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1
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Choi SY, Song P, Hwang JS, Lee YK, Shin MS, Son HJ, Kim YJ, Kim W, Lee KM. Cereblon deficiency ameliorates carbon tetrachloride-induced acute hepatotoxicity in HepG2 cells by suppressing MAPK-mediated apoptosis. Front Immunol 2024; 15:1457636. [PMID: 39139558 PMCID: PMC11319158 DOI: 10.3389/fimmu.2024.1457636] [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: 07/01/2024] [Accepted: 07/16/2024] [Indexed: 08/15/2024] Open
Abstract
The liver is vulnerable to various hepatotoxins, including carbon tetrachloride (CCl4), which induces oxidative stress and apoptosis by producing reactive oxygen species (ROS) and activating the mitogen-activated protein kinase (MAPK) pathway. Cereblon (CRBN), a multifunctional protein implicated in various cellular processes, functions in the pathogenesis of various diseases; however, its function in liver injury remains unknown. We established a CRBN-knockout (KO) HepG2 cell line and examined its effect on CCl4-induced hepatocellular damage. CRBN-KO cells exhibited reduced sensitivity to CCl4-induced cytotoxicity, as evidenced by decreased levels of apoptosis markers, such as cleaved caspase-3, and aspartate aminotransferase (AST) and alanine aminotransferase (ALT) activities. CRBN deficiency enhanced antioxidant defense, with increased superoxide dismutase activity and glutathione ratios (GSH/GSSG), as well as reduced pro-inflammatory cytokine expression. Mechanistically, the protective effects of CRBN deficiency appeared to involve the attenuation of the MAPK-mediated pathways, particularly through decreased phosphorylation of JNK and ERK. Overall, these results suggest the crucial role of CRBN in mediating the hepatocellular response to oxidative stress and inflammation triggered by CCl4 exposure, offering potential clinical implications for liver injury in a wide range of liver diseases.
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Affiliation(s)
- Seo Young Choi
- Department of Life Science and Environmental Biochemistry, Pusan National University, Miryang, Republic of Korea
| | - Parkyong Song
- Department of Convergence Medicine, Pusan National University School of Medicine, Yangsan, Republic of Korea
| | - Ji Sun Hwang
- New Drug Development Center, Daegu–Gyeongbuk Medical Innovation Foundation, Daegu, Republic of Korea
| | - You Kyeong Lee
- Department of Life Science and Environmental Biochemistry, Pusan National University, Miryang, Republic of Korea
| | - Mi Song Shin
- Department of Life Science and Environmental Biochemistry, Pusan National University, Miryang, Republic of Korea
| | - Hong-Joo Son
- Department of Life Science and Environmental Biochemistry, Pusan National University, Miryang, Republic of Korea
| | - Yu-Jin Kim
- Department of Life Science and Environmental Biochemistry, Pusan National University, Miryang, Republic of Korea
| | - Wanil Kim
- Department of Biochemistry, Department of Convergence Medical Science, and Institute of Medical Science, School of Medicine, Gyeongsang National University, Jinju, Republic of Korea
| | - Kwang Min Lee
- Department of Life Science and Environmental Biochemistry, Pusan National University, Miryang, Republic of Korea
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2
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Cinar D, Altinoz E, Elbe H, Bicer Y, Cetinavci D, Ozturk I, Colak T. Therapeutic Effect of Melatonin on CCl 4-Induced Fibrotic Liver Model by Modulating Oxidative Stress, Inflammation, and TGF-β1 Signaling Pathway in Pinealectomized Rats. Inflammation 2024:10.1007/s10753-024-02101-7. [PMID: 39007940 DOI: 10.1007/s10753-024-02101-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/23/2024] [Revised: 07/05/2024] [Accepted: 07/08/2024] [Indexed: 07/16/2024]
Abstract
The study aimed to determine the CCl4-induced liver fibrosis model in pinealectomized rats and biochemically, immunohistochemically, and histopathologically investigate the therapeutic effect of melatonin on liver fibrosis. The surgical procedure for pinealectomy was performed at the beginning of the study, and the sham and pinealectomized rats were administered CCl4 dissolved in corn oil (1:1) alone every other day to induce liver fibrosis or together with melatonin (10 mg/kg) therapy for 15 days. Melatonin is an essential therapeutic agent and offers an alternative therapeutic strategy in CCl4-induced liver fibrosis by suppressing inflammation, oxidative stress, and the TGF-β1 signaling pathway. Treatment with melatonin ameliorated CCl4-induced liver fibrosis by restoring hepatocellular damage and reducing plasma AST, ALT, and ALP values. Melatonin increases the activity of SOD and CAT, which are important enzymes for antioxidant defence, and raises GSH levels, which further enhances antioxidant function. Also, melatonin reduced hepatic inflammation (IL-6 and IL-1β) and oxidative stress indices. Moreover, histopathological changes and immunohistochemical expression of TGF-β1 were restored following melatonin supplementation in the CCl4-induced liver fibrosis model in pinealectomized rats. Our study shows that melatonin supplementation has a beneficial effect in protecting the liver fibrosis induced by CCl4 in pinealectomized rats.
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Affiliation(s)
- Derya Cinar
- Department of Anatomy, School of Health Science, Karabuk University, Karabuk, Turkey
| | - Eyup Altinoz
- Department of Medical Biochemistry, Faculty of Medicine, Karabuk University, Karabuk, Turkey
| | - Hulya Elbe
- Department of Histology and Embryology, Faculty of Medicine, Mugla Sıtkı Kocman University, Mugla, Turkey
| | - Yasemin Bicer
- Department of Medical Biochemistry, Faculty of Medicine, Karabuk University, Karabuk, Turkey
| | - Dilan Cetinavci
- Department of Histology and Embryology, Mugla Training and Research Hospital, Mugla, Turkey
| | - Ipek Ozturk
- Department of Medical Biochemistry, Faculty of Medicine, Karabuk University, Karabuk, Turkey
| | - Tuncay Colak
- Department of Anatomy, Faculty of Medicine, Kocaeli University, Kocaeli, Turkey.
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3
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Li H, Wang S, Yang Z, Meng X, Niu M. Nanomaterials modulate tumor-associated macrophages for the treatment of digestive system tumors. Bioact Mater 2024; 36:376-412. [PMID: 38544737 PMCID: PMC10965438 DOI: 10.1016/j.bioactmat.2024.03.003] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/29/2023] [Revised: 02/25/2024] [Accepted: 03/03/2024] [Indexed: 11/25/2024] Open
Abstract
The treatment of digestive system tumors presents challenges, particularly in immunotherapy, owing to the advanced immune tolerance of the digestive system. Nanomaterials have emerged as a promising approach for addressing these challenges. They provide targeted drug delivery, enhanced permeability, high bioavailability, and low toxicity. Additionally, nanomaterials target immunosuppressive cells and reshape the tumor immune microenvironment (TIME). Among the various cells in the TIME, tumor-associated macrophages (TAMs) are the most abundant and play a crucial role in tumor progression. Therefore, investigating the modulation of TAMs by nanomaterials for the treatment of digestive system tumors is of great significance. Here, we present a comprehensive review of the utilization of nanomaterials to modulate TAMs for the treatment of gastric cancer, colorectal cancer, hepatocellular carcinoma, and pancreatic cancer. We also investigated the underlying mechanisms by which nanomaterials modulate TAMs to treat tumors in the digestive system. Furthermore, this review summarizes the role of macrophage-derived nanomaterials in the treatment of digestive system tumors. Overall, this research offers valuable insights into the development of nanomaterials tailored for the treatment of digestive system tumors.
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Affiliation(s)
- Hao Li
- Department of Interventional Radiology, First Hospital of China Medical University, Shenyang, China
| | - Shuai Wang
- Department of Interventional Radiology, First Hospital of China Medical University, Shenyang, China
| | - Zhengqiang Yang
- Department of Interventional Therapy, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Xianwei Meng
- Laboratory of Controllable Preparation and Application of Nanomaterials, Technical Institute of Physics and Chemistry, Chinese Academy of Sciences, Beijing, China
| | - Meng Niu
- China Medical University, Shenyang, China
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4
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Yu L, Gao F, Li Y, Su D, Han L, Li Y, Zhang X, Feng Z. Role of pattern recognition receptors in the development of MASLD and potential therapeutic applications. Biomed Pharmacother 2024; 175:116724. [PMID: 38761424 DOI: 10.1016/j.biopha.2024.116724] [Citation(s) in RCA: 6] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2024] [Revised: 04/23/2024] [Accepted: 05/06/2024] [Indexed: 05/20/2024] Open
Abstract
Metabolic dysfunction-associated steatotic liver disease (MASLD) has become one of the most prevalent liver diseases worldwide, and its occurrence is strongly associated with obesity, insulin resistance (IR), genetics, and metabolic stress. Ranging from simple fatty liver to metabolic dysfunction-associated steatohepatitis (MASH), even to severe complications such as liver fibrosis and advanced cirrhosis or hepatocellular carcinoma, the underlying mechanisms of MASLD progression are complex and involve multiple cellular mediators and related signaling pathways. Pattern recognition receptors (PRRs) from the innate immune system, including Toll-like receptors (TLRs), C-type lectin receptors (CLRs), NOD-like receptors (NLRs), RIG-like receptors (RLRs), and DNA receptors, have been demonstrated to potentially contribute to the pathogenesis for MASLD. Their signaling pathways can induce inflammation, mediate oxidative stress, and affect the gut microbiota balance, ultimately resulting in hepatic steatosis, inflammatory injury and fibrosis. Here we review the available literature regarding the involvement of PRR-associated signals in the pathogenic and clinical features of MASLD, in vitro and in animal models of MASLD. We also discuss the emerging targets from PRRs for drug developments that involved agent therapies intended to arrest or reverse disease progression, thus enabling the refinement of therapeutic targets that can accelerate drug development.
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Affiliation(s)
- Lili Yu
- School of Basic Medical Sciences, Xinxiang Medical University, Xinxiang, Henan, China; The Third Affiliated Hospital of Xinxiang Medical University, Xinxiang Medical University, Xinxiang, Henan, China; Institute of Precision Medicine, Xinxiang Medical University, Xinxiang, Henan, China; Xinxiang Engineering Technology Research Center of immune checkpoint drug for Liver-Intestinal Tumors, Xinxiang Medical University, Xinxiang, Henan 453000, P.R.China
| | - Feifei Gao
- School of Basic Medical Sciences, Xinxiang Medical University, Xinxiang, Henan, China; Institute of Precision Medicine, Xinxiang Medical University, Xinxiang, Henan, China; Xinxiang Engineering Technology Research Center of immune checkpoint drug for Liver-Intestinal Tumors, Xinxiang Medical University, Xinxiang, Henan 453000, P.R.China
| | - Yaoxin Li
- School of Basic Medical Sciences, Xinxiang Medical University, Xinxiang, Henan, China; Institute of Precision Medicine, Xinxiang Medical University, Xinxiang, Henan, China; Xinxiang Engineering Technology Research Center of immune checkpoint drug for Liver-Intestinal Tumors, Xinxiang Medical University, Xinxiang, Henan 453000, P.R.China
| | - Dan Su
- School of Basic Medical Sciences, Xinxiang Medical University, Xinxiang, Henan, China; Institute of Precision Medicine, Xinxiang Medical University, Xinxiang, Henan, China; Xinxiang Engineering Technology Research Center of immune checkpoint drug for Liver-Intestinal Tumors, Xinxiang Medical University, Xinxiang, Henan 453000, P.R.China
| | - Liping Han
- The Third Affiliated Hospital of Xinxiang Medical University, Xinxiang Medical University, Xinxiang, Henan, China
| | - Yueming Li
- School of Basic Medical Sciences, Xinxiang Medical University, Xinxiang, Henan, China; Institute of Precision Medicine, Xinxiang Medical University, Xinxiang, Henan, China; Xinxiang Engineering Technology Research Center of immune checkpoint drug for Liver-Intestinal Tumors, Xinxiang Medical University, Xinxiang, Henan 453000, P.R.China
| | - Xuehan Zhang
- School of Basic Medical Sciences, Xinxiang Medical University, Xinxiang, Henan, China; Institute of Precision Medicine, Xinxiang Medical University, Xinxiang, Henan, China; Xinxiang Engineering Technology Research Center of immune checkpoint drug for Liver-Intestinal Tumors, Xinxiang Medical University, Xinxiang, Henan 453000, P.R.China
| | - Zhiwei Feng
- School of Basic Medical Sciences, Xinxiang Medical University, Xinxiang, Henan, China; Institute of Precision Medicine, Xinxiang Medical University, Xinxiang, Henan, China; Xinxiang Engineering Technology Research Center of immune checkpoint drug for Liver-Intestinal Tumors, Xinxiang Medical University, Xinxiang, Henan 453000, P.R.China.
