicine, The First Affiliated Hospital of Xiamen University, Xiamen, China; The First Affiliated Hospital of Xiamen University, Xiamen, China.
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Zhang N, Wu X, Zhang W, Sun Y, Yan X, Xu A, Han Q, Yang A, You H, Chen W. Targeting thrombospondin-2 retards liver fibrosis by inhibiting TLR4-FAK/TGF-β signaling. JHEP Rep 2024; 6:101014. [PMID: 38379585 PMCID: PMC10877131 DOI: 10.1016/j.jhepr.2024.101014] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/25/2023] [Revised: 12/13/2023] [Accepted: 01/08/2024] [Indexed: 02/22/2024] Open
Abstract
Background & Aims Thrombospondin-2 (THBS2) expression is associated with liver fibrosis regardless of etiology. However, the role of THBS2 in the pathogenesis of liver fibrosis has yet to be elucidated. Methods The in vivo effects of silencing Thbs2 in hepatic stellate cells (HSCs) were examined using an adeno-associated virus vector (serotype 6, AAV6) containing short-hairpin RNAs targeting Thbs2, under the regulatory control of cytomegalovirus, U6 or the α-smooth muscle promoter, in mouse models of carbon tetrachloride or methionine-choline deficient (MCD) diet-induced liver fibrosis. Crosstalk between THBS2 and toll-like receptor 4 (TLR4), as well as the cascaded signaling, was systematically investigated using mouse models, primary HSCs, and human HSC cell lines. Results THBS2 was predominantly expressed in activated HSCs and dynamically increased with liver fibrosis progression and decreased with regression. Selective interference of Thbs2 in HSCs retarded intrahepatic inflammatory infiltration, steatosis accumulation, and fibrosis progression following carbon tetrachloride challenge or in a dietary model of metabolic dysfunction-associated steatohepatitis. Mechanically, extracellular THBS2, as a dimer, specifically recognized and directly bound to TLR4, activating HSCs by stimulating downstream profibrotic focal adhesion kinase (FAK)/transforming growth factor beta (TGF-β) pathways. Disruption of the THBS2-TLR4-FAK/TGF-β signaling axis notably alleviated HSC activation and liver fibrosis aggravation. Conclusions THBS2 plays a crucial role in HSC activation and liver fibrosis progression through TLR4-FAK/TGF-β signaling in an autocrine manner, representing an attractive potential therapeutic target for liver fibrosis. Impact and implications Thrombospondin-2 (THBS2) is emerging as a factor closely associated with liver fibrosis regardless of etiology. However, the mechanisms by which THBS2 is involved in liver fibrosis remain unclear. Here, we showed that THBS2 plays a prominent role in the pathogenesis of liver fibrosis by activating the TLR4-TGF-β/FAK signaling axis and hepatic stellate cells in an autocrine manner, providing a potential therapeutic target for the treatment of liver fibrosis.
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Affiliation(s)
- Ning Zhang
- Liver Research Center, Beijing Friendship Hospital, Capital Medical University, No. 95 Yong’an Road, Xicheng District, Beijing 100050, China
- State Key Lab of Digestive Health, Beijing Friendship Hospital, Capital Medical University, No. 95 Yong’an Road, Xicheng District, Beijing 100050, China
- National Clinical Research Center of Digestive Diseases, Beijing Friendship Hospital, Capital Medical University, No. 95 Yong’an Road, Xicheng District, Beijing 100050, China
| | - Xiaoning Wu
- Liver Research Center, Beijing Friendship Hospital, Capital Medical University, No. 95 Yong’an Road, Xicheng District, Beijing 100050, China
- State Key Lab of Digestive Health, Beijing Friendship Hospital, Capital Medical University, No. 95 Yong’an Road, Xicheng District, Beijing 100050, China
- National Clinical Research Center of Digestive Diseases, Beijing Friendship Hospital, Capital Medical University, No. 95 Yong’an Road, Xicheng District, Beijing 100050, China
| | - Wen Zhang
- Liver Research Center, Beijing Friendship Hospital, Capital Medical University, No. 95 Yong’an Road, Xicheng District, Beijing 100050, China
- State Key Lab of Digestive Health, Beijing Friendship Hospital, Capital Medical University, No. 95 Yong’an Road, Xicheng District, Beijing 100050, China
- National Clinical Research Center of Digestive Diseases, Beijing Friendship Hospital, Capital Medical University, No. 95 Yong’an Road, Xicheng District, Beijing 100050, China
| | - Yameng Sun
- Liver Research Center, Beijing Friendship Hospital, Capital Medical University, No. 95 Yong’an Road, Xicheng District, Beijing 100050, China
- State Key Lab of Digestive Health, Beijing Friendship Hospital, Capital Medical University, No. 95 Yong’an Road, Xicheng District, Beijing 100050, China
- National Clinical Research Center of Digestive Diseases, Beijing Friendship Hospital, Capital Medical University, No. 95 Yong’an Road, Xicheng District, Beijing 100050, China
| | - Xuzhen Yan
- State Key Lab of Digestive Health, Beijing Friendship Hospital, Capital Medical University, No. 95 Yong’an Road, Xicheng District, Beijing 100050, China
- National Clinical Research Center of Digestive Diseases, Beijing Friendship Hospital, Capital Medical University, No. 95 Yong’an Road, Xicheng District, Beijing 100050, China
- Beijing Clinical Research Institute, Beijing Friendship Hospital, Capital Medical University, No. 95 Yong’an Road, Xicheng District, Beijing 100050, China
- Experimental and Translational Research Center, Beijing Friendship Hospital, Capital Medical University, No. 95 Yong’an Road, Xicheng District, Beijing 100050, China
| | - Anjian Xu
- State Key Lab of Digestive Health, Beijing Friendship Hospital, Capital Medical University, No. 95 Yong’an Road, Xicheng District, Beijing 100050, China
- National Clinical Research Center of Digestive Diseases, Beijing Friendship Hospital, Capital Medical University, No. 95 Yong’an Road, Xicheng District, Beijing 100050, China
- Beijing Clinical Research Institute, Beijing Friendship Hospital, Capital Medical University, No. 95 Yong’an Road, Xicheng District, Beijing 100050, China
- Experimental and Translational Research Center, Beijing Friendship Hospital, Capital Medical University, No. 95 Yong’an Road, Xicheng District, Beijing 100050, China
| | - Qi Han
- Liver Research Center, Beijing Friendship Hospital, Capital Medical University, No. 95 Yong’an Road, Xicheng District, Beijing 100050, China
- State Key Lab of Digestive Health, Beijing Friendship Hospital, Capital Medical University, No. 95 Yong’an Road, Xicheng District, Beijing 100050, China
- National Clinical Research Center of Digestive Diseases, Beijing Friendship Hospital, Capital Medical University, No. 95 Yong’an Road, Xicheng District, Beijing 100050, China
| | - Aiting Yang
- State Key Lab of Digestive Health, Beijing Friendship Hospital, Capital Medical University, No. 95 Yong’an Road, Xicheng District, Beijing 100050, China
- National Clinical Research Center of Digestive Diseases, Beijing Friendship Hospital, Capital Medical University, No. 95 Yong’an Road, Xicheng District, Beijing 100050, China
- Beijing Clinical Research Institute, Beijing Friendship Hospital, Capital Medical University, No. 95 Yong’an Road, Xicheng District, Beijing 100050, China
- Experimental and Translational Research Center, Beijing Friendship Hospital, Capital Medical University, No. 95 Yong’an Road, Xicheng District, Beijing 100050, China
| | - Hong You
- Liver Research Center, Beijing Friendship Hospital, Capital Medical University, No. 95 Yong’an Road, Xicheng District, Beijing 100050, China
- State Key Lab of Digestive Health, Beijing Friendship Hospital, Capital Medical University, No. 95 Yong’an Road, Xicheng District, Beijing 100050, China
- National Clinical Research Center of Digestive Diseases, Beijing Friendship Hospital, Capital Medical University, No. 95 Yong’an Road, Xicheng District, Beijing 100050, China
| | - Wei Chen
- State Key Lab of Digestive Health, Beijing Friendship Hospital, Capital Medical University, No. 95 Yong’an Road, Xicheng District, Beijing 100050, China
- National Clinical Research Center of Digestive Diseases, Beijing Friendship Hospital, Capital Medical University, No. 95 Yong’an Road, Xicheng District, Beijing 100050, China
- Beijing Clinical Research Institute, Beijing Friendship Hospital, Capital Medical University, No. 95 Yong’an Road, Xicheng District, Beijing 100050, China
- Experimental and Translational Research Center, Beijing Friendship Hospital, Capital Medical University, No. 95 Yong’an Road, Xicheng District, Beijing 100050, China
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11
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Zhu J, Zhou T, Menggen M, Aimulajiang K, Wen H. Ghrelin regulating liver activity and its potential effects on liver fibrosis and Echinococcosis. Front Cell Infect Microbiol 2024; 13:1324134. [PMID: 38259969 PMCID: PMC10800934 DOI: 10.3389/fcimb.2023.1324134] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2023] [Accepted: 12/15/2023] [Indexed: 01/24/2024] Open
Abstract
Ghrelin widely exists in the central nervous system and peripheral organs, and has biological activities such as maintaining energy homeostasis, regulating lipid metabolism, cell proliferation, immune response, gastrointestinal physiological activities, cognition, memory, circadian rhythm and reward effects. In many benign liver diseases, it may play a hepatoprotective role against steatosis, chronic inflammation, oxidative stress, mitochondrial dysfunction, endoplasmic reticulum stress and apoptosis, and improve liver cell autophagy and immune response to improve disease progression. However, the role of Ghrelin in liver Echinococcosis is currently unclear. This review systematically summarizes the molecular mechanisms by which Ghrelin regulates liver growth metabolism, immune-inflammation, fibrogenesis, proliferation and apoptosis, as well as its protective effects in liver fibrosis diseases, and further proposes the role of Ghrelin in liver Echinococcosis infection. During the infectious process, it may promote the parasitism and survival of parasites on the host by improving the immune-inflammatory microenvironment and fibrosis state, thereby accelerating disease progression. However, there is currently a lack of targeted in vitro and in vivo experimental evidence for this viewpoint.
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Affiliation(s)
- Jiang Zhu
- State Key Laboratory of Pathogenesis, Prevention and Treatment of High Incidence Diseases in Central Asia, Clinical Medicine Institute, The First Affiliated Hospital of Xinjiang Medical University, Urumqi, Xinjiang, China
- Department of Hepatobiliary and Hydatid Disease, Digestive and Vascular Surgery Center Therapy Center, The First Affiliated Hospital of Xinjiang Medical University, Urumqi, Xinjiang, China
| | - Tanfang Zhou
- State Key Laboratory of Pathogenesis, Prevention and Treatment of High Incidence Diseases in Central Asia, Clinical Medicine Institute, The First Affiliated Hospital of Xinjiang Medical University, Urumqi, Xinjiang, China
- Department of Hepatobiliary and Hydatid Disease, Digestive and Vascular Surgery Center Therapy Center, The First Affiliated Hospital of Xinjiang Medical University, Urumqi, Xinjiang, China
| | - Meng Menggen
- State Key Laboratory of Pathogenesis, Prevention and Treatment of High Incidence Diseases in Central Asia, Clinical Medicine Institute, The First Affiliated Hospital of Xinjiang Medical University, Urumqi, Xinjiang, China
| | - Kalibixiati Aimulajiang
- State Key Laboratory of Pathogenesis, Prevention and Treatment of High Incidence Diseases in Central Asia, Clinical Medicine Institute, The First Affiliated Hospital of Xinjiang Medical University, Urumqi, Xinjiang, China
| | - Hao Wen
- State Key Laboratory of Pathogenesis, Prevention and Treatment of High Incidence Diseases in Central Asia, Clinical Medicine Institute, The First Affiliated Hospital of Xinjiang Medical University, Urumqi, Xinjiang, China
- Department of Hepatobiliary and Hydatid Disease, Digestive and Vascular Surgery Center Therapy Center, The First Affiliated Hospital of Xinjiang Medical University, Urumqi, Xinjiang, China
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12
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Ortega-Ribera M, Babuta M, Szabo G. Sinusoidal cell interactions—From soluble factors to exosomes. SINUSOIDAL CELLS IN LIVER DISEASES 2024:23-52. [DOI: 10.1016/b978-0-323-95262-0.00002-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
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13
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Hong YJ, Kim GH, Park Y, Jo HJ, Nam MW, Kim DG, Cho H, Shim HJ, Jin JS, Rho H, Han CY. Suaeda glauca Attenuates Liver Fibrosis in Mice by Inhibiting TGFβ1-Smad2/3 Signaling in Hepatic Stellate Cells. Nutrients 2023; 15:3740. [PMID: 37686772 PMCID: PMC10490352 DOI: 10.3390/nu15173740] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2023] [Revised: 08/18/2023] [Accepted: 08/23/2023] [Indexed: 09/10/2023] Open
Abstract
Chronic liver injury due to various hepatotoxic stimuli commonly leads to fibrosis, which is a crucial factor contributing to liver disease-related mortality. Despite the potential benefits of Suaeda glauca (S. glauca) as a natural product, its biological and therapeutic effects are barely known. This study investigated the effects of S. glauca extract (SGE), obtained from a smart farming system utilizing LED lamps, on the activation of hepatic stellate cells (HSCs) and the development of liver fibrosis. C57BL/6 mice received oral administration of either vehicle or SGE (30 or 100 mg/kg) during CCl4 treatment for 6 weeks. The supplementation of SGE significantly reduced liver fibrosis induced by CCl4 in mice as evidenced by histological changes and a decrease in collagen accumulation. SGE treatment also led to a reduction in markers of HSC activation and inflammation as well as an improvement in blood biochemical parameters. Furthermore, SGE administration diminished fibrotic responses following acute liver injury. Mechanistically, SGE treatment prevented HSC activation and inhibited the phosphorylation and nuclear translocation of Smad2/3, which are induced by transforming growth factor (TGF)-β1 in HSCs. Our findings indicate that SGE exhibits anti-fibrotic effects by inhibiting TGFβ1-Smad2/3 signaling in HSCs.
