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Wang H, Ma L, Su W, Liu Y, Xie N, Liu J. NLRP3 inflammasome in health and disease (Review). Int J Mol Med 2025; 55:48. [PMID: 39930811 PMCID: PMC11781521 DOI: 10.3892/ijmm.2025.5489] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2024] [Accepted: 12/16/2024] [Indexed: 02/13/2025] Open
Abstract
Activation of inflammasomes is the activation of inflammation‑related caspase mediated by the assembly signal of multi‑protein complex and the maturity of inflammatory factors, such as IL‑1β and IL‑18. Among them, the Nod‑like receptor family pyrin domain containing 3 (NLRP3) inflammasome is the most thoroughly studied type of inflammatory corpuscle at present, which is involved in the occurrence and development of numerous human diseases. Therefore, targeting the NLRP3 inflammasome has become the focus of drug development for related diseases. In this paper, the research progress of the NLRP3 inflammasome in recent years is summarized, including the activation and regulation of NLRP3 and its association with diseases. A deep understanding of the regulatory mechanism of NLRP3 will be helpful to the discovery of new drug targets and the development of therapeutic drugs.
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Affiliation(s)
- Haoran Wang
- Department of Orthopaedics, Tongji Hospital Affiliated to Tongji University, Shanghai 200065, P.R. China
| | - Li Ma
- Department of Oncology, The Second Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu 210011, P.R. China
| | - Weiran Su
- Department of Internal Medicine, Jiading District Central Hospital, Shanghai 201800, P.R. China
| | - Yangruoyu Liu
- Department of Orthopaedics, Tongji Hospital Affiliated to Tongji University, Shanghai 200065, P.R. China
| | - Ning Xie
- Department of Orthopaedics, Tongji Hospital Affiliated to Tongji University, Shanghai 200065, P.R. China
| | - Jun Liu
- Department of Orthopaedics, The Second Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu 210011, P.R. China
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Yu M, Zheng C, Li X, Ji X, Hu X, Wang X, Zhang J. Neutrophil extracellular traps-induced pyroptosis of liver sinusoidal endothelial cells exacerbates intrahepatic coagulation in cholestatic mice. Biochim Biophys Acta Mol Basis Dis 2025; 1871:167700. [PMID: 39914029 DOI: 10.1016/j.bbadis.2025.167700] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2024] [Revised: 01/06/2025] [Accepted: 01/27/2025] [Indexed: 02/20/2025]
Abstract
BACKGROUND Neutrophil extracellular traps (NETs) and NOD-like receptor protein 3 (NLRP3) inflammation are key contributors to cholestatic liver disease (CLD). However, the relationship between NETs release and inflammasome activation, as well as its contribution to intrahepatic coagulation in CLD, remains unexplored. This study explores NETs-induced liver sinusoidal endothelial cells (LSECs) pyroptosis on intrahepatic coagulation in CLD. METHODS Wild-type (WT) and PAD4-/- mice underwent bile duct ligation (BDL) or sham surgery for 7 or 14 days. The liver analysis assessed intrahepatic coagulation, inflammation, fibrosis, NETs release, and NLRP3 activation. Primary LSECs were exposed to NETs with or without MCC950. Pyroptosis and LSECs procoagulant activity were quantified. RESULTS BDL mice exhibited significantly increased inflammation, tissue factor (TF), and fibrin deposition compared with controls. NETs release in the liver was increased significantly in WT BDL mice and was responsible for intrahepatic coagulation. PAD4 deficiency reduced TF and fibrin expression, improving hepatic sinusoid function. RNA-seq revealed BDL-induced enrichment of coagulation, neutrophil activation, and pyroptosis pathways. In vivo, NETs increased intrahepatic NLRP3 and IL-1β expression in BDL mice. However, NLRP3 inhibition (MCC950) or activation (BMS-986299) did not alter NETs release. Furthermore, NETs-induced NLRP3 activation increased intrahepatic coagulation, inflammation, and fibrosis. Finally, we demonstrated that NETs triggered LSECs dysfunction and pyroptosis, upregulating TF and phosphatidylserine production and enhancing procoagulant activity. CONCLUSIONS NETs-induced LSECs pyroptosis exacerbates intrahepatic coagulation in cholestasis. Targeting NETs and LSECs pyroptosis holds promise for treating chronic liver injury in CLD.
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Affiliation(s)
- Muxin Yu
- College of Medicine, Jiaxing University, Jiaxing 314000, China
| | - Chuwei Zheng
- Department of Gastroenterology, The Second Affiliated Hospital of Jiaxing University, Jiaxing 314000, China
| | - Xiaowen Li
- Department of Pathology, The Second Affiliated Hospital of Jiaxing University, Jiaxing 314000, China
| | - Xia Ji
- Department of Gastroenterology, The Second Affiliated Hospital of Jiaxing University, Jiaxing 314000, China
| | - Xiaolan Hu
- Department of Pathology, The Second Affiliated Hospital of Jiaxing University, Jiaxing 314000, China
| | - Xiaoguang Wang
- Department of Hepatic Surgery, The Second Affiliated Hospital of Jiaxing University, Jiaxing 314000, China
| | - Jinming Zhang
- Department of Gastroenterology, The Second Affiliated Hospital of Jiaxing University, Jiaxing 314000, China.
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Qiu J, Qu Y, Li Y, Li C, Wang J, Meng L, Jing X, Fu J, Xu Y, Chai Y. Inhibition of RAC1 activator DOCK2 ameliorates cholestatic liver injury via regulating macrophage polarisation and hepatic stellate cell activation. Biol Direct 2025; 20:21. [PMID: 39923106 PMCID: PMC11807328 DOI: 10.1186/s13062-025-00612-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2024] [Accepted: 01/28/2025] [Indexed: 02/10/2025] Open
Abstract
BACKGROUND The Rho GTPase Rac family small GTPase 1 (RAC1) is considered a promising fibrotic therapeutic target, but the role of its activator, dedicator of cytokinesis 2 (DOCK2), in liver fibrosis is largely unknown. This study aimed to investigate the expression and role of DOCK2 in cholestasis-induced liver fibrosis and to further explore the potential mechanisms. RESULTS Cholestasis was induced in male C57BL/6 mice by bile duct ligation (BDL). DOCK2 knockdown was achieved by tail vein injection of adenovirus containing DOCK2-targeting shRNA. The effect of DOCK2 knockdown on cholestatic liver injury was evaluated at different time points after BDL. Hepatic DOCK2 expression gradually increased after BDL. Knockdown of DOCK2 reduced the necrotic area in BDL liver and downregulated serum levels of liver injury indicators. At 3d post-BDL (acute phase), DOCK2 knockdown alleviated M1 macrophage inflammation in the liver, as evidenced by reduced infiltrating iNOS + macrophages and inflammatory cytokines and mitigated NLRP3 inflammasome activation. At 14d post-BDL (chronic phase), DOCK2 knockdown suppressed hepatic stellate cell (HSC) activation and liver fibrosis as indicated by decreased α-SMA + HSCs and extracellular matrix deposition. In vitro experiments further demonstrated that DOCK2 knockdown suppressed M1 macrophage polarisation and HSC to myofibroblast transition, accompanied by inhibition of RAC1 activation. CONCLUSIONS In summary, this study demonstrates for the first time that the RAC1 activator DOCK2 regulates M1 macrophage polarisation and hepatic stellate cell activation to promote cholestasis-induced liver inflammation and fibrosis, suggesting that DOCK2 may be a potential therapeutic target in cholestatic liver injury.
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Affiliation(s)
- Jianli Qiu
- Department of Pediatrics, The First Affiliated Hospital of Henan University of Chinese Medicine, Zhengzhou, Henan, China.
- Department of Pediatrics, Henan University of Chinese Medicine, Zhengzhou, Henan, China.
| | - Yitong Qu
- Department of Pediatrics, The First Affiliated Hospital of Henan University of Chinese Medicine, Zhengzhou, Henan, China
- Department of Pediatrics, Henan University of Chinese Medicine, Zhengzhou, Henan, China
| | - Yinli Li
- Department of Pediatrics, The First Affiliated Hospital of Henan University of Chinese Medicine, Zhengzhou, Henan, China
- Department of Pediatrics, Henan University of Chinese Medicine, Zhengzhou, Henan, China
| | - Cancan Li
- Department of Pediatrics, The First Affiliated Hospital of Henan University of Chinese Medicine, Zhengzhou, Henan, China
- Department of Pediatrics, Henan University of Chinese Medicine, Zhengzhou, Henan, China
| | - Junling Wang
- Department of Pediatrics, The First Affiliated Hospital of Henan University of Chinese Medicine, Zhengzhou, Henan, China
- Department of Pediatrics, Henan University of Chinese Medicine, Zhengzhou, Henan, China
| | - Lu Meng
- Department of Pediatrics, The First Affiliated Hospital of Henan University of Chinese Medicine, Zhengzhou, Henan, China
- Department of Pediatrics, Henan University of Chinese Medicine, Zhengzhou, Henan, China
| | - Xiaojin Jing
- Department of Pediatrics, The First Affiliated Hospital of Henan University of Chinese Medicine, Zhengzhou, Henan, China
- Department of Pediatrics, Henan University of Chinese Medicine, Zhengzhou, Henan, China
| | - Jiangping Fu
- Department of Pediatrics, The First Affiliated Hospital of Henan University of Chinese Medicine, Zhengzhou, Henan, China
- Department of Pediatrics, Henan University of Chinese Medicine, Zhengzhou, Henan, China
| | - Yan Xu
- Department of Pediatrics, The First Affiliated Hospital of Henan University of Chinese Medicine, Zhengzhou, Henan, China.
- Department of Pediatrics, Henan University of Chinese Medicine, Zhengzhou, Henan, China.
| | - Yuna Chai
- Department of Pharmacy, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China.
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Liu JJ, Yang JB, Wang Y, Hu XR, Wang YD, Nie LX, Wei F, Yu JD, Yao LW, Xu BL, Ma SC, Jin HY. Integrating network pharmacology and experimental validation to investigate the effects and mechanism of Renshen Shouwu decoction for ameliorating Alzheimer's disease. PHARMACEUTICAL BIOLOGY 2024; 62:767-780. [PMID: 39417324 PMCID: PMC11488172 DOI: 10.1080/13880209.2024.2415660] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/04/2023] [Revised: 09/29/2024] [Accepted: 10/08/2024] [Indexed: 10/19/2024]
Abstract
CONTEXT The mechanism of Renshen Shouwu Decoction (RSSW) in treating Alzheimer's disease (AD) remains unknown. OBJECTIVE This study investigates the effects and mechanism of RSSW for ameliorating AD. MATERIALS AND METHODS Ten SAMR1 mice and 40 SAMP8 mice were divided into five groups: control (SAMR1), model (SAMP8), positive drug (Donepezil, 1.3 mg/kg/d), and RSSW (Low-dose, 117 mg/kg/d; High-dose, 234 mg/kg/d). Starting from 6 months of age, the medications were administered intragastrically for a total of 60 days. Subsequently, memory improvement in rapidly aging mice was assessed using the novel object recognition test and Morris water maze test. Through the identification of absorbed blood components and analysis of network pharmacology, active ingredients and potential targets involved in the treatment of AD were identified. Finally, AD-related biological indicators were detected using western blotting and ELISA. RESULT Our results demonstrated that RSSW effectively ameliorated memory impairments, inhibited tau hyperphosphorylation, and reduced β-amyloid plaque deposition in SAMP8 mice. Thirty absorbed blood components in RSSW were identified, revealing identified 96 major targets that play a key role in alleviating AD. Notably, the obtained main targets were highly enriched in SIRT1-mediated signaling pathways. Subsequent experimental validation confirmed that RSSW activated the SIRT1/NF-κB, SIRT1/AMPK, and SIRT1/p53 signaling cascades. Nine potential active ingredients were predicted through molecular docking. DISCUSSION AND CONCLUSIONS Our research findings suggest the mechanism of RSSW treatment for AD, which ameliorates memory impairments by reducing cortical tissue inflammation and apoptosis.
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Affiliation(s)
- Jing-jing Liu
- Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China
- National Institutes for Food and Drug Control, Beijing, China
| | - Jian-bo Yang
- National Institutes for Food and Drug Control, Beijing, China
| | - Ying Wang
- National Institutes for Food and Drug Control, Beijing, China
| | - Xiao-ru Hu
- National Institutes for Food and Drug Control, Beijing, China
| | - Ya-dan Wang
- National Institutes for Food and Drug Control, Beijing, China
| | - Li-xing Nie
- National Institutes for Food and Drug Control, Beijing, China
| | - Feng Wei
- National Institutes for Food and Drug Control, Beijing, China
| | - Jian-dong Yu
- National Institutes for Food and Drug Control, Beijing, China
| | - Ling-wen Yao
- National Institutes for Food and Drug Control, Beijing, China
| | - Bei-lei Xu
- School of Pharmacy, Harbin University of Commerce, Harbin, China
| | - Shuang-cheng Ma
- Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China
- National Institutes for Food and Drug Control, Beijing, China
| | - Hong-yu Jin
- Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China
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Martins B, Mossemann J, Aguilar F, Zhao S, Bilan PJ, Sayed BA. Liver Transplantation: A Test of Cellular Physiology, Preservation, and Injury. Physiology (Bethesda) 2024; 39:401-411. [PMID: 39078382 DOI: 10.1152/physiol.00020.2024] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2024] [Revised: 07/26/2024] [Accepted: 07/26/2024] [Indexed: 07/31/2024] Open
Abstract
Liver transplantation has evolved into a mature clinical field, but scarcity of usable organs poses a unique challenge. Expanding the donor pool requires novel approaches for protecting hepatic physiology and cellular homeostasis. Here we define hepatocellular injury during transplantation, with an emphasis on modifiable cell death pathways as future therapeutics.