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Alghamdi W, Mosli M, Alqahtani SA. Gut microbiota in MAFLD: therapeutic and diagnostic implications. Ther Adv Endocrinol Metab 2024; 15:20420188241242937. [PMID: 38628492 PMCID: PMC11020731 DOI: 10.1177/20420188241242937] [Citation(s) in RCA: 5] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/13/2023] [Accepted: 02/22/2024] [Indexed: 04/19/2024] Open
Abstract
Metabolic dysfunction-associated fatty liver disease (MAFLD), formerly known as nonalcoholic fatty liver disease, is becoming a significant contributor to chronic liver disease globally, surpassing other etiologies, such as viral hepatitis. Prevention and early treatment strategies to curb its growing prevalence are urgently required. Recent evidence suggests that targeting the gut microbiota may help treat and alleviate disease progression in patients with MAFLD. This review aims to explore the complex relationship between MAFLD and the gut microbiota in relation to disease pathogenesis. Additionally, it delves into the therapeutic strategies targeting the gut microbiota, such as diet, exercise, antibiotics, probiotics, synbiotics, glucagon-like peptide-1 receptor agonists, and fecal microbiota transplantation, and discusses novel biomarkers, such as microbiota-derived testing and liquid biopsy, for their diagnostic and staging potential. Overall, the review emphasizes the urgent need for preventive and therapeutic strategies to address the devastating consequences of MAFLD at both individual and societal levels and recognizes that further exploration of the gut microbiota may open avenues for managing MAFLD effectively in the future.
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Affiliation(s)
- Waleed Alghamdi
- Division of Gastroenterology, Department of Medicine, King Abdulaziz University, Jeddah, Saudi Arabia
| | - Mahmoud Mosli
- Division of Gastroenterology, Department of Medicine, King Abdulaziz University, Jeddah, Saudi Arabia
| | - Saleh A. Alqahtani
- Organ Transplant Center of Excellence, King Faisal Specialist Hospital & Research Center, Riyadh 11211, Saudi Arabia
- Division of Gastroenterology & Hepatology, Johns Hopkins University, Baltimore, MD, USA
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6
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Shen B, Gu T, Shen Z, Zhou C, Guo Y, Wang J, Li B, Xu X, Li F, Zhang Q, Cai X, Dong H, Lu L. Escherichia coli Promotes Endothelial to Mesenchymal Transformation of Liver Sinusoidal Endothelial Cells and Exacerbates Nonalcoholic Fatty Liver Disease Via Its Flagellin. Cell Mol Gastroenterol Hepatol 2023; 16:857-879. [PMID: 37572735 PMCID: PMC10598062 DOI: 10.1016/j.jcmgh.2023.08.001] [Citation(s) in RCA: 18] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/01/2022] [Revised: 08/01/2023] [Accepted: 08/01/2023] [Indexed: 08/14/2023]
Abstract
BACKGROUND＆AIMS: Gut bacteria translocate into the liver through a disrupted gut vascular barrier, which is an early and common event in the development of nonalcoholic fatty liver disease (NAFLD). Liver sinusoidal endothelial cells (LSECs) are directly exposed to translocated gut microbiota in portal vein blood. Escherichia coli, a commensal gut bacterium with flagella, is markedly enriched in the gut microbiota of patients with NAFLD. However, the impact of E coli on NAFLD progression and its underlying mechanisms remains unclear. METHODS The abundance of E coli was analyzed by using 16S ribosomal RNA sequencing in a cohort of patients with NAFLD and healthy controls. The role of E coli was assessed in NAFLD mice after 16 weeks of administration, and the features of NAFLD were evaluated. Endothelial to mesenchymal transition (EndMT) in LSECs induced by E coli was analyzed through Western blotting and immunofluorescence. RESULTS The abundance of gut Enterobacteriaceae increased in NAFLD patients with severe fat deposition and fibrosis. Importantly, translocated E coli in the liver aggravated hepatic steatosis, inflammation, and fibrosis in NAFLD mice. Mechanistically, E coli induced EndMT in LSECs through the TLR5/MYD88/TWIST1 pathway during NAFLD development. The toll-like receptor 5 inhibitor attenuated E coli-induced EndMT in LSECs and liver injury in NAFLD mice. Interestingly, flagellin-deficient E coli promoted less EndMT in LSECs and liver injury in NAFLD mice. CONCLUSIONS E coli promoted the development of NAFLD and promoted EndMT in LSECs through toll-like receptor 5/nuclear factor kappa B-dependent activation of TWIST1 mediated by flagellin. Therapeutic interventions targeting E coli and/or flagellin may represent a promising candidate for NAFLD treatment.
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Affiliation(s)
- Bo Shen
- Department of Gastroenterology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Tianyi Gu
- Department of Gastroenterology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Zhenyang Shen
- Department of Gastroenterology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Cui Zhou
- Department of Gastroenterology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Yuecheng Guo
- Department of Gastroenterology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Junjun Wang
- Department of Gastroenterology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Binghang Li
- Department of Gastroenterology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Xianjun Xu
- Department of Gastroenterology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Fei Li
- Department of Gastroenterology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Qidi Zhang
- Department of Gastroenterology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Xiaobo Cai
- Department of Gastroenterology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Hui Dong
- Department of Gastroenterology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
| | - Lungen Lu
- Department of Gastroenterology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
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7
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Di Fazio P, Mielke S, Böhm IT, Buchholz M, Matrood S, Schuppan D, Wissniowski T. Toll-like receptor 5 tunes hepatic and pancreatic stellate cells activation. BMJ Open Gastroenterol 2023; 10:e001148. [PMID: 37433685 PMCID: PMC10347502 DOI: 10.1136/bmjgast-2023-001148] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/22/2023] [Accepted: 06/21/2023] [Indexed: 07/13/2023] Open
Abstract
OBJECTIVE Stellate cells are responsible for liver and pancreas fibrosis and strictly correlate with tumourigenesis. Although their activation is reversible, an exacerbated signalling triggers chronic fibrosis. Toll-like receptors (TLRs) modulate stellate cells transition. TLR5 transduces the signal deriving by the binding to bacterial flagellin from invading mobile bacteria. DESIGN Human hepatic and pancreatic stellate cells were activated by the administration of transforming growth factor-beta (TGF-β). TLR5 was transiently knocked down by short-interference RNA transfection. Reverse Transcription-quantitativePCR and western blot were performed to analyse the transcript and protein level of TLR5 and the transition players. Fluorescence microscopy was performed to identify these targets in spheroids and in the sections of murine fibrotic liver. RESULTS TGF-β-activated human hepatic and pancreatic stellate cells showed an increase of TLR5 expression. TLR5 knockdown blocked the activation of those stellate cells. Furthermore, TLR5 busted during murine liver fibrosis and co-localised with the inducible Collagen I. Flagellin suppressed TLR5, COL1A1 and ACTA2 expression after the administration of TGF-β. Instead, the antagonist of TLR5 did not block the effect of TGF-β. Wortmannin, a specific AKT inhibitor, induced TLR5 but not COL1A1 and ACTA2 transcript and protein level. CONCLUSION TGF-β-mediated activation of hepatic and pancreatic stellate cells requires the over-expression of TLR5. Instead, its autonomous signalling inhibits the activation of the stellate cells, thus prompting a signalling through different regulatory pathways.
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Affiliation(s)
- Pietro Di Fazio
- Department of Visceral Thoracic and Vascular Surgery, Philipps-Universität Marburg, Marburg, Germany
| | - Sophia Mielke
- Department of Visceral Thoracic and Vascular Surgery, Philipps-Universität Marburg, Marburg, Germany
| | - Isabell T Böhm
- Department of Visceral Thoracic and Vascular Surgery, Philipps-Universität Marburg, Marburg, Germany
| | - Malte Buchholz
- Department of Gastroenterology, Philipps-Universität Marburg, Marburg, Germany
| | - Sami Matrood
- Department of Visceral Thoracic and Vascular Surgery, Philipps-Universität Marburg, Marburg, Germany
| | - Detlef Schuppan
- Institute of Translational Immunology, Johannes Gutenberg Universitat Mainz, Mainz, Germany
- Division of Gastroenterology, Beth Israel Deaconess Medical Center, Boston, Massachusetts, USA
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Han F, Wang K, Shen K, Wang J, Han S, Hu D, Wu G. Extracellular vesicles from Lactobacillus druckerii inhibit hypertrophic scar fibrosis. J Nanobiotechnology 2023; 21:113. [PMID: 36978136 PMCID: PMC10053340 DOI: 10.1186/s12951-023-01861-y] [Citation(s) in RCA: 19] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2023] [Accepted: 03/16/2023] [Indexed: 03/30/2023] Open
Abstract
BACKGROUND Hypertrophic scars (HS) affect millions of people each year and require better treatment strategies. Bacterial extracellular vesicles (EVs) are advantaged by low cost and high yield which was commonly used in the treatment of diseases. Here, we investigated the therapeutic efficacy of EVs obtained from Lactobacillus druckerii in hypertrophic scar. In vitro, the effects of Lactobacillus druckerii-derived EVs (LDEVs) on Collagen I/III and α-SMA in fibroblasts obtained from HS. In vivo, a scleroderma mouse model was used to investigate the effects of LDEVs on fibrosis. The impact of LDEVs on excisional wound healing was explored. The different proteins between PBS and LDEVs treated fibroblasts derived from hypertrophic scar were studied by untargeted proteomic analysis. RESULTS In vitro, LDEVs treatment significantly inhibited the expression of Collagen I/III and α-SMA and cell proliferation of fibroblasts derived from HS. In vivo, LDEVs withdrawn the hypertrophic scar formation in scleroderma mouse model and decreased the expression of α-SMA. LDEVs promoted the proliferation of skin cells, new blood vessel formation and wound healing in excisional wound healing mice model. Moreover, proteomics has shown that LDEVs inhibit hypertrophic scar fibrosis through multiple pathways. CONCLUSIONS Our results indicated that Lactobacillus druckerii-derived EVs has the potential application in the treatment of hypertrophic scars and any other fibrosis diseases.
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Affiliation(s)
- Fu Han
- Department of Burns and Cutaneous Surgery, Xijing Hospital, Air Force Medical University, Xi'an, 710032, Shaanxi, China
| | - Kejia Wang
- Department of Burns and Cutaneous Surgery, Xijing Hospital, Air Force Medical University, Xi'an, 710032, Shaanxi, China
| | - Kuo Shen
- Department of Burns and Cutaneous Surgery, Xijing Hospital, Air Force Medical University, Xi'an, 710032, Shaanxi, China
| | - Jing Wang
- Department of Nursing, Air Force Medical University, Xi'an, 710032, Shaanxi, China
| | - Shichao Han
- Department of Urology, Xijing Hospital, Air Force Medical University, Xi'an, 710032, Shaanxi, China
| | - Dahai Hu
- Department of Burns and Cutaneous Surgery, Xijing Hospital, Air Force Medical University, Xi'an, 710032, Shaanxi, China.
| | - Gaofeng Wu
- Department of Burns and Cutaneous Surgery, Xijing Hospital, Air Force Medical University, Xi'an, 710032, Shaanxi, China.
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Bacil GP, Romualdo GR, Piagge PMFD, Cardoso DR, Vinken M, Cogliati B, Barbisan LF. Unraveling Hepatic Metabolomic Profiles and Morphological Outcomes in a Hybrid Model of NASH in Different Mouse Strains. Antioxidants (Basel) 2023; 12:antiox12020290. [PMID: 36829849 PMCID: PMC9952348 DOI: 10.3390/antiox12020290] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2022] [Revised: 12/27/2022] [Accepted: 12/29/2022] [Indexed: 01/31/2023] Open
Abstract
Nonalcoholic fatty liver disease (NAFLD) encompasses nonalcoholic steatohepatitis (NASH) and affects 25% of the global population. Although a plethora of experimental models for studying NASH have been proposed, still scarce findings regarding the hepatic metabolomic/molecular profile. In the present study, we sought to unravel the hepatic metabolomic profile of mice subjected to a hybrid model of NASH, by combining a Western diet and carbon tetrachloride administration, for 8 weeks, in male C57BL/6J and BALB/c mice. In both mouse strains, the main traits of NASH-metabolic (glucose intolerance profile), morphologic (extensive microvesicular steatosis and fibrosis, lobular inflammation, and adipose tissue-related inflammation/hypertrophy), and molecular (impaired Nrf2/NF-κB pathway dynamics and altered metabolomic profile)-were observed. The hepatic metabolomic profile revealed that the hybrid protocol impaired, in both strains, the abundance of branched chain-aromatic amino acids, carboxylic acids, and glycosyl compounds, that might be linked to the Nrf2 pathway activation. Moreover, we observed a strain-dependent hepatic metabolomic signature, in which the tricarboxylic acid metabolites and pyruvate metabolism were dissimilarly modulated in C57BL/6J and BALB/c mice. Thus, we provide evidence that the strain-dependent hepatic metabolomic profile might be linked to the distinct underlying mechanisms of NASH, also prospecting potential mechanistic insights into the corresponding disease.