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Affiliation(s)
- You-Jung Hong
- Institute of New Drug Development, School of Pharmacy, Jeonbuk National University, Jeonju 54896, Jeonbuk, Republic of Korea
| | - Gil-Hwan Kim
- Institute of New Drug Development, School of Pharmacy, Jeonbuk National University, Jeonju 54896, Jeonbuk, Republic of Korea
| | - Yongdo Park
- Institute of New Drug Development, School of Pharmacy, Jeonbuk National University, Jeonju 54896, Jeonbuk, Republic of Korea
| | - Hye-Jin Jo
- Institute of New Drug Development, School of Pharmacy, Jeonbuk National University, Jeonju 54896, Jeonbuk, Republic of Korea
| | - Min-Woo Nam
- LED Agri-Bio Fusion Technology Research Center, Jeonbuk National University, Iksan 54596, Jeonbuk, Republic of Korea
| | - Dong-Gu Kim
- Department of Oriental Medicine Resources, Jeonbuk National University, Iksan 54596, Jeonbuk, Republic of Korea
| | - Hwangeui Cho
- Institute of New Drug Development, School of Pharmacy, Jeonbuk National University, Jeonju 54896, Jeonbuk, Republic of Korea
| | - Hyun-Joo Shim
- Institute of New Drug Development, School of Pharmacy, Jeonbuk National University, Jeonju 54896, Jeonbuk, Republic of Korea
| | - Jong-Sik Jin
- LED Agri-Bio Fusion Technology Research Center, Jeonbuk National University, Iksan 54596, Jeonbuk, Republic of Korea
- Department of Oriental Medicine Resources, Jeonbuk National University, Iksan 54596, Jeonbuk, Republic of Korea
| | - Hyunsoo Rho
- Institute of New Drug Development, School of Pharmacy, Jeonbuk National University, Jeonju 54896, Jeonbuk, Republic of Korea
| | - Chang-Yeob Han
- Institute of New Drug Development, School of Pharmacy, Jeonbuk National University, Jeonju 54896, Jeonbuk, Republic of Korea
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Zeng J, An M, Tian W, Wang K, Du B, Li P. Sacha inchi albumin delays skin-aging by alleviating inflammation, oxidative stress and regulating gut microbiota in d-galactose induced-aging mice. JOURNAL OF THE SCIENCE OF FOOD AND AGRICULTURE 2023; 103:4470-4480. [PMID: 36919865 DOI: 10.1002/jsfa.12555] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/24/2022] [Revised: 02/02/2023] [Accepted: 03/15/2023] [Indexed: 06/06/2023]
Abstract
BACKGROUND Sacha inchi albumin exhibits considerable functional activity with notable anti-inflammatory and antioxidation properties, which could delay skin aging. However, its underlying mechanisms for delaying skin aging have not been elucidated. The aim of the present study was to investigate the anti-skin-aging effect of sacha inchi albumin (SIA) in d-galactose induced-aging mice. RESULTS Sacha inchi albumin improved moisture content, collagen level, and the state of aged skin in rats. Sacha inchi albumin intervention markedly increased the skin antioxidant enzymatic activities including those of glutathione peroxidase, and catalase, but decreased the malondialdehyde content. It also regulated inflammation by reducing the level of tumor necrosis factor-α (TNF-α) and increasing the level of interleukin-6 (IL-6). Administration of SIA also increased the expression level of collagen I and III, increased the expression of tissue inhibitor of metalloprotease-1, and decreased the expression of metalloproteinases. Sacha inchi albumin can also activate the transforming growth factor-β (TGF-β)/Smad pathway. Meanwhile, 16S rRNA sequencing analysis revealed that SIA treatment altered the composition of microbiota, and increased the relative abundance of Lactobacillus, but decreased the relative abundance of Alloprevotella and Helicobacter, etc. Helicobacter was positively associated with malondialdehyde (MDA) content and was negatively related to IL-6. CONCLUSION Sacha inchi albumin exhibits excellent anti-skin-aging effect, which provide a new insight for the development of functional sacha inchi albumin. © 2023 Society of Chemical Industry.
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Affiliation(s)
- Jieyu Zeng
- College of Food Science, South China Agricultural University, Guangzhou, 510640, China
| | - Miaoqing An
- College of Food Science, South China Agricultural University, Guangzhou, 510640, China
| | - Wenni Tian
- College of Food Science, South China Agricultural University, Guangzhou, 510640, China
| | - Kun Wang
- College of Food Science, South China Agricultural University, Guangzhou, 510640, China
| | - Bing Du
- College of Food Science, South China Agricultural University, Guangzhou, 510640, China
| | - Pan Li
- College of Food Science, South China Agricultural University, Guangzhou, 510640, China
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15
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Zhang N, Guo F, Song Y. HOXC8/TGF-β1 positive feedback loop promotes liver fibrosis and hepatic stellate cell activation via activating Smad2/Smad3 signaling. Biochem Biophys Res Commun 2023; 662:39-46. [PMID: 37099809 DOI: 10.1016/j.bbrc.2023.04.011] [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: 03/07/2023] [Revised: 03/30/2023] [Accepted: 04/06/2023] [Indexed: 04/28/2023]
Abstract
Liver fibrosis occurs in any chronic liver disease, where extraordinary increase of extracellular matrix components is caused by the hepatic stellate cell (HSC) activation. HOXC8 has been disclosed to participate inregulating cell proliferation and fibrosis in tumors. However, the role of HOXC8 in liver fibrosis and the underlying molecular mechanisms has not yet been investigated. In this study, we founded that HOXC8 mRNA and protein was elevated in a carbon tetrachloride (CCl4)-induced liver fibrosis mouse model and transforming growth factor-β (TGF-β)-treated human (LX-2) HSC cells. Importantly, we observed that downregulating HOXC8 alleviates liver fibrosis and suppressed the fibrogenic gene induction induced by CCl4 in vivo. In addition, inhibition of HOXC8 suppressed the HSC activation and the expression of fibrosis-associated genes (α-SMA and COL1a1) induced by TGF-β1 in LX-2 cells in vitro, while HOXC8 overexpression had the opposite effects. Mechanistically, we demonstrated HOXC8 activates TGFβ1 transcription and enhanced the phosphorylated Smad2/Smad3 levels, suggesting a positive feedback loop between HOXC8 and TGF-β1 that facilitates TGF-β signaling and subsequent HSCs activation. Collectively, our data strongly indicated that a HOXC8/TGF-β1 positive feedback loop plays as a critical role in controlling the HSC activation and in the liver fibrosis process, suggesting that inhibition of HOXC8 may serve as a promoting therapeutic strategy for diseases characterized by liver fibrosis.
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Affiliation(s)
- Ning Zhang
- Department of Gastroenterology, Heping Hospital Affiliated to Changzhi Medical College, Changzhi, 046000, Shanxi, China.
| | - Fang Guo
- Department of Gastroenterology, Heping Hospital Affiliated to Changzhi Medical College, Changzhi, 046000, Shanxi, China
| | - Yuanyuan Song
- Department of Gastroenterology, Heping Hospital Affiliated to Changzhi Medical College, Changzhi, 046000, Shanxi, China
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16
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Sahu R, Goswami S, Narahari Sastry G, Rawal RK. The Preventive and Therapeutic Potential of the Flavonoids in Liver Cirrhosis: Current and Future Perspectives. Chem Biodivers 2023; 20:e202201029. [PMID: 36703592 DOI: 10.1002/cbdv.202201029] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2022] [Accepted: 01/12/2023] [Indexed: 01/28/2023]
Abstract
Non-alcoholic fatty liver disease (NAFLD) may vary from moderately mild non-alcohol fatty liver (NAFL) towards the malignant variant known as non-alcoholic steatohepatitis (NASH), which is marked by fatty liver inflammation and may progress to liver cirrhosis (LC), liver cancer, fibrosis, or liver failure. Flavonoids can protect the liver from toxins through their anti-inflammatory, antioxidant, anti-cancer, and antifibrogenic pharmacological activities. Furthermore, flavonoids protect against LC by regulation of hepatic stellate cells (HSCs) trans-differentiation, inhibiting growth factors like TGF-β and platelets-derived growth factor (PDGF), vascular epithelial growth factor (VEGF), viral infections like hepatitis-B, C and D viruses (HBV, HCV & HDV), autoimmune-induced, alcohol-induced, metabolic disorder-induced, causing by apoptosis, and regulating MAPK pathways. These flavonoids may be explored in the future as a therapeutic solution for hepatic diseases.
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Affiliation(s)
- Rakesh Sahu
- Natural Product Chemistry Group, Chemical Sciences and Technology Division, CSIR-North East Institute of Science and Technology, Jorhat, 785006, Assam, India
| | - Sourav Goswami
- Natural Product Chemistry Group, Chemical Sciences and Technology Division, CSIR-North East Institute of Science and Technology, Jorhat, 785006, Assam, India
| | - G Narahari Sastry
- Natural Product Chemistry Group, Chemical Sciences and Technology Division, CSIR-North East Institute of Science and Technology, Jorhat, 785006, Assam, India.,Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, 201 002, Uttar Pradesh, India
| | - Ravindra K Rawal
- Natural Product Chemistry Group, Chemical Sciences and Technology Division, CSIR-North East Institute of Science and Technology, Jorhat, 785006, Assam, India.,Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, 201 002, Uttar Pradesh, India
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17
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Zhang FM, Wang B, Hu H, Zhang YY, Chen HH, Jiang ZJ, Zeng MX, Liu XJ. Transcriptional profiles of TGF-β superfamily members in the lumbar DRGs and the effects of activins A and C on inflammatory pain in rats. J Physiol Biochem 2023:10.1007/s13105-022-00943-z. [PMID: 36696051 DOI: 10.1007/s13105-022-00943-z] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2022] [Accepted: 12/28/2022] [Indexed: 01/26/2023]
Abstract
Signaling by the transforming growth factor (TGF)-β superfamily is necessary for proper neural development and is involved in pain processing under both physiological and pathological conditions. Sensory neurons that reside in the dorsal root ganglia (DRGs) initially begin to perceive noxious signaling from their innervating peripheral target tissues and further convey pain signaling to the central nervous system. However, the transcriptional profile of the TGF-β superfamily members in DRGs during chronic inflammatory pain remains elusive. We developed a custom microarray to screen for transcriptional changes in members of the TGF-β superfamily in lumbar DRGs of rats with chronic inflammatory pain and found that the transcription of the TGF-β superfamily members tends to be downregulated. Among them, signaling of the activin/inhibin and bone morphogenetic protein/growth and differentiation factor (BMP/GDF) families dramatically decreased. In addition, peripherally pre-local administration of activins A and C worsened formalin-induced acute inflammatory pain, whereas activin C, but not activin A, improved formalin-induced persistent inflammatory pain by inhibiting the activation of astrocytes. This is the first report of the TGF-β superfamily transcriptional profiles in lumbar DRGs under chronic inflammatory pain conditions, in which transcriptional changes in cytokines or pathway components were found to contribute to, or be involved in, inflammatory pain processing. Our data will provide more targets for pain research.