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Affiliation(s)
- B Martins
- Cell Biology Program, Hospital for Sick Children, Toronto, Ontario, Canada
| | - J Mossemann
- Cell Biology Program, Hospital for Sick Children, Toronto, Ontario, Canada
| | - F Aguilar
- Cell Biology Program, Hospital for Sick Children, Toronto, Ontario, Canada
| | - S Zhao
- Neuroscience and Mental Health Program, Hospital for Sick Children, Toronto, Ontario, Canada
| | - P J Bilan
- Cell Biology Program, Hospital for Sick Children, Toronto, Ontario, Canada
| | - B A Sayed
- Cell Biology Program, Hospital for Sick Children, Toronto, Ontario, Canada
- Division of General Surgery, Hospital for Sick Children, Toronto, Ontario, Canada
- Ajmera Transplant Centre, University Health Network, Toronto, Ontario, Canada
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Zhuang L, Jia N, Zhang L, Zhang Q, Antwi SO, Sartorius K, Wu K, Sun D, Xi D, Lu Y. Gpbar-1/cAMP/PKA signaling mitigates macrophage-mediated acute cholestatic liver injury via antagonizing NLRP3-ASC inflammasome. Biochim Biophys Acta Mol Basis Dis 2024; 1870:167266. [PMID: 38806072 DOI: 10.1016/j.bbadis.2024.167266] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2023] [Revised: 05/17/2024] [Accepted: 05/20/2024] [Indexed: 05/30/2024]
Abstract
Acute cholestatic liver injury (ACLI) is a disease associated with bile duct obstruction that causes liver inflammation and apoptosis. Although G protein-coupled bile acid receptor1 (Gpbar-1) has diverse metabolic roles, its involvement in ACLI-associated immune activation remains unclear. Liver tissues and blood samples from 20 patients with ACLI and 20 healthy individuals were analyzed using biochemical tests, H&E staining, western blotting, and immunohistochemistry to verify liver damage and expression of Gpbar-1. The expression of Gpbar-1, cAMP/PKA signaling, and the NLRP3 inflammasome was tested in wild-type (WT) and Gpbar-1 knockdown (si-Gpbar-1) mice with ACLI induced by bile duct ligation (BDL) and in primary Kupffer cells (KCs) with or without Gpbar-1-siRNA. The results showed that total bile acids and Gpbar-1 expressions were elevated in patients with ACLI. Gpbar-1 knockdown significantly worsened BDL-induced acute hepatic damage, inflammation, and liver apoptosis in vivo. Knockdown of Gpbar-1 heightened KC sensitivity to lipopolysaccharide (LPS) stimulation. Gpbar-1 activation inhibited LPS-induced pro-inflammatory responses in normal KCs but not in Gpbar-1-knockdown KCs. Notably, NLRP3-ASC inflammasome expression was effectively enhanced by Gpbar-1 deficiency. Additionally, Gpbar-1 directly increased intracellular cAMP levels and PKA phosphorylation, thus disrupting the NLRP3-ASC inflammasome. The pro-inflammatory characteristic of Gpbar-1 deficiency was almost neutralized by the NLRP3 inhibitor CY-09. In vitro, M1 polarization was accelerated in LPS-stimulated Gpbar-1-knockdown KCs. Therapeutically, Gpbar-1 deficiency exacerbated BDL-induced ACLI, which could be rescued by inhibition of the NLRP3-ASC inflammasome. Our study reveal that Gpbar-1 may act as a novel immune-mediated regulator of ACLI by inhibiting the NLRP3-ASC inflammasome.
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Affiliation(s)
- Lin Zhuang
- The First People's Hospital of Changzhou, The Third Affiliated Hospital of Soochow University, Changzhou, Jiangsu 213000, China; Department of General Surgery, Wujin Affiliated Hospital of Jiangsu University and The Wujin clinical college of Xuzhou medical university, Changzhou Key Laboratory of Molecular Diagnostics and Precision Cancer Medicine, Wujin Institute of Molecular Diagnostics and Precision Cancer Medicine of Jiangsu University, Changzhou, Jiangsu 213000, China
| | - Naixin Jia
- Department of Hepatobiliary Surgery, Kunshan First People's Hospital affiliated to Jiangsu University, Kunshan, Jiangsu 215300, China
| | - Li Zhang
- The First People's Hospital of Changzhou, The Third Affiliated Hospital of Soochow University, Changzhou, Jiangsu 213000, China
| | - Qi Zhang
- Department of Oncology, Wujin Affiliated Hospital of Jiangsu University and The Wujin clinical college of Xuzhou Medical University, Changzhou Key Laboratory of Molecular Diagnostics and Precision Cancer Medicine, Wujin Institute of Molecular Diagnostics and Precision Cancer Medicine of Jiangsu University, Changzhou, Jiangsu 213000, China
| | - Samuel O Antwi
- Department of Quantitative Health Sciences, Mayo Clinic, Jacksonville, FL 32224, USA; The Africa Hepatopancreatobiliary Cancer Consortium (AHPBCC), Mayo Clinic, Jacksonville, FL 32224, USA
| | - Kurt Sartorius
- The Africa Hepatopancreatobiliary Cancer Consortium (AHPBCC), Mayo Clinic, Jacksonville, FL 32224, USA; School of Laboratory Medicine and Molecular Sciences, College of Health Sciences, University of Kwazulu-Natal, Durban 4041, South Africa; UKZN Gastrointestinal Cancer Research Unit, University of Kwazulu-Natal, Durban 4041, South Africa
| | - Kejia Wu
- The First People's Hospital of Changzhou, The Third Affiliated Hospital of Soochow University, Changzhou, Jiangsu 213000, China
| | - Donglin Sun
- The First People's Hospital of Changzhou, The Third Affiliated Hospital of Soochow University, Changzhou, Jiangsu 213000, China.
| | - Dong Xi
- Department of Oncology, Wujin Affiliated Hospital of Jiangsu University and The Wujin clinical college of Xuzhou Medical University, Changzhou Key Laboratory of Molecular Diagnostics and Precision Cancer Medicine, Wujin Institute of Molecular Diagnostics and Precision Cancer Medicine of Jiangsu University, Changzhou, Jiangsu 213000, China.
| | - Yunjie Lu
- Department of General Surgery, Wujin Affiliated Hospital of Jiangsu University and The Wujin clinical college of Xuzhou medical university, Changzhou Key Laboratory of Molecular Diagnostics and Precision Cancer Medicine, Wujin Institute of Molecular Diagnostics and Precision Cancer Medicine of Jiangsu University, Changzhou, Jiangsu 213000, China; The Africa Hepatopancreatobiliary Cancer Consortium (AHPBCC), Mayo Clinic, Jacksonville, FL 32224, USA; Department of Hepatopancreatobiliary surgery, The First Affiliated Hospital of Soochow University, Suzhou 215100, China.
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ALRashdi BM, Massoud D, Rashwan HK, Mahgoub S, Abuelezz NZ, Nasr AM, Kassab RB, Amin HK. The Protecting Role of Black Seed Oil and Its Nano-Formulation in LPS-Induced Acute Kidney Injury in Mice: Evaluation of Oxidative Stress, Biochemical & Molecular Parameters. J Inflamm Res 2024; 17:4747-4763. [PMID: 39051058 PMCID: PMC11268590 DOI: 10.2147/jir.s463369] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2024] [Accepted: 06/26/2024] [Indexed: 07/27/2024] Open
Abstract
Background Acute kidney injury (AKI) is a medical concern that is accompanied by the rapid deterioration of kidney function. It can be triggered by lipopolysaccharide (LPS) of gram-negative bacteria as it activates a complicated immune response, resulting in widespread inflammation and potential organ dysfunction. Black seed oil (BSO) is rich in beneficial constituents and has been widely used owing to its nutritional advantages. Purpose This research is aimed to investigate the potential protective effects of BSO and its nano-formulation on AKI induced by LPS. It also aimed to compare their anti-inflammatory activity with indomethacin, a known synthetic anti-inflammatory drug. Materials and Methods Forty-eight mice were placed randomly into 8 groups. A single intraperitoneal (i.p.) injection of 2.5 mg/kg B.W. of LPS was used to trigger inflammation, and pretreatment with BSO and its nano-formulation was at 0.2 mL/kg/day for 14 consecutive days. Indomethacin was used as a reference drug and its efficacy was tested alone or in combination with BSO at lower doses. Renal function was assessed using urea, creatinine, neutrophil gelatinase-associated lipocalin (NGAL) and kidney injury molecule-1 (KIM-1). Also, oxidative and inflammatory markers were assessed by measuring levels of reduced glutathione (GSH), nitric oxide (NO), cyclooxygenase-2 (COX-2), tumor necrosis factor alpha (TNF-α), and toll-like receptor-4 (TLR-4). Histopathological examination of the kidney tissues was also performed. Results The study showed that BSO and its nano-formulation had anti-inflammatory effects comparable to or better than those of indomethacin. They greatly decreased the oxidative stress and inflammatory markers induced by LPS. Their protective effect against pathological alterations in kidney tissues was significantly noticed. Conclusion BSO and its nano-formulation could be used as nephroprotective and anti-inflammatory supplements.
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Affiliation(s)
- Barakat M ALRashdi
- Department of Biology, College of Science, Jouf University, Sakaka, Saudi Arabia
| | - Diaa Massoud
- Department of Biology, College of Science, Jouf University, Sakaka, Saudi Arabia
| | - Hager K Rashwan
- Department of Biochemistry, College of Pharmaceutical Sciences and Drug Manufacturing, Misr University for Science and Technology, Giza, Egypt
| | - Shahenda Mahgoub
- Department of Biochemistry and Molecular Biology, Faculty of Pharmacy, Helwan University, Cairo, Egypt
| | - Nermeen Z Abuelezz
- Department of Biochemistry, College of Pharmaceutical Sciences and Drug Manufacturing, Misr University for Science and Technology, Giza, Egypt
| | - Ali M Nasr
- Department of Pharmaceutics, Faculty of Pharmacy, Port Said University, Port Said, 42526, Egypt
- Department of Pharmaceutics and Industrial Pharmacy, Faculty of Pharmacy, Galala University, New Galala, 43713, Egypt
| | - Rami B Kassab
- Department of Zoology and Entomology, Faculty of Science, Helwan University, Cairo, Egypt
| | - Hatem K Amin
- Department of Biochemistry and Molecular Biology, Faculty of Pharmacy, Helwan University, Cairo, Egypt
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Lopes FB, Sarandy MM, Novaes RD, Valacchi G, Gonçalves RV. OxInflammatory Responses in the Wound Healing Process: A Systematic Review. Antioxidants (Basel) 2024; 13:823. [PMID: 39061892 PMCID: PMC11274091 DOI: 10.3390/antiox13070823] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2024] [Revised: 06/11/2024] [Accepted: 06/27/2024] [Indexed: 07/28/2024] Open
Abstract
Significant sums are spent every year to find effective treatments to control inflammation and speed up the repair of damaged skin. This study investigated the main mechanisms involved in the skin wound cure. Consequently, it offered guidance to develop new therapies to control OxInflammation and infection and decrease functional loss and cost issues. This systematic review was conducted using the PRISMA guidelines, with a structured search in the MEDLINE (PubMed), Scopus, and Web of Science databases, analyzing 23 original studies. Bias analysis and study quality were assessed using the SYRCLE tool (Prospero number is CRD262 936). Our results highlight the activation of membrane receptors (IFN-δ, TNF-α, toll-like) in phagocytes, especially macrophages, during early wound healing. The STAT1, IP3, and NF-kβ pathways are positively regulated, while Ca2+ mobilization correlates with ROS production and NLRP3 inflammasome activation. This pathway activation leads to the proteolytic cleavage of caspase-1, releasing IL-1β and IL-18, which are responsible for immune modulation and vasodilation. Mediators such as IL-1, iNOS, TNF-α, and TGF-β are released, influencing pro- and anti-inflammatory cascades, increasing ROS levels, and inducing the oxidation of lipids, proteins, and DNA. During healing, the respiratory burst depletes antioxidant defenses (SOD, CAT, GST), creating a pro-oxidative environment. The IFN-δ pathway, ROS production, and inflammatory markers establish a positive feedback loop, recruiting more polymorphonuclear cells and reinforcing the positive interaction between oxidative stress and inflammation. This process is crucial because, in the immune system, the vicious positive cycle between ROS, the oxidative environment, and, above all, the activation of the NLRP3 inflammasome inappropriately triggers hypoxia, increases ROS levels, activates pro-inflammatory cytokines and inhibits the antioxidant action and resolution of anti-inflammatory cytokines, contributing to the evolution of chronic inflammation and tissue damage.
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Affiliation(s)
- Fernanda Barbosa Lopes
- Department of General Biology, Federal University of Viçosa, Viçosa 36570-900, Minas Gerais, Brazil
| | - Mariáurea Matias Sarandy
- Department of General Biology, Federal University of Viçosa, Viçosa 36570-900, Minas Gerais, Brazil
- Plants for Human Health Institute, Animal Science Department, North Carolina State University, North Carolina Research Campus, Kannapolis, NC 28081, USA
| | - Rômulo Dias Novaes
- Department of Structural Biology, Federal University of Alfenas, Alfenas 37130-001, Minas Gerais, Brazil
- Department of Animal Biology, Federal University of Viçosa, Viçosa 36570-900, Minas Gerais, Brazil
| | - Giuseppe Valacchi
- Plants for Human Health Institute, Animal Science Department, North Carolina State University, North Carolina Research Campus, Kannapolis, NC 28081, USA
- Department of Environmental and Prevention Sciences, University of Ferrara, 44121 Ferrara, Italy
- Department of Food and Nutrition, Kyung Hee University, Seoul 02447, Republic of Korea
| | - Reggiani Vilela Gonçalves
- Department of General Biology, Federal University of Viçosa, Viçosa 36570-900, Minas Gerais, Brazil
- Plants for Human Health Institute, Animal Science Department, North Carolina State University, North Carolina Research Campus, Kannapolis, NC 28081, USA
- Department of Animal Biology, Federal University of Viçosa, Viçosa 36570-900, Minas Gerais, Brazil
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Qian Z, Xiong W, Mao X, Li J. Macrophage Perspectives in Liver Diseases: Programmed Death, Related Biomarkers, and Targeted Therapy. Biomolecules 2024; 14:700. [PMID: 38927103 PMCID: PMC11202214 DOI: 10.3390/biom14060700] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2024] [Revised: 06/06/2024] [Accepted: 06/10/2024] [Indexed: 06/28/2024] Open
Abstract
Macrophages, as important immune cells of the organism, are involved in maintaining intrahepatic microenvironmental homeostasis and can undergo rapid phenotypic changes in the injured or recovering liver. In recent years, the crucial role of macrophage-programmed cell death in the development and regression of liver diseases has become a research hotspot. Moreover, macrophage-targeted therapeutic strategies are emerging in both preclinical and clinical studies. Given the macrophages' vital role in complex organismal environments, there is tremendous academic interest in developing novel therapeutic strategies that target these cells. This review provides an overview of the characteristics and interactions between macrophage polarization, programmed cell death, related biomarkers, and macrophage-targeted therapies. It aims to deepen the understanding of macrophage immunomodulation and molecular mechanisms and to provide a basis for the treatment of macrophage-associated liver diseases.