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Affiliation(s)
- Gabriel P. Bacil
- Department of Pathology, Botucatu Medical School (FMB), São Paulo State University (UNESP), Botucatu 18618-689, Brazil
| | - Guilherme R. Romualdo
- Department of Pathology, Botucatu Medical School (FMB), São Paulo State University (UNESP), Botucatu 18618-689, Brazil
- Department of Structural and Functional Biology, Biosciences Institute, São Paulo State University (UNESP), Botucatu 18618-689, Brazil
| | - Priscila M. F. D. Piagge
- Department of Chemistry and Molecular Physics, São Carlos Institute of Chemistry (IQSC), University of São Paulo (USP), São Carlos 13566-590, Brazil
| | - Daniel R. Cardoso
- Department of Chemistry and Molecular Physics, São Carlos Institute of Chemistry (IQSC), University of São Paulo (USP), São Carlos 13566-590, Brazil
| | - Mathieu Vinken
- Department of Pharmaceutical and Pharmacological Sciences, University of Vrije, 1090 Brussel, Belgium
| | - Bruno Cogliati
- Department of Pathology, School of Veterinary Medicine and Animal Science, University of São Paulo (USP), São Paulo 05508-270, Brazil
| | - Luís F. Barbisan
- Department of Structural and Functional Biology, Biosciences Institute, São Paulo State University (UNESP), Botucatu 18618-689, Brazil
- Correspondence: ; Tel.: +55-14-3880-0469
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10
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Zhang L, Wu F, Fan C, Huang S, Ma Y, Chen S, Zhang J, Jiang H. Quantitative phosphoproteomic analysis of mice with liver fibrosis by DIA mass spectrometry analysis with PRM verification. J Proteomics 2023; 271:104768. [PMID: 36336261 DOI: 10.1016/j.jprot.2022.104768] [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: 08/03/2022] [Revised: 10/21/2022] [Accepted: 10/24/2022] [Indexed: 11/06/2022]
Abstract
Liver fibrosis (LF), commonly associated with chronic liver diseases, is a major public health problem worldwide. Protein phosphorylation is not only an important form of protein modification in organisms but also the most important mechanism to regulate and control the activity and function of proteins, affecting the occurrence and development of many diseases. However, comprehensive phosphoproteomic profiling in LF has not been fully elucidated. In this study, data-independent acquisition (DIA) was used to analyse the phosphoproteomics of mice with LF. A total of 553 phosphopeptides (representing 440 phosphoproteins) had significant phosphorylation levels. Among these phosphoproteins, 49 were upregulated and 401 were downregulated, and 5 phosphoserine (P-Ser) motifs and 2 phosphothreonine (P-Thr) motifs were conserved in LF. GO and KEGG pathway enrichment analyses identified 769 significant GO terms and 49 significant KEGG pathways. Four phosphorylated proteins were selected for parallel reaction monitoring (PRM) verification, and the results were consistent with DIA data. Together, there were significantly different phosphoproteomic profiles in LF, suggesting that protein phosphorylation was related to the occurrence and progression of LF, which could pave the way for further investigation into the related regulatory mechanisms. SIGNIFICANCE: LF is a necessary stage in the development of chronic liver disease to liver cirrhosis and has attracted wide attention. To the best of our knowledge, there are few reports on the phosphorylated proteomics of LF. In this study, DIA and PRM techniques were used to study the liver tissue of mice induced by CCl4. The results showed that phosphorylation had a significant effect on the activity and function of proteins, and the PRM results were consistent with the trend observed in DIA analysis. This study will help to better reveal the relationship of phosphorylated proteins in LF and lay a foundation for further study of related regulatory mechanisms.
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Affiliation(s)
- Lili Zhang
- Experimental Center of Clinical Research, The First Affiliated Hospital of Anhui University of Chinese Medicine, Hefei, China; School of Pharmacy, Anhui University of Chinese Medicine, Hefei, China.
| | - Furong Wu
- Department of Pharmacy, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China.
| | - Chang Fan
- Experimental Center of Clinical Research, The First Affiliated Hospital of Anhui University of Chinese Medicine, Hefei, China; School of Pharmacy, Anhui University of Chinese Medicine, Hefei, China.
| | - Shaopeng Huang
- Experimental Center of Clinical Research, The First Affiliated Hospital of Anhui University of Chinese Medicine, Hefei, China; School of Pharmacy, Anhui University of Chinese Medicine, Hefei, China.
| | - Yanzhen Ma
- Experimental Center of Clinical Research, The First Affiliated Hospital of Anhui University of Chinese Medicine, Hefei, China; School of Pharmacy, Anhui University of Chinese Medicine, Hefei, China.
| | - Sen Chen
- Experimental Center of Clinical Research, The First Affiliated Hospital of Anhui University of Chinese Medicine, Hefei, China; School of Pharmacy, Anhui University of Chinese Medicine, Hefei, China.
| | - Jiafu Zhang
- Department of Pharmacy, The First Affiliated Hospital of Anhui University of Chinese Medicine, Hefei, China.
| | - Hui Jiang
- Experimental Center of Clinical Research, The First Affiliated Hospital of Anhui University of Chinese Medicine, Hefei, China; School of Pharmacy, Anhui University of Chinese Medicine, Hefei, China.
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Tourkochristou E, Assimakopoulos SF, Thomopoulos K, Marangos M, Triantos C. NAFLD and HBV interplay - related mechanisms underlying liver disease progression. Front Immunol 2022; 13:965548. [PMID: 36544761 PMCID: PMC9760931 DOI: 10.3389/fimmu.2022.965548] [Citation(s) in RCA: 29] [Impact Index Per Article: 9.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2022] [Accepted: 11/15/2022] [Indexed: 12/08/2022] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD) and Hepatitis B virus infection (HBV) constitute common chronic liver diseases with worldwide distribution. NAFLD burden is expected to grow in the coming decade, especially in western countries, considering the increased incidence of diabetes and obesity. Despite the organized HBV vaccinations and use of anti-viral therapies globally, HBV infection remains endemic and challenging public health issue. As both NAFLD and HBV have been associated with the development of progressive fibrosis, cirrhosis and hepatocellular carcinoma (HCC), the co-occurrence of both diseases has gained great research and clinical interest. The causative relationship between NAFLD and HBV infection has not been elucidated so far. Dysregulated fatty acid metabolism and lipotoxicity in NAFLD disease seems to initiate activation of signaling pathways that enhance pro-inflammatory responses and disrupt hepatocyte cell homeostasis, promoting progression of NAFLD disease to NASH, fibrosis and HCC and can affect HBV replication and immune encountering of HBV virus, which may further have impact on liver disease progression. Chronic HBV infection is suggested to have an influence on metabolic changes, which could lead to NAFLD development and the HBV-induced inflammatory responses and molecular pathways may constitute an aggravating factor in hepatic steatosis development. The observed altered immune homeostasis in both HBV infection and NAFLD could be associated with progression to HCC development. Elucidation of the possible mechanisms beyond HBV chronic infection and NAFLD diseases, which could lead to advanced liver disease or increase the risk for severe complications, in the case of HBV-NAFLD co-existence is of high clinical significance in the context of designing effective therapeutic targets.
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Affiliation(s)
- Evanthia Tourkochristou
- Division of Gastroenterology, Department of Internal Medicine, Medical School, University of Patras, Patras, Greece
| | - Stelios F. Assimakopoulos
- Division of Infectious Diseases, Department of Internal Medicine, Medical School, University of Patras, Patras, Greece
| | - Konstantinos Thomopoulos
- Division of Gastroenterology, Department of Internal Medicine, Medical School, University of Patras, Patras, Greece
| | - Markos Marangos
- Division of Infectious Diseases, Department of Internal Medicine, Medical School, University of Patras, Patras, Greece
| | - Christos Triantos
- Division of Gastroenterology, Department of Internal Medicine, Medical School, University of Patras, Patras, Greece
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12
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Khanmohammadi S, Kuchay MS. Toll-like receptors and metabolic (dysfunction)-associated fatty liver disease. Pharmacol Res 2022; 185:106507. [DOI: 10.1016/j.phrs.2022.106507] [Citation(s) in RCA: 56] [Impact Index Per Article: 18.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/11/2022] [Revised: 10/05/2022] [Accepted: 10/10/2022] [Indexed: 10/31/2022]
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Wei X, Lan Y, Nong Z, Li C, Feng Z, Mei X, Zhai Y, Zou M. Ursolic acid represses influenza A virus-triggered inflammation and oxidative stress in A549 cells by modulating the miR-34c-5p/TLR5 axis. Cytokine 2022; 157:155947. [PMID: 35780710 DOI: 10.1016/j.cyto.2022.155947] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2021] [Revised: 06/09/2022] [Accepted: 06/13/2022] [Indexed: 02/05/2023]
Abstract
BACKGROUND Ursolic acid (UA) is a pentacyclic triterpenoid compound with a wide range of anti-tumor, anti-inflammatory, hypotensive and other pharmacological effects. Here, the biological roles and regulatory mechanisms of UA in influenza A virus (IAV)-treated A549 cells were investigated. METHOD The cytotoxic impacts of UA on A549 cells with or without IAV treatment were determined using MTT and LDH assays. The inflammatory responses and oxidative stress of IAV-treated A549 cells were measured by RT-qPCR, ELISA, DCFH-DA probe, and colorimetric assays. A dual luciferase assay was carried out to validate the molecular interaction between miR-34c-5p and TLR5. Promoter methylation was detected by MSP experiment. Methylation-related proteins were quantified by western blot. Virus replication was assessed by TCID50 and western blot assays. RESULTS UA significantly ameliorated IAV-triggered cell injury and inflammatory response, virus replication and oxidative stress by elevating cell viability, ROS level and the activities of SOD and GSH-Px but reducing the LDH, MDA, and TCID50 values and the expression of virus-related proteins (NP) and cytokines (TNF-α, IL-1β, IL-6, and IL-18). Moreover, UA promoted miR-34c-5p expression by repressing DNMTs-mediated methylation. TLR5 was verified to be a direct target of miR-34c-5p and could be downregulated by UA. Rescue experiments revealed that silencing miR-34c-5p diminished the regulatory roles of UA in IAV-treated A549 cells. CONCLUSION Our data elucidated that UA attenuated IAV-triggered inflammatory responses and oxidative stress in A549 cells by regulating the miR-34c-5p/TLR5 axis, suggesting that UA plays a protective role in IAV-induced pneumonia.
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Affiliation(s)
- Xing Wei
- Zhuang Medical College, Guangxi University of Chinese Medicine, Nanning 530200, Guangxi Province, China
| | - Yuying Lan
- Zhuang Medical College, Guangxi University of Chinese Medicine, Nanning 530200, Guangxi Province, China
| | - Zhifei Nong
- Department of Pediatrics, Affiliated Hospital of Guangxi University of Chinese Medicine, Nanning 530022, Guangxi Province, China
| | - Chongjin Li
- Department of Pediatrics, Maoming Hospital of Traditional Chinese Medicine, Maoming 525000, Guangdong Province, China
| | - Zhiqiong Feng
- Department of Pediatrics, Jinshazhou Hospital of Guangzhou University of Traditional Chinese Medicine, Guangzhou 510000, Guangdong Province, China
| | - Xiaoping Mei
- Department of Pediatrics, Guangxi International Zhuang Medicine Hospital, Nanning 530200, Guangxi Province, China
| | - Yang Zhai
- Zhuang Medical College, Guangxi University of Chinese Medicine, Nanning 530200, Guangxi Province, China; Guangxi Key Laboratory of Chinese Medicine Foundation Research, Nanning 530200, Guangxi Province, China; Department of International Medical, Guangxi International Zhuang Medicine Hospital, Nanning 530200, Guangxi Province, China
| | - Min Zou
- Department of Pediatrics, Guangxi International Zhuang Medicine Hospital, Nanning 530200, Guangxi Province, China.