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Affiliation(s)
- Feng-Ming Zhang
- School of Pharmacy, Nantong University, Jiangsu Province, 226001, Nantong, China
- Department of Anesthesiology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, 210029, Jiangsu Province, China
- Pain and Related Disease Research Lab, Shantou University Medical College, Shantou, 515041, Guangdong Province, China
| | - Bing Wang
- School of Pharmacy, Nantong University, Jiangsu Province, 226001, Nantong, China
| | - Han Hu
- Institute of Apicultural Research/Key Laboratory of Pollinating Insect Biology, Ministry of Agriculture, Chinese Academy of Agricultural Sciences, No. 1 Beigou Xiangshan, Beijing, 100093, China
| | - Ying-Ying Zhang
- School of Pharmacy, Nantong University, Jiangsu Province, 226001, Nantong, China
| | - Hao-Hao Chen
- Pain and Related Disease Research Lab, Shantou University Medical College, Shantou, 515041, Guangdong Province, China
| | - Zuo-Jie Jiang
- Pain and Related Disease Research Lab, Shantou University Medical College, Shantou, 515041, Guangdong Province, China
| | - Mei-Xing Zeng
- Pain and Related Disease Research Lab, Shantou University Medical College, Shantou, 515041, Guangdong Province, China
| | - Xing-Jun Liu
- School of Pharmacy, Nantong University, Jiangsu Province, 226001, Nantong, China.
- Pain and Related Disease Research Lab, Shantou University Medical College, Shantou, 515041, Guangdong Province, China.
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Zhang FM, Wang B, Hu H, Li QY, Chen HH, Luo LT, Jiang ZJ, Zeng MX, Liu XJ. Transcriptional Profiling of TGF-β Superfamily Members in Lumbar DRGs of Rats Following Sciatic Nerve Axotomy and Activin C Inhibits Neuropathic Pain. Endocr Metab Immune Disord Drug Targets 2023; 23:375-388. [PMID: 36201267 DOI: 10.2174/1871530322666221006114557] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/26/2022] [Revised: 08/04/2022] [Accepted: 09/29/2022] [Indexed: 02/05/2023]
Abstract
BACKGROUND Neuroinflammation and cytokines play critical roles in neuropathic pain and axon degeneration/regeneration. Cytokines of transforming growth factor-β superfamily have implications in pain and injured nerve repair processing. However, the transcriptional profiles of the transforming growth factor-β superfamily members in dorsal root ganglia under neuropathic pain and axon degeneration/regeneration conditions remain elusive. OBJECTIVE We aimed to plot the transcriptional profiles of transforming growth factor-β superfamily components in lumbar dorsal root ganglia of sciatic nerve-axotomized rats and to further verify the profiles by testing the analgesic effect of activin C, a representative cytokine, on neuropathic pain. METHODS Adult male rats were axotomized in sciatic nerves, and lumbar dorsal root ganglia were isolated for total RNA extraction or section. A custom microarray was developed and employed to plot the gene expression profiles of transforming growth factor-β superfamily components. Realtime RT-PCR was used to confirm changes in the expression of activin/inhibin family genes, and then in situ hybridization was performed to determine the cellular locations of inhibin α, activin βC, BMP-5 and GDF-9 mRNAs. The rat spared nerve injury model was performed, and a pain test was employed to determine the effect of activin C on neuropathic pain. RESULTS The expression of transforming growth factor-β superfamily cytokines and their signaling, including some receptors and signaling adaptors, were robustly upregulated. Activin βC subunit mRNAs were expressed in the small-diameter dorsal root ganglion neurons and upregulated after axotomy. Single intrathecal injection of activin C inhibited neuropathic pain in spared nerve injury model. CONCLUSION This is the first report to investigate the transcriptional profiles of members of transforming growth factor-β superfamily in axotomized dorsal root ganglia. The distinct cytokine profiles observed here might provide clues toward further study of the role of transforming growth factor-β superfamily in the pathogenesis of neuropathic pain and axon degeneration/regeneration after peripheral nerve injury.
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Affiliation(s)
- Feng-Ming Zhang
- School of Pharmacy, Nantong University, Nantong, Jiangsu Province, 226001, China
- Department of Anesthesiology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu Province, 210029, China
| | - Bing Wang
- School of Pharmacy, Nantong University, Nantong, Jiangsu Province, 226001, China
| | - Han Hu
- Institute of Apicultural Research/Key Laboratory of Pollinating Insect Biology, Ministry of Agriculture, Chinese Academy of Agricultural Sciences, No. 1 Beigou Xiangshan, Beijing, 100093, China
| | - Qing-Yi Li
- Pain and Related Disease Research Lab, Shantou University Medical College, Shantou, Guangdong Province, 515041, China
| | - Hao-Hao Chen
- Pain and Related Disease Research Lab, Shantou University Medical College, Shantou, Guangdong Province, 515041, China
| | - Li-Ting Luo
- School of Pharmacy, Nantong University, Nantong, Jiangsu Province, 226001, China
| | - Zuo-Jie Jiang
- Pain and Related Disease Research Lab, Shantou University Medical College, Shantou, Guangdong Province, 515041, China
| | - Mei-Xing Zeng
- Pain and Related Disease Research Lab, Shantou University Medical College, Shantou, Guangdong Province, 515041, China
| | - Xing-Jun Liu
- School of Pharmacy, Nantong University, Nantong, Jiangsu Province, 226001, China
- Pain and Related Disease Research Lab, Shantou University Medical College, Shantou, Guangdong Province, 515041, China
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Fang J, Ji Q, Gao S, Xiao Z, Liu W, Hu Y, Lv Y, Chen G, Mu Y, Cai H, Chen J, Liu P. PDGF-BB is involved in HIF-1α/CXCR4/CXCR7 axis promoting capillarization of hepatic sinusoidal endothelial cells. Heliyon 2023; 9:e12715. [PMID: 36685431 PMCID: PMC9852936 DOI: 10.1016/j.heliyon.2022.e12715] [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: 06/15/2022] [Revised: 10/24/2022] [Accepted: 12/22/2022] [Indexed: 01/01/2023] Open
Abstract
BACKGROUND The activation of HIF-1α/CXCR4 pathway in liver sinusoidal endothelial cells (LSECs) could downregulate CXCR7, leading to the capillarization of LSECs to promote hepatic fibrosis. However, the mechanism between CXCR4 and CXCR7 is still undefined. The aim is to investigate the role of PDGF-BB in the dedifferentiation of LSECs and hepatic stellate cells (HSCs) activation. METHODS The activation of HIF-1α/CXCR4 pathway in two kinds of liver fibrosis models were observed. The effects of HIF-1α, CXCR4, PDGF-BB on the dedifferentiation of LSECs were investigated by using the inhibitors of HIF-1α, CXCR4 or PDGFR-β separately or transfecting with a CXCR4 knockdown lentiviral vector. In addition, the relationship between LSECs and HSCs was demonstrated by co-culture of LSECs and HSCs using the transwell chamber. RESULTS CXCR4 upregulation and CXCR7 downregulation were accompanied by LSECs capillarization and HSCs activation both in CCl4-induced and BDL-induced fibrotic liver. In vitro, downregulation of HIF-1α significantly descreased CXCR4 and CD31 expression, and enhanced the expressions of CXCR7, CD44 and LYVE1. Downregulation of CXCR4 in LSECs significantly downregulated PDGF-BB, PDGFR-β and CD31, and enhanced CXCR7, CD44 and LYVE1 expression, while the expression of HIF-1α did not change significantly. STI571, a PDGF receptor inhibitor, could significantly downregulate PDGFR-β and increase the expression of CXCR7 to inhibit the dedifferentiation of LSECs. In addition, alleviateion the dedifferentiation of LSECs could decrease the expression of PDGFR-β of HSCs, then inhibiting the activation of HSCs. CONCLUSIONS This study revealed that HIF-1α/CXCR4/PDGF-BB/CXCR7 axis promoted the dedifferentiation of LSECs, consequently triggering HSCs activation and liver fibrosis.
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Affiliation(s)
- Jing Fang
- Institute of Liver Diseases, Key Laboratory of Liver and Kidney Diseases (Ministry of Education), Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China
- Shanghai Key Laboratory of Traditional Chinese Clinical Medicine, Shanghai, 201203, China
| | - Qiang Ji
- Institute of Liver Diseases, Key Laboratory of Liver and Kidney Diseases (Ministry of Education), Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China
- Shanghai Key Laboratory of Traditional Chinese Clinical Medicine, Shanghai, 201203, China
| | - Siqi Gao
- Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China
| | - Zhun Xiao
- Institute of Liver Diseases, Key Laboratory of Liver and Kidney Diseases (Ministry of Education), Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China
- Shanghai Key Laboratory of Traditional Chinese Clinical Medicine, Shanghai, 201203, China
- Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China
| | - Wei Liu
- Institute of Liver Diseases, Key Laboratory of Liver and Kidney Diseases (Ministry of Education), Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China
- Shanghai Key Laboratory of Traditional Chinese Clinical Medicine, Shanghai, 201203, China
| | - Yonghong Hu
- Institute of Liver Diseases, Key Laboratory of Liver and Kidney Diseases (Ministry of Education), Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China
- Shanghai Key Laboratory of Traditional Chinese Clinical Medicine, Shanghai, 201203, China
| | - Ying Lv
- Institute of Liver Diseases, Key Laboratory of Liver and Kidney Diseases (Ministry of Education), Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China
- Shanghai Key Laboratory of Traditional Chinese Clinical Medicine, Shanghai, 201203, China
| | - Gaofeng Chen
- Institute of Liver Diseases, Key Laboratory of Liver and Kidney Diseases (Ministry of Education), Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China
- Shanghai Key Laboratory of Traditional Chinese Clinical Medicine, Shanghai, 201203, China
| | - Yongping Mu
- Institute of Liver Diseases, Key Laboratory of Liver and Kidney Diseases (Ministry of Education), Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China
- Shanghai Key Laboratory of Traditional Chinese Clinical Medicine, Shanghai, 201203, China
| | - Hong Cai
- Xiamen Hospital of Traditional Chinese Medicine, Xiamen, 361015, China
| | - Jiamei Chen
- Institute of Liver Diseases, Key Laboratory of Liver and Kidney Diseases (Ministry of Education), Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China
- Shanghai Key Laboratory of Traditional Chinese Clinical Medicine, Shanghai, 201203, China
| | - Ping Liu
- Institute of Liver Diseases, Key Laboratory of Liver and Kidney Diseases (Ministry of Education), Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China
- Shanghai Key Laboratory of Traditional Chinese Clinical Medicine, Shanghai, 201203, China
- Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China
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Yang W, Pan L, Cheng Y, Wu X, Tang B, Zhu H, Zhang M, Zhang Y. Nintedanib alleviates pulmonary fibrosis in vitro and in vivo by inhibiting the FAK/ERK/S100A4 signalling pathway. Int Immunopharmacol 2022; 113:109409. [PMID: 36461602 DOI: 10.1016/j.intimp.2022.109409] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2022] [Revised: 10/18/2022] [Accepted: 10/28/2022] [Indexed: 11/09/2022]
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Wang S, Zhang J, Chen H, Zhan X, Nie H, Wang C, Zhang Y, Zheng B, Gong Q. MicroRNA-181b promotes schistosomiasis-induced hepatic fibrosis by targeting Smad7. Mol Biochem Parasitol 2022; 252:111523. [PMID: 36195241 DOI: 10.1016/j.molbiopara.2022.111523] [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: 09/10/2021] [Revised: 09/08/2022] [Accepted: 09/29/2022] [Indexed: 12/31/2022]
Abstract
Schistosomiasis is a common parasitic disease. Hepatosplenic schistosomiasis, caused by Schistosoma japonicum and Schistosoma mansoni, involves pathological changes, including worm egg-induced hepatic granuloma and fibrosis, which can markedly affect the liver's physiological functions. Although the drug praziquantel (PZQ) is used to treat schistosomiasis, drugs against schistosomiasis-induced liver fibrosis are rare in the clinical setting. Therefore, developing effective strategies to prevent and treat schistosomiasis-induced liver fibrosis is crucial. Previous studies have shown that miRNAs are involved in various liver diseases. In this study, we found a gradual increase in miR-181b expression in the murine liver as S. japonicum infection progressed, while the expression of Smad7 decreased. Down-regulating miR-181b significantly alleviated S. japonicum-induced hepatic granuloma and liver fibrosis. In vitro experiments showed that treatment with TGF-β1 upregulated miR-181b levels in the hepatic stellate cell (HSC) line LX2 in a concentration- and time-dependent manner. Downregulation of miR-181b significantly decreased collagen type I alpha 1 chain (COL1A1) expression in TGF-β1-stimulated LX2 cells. These findings indicate that miR-181b promotes HSC activation by down-regulating Smad7 expression, activating the TGF-β1/Smad signaling pathway, and leading to excess collagen expression and deposition. Our findings suggest that miR-181b might be a potentially novel therapeutic target for schistosomiasis-induced liver fibrosis.