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Affiliation(s)
- Zibing Qian
- The First Clinical Medical College of Lanzhou University, Lanzhou 730000, China; (Z.Q.); (W.X.)
| | - Wanyuan Xiong
- The First Clinical Medical College of Lanzhou University, Lanzhou 730000, China; (Z.Q.); (W.X.)
| | - Xiaorong Mao
- The First Clinical Medical College of Lanzhou University, Lanzhou 730000, China; (Z.Q.); (W.X.)
- Department of Infectious Disease, The First Hospital of Lanzhou University, Lanzhou 730000, China
| | - Junfeng Li
- The First Clinical Medical College of Lanzhou University, Lanzhou 730000, China; (Z.Q.); (W.X.)
- Institute of Infectious Diseases, The First Hospital of Lanzhou University, Lanzhou 730000, China
- Department of Hepatology, The First Hospital of Lanzhou University, Lanzhou 730000, China
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10
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Yao Y, Zuo X, Shao F, Yu K, Liang Q. Jaceosidin attenuates the progression of hepatic fibrosis by inhibiting the VGLL3/HMGB1/TLR4 signaling pathway. PHYTOMEDICINE : INTERNATIONAL JOURNAL OF PHYTOTHERAPY AND PHYTOPHARMACOLOGY 2024; 128:155502. [PMID: 38489889 DOI: 10.1016/j.phymed.2024.155502] [Citation(s) in RCA: 7] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/01/2023] [Revised: 02/19/2024] [Accepted: 02/27/2024] [Indexed: 03/17/2024]
Abstract
BACKGROUND Jaceosidin (JA) is a natural flavone extracted from Artemisia that is used as a food and traditional medicinal herb. It has been reported to possess numerous biological activities. However, the regulatory mechanisms underlying amelioration of hepatic fibrosis remain unclear. HYPOTHESIS/PURPOSE We hypothesized that jaceosidin acid (JA) modulates hepatic fibrosis and inflammation. METHODS Thioacetamide (TAA) was used to establish an HF mouse model. In vitro, mouse primary hepatocytes and HSC-T6 cells were induced by TGF-β, whereas mouse peritoneal macrophages received a treatment lipopolysaccharide (LPS)/ATP. RESULTS JA decreased serum transaminase levels and improved hepatic histological pathology in TAA-treated mice stimulated by TAA. Moreover, the expression of pro-fibrogenic biomarkers associated with the activation of liver stellate cells was downregulated by JA. Likewise, JA down-regulated the expression of vestigial-like family member 3 (VGLL3), high mobility group protein B1 (HMGB1), toll-like receptors 4 (TLR4), and nucleotide-binding domain-(NOD-) like receptor protein 3 (NLRP3), thereby inhibiting the inflammatory response and inhibiting the release of mature-IL-1β in TAA-stimulated mice. Additionally, JA suppressed HMGB1 release and NLRP3/ASC inflammasome activation in LPS/ATP-stimulated murine peritoneal macrophages. JA decreases the expression of pro-fibrogenic biomarkers related to liver stellate cell activation and inhibits inflammasome activation in mouse primary hepatocytes. It also down-regulated α-SMA and VGLL3 expressions and also suppressed inflammasome activation in HSC-T6 cells. VGLL3 and α-SMA expression levels were decreased in TGF-β-stimulated HSC-T6 cells following Vgll3 knockdown. In addition, the expression levels of NLRP3 and cleaved-caspase-1 were decreased in Vgll3-silenced HSC-T6 cells. JA enhanced the inhibitory effects on Vgll3-silenced HSC-T6 cells. Finally, Vgll3 overexpression in HSC-T6 cells affected the expression levels of α-SMA, NLRP3, and cleaved-caspase-1. CONCLUSION JA effectively modulates hepatic fibrosis by suppressing fibrogenesis and inflammation via the VGLL3/HMGB1/TLR4 axis. Therefore, JA may be a candidate therapeutic agent for the management of hepatic fibrosis. Understanding the mechanism of action of JA is a novel approach to hepatic fibrosis therapy.
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Affiliation(s)
- Youli Yao
- College of Electronic and Information Engineering, Shandong University of Science and Technology, Qingdao, Shandong Province 266000, China
| | - Xiaoling Zuo
- College of Electronic and Information Engineering, Shandong University of Science and Technology, Qingdao, Shandong Province 266000, China
| | - Feng Shao
- Qingdao Jinmotang Biotechnology Co., Ltd, Qingdao, Shandong Province 266000, China
| | - Kexin Yu
- College of Electronic and Information Engineering, Shandong University of Science and Technology, Qingdao, Shandong Province 266000, China
| | - Quanquan Liang
- College of Electronic and Information Engineering, Shandong University of Science and Technology, Qingdao, Shandong Province 266000, China.
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Tutusaus A, Sanduzzi-Zamparelli M, Boix L, Rider P, Subías S, García de Frutos P, Colell A, Marí M, Reig M, Morales A. Induction of the Inflammasome Pathway by Tyrosine Kinase Inhibitors Provides an Actionable Therapeutic Target for Hepatocellular Carcinoma. Cancers (Basel) 2024; 16:1491. [PMID: 38672578 PMCID: PMC11048610 DOI: 10.3390/cancers16081491] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2024] [Revised: 04/04/2024] [Accepted: 04/10/2024] [Indexed: 04/28/2024] Open
Abstract
During the last decade, tyrosine kinase inhibitors (TKIs) sorafenib and regorafenib have been standard systemic treatments for advanced hepatocellular carcinoma (HCC). Previous data associated sorafenib with inflammasome activation. However, the role of the inflammasome in sorafenib and regorafenib signaling has not been described in liver cancer patients. For this purpose, we analyzed inflammasome-related transcriptomic changes in a murine HCC model. Our data confirmed inflammasome activation after both TKI treatments, sharing a similar pattern of increased gene expression. According to human database results, transcriptional increase of inflammasome genes is associated with poorer prognosis for male liver cancer patients, suggesting a sex-dependent role for inflammasome activation in HCC therapy. In biopsies of HCC and its surrounding tissue, we detected durable increases in the inflammasome activation pattern after sorafenib or regorafenib treatment in male patients. Further supporting its involvement in sorafenib action, inflammasome inhibition (MCC950) enhanced sorafenib anticancer activity in experimental HCC models, while no direct in vitro effect was observed in HCC cell lines. Moreover, activated human THP-1 macrophages released IL-1β after sorafenib administration, while 3D Hep3B spheres displayed increased tumor growth after IL-1β addition, pointing to the liver microenvironment as a key player in inflammasome action. In summary, our results unveil the inflammasome pathway as an actionable target in sorafenib or regorafenib therapy and associate an inflammasome signature in HCC and surrounding tissue with TKI administration. Therefore, targeting inflammasome activation, principally in male patients, could help to overcome sorafenib or regorafenib resistance and enhance the efficacy of TKI treatments in HCC.
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Affiliation(s)
- Anna Tutusaus
- Department of Cell Death and Proliferation, IIBB-CSIC, Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), 08036 Barcelona, Spain; (A.T.); (P.R.); (P.G.d.F.); (A.C.); (M.M.)
- Barcelona Clinic Liver Cancer (BCLC) Group, Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), 08036 Barcelona, Spain; (M.S.-Z.); (L.B.)
| | - Marco Sanduzzi-Zamparelli
- Barcelona Clinic Liver Cancer (BCLC) Group, Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), 08036 Barcelona, Spain; (M.S.-Z.); (L.B.)
- Liver Unit, Hospital Clinic de Barcelona, Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), 08036 Barcelona, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas, CIBEREHD, ISCIII, 28029 Madrid, Spain
- Departament de Medicina, Facultat de Medicina, Universitat de Barcelona, 08036 Barcelona, Spain
| | - Loreto Boix
- Barcelona Clinic Liver Cancer (BCLC) Group, Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), 08036 Barcelona, Spain; (M.S.-Z.); (L.B.)
- Liver Unit, Hospital Clinic de Barcelona, Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), 08036 Barcelona, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas, CIBEREHD, ISCIII, 28029 Madrid, Spain
| | - Patricia Rider
- Department of Cell Death and Proliferation, IIBB-CSIC, Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), 08036 Barcelona, Spain; (A.T.); (P.R.); (P.G.d.F.); (A.C.); (M.M.)
- Departament de Biomedicina, Facultat de Medicina, Universitat de Barcelona, 08036 Barcelona, Spain
| | - Silvia Subías
- Department of Cell Death and Proliferation, IIBB-CSIC, Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), 08036 Barcelona, Spain; (A.T.); (P.R.); (P.G.d.F.); (A.C.); (M.M.)
| | - Pablo García de Frutos
- Department of Cell Death and Proliferation, IIBB-CSIC, Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), 08036 Barcelona, Spain; (A.T.); (P.R.); (P.G.d.F.); (A.C.); (M.M.)
- Unidad Asociada (IMIM), IIBB-CSIC, 08036 Barcelona, Spain
- CIBERCV, ISCIII, 28029 Madrid, Spain
| | - Anna Colell
- Department of Cell Death and Proliferation, IIBB-CSIC, Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), 08036 Barcelona, Spain; (A.T.); (P.R.); (P.G.d.F.); (A.C.); (M.M.)
- Centro de Investigación Biomédica en Red en Enfermedades Neurodegenerativas (CIBERNED), ISCIII, 28029 Madrid, Spain
| | - Montserrat Marí
- Department of Cell Death and Proliferation, IIBB-CSIC, Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), 08036 Barcelona, Spain; (A.T.); (P.R.); (P.G.d.F.); (A.C.); (M.M.)
| | - María Reig
- Barcelona Clinic Liver Cancer (BCLC) Group, Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), 08036 Barcelona, Spain; (M.S.-Z.); (L.B.)
- Liver Unit, Hospital Clinic de Barcelona, Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), 08036 Barcelona, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas, CIBEREHD, ISCIII, 28029 Madrid, Spain
- Departament de Medicina, Facultat de Medicina, Universitat de Barcelona, 08036 Barcelona, Spain
| | - Albert Morales
- Department of Cell Death and Proliferation, IIBB-CSIC, Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), 08036 Barcelona, Spain; (A.T.); (P.R.); (P.G.d.F.); (A.C.); (M.M.)
- Barcelona Clinic Liver Cancer (BCLC) Group, Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), 08036 Barcelona, Spain; (M.S.-Z.); (L.B.)
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Kim MY, Jeong B, Lee GS, Jeon H, Yang YM, Yang H, Han YH. Panaxydol extracted from Panax ginseng inhibits NLRP3 inflammasome activation to ameliorate NASH-induced liver injury. Int Immunopharmacol 2024; 128:111565. [PMID: 38262161 DOI: 10.1016/j.intimp.2024.111565] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2023] [Revised: 01/15/2024] [Accepted: 01/16/2024] [Indexed: 01/25/2024]
Abstract
Activation of NOD-like receptor protein 3 (NLRP3) inflammasome exacerbates liver inflammation and fibrosis in nonalcoholic steatohepatitis (NASH), suggesting that development of inflammasome inhibitor can become leading candidate to ameliorate NASH. Panax ginseng (P. ginseng) contains numerous bioactive natural components to reduce inflammation. This study aims to identify inhibitory components of P. ginseng for NLRP3 inflammasome activation. We separated polar and non-polar fractions of P. ginseng and tested modulation of NLRP3 inflammasome, and then identified pure component for inflammasome inhibitor which ameliorates diet-induced NASH. Non-polar P. ginseng fractions obtained from ethyl acetate solvent attenuated IL-1β secretion and expression of active caspase-1. We revealed that panaxydol (PND) is pure component to inhibit NLRP3 inflammasome activation. PND blocked inflammasome cytokines release, pyroptotic cell death, caspase-1 activation and specking of inflammasome complex. Inhibitory effect of PND was specific to NLRP3-dependent pathway via potential interaction with ATP binding motif of NLRP3. Moreover, in vivo studies showed that PND plays beneficial roles to reduce tissue inflammations through disruption of NLRP3 inflammasome and to ameliorate the development of NASH. These results provide new insight of natural products, panaxydol, for NLRP3 inflammasome inhibitor and could offer potential therapeutic candidate for reliving NASH.
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Affiliation(s)
- Mi-Yeon Kim
- Laboratory of Pathology and Physiology, College of Pharmacy, Kangwon National University, Chuncheon 24341, South Korea
| | - Birang Jeong
- Laboratory of Natural Products Chemistry, College of Pharmacy, Kangwon National University, Chuncheon 24341, South Korea
| | - Geun-Shik Lee
- College of Veterinary Medicine and Institute of Veterinary Science, Kangwon National University, Chuncheon 24341, South Korea
| | - Hongjun Jeon
- Therapeutics & Biotechnology Division, Korea Research Institute of Chemical Technology, Daejeon 34114, South Korea
| | - Yoon Mee Yang
- Multidimensional Genomics Research Center, Kangwon National University, Chuncheon 24341, South Korea; College of Pharmacy, Kangwon National University, Chuncheon 24341, South Korea
| | - Heejung Yang
- Laboratory of Natural Products Chemistry, College of Pharmacy, Kangwon National University, Chuncheon 24341, South Korea.
| | - Yong-Hyun Han
- Laboratory of Pathology and Physiology, College of Pharmacy, Kangwon National University, Chuncheon 24341, South Korea; Multidimensional Genomics Research Center, Kangwon National University, Chuncheon 24341, South Korea.