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Wang T, Zhu J, Gao L, Wei M, Zhang D, Chen L, Wu H, Ma J, Li L, Zhang N, Wang Y, Xing Q, He L, Hong F, Qin S. Identification of circular RNA biomarkers for Pien Tze Huang treatment of CCl4‑induced liver fibrosis using RNA‑sequencing. Mol Med Rep 2022; 26:309. [PMID: 36004475 PMCID: PMC9437966 DOI: 10.3892/mmr.2022.12825] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2021] [Accepted: 10/26/2021] [Indexed: 11/26/2022] Open
Abstract
Pien Tze Huang (PZH), a common hepatoprotective Traditional Chinese Medicine that has been found to be an effective treatment for carbon tetrachloride-induced hepatic damage, including liver fibrosis. Circular RNAs (circRNAs) serve a crucial role in regulating gene expression levels via circRNA/micro (mi)RNA/mRNA networks in several human diseases and biological processes. However, whether circRNAs are involved in the underlying mechanism of the therapeutic effects of PZH on liver fibrosis remains unclear. Therefore, the aim of the present study was to investigate these effects using circRNA expression profiles from PZH-treated fibrotic livers in model mice. A case-control study on >59,476 circRNAs from CCl4-induced (control group, n=6) and PZH-treated (case group, n=6) mice was performed using circRNA sequencing in liver tissues. PZH treatment resulted in the differential expression of 91 circRNAs, including 58 upregulated and 33 downregulated circRNAs. Furthermore, the construction of competing endogenous networks also indicated that differentially expressed circRNAs acted as miRNA sponges. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathway enrichment analysis of miRNA targets demonstrated that PZH-affected circRNAs were mainly involved in biological processes such as ‘positive regulation of fibroblast proliferation’, ‘cellular response to interleukin-1’ and ‘regulation of DNA-templated transcription in response to stress’ and in a number of important pathways, such as ‘TNF signaling pathway’, ‘PI3K-Akt signaling pathway’, ‘IL-17 signaling pathway’ and ‘MAPK signaling pathway’. To further validate the bioinformatics data, reverse transcription–quantitative PCR was performed on seven miRNA targets in a human hepatic stellate LX-2 cell model. The results suggested that seven of the miRNAs exhibited regulatory patterns that were consistent with those of the transcriptome sequencing results. Kaplan-Meier survival analysis demonstrated that the expression levels of dihydrodiol dehydrogenase and solute carrier family 7, member 11 gene were significantly associated with patient survival, 269 patients with liver hepatocellular carcinoma from The Cancer Genome Atlas database. To the best of our knowledge, this was the first study to provide evidence that PZH affects circRNA expression levels, which may serve important roles in PZH-treated fibrotic liver through the regulation of functional gene expression. In conclusion, the present study provided new insights into the mechanism underlying the pathogenesis of liver fibrosis and identified potential novel, efficient, therapeutic targets against liver injury.
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Affiliation(s)
- Ting Wang
- Bio‑X Institutes, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders (Ministry of Education), Shanghai Jiao Tong University, Shanghai 200030, P.R. China
| | - Jinhang Zhu
- Bio‑X Institutes, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders (Ministry of Education), Shanghai Jiao Tong University, Shanghai 200030, P.R. China
| | - Longhui Gao
- Bio‑X Institutes, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders (Ministry of Education), Shanghai Jiao Tong University, Shanghai 200030, P.R. China
| | - Muyun Wei
- Bio‑X Institutes, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders (Ministry of Education), Shanghai Jiao Tong University, Shanghai 200030, P.R. China
| | - Di Zhang
- Bio‑X Institutes, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders (Ministry of Education), Shanghai Jiao Tong University, Shanghai 200030, P.R. China
| | - Luan Chen
- Bio‑X Institutes, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders (Ministry of Education), Shanghai Jiao Tong University, Shanghai 200030, P.R. China
| | - Hao Wu
- Bio‑X Institutes, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders (Ministry of Education), Shanghai Jiao Tong University, Shanghai 200030, P.R. China
| | - Jingsong Ma
- Bio‑X Institutes, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders (Ministry of Education), Shanghai Jiao Tong University, Shanghai 200030, P.R. China
| | - Lixing Li
- Department of General Surgery, Shanghai General Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200240, P.R. China
| | - Na Zhang
- Bio‑X Institutes, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders (Ministry of Education), Shanghai Jiao Tong University, Shanghai 200030, P.R. China
| | - Yanjing Wang
- State Key Laboratory of Microbial Metabolism, Joint Laboratory of International Cooperation in Metabolic and Developmental Sciences, School of Sciences and Biotechnology, Shanghai Jiao Tong University, Shanghai 200240, P.R. China
| | - Qinghe Xing
- Institutes of Biomedical Sciences and Children's Hospital, Fudan University, Shanghai 201102, P.R. China
| | - Lin He
- Bio‑X Institutes, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders (Ministry of Education), Shanghai Jiao Tong University, Shanghai 200030, P.R. China
| | - Fei Hong
- Fujian Provincial Key Laboratory of Pien Tze Huang Natural Medicine Research and Development, Zhangzhou Pien Tze Huang Pharmaceutical Co., Ltd., Zhangzhou, Fujian 363000, P.R. China
| | - Shengying Qin
- Bio‑X Institutes, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders (Ministry of Education), Shanghai Jiao Tong University, Shanghai 200030, P.R. China
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Xie Y, Du D, Zhang L, Yang Y, Zou Z, Li Z, Zhou L, Shang R, Zhou P. TJ-M2010-5, A self-developed MyD88 inhibitor, attenuates liver fibrosis by inhibiting the NF-κB pathway. Chem Biol Interact 2022; 354:109839. [PMID: 35101388 DOI: 10.1016/j.cbi.2022.109839] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2021] [Revised: 01/17/2022] [Accepted: 01/26/2022] [Indexed: 02/09/2023]
Abstract
Liver fibrosis is the result of most chronic inflammatory liver damage and seriously endangers human health. However, no drugs have been approved to treat this disease. Previous studies showed that the Toll-like receptors (TLRs)/myeloid differentiation factor-88 (MyD88)/nuclear factor-κB (NF-κB) pathway plays a key role in liver fibrosis. TJ-M2010-5 is a self-developed small molecule MyD88 inhibitor, which has been proven to have a good protective effect in a variety of inflammatory disease models. In the present study, to investigate the anti-fibrotic effect of TJ-M2010-5, mice were injected with carbon tetrachloride (CCl4) in vivo and LX2 cells (a human hepatic stellate cell line) were treated with TGF-β1 in vitro to induce liver fibrosis. In vivo studies showed that TJ-M2010-5 attenuated the CCl4-induced liver damage, collagen accumulation, and the activation of hepatic stellate cells by inhibiting the nuclear transfer of NF-κB. Moreover, in vitro experiments of LX2 cells stimulated with TGF-β1 further indicated that the NF-κB pathway is involved in the development of liver fibrosis. TJ-M2010-5 significantly inhibited the proliferation and activation of LX2 cells. In addition, TJ-M2010-5 upregulated the expression of bone morphogenetic protein and membrane-bound inhibitor (BAMBI) in LX2 cells by blocking the activation of MyD88/NF-κB, thereby inhibiting the phosphorylation of Smad2/3 and the expression of collagen I (COL1A1) induced by TGF-β1. In conclusion, this study illustrates the anti-hepatic fibrosis effect of TJ-M2010-5 and provides a new treatment method for liver fibrosis.
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Affiliation(s)
- Yalong Xie
- Institute of Organ Transplantation, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China; Key Laboratory of Organ Transplantation, Ministry of Education, China; NHC Key Laboratory of Organ Transplantation, China; Key Laboratory of Organ Transplantation, Chinese Academy of Medical Sciences, Wuhan, China
| | - Dunfeng Du
- Institute of Organ Transplantation, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China; Key Laboratory of Organ Transplantation, Ministry of Education, China; NHC Key Laboratory of Organ Transplantation, China; Key Laboratory of Organ Transplantation, Chinese Academy of Medical Sciences, Wuhan, China
| | - Limin Zhang
- Institute of Organ Transplantation, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China; Key Laboratory of Organ Transplantation, Ministry of Education, China; NHC Key Laboratory of Organ Transplantation, China; Key Laboratory of Organ Transplantation, Chinese Academy of Medical Sciences, Wuhan, China
| | - Yang Yang
- Institute of Organ Transplantation, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China; Key Laboratory of Organ Transplantation, Ministry of Education, China; NHC Key Laboratory of Organ Transplantation, China; Key Laboratory of Organ Transplantation, Chinese Academy of Medical Sciences, Wuhan, China
| | - Zhimiao Zou
- Institute of Organ Transplantation, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China; Key Laboratory of Organ Transplantation, Ministry of Education, China; NHC Key Laboratory of Organ Transplantation, China; Key Laboratory of Organ Transplantation, Chinese Academy of Medical Sciences, Wuhan, China
| | - Zeyang Li
- Institute of Organ Transplantation, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China; Key Laboratory of Organ Transplantation, Ministry of Education, China; NHC Key Laboratory of Organ Transplantation, China; Key Laboratory of Organ Transplantation, Chinese Academy of Medical Sciences, Wuhan, China
| | - Liang Zhou
- Institute of Organ Transplantation, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China; Key Laboratory of Organ Transplantation, Ministry of Education, China; NHC Key Laboratory of Organ Transplantation, China; Key Laboratory of Organ Transplantation, Chinese Academy of Medical Sciences, Wuhan, China
| | - Runshi Shang
- Institute of Organ Transplantation, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China; Key Laboratory of Organ Transplantation, Ministry of Education, China; NHC Key Laboratory of Organ Transplantation, China; Key Laboratory of Organ Transplantation, Chinese Academy of Medical Sciences, Wuhan, China
| | - Ping Zhou
- Institute of Organ Transplantation, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China; Key Laboratory of Organ Transplantation, Ministry of Education, China; NHC Key Laboratory of Organ Transplantation, China; Key Laboratory of Organ Transplantation, Chinese Academy of Medical Sciences, Wuhan, China.
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Raftar SKA, Ashrafian F, Abdollahiyan S, Yadegar A, Moradi HR, Masoumi M, Vaziri F, Moshiri A, Siadat SD, Zali MR. The anti-inflammatory effects of Akkermansia muciniphila and its derivates in HFD/CCL4-induced murine model of liver injury. Sci Rep 2022; 12:2453. [PMID: 35165344 PMCID: PMC8844054 DOI: 10.1038/s41598-022-06414-1] [Citation(s) in RCA: 55] [Impact Index Per Article: 18.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2021] [Accepted: 01/24/2022] [Indexed: 12/14/2022] Open
Abstract
Inflammation plays a critical role in the promotion of hepatocyte damage and liver fibrosis. In recent years the protective role of Akkermansia muciniphila, a next-generation beneficial microbe, has been suggested for metabolic and inflammatory disorders. In this study, we aimed to evaluate the effects of live and pasteurized A. muciniphila and its extra cellular vesicles (EVs) on inflammatory markers involved in liver fibrosis in a mouse model of a high-fat diet (HFD)/carbon tetrachloride (CCl4)-induced liver injury. Firstly, the responses of hepatic stellate cells (HSCs) to live and pasteurized A. muciniphila and its EVs were examined in the quiescent and LPS-activated LX-2 cells. Next, the anti-inflammatory effects of different forms of A. muciniphila were examined in the mouse model of HFD/CCl4-induced liver injury. The gene expression of various inflammatory markers was evaluated in liver, colon, and white adipose tissues. The cytokine secretion in the liver and white adipose tissues was also measured by ELISA. The results showed that administration of live and pasteurized A. muciniphila and its EVs leads to amelioration in HSCs activation. Based on data obtained from the histopathological analysis, an improvement in gut health was observed through enhancing the epithelium and mucosal layer thickness and strengthening the intestinal integrity in all treatments. Moreover, live A. muciniphila and its EVs had inhibitory effects on liver inflammation and hepatocytes damage. In addition, the tissue cytokine production and inflammatory gene expression levels revealed that live A. muciniphila and its EVs had more pronounced anti-inflammatory effects on liver and adipose tissues. Furthermore, EVs had better effects on the modulation of gene expression related to TLRs, PPARs, and immune response in the liver. In conclusion, the present results showed that oral administration of A. muciniphila and its derivatives for four weeks could enhance the intestinal integrity and anti-inflammatory responses of the colon, adipose, and liver tissues and subsequently prevent liver injury in HFD/CCL4 mice.