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Affiliation(s)
- Shu Wang
- Department of Immunology, School of Medicine, Yangtze University, Jingzhou, China
| | - Jianqiang Zhang
- Department of Immunology, School of Medicine, Yangtze University, Jingzhou, China; Department of Nephrology, Ezhou Central Hospital, Ezhou, China
| | - Hui Chen
- Department of Immunology, School of Medicine, Yangtze University, Jingzhou, China; Department of Laboratory Medicine, First Affiliated Hospital of Yangtze University, Jingzhou, China
| | - Xiang Zhan
- Department of Immunology, School of Medicine, Yangtze University, Jingzhou, China
| | - Hao Nie
- Department of Immunology, School of Medicine, Yangtze University, Jingzhou, China; Clinical Molecular Immunology Center, School of Medicine, Yangtze University, Jingzhou, China
| | - Chao Wang
- Department of Immunology, School of Medicine, Yangtze University, Jingzhou, China; Clinical Molecular Immunology Center, School of Medicine, Yangtze University, Jingzhou, China
| | - Yanxiang Zhang
- Clinical Molecular Immunology Center, School of Medicine, Yangtze University, Jingzhou, China
| | - Bing Zheng
- Department of Immunology, School of Medicine, Yangtze University, Jingzhou, China; Clinical Molecular Immunology Center, School of Medicine, Yangtze University, Jingzhou, China.
| | - Quan Gong
- Department of Immunology, School of Medicine, Yangtze University, Jingzhou, China; Clinical Molecular Immunology Center, School of Medicine, Yangtze University, Jingzhou, China.
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22
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Chen QT, Zhang ZY, Huang QL, Chen HZ, Hong WB, Lin T, Zhao WX, Wang XM, Ju CY, Wu LZ, Huang YY, Hou PP, Wang WJ, Zhou D, Deng X, Wu Q. HK1 from hepatic stellate cell-derived extracellular vesicles promotes progression of hepatocellular carcinoma. Nat Metab 2022; 4:1306-1321. [PMID: 36192599 PMCID: PMC9584821 DOI: 10.1038/s42255-022-00642-5] [Citation(s) in RCA: 65] [Impact Index Per Article: 21.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/21/2021] [Accepted: 08/17/2022] [Indexed: 01/20/2023]
Abstract
Extracellular vesicles play crucial roles in intercellular communication in the tumor microenvironment. Here we demonstrate that in hepatic fibrosis, TGF-β stimulates the palmitoylation of hexokinase 1 (HK1) in hepatic stellate cells (HSCs), which facilitates the secretion of HK1 via large extracellular vesicles in a TSG101-dependent manner. The large extracellular vesicle HK1 is hijacked by hepatocellular carcinoma (HCC) cells, leading to accelerated glycolysis and HCC progression. In HSCs, the nuclear receptor Nur77 transcriptionally activates the expression of depalmitoylase ABHD17B to inhibit HK1 palmitoylation, consequently attenuating HK1 release. However, TGF-β-activated Akt functionally represses Nur77 by inducing Nur77 phosphorylation and degradation. We identify the small molecule PDNPA that binds Nur77 to generate steric hindrance to block Akt targeting, thereby disrupting Akt-mediated Nur77 degradation and preserving Nur77 inhibition of HK1 release. Together, this study demonstrates an overlooked function of HK1 in HCC upon its release from HSCs and highlights PDNPA as a candidate compound for inhibiting HCC progression.
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Affiliation(s)
- Qi-Tao Chen
- State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Biology, School of Life Sciences, Xiamen University, Xiamen, China
| | - Zhi-Yuan Zhang
- State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Biology, School of Life Sciences, Xiamen University, Xiamen, China
| | - Qiao-Ling Huang
- State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Biology, School of Life Sciences, Xiamen University, Xiamen, China
| | - Hang-Zi Chen
- State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Biology, School of Life Sciences, Xiamen University, Xiamen, China.
| | - Wen-Bin Hong
- State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Biology, School of Life Sciences, Xiamen University, Xiamen, China
| | - Tianwei Lin
- State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Biology, School of Life Sciences, Xiamen University, Xiamen, China
| | - Wen-Xiu Zhao
- Fujian Provincial Key Laboratory of Chronic Liver Disease and Hepatocellular Carcinoma, Xiamen University Affiliated ZhongShan Hospital, Xiamen, China
| | - Xiao-Min Wang
- Fujian Provincial Key Laboratory of Chronic Liver Disease and Hepatocellular Carcinoma, Xiamen University Affiliated ZhongShan Hospital, Xiamen, China
| | - Cui-Yu Ju
- State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Biology, School of Life Sciences, Xiamen University, Xiamen, China
| | - Liu-Zheng Wu
- State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Biology, School of Life Sciences, Xiamen University, Xiamen, China
| | - Ya-Ying Huang
- State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Biology, School of Life Sciences, Xiamen University, Xiamen, China
| | - Pei-Pei Hou
- State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Biology, School of Life Sciences, Xiamen University, Xiamen, China
| | - Wei-Jia Wang
- State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Biology, School of Life Sciences, Xiamen University, Xiamen, China
| | - Dawang Zhou
- State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Biology, School of Life Sciences, Xiamen University, Xiamen, China
| | - Xianming Deng
- State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Biology, School of Life Sciences, Xiamen University, Xiamen, China
| | - Qiao Wu
- State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Biology, School of Life Sciences, Xiamen University, Xiamen, China.
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23
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Bu FT, Jia PC, Zhu Y, Yang YR, Meng HW, Bi YH, Huang C, Li J. Emerging therapeutic potential of adeno-associated virus-mediated gene therapy in liver fibrosis. Mol Ther Methods Clin Dev 2022; 26:191-206. [PMID: 35859692 PMCID: PMC9271983 DOI: 10.1016/j.omtm.2022.06.009] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/27/2022]
Abstract
Liver fibrosis is a wound-healing response that results from various chronic damages. If the causes of damage are not removed or effective treatments are not given in a timely manner, it will progress to cirrhosis, even liver cancer. Currently, there are no specific medical therapies for liver fibrosis. Adeno-associated virus (AAV)-mediated gene therapy, one of the frontiers of modern medicine, has gained more attention in many fields due to its high safety profile, low immunogenicity, long-term efficacy in mediating gene expression, and increasingly known tropism. Notably, increasing evidence suggests a promising therapeutic potential for AAV-mediated gene therapy in different liver fibrosis models, which helps to correct abnormally changed target genes in the process of fibrosis and improve liver fibrosis at the molecular level. Moreover, the addition of cell-specific promoters to the genome of recombinant AAV helps to limit gene expression in specific cells, thereby producing better therapeutic efficacy in liver fibrosis. However, animal models are considered to be powerless predictive of tissue tropism, immunogenicity, and genotoxic risks in humans. Thus, AAV-mediated gene therapy will face many challenges. This review systemically summarizes the recent advances of AAV-mediated gene therapy in liver fibrosis, especially focusing on cellular and molecular mechanisms of transferred genes, and presents prospective challenges.
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Affiliation(s)
- Fang-Tian Bu
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, 81 Mei Shan Road, Hefei, Anhui Province 230032, China.,Institute for Liver Diseases of Anhui Medical University, Hefei, China
| | - Peng-Cheng Jia
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, 81 Mei Shan Road, Hefei, Anhui Province 230032, China.,Institute for Liver Diseases of Anhui Medical University, Hefei, China
| | - Yan Zhu
- The First Affiliated Hospital of Anhui Medical University, Hefei, China
| | - Ya-Ru Yang
- The Second Affiliated Hospital of Anhui Medical University, Hefei, China
| | - Hong-Wu Meng
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, 81 Mei Shan Road, Hefei, Anhui Province 230032, China.,Institute for Liver Diseases of Anhui Medical University, Hefei, China
| | - Yi-Hui Bi
- The Second Affiliated Hospital of Anhui Medical University, Hefei, China
| | - Cheng Huang
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, 81 Mei Shan Road, Hefei, Anhui Province 230032, China.,Institute for Liver Diseases of Anhui Medical University, Hefei, China
| | - Jun Li
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, 81 Mei Shan Road, Hefei, Anhui Province 230032, China.,Institute for Liver Diseases of Anhui Medical University, Hefei, China
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The Role of miR-29 Family in TGF-β Driven Fibrosis in Glaucomatous Optic Neuropathy. Int J Mol Sci 2022; 23:ijms231810216. [PMID: 36142127 PMCID: PMC9499597 DOI: 10.3390/ijms231810216] [Citation(s) in RCA: 20] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/07/2022] [Revised: 08/30/2022] [Accepted: 09/02/2022] [Indexed: 11/17/2022] Open
Abstract
Primary open angle glaucoma (POAG), a chronic optic neuropathy, remains the leading cause of irreversible blindness worldwide. It is driven in part by the pro-fibrotic cytokine transforming growth factor beta (TGF-β) and leads to extracellular matrix remodelling at the lamina cribrosa of the optic nerve head. Despite an array of medical and surgical treatments targeting the only known modifiable risk factor, raised intraocular pressure, many patients still progress and develop significant visual field loss and eventual blindness. The search for alternative treatment strategies targeting the underlying fibrotic transformation in the optic nerve head and trabecular meshwork in glaucoma is ongoing. MicroRNAs are small non-coding RNAs known to regulate post-transcriptional gene expression. Extensive research has been undertaken to uncover the complex role of miRNAs in gene expression and miRNA dysregulation in fibrotic disease. MiR-29 is a family of miRNAs which are strongly anti-fibrotic in their effects on the TGF-β signalling pathway and the regulation of extracellular matrix production and deposition. In this review, we discuss the anti-fibrotic effects of miR-29 and the role of miR-29 in ocular pathology and in the development of glaucomatous optic neuropathy. A better understanding of the role of miR-29 in POAG may aid in developing diagnostic and therapeutic strategies in glaucoma.
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Karmacharya MB, Hada B, Park SR, Kim KH, Choi BH. Granulocyte-macrophage colony-stimulating factor (GM-CSF) shows therapeutic effect on dimethylnitrosamine (DMN)-induced liver fibrosis in rats. PLoS One 2022; 17:e0274126. [PMID: 36054162 PMCID: PMC9439244 DOI: 10.1371/journal.pone.0274126] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/20/2022] [Accepted: 08/22/2022] [Indexed: 11/18/2022] Open
Abstract
This study was undertaken to investigate the inhibitory effects of granulocyte-macrophage colony-stimulating factor (GM-CSF) on dimethylnitrosamine (DMN)-induced liver fibrosis in rats. Liver fibrosis was induced in Sprague-Dawley rats by injecting DMN intraperitoneally (at 10 mg/kg of body weight) daily for three consecutive days per week for 4 weeks. To investigate the effect of GM-CSF on disease onset, GM-CSF (50 μg/kg of body weight) was co-treated with DMN for 2 consecutive days per week for 4 weeks (4-week groups). To observe the effect of GM-CSF on the progression of liver fibrosis, GM-CSF was post-treated alone at 5–8 weeks after the 4 weeks of DMN injection (8-week groups). We found that DMN administration for 4 weeks produced molecular and pathological manifestations of liver fibrosis, that is, it increased the expressions of collagen type I, alpha-smooth muscle actin (α-SMA), and transforming growth factor-β1 (TGF-β1), and decreased peroxisome proliferator-activated receptor gamma (PPAR-γ) expression. In addition, elevated serum levels of aspartate aminotransferase (AST), total bilirubin level (TBIL), and decreased albumin level (ALB) were observed. In both the 4-week and 8-week groups, GM-CSF clearly improved the pathological liver conditions in the gross and histological observations, and significantly recovered DMN-induced increases in AST and TBIL and decreases in ALB serum levels to normal. GM-CSF also significantly decreased DMN-induced increases in collagen type I, α-SMA, and TGF-β1 and increased DMN-induced decreases in PPAR-γ expression. In the DMN groups, survival decreased continuously for 8 weeks after DMN treatment for the first 4 weeks. GM-CSF showed a survival benefit when co-treated for the first 4 weeks but a marginal effect when post-treated for 5–8 weeks. In conclusion, co-treatment of GM-CSF showed therapeutic effects on DMN-induced liver fibrosis and survival rates in rats, while post-treatment efficiently blocked liver fibrosis.