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13
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de Carvalho Ribeiro M, Babuta M, Szabo G. Reply: Alcohol-induced extracellular ASC specks perpetuate liver inflammation and damage in alcohol-associated hepatitis even after alcohol cessation. Hepatology 2024; 79:E28-E29. [PMID: 37972945 DOI: 10.1097/hep.0000000000000686] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/04/2023] [Accepted: 10/04/2023] [Indexed: 11/19/2023]
Affiliation(s)
- Marcelle de Carvalho Ribeiro
- Department of Medicine, Beth Israel Deaconess Medical Center and 330 Brookline Ave, ST-214B, Boston, MA 02215, USA
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Kim ME, Lee JS, Kim TW, Park MH, Kim DH. FoxO6-Mediated TXNIP Induces Lipid Accumulation in the Liver through NLRP3 Inflammasome Activation. Endocrinol Metab (Seoul) 2024; 39:127-139. [PMID: 38417829 PMCID: PMC10901662 DOI: 10.3803/enm.2023.1826] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/15/2023] [Revised: 11/02/2023] [Accepted: 11/13/2023] [Indexed: 03/01/2024] Open
Abstract
BACKGRUOUND Hepatic steatosis, which involves the excessive accumulation of lipid droplets in hepatocytes, presents a significant global health concern due to its association with obesity and metabolic disorders. Inflammation plays a crucial role in the progression of hepatic steatosis; however, the precise molecular mechanisms responsible for this process remain unknown. METHODS This study investigated the involvement of the nucleotide-binding oligomerization domain-like receptor pyrin domain-containing-3 (NLRP3) inflammasome and the forkhead box O6 (FoxO6) transcription factor in the pathogenesis of hepatic steatosis. We monitored the NLRP3 inflammasome and lipogenesis in mice overexpressing the constitutively active (CA)-FoxO6 allele and FoxO6-null mice. In an in vitro study, we administered palmitate to liver cells overexpressing CA-FoxO6 and measured changes in lipid metabolism. RESULTS We administered palmitate treatment to clarify the mechanisms through which FoxO6 activates cytokine interleukin (IL)-1β through the NLRP3 inflammasome. The initial experiments revealed that dephosphorylation led to palmitate-induced FoxO6 transcriptional activity. Further palmitate experiments showed increased expression of IL-1β and the hepatic NLRP3 inflammasome complex, including adaptor protein apoptotic speck protein containing a caspase recruitment domain (ASC) and pro-caspase-1. Furthermore, thioredoxin-interacting protein (TXNIP), a key regulator of cellular redox conditions upstream of the NLRP3 inflammasome, was induced by FoxO6 in the liver and HepG2 cells. CONCLUSION The findings of this study shed light on the molecular mechanisms underpinning the FoxO6-NLRP3 inflammasome axis in promoting inflammation and lipid accumulation in the liver.
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Affiliation(s)
- Mi Eun Kim
- Department of Life Sciences, Chosun University College of Natural Science, Gwangju, Korea
| | - Jun Sik Lee
- Department of Life Sciences, Chosun University College of Natural Science, Gwangju, Korea
| | - Tae Won Kim
- Department of Pharmacy, Kyungsung University College of Pharmacy, Busan, Korea
| | - Min Hi Park
- Department of Pharmacy, Kyungsung University College of Pharmacy, Busan, Korea
| | - Dae Hyun Kim
- Department of Food Science & Technology, Pusan National University College of Natural Resources and Life Science, Miryang, Korea
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15
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Kouroumalis E, Tsomidis I, Voumvouraki A. Viral Liver Disease and Intestinal Gut–Liver Axis. GASTROINTESTINAL DISORDERS 2024; 6:64-93. [DOI: 10.3390/gidisord6010005] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/03/2025] Open
Abstract
The intestinal microbiota is closely related to liver diseases via the intestinal barrier and bile secretion to the gut. Impairment of the barrier can translocate microbes or their components to the liver where they can contribute to liver damage and fibrosis. The components of the barrier are discussed in this review along with the other elements of the so-called gut–liver axis. This bidirectional relation has been widely studied in alcoholic and non-alcoholic liver disease. However, the involvement of microbiota in the pathogenesis and treatment of viral liver diseases have not been extensively studied, and controversial data have been published. Therefore, we reviewed data regarding the integrity and function of the intestinal barrier and the changes of the intestinal microbioma that contribute to progression of Hepatitis B (HBV) and Hepatitis C (HCV) infection. Their consequences, such as cirrhosis and hepatic encephalopathy, were also discussed in connection with therapeutic interventions such as the effects of antiviral eradication and the use of probiotics that may influence the outcome of liver disease. Profound alterations of the microbioma with significant reduction in microbial diversity and changes in the abundance of both beneficial and pathogenic bacteria were found.
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Affiliation(s)
- Elias Kouroumalis
- Department of Gastroenterology, Medical School, University of Crete, 71500 Heraklion, Greece
| | - Ioannis Tsomidis
- Department of Gastroenterology, Medical School, University of Crete, 71500 Heraklion, Greece
| | - Argyro Voumvouraki
- 1st Department of Internal Medicine, AHEPA University Hospital, 54621 Thessaloniki, Greece
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He W, Xu C, Mao D, Zheng Y, Wang N, Wang M, Mao N, Wang T, Li Y. Recent advances in pyroptosis, liver disease, and traditional Chinese medicine: A review. Phytother Res 2023; 37:5473-5494. [PMID: 37622684 DOI: 10.1002/ptr.7989] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2023] [Revised: 07/29/2023] [Accepted: 08/09/2023] [Indexed: 08/26/2023]
Abstract
In recent years, the incidence of liver disease has increased, becoming a major cause of death. Various liver diseases are intricately linked to pyroptosis, which is one of the most common forms of programmed cell death. As a powerful weapon in the fight against liver diseases, traditional Chinese medicine (TCM) can affect pyroptosis via a number of routes, including the classical, nucleotide oligomerization domain-like receptors protein 3/caspase-1/gasdermin D (GSDMD) pathway, the nonclassical lipopolysaccharide/caspase-11/GSDMD pathway, the ROS/caspase-3/gasdermin E pathway, the caspase-9/caspase-3/GSDMD pathway, and the Apaf-1/caspase-11/caspase-3 pathway. In this review, we provide an overview of pyroptosis, the interplay between pyroptosis and liver diseases, and the mechanisms through which TCM regulates pyroptosis in liver diseases. The information used in the text was collected and compiled from the databases of PubMed, Web of Science, Scopus, CNKI, and Wanfang Data up to June 2023. The search was not limited with regard to the language and country of the articles. Research and review articles were included, and papers with duplicate results or unrelated content were excluded. We examined the current understanding of the relationship between pyroptosis and liver diseases as well as the advances in TCM interventions to provide a resource for the identification of potential targets for TCM in the treatment of liver diseases.
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Affiliation(s)
- Wenxing He
- Faculty of Chinese Medicine Science, Guangxi University of Chinese Medicine, Nanning, Guangxi, China
| | - Canli Xu
- Faculty of Chinese Medicine Science, Guangxi University of Chinese Medicine, Nanning, Guangxi, China
| | - Dewen Mao
- Department of Hepatology, The First Affiliated Hospital of Guangxi University of Chinese Medicine, Nanning, Guangxi, China
| | - Yang Zheng
- Faculty of Chinese Medicine Science, Guangxi University of Chinese Medicine, Nanning, Guangxi, China
| | - Na Wang
- Department of Hepatology, The First Affiliated Hospital of Guangxi University of Chinese Medicine, Nanning, Guangxi, China
| | - Minggang Wang
- Department of Hepatology, The First Affiliated Hospital of Guangxi University of Chinese Medicine, Nanning, Guangxi, China
| | - Nan Mao
- Department of Acupuncture-Moxibustion and Tuina, Jiangbin Hospital of Guangxi Zhuang Autonomous Region, Nanning, Guangxi, China
| | - Ting Wang
- The First Clinical Medical College, Guangxi University of Chinese Medicine, Nanning, Guangxi, China
| | - Yanjie Li
- Department of Hepatology, The First Affiliated Hospital of Guangxi University of Chinese Medicine, Nanning, Guangxi, China
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Pratim Das P, Medhi S. Role of inflammasomes and cytokines in immune dysfunction of liver cirrhosis. Cytokine 2023; 170:156347. [PMID: 37639845 DOI: 10.1016/j.cyto.2023.156347] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2023] [Revised: 07/28/2023] [Accepted: 08/21/2023] [Indexed: 08/31/2023]
Abstract
Liver cirrhosis develops as a result of persistent inflammation and liver injury. The prolonged inflammation triggers the buildup of fibrous tissue and regenerative nodules within the liver, leading to the distortion of the hepatic vascular structure and impaired liver function. Cirrhosis disrupts the ability of liver function to maintain homeostasis and hepatic immunosurveillance which causes immunological dysfunction in the body. In pathological conditions, the production of cytokines in the liver is carefully regulated by various cells in response to tissue stimulation. Cytokines and inflammasomes are the key regulators and systematically contribute to the development of cirrhosis which involves an inflammatory response. However, the crosstalk role of different cytokines in the cirrhosis progression is poorly understood. Tumour necrosis factor-alpha (TNF-α), interleukin-1 (IL-1), interleukin-6 (IL-6), and interferon-gamma (IFN-γ), among others, are proinflammatory cytokines that contribute to liver cell necrosis, which in turn causes the development of fibrosis. While IL-10 exhibits a potent anti-inflammatory effect on the liver by inhibiting immune cell activation and neutralizing pro-inflammatory cytokine activity. Inflammasomes have also been implicated in the profibrotic processes of liver cirrhosis, as well as the production of chemokines such as CCL2/MCP-1. It is evident that inflammasomes have a role in the proinflammatory response seen in chronic liver illnesses. In conclusion, cirrhosis significantly impacts the immune system, leading to immunological dysfunction and alterations in both innate and acquired immunity. Proinflammatory cytokines like TNF-α, IL-1β, IL-6, and IFNγ are upregulated in cirrhosis, contributing to liver cell necrosis and fibrosis development. Managing cytokine-mediated inflammation and fibrosis is a key therapeutic approach to alleviate portal hypertension and its associated liver complications. This review attempted to focus largely on the role of immune dysfunction mediated by different cytokines and inflammasomes involved in the progression, regulation and development of liver cirrhosis.
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Affiliation(s)
- Partha Pratim Das
- Dept. of Bioengineering & Technology, Gauhati University, Assam 781014, India
| | - Subhash Medhi
- Dept. of Bioengineering & Technology, Gauhati University, Assam 781014, India.
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Li H, Zhang R, Hu Y, Li J, Yang Y, Wu D, Gu X, Zhang F, Zhou H, Yang C. Axitinib attenuates the progression of liver fibrosis by restoring mitochondrial function. Int Immunopharmacol 2023; 122:110555. [PMID: 37399607 DOI: 10.1016/j.intimp.2023.110555] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2023] [Revised: 06/21/2023] [Accepted: 06/21/2023] [Indexed: 07/05/2023]
Abstract
Liver fibrosis can progress to cirrhosis and hepatocellular carcinoma, which may eventually lead to liver failure and even death. No direct anti-fibrosis drugs are available at present. Axitinib is a new generation of potent multitarget tyrosine kinase receptor inhibitors, but its role in liver fibrosis remains unclear. In this study, a CCl4-induced hepatic fibrosis mouse model and a TGF-β1-induced hepatic stellate cell model were used to explore the effect and mechanism of axitinib on hepatic fibrosis. Results confirmed that axitinib could alleviate the pathological damage of liver tissue induced by CCl4 and inhibit the production of glutamic-oxalacetic transaminase and glutamic-pyruvic transaminase. It also inhibited collagen and hydroxyproline deposition and the protein expression of Col-1 and α-SMA in CCl4-induced liver fibrosis. In addition, axitinib inhibited the expression of CTGF and α-SMA in TGF-β1-induced hepatic stellate cells. Further studies showed that axitinib inhibited mitochondrial damage and reduced oxidative stress and NLRP3 maturation. The use of rotenone and antimycin A confirmed that axitinib could restore the activity of mitochondrial complexes I and III, thereby inhibiting the maturation of NLRP3. In summary, axitinib inhibits the activation of HSCs by enhancing the activity of mitochondrial complexes I and III, thereby alleviating the progression of liver fibrosis. This study reveals the strong potential of axitinib in the treatment of liver fibrosis.
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Affiliation(s)
- Hailong Li
- The State Key Laboratory of Medicinal Chemical Biology, College of Pharmacy and Key Laboratory of Molecular Drug Research, Nankai University, Tianjin 300350, China
| | - Ruotong Zhang
- The State Key Laboratory of Medicinal Chemical Biology, College of Pharmacy and Key Laboratory of Molecular Drug Research, Nankai University, Tianjin 300350, China; High-throughput Molecular Drug Screening Centre, Tianjin International Joint Academy of Biomedicine, Tianjin 300350, China
| | - Yayue Hu
- The State Key Laboratory of Medicinal Chemical Biology, College of Pharmacy and Key Laboratory of Molecular Drug Research, Nankai University, Tianjin 300350, China; High-throughput Molecular Drug Screening Centre, Tianjin International Joint Academy of Biomedicine, Tianjin 300350, China
| | - Jinhe Li
- The State Key Laboratory of Medicinal Chemical Biology, College of Pharmacy and Key Laboratory of Molecular Drug Research, Nankai University, Tianjin 300350, China; High-throughput Molecular Drug Screening Centre, Tianjin International Joint Academy of Biomedicine, Tianjin 300350, China
| | - Ying Yang
- The State Key Laboratory of Medicinal Chemical Biology, College of Pharmacy and Key Laboratory of Molecular Drug Research, Nankai University, Tianjin 300350, China
| | - Dan Wu
- The State Key Laboratory of Medicinal Chemical Biology, College of Pharmacy and Key Laboratory of Molecular Drug Research, Nankai University, Tianjin 300350, China
| | - Xiaoting Gu
- The State Key Laboratory of Medicinal Chemical Biology, College of Pharmacy and Key Laboratory of Molecular Drug Research, Nankai University, Tianjin 300350, China
| | - Fubo Zhang
- Organ Transplantation Center, Tianjin First Central Hospital, No. 24 Fukang Road, Nankai District, Tianjin 300192, China.
| | - Honggang Zhou
- The State Key Laboratory of Medicinal Chemical Biology, College of Pharmacy and Key Laboratory of Molecular Drug Research, Nankai University, Tianjin 300350, China; High-throughput Molecular Drug Screening Centre, Tianjin International Joint Academy of Biomedicine, Tianjin 300350, China.
| | - Cheng Yang
- The State Key Laboratory of Medicinal Chemical Biology, College of Pharmacy and Key Laboratory of Molecular Drug Research, Nankai University, Tianjin 300350, China; High-throughput Molecular Drug Screening Centre, Tianjin International Joint Academy of Biomedicine, Tianjin 300350, China.
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Seo HY, Lee SH, Park JY, Han E, Han S, Hwang JS, Kim MK, Jang BK. Lobeglitazone inhibits LPS-induced NLRP3 inflammasome activation and inflammation in the liver. PLoS One 2023; 18:e0290532. [PMID: 37616215 PMCID: PMC10449201 DOI: 10.1371/journal.pone.0290532] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2023] [Accepted: 08/10/2023] [Indexed: 08/26/2023] Open
Abstract
Liver inflammation is a common feature of chronic liver disease and is often associated with increased exposure of the liver to lipopolysaccharide (LPS). Kupffer cells (KCs) are macrophages in the liver and produce various cytokines. Activation of KCs through the NLRP3 inflammasome pathway leads to release of proinflammatory cytokines and induces hepatocyte injury and hepatic stellate cell (HSC) activation. Lobeglitazone is a peroxisome proliferator-activated receptor gamma ligand and a type of thiazolidinedione that elicits anti-inflammatory effects. However, there is no clear evidence that it has direct anti-inflammatory effects in the liver. This study showed that lobeglitazone reduces LPS-induced NLPR3 inflammasome activation and production of proinflammatory cytokines in primary KCs and hepatocytes. Cytokines secreted by activated KCs increased hepatocyte inflammation and HSC activation, and lobeglitazone inhibited these responses. In addition, lobeglitazone suppressed liver fibrosis by inhibiting LPS-induced transforming growth factor (TGF)-β secretion and TGF-β-induced CTGF expression. The inhibitory effect of lobeglitazone on inflammasome activation was associated with suppression of liver fibrosis. These results suggest that lobeglitazone may be a treatment option for inflammation and fibrosis in the liver.