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Owojuyigbe OS, Larbie C, Firempong CK, Komlaga G, Emikpe BO, Oyagbemi AA. Hura crepitans stem bark extract: A potential remedy to sub-acute liver damage. JOURNAL OF ETHNOPHARMACOLOGY 2022; 284:114768. [PMID: 34688802 DOI: 10.1016/j.jep.2021.114768] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/26/2020] [Revised: 10/13/2021] [Accepted: 10/19/2021] [Indexed: 06/13/2023]
Abstract
ETHNOPHARMACOLOGICAL SIGNIFICANCE AND AIM Hura crepitans is commonly used to treat liver diseases in Nigeria and Ghana. Previous studies have supported its ethnomedicinal use in protecting the liver. The present study aimed at assessing the effect of H. crepitans stem bark on the subacute carbon tetrachloride (CCl4)-induced liver damage in rats. MATERIALS AND METHODS The protective activities of ethanolic extract of H. crepitans stem bark was evaluated in CCl4-induced subacute liver damage in rats (1:1 v/v in olive oil, intraperitoneally (i.p.), twice weekly for 8 weeks). Blood samples were obtained from the rats and used for some biochemical analysis such as liver function test (Aspartate transaminase, AST; Alanine aminotransferase, ALT; and Alkaline phosphatase, ALP), liver fibrotic indices (Aspartate platelet ratio index, APRI; AST/ALT and AST/PLT ratios) and oxidative stress markers (Malondialdehyde, MDA; Reduced glutathione, GSH; Glutathione S-transferase, GST; Glutathione peroxidase, GPx; and superoxide dismutase, SOD). Histopathological analyses were carried out to determine the expression of pro-inflammatory (NF-κB, COX-2, IL-17 and IL-23) using immunohistochemical techniques. RESULTS Oral administration of H. crepitans to CCl4-induced hepatic injured rats significantly decreased oxidative stress, increased the levels of SOD, GSH, GST and GPx with reduced MDA levels. The plant also mitigated liver injury as evidenced in the significantly reduced levels of AST, ALT and ALP, while it inhibited the inflammatory process via the inhibition of NF-κB, and consequently down-regulateed the pro-inflammatory cytokines COX-2, IL-17 and IL-23, respectively. Biochemical observations were supported by improvement in liver microarchitecture. CONCLUSION The Hura crepitans demonstrated antioxidant, antiinflammatory and antifibrotic effect in hepatic injured rats. The study in a way justifies the traditional use of the plant for the treatment of subacute liver diseases in Nigerian Traditional medicine.
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Affiliation(s)
- Oluwole S Owojuyigbe
- Department of Biochemistry and Biotechnology, KNUST, Kumasi, Ghana; Department of Science Laboratory Technology, Federal Polytechnic Ede, Nigeria
| | | | | | | | | | - Ademola A Oyagbemi
- Department of Veterinary Physiology and Biochemistry, University of Ibadan, Nigeria
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New advances of DNA/RNA methylation modification in liver fibrosis. Cell Signal 2021; 92:110224. [PMID: 34954394 DOI: 10.1016/j.cellsig.2021.110224] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2021] [Revised: 12/15/2021] [Accepted: 12/20/2021] [Indexed: 11/23/2022]
Abstract
Liver fibrosis is a complex pathological process caused by multiple pathogenic factors，such as ethanol, viruses, toxins, drugs or cholestasis, and it can eventually develop into liver cirrhosis without effective treatment. Activation of hepatic stellate cells (HSCs) is a pivotal cellular event in the pathogenesis of liver fibrosis. However, the pathogenesis of liver fibrosis has not been fully elucidated. DNA/RNA methylation can regulate gene expression without alteration in its sequence, and numerous studies have shown the involvement of DNA methylation in the activation of HSCs and then promote the progression of liver fibrosis. In addition, RNA methylation has recently been reported to play a regulatory role in this process. In this review, we focus on the aberrant DNA/RNA methylation of selected genes and explore their functional mechanism in regulating HSCs activation and liver fibrogenesis. All of these findings will enhance our understanding of DNA/RNA methylation and their roles in liver fibrosis and provide the basis to identify effective therapeutic targets.
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Nischalke HD, Fischer J, Klüners A, Matz-Soja M, Krämer B, Langhans B, Goeser F, Soyka M, Stickel F, Spengler U, Nattermann J, Strassburg CP, Berg T, Lutz P. A genetic variant in toll-like receptor 5 is linked to chemokine levels and hepatocellular carcinoma in steatohepatitis. Liver Int 2021; 41:2139-2148. [PMID: 34051061 DOI: 10.1111/liv.14980] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/07/2020] [Revised: 04/26/2021] [Accepted: 05/19/2021] [Indexed: 12/15/2022]
Abstract
BACKGROUND & AIMS Bacterial translocation drives liver disease progression. We investigated whether functional genetic variants in toll-like receptor 5 (TLR5), the receptor for bacterial flagellin, affect the risk for hepatocellular carcinoma (HCC). METHODS Healthy controls (n = 212), patients with alcohol abuse without liver disease (n = 382), and patients from a discovery cohort of alcohol-associated cirrhosis (n = 372 including 79 HCC cases), a validation cohort of alcohol-associated cirrhosis (n = 355 including 132 HCC cases), and a cohort of cirrhosis due to nonalcoholic steatohepatitis (NASH) (n = 145 including 62 HCC cases) were genotyped for the TLR5 rs5744174 and rs5744168 polymorphisms. Chemokine levels were measured by ELISA in patients' sera and supernatants of flagellin-stimulated healthy monocytes. RESULTS Frequency of the TLR5 rs5744174 TT genotype was similar in healthy controls (33%), controls with alcohol abuse (34%), and patients with alcohol-associated cirrhosis in the discovery (28%), validation (33%), and NASH cohort (31%). The TT genotype was enriched in patients with versus without HCC in the discovery, validation, and NASH cohort (41% vs 25%; 39% vs 29%; 40% vs 24%; p < .05 each). This genotype remained a risk factor for HCC (OR = 1.9; p = .01) after multivariate correction for age, gender, diabetes, and carriage of the PNPLA3 148M variant. Interleukin-8 induction in monocytes from healthy controls and serum levels of interleukin-8 and CXCL1 from cirrhotic patients with the TT genotype were significantly increased versus C allele carriers. CONCLUSION The TLR5 rs5744174 polymorphism, affecting immune response to flagellin, is linked to occurrence of HCC in cirrhosis caused by steatohepatitis.
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Affiliation(s)
- Hans Dieter Nischalke
- Department of Internal Medicine I, University Hospital, University of Bonn, Bonn, Germany
| | - Janett Fischer
- Division of Hepatology, Department of Oncology, Gastroenterology, Hepatology, Pulmonology and Infectious Diseases, Leipzig University Medical Center, Leipzig, Germany
| | - Alexandra Klüners
- Department of Internal Medicine I, University Hospital, University of Bonn, Bonn, Germany
| | - Madlen Matz-Soja
- Division of Hepatology, Department of Oncology, Gastroenterology, Hepatology, Pulmonology and Infectious Diseases, Leipzig University Medical Center, Leipzig, Germany
| | - Benjamin Krämer
- Department of Internal Medicine I, University Hospital, University of Bonn, Bonn, Germany
| | - Bettina Langhans
- Department of Internal Medicine I, University Hospital, University of Bonn, Bonn, Germany
| | - Felix Goeser
- Department of Internal Medicine I, University Hospital, University of Bonn, Bonn, Germany
| | - Michael Soyka
- Psychiatric Hospital, Ludwig Maximilians University, Munich, Germany
| | - Felix Stickel
- Department of Gastroenterology and Hepatology, University Hospital of Zürich, Zürich, Switzerland
| | - Ulrich Spengler
- Department of Internal Medicine I, University Hospital, University of Bonn, Bonn, Germany
| | - Jacob Nattermann
- Department of Internal Medicine I, University Hospital, University of Bonn, Bonn, Germany
| | - Christian P Strassburg
- Department of Internal Medicine I, University Hospital, University of Bonn, Bonn, Germany
| | - Thomas Berg
- Division of Hepatology, Department of Oncology, Gastroenterology, Hepatology, Pulmonology and Infectious Diseases, Leipzig University Medical Center, Leipzig, Germany
| | - Philipp Lutz
- Department of Internal Medicine I, University Hospital, University of Bonn, Bonn, Germany
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Ravan AP, Goudarzi F, Rafieemehr H, Bahmani M, Rad F, Jafari M, Mahmoodi M. Human umbilical cord-mesenchymal stem cells conditioned medium attenuates CCl 4 induced chronic liver fibrosis. TOXIN REV 2021. [DOI: 10.1080/15569543.2019.1590849] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Affiliation(s)
- Alireza Pouyandeh Ravan
- Department of Medical Laboratory Sciences, School of Paramedicine, Hamadan University of Medical Sciences, Hamadan, Iran
| | - Farjam Goudarzi
- Regenerative Medicine Research Center, Kermanshah University of Medical Sciences, Kermanshah, Iran
| | - Hassan Rafieemehr
- Department of Medical Laboratory Sciences, School of Paramedicine, Hamadan University of Medical Sciences, Hamadan, Iran
| | - Mahdi Bahmani
- Cellular and Molecular Research Center, Yasuj University of Medical Sciences, Yasuj, Iran
| | - Fariba Rad
- Molecular Research Center, Yasuj University of Medical Sciences, Yasuj, Iran
| | - Mohammad Jafari
- Department of Pathology, School of Medicine, Hamadan University of Medical Sciences, Hamadan, Iran
| | - Marzieh Mahmoodi
- Department of Biostatistics, School of Health and Nutrition, Bushehr University of Medical Sciences, Bushehr, Iran
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21
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Zhang Y, Zhou J, Liu J, Li S, Zhou S, Zhang C, Wang Y, Shi J, Liu J, Wu Q. RNA-Seq analysis of the protection by Dendrobium nobile alkaloids against carbon tetrachloride hepatotoxicity in mice. Biomed Pharmacother 2021; 137:111307. [PMID: 33561648 DOI: 10.1016/j.biopha.2021.111307] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2020] [Revised: 11/30/2020] [Accepted: 12/26/2020] [Indexed: 01/04/2023] Open
Abstract
OBJECTIVE Dendrobium nobile is a genuine Chinese medicine. Dendrobium nobile Lindl. alkaloids (DNLA) protects against CCl4-induced acute liver injury. This study used RNA-Seq to explore the mechanisms. METHODS Mice were pretreated with DNLA (10 and 20 mg/kg, po) for 7 days, and subsequently intoxicated with CCl4 (20 μL/kg, ip for 24 h). Liver RNA was extracted and subjected to RNA-Seq. The bioinformatics, including PCA, GO, KEGG, two-dimensional clustering, Ingenuity Pathways Analysis (IPA), and Illumina BaseSpace Correlation Engine (BSCE) were used to analyze the data. qPCR was performed on selected genes to verify RNA-Seq results. RESULTS DNLA protection against CCl4 hepatotoxicity was confirmed by histopathology. PCA revealed the distinct gene expression patterns between the different treatment groups. GO showed that CCl4 induced the activation, adhesion and proliferation of immune cells. KEGG showed CCl4 induced oxidative stress, diseases and compromised adaptive responses. CCl4 induced differentially expressed genes (DEGs) were identified by DESeq2 with Padj < 0.05 and 2D-clustered with other groups. DNLA reverted CCl4-induced DEGs in a dose-dependent manner. qPCR analysis of S100 g, Sprr1, CCL3/7, Saa2/3, IL1rn, Cox7a2 and Rad15 confirmed RNA-Seq results. IPA showed that CCl4 treatment altered some signaling and metabolic pathways, which were ameliorated or returned to normal following DNLA treatment. The CCl4-activated mitochondrial oxidative phosphorylation was illustrated as an example. IPA Upstream Regulator Analysis further revealed the activated or inhibited molecules and chemicals that are responsible for CCl4-induced DEGs, and DNLA attenuated these changes. BSCE analysis verified that CCl4-induced DEGs were highly correlated with the GEO database of CCl4 hepatotoxicity in rodents, and DNLA dose-dependently attenuated such correlation. CONCLUSION RNA-Seq revealed CCl4-induced DEGs, disruption of canonical pathways, activation or inhibition of upstream regulators, which are highly correlated with database for CCl4 hepatotoxicity. All these changes were attenuated or returned to normal by DNLA, demonstrating the mechanisms for DNLA to protect against CCl4 hepatotoxicity.
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Affiliation(s)
- Ya Zhang
- Key Laboratory of Basic Pharmacology of Ministry of Education and Joint International Research Laboratory of Ethnocentric of Ministry of Education, Zunyi Medical University, Zunyi, China.
| | - Jinxin Zhou
- Key Laboratory of Basic Pharmacology of Ministry of Education and Joint International Research Laboratory of Ethnocentric of Ministry of Education, Zunyi Medical University, Zunyi, China.
| | - Jiajia Liu
- Key Laboratory of Basic Pharmacology of Ministry of Education and Joint International Research Laboratory of Ethnocentric of Ministry of Education, Zunyi Medical University, Zunyi, China.
| | - Shujun Li
- Key Laboratory of Basic Pharmacology of Ministry of Education and Joint International Research Laboratory of Ethnocentric of Ministry of Education, Zunyi Medical University, Zunyi, China.
| | - Shaoyu Zhou
- Key Laboratory of Basic Pharmacology of Ministry of Education and Joint International Research Laboratory of Ethnocentric of Ministry of Education, Zunyi Medical University, Zunyi, China.
| | - Chengchen Zhang
- Key Laboratory of Basic Pharmacology of Ministry of Education and Joint International Research Laboratory of Ethnocentric of Ministry of Education, Zunyi Medical University, Zunyi, China.
| | - Yan Wang
- Key Laboratory of Basic Pharmacology of Ministry of Education and Joint International Research Laboratory of Ethnocentric of Ministry of Education, Zunyi Medical University, Zunyi, China.
| | - Jingshan Shi
- Key Laboratory of Basic Pharmacology of Ministry of Education and Joint International Research Laboratory of Ethnocentric of Ministry of Education, Zunyi Medical University, Zunyi, China.
| | - Jie Liu
- Key Laboratory of Basic Pharmacology of Ministry of Education and Joint International Research Laboratory of Ethnocentric of Ministry of Education, Zunyi Medical University, Zunyi, China.
| | - Qin Wu
- Key Laboratory of Basic Pharmacology of Ministry of Education and Joint International Research Laboratory of Ethnocentric of Ministry of Education, Zunyi Medical University, Zunyi, China.