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Affiliation(s)
| | - Binika Hada
- Department of Biomedical Sciences, Inha University College of Medicine, Incheon, South Korea
| | - So Ra Park
- Department of Physiology and Biophysics, Inha University College of Medicine, Incheon, South Korea
| | - Kil Hwan Kim
- Veterans Medical Research Institute, Veterans Health Service Medical Center, Seoul, South Korea
- * E-mail: (BHC); (KHK)
| | - Byung Hyune Choi
- Department of Biomedical Sciences, Inha University College of Medicine, Incheon, South Korea
- * E-mail: (BHC); (KHK)
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Salehipour Bavarsad S, Jalali MT, Bijan Nejad D, Alypoor B, Babaahmadi Rezaei H, Mohammadtaghvaei N. TGFβ1-Pretreated Exosomes of Wharton Jelly Mesenchymal Stem Cell as a Therapeutic Strategy for Improving Liver Fibrosis. HEPATITIS MONTHLY 2022; 22. [DOI: 10.5812/hepatmon-123416] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/16/2022] [Revised: 05/14/2022] [Accepted: 05/26/2022] [Indexed: 01/03/2025]
Abstract
Background: Mesenchymal stem cells (MSCs) are the most promising tools for cell treatment and human tissue regeneration, e.g., in liver fibrosis. Mesenchymal stem cells repair tissue damage through paracrine mediators such as exosomes. Types and concentrations of inflammatory mediators, including transforming growth factor-beta (TGFβ1), in MSCs microenvironment can affect MSCs’ function and therapeutic potency. Objectives: This experimental study aimed to explore the effects of Wharton jelly MSCs (WJ-MSCs) exosomes on fibrotic gene expression and Smad2/3 phosphorylation (phospho-Smad2/3 (p-Smad2/3)). Moreover, we further investigated whether WJ-MSCs pretreatment with different concentrations of TGFβ1 changes the anti-fibrotic properties of their exosomes. Methods: After isolation from the umbilical cord, WJ-MSCs were characterized by observing differentiation and measuring surface biomarkers using flowcytometry. The WJ-MSC-derived exosomes were extracted and identified using transmission electron microscopy (TEM), dynamic light scattering (DLS), and western blotting. Real-time PCR and western blot for extracellular matrix (ECM) and p-Smad2/3 expression detection were used to investigate the effect of exosomes from untreated and TGFβ1-pretreated WJ-MSCs on activated hepatic stellate cells (HSCs). Results: Phospho-Smad2/3, α-smooth muscle actin (α-SMA), and collagen1α1 levels were enhanced following treatment with TGFβ1, whereas E-cadherin was decreased. However, the outcomes were reversed after treatment with WJ-MSC-derived exosomes. Exosomes from TGFβ1-pretreated WJ-MSCs induced a significant decrease in p-Smad2/3 levels in activated HSCs, accompanied by the upregulation of E-cadherin gene expression and downregulation of α-SMA and collagen1α1 when compared to untreated WJ-MSC-derived exosomes. The p-Smad2/3 proteins were significantly decreased (fold change: 0.23, P-value < 0.0001) after exposure to low-dose TGFβ1-pretreated WJ-MSC-derived exosomes (0.1 ng/mL), showing the best effect on activated HSCs. Conclusions: Exosomes derived from untreated WJ-MSCs could regress TGFβ-Smad2/3 signaling and the expression of fibrotic markers in activated LX-2 cells. However, these effects were significantly profound with applying exosomes derived from 0.1 ng/mL TGFβ-pretreated WJ-MSCs. We also observed the dose-response effects of TGFβ on WJ-MSCs-derived exosomes. Therefore, exosomes derived from TGFβ-pretreated WJ-MSCs may be critical in improving fibrosis and benefit liver fibrosis patients.
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Du W, Wang L. The Crosstalk Between Liver Sinusoidal Endothelial Cells and Hepatic Microenvironment in NASH Related Liver Fibrosis. Front Immunol 2022; 13:936196. [PMID: 35837401 PMCID: PMC9274003 DOI: 10.3389/fimmu.2022.936196] [Citation(s) in RCA: 25] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2022] [Accepted: 06/03/2022] [Indexed: 11/13/2022] Open
Abstract
Chronic liver injury can be caused by many factors, including virus infection, alcohol intake, cholestasis and abnormal fat accumulation. Nonalcoholic steatohepatitis (NASH) has become the main cause of liver fibrosis worldwide. Recently, more and more evidences show that hepatic microenvironment is involved in the pathophysiological process of liver fibrosis induced by NASH. Hepatic microenvironment consists of various types of cells and intercellular crosstalk among different cells in the liver sinusoids. Liver sinusoidal endothelial cells (LSECs), as the gatekeeper of liver microenvironment, play an irreplaceable role in the homeostasis and alterations of liver microenvironment. Many recent studies have reported that during the progression of NASH to liver fibrosis, LSECs are involved in various stages mediated by a series of mechanisms. Therefore, here we review the key role of crosstalk between LSECs and hepatic microenvironment in the progression of NASH to liver fibrosis (steatosis, inflammation, and fibrosis), as well as promising therapeutic strategies targeting LSECs.
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Affiliation(s)
- Wei Du
- Department of Hepatobiliary Surgery, Xi-Jing Hospital, The Fourth Military Medical University, Xi'an, China
| | - Lin Wang
- Department of Hepatobiliary Surgery, Xi-Jing Hospital, The Fourth Military Medical University, Xi'an, China
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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: 22] [Impact Index Per Article: 7.3] [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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Leilei L, Wenke Q, Yuyuan L, Sihang L, Xue S, Weiqiang C, Lianbao Y, Ying W, Yan L, Ming L. Oleanolic acid-loaded nanoparticles attenuate activation of hepatic stellate cells via suppressing TGF-β1 and oxidative stress in PM2.5-exposed hepatocytes. Toxicol Appl Pharmacol 2022; 437:115891. [PMID: 35077758 DOI: 10.1016/j.taap.2022.115891] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2021] [Revised: 01/08/2022] [Accepted: 01/18/2022] [Indexed: 12/24/2022]
Abstract
Liver fibrosis has the potential to progress into liver cirrhosis, liver failure, and even death. Hepatic stellate cells (HSCs) activation play a central role in liver fibrosis, and persistently damaged hepatocytes secrete soluble factors that activate transdifferentiation of HSCs into myofibroblasts. Our previous studies indicated that fine particulate matter (PM2.5) can activate HSCs by stimulating hepatocytes to secrete TGF-β1. However, whether PM2.5 activates HSCs by regulating oxidative stress in hepatocytes remains uncertain. Oleanolic acid (OA) has been widely used in the clinic for hepatoprotection in Chinese medicine. In the present study, OA-loaded nanoparticles (OA-NP) with high solubility were used to attenuate the activation of HSCs induced by PM2.5-treated hepatocytes, and further studies were performed to explore the mechanism in which OA-NP plays a vital part. Our results showed that consistently PM2.5 treatment induced oxidative stress in hepatocytes. Moreover, the activation of HSCs induced by PM2.5-treated hepatocytes was reversed by antioxidant N-acetylcysteine treatment. Hence, PM2.5 may participate in the activation of HSCs by regulating oxidative stress in hepatocytes. Using a co-cultivation system, our results proved pretreatment with OA-NP significantly attenuates the activation of HSCs induced by PM2.5-exposed hepatocytes. In addition, the TGF-β1 expression and oxidative stress in hepatocytes with PM2.5 treated were reduced by the incubation with OA-NP. These observations demonstrated that OA-NP protects against the activation of HSCs by decreasing the TGF-β1 level and oxidative stress in PM2.5-exposed hepatocytes.
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Affiliation(s)
- Lin Leilei
- School of Life Science and Biopharmaceutics, Guangdong Pharmaceutical University, Guangdong, China
| | - Qiu Wenke
- School of Pharmacy, Guangdong Pharmaceutical University, Guangdong, China
| | - Luo Yuyuan
- School of Life Science and Biopharmaceutics, Guangdong Pharmaceutical University, Guangdong, China; First Affiliated Hospital, Guangzhou Medical University, Guangdong, China
| | - Lin Sihang
- School of Life Science and Biopharmaceutics, Guangdong Pharmaceutical University, Guangdong, China
| | - Sun Xue
- School of Basic Medical Sciences, Guangzhou University of Chinese Medicine, Guangdong, China
| | - Chen Weiqiang
- School of Life Science and Biopharmaceutics, Guangdong Pharmaceutical University, Guangdong, China
| | - Ye Lianbao
- School of Pharmacy, Guangdong Pharmaceutical University, Guangdong, China
| | - Wang Ying
- School of Life Science and Biopharmaceutics, Guangdong Pharmaceutical University, Guangdong, China
| | - Li Yan
- School of Basic Medical Sciences, Guangzhou University of Chinese Medicine, Guangdong, China.
| | - Li Ming
- School of Life Science and Biopharmaceutics, Guangdong Pharmaceutical University, Guangdong, China.
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Kalai FZ, Boulaaba M, Ferdousi F, Isoda H. Effects of Isorhamnetin on Diabetes and Its Associated Complications: A Review of In Vitro and In Vivo Studies and a Post Hoc Transcriptome Analysis of Involved Molecular Pathways. Int J Mol Sci 2022; 23:704. [PMID: 35054888 PMCID: PMC8775402 DOI: 10.3390/ijms23020704] [Citation(s) in RCA: 41] [Impact Index Per Article: 13.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2021] [Revised: 01/06/2022] [Accepted: 01/06/2022] [Indexed: 02/01/2023] Open
Abstract
Diabetes mellitus, especially type 2 (T2DM), is a major public health problem globally. DM is characterized by high levels of glycemia and insulinemia due to impaired insulin secretion and insulin sensitivity of the cells, known as insulin resistance. T2DM causes multiple and severe complications such as nephropathy, neuropathy, and retinopathy causing cell oxidative damages in different internal tissues, particularly the pancreas, heart, adipose tissue, liver, and kidneys. Plant extracts and their bioactive phytochemicals are gaining interest as new therapeutic and preventive alternatives for T2DM and its associated complications. In this regard, isorhamnetin, a plant flavonoid, has long been studied for its potential anti-diabetic effects. This review describes its impact on reducing diabetes-related disorders by decreasing glucose levels, ameliorating the oxidative status, alleviating inflammation, and modulating lipid metabolism and adipocyte differentiation by regulating involved signaling pathways reported in the in vitro and in vivo studies. Additionally, we include a post hoc whole-genome transcriptome analysis of biological activities of isorhamnetin using a stem cell-based tool.
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Affiliation(s)
- Feten Zar Kalai
- Alliance for Research on the Mediterranean and North Africa (ARENA), University of Tsukuba, Tsukuba 305-8572, Japan; (F.Z.K.); (M.B.); (F.F.)
- Laboratory of Aromatic and Medicinal Plants, Center of Biotechnology, Technopark of Borj Cedria, BP 901, Hammam-Lif 2050, Tunisia
| | - Mondher Boulaaba
- Alliance for Research on the Mediterranean and North Africa (ARENA), University of Tsukuba, Tsukuba 305-8572, Japan; (F.Z.K.); (M.B.); (F.F.)
- Laboratory of Aromatic and Medicinal Plants, Center of Biotechnology, Technopark of Borj Cedria, BP 901, Hammam-Lif 2050, Tunisia
| | - Farhana Ferdousi
- Alliance for Research on the Mediterranean and North Africa (ARENA), University of Tsukuba, Tsukuba 305-8572, Japan; (F.Z.K.); (M.B.); (F.F.)
- Faculty of Life and Environmental Sciences, University of Tsukuba, Tsukuba 305-8575, Japan
| | - Hiroko Isoda
- Alliance for Research on the Mediterranean and North Africa (ARENA), University of Tsukuba, Tsukuba 305-8572, Japan; (F.Z.K.); (M.B.); (F.F.)
- Faculty of Life and Environmental Sciences, University of Tsukuba, Tsukuba 305-8575, Japan
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Sanjay K, Vishwakarma S, Zope BR, Mane VS, Mohire S, Dhakshinamoorthy S. ATP citrate lyase inhibitor Bempedoic Acid alleviate long term HFD induced NASH through improvement in glycemic control, reduction of hepatic triglycerides & total cholesterol, modulation of inflammatory & fibrotic genes and improvement in NAS score. CURRENT RESEARCH IN PHARMACOLOGY AND DRUG DISCOVERY 2021; 2:100051. [PMID: 34909677 PMCID: PMC8663992 DOI: 10.1016/j.crphar.2021.100051] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2021] [Revised: 08/20/2021] [Accepted: 08/31/2021] [Indexed: 12/20/2022] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD) and Non-alcoholic steatohepatitis (NASH) are chronic liver disorders, the prevalence of which is increasing worldwide. Long term High Fat Diet (HFD) induced NASH animal models closely mimic the characteristics of human NASH and hence used by investigators as a model system for studying the mechanism of action of new drugs. Bempedoic acid (ETC-1002), a ATP citrate lyase (ACLY) inhibitor that lowers the LDL cholesterol was recently approved by US FDA for the treatment of heterozygous familial hypercholesterolemia (HeFH) and established atherosclerotic cardiovascular disease (ASCVD). ACLY is one of the genes modulated in NASH patients and hence we studied the effect of ACLY inhibitor Bempedoic acid in long term HFD induced NASH animal model to understand the pharmacological benefits and the associated mechanism of action of this newly approved drug in NASH. Mice fed with 60% Kcal High Fat Diet for 32 weeks were used for the study and the animals were given Bempedoic acid for 5 weeks at doses of 10 mg kg−1, po, qd, and 30 mg kg−1, po, qd. Bempedoic acid treatment resulted in inhibition of body weight gain and improved the glycemic control. Bempedoic acid treated group showed statistically significant reduction in plasma ALT, AST, hepatic triglycerides (TG) and total cholesterol (TC), along with statistically significant reduction in steatosis score by histological analysis. Hepatic gene expression analysis showed significant reduction in inflammatory and fibrotic genes such as Mcp-1/Ccl2, Timp-1 & Col1α1. Histological analysis showed significant improvement in NAS score. Overall, Bempedoic acid alleviated HFD induced Non-Alcoholic Steatohepatitis through inhibition of body weight gain, improvement in glycemic control, reduction of hepatic triglycerides & total cholesterol, modulation of inflammatory & fibrotic genes, and improvement in NAS score. Hence, Bempedoic acid can be a potential therapeutic option for metabolic syndrome and NASH.