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Affiliation(s)
- Hye-Young Seo
- Department of Internal Medicine, School of Medicine, Institute for Medical Science, Keimyung University, Daegu, Korea
| | - So-Hee Lee
- Department of Internal Medicine, School of Medicine, Institute for Medical Science, Keimyung University, Daegu, Korea
| | - Ji Yeon Park
- Department of Internal Medicine, School of Medicine, Institute for Medical Science, Keimyung University, Daegu, Korea
| | - Eugene Han
- Department of Internal Medicine, School of Medicine, Institute for Medical Science, Keimyung University, Daegu, Korea
| | - Sol Han
- Department of Physiology, University of Washington, Seattle, WA, United States of America
| | - Jae Seok Hwang
- Department of Internal Medicine, School of Medicine, Institute for Medical Science, Keimyung University, Daegu, Korea
| | - Mi Kyung Kim
- Department of Internal Medicine, School of Medicine, Institute for Medical Science, Keimyung University, Daegu, Korea
| | - Byoung Kuk Jang
- Department of Internal Medicine, School of Medicine, Institute for Medical Science, Keimyung University, Daegu, Korea
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20
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Charan HV, Dwivedi DK, Khan S, Jena G. Mechanisms of NLRP3 inflammasome-mediated hepatic stellate cell activation: Therapeutic potential for liver fibrosis. Genes Dis 2023; 10:480-494. [PMID: 37223529 PMCID: PMC10201559 DOI: 10.1016/j.gendis.2021.12.006] [Citation(s) in RCA: 20] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2021] [Revised: 11/09/2021] [Accepted: 12/01/2021] [Indexed: 01/18/2023] Open
Abstract
The liver injury leads to an inflammatory response, which causes the activation of hepatic stellate cells (HSCs) that further secrete ECM proteins and play an important role in liver fibrosis. Moreover, the inflammatory response is a driving force for fibrogenesis, which is triggered by many types of injuries. Exaggerated inflammatory immune responses are mediated by cytoplasmic protein complexes known as inflammasomes, which are involved in many chronic liver diseases. Inflammasomes are pattern recognition receptors (PRRs) that can sense any microbial motifs known as pathogen-associated molecular patterns (PAMPs), and host- or environmental-derived stress signals known as damage-associated molecular patterns (DAMPs). The inflammasomes cause caspase-mediated proteolytic cleavage of pro-IL-1β and pro-IL-18 into active IL-1β and IL-18. In this review, we provide a comprehensive summary of the important roles of NLRP3 inflammasome in the pathogenesis of liver fibrosis with an emphasis on several direct and indirect pathways responsible for the NLRP3 inflammasome-mediated HSCs activation and fibrogenesis. In addition, we discuss the general pharmacological and genetics strategies for the inhibition of NLRP3 inflammasome activation and its downstream signaling with examples of emerging pharmacotherapeutics, targeting the NLRP3 inflammasome signaling as well as a possible way to develop effective and safer NLRP3 inflammasome inhibitors.
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Affiliation(s)
- Harsh Vardhan Charan
- Facility for Risk Assessment and Intervention Studies, Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research, Sector-67, S.A.S. Nagar, Punjab 160062, India
| | - Durgesh Kumar Dwivedi
- Facility for Risk Assessment and Intervention Studies, Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research, Sector-67, S.A.S. Nagar, Punjab 160062, India
| | - Sabbir Khan
- Facility for Risk Assessment and Intervention Studies, Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research, Sector-67, S.A.S. Nagar, Punjab 160062, India
- Department of Neuro-Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Gopabandhu Jena
- Facility for Risk Assessment and Intervention Studies, Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research, Sector-67, S.A.S. Nagar, Punjab 160062, India
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21
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Wang J, Wang L, Zhang XJ, Zhang P, Cai J, She ZG, Li H. Recent updates on targeting the molecular mediators of NAFLD. J Mol Med (Berl) 2023; 101:101-124. [PMID: 36792729 DOI: 10.1007/s00109-022-02282-4] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2022] [Revised: 11/29/2022] [Accepted: 12/21/2022] [Indexed: 02/17/2023]
Abstract
Nonalcoholic fatty liver disease (NAFLD) is rapidly becoming the most common disease worldwide in an era of rapid economic growth. NAFLD is a multifactorial disease, involving multiple genetic, metabolic, and environmental factors, and is closely associated with metabolic syndrome, obesity, and cardiovascular disease. NAFLD can be classified into nonalcoholic fatty liver disease (NAFL) and nonalcoholic steatohepatitis (NASH), which can both progress to cirrhosis and even hepatocellular carcinoma (HCC). Due to the enormous burden of NAFLD and its complications, no FDA-approved drugs for the treatment of NAFLD are on the market, and therapeutic targets and drug therapies are being actively investigated. In view of the various pathological mechanisms of NAFLD, numbers of preclinical studies and clinical trials have made rapid progress. This review mainly summarizes the most recently characterized mechanisms and therapeutic targets in each mechanism of NAFLD, focusing on the mechanism and application potential.
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Affiliation(s)
- Jia Wang
- Department of Cardiology, Renmin Hospital of Wuhan University, Luojia Mount Wuchang, Wuhan, China
- Institute of Model Animal, Wuhan University, Wuhan, China
| | - Lei Wang
- Department of Neurosurgery, Huanggang Central Hospital of Yangtze University, Huanggang, China
- Translation Medicine Research Center, Yangtze University, Huanggang, China
| | - Xiao-Jing Zhang
- Institute of Model Animal, Wuhan University, Wuhan, China
- School of Basic Medical Sciences, Wuhan University, Wuhan, China
| | - Peng Zhang
- Institute of Model Animal, Wuhan University, Wuhan, China
- School of Basic Medical Sciences, Wuhan University, Wuhan, China
| | - Jingjing Cai
- Institute of Model Animal, Wuhan University, Wuhan, China
- Department of Cardiology, The Third Xiangya Hospital, Central South University, The Third Xiangya Hospital, Changsha, China
| | - Zhi-Gang She
- Department of Cardiology, Renmin Hospital of Wuhan University, Luojia Mount Wuchang, Wuhan, China.
- Institute of Model Animal, Wuhan University, Wuhan, China.
| | - Hongliang Li
- Department of Cardiology, Renmin Hospital of Wuhan University, Luojia Mount Wuchang, Wuhan, China.
- Institute of Model Animal, Wuhan University, Wuhan, China.
- Translation Medicine Research Center, Yangtze University, Huanggang, China.
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22
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Chen F, Li B, Li W, Chen W, Huang Y, Tian Y, Yang B, Yuan M, Xu D, Cao N. Polysaccharide of Atractylodes macrocephala Koidz alleviate lipopolysaccharide-stimulated liver inflammation injury of goslings through miR-223/NLRP3 axis. Poult Sci 2023; 102:102285. [PMID: 36436369 PMCID: PMC9706645 DOI: 10.1016/j.psj.2022.102285] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2022] [Revised: 10/08/2022] [Accepted: 10/19/2022] [Indexed: 11/05/2022] Open
Abstract
Lipopolysaccharide (LPS) infection could cause severe liver inflammation and lead to liver damage, even death. Previous studies have shown that polysaccharide of Atractylodes macrocephala Koidz (PAMK) could protect liver from inflammation caused by LPS in mice. However, whether PAMK could alleviate liver inflammatory injury in other animals with LPS is still unknown. For evaluating whether PAMK could alleviate liver inflammatory injury in goslings with LPS, a total of 80 healthy 1-day old Magang goslings were randomly divided into 4 groups (control group, PAMK group, LPS group, and PAMK+LPS group). Goslings in control group and LPS group were fed with basal diet, and goslings in PAMK group and PAMK+LPS group were fed basal diet supplemented with 400 mg/kg PAMK to the end of trial. On 24 d of age, goslings in the control group and PAMK group were intraperitoneal injected 0.5 mL normal saline, and goslings in LPS and PAMK+LPS groups were intraperitoneal injected with LPS at 5 mg/kg BW. The serum and liver samples were collected for further analysis after treatment of LPS at 6, 12, 24, and 48 h. Furthermore, the hepatocytes were extracted from goose embryo to measure the expression of the key genes of miR-223/NLRP3 axis. The results showed that PAMK pretreatment could maintain normal cell morphology of liver, alleviate the enhanced levels of biochemical indexes ALT and AST, decrease the levels of IL-1β and IL-18, increase the relative mRNA expression of miR-223, and decrease the expression of NLRP3, Caspase-1, and cleaved Caspase-1 in liver and hepatocytes of goslings induced by LPS. These results indicated that PAMK could relieve inflammatory liver tissue damage after LPS treatment and downregulate the level of inflammation factors via miR-223/NLRP3 axis, thus playing a liver protective role in liver inflammation injury in goslings.
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Affiliation(s)
- Feiyue Chen
- College of Animal Science & Technology, Zhongkai University of Agriculture and Engineering, Guangzhou 510225, China; Guangdong Province Key Laboratory of Waterfowl Healthy Breeding, Guangzhou 510225, China
| | - Bingxin Li
- College of Animal Science & Technology, Zhongkai University of Agriculture and Engineering, Guangzhou 510225, China; Guangdong Province Key Laboratory of Waterfowl Healthy Breeding, Guangzhou 510225, China
| | - Wanyan Li
- College of Animal Science & Technology, Zhongkai University of Agriculture and Engineering, Guangzhou 510225, China; Guangdong Province Key Laboratory of Waterfowl Healthy Breeding, Guangzhou 510225, China
| | - Wenbin Chen
- College of Animal Science & Technology, Zhongkai University of Agriculture and Engineering, Guangzhou 510225, China; Guangdong Province Key Laboratory of Waterfowl Healthy Breeding, Guangzhou 510225, China
| | - Yunmao Huang
- College of Animal Science & Technology, Zhongkai University of Agriculture and Engineering, Guangzhou 510225, China; Guangdong Province Key Laboratory of Waterfowl Healthy Breeding, Guangzhou 510225, China
| | - Yunbo Tian
- College of Animal Science & Technology, Zhongkai University of Agriculture and Engineering, Guangzhou 510225, China; Guangdong Province Key Laboratory of Waterfowl Healthy Breeding, Guangzhou 510225, China
| | - Baohe Yang
- Yunnan Kuaidaduo Animal Husbandry Technology Co., Ltd, Yuxi 653100, China
| | - Mingfeng Yuan
- Yunnan Kuaidaduo Animal Husbandry Technology Co., Ltd, Yuxi 653100, China
| | - Danning Xu
- College of Animal Science & Technology, Zhongkai University of Agriculture and Engineering, Guangzhou 510225, China; Guangdong Province Key Laboratory of Waterfowl Healthy Breeding, Guangzhou 510225, China
| | - Nan Cao
- College of Animal Science & Technology, Zhongkai University of Agriculture and Engineering, Guangzhou 510225, China; Guangdong Province Key Laboratory of Waterfowl Healthy Breeding, Guangzhou 510225, China.
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23
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Wan Y, Zhang W, Huang C, Jian J, Zhang Y, Liu Q, Chen P, Zhu X. Ursolic acid alleviates Kupffer cells pyroptosis in liver fibrosis by the NOX2/NLRP3 inflammasome signaling pathway. Int Immunopharmacol 2022; 113:109321. [DOI: 10.1016/j.intimp.2022.109321] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2022] [Revised: 09/30/2022] [Accepted: 10/04/2022] [Indexed: 11/05/2022]
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24
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Caffeine Inhibits NLRP3 Inflammasome Activation by Downregulating TLR4/MAPK/NF-κB Signaling Pathway in an Experimental NASH Model. Int J Mol Sci 2022; 23:ijms23179954. [PMID: 36077357 PMCID: PMC9456282 DOI: 10.3390/ijms23179954] [Citation(s) in RCA: 29] [Impact Index Per Article: 9.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/15/2022] [Revised: 08/26/2022] [Accepted: 08/29/2022] [Indexed: 12/13/2022] Open
Abstract
Caffeine elicits protective effects against liver diseases, such as NASH; however, its mechanism of action involving the pyrin domain-containing-3 (NLRP3) inflammasome signaling pathway remains to be elucidated. This study aimed to evaluate the effect of caffeine on the NLRP3 inflammasome signaling pathway in a rat model of NASH. NASH was induced by feeding rats a high-fat, -sucrose, and -cholesterol diet (HFSCD) for 15 weeks along with a weekly low dose (400 mg/kg, i.p.) of CCl4. Caffeine was administered at 50 mg/kg p.o. The effects of HFSCD+CCl4 and caffeine on the liver were evaluated using biochemical, ultrastructural, histological, and molecular biological approaches. The HFSCD+CCl4-treated rats showed fat accumulation in the liver, elevated levels of inflammatory mediators, NLRP3 inflammasome activation, antioxidant dysregulation, and liver fibrosis. Caffeine reduced necrosis, cholestasis, oxidative stress, and fibrosis. Caffeine exhibited anti-inflammatory effects by attenuating NLRP3 inflammasome activation. Moreover, caffeine prevented increases in toll-like receptor 4 (TLR4) and nuclear factor-κB (NF-κB) protein levels and mitigated the phosphorylation of mitogen-activated protein kinase (MAPK). Importantly, caffeine prevented the activation of hepatic stellate cells. This study is the first to report that caffeine ameliorates NASH by inhibiting NLRP3 inflammasome activation through the suppression of the TLR4/MAPK/NF-κB signaling pathway.