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Scutellarein Aggravated Carbon Tetrachloride-Induced Chronic Liver Injury in Gut Microbiota-Dysbiosis Mice. EVIDENCE-BASED COMPLEMENTARY AND ALTERNATIVE MEDICINE 2021; 2020:8811021. [PMID: 33381208 PMCID: PMC7755479 DOI: 10.1155/2020/8811021] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/14/2020] [Revised: 11/24/2020] [Accepted: 11/30/2020] [Indexed: 12/12/2022]
Abstract
Scutellarein (SCU) is an herbal flavonoid, showing hepatoprotective potentials. The study was aimed to investigate whether the hepatoprotective effect of SCU is dependent on the integrity of gut microbiota. Mice received repeated intraperitoneal injections of CCl4, followed with or without SCU treatment (15, 30, and 60 mg/kg). Gut microbial community of mice was disrupted by administrating a cocktail of antibiotics (ampicillin, neomycin sulfate, metronidazole, and vancomycin) in drinking water. The results showed SCU plus antibiotics aggravated CCl4-induced chronic liver injury, as demonstrated by liver function analysis, histological analysis, and TUNEL assay. SCU activated CYP2E1 expression and worsened CYP2E1-mediated lipid peroxidation and oxidative stress as coadministered with antibiotics. Moreover, when gut microbiota was disrupted by antibiotics, SCU activated IκBα/NF-κB pathway and promoted the release of subsequent proinflammatory cytokines including interleukin-6 (IL-6), interleukin-1β (IL-1β), and tumor necrosis factor-α (TNF-α). Remarkably, the 16 S rRNA sequencing demonstrated that SCU greatly decreased the relative abundance of Bifidobacterium and Lactobacillus and increased the relative abundance of Enterococcus in gut microbiota-dysbiosis mice. Spearman correlation analysis showed that Lactobacillus was positively correlated with SOD and negatively correlated with AST. Collectively, the hepatoprotective effect of SCU is reversed under antibiotics intervention, which may partly involve the activation of CYP2E1 and IκBα/NF-κB pathway and diminishment of Lactobacillus.
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23
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Qi X, Yang M, Stenberg J, Dey R, Fogwe L, Alam MS, Kimchi ET, Staveley-O'Carroll KF, Li G. Gut microbiota mediated molecular events and therapy in liver diseases. World J Gastroenterol 2020; 26:7603-7618. [PMID: 33505139 PMCID: PMC7789060 DOI: 10.3748/wjg.v26.i48.7603] [Citation(s) in RCA: 22] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/20/2020] [Revised: 11/24/2020] [Accepted: 12/06/2020] [Indexed: 02/06/2023] Open
Abstract
Gut microbiota is a community of microorganisms that reside in the gastrointestinal tract. An increasing number of studies has demonstrated that the gut-liver axis plays a critical role in liver homeostasis. Dysbiosis of gut microbiota can cause liver diseases, including nonalcoholic fatty liver disease and alcoholic liver disease. Preclinical and clinical investigations have substantiated that the metabolites and other molecules derived from gut microbiota and diet interaction function as mediators to cause liver fibrosis, cirrhosis, and final cancer. This effect has been demonstrated to be associated with dysregulation of intrahepatic immunity and liver metabolism. Targeting these findings have led to the development of novel preventive and therapeutic strategies. Here, we review the cellular and molecular mechanisms underlying gut microbiota-mediated impact on liver disease. We also summarize the advancement of gut microbiota-based therapeutic strategies in the control of liver diseases.
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Affiliation(s)
- Xiaoqiang Qi
- Department of Surgery, University of Missouri, Columbia, MO 65212, United States
- Ellis Fischel Cancer Center, University of Missouri, Columbia, MO 65212, United States
- VA Hospital, Harry S Truman Memorial VA Hospital, Columbia, MO 65201, United States
| | - Ming Yang
- Department of Surgery, University of Missouri, Columbia, MO 65212, United States
- Ellis Fischel Cancer Center, University of Missouri, Columbia, MO 65212, United States
- VA Hospital, Harry S Truman Memorial VA Hospital, Columbia, MO 65201, United States
| | - Joseph Stenberg
- Department of Surgery, University of Missouri, Columbia, MO 65212, United States
| | - Rahul Dey
- Department of Surgery, University of Missouri, Columbia, MO 65212, United States
| | - Leslie Fogwe
- Department of Surgery, University of Missouri, Columbia, MO 65212, United States
| | | | - Eric T Kimchi
- Department of Surgery, University of Missouri, Columbia, MO 65212, United States
- Ellis Fischel Cancer Center, University of Missouri, Columbia, MO 65212, United States
- VA Hospital, Harry S Truman Memorial VA Hospital, Columbia, MO 65201, United States
| | - Kevin F Staveley-O'Carroll
- Department of Surgery, University of Missouri, Columbia, MO 65212, United States
- Ellis Fischel Cancer Center, University of Missouri, Columbia, MO 65212, United States
- VA Hospital, Harry S Truman Memorial VA Hospital, Columbia, MO 65201, United States
| | - Guangfu Li
- Department of Surgery, University of Missouri, Columbia, MO 65212, United States
- Ellis Fischel Cancer Center, University of Missouri, Columbia, MO 65212, United States
- VA Hospital, Harry S Truman Memorial VA Hospital, Columbia, MO 65201, United States
- Department of Molecular Microbiology and Immunology, University of Missouri, Columbia, MO 65212, United States
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Latief U, Ahmad R. β-carotene inhibits NF-κB and restrains diethylnitrosamine-induced hepatic inflammation in Wistar rats. INT J VITAM NUTR RES 2020; 92:301-310. [PMID: 32686990 DOI: 10.1024/0300-9831/a000665] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/26/2022]
Abstract
β-Carotene exhibits antioxidant and hepatoprotective activities via a multitude of biochemical mechanisms. However, the action mechanism involved in antioxidant and anti-inflammatory effects of this carotene in chronic liver diseases is not fully understood. In the present investigation, we have attempted to outline a plausible mechanism of β-carotene action against liver fibrosis in albino Wistar rats. To induce hepatic fibrosis, diethylnitrosamine (DEN) was administered in experimental rats for two weeks. DEN treated rats were divided into four groups, wherein each group comprised of five rats. β-Carotene supplement attenuated DEN-induced elevation in LFT markers (P < 0.05); averted depletion of glycogen (24%, P < 0.05) and, increased nitrite (P < 0.05), hydroxyproline (~67%, P < 0.05) and collagen levels (~65%, P < 0.05). Confocal microscopy of tissue sections stained with picrosirius red revealed accrued collagen in DEN-administered group, which was found to be reduced by β-carotene supplementation. Furthermore, β-carotene decreased the expression of iNOS/NOS-2 and NF-κB, as revealed by immunohistochemistry and Western immunoblotting. Collectively, these results demonstrate that β-carotene mitigates experimental liver fibrosis via inhibition of iNOS and NF-κB in-vivo. Thus, β-carotene may be suggested as a possible nutraceutical to curb experimental liver fibrosis.
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Affiliation(s)
- Uzma Latief
- Section of Genetics, Department of Zoology, Faculty of Life Sciences, Aligarh Muslim University, Aligarh, India
| | - Riaz Ahmad
- Section of Genetics, Department of Zoology, Faculty of Life Sciences, Aligarh Muslim University, Aligarh, India
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25
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Selective deletion of MyD88 signaling in α-SMA positive cells ameliorates experimental intestinal fibrosis via post-transcriptional regulation. Mucosal Immunol 2020; 13:665-678. [PMID: 32020030 PMCID: PMC7316631 DOI: 10.1038/s41385-020-0259-9] [Citation(s) in RCA: 43] [Impact Index Per Article: 8.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/18/2019] [Revised: 01/08/2020] [Accepted: 01/13/2020] [Indexed: 02/04/2023]
Abstract
Intestinal fibrosis leading to strictures remains a significant clinical problem in inflammatory bowel diseases (IBD). The role of bacterial components in activating intestinal mesenchymal cells and driving fibrogenesis is largely unexplored. Tamoxifen-inducible α-SMA promoter Cre mice crossed with floxed MyD88 mice were subjected to chronic dextran sodium sulfate colitis. MyD88 was deleted prior to or after induction of colitis. Human intestinal myofibroblasts (HIMF) were exposed to various bacterial components and assessed for fibronectin (FN) and collagen I (Col1) production. RNA sequencing was performed. Post-transcriptional regulation was assessed by polysome profiling assay. Selective deletion of MyD88 in α-SMA-positive cells prior to, but not after induction of, experimental colitis decreased the degree of intestinal fibrosis. HIMF selectively responded to flagellin with enhanced FN or Col1 protein production in a MyD88-dependent manner. RNA sequencing suggested minimal transcriptional changes induced by flagellin in HIMF. Polysome profiling revealed higher proportions of FN and Col1 mRNA in the actively translated fractions of flagellin exposed HIMF, which was mediated by eIF2 alpha and 4EBP1. In conclusion, selectivity of flagellin-induced ECM secretion in HIMF is post-transcriptionally regulated. The results may represent a novel and targetable link between the gut microbiota and intestinal fibrogenesis.
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26
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Zhou Z, Kim JW, Qi J, Eo SK, Lim CW, Kim B. Toll-Like Receptor 5 Signaling Ameliorates Liver Fibrosis by Inducing Interferon β-Modulated IL-1 Receptor Antagonist in Mice. THE AMERICAN JOURNAL OF PATHOLOGY 2020; 190:614-629. [PMID: 31972159 DOI: 10.1016/j.ajpath.2019.11.012] [Citation(s) in RCA: 29] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/01/2019] [Revised: 09/17/2019] [Accepted: 11/05/2019] [Indexed: 02/08/2023]
Abstract
Bacterial flagellin, recognized by cell surface of Toll-like receptor (TLR) 5, is a potent activator of many types of cells, leading to the activation of innate or adaptive immunity, which are pivotal in regulating fibrotic process. However, the exact role of TLR5 signaling in hepatic fibrogenesis remains unclear, and this study aims to elucidate its underlying mechanisms. Flagellin was injected to hepatotoxin- and cholestasis-induced liver fibrosis murine models. Flagellin-induced TLR5 activation significantly decreased the severity of liver fibrosis. Interestingly, the expression levels of IL-1 receptor antagonist (IL1RN) and interferon (IFN)β markedly increased in fibrotic livers on flagellin treatment. Consistently, in vivo activation of TLR5 signaling markedly increased IFNβ and IL1RN expression in the livers. Notably, flagellin injection significantly exacerbated the severity of liver fibrosis in IFN-α/β receptor 1 (IFNAR1) knockout mice. Furthermore, hepatic expression of IL1RN in the fibrotic livers of IFNAR1 knockout mice was significantly lower than those of wild-type mice. In support of these findings, flagellin-mediated IL1RN production is not sufficient to alleviate the severity of hepatic fibroinflammatory responses in IFNAR1-deficient milieu. Finally, hepatic stellate cells treated with IL1RN had significantly decreased cellular activation and its associated fibrogenic responses. Collectively, manipulation of TLR5 signaling may be a promising therapeutic strategy for the treatment of liver fibrosis.
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Affiliation(s)
- Zixiong Zhou
- Biosafety Research Institute, and the BK21 Plus Program, College of Veterinary Medicine, Jeonbuk National University, Iksan, Jeonbuk, South Korea
| | - Jong-Won Kim
- Biosafety Research Institute, and the BK21 Plus Program, College of Veterinary Medicine, Jeonbuk National University, Iksan, Jeonbuk, South Korea
| | - Jing Qi
- Biosafety Research Institute, and the BK21 Plus Program, College of Veterinary Medicine, Jeonbuk National University, Iksan, Jeonbuk, South Korea
| | - Seong Kug Eo
- Biosafety Research Institute, and the BK21 Plus Program, College of Veterinary Medicine, Jeonbuk National University, Iksan, Jeonbuk, South Korea
| | - Chae Woong Lim
- Biosafety Research Institute, and the BK21 Plus Program, College of Veterinary Medicine, Jeonbuk National University, Iksan, Jeonbuk, South Korea
| | - Bumseok Kim
- Biosafety Research Institute, and the BK21 Plus Program, College of Veterinary Medicine, Jeonbuk National University, Iksan, Jeonbuk, South Korea.