Bempedoic acid alleviated HFD induced Non-Alcoholic Steatohepatitis in a long term HFD induced NASH animal model. Mechanism of action includes modulation of lipid profile, inflammatory & fibrotic genes and inhibition of body weight gain. Overall improvement in NAS score was observed with Bempedoic acid treatment. Our study shows a promising role for Bempedoic acid in amelioration of metabolic disorders and NASH.
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TGF-β1 signaling can worsen NAFLD with liver fibrosis backdrop. Exp Mol Pathol 2021; 124:104733. [PMID: 34914973 DOI: 10.1016/j.yexmp.2021.104733] [Citation(s) in RCA: 31] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2021] [Revised: 11/08/2021] [Accepted: 12/08/2021] [Indexed: 12/11/2022]
Abstract
Non-Alcoholic Fatty Liver Disease (NAFLD) is characterized by the accumulation of fats in the liver. Relatively benign NAFLD often progresses to fibrosis, cirrhosis, and liver malignancies. Although NAFLD precedes fibrosis, continuous lipid overload keeps fueling fibrosis and the process of disease progression remains unhindered. It is well known that TGF-β1 plays its part in liver fibrosis, yet its effects on liver lipid overload remain unknown. As TGF-β1 signaling has been increasingly attempted to manage liver fibrosis, its actions on the primary suspect (NAFLD) are easily ignored. The complex interaction of inflammatory stress and lipid accumulation aided by mediators scuh as pro-inflammatory interleukins and TGF-β1 forms the basis of NAFLD progression. Anticipatorily, the inhibition of TGF-β1 signaling during anti-fibrotic treatment should reverse the NAFLD though the data remain scattered on this subject to date. TGF-β1 signaling pathway is an important drug target in liver fibrosis and abundant literature is available on it, but its direct effects on NAFLD are rarely studied. This review aims to cover the pathogenesis of NAFLD focusing on the role of the TGF-β1 in the disease progression, especially in the backdrop of liver fibrosis.
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Xiao Z, Ji Q, Fu YD, Gao SQ, Hu YH, Liu W, Chen GF, Mu YP, Chen JM, Liu P. Amygdalin Ameliorates Liver Fibrosis through Inhibiting Activation of TGF-β/Smad Signaling. Chin J Integr Med 2021; 29:316-324. [PMID: 34816365 DOI: 10.1007/s11655-021-3304-y] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 01/22/2021] [Indexed: 11/25/2022]
Abstract
OBJECTIVE To observe the effect of amygdalin on liver fibrosis in a liver fibrosis mouse model, and the underlying mechanisms were partly dissected in vivo and in vitro. METHODS Thirty-two male mice were randomly divided into 4 groups, including control, model, low- and high-dose amygdalin-treated groups, 8 mice in each group. Except the control group, mice in the other groups were injected intraperitoneally with 10% carbon tetrachloride (CCl4)-olive oil solution 3 times a week for 6 weeks to induce liver fibrosis. At the first 3 weeks, amygdalin (1.35 and 2.7 mg/kg body weight) were administered by gavage once a day. Mice in the control group received equal quantities of subcutaneous olive oil and intragastric water from the fourth week. At the end of 6 weeks, liver tissue samples were harvested to detect the content of hydroxyproline (Hyp). Hematoxylin and eosin and Sirius red staining were used to observe the inflammation and fibrosis of liver tissue. The expressions of collagen I (Col-I), alpha-smooth muscle actin (α-SMA), CD31 and transforming growth factor β (TGF-β)/Smad signaling pathway were observed by immunohistochemistry, quantitative real-time polymerase chain reaction and Western blot, respectively. The activation models of hepatic stellate cells, JS-1 and LX-2 cells induced by TGF-β1 were used in vitro with or without different concentrations of amygdalin (0.1, 1, 10 µmol/L). LSECs. The effect of different concentrations of amygdalin on the expressions of liver sinusoidal endothelial cells (LSECs) dedifferentiation markers CD31 and CD44 were observed. RESULTS High-dose of amygdalin significantly reduced the Hyp content and percentage of collagen positive area, and decreased the mRNA and protein expressions of Col-I, α-SMA, CD31 and p-Smad2/3 in liver tissues of mice compared to the model group (P<0.01). Amygdalin down-regulated the expressions of Col-I and α-SMA in JS-1 and LX-2 cells, and TGFβ R1, TGFβ R2 and p-Smad2/3 in LX-2 cells compared to the model group (P<0.05 or P<0.01). Moreover, 1 and 10 µmol/L amygdalin inhibited the mRNA and protein expressions of CD31 in LSECs and increased CD44 expression compared to the model group (P<0.05 or P<0.01). CONCLUSIONS Amygdalin can dramatically alleviate liver fibrosis induced by CCl4 in mice and inhibit TGF-β/Smad signaling pathway, consequently suppressing HSCs activation and LSECs dedifferentiation to improve angiogenesis.
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Affiliation(s)
- Zhun Xiao
- Institute of Liver Diseases, Key Laboratory of Liver and Kidney Diseases (Ministry of Education), Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China
- E-Institute of Shanghai Municipal Education Commission Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China
- Shanghai Key Laboratory of Traditional Chinese Medicine, Shanghai, 201203, China
| | - Qiang Ji
- Institute of Liver Diseases, Key Laboratory of Liver and Kidney Diseases (Ministry of Education), Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China
- Shanghai Key Laboratory of Traditional Chinese Medicine, Shanghai, 201203, China
| | - Ya-Dong Fu
- Institute of Liver Diseases, Key Laboratory of Liver and Kidney Diseases (Ministry of Education), Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China
- E-Institute of Shanghai Municipal Education Commission Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China
- Shanghai Key Laboratory of Traditional Chinese Medicine, Shanghai, 201203, China
| | - Si-Qi Gao
- Institute of Liver Diseases, Key Laboratory of Liver and Kidney Diseases (Ministry of Education), Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China
- E-Institute of Shanghai Municipal Education Commission Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China
- Shanghai Key Laboratory of Traditional Chinese Medicine, Shanghai, 201203, China
| | - Yong-Hong Hu
- Institute of Liver Diseases, Key Laboratory of Liver and Kidney Diseases (Ministry of Education), Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China
- Shanghai Key Laboratory of Traditional Chinese Medicine, Shanghai, 201203, China
| | - Wei Liu
- Institute of Liver Diseases, Key Laboratory of Liver and Kidney Diseases (Ministry of Education), Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China
- Shanghai Key Laboratory of Traditional Chinese Medicine, Shanghai, 201203, China
| | - Gao-Feng Chen
- Institute of Liver Diseases, Key Laboratory of Liver and Kidney Diseases (Ministry of Education), Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China
- Shanghai Key Laboratory of Traditional Chinese Medicine, Shanghai, 201203, China
| | - Yong-Ping Mu
- Institute of Liver Diseases, Key Laboratory of Liver and Kidney Diseases (Ministry of Education), Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China
- Shanghai Key Laboratory of Traditional Chinese Medicine, Shanghai, 201203, China
| | - Jia-Mei Chen
- Institute of Liver Diseases, Key Laboratory of Liver and Kidney Diseases (Ministry of Education), Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China.
- Shanghai Key Laboratory of Traditional Chinese Medicine, Shanghai, 201203, China.
| | - Ping Liu
- Institute of Liver Diseases, Key Laboratory of Liver and Kidney Diseases (Ministry of Education), Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China
- E-Institute of Shanghai Municipal Education Commission Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China
- Shanghai Key Laboratory of Traditional Chinese Medicine, Shanghai, 201203, China
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Han B, Wang X, Wu P, Jiang H, Yang Q, Li S, Li J, Zhang Z. Pulmonary inflammatory and fibrogenic response induced by graphitized multi-walled carbon nanotube involved in cGAS-STING signaling pathway. JOURNAL OF HAZARDOUS MATERIALS 2021; 417:125984. [PMID: 34020360 DOI: 10.1016/j.jhazmat.2021.125984] [Citation(s) in RCA: 52] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/29/2020] [Revised: 04/09/2021] [Accepted: 04/23/2021] [Indexed: 06/12/2023]
Abstract
Graphitized multi-walled carbon nanotubes (GMWCNTs) are a new type of nanomaterial. Recently, their production and application in biological medicine have grown rapidly. However, GMWCNTs may cause adverse health effects, including the common occupational disease of pulmonary fibrosis. Pulmonary fibrosis is a serious progressive disease that often leads to lung failure, high mortality, and disability, and there is no effective therapy currently available. Therefore, identifying new biomarkers of the disease is important to better understand the disease mechanisms and explore new therapeutic strategies. In this study, 40 μg of GMWCNTs was used to treat mice in vivo by pharyngeal aspiration, and different genes were screened by transcriptome sequencing. Activation of the cyclic GMP-AMP synthase (cGAS)-stimulator of interferon gene (STING) signal pathway had an important effect on the development of pulmonary inflammation and fibrosis. GMWCNTs were then administered to the mice with a STING inhibitor (C-176). Inhibition of STING effectively decreased pulmonary inflammation and fibrosis in mice induced by GMWCNTs. Collectively, activation of the cGAS-STING signaling pathway is involved in GMWCNT-induced pulmonary inflammation and fibrosis in mice.
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Affiliation(s)
- Bing Han
- College of Veterinary Medicine, Northeast Agricultural University, Harbin 150030, China
| | - Xiaoqiao Wang
- College of Veterinary Medicine, Northeast Agricultural University, Harbin 150030, China
| | - Pengfei Wu
- College of Veterinary Medicine, Northeast Agricultural University, Harbin 150030, China
| | - Huijie Jiang
- College of Veterinary Medicine, Northeast Agricultural University, Harbin 150030, China
| | - Qingyue Yang
- College of Veterinary Medicine, Northeast Agricultural University, Harbin 150030, China
| | - Siyu Li
- College of Veterinary Medicine, Northeast Agricultural University, Harbin 150030, China
| | - Jiayi Li
- College of Veterinary Medicine, Northeast Agricultural University, Harbin 150030, China
| | - Zhigang Zhang
- College of Veterinary Medicine, Northeast Agricultural University, Harbin 150030, China; Heilongjiang Key Laboratory for Laboratory Animals and Comparative Medicine, Harbin 150030, China.
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Yang F, Li H, Li Y, Hao Y, Wang C, Jia P, Chen X, Ma S, Xiao Z. Crosstalk between hepatic stellate cells and surrounding cells in hepatic fibrosis. Int Immunopharmacol 2021; 99:108051. [PMID: 34426110 DOI: 10.1016/j.intimp.2021.108051] [Citation(s) in RCA: 36] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2021] [Revised: 07/28/2021] [Accepted: 08/04/2021] [Indexed: 02/08/2023]
Abstract
Hepatic fibrosis represents as a dynamic pathological process characterized by the net accumulation of extracellular matrix in the progression of various chronic liver diseases, including viral hepatitis, alcoholic liver disease, and metabolic associated fatty liver disease (MAFLD). Activation of hepatic stellate cells (HSCs) is well-defined to play a central role in the initiation and progression of hepatic fibrosis. However, the activation of HSCs is affected by the complicated microenvironments in liver, which largely attributes to the communication between hepatocytes and multiple tissue-resident cells, including sinusoidal endothelial cells, bile duct epithelial cells, platelets, T cells, B cells, macrophages, natural killer cells, neutrophils, dendritic cells, in the direct or indirect mechanisms. Cellular crosstalk between HSCs and surrounding cells contributes to the activation of HSCs and the progression of hepatic fibrosis. Currently, accumulating evidence have proven the complexity and plasticity of HSCs activation, and further clarification of cellular communication between HSCs and surrounding cells will provide sufficient clue to the development of novel diagnostic methods and therapeutic strategies for hepatic fibrosis.
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Affiliation(s)
- Fangming Yang
- Department of Digestive Diseases, The First Affiliated Hospital of Henan University of Traditional Chinese Medicine, Zhengzhou, China
| | - Heng Li
- Laboratory of Anti-inflammation and Immunopharmacology, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China
| | - Yanmin Li
- Department of Digestive Diseases, The First Affiliated Hospital of Henan University of Traditional Chinese Medicine, Zhengzhou, China
| | - Yaokun Hao
- Department of Digestive Diseases, The First Affiliated Hospital of Henan University of Traditional Chinese Medicine, Zhengzhou, China
| | - Chenxiao Wang
- Department of Digestive Diseases, The First Affiliated Hospital of Henan University of Traditional Chinese Medicine, Zhengzhou, China
| | - Pan Jia
- Department of Digestive Diseases, The First Affiliated Hospital of Henan University of Traditional Chinese Medicine, Zhengzhou, China
| | - Xinju Chen
- Department of Digestive Diseases, The First Affiliated Hospital of Henan University of Traditional Chinese Medicine, Zhengzhou, China.
| | - Suping Ma
- Department of Digestive Diseases, The First Affiliated Hospital of Henan University of Traditional Chinese Medicine, Zhengzhou, China.
| | - Zhun Xiao
- Department of Digestive Diseases, The First Affiliated Hospital of Henan University of Traditional Chinese Medicine, Zhengzhou, China.