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25
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Distinct Patterns of GR Transcriptional Regulation in Liver and Muscle of LPS-Challenged Weaning Piglets. Int J Mol Sci 2022; 23:ijms23158072. [PMID: 35897645 PMCID: PMC9331734 DOI: 10.3390/ijms23158072] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2022] [Revised: 07/17/2022] [Accepted: 07/19/2022] [Indexed: 11/17/2022] Open
Abstract
Glucocorticoid receptor (GR), which is ubiquitously expressed in nearly all cell types of various organs, mediates the tissue-specific metabolic and immune responses to maintain homeostasis and ensure survival under stressful conditions or pathological challenges. The neonatal period is metabolically demanding, and piglets are subjected to multiple stressors in modern intensive farms, especially around weaning. The liver is more responsive to LPS challenge compared to muscle, which is indicated by significantly increased TLR4 and p-p65, TNF-α, and IL-6 levels in association with GR down-regulation at both mRNA and protein levels. GR binding to the putative nGRE on TNF-α and IL-6 gene promoters decreased in the liver, but not muscle, upon LPS stimulation. The transcriptional regulation of GR also showed striking differences between liver and muscle. GR exon 1 mRNA variants 1–4, 1–5, and 1–6 were down-regulated in both liver and muscle, but a significant up-regulation of GR exon 1–9/10 mRNA variants abolished the change of total GR mRNA in the muscle in response to LPS stimulation. The significant down-regulation of GR in the liver corresponded with significantly decreased binding of p-GR and diminished histone acetylation in GR gene promoters. These results indicate that tissue-specific GR transcriptional regulation is involved in the differential inflammation responses between liver and muscle.
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26
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Pal N, Joy PS, Sergi CM. Biliary Atresia Animal Models: Is the Needle in a Haystack? Int J Mol Sci 2022; 23:7838. [PMID: 35887185 PMCID: PMC9324346 DOI: 10.3390/ijms23147838] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2022] [Revised: 07/11/2022] [Accepted: 07/13/2022] [Indexed: 02/06/2023] Open
Abstract
Biliary atresia (BA) is a progressive fibro-obliterative process with a variable degree of inflammation involving the hepatobiliary system. Its consequences are incalculable for the patients, the affected families, relatives, and the healthcare system. Scientific communities have identified a rate of about 1 case per 10,000-20,000 live births, but the percentage may be higher, considering the late diagnoses. The etiology is heterogeneous. BA, which is considered in half of the causes leading to orthotopic liver transplantation, occurs in primates and non-primates. To consolidate any model, (1) more transport and cell membrane studies are needed to identify the exact mechanism of noxa-related hepatotoxicity; (2) an online platform may be key to share data from pilot projects and new techniques; and (3) the introduction of differentially expressed genes may be useful in investigating the liver metabolism to target the most intricate bilio-toxic effects of pharmaceutical drugs and toxins. As a challenge, such methodologies are still limited to very few centers, making the identification of highly functional animal models like finding a "needle in a haystack". This review compiles models from the haystack and hopes that a combinatorial search will eventually be the root for a successful pathway.
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Affiliation(s)
- Nutan Pal
- Jefferson Graduate School of Biomedical Sciences, Thomas Jefferson University, Philadelphia, PA 19107, USA;
| | - Parijat S. Joy
- Department of Internal Medicine, University of Iowa Hospitals and Clinics, Iowa City, IA 52242, USA;
| | - Consolato M. Sergi
- Anatomic Pathology Division, Department of Laboratory Medicine and Pathology, Children’s Hospital of Eastern Ontario, University of Ottawa, Ottawa, ON K1N 6N5, Canada
- Department of Lab. Medicine and Pathology, Stollery Children’s Hospital, University of Alberta, Edmonton, AB T6G 2B7, Canada
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27
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Wu T, Zhang C, Shao T, Chen J, Chen D. The Role of NLRP3 Inflammasome Activation Pathway of Hepatic Macrophages in Liver Ischemia-Reperfusion Injury. Front Immunol 2022; 13:905423. [PMID: 35757691 PMCID: PMC9229592 DOI: 10.3389/fimmu.2022.905423] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2022] [Accepted: 05/12/2022] [Indexed: 11/13/2022] Open
Abstract
Ischemia-reperfusion injury (IRI) is considered an inherent component involved in liver transplantation, which induce early organ dysfunction and failure. And the accumulating evidences indicate that the activation of host innate immune system, especially hepatic macrophages, play a pivotal role in the progression of LIRI. Inflammasomes is a kind of intracellular multimolecular complexes that actively participate in the innate immune responses and proinflammatory signaling pathways. Among them, NLRP3 inflammasome is the best characterized and correspond to regulate caspase-1 activation and the secretion of proinflammatory cytokines in response to various pathogen-derived as well as danger-associated signals. Additionally, NLRP3 is highly expressed in hepatic macrophages, and the assembly of NLRP3 inflammasome could lead to LIRI, which makes it a promising therapeutic target. However, detailed mechanisms about NLRP3 inflammasome involving in the hepatic macrophages-related LIRI is rarely summarized. Here, we review the potential role of the NLRP3 inflammasome pathway of hepatic macrophages in LIRI, with highlights on currently available therapeutic options.
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Affiliation(s)
- Tong Wu
- School of Medicine, Zhejiang University, Hangzhou, China
| | - Cheng Zhang
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Tianfeng Shao
- Department of General Practice, Shaoxing Yuecheng District Tashan Street Community Health Service Center, Shaoxing, China
| | - Jianzhong Chen
- Institute of Immunology, School of Medicine, Zhejiang University, Hangzhou, China
| | - Diyu Chen
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
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28
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Role of Inflammasomes in Keloids and Hypertrophic Scars-Lessons Learned from Chronic Diabetic Wounds and Skin Fibrosis. Int J Mol Sci 2022; 23:ijms23126820. [PMID: 35743263 PMCID: PMC9223684 DOI: 10.3390/ijms23126820] [Citation(s) in RCA: 26] [Impact Index Per Article: 8.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2022] [Revised: 06/13/2022] [Accepted: 06/14/2022] [Indexed: 02/06/2023] Open
Abstract
Keloids and hypertrophic scars are pathological cutaneous scars. They arise from excessive wound healing, which induces chronic dermal inflammation and results in overwhelming fibroblast production of extracellular matrix. Their etiology is unclear. Inflammasomes are multiprotein complexes that are important in proinflammatory innate-immune system responses. We asked whether inflammasomes participate in pathological scarring by examining the literature on scarring, diabetic wounds (also characterized by chronic inflammation), and systemic sclerosis (also marked by fibrosis). Pathological scars are predominantly populated by anti-inflammatory M2 macrophages and recent literature hints that this could be driven by non-canonical inflammasome signaling. Diabetic-wound healing associates with inflammasome activation in immune (macrophages) and non-immune (keratinocytes) cells. Fibrotic conditions associate with inflammasome activation and inflammasome-induced transition of epithelial cells/endothelial cells/macrophages into myofibroblasts that deposit excessive extracellular matrix. Studies suggest that mechanical stimuli activate inflammasomes via the cytoskeleton and that mechanotransduction-inflammasome crosstalk is involved in fibrosis. Further research should examine (i) the roles that various inflammasome types in macrophages, (myo)fibroblasts, and other cell types play in keloid development and (ii) how mechanical stimuli interact with inflammasomes and thereby drive scar growth. Such research is likely to significantly advance our understanding of pathological scarring and aid the development of new therapeutic strategies.
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29
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Galatou E, Mourelatou E, Hatziantoniou S, Vizirianakis IS. Nonalcoholic Steatohepatitis (NASH) and Atherosclerosis: Explaining Their Pathophysiology, Association and the Role of Incretin-Based Drugs. Antioxidants (Basel) 2022; 11:1060. [PMID: 35739957 PMCID: PMC9220192 DOI: 10.3390/antiox11061060] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2022] [Revised: 05/23/2022] [Accepted: 05/24/2022] [Indexed: 11/17/2022] Open
Abstract
Nonalcoholic steatohepatitis (NASH) is the most severe manifestation of nonalcoholic fatty liver disease (NAFLD), a common complication of type 2 diabetes, and may lead to cirrhosis and hepatocellular carcinoma. Oxidative stress and liver cell damage are the major triggers of the severe hepatic inflammation that characterizes NASH, which is highly correlated with atherosclerosis and coronary artery disease. Regarding drug therapy, research on the role of GLP-1 analogues and DPP4 inhibitors, novel classes of antidiabetic drugs, is growing. In this review, we outline the association between NASH and atherosclerosis, the underlying molecular mechanisms, and the effects of incretin-based drugs, especially GLP-1 RAs, for the therapeutic management of these conditions.
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Affiliation(s)
- Eleftheria Galatou
- Department of Life & Health Sciences, School of Sciences and Engineering, University of Nicosia, 2417 Nicosia, Cyprus;
| | - Elena Mourelatou
- Department of Life & Health Sciences, School of Sciences and Engineering, University of Nicosia, 2417 Nicosia, Cyprus;
| | - Sophia Hatziantoniou
- Laboratory of Pharmaceutical Technology, Department of Pharmacy, School of Health Sciences, University of Patras, 26504 Patras, Greece;
| | - Ioannis S. Vizirianakis
- Department of Life & Health Sciences, School of Sciences and Engineering, University of Nicosia, 2417 Nicosia, Cyprus;
- Laboratory of Pharmacology, School of Pharmacy, Aristotle University of Thessaloniki, 54124 Thessaloniki, Greece
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30
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Torres S, Segalés P, García-Ruiz C, Fernández-Checa JC. Mitochondria and the NLRP3 Inflammasome in Alcoholic and Nonalcoholic Steatohepatitis. Cells 2022; 11:1475. [PMID: 35563780 PMCID: PMC9105698 DOI: 10.3390/cells11091475] [Citation(s) in RCA: 29] [Impact Index Per Article: 9.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2022] [Revised: 04/18/2022] [Accepted: 04/25/2022] [Indexed: 12/12/2022] Open
Abstract
Alcoholic (ASH) and nonalcoholic steatohepatitis (NASH) are advanced stages of fatty liver disease and two of the most prevalent forms of chronic liver disease. ASH and NASH are associated with significant risk of further progression to cirrhosis and hepatocellular carcinoma (HCC), the most common type of liver cancer, and a major cause of cancer-related mortality. Despite extensive research and progress in the last decades to elucidate the mechanisms of the development of ASH and NASH, the pathogenesis of both diseases is still poorly understood. Mitochondrial damage and activation of inflammasome complexes have a role in inducing and sustaining liver damage. Mitochondrial dysfunction produces inflammatory factors that activate the inflammasome complexes. NLRP3 inflammasome (nucleotide-binding oligomerization domain-like receptor protein 3) is a multiprotein complex that activates caspase 1 and the release of pro-inflammatory cytokines, including interleukin-1β (IL-1β) and interleukin-18 (IL-18), and contributes to inflammatory pyroptotic cell death. The present review, which is part of the issue "Mitochondria in Liver Pathobiology", provides an overview of the role of mitochondrial dysfunction and NLRP3 activation in ASH and NASH.
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Affiliation(s)
- Sandra Torres
- Department of Cell Death and Proliferation, Institute of Biomedical Research of Barcelona (IIBB), Spanish National Research Council (CSIC), 08036 Barcelona, Spain; (S.T.); (P.S.)
- Liver Unit, Hospital Clinic I Provincial de Barcelona, Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), 08036 Barcelona, Spain
- Center for the Study of Liver and Gastrointestinal Diseases (CIBERehd), Carlos III National Institute of Health, 28029 Madrid, Spain
| | - Paula Segalés
- Department of Cell Death and Proliferation, Institute of Biomedical Research of Barcelona (IIBB), Spanish National Research Council (CSIC), 08036 Barcelona, Spain; (S.T.); (P.S.)
- Liver Unit, Hospital Clinic I Provincial de Barcelona, Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), 08036 Barcelona, Spain
- Center for the Study of Liver and Gastrointestinal Diseases (CIBERehd), Carlos III National Institute of Health, 28029 Madrid, Spain
| | - Carmen García-Ruiz
- Department of Cell Death and Proliferation, Institute of Biomedical Research of Barcelona (IIBB), Spanish National Research Council (CSIC), 08036 Barcelona, Spain; (S.T.); (P.S.)
- Liver Unit, Hospital Clinic I Provincial de Barcelona, Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), 08036 Barcelona, Spain
- Center for the Study of Liver and Gastrointestinal Diseases (CIBERehd), Carlos III National Institute of Health, 28029 Madrid, Spain
- Division of Gastrointestinal and Liver Diseases, Department of Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA
| | - José C. Fernández-Checa
- Department of Cell Death and Proliferation, Institute of Biomedical Research of Barcelona (IIBB), Spanish National Research Council (CSIC), 08036 Barcelona, Spain; (S.T.); (P.S.)
- Liver Unit, Hospital Clinic I Provincial de Barcelona, Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), 08036 Barcelona, Spain
- Center for the Study of Liver and Gastrointestinal Diseases (CIBERehd), Carlos III National Institute of Health, 28029 Madrid, Spain
- Division of Gastrointestinal and Liver Diseases, Department of Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA
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31
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Yang H, Wang J, Liu ZG. Multi-faceted role of pyroptosis mediated by inflammasome in liver fibrosis. J Cell Mol Med 2022; 26:2757-2765. [PMID: 35415891 PMCID: PMC9097829 DOI: 10.1111/jcmm.17277] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2021] [Revised: 02/16/2022] [Accepted: 02/27/2022] [Indexed: 12/18/2022] Open
Abstract
Liver fibrosis is a reversible pathological overreaction during the self-repair of liver injuries, and it is the common period of chronic liver diseases induced by different pathogenesis progress into cirrhosis and even hepatocellular carcinoma. Pyroptosis, a novel form of programmed cell death, is reported to take part in the pathogenesis and progression of acute or chronic liver diseases and liver fibrosis. Caspase-1 dependent canonical pathway and caspase-4/-5/-11 mediated noncanonical pathway are the two signalling pathways to induce pyroptosis. The activation of inflammasomes under the stimulation of pathogenic microorganisms and danger signals can initiate the pyroptotic pathway and release large amounts of proinflammatory and profibrotic cytokines. This article comprehensively summarizes recent researches focused on the mechanism of pyroptosis and its role in major hepatic cells, which can provide potential therapeutic strategies for liver fibrosis.