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Feng R, Du W, Lui P, Zhang J, Liu Y. CAPN2 acts as an indicator of hepatitis B virus to induce hepatic fibrosis. J Cell Biochem 2019; 121:2428-2436. [PMID: 31680308 DOI: 10.1002/jcb.29465] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2018] [Accepted: 03/15/2019] [Indexed: 12/16/2022]
Abstract
This study is aimed to investigate whether calpain 2 (CAPN2) serves as an indicator of the hepatitis B virus (HBV) to induce hepatic fibrosis. Differentially-expressed genes (DEGs) in HBV-induced hepatic fibrosis and normal liver tissues were analyzed, and signal pathway which was analyzed by the Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis using DEGs. Next, the gene-related network map was constructed using the Search Tool for the Retrieval of Interacting Genes. Moreover, CAPN2 protein expression, level of hepatic fibrosis, CAPN2 messenger RNA level, and protein levels of CAPN2, a-SAM, COL3A1, COL1A1, and MAPK1 were determined using Immunohistochemistry (IHC), hematoxylin and eosin, RT-qPCR, and western blot (WB), respectively. There were 420 DEGs screened in HBV-induced hepatic fibrosis and normal liver tissues, among which, 373 were significantly upregulated and 47 were obviously downregulated. KEGG analysis showed that the upregulated DEGs were mainly concentrated in extracellular matrix-receptor interaction, protein digestion, and absorption signaling pathways. The network diagram analysis showed that the DEGs, such as CAPN2, ITGAV, and CCR2, play the key role in the DEG network map, and CAPN2 related to hepatic fibrosis via MAPK1. The increased CAPN2 expression and obvious hepatic fibrosis was displayed in the HBV-induced hepatic fibrosis tissues. In addition, HBV could induce CAPN2 expression, and the interference of CAPN2 could inhibit the expression of hepatic fibrosis markers, including a-SAM, COL3A1, COL1A1, and MAPK1. CAPN2 is regarded as a biomarker of hepatic fibrosis induced by HBV.
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Affiliation(s)
- Rui Feng
- Department of Infectious Diseases, Renmin Hospital, Hubei University of Medicine, Shiyan, China
| | - Weixing Du
- Department of Infectious Diseases, Renmin Hospital, Hubei University of Medicine, Shiyan, China
| | - Ping Lui
- Department of Infectious Diseases, Renmin Hospital, Hubei University of Medicine, Shiyan, China
| | - Jun Zhang
- Department of Oncology, Renmin Hospital, Hubei University of Medicine, Shiyan, China
| | - Yanqing Liu
- Department of Infectious Diseases, Renmin Hospital, Hubei University of Medicine, Shiyan, China
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Chen D, Le TH, Shahidipour H, Read SA, Ahlenstiel G. The Role of Gut-Derived Microbial Antigens on Liver Fibrosis Initiation and Progression. Cells 2019; 8:E1324. [PMID: 31717860 PMCID: PMC6912265 DOI: 10.3390/cells8111324] [Citation(s) in RCA: 38] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2019] [Revised: 10/22/2019] [Accepted: 10/23/2019] [Indexed: 12/12/2022] Open
Abstract
Intestinal dysbiosis has recently become known as an important driver of gastrointestinal and liver disease. It remains poorly understood, however, how gastrointestinal microbes bypass the intestinal mucosa and enter systemic circulation to enact an inflammatory immune response. In the context of chronic liver disease (CLD), insults that drive hepatic inflammation and fibrogenesis (alcohol, fat) can drastically increase intestinal permeability, hence flooding the liver with gut-derived microbiota. Consequently, this may result in exacerbated liver inflammation and fibrosis through activation of liver-resident Kupffer and stellate cells by bacterial, viral, and fungal antigens transported to the liver via the portal vein. This review summarizes the current understanding of microbial translocation in CLD, the cell-specific hepatic response to intestinal antigens, and how this drives the development and progression of hepatic inflammation and fibrosis. Further, we reviewed current and future therapies targeting intestinal permeability and the associated, potentially harmful anti-microbial immune response with respect to their potential in terms of limiting the development and progression of liver fibrosis and end-stage cirrhosis.
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Affiliation(s)
- Dishen Chen
- Storr Liver Centre, The Westmead Institute for Medical Research, University of Sydney, Westmead 2145, NSW, Australia; (D.C.); (T.H.L.); (H.S.)
| | - Thanh H. Le
- Storr Liver Centre, The Westmead Institute for Medical Research, University of Sydney, Westmead 2145, NSW, Australia; (D.C.); (T.H.L.); (H.S.)
- School of Medicine, Western Sydney University, Campbelltown 2560, NSW, Australia
| | - Haleh Shahidipour
- Storr Liver Centre, The Westmead Institute for Medical Research, University of Sydney, Westmead 2145, NSW, Australia; (D.C.); (T.H.L.); (H.S.)
- Blacktown Medical School, Western Sydney University, Blacktown 2148, NSW, Australia
| | - Scott A. Read
- Storr Liver Centre, The Westmead Institute for Medical Research, University of Sydney, Westmead 2145, NSW, Australia; (D.C.); (T.H.L.); (H.S.)
- Blacktown Medical School, Western Sydney University, Blacktown 2148, NSW, Australia
| | - Golo Ahlenstiel
- Storr Liver Centre, The Westmead Institute for Medical Research, University of Sydney, Westmead 2145, NSW, Australia; (D.C.); (T.H.L.); (H.S.)
- Blacktown Medical School, Western Sydney University, Blacktown 2148, NSW, Australia
- Blacktown Hospital, Blacktown 2148, NSW, Australia
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29
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Wu B, Wang R, Li S, Wang Y, Song F, Gu Y, Yuan Y. Antifibrotic effects of Fraxetin on carbon tetrachloride-induced liver fibrosis by targeting NF-κB/IκBα, MAPKs and Bcl-2/Bax pathways. Pharmacol Rep 2019; 71:409-416. [PMID: 31003150 DOI: 10.1016/j.pharep.2019.01.008] [Citation(s) in RCA: 38] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2018] [Revised: 12/18/2018] [Accepted: 01/14/2019] [Indexed: 01/15/2023]
Abstract
BACKGROUND Liver fibrosis is a chronic lesion which ultimately results in cirrhosis and possible death. Although the high incidence and lethality, few therapies are effective for liver fibrosis. Fraxetin (7,8-dihydroxy-6-methoxy coumarin), a natural product extracted from cortex fraxini, has exhibited a significant hepatoprotective and anti-fibrotic properties. However, the underlying mechanism of the anti-hepatic fibrotic property remains unknown. METHODS 48 Male Sprague Dawley rats were divided into four groups at random which were named as normal group, model group, fraxetin 25 mg/kg and 50 mg/kg group. The experimental model of liver fibrosis was founded by carbon tetrachloride (CCl4) rats which were simultaneously treated with fraxetin (25 mg/kg or 50 mg/kg). Normal groups received equal volumes of saline and peanut oil. RESULTS Results showed that fraxetin ameliorated CCl4 induced liver damage and fibrosis. Furthermore, histopathology examinations revealed that fraxetin improved the morphology and alleviated collagen deposition in fibrotic liver. Fraxetin inhibited inflammation and hepatocytes apoptosis by modulating the NF-κB/IκBα, MAPKs and Bcl-2/Bax signaling pathways. CONCLUSION Our findings indicate that fraxetin is effective in preventing liver fibrosis through inhibiting inflammation and hepatocytes apoptosis which is associated with regulating NF-κB/IκBα, MAPKs and Bcl-2/Bax signaling pathways in rats.
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Affiliation(s)
- Bin Wu
- Department of Pharmacy, Shanghai 9th People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Rong Wang
- Department of Pharmacy, Shanghai 9th People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Shengnan Li
- Department of Pharmacy, Shanghai 9th People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Yuanyuan Wang
- Department of Pharmacy, Shanghai 9th People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Fuxing Song
- Department of Pharmacy, Shanghai 9th People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Yanqiu Gu
- Department of Pharmacy, Shanghai 9th People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Yongfang Yuan
- Department of Pharmacy, Shanghai 9th People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
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TLR5 silencing reduced hyperammonaemia-induced liver injury by inhibiting oxidative stress and inflammation responses via inactivating NF-κB and MAPK signals. Chem Biol Interact 2018; 299:102-110. [PMID: 30508503 DOI: 10.1016/j.cbi.2018.11.026] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2018] [Revised: 11/20/2018] [Accepted: 11/29/2018] [Indexed: 02/07/2023]
Abstract
BACKGROUND Liver injury is a serious threat for human health and life. Toll-like receptor 5 (TLR5) has reported to be a vital mediator in flagellin or tetrachloride (CCl4)-induced liver injury. However, the roles and etiology of TLR5 in hyperammonaemia (HA)-induced liver injury are poor defined. METHODS HA rats were generated by intragastric administration using ammonium chloride solution. Liver status was assessed by haematoxylin and eosin (H&E) staining and measuring serum levels of liver injury markers. Immunohistochemistry (IHC) assay was used to visualize protein expression in tissues. Apoptotic index in tissues was determined by TUNEL assay. RT-qPCR assay was employed to test mRNA expression. Oxidative stress responses was assessed by detecting levels of reactive oxygen species (ROS) and related indicators. NF-κB activity was examined by TransAM NF-κB colorimetric kit. RESULTS TLR5 was highly expressed in liver tissues of HA rats. TLR5 knockdown ameliorated HA-induced liver injury by inhibiting liver cell apoptosis. TLR5 depletion inhibited HA-induced pro-inflammatory cytokine expression in liver tissues, but had no effect on the infiltration of T and macrophage cells into liver tissues. TLR5 silencing impaired HA-induced oxidative stress responses in hepatocytes, but not in hepatic stellate cells (HSCs). TLR5 downregulation inhibited HA-induced activation on TLR5/NF-κB and TLR5/MAPK signaling pathways. CONCLUSION TLR5 silencing reduced HA-induced liver injury by inhibiting hepatocyte apoptosis, oxidative stress and inflammation responses via inactivating NF-κB and MAPK signals, deepening our understanding on the molecular mechanism of HA-induced liver injury and providing a potential therapeutic target for alleviating liver injury.
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Yoshioka H, Nonogaki T, Fukaya S, Ichimaru Y, Nagatsu A, Yoshikawa M, Fujii H, Nakao M. Sasa veitchii extract protects against carbon tetrachloride-induced hepatic fibrosis in mice. Environ Health Prev Med 2018; 23:49. [PMID: 30322375 PMCID: PMC6190662 DOI: 10.1186/s12199-018-0739-7] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2018] [Accepted: 10/01/2018] [Indexed: 12/21/2022] Open
Abstract
BACKGROUND The current study aimed to investigate the hepatoprotective effects of Sasa veitchii extract (SE) on carbon tetrachloride (CCl4)-induced liver fibrosis in mice. METHODS Male C57BL/6J mice were intraperitoneally injected with CCl4 dissolved in olive oil (1 g/kg) twice per week for 8 weeks. SE (0.1 mL) was administered orally once per day throughout the study, and body weight was measured weekly. Seventy-two hours after the final CCl4 injection, mice were euthanized and plasma samples were collected. The liver and kidneys were collected and weighed. RESULTS CCl4 administration increased liver weight, decreased body weight, elevated plasma alanine aminotransferase, and aspartate aminotransferase and increased liver oxidative stress (malondialdehyde and glutathione). These increases were attenuated by SE treatment. Overexpression of tumor necrosis factor-α was also reversed following SE treatment. Furthermore, CCl4-induced increases in α-smooth muscle actin, a marker for hepatic fibrosis, were attenuated in mice treated with SE. Moreover, SE inhibited CCl4-induced nuclear translocation of hepatic nuclear factor kappa B (NF-κB) p65 and phosphorylation of mitogen-activated protein kinase (MAPK). CONCLUSION These results suggested that SE prevented CCl4-induced hepatic fibrosis by inhibiting the MAPK and NF-κB signaling pathways.