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Mohammadtaghvaei N, Afarin R, Mavalizadeh F, Shakerian E, Salehipour Bavarsad S, Mohammadzadeh G. Effect of Quercetin on the Expression of NOXs and P-Smad3C in TGF-Β-Activated Hepatic Stellate Cell Line LX-2. HEPATITIS MONTHLY 2021; 21. [DOI: 10.5812/hepatmon.116875] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/05/2025]
Abstract
Background: Hepatic stellate cells (HSCs) play a primary role in liver fibrogenesis. NOXs are the main origin of reactive oxygen species (ROS) in the liver. Among them, NOX1, NOX2, and NOX4 are expressed more in HSCs and are involved in the development of liver fibrosis. Quercetin, an abundant citrus flavonoid, is known to have beneficial effects on liver injury and hepatic fibrosis. Objectives: In this study, the effect of quercetin on NOX1, NOX2, and NOX4 expression and Smad3 phosphorylation induced by TGF-β in the human hepatic LX2 cell line was investigated. Methods: The cytotoxic effects of quercetin on the cells were determined by MTT assay. The cells were activated with 2 ng/mL of TGF-β for 24 h and then treated with different concentrations of Quercetin. The mRNA expression rates of NOX1, NOX2, NOX4, and phosphorylated Smad 3C (p-Smad3C) were analyzed using real-time polymerase chain reaction (PCR) and western blot assays. Results: TGF-β increased the mRNA expression of NOX1, NOX2, and NOX4 and the protein level of p-Smad3C in the LX2 cell line. Quercetin significantly decreased the mRNA expression of NOX1, NOX2, and NOX4 in the LX-2 cells. Moreover, quercetin significantly diminished the p-Smad3C level in the LX-2 cell line activated with TGF-β. Conclusions: Quercetin may be effective in improving hepatic fibrosis via the reduction of NOX1, NOX2, and NOX4 expression in activated HSCs. The main mechanism through which quercetin reduces the expression of these target genes may be related to the reduction of the p-Smad3C level.
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PM2.5-exposed hepatocytes induce hepatic stellate cells activation by releasing TGF-β1. Biochem Biophys Res Commun 2021; 569:125-131. [PMID: 34243068 DOI: 10.1016/j.bbrc.2021.07.002] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2021] [Revised: 06/30/2021] [Accepted: 07/01/2021] [Indexed: 12/12/2022]
Abstract
The interaction between various types of hepatic cells is related to liver fibrosis. Recent studies demonstrated that fine particulate matter (PM2.5) exposure is an important risk factor for the occurrence of liver fibrosis, but its molecular mechanism is still obscure. In this study, we aimed to investigate whether transforming growth factor- β1 (TGF- β1) secreted from PM2.5-treated hepatocytes (L-O2) are shuttled to hepatic stellate cells (HSCs) and to establish their effects on HSCs. We have observed that the conditioned medium from L-O2 cells stimulated with PM2.5 induced the activation of LX-2 cells, and at the same time, the same results were obtained when we co-cultured LX-2 in PM2.5-exposed L-O2 cells. In addition, analysis of L-O2 cells stimulated with PM2.5 revealed significant increases in TGF-β1 expression. Moreover, we found that the TGF-β1 receptor inhibitor, SB-525334, decreases the proliferation and migration of LX-2 cells in the co-culture system. In addition, the expression of α-smooth muscle actin and type I collagen in LX-2 cells induced by PM2.5-treated L-O2 cells were also blocked by pretreated with SB-525334. These observations imply that PM2.5 induces TGF- β1expression in hepatocytes, which leads to HSCs activation.
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Ai Y, Shi W, Zuo X, Sun X, Chen Y, Wang Z, Li R, Song X, Dai W, Mu W, Ding K, Li Z, Li Q, Xiao X, Zhan X, Bai Z. The Combination of Schisandrol B and Wedelolactone Synergistically Reverses Hepatic Fibrosis Via Modulating Multiple Signaling Pathways in Mice. Front Pharmacol 2021; 12:655531. [PMID: 34149411 PMCID: PMC8211319 DOI: 10.3389/fphar.2021.655531] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2021] [Accepted: 05/12/2021] [Indexed: 12/16/2022] Open
Abstract
Hepatic fibrosis represents an important event in the progression of chronic liver injury to cirrhosis, and is characterized by excessive extracellular matrix proteins aggregation. Early fibrosis can be reversed by inhibiting hepatocyte injury, inflammation, or hepatic stellate cells activation, so the development of antifibrotic drugs is important to reduce the incidence of hepatic cirrhosis or even hepatic carcinoma. Here we demonstrate that Schisandrol B (SolB), one of the major active constituents of traditional hepato-protective Chinese medicine, Schisandra sphenanthera, significantly protects against hepatocyte injury, while Wedelolactone (WeD) suppresses the TGF-β1/Smads signaling pathway in hepatic stellate cells (HSCs) and inflammation, the combination of the two reverses hepatic fibrosis in mice and the inhibitory effect of the combination on hepatic fibrosis is superior to that of SolB or WeD treatment alone. Combined pharmacotherapy represents a promising strategy for the prevention and treatment of liver fibrosis.
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Affiliation(s)
- Yongqiang Ai
- Department of Hepatology, The Fifth Medical Centre, Chinese PLA General Hospital, Beijing, China
| | - Wei Shi
- Department of Hepatology, The Fifth Medical Centre, Chinese PLA General Hospital, Beijing, China
| | - Xiaobin Zuo
- Department of Hepatology, The Fifth Medical Centre, Chinese PLA General Hospital, Beijing, China
| | - Xiaoming Sun
- Department of Hepatology, The Fifth Medical Centre, Chinese PLA General Hospital, Beijing, China
| | - Yuanyuan Chen
- Department of Hepatology, The Fifth Medical Centre, Chinese PLA General Hospital, Beijing, China
| | - Zhilei Wang
- Department of Hepatology, The Fifth Medical Centre, Chinese PLA General Hospital, Beijing, China
| | - Ruisheng Li
- Research Center for Clinical and Translational Medicine, The Fifth Medical Center of Chinese PLA General Hospital, Beijing, China
| | - Xueai Song
- China Military Institute of Chinese Materia, The Fifth Medical Centre, Chinese PLA General Hospital, Beijing, China
| | - Wenzhang Dai
- Department of Hepatology, The Fifth Medical Centre, Chinese PLA General Hospital, Beijing, China
| | - Wenqing Mu
- Department of Hepatology, The Fifth Medical Centre, Chinese PLA General Hospital, Beijing, China
| | - Kaixin Ding
- Department of Hepatology, The Fifth Medical Centre, Chinese PLA General Hospital, Beijing, China
| | - Zhiyong Li
- Department of Hepatology, The Fifth Medical Centre, Chinese PLA General Hospital, Beijing, China
| | - Qiang Li
- Department of Hepatology, The Fifth Medical Centre, Chinese PLA General Hospital, Beijing, China
| | - Xiaohe Xiao
- Department of Hepatology, The Fifth Medical Centre, Chinese PLA General Hospital, Beijing, China.,China Military Institute of Chinese Materia, The Fifth Medical Centre, Chinese PLA General Hospital, Beijing, China
| | - Xiaoyan Zhan
- Department of Hepatology, The Fifth Medical Centre, Chinese PLA General Hospital, Beijing, China.,China Military Institute of Chinese Materia, The Fifth Medical Centre, Chinese PLA General Hospital, Beijing, China
| | - Zhaofang Bai
- Department of Hepatology, The Fifth Medical Centre, Chinese PLA General Hospital, Beijing, China.,China Military Institute of Chinese Materia, The Fifth Medical Centre, Chinese PLA General Hospital, Beijing, China
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DiNicolantonio JJ, McCarty MF, Barroso-Aranda J, Assanga S, Lujan LML, O'Keefe JH. A nutraceutical strategy for downregulating TGFβ signalling: prospects for prevention of fibrotic disorders, including post-COVID-19 pulmonary fibrosis. Open Heart 2021; 8:openhrt-2021-001663. [PMID: 33879509 PMCID: PMC8061562 DOI: 10.1136/openhrt-2021-001663] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 03/30/2021] [Indexed: 12/14/2022] Open
Affiliation(s)
- James J DiNicolantonio
- Preventive Cardiology, Saint Luke's Mid America Heart Institute, Kansas City, Missouri, USA
| | | | | | - Simon Assanga
- Department of Research and Postgraduate Studies in Food, University of Sonora, Sonora, Mexico
| | | | - James H O'Keefe
- University of Missouri-Kansas City, Saint Lukes Mid America Heart Institute, Kansas City, Missouri, USA
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Shojaei Jeshvaghani Z, Arefian E, Asgharpour S, Soleimani M. Latency-Associated Transcript-Derived MicroRNAs in Herpes Simplex Virus Type 1 Target SMAD3 and SMAD4 in TGF-β/Smad Signaling Pathway. IRANIAN BIOMEDICAL JOURNAL 2021; 25:169-79. [PMID: 33546553 DOI: 10.29252/ibj.25.3.169] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Subscribe] [Scholar Register] [Indexed: 10/31/2022]
Abstract
Background During its latent infection, hepatic stellate cell (HSV-1) produces only a micro RNA (miRNA) precursor called latency-associated transcript (LAT), which encodes six distinct miRNAs. Recent studies have suggested that some of these miRNAs could target cellular mRNAs. One of the key cell signaling pathways that can be affected by HSV-1 is the TGF-β/Smad pathway. Herein, we investigated the potential role of the LAT as well as three LAT-derived miRNAs in targeting SMAD3 and SMAD4, as two main mediators in TGF-β/Smad. Methods The selection of LAT-derived miRNAs was based on the search results obtained from an online miRNA prediction tool. HEK293T cells were transfected with each miRNA-expressing lentivector and with the construct-expressing LAT. To survey the effect of LAT on the expression of pro-fibrotic markers, we transfected LX-2 cells with LAT construct. The impact of viral miRNA overexpression on SMADs and fibrotic markers was measured by quantitative PCR and luciferase assays. Results Among the LAT-derived miRNAs, miR-H2, miR-H3, and miR-H4 were selected for the study. Our results demonstrated that while miR-H2 binds to both SMAD mRNAs, miR-H3 and miR-H4 inhibit only the expression of the SMAD4 and SMAD3, respectively. Transfection of the LX-2 with LAT also decreased pro-fibrotic genes expression. Conclusion Our findings display that LAT negatively regulates TGF-β/Smad through targeting SMAD3 and SMAD4 by its miRNAs. These viral miRNAs can also contribute to the development of therapeutic interventions in diseases for which prevention or treatment can be achieved through targeting TGF-β pathway.
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Affiliation(s)
| | - Ehsan Arefian
- Department of Microbiology, School of Biology, College of Science, University of Tehran, Tehran, Iran
| | | | - Masoud Soleimani
- Department of Hematology, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran
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Cheng QN, Yang X, Wu JF, Ai WB, Ni YR. Interaction of non‑parenchymal hepatocytes in the process of hepatic fibrosis (Review). Mol Med Rep 2021; 23:364. [PMID: 33760176 PMCID: PMC7986015 DOI: 10.3892/mmr.2021.12003] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/03/2020] [Accepted: 03/02/2021] [Indexed: 02/07/2023] Open
Abstract
Hepatic fibrosis (HF) is the process of fibrous scar formation caused by chronic liver injury of different etiologies. Previous studies have hypothesized that the activation of hepatic stellate cells (HSCs) is the central process in HF. The interaction between HSCs and surrounding cells is also crucial. Additionally, hepatic sinusoids capillarization, inflammation, angiogenesis and fibrosis develop during HF. The process involves multiple cell types that are highly connected and work in unison to maintain the homeostasis of the hepatic microenvironment, which serves a key role in the initiation and progression of HF. The current review provides novel insight into the intercellular interaction among liver sinusoidal endothelial cells, HSCs and Kupffer cells, as well as the hepatic microenvironment in the development of HF.