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Affiliation(s)
- Hui Yang
- Department of Infectious Disease, The Third Xiangya hospital, Central South University, Changsha, China
| | - Juan Wang
- Department of Infectious Disease, The Third Xiangya hospital, Central South University, Changsha, China
| | - Zhen-Guo Liu
- Department of Infectious Disease, The Third Xiangya hospital, Central South University, Changsha, China.,Hunan Key Laboratory of Viral Hepatitis, Xiyang Hospital, Central South University, Changsha, China
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32
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Abstract
The involvement of inflammasomes in the proinflammatory response observed in chronic liver diseases, such as alcohol-associated liver disease (ALD) and nonalcoholic fatty liver disease (NAFLD), is widely recognized. Although there are different types of inflammasomes, most studies to date have given attention to NLRP3 (nucleotide-binding oligomerization domain-like receptor family, pyrin domain containing 3) in the pathogenesis of ALD, NAFLD/nonalcoholic steatohepatitis, and fibrosis. Canonical inflammasomes are intracellular multiprotein complexes that are assembled after the sensing of danger signals and activate caspase-1, which matures interleukin (IL)-1β, IL-18, and IL-37 and also induces a form of cell death called pyroptosis. Noncanonical inflammasomes activate caspase-11 to induce pyroptosis. We discuss the different types of inflammasomes involved in liver diseases with a focus on (a) signals and mechanisms of inflammasome activation, (b) the role of different types of inflammasomes and their products in the pathogenesis of liver diseases, and (c) potential therapeutic strategies targeting components of the inflammasomes or cytokines produced upon inflammasome activation.
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Affiliation(s)
- Marcelle de Carvalho Ribeiro
- Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts 02215, USA; ,
| | - Gyongyi Szabo
- Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts 02215, USA; ,
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33
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Ge S, Yang W, Chen H, Yuan Q, Liu S, Zhao Y, Zhang J. MyD88 in Macrophages Enhances Liver Fibrosis by Activation of NLRP3 Inflammasome in HSCs. Int J Mol Sci 2021; 22:ijms222212413. [PMID: 34830293 PMCID: PMC8622429 DOI: 10.3390/ijms222212413] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2021] [Revised: 11/04/2021] [Accepted: 11/15/2021] [Indexed: 12/12/2022] Open
Abstract
Chronic liver disease mediated by the activation of hepatic stellate cells (HSCs) leads to liver fibrosis. The signal adaptor MyD88 of Toll-like receptor (TLR) signaling is involved during the progression of liver fibrosis. However, the specific role of MyD88 in myeloid cells in liver fibrosis has not been thoroughly investigated. In this study, we used a carbon tetrachloride (CCl4)-induced mouse fibrosis model in which MyD88 was selectively depleted in myeloid cells. MyD88 deficiency in myeloid cells attenuated liver fibrosis in mice and decreased inflammatory cell infiltration. Furthermore, deficiency of MyD88 in macrophages inhibits the secretion of CXC motif chemokine 2 (CXCL2), which restrains the activation of HSCs characterized by NLR Family Pyrin Domain Containing 3 (NLRP3) inflammasome activation. Moreover, targeting CXCL2 by CXCR2 inhibitors attenuated the activation of HSCs and reduced liver fibrosis. Thus, MyD88 may represent a potential candidate target for the prevention and treatment of liver fibrosis.
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Affiliation(s)
- Shuang Ge
- National Center for International Research of Bio-Targeting Theranostics, Guangxi Key Laboratory of Bio-Targeting Theranostics, Collaborative Innovation Center for Targeting Tumor Diagnosis and Therapy, Guangxi Talent Highland of Bio-Targeting Theranostics, Guangxi Medical University, Nanning 530021, China; (S.G.); (W.Y.)
| | - Wei Yang
- National Center for International Research of Bio-Targeting Theranostics, Guangxi Key Laboratory of Bio-Targeting Theranostics, Collaborative Innovation Center for Targeting Tumor Diagnosis and Therapy, Guangxi Talent Highland of Bio-Targeting Theranostics, Guangxi Medical University, Nanning 530021, China; (S.G.); (W.Y.)
| | - Haiqiang Chen
- College of Life Science and Bioengineering, Beijing Jiaotong University, Beijing 100044, China; (H.C.); (Q.Y.); (S.L.)
| | - Qi Yuan
- College of Life Science and Bioengineering, Beijing Jiaotong University, Beijing 100044, China; (H.C.); (Q.Y.); (S.L.)
| | - Shi Liu
- College of Life Science and Bioengineering, Beijing Jiaotong University, Beijing 100044, China; (H.C.); (Q.Y.); (S.L.)
| | - Yongxiang Zhao
- National Center for International Research of Bio-Targeting Theranostics, Guangxi Key Laboratory of Bio-Targeting Theranostics, Collaborative Innovation Center for Targeting Tumor Diagnosis and Therapy, Guangxi Talent Highland of Bio-Targeting Theranostics, Guangxi Medical University, Nanning 530021, China; (S.G.); (W.Y.)
- Correspondence: (Y.Z.); (J.Z.)
| | - Jinhua Zhang
- National Center for International Research of Bio-Targeting Theranostics, Guangxi Key Laboratory of Bio-Targeting Theranostics, Collaborative Innovation Center for Targeting Tumor Diagnosis and Therapy, Guangxi Talent Highland of Bio-Targeting Theranostics, Guangxi Medical University, Nanning 530021, China; (S.G.); (W.Y.)
- College of Life Science and Bioengineering, Beijing Jiaotong University, Beijing 100044, China; (H.C.); (Q.Y.); (S.L.)
- Correspondence: (Y.Z.); (J.Z.)
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Li X, Feng M, Zhao Y, Zhang Y, Zhou R, Zhou H, Pang Z, Tachibana H, Cheng X. A Novel TLR4-Binding Domain of Peroxiredoxin From Entamoeba histolytica Triggers NLRP3 Inflammasome Activation in Macrophages. Front Immunol 2021; 12:758451. [PMID: 34659265 PMCID: PMC8515043 DOI: 10.3389/fimmu.2021.758451] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2021] [Accepted: 09/15/2021] [Indexed: 12/24/2022] Open
Abstract
Macrophages promote early host responses to infection by releasing pro-inflammatory cytokines, and they are crucial to combat amoebiasis, a disease affecting millions of people worldwide. Macrophages elicit pro-inflammatory responses following direct cell/cell interaction of Entamoeba histolytica, inducing NLRP3 inflammasome activation with high-output IL-1β/IL-18 secretion. Here, we found that trophozoites could upregulate peroxiredoxins (Prx) expression and abundantly secrete Prxs when encountering host cells. The C-terminal of Prx was identified as the key functional domain in promoting NLRP3 inflammasome activation, and a recombinant C-terminal domain could act directly on macrophage. The Prxs derived from E. histolytica triggered toll-like receptor 4-dependent activation of NLRP3 inflammasome in a cell/cell contact-independent manner. Through genetic, immunoblotting or pharmacological inhibition methods, NLRP3 inflammasome activation was induced through caspase-1-dependent canonical pathway. Our data suggest that E. histolytica Prxs had stable and durable cell/cell contact-independent effects on macrophages following abundantly secretion during invasion, and the C-terminal of Prx was responsible for activating NLRP3 inflammasome in macrophages. This new alternative pathway may represent a potential novel therapeutic approach for amoebiasis, a global threat to millions.
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Affiliation(s)
- Xia Li
- Department of Medical Microbiology and Parasitology, School of Basic Medical Sciences, Fudan University, Shanghai, China
| | - Meng Feng
- Department of Medical Microbiology and Parasitology, School of Basic Medical Sciences, Fudan University, Shanghai, China
| | - Yanqing Zhao
- Department of Medical Microbiology and Parasitology, School of Basic Medical Sciences, Fudan University, Shanghai, China
| | - Yuhan Zhang
- Department of Medical Microbiology and Parasitology, School of Basic Medical Sciences, Fudan University, Shanghai, China
| | - Ruixue Zhou
- Department of Medical Microbiology and Parasitology, School of Basic Medical Sciences, Fudan University, Shanghai, China
| | - Hang Zhou
- Department of Medical Microbiology and Parasitology, School of Basic Medical Sciences, Fudan University, Shanghai, China
| | - Zhen Pang
- Department of Medical Microbiology and Parasitology, School of Basic Medical Sciences, Fudan University, Shanghai, China
| | - Hiroshi Tachibana
- Department of Infectious Diseases, Tokai University School of Medicine, Isehara, Japan
| | - Xunjia Cheng
- Department of Medical Microbiology and Parasitology, School of Basic Medical Sciences, Fudan University, Shanghai, China.,Department of Infectious Diseases, Tokai University School of Medicine, Isehara, Japan
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35
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Zhao Y, Liu X, Zheng Y, Liu W, Ding C. Aronia melanocarpa polysaccharide ameliorates inflammation and aging in mice by modulating the AMPK/SIRT1/NF-κB signaling pathway and gut microbiota. Sci Rep 2021; 11:20558. [PMID: 34663844 PMCID: PMC8523697 DOI: 10.1038/s41598-021-00071-6] [Citation(s) in RCA: 37] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2021] [Accepted: 10/06/2021] [Indexed: 12/11/2022] Open
Abstract
Aronia melanocarpa is a natural medicinal plant that has a variety of biological activities, its fruit is often used for food and medicine. Aronia melanocarpa polysaccharide (AMP) is the main component of the Aronia melanocarpa fruit. This research evaluated the delay and protection of AMP obtained from Aronia melanocarpa fruit on aging mice by D-Galactose (D-Gal) induction and explored the effect of supplementing AMP on the metabolism of the intestinal flora of aging mice. The aging model was established by intraperitoneal injection of D-Gal (200 mg/kg to 1000 mg/kg) once per 3 days for 12 weeks. AMP (100 and 200 mg/kg) was given daily by oral gavage after 6 weeks of D-Gal-induced. The results showed that AMP treatment significantly improved the spatial learning and memory impairment of aging mice determined by the eight-arm maze test. H&E staining showed that AMP significantly reversed brain tissue pathological damage and structural disorders. AMP alleviated inflammation and oxidative stress injury in aging brain tissue by regulating the AMPK/SIRT1/NF-κB and Nrf2/HO-1 signaling pathways. Particularly, AMP reduced brain cell apoptosis and neurological deficits by activating the PI3K/AKT/mTOR signaling pathway and its downstream apoptotic protein family. Importantly, 16S rDNA analysis indicated the AMP treatment significantly retarded the aging process by improving the composition of intestinal flora and abundance of beneficial bacteria. In summary, this study found that AMP delayed brain aging in mice by inhibiting inflammation and regulating intestinal microbes, which providing the possibility for the amelioration and treatment of aging and related metabolic diseases.
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Affiliation(s)
- Yingchun Zhao
- College of Chinese Medicinal Materials, Jilin Agricultural University, Changchun, 130118, China
| | - Xinglong Liu
- College of Chinese Medicinal Materials, Jilin Agricultural University, Changchun, 130118, China
| | - Yinan Zheng
- College of Chinese Medicinal Materials, Jilin Agricultural University, Changchun, 130118, China
- National & Local Joint Engineering Research Center for Ginseng Breeding and Development, Changchun, 130118, China
| | - Wencong Liu
- College of Chinese Medicinal Materials, Jilin Agricultural University, Changchun, 130118, China.
- National & Local Joint Engineering Research Center for Ginseng Breeding and Development, Changchun, 130118, China.
| | - Chuanbo Ding
- College of Chinese Medicinal Materials, Jilin Agricultural University, Changchun, 130118, China.
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36
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Koh EH, Yoon JE, Ko MS, Leem J, Yun JY, Hong CH, Cho YK, Lee SE, Jang JE, Baek JY, Yoo HJ, Kim SJ, Sung CO, Lim JS, Jeong WI, Back SH, Baek IJ, Torres S, Solsona-Vilarrasa E, Conde de la Rosa L, Garcia-Ruiz C, Feldstein AE, Fernandez-Checa JC, Lee KU. Sphingomyelin synthase 1 mediates hepatocyte pyroptosis to trigger non-alcoholic steatohepatitis. Gut 2021; 70:1954-1964. [PMID: 33208407 PMCID: PMC8458090 DOI: 10.1136/gutjnl-2020-322509] [Citation(s) in RCA: 111] [Impact Index Per Article: 27.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/10/2020] [Revised: 10/26/2020] [Accepted: 10/26/2020] [Indexed: 02/06/2023]
Abstract
OBJECTIVE Lipotoxic hepatocyte injury is a primary event in non-alcoholic steatohepatitis (NASH), but the mechanisms of lipotoxicity are not fully defined. Sphingolipids and free cholesterol (FC) mediate hepatocyte injury, but their link in NASH has not been explored. We examined the role of free cholesterol and sphingomyelin synthases (SMSs) that generate sphingomyelin (SM) and diacylglycerol (DAG) in hepatocyte pyroptosis, a specific form of programmed cell death associated with inflammasome activation, and NASH. DESIGN Wild-type C57BL/6J mice were fed a high fat and high cholesterol diet (HFHCD) to induce NASH. Hepatic SMS1 and SMS2 expressions were examined in various mouse models including HFHCD-fed mice and patients with NASH. Pyroptosis was estimated by the generation of the gasdermin-D N-terminal fragment. NASH susceptibility and pyroptosis were examined following knockdown of SMS1, protein kinase Cδ (PKCδ), or the NLR family CARD domain-containing protein 4 (NLRC4). RESULTS HFHCD increased the hepatic levels of SM and DAG while decreasing the level of phosphatidylcholine. Hepatic expression of Sms1 but not Sms2 was higher in mouse models and patients with NASH. FC in hepatocytes induced Sms1 expression, and Sms1 knockdown prevented HFHCD-induced NASH. DAG produced by SMS1 activated PKCδ and NLRC4 inflammasome to induce hepatocyte pyroptosis. Depletion of Nlrc4 prevented hepatocyte pyroptosis and the development of NASH. Conditioned media from pyroptotic hepatocytes activated the NOD-like receptor family pyrin domain containing 3 inflammasome (NLRP3) in Kupffer cells, but Nlrp3 knockout mice were not protected against HFHCD-induced hepatocyte pyroptosis. CONCLUSION SMS1 mediates hepatocyte pyroptosis through a novel DAG-PKCδ-NLRC4 axis and holds promise as a therapeutic target for NASH.