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Affiliation(s)
- Hiroki Yoshioka
- College of Pharmacy, Kinjo Gakuin University, 2-1723 Omori, Moriyamaku, Nagoya, Aichi, 463-8521, Japan.
| | - Tsunemasa Nonogaki
- College of Pharmacy, Kinjo Gakuin University, 2-1723 Omori, Moriyamaku, Nagoya, Aichi, 463-8521, Japan
| | - Shiori Fukaya
- College of Pharmacy, Kinjo Gakuin University, 2-1723 Omori, Moriyamaku, Nagoya, Aichi, 463-8521, Japan
| | - Yoshimi Ichimaru
- College of Pharmacy, Kinjo Gakuin University, 2-1723 Omori, Moriyamaku, Nagoya, Aichi, 463-8521, Japan
| | - Akito Nagatsu
- College of Pharmacy, Kinjo Gakuin University, 2-1723 Omori, Moriyamaku, Nagoya, Aichi, 463-8521, Japan
| | - Masae Yoshikawa
- College of Pharmacy, Kinjo Gakuin University, 2-1723 Omori, Moriyamaku, Nagoya, Aichi, 463-8521, Japan
| | - Hirohisa Fujii
- College of Pharmacy, Kinjo Gakuin University, 2-1723 Omori, Moriyamaku, Nagoya, Aichi, 463-8521, Japan
| | - Makoto Nakao
- College of Pharmacy, Kinjo Gakuin University, 2-1723 Omori, Moriyamaku, Nagoya, Aichi, 463-8521, Japan
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Wang R, Wang J, Song F, Li S, Yuan Y. Tanshinol ameliorates CCl 4-induced liver fibrosis in rats through the regulation of Nrf2/HO-1 and NF-κB/IκBα signaling pathway. Drug Des Devel Ther 2018; 12:1281-1292. [PMID: 29844659 PMCID: PMC5961642 DOI: 10.2147/dddt.s159546] [Citation(s) in RCA: 55] [Impact Index Per Article: 7.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Tanshinol, a water-soluble component isolated from Salvia miltiorrhiza Bunge, has a variety of biological activities involving anti-fibrotic effect. However, the exact role and the underlying mechanisms remain largely unclear. This study mainly focused on the anti-hepatic fibrotic activities and mechanisms of tanshinol on carbon tetrachloride (CCl4)-induced liver fibrosis in rats via anti-oxidative and anti-inflammation pathways. The rats were divided into 4 groups as follows: control, model, tanshinol 20 mg/kg, and tanshinol 40 mg/kg. Except for the control group, CCl4 was used to induce liver fibrosis processing for 8 weeks, meanwhile rats in tanshinol groups were intraperitoneally injected with additional tanshinol. Control group simultaneously received the same volumes of olive oil and saline. The potentially protective effect and mechanisms of tanshinol on liver fibrosis in rats were evaluated. The serum levels of alanine aminotransferase, aspartate aminotransferase, and total bilirubin were obviously lower in the tanshinol treatment groups related to model group. Compared with the model group, the levels of hyaluronic acid, type IV collagen, Laminin (LN), and procollagen III peptide (PIIIP) in serum were significantly decreased after tanshinol treatment. Furthermore, tanshinol could regulate Nrf2/HO-1 signaling pathway and increase the level of superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px), and also decrease the level of malondialdehyde (MDA) to against damage induced by oxidative stress. Simultaneously tanshinol could regulate nuclear factor kappa B signaling pathway to inhibit expression of inflammation factors, including transforming growth factor-β, tumor necrosis factor-α, Cox-2, interleukin-1β, and interleukin-6. In summary, our research demonstrated that tanshinol has protective effect on CCl4-induced liver fibrosis via inhibiting oxidative stress and inflammation, which may be associated with the regulation of nuclear factor erythroid2-related factor 2/hemeoxygenase-a and nuclear factor kappa B/inhibitor of kappa B alpha signaling pathways.
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Affiliation(s)
- Rong Wang
- Department of Pharmacy, Shanghai 9th People’s Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Jing Wang
- Department of Pharmacy, Shanghai 9th People’s Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Fuxing Song
- Department of Pharmacy, Shanghai 9th People’s Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Shengnan Li
- Department of Pharmacy, Shanghai 9th People’s Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Yongfang Yuan
- Department of Pharmacy, Shanghai 9th People’s Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
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Fighting Fatty Liver Diseases with Nutritional Interventions, Probiotics, Symbiotics, and Fecal Microbiota Transplantation (FMT). ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2018; 1125:85-100. [DOI: 10.1007/5584_2018_318] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
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Peng Z, Gong X, Yang Y, Huang L, Zhang Q, Zhang P, Wan R, Zhang B. Hepatoprotective effect of quercetin against LPS/d-GalN induced acute liver injury in mice by inhibiting the IKK/NF-κB and MAPK signal pathways. Int Immunopharmacol 2017; 52:281-289. [PMID: 28963941 DOI: 10.1016/j.intimp.2017.09.022] [Citation(s) in RCA: 75] [Impact Index Per Article: 9.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2017] [Revised: 09/10/2017] [Accepted: 09/23/2017] [Indexed: 01/18/2023]
Abstract
Quercetin is regarded as a potential hepatoprotective agent in the treatment of acute liver injury. However, the underlying mechanism of how quercetin to protect against lipopolysaccharides/d-galactosamine (LPS/d-GalN) induced acute liver injury remains unclear. To investigate the mechanism, the antioxidative, anti-inflammatory and antiapoptotic responses were performed. The results showed that quercetin pretreatment improved the survival rate and substantially reduced the liver histopathological changes in mice. It also alleviated the hepatic damage and reduced the productions of oxidative markers induced by LPS/d-GalN. In addition, quercetin pretreatment significantly diminished the production of inflammatory cytokines, including TNF-α, IL-6 and IL-1β, and inhibited the activation of the NF-κB and MAPK signaling pathways as well as the expression of apoptotic-related proteins induced by LPS/d-GalN. We found that the potential mechanism of this quercetin-induced protection is mainly mediated through its powerful antioxidative capacity, inhibition of hepatocyte apoptosis and suppression of inflammatory cytokines through the IKK/NF-κB and MAPK signaling pathways. Thus, quercetin shows a promising therapeutic effect on acute liver injury in mice.
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Affiliation(s)
- Zhixin Peng
- College of Pharmaceutical Sciences, Southwest University, Chongqing, China
| | - Xiaobao Gong
- College of Pharmaceutical Sciences, Southwest University, Chongqing, China
| | - You Yang
- College of Animal Science and Technology, Southwest University, Chongqing, China
| | - Ligua Huang
- College of Pharmaceutical Sciences, Southwest University, Chongqing, China
| | - Qingyan Zhang
- The Ninth People's Hospital of Chongqing, Chongqing, China
| | - Peng Zhang
- The Ninth People's Hospital of Chongqing, Chongqing, China
| | - Rongzhen Wan
- The Ninth People's Hospital of Chongqing, Chongqing, China.
| | - Baoshun Zhang
- College of Pharmaceutical Sciences, Southwest University, Chongqing, China.
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Kagan P, Sultan M, Tachlytski I, Safran M, Ben-Ari Z. Both MAPK and STAT3 signal transduction pathways are necessary for IL-6-dependent hepatic stellate cells activation. PLoS One 2017; 12:e0176173. [PMID: 28472150 PMCID: PMC5417441 DOI: 10.1371/journal.pone.0176173] [Citation(s) in RCA: 67] [Impact Index Per Article: 8.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2017] [Accepted: 04/06/2017] [Indexed: 12/16/2022] Open
Abstract
Background During liver injury, hepatic stellate cells (HSCs) can undergo activation and transform into alpha-smooth muscle actin (αSMA)-expressing contractile myofibroblast-like cells, leading to deposition of excessive scar matrix. We have recently demonstrated that depletion of adenosine deaminase acting on double-stranded RNA (ADAR1) from mouse hepatocytes leads to HSC activation and induction of inflammation and hepatic fibrosis that is mediated by interleukin 6 (IL-6). Our aim was to identify and characterize the molecular pathways involved in the direct, inflammation-independent activation of HSCs by IL-6. Methods Primary HSCs were isolated from mouse livers. mRNA levels of αSMA and Col1a were analyzed using qRT-PCR. Protein levels of αSMA, MAPK, p-MAPK, p38, p-p38, STAT3 and p-STAT3 were assessed by Western Blot analysis. The effect of specific signal transduction pathway inhibitors (i.e., SB203580 (P-38 inhibitor), U0126 (MAPK inhibitor), S3I-201 (STAT3 inhibitor) and Ruxolitinib (Jak1/2 inhibitor)) was also studied. Results Primary HSCs treated with IL-6 demonstrated upregulation of αSMA and Col1a mRNA levels as well as increased αSMA protein levels. Moreover, the phenotypic transition of quiescent HSCs toward myofibroblast-like cells was noted upon administration of IL-6 and not in untreated samples. In addition, the phosphorylation levels of p38, MAPK and STAT3 increased 30 minutes after treatment, and was followed by a decline in the phosphorylation levels 2–4 hours post-treatment. However, addition of specific signal transduction pathway inhibitors curbed this effect, and resulted in αSMA and Col1a expression levels similar to those measured in untreated control samples. Conclusion IL-6 can directly induce the transition of HSCs toward myofibroblast-like cells. The effect is mediated by the activation of both MAPK and JAK/STAT signaling pathways. Elimination of either MAPK or JAK/STAT signaling pathways inhibits HSC stimulation. These results might pave the road toward the development of potential therapeutic interventions for hepatic fibrosis.
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Affiliation(s)
- Polina Kagan
- Liver Research Laboratory, Sheba Medical Center, Ramat Gan, Israel
- The Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - Maya Sultan
- Liver Research Laboratory, Sheba Medical Center, Ramat Gan, Israel
| | - Irina Tachlytski
- Liver Research Laboratory, Sheba Medical Center, Ramat Gan, Israel
| | - Michal Safran
- Liver Research Laboratory, Sheba Medical Center, Ramat Gan, Israel
| | - Ziv Ben-Ari
- Liver Research Laboratory, Sheba Medical Center, Ramat Gan, Israel
- The Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel
- Liver Disease Center, Sheba Medical Center, Ramat Gan, Israel
- * E-mail:
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Proteomic Analysis of HDAC3 Selective Inhibitor in the Regulation of Inflammatory Response of Primary Microglia. Neural Plast 2017; 2017:6237351. [PMID: 28293439 PMCID: PMC5331322 DOI: 10.1155/2017/6237351] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2016] [Revised: 12/27/2016] [Accepted: 01/12/2017] [Indexed: 12/11/2022] Open
Abstract
HDAC3 has been shown to regulate inflammation. However, the role of HDAC3 in primary microglia is largely unknown. RGFP966 is a newly discovered selective HDAC3 inhibitor. In this study, we used protein mass spectrometry to analyze protein alterations in LPS-treated primary microglia with the application of RGFP966. Generally, about 2000 proteins were studied. 168 of 444 (37.8%) LPS-induced proteins were significantly reduced with the treatment of RGFP966, which mainly concentrated on Toll-like receptor signaling pathway. In this regard, we selected Toll-like receptor 2 (TLR2), TLR3, TLR6, MAPK p38, CD36, and spleen tyrosine kinase (SYK) for further validation and found that they were all significantly upregulated after LPS stimulation and downregulated in the presence of RGFP966. Additionally, RGFP966 inhibited supernatant tumor necrosis factor (TNF)-α and Interleukin 6 (IL-6) concentrations. Activation of STAT3 and STAT5 was partially blocked by RGFP966 at 2 h after LPS-stimulation. The fluorescence intensity of CD16/32 was significantly decreased in LPS + RGFP966-treated group. In conclusion, our data provided a hint that RGFP966 may be a potential therapeutic medication combating microglia activation and inflammatory response in central nervous system, which was probably related to its repressive impacts on TLR signaling pathways and STAT3/STAT5 pathways.
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Kiziltas S. Toll-like receptors in pathophysiology of liver diseases. World J Hepatol 2016; 8:1354-1369. [PMID: 27917262 PMCID: PMC5114472 DOI: 10.4254/wjh.v8.i32.1354] [Citation(s) in RCA: 125] [Impact Index Per Article: 13.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/12/2016] [Revised: 08/17/2016] [Accepted: 09/21/2016] [Indexed: 02/06/2023] Open
Abstract
Toll-like receptors (TLRs) are pattern recognition receptors that participate in host defense by recognizing pathogen-associated molecular patterns alongside inflammatory processes by recognizing damage associated molecular patterns. Given constant exposure to pathogens from gut, strict control of TLR-associated signaling pathways is essential in the liver, which otherwise may lead to inappropriate production of pro-inflammatory cytokines and interferons and may generate a predisposition to several autoimmune and chronic inflammatory diseases. The liver is considered to be a site of tolerance induction rather than immunity induction, with specificity in hepatic cell functions and distribution of TLR. Recent data emphasize significant contribution of TLR signaling in chronic liver diseases via complex immune responses mediating hepatocyte (i.e., hepatocellular injury and regeneration) or hepatic stellate cell (i.e., fibrosis and cirrhosis) inflammatory or immune pathologies. Herein, we review the available data on TLR signaling, hepatic expression of TLRs and associated ligands, as well as the contribution of TLRs to the pathophysiology of hepatic diseases.
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Affiliation(s)
- Safak Kiziltas
- Safak Kiziltas, Department of Gastroenterology, Baskent University Istanbul Hospital, 34662 Istanbul, Turkey
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