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Affiliation(s)
- Qi-Ni Cheng
- Medical College, China Three Gorges University, Yichang, Hubei 443002, P.R. China
- Institute of Organ Fibrosis and Targeted Drug Delivery, China Three Gorges University, Yichang, Hubei 443002, P.R. China
- Hubei Key Laboratory of Tumor Microenvironment and Immunotherapy, China Three Gorges University, Yichang, Hubei 443002, P.R. China
| | - Xue Yang
- Medical College, China Three Gorges University, Yichang, Hubei 443002, P.R. China
- Institute of Organ Fibrosis and Targeted Drug Delivery, China Three Gorges University, Yichang, Hubei 443002, P.R. China
- Hubei Key Laboratory of Tumor Microenvironment and Immunotherapy, China Three Gorges University, Yichang, Hubei 443002, P.R. China
| | - Jiang-Feng Wu
- Medical College, China Three Gorges University, Yichang, Hubei 443002, P.R. China
- Institute of Organ Fibrosis and Targeted Drug Delivery, China Three Gorges University, Yichang, Hubei 443002, P.R. China
- Hubei Key Laboratory of Tumor Microenvironment and Immunotherapy, China Three Gorges University, Yichang, Hubei 443002, P.R. China
- The People's Hospital of China Three Gorges University, Yichang, Hubei 443000, P.R. China
| | - Wen-Bing Ai
- The Yiling Hospital of Yichang, Yichang, Hubei 443100, P.R. China
| | - Yi-Ran Ni
- Medical College, China Three Gorges University, Yichang, Hubei 443002, P.R. China
- Institute of Organ Fibrosis and Targeted Drug Delivery, China Three Gorges University, Yichang, Hubei 443002, P.R. China
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Shen Z, Su T, Chen J, Xie Z, Li J. Collagen triple helix repeat containing-1 exerts antifibrotic effects on human skin fibroblast and bleomycin-induced dermal fibrosis models. ANNALS OF TRANSLATIONAL MEDICINE 2021; 9:801. [PMID: 34268414 PMCID: PMC8246160 DOI: 10.21037/atm-21-1884] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/22/2021] [Accepted: 05/08/2021] [Indexed: 11/29/2022]
Abstract
Background Systemic scleroderma (SSc) is an acquired disorder characterized by excessive deposition of extracellular matrix in the skin and internal organs. So far, the molecular mechanisms underpinning the pathogenesis of SSc have remained unknown. Collagen triple helix repeat containing-1 (CTHRC1) has been indicated to be a cell type-specific inhibitor of transforming growth factor-β (TGF-β), which could have the potential for extensive clinical application owing to its ability to reduce collagen deposition. Our previous studies showed that CTHRC1 inhibited TGF-β1-induced collagen type I synthesis in keloid fibroblasts. In our present research, we attempted to probe the role of CTHRC1 in dermal fibrosis in bleomycin (BLM)-treated mice. Methods CTHRC1 and TGF-β1 expression was detected in dermal tissues from patients with SSc and BLM-treated mice by immunohistochemistry. A 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2H-tetrazolium bromide assay was used to assess TGF-β1-induced proliferation of human dermal fibroblasts. Collagen expression and fibroblast synthesis were evaluated by quantitative real-time polymerase chain reaction and the 3H-proline incorporation. Masson’s trichrome staining and western blotting were carried out to analyze the deposits and protein levels of type I collagen, respectively. Results Compared with those in normal tissues, the levels of CTHRC1 and TGF-β1 were elevated in dermal tissues from patients with SSc and in skin tissues from BLM-treated mice, respectively. Furthermore, recombinant CTHRC1 was found to inhibit TGF-β1-stimulated collagen deposition by fibroblasts. Finally, the in vivo experiments showed that CTHRC1 alleviated BLM-induced dermal fibrotic changes. Conclusions CTHRC1 can inhibit human dermal fibroblast collagen deposition and can also exert protective effects against BLM-induced dermal fibrosis in mice. This research provides an indication that CTHRC1 may be a promising treatment choice for dermal fibrosis in SSc patients.
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Affiliation(s)
- Zhu Shen
- Department of Dermatology, Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, Chengdu, China.,Chinese Academy of Sciences Sichuan Translational Medicine Research Hospital, Chengdu, China
| | - Tangfeng Su
- Department of Pediatrics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Jin Chen
- Department of Dermatology, Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, Chengdu, China.,Chinese Academy of Sciences Sichuan Translational Medicine Research Hospital, Chengdu, China
| | - Zhen Xie
- Department of Dermatology, Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, Chengdu, China.,Chinese Academy of Sciences Sichuan Translational Medicine Research Hospital, Chengdu, China
| | - Juan Li
- Department of Dermatology, Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, Chengdu, China.,Chinese Academy of Sciences Sichuan Translational Medicine Research Hospital, Chengdu, China
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Latency-Associated Transcript-Derived MicroRNAs in Herpes Simplex Virus Type 1 Target SMAD3 and SMAD4 in TGF-β/Smad Signaling Pathway. IRANIAN BIOMEDICAL JOURNAL 2021. [PMID: 33546553 PMCID: PMC8183387 DOI: 10.52547/ibj.25.3.169] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 11/24/2022]
Abstract
Background: During its latent infection, HSV-1 produces only a miRNA precursor called LAT, which encodes six distinct miRNAs. Recent studies have suggested that some of these miRNAs could target cellular mRNAs. One of the key cell signaling pathways that can be affected by HSV-1 is the TGF-β/Smad pathway. Herein, we investigated the potential role of the LAT as well as three LAT-derived miRNAs in targeting SMAD3 and SMAD4, as two main mediators in TGF-β/Smad. Methods: The selection of LAT-derived miRNAs was based on the search results obtained from an online miRNA prediction tool. HEK293T cells were transfected with each miRNA-expressing lentivector and with the construct-expressing LAT. To survey the effect of LAT on the expression of pro-fibrotic markers, we transfected LX-2 cells with LAT construct. The impact of viral miRNA overexpression on SMADs and fibrotic markers was measured by qPCR and luciferase assays. Results: Among the LAT-derived miRNAs, miR-H2, miR-H3, and miR-H4 were selected for the study. Our results demonstrated that while miR-H2 binds to both SMAD mRNAs, miR-H3 and miR-H4 inhibit only the expression of the SMAD4 and SMAD3, respectively. Transfection of the LX-2 with LAT also decreased pro-fibrotic genes expression. Conclusion: Our findings display that LAT negatively regulates TGF-β/Smad through targeting SMAD3 and SMAD4 by its miRNAs. These viral miRNAs can also contribute to the development of therapeutic interventions in diseases for which prevention or treatment can be achieved through targeting TGF-β pathway.
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Sharawy MH, El-Awady MS, Makled MN. Protective effects of paclitaxel on thioacetamide-induced liver fibrosis in a rat model. J Biochem Mol Toxicol 2021; 35:e22745. [PMID: 33749060 DOI: 10.1002/jbt.22745] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2020] [Revised: 01/13/2021] [Accepted: 02/10/2021] [Indexed: 01/18/2023]
Abstract
Liver fibrosis is a public health burden that is highly associated with morbidity and mortality. Therefore, this study aims to explore the anti-fibrotic effects of low dose of paclitaxel (PTX) against thioacetamide (TAA)-induced liver fibrosis in rats and the possible mechanisms involved. TAA was administered at a dose of 200 mg/kg twice weekly for 6 weeks in rats to induce liver fibrosis similar to that in humans. Liver dysfunction was shown by increased alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, and γ-glutamyl transferase, along with histopathological changes. Liver fibrosis was confirmed by Masson's Trichome staining, increased collagen content, and elevated α-smooth muscle actin (α-SMA) protein expression. In addition, TAA induced liver apoptosis as indicated by the increased terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL)-positive cells in liver tissues. This study demonstrated that the administration of PTX (0.3 mg/kg/i.p.) three times a week for 6 weeks significantly alleviated functional and biochemical changes induced by TAA in addition to improving the liver architecture. PTX attenuated liver fibrosis as reflected by the decreased collagen content and α-SMA protein expression. Additionally, PTX attenuated liver apoptosis as indicated by the decreased TUNEL-positive cells. Moreover, PTX prevented TAA-induced elevation of transforming growth factor-β1 (TGF-β1), platelet-derived growth factor-BB (PDGF-BB), and tissue inhibitor of metalloproteinase 1 (TIMP-1) levels in liver tissues. These findings suggest that the low dose of PTX prevented TAA-induced liver fibrosis in rats, possibly by inhibiting the expression of TGF-β1 and PDGF-BB and subsequently suppressing the apoptosis and the expression of TIMP-1.
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Affiliation(s)
- Maha H Sharawy
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Mansoura University, Mansoura, Egypt
| | - Mohammed S El-Awady
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Mansoura University, Mansoura, Egypt.,Department of Pharmacology and Toxicology, College of Pharmacy, Taibah University, Al-Madinah Al-Munawwarah, Saudi Arabia
| | - Mirhan N Makled
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Mansoura University, Mansoura, Egypt
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Hepatoprotective Potency of Chrysophanol 8- O-Glucoside from Rheum palmatum L. against Hepatic Fibrosis via Regulation of the STAT3 Signaling Pathway. Int J Mol Sci 2020; 21:ijms21239044. [PMID: 33261209 PMCID: PMC7730872 DOI: 10.3390/ijms21239044] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2020] [Revised: 11/25/2020] [Accepted: 11/25/2020] [Indexed: 02/07/2023] Open
Abstract
Rhubarb is a well-known herb worldwide and includes approximately 60 species of the Rheum genus. One of the representative plants is Rheum palmatum, which is prescribed as official rhubarb due to its pharmacological potential in the Korean and Chinese pharmacopoeia. In our bioactive screening, we found out that the EtOH extract of R. palmatum inhibited hepatic stellate cell (HSC) activation by transforming growth factor β1 (TGF-β1). Chemical investigation of the EtOH extract led to the isolation of chrysophanol 8-O-glucoside, which was determined by structural analysis using NMR spectroscopic techniques and electrospray ionization mass spectrometry (ESIMS). To elucidate the effects of chrysophanol 8-O-glucoside on HSC activation, activated LX-2 cells were treated for 48 h with chrysophanol 8-O-glucoside, and α-SMA and collagen, HSC activation markers, were measured by comparative quantitative real-time PCR (qPCR) and western blotting analysis. Chrysophanol 8-O-glucoside significantly inhibited the protein and mRNA expression of α-SMA and collagen compared with that in TGF-β1-treated LX-2 cells. Next, the expression of phosphorylated SMAD2 (p-SMAD2) and p-STAT3 was measured and the translocation of p-STAT3 to the nucleus was analyzed by western blotting analysis. The expression of p-SMAD2 and p-STAT3 showed that chrysophanol 8-O-glucoside strongly downregulated STAT3 phosphorylation by inhibiting the nuclear translocation of p-STAT3, which is an important mechanism in HSC activation. Moreover, chrysophanol 8-O-glucoside suppressed the expression of p-p38, not that of p-JNK or p-Erk, which can activate STAT3 phosphorylation and inhibit MMP2 expression, the downstream target of STAT3 signaling. These findings provided experimental evidence concerning the hepatoprotective effects of chrysophanol 8-O-glucoside against liver damage and revealed the molecular basis underlying its anti-fibrotic effects through the blocking of HSC activation.
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Xu XY, Du Y, Liu X, Ren Y, Dong Y, Xu HY, Shi JS, Jiang D, Xu X, Li L, Xu ZH, Geng Y. Targeting Follistatin like 1 ameliorates liver fibrosis induced by carbon tetrachloride through TGF-β1-miR29a in mice. Cell Commun Signal 2020; 18:151. [PMID: 32933544 PMCID: PMC7493388 DOI: 10.1186/s12964-020-00610-0] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2020] [Accepted: 06/08/2020] [Indexed: 12/11/2022] Open
Abstract
Background Hepatic fibrosis is a pathological response of the liver to a variety of chronic stimuli. Hepatic stellate cells (HSCs) are the major source of myofibroblasts in the liver. Follistatin like 1 (Fstl1) is a secreted glycoprotein induced by transforming growth factor-β1 (TGF-β1). However, the precise functions and regulation mechanisms of Fstl1 in liver fibrogenesis remains unclear. Methods Hepatic stellate cell (HSC) line LX-2 stimulated by TGF-β1, primary culture of mouse HSCs and a model of liver fibrosis induced by CCl4 in mice was used to assess the effect of Fstl1 in vitro and in vivo. Results Here, we found that Fstl1 was significantly up regulated in human and mouse fibrotic livers, as well as activated HSCs. Haplodeficiency of Fstl1 or blockage of Fstl1 with a neutralizing antibody 22B6 attenuated CCl4-induced liver fibrosis in vivo. Fstl1 modulates TGF-β1 classic Samd2 and non-classic JNK signaling pathways. Knockdown of Fstl1 in HSCs significantly ameliorated cell activation, cell migration, chemokines C-C Motif Chemokine Ligand 2 (CCL2) and C-X-C Motif Chemokine Ligand 8 (CXCL8) secretion and extracellular matrix (ECM) production, and also modulated microRNA-29a (miR29a) expression. Furthermore, we identified that Fstl1 was a target gene of miR29a. And TGF-β1 induction of Fstl1 expression was partially through down regulation of miR29a in HSCs. Conclusions Our data suggests TGF-β1-miR29a-Fstl1 regulatory circuit plays a key role in regulation the HSC activation and ECM production, and targeting Fstl1 may be a strategy for the treatment of liver fibrosis.
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