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Affiliation(s)
- Eun Hee Koh
- Department of Internal Medicine, Asan Medical Center, University of Ulsan College of Medicine, Seoul, South Korea
| | - Ji Eun Yoon
- Department of Medical Science, Asan Medical Institute of Convergence Science and Technology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, South Korea
| | - Myoung Seok Ko
- Biomedical Research Center, Asan Institute for Life Sciences, Asan Medical Center, University of Ulsan College of Medicine, Seoul, South Korea
| | - Jaechan Leem
- Department of Internal Medicine, Asan Medical Center, University of Ulsan College of Medicine, Seoul, South Korea
| | - Ji-Young Yun
- Biomedical Research Center, Asan Institute for Life Sciences, Asan Medical Center, University of Ulsan College of Medicine, Seoul, South Korea
| | - Chung Hwan Hong
- Department of Medical Science, Asan Medical Institute of Convergence Science and Technology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, South Korea
| | - Yun Kyung Cho
- Department of Internal Medicine, Asan Medical Center, University of Ulsan College of Medicine, Seoul, South Korea
| | - Seung Eun Lee
- Department of Internal Medicine, Asan Medical Center, University of Ulsan College of Medicine, Seoul, South Korea
| | - Jung Eun Jang
- Department of Internal Medicine, Asan Medical Center, University of Ulsan College of Medicine, Seoul, South Korea
| | - Ji Yeon Baek
- Department of Internal Medicine, Asan Medical Center, University of Ulsan College of Medicine, Seoul, South Korea
| | - Hyun Ju Yoo
- The Convergence Medicine Research Center, Asan Institute for Life Sciences, Asan Medical Center, University of Ulsan College of Medicine, Seoul, South Korea
| | - Su Jung Kim
- The Convergence Medicine Research Center, Asan Institute for Life Sciences, Asan Medical Center, University of Ulsan College of Medicine, Seoul, South Korea
| | - Chang Ohk Sung
- Department of Pathology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, South Korea
| | - Joon Seo Lim
- Clinical Research Center, Asan Institute for Life Sciences, Asan Medical Center, University of Ulsan College of Medicine, Seoul, South Korea
| | - Won-Il Jeong
- Laboratory of Liver Research, Graduate School of Medical Science and Engineering, KAIST, Daejeon, South Korea
| | - Sung Hoon Back
- School of Biological Sciences, University of Ulsan, Ulsan, South Korea
| | - In-Jeoung Baek
- The Convergence Medicine Research Center, Asan Institute for Life Sciences, Asan Medical Center, University of Ulsan College of Medicine, Seoul, South Korea
| | - Sandra Torres
- Department of Cell Death and Proliferation, Instituto Investigaciones Biomédicas de Barcelona (IIBB), CSIC, Barcelona, Spain and Liver Unit-IDIBAPS and Centro de Investigación Biomédica en Red (CIBERehd), Barcelona, Spain
| | - Estel Solsona-Vilarrasa
- Department of Cell Death and Proliferation, Instituto Investigaciones Biomédicas de Barcelona (IIBB), CSIC, Barcelona, Spain and Liver Unit-IDIBAPS and Centro de Investigación Biomédica en Red (CIBERehd), Barcelona, Spain
| | - Laura Conde de la Rosa
- Department of Cell Death and Proliferation, Instituto Investigaciones Biomédicas de Barcelona (IIBB), CSIC, Barcelona, Spain and Liver Unit-IDIBAPS and Centro de Investigación Biomédica en Red (CIBERehd), Barcelona, Spain
| | - Carmen Garcia-Ruiz
- Department of Cell Death and Proliferation, Instituto Investigaciones Biomédicas de Barcelona (IIBB), CSIC, Barcelona, Spain and Liver Unit-IDIBAPS and Centro de Investigación Biomédica en Red (CIBERehd), Barcelona, Spain,University of Southern California Research Center for Alcoholic Liver and Pancreatic Diseases and Cirrhosis, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA
| | - Ariel E Feldstein
- Department of Pediatrics, University of California San Diego, La Jolla, CA, USA
| | - Jose C Fernandez-Checa
- Department of Cell Death and Proliferation, Instituto Investigaciones Biomédicas de Barcelona (IIBB), CSIC, Barcelona, Spain and Liver Unit-IDIBAPS and Centro de Investigación Biomédica en Red (CIBERehd), Barcelona, Spain .,University of Southern California Research Center for Alcoholic Liver and Pancreatic Diseases and Cirrhosis, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA
| | - Ki-Up Lee
- Department of Internal Medicine, Asan Medical Center, University of Ulsan College of Medicine, Seoul, South Korea
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37
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Domerecka W, Kowalska-Kępczyńska A, Michalak A, Homa-Mlak I, Mlak R, Cichoż-Lach H, Małecka-Massalska T. Etiopathogenesis and Diagnostic Strategies in Autoimmune Hepatitis. Diagnostics (Basel) 2021; 11:1418. [PMID: 34441353 PMCID: PMC8393562 DOI: 10.3390/diagnostics11081418] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2021] [Revised: 07/29/2021] [Accepted: 08/03/2021] [Indexed: 01/10/2023] Open
Abstract
Autoimmune hepatitis (AIH) is a chronic liver disease with the incidence of 10 to 17 per 100,000 people in Europe. It affects people of any age, but most often occurs in the 40-60 age group. The clinical picture is varied, from asymptomatic to severe acute hepatitis or liver failure. The disease onset is probably associated with the impaired function of T lymphocytes, the development of molecular mimicry, intestinal dysbiosis, or infiltration with low density neutrophils, which, alongside autoantibodies (i.e., ANA, ASMA), implicate the formation of neutrophil extracellular traps (NETs), as a component of the disease process, and mediate the inappropriate immune response. AIH is characterized with an increased activity of aminotransferases, elevated concentration of serum immunoglobulin G, the presence of circulating autoantibodies and liver inflammation. The result of the histological examination of the liver and the presence of autoantibodies, although not pathognomonic, still remain a distinguishing feature. The diagnosis of AIH determines lifelong treatment in most patients. The treatment is implemented to prevent the development of cirrhosis and end-stage liver failure. This work focuses mainly on the etiopathogenesis and diagnosis of AIH.
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Affiliation(s)
- Weronika Domerecka
- Chair and Department of Human Physiology, Medical University of Lublin, 20-080 Lublin, Poland; (I.H.-M.); (R.M.); (T.M.-M.)
| | - Anna Kowalska-Kępczyńska
- Department of Biochemical Diagnostics, Chair of Laboratory Diagnostics, Medical University of Lublin, 20-081 Lublin, Poland;
| | - Agata Michalak
- Department of Gastroenterology with Endoscopy Unit, Medical University of Lublin, 20-090 Lublin, Poland; (A.M.); (H.C.-L.)
| | - Iwona Homa-Mlak
- Chair and Department of Human Physiology, Medical University of Lublin, 20-080 Lublin, Poland; (I.H.-M.); (R.M.); (T.M.-M.)
| | - Radosław Mlak
- Chair and Department of Human Physiology, Medical University of Lublin, 20-080 Lublin, Poland; (I.H.-M.); (R.M.); (T.M.-M.)
| | - Halina Cichoż-Lach
- Department of Gastroenterology with Endoscopy Unit, Medical University of Lublin, 20-090 Lublin, Poland; (A.M.); (H.C.-L.)
| | - Teresa Małecka-Massalska
- Chair and Department of Human Physiology, Medical University of Lublin, 20-080 Lublin, Poland; (I.H.-M.); (R.M.); (T.M.-M.)
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38
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Shi YS, Li XX, Li HT, Zhang Y. Pelargonidin ameliorates CCl 4-induced liver fibrosis by suppressing the ROS-NLRP3-IL-1β axis via activating the Nrf2 pathway. Food Funct 2021; 11:5156-5165. [PMID: 32432601 DOI: 10.1039/d0fo00660b] [Citation(s) in RCA: 31] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/09/2023]
Abstract
Liver fibrosis is a histological change that often occurs due to hepatic stellate cell (HSC) activation and excessive formation of an extracellular matrix in the liver. Pelargonidin (PEL) is a natural anthocyanidin existing in blueberries, berries, strawberries, and red radishes and has been demonstrated to possess health beneficial effects. Herein, we investigated the effect of PEL on liver fibrosis induced by CCl4 and hepatic stellate cells induced by transforming growth factor-β (TGF-β). We found that PEL administration prevented liver injury and liver fibrosis induced by CCl4 in a dose-dependent manner. Further data revealed that PEL increased liver nuclear factor E2-related factor 2 (Nrf2) and reduced liver oxidative stress and the expression levels of NLRP3, caspase-1 and IL-1β. In TGF-β-challenged HSCs (LX-2 cells), PEL effectively inhibited the LX-2 cell activation. In addition, the anti-fibrosis effects of PEL in LX-2 cells were abolished by Nrf2 knockdown. In summary, our study demonstrated that PEL ameliorated CCl4-induced liver fibrosis and HSC activation induced by TGF-β. The possible molecular mechanisms of PEL in liver fibrosis may be attributed to its suppression of ROS-NLRP3-IL-1β signaling by Nrf2 activation.
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Affiliation(s)
- Yu-Sheng Shi
- Key Laboratory of Biotechnology and Bioresources Utilization, Educational of Minister, College of Life Science, Dalian Nationalities University, Dalian 116600, People's Republic of China and School of Traditional Chinese Medicine, Southern Medical University, Guangzhou 510515, People's Republic of China.
| | - Xiao-Xing Li
- School of Bioengineering, Dalian University of Technology, Dalian,116024, People's Republic of China
| | - Hao-Tian Li
- Key Laboratory of Biotechnology and Bioresources Utilization, Educational of Minister, College of Life Science, Dalian Nationalities University, Dalian 116600, People's Republic of China
| | - Yan Zhang
- School of Traditional Chinese Medicine, Southern Medical University, Guangzhou 510515, People's Republic of China.
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39
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Frissen M, Liao L, Schneider KM, Djudjaj S, Haybaeck J, Wree A, Rolle-Kampczyk U, von Bergen M, Latz E, Boor P, Trautwein C. Bidirectional Role of NLRP3 During Acute and Chronic Cholestatic Liver Injury. Hepatology 2021; 73:1836-1854. [PMID: 32748971 DOI: 10.1002/hep.31494] [Citation(s) in RCA: 69] [Impact Index Per Article: 17.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/19/2019] [Revised: 05/29/2020] [Accepted: 06/08/2020] [Indexed: 12/12/2022]
Abstract
BACKGROUND AND AIMS Cholestatic liver injury leads to cell death and subsequent inflammation and fibrosis. As shown for primary biliary cholangitis (PBC), the mechanisms and circuits between different cell death pathways leading to disease progression are incompletely defined. Common bile duct ligation (BDL) is a well-established murine model to mimic cholestatic liver injury. Here, we hypothesized that pyroptotic cell death by the Nucleotide-Binding Domain, Leucine-Rich-Containing Family, Pyrin Domain-Containing-3 (Nlrp3) inflammasome plays an essential role during human and murine cholestasis. APPROACH AND RESULTS NLRP3 activation was analyzed in humans with cholestatic liver injury. Wild-type (WT) and Nlrp3-/- mice were subjected to BDL for 2 or 28 days. Chronic cholestasis in humans and mice is associated with NLRP3 activation and correlates with disease activity. Acute BDL in Nlrp3-deficient mice triggered increased inflammation as well as liver injury, associated with stronger apoptotic and necroptotic cell death. In contrast, NLRP3 deletion led to decreased liver injury and inflammation in chronic cholestasis. Moreover, bridging fibrosis was observed in WT, but not in NLRP3 knockout, mice 28 days after BDL. In contrast, lack of NLRP3 expression attenuated kidney injury and fibrosis after acute and chronic BDL. Importantly, administration of MCC950, an NLRP3 small molecule inhibitor, reduced BDL-induced disease progression in WT mice. CONCLUSIONS NLRP3 activation correlates with disease activity in patients with PBC. NLRP3 has a differential role during acute and chronic cholestatic liver injury in contrast to kidney injury. Disease progression during chronic cholestasis can be targeted through small molecules and thus suggests a potential clinical benefit for humans, attenuating liver and kidney injury.
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Affiliation(s)
- Mick Frissen
- Department of Internal Medicine III, University Hospital RWTH Aachen, Aachen, Germany
| | - Lijun Liao
- Department of Internal Medicine III, University Hospital RWTH Aachen, Aachen, Germany
| | - Kai Markus Schneider
- Department of Internal Medicine III, University Hospital RWTH Aachen, Aachen, Germany
| | - Sonja Djudjaj
- Institute of Pathology, RWTH Aachen University, Aachen, Germany
| | - Johannes Haybaeck
- Diagnostic & Research Center for Molecular BioMedicine, Institute of Pathology, Medical University of Graz, Graz, Austria.,Department of Pathology, Medical Faculty, Otto-von-Guericke University Magdeburg, Magdeburg, Germany.,Department of Pathology, Neuropathology, and Molecular Pathology, Medical University of Innsbruck, Innsbruck, Austria
| | - Alexander Wree
- Department of Internal Medicine III, University Hospital RWTH Aachen, Aachen, Germany
| | - Ulrike Rolle-Kampczyk
- Department of Molecular Systems Biology, Helmholtz Centre for Environmental Research, Leipzig, Germany
| | - Martin von Bergen
- Department of Molecular Systems Biology, Helmholtz Centre for Environmental Research, Leipzig, Germany
| | - Eicke Latz
- Institute for Innate Immunity, University Clinic Bonn, Bonn, Germany
| | - Peter Boor
- Institute of Pathology, RWTH Aachen University, Aachen, Germany.,Department of Nephrology and Immunology, RWTH Aachen University, Aachen, Germany
| | - Christian Trautwein
- Department of Internal Medicine III, University Hospital RWTH Aachen, Aachen, Germany
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Chen TT, Xiao F, Li N, Shan S, Qi M, Wang ZY, Zhang SN, Wei W, Sun WY. Inflammasome as an Effective Platform for Fibrosis Therapy. J Inflamm Res 2021; 14:1575-1590. [PMID: 33907438 PMCID: PMC8069677 DOI: 10.2147/jir.s304180] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2021] [Accepted: 03/19/2021] [Indexed: 12/11/2022] Open
Abstract
Fibrosis is the final stage of the development of chronic inflammation. It is characterized by excessive deposition of the extracellular matrix, leading to tissue structure damage and organ dysfunction, which is a serious threat to human health and life. However, the molecular mechanism of fibrosis is still unclear. Inflammasome is a molecular complex of proteins that has been becoming a key innate sensor for host immunity and is involved in pyroptosis, pathogen infection, metabolic syndrome, cellular stress, and tumor metastasis. Inflammasome signaling and downstream cytokine responses mediated by the inflammasome have been found to play an important role in fibrosis. The inflammasome regulates the secretion of IL-1β and IL-18, which are both critical for the process of fibrosis. Recently, researches on the function of inflammasome have attracted extensive attention, and data derived from these researches have increased our understanding of the effects and regulation of inflammasome during fibrosis. In this review, we emphasize the growing evidence for both indirect and direct effects of inflammasomes in triggering fibrosis as well as potential novel targets for antifibrotic therapies.
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Affiliation(s)
- Ting-Ting Chen
- Institute of Clinical Pharmacology, Anhui Medical University, Key Laboratory of Anti-Inflammatory and Immune Medicine, Ministry of Education, Anhui Collaborative Innovation Center of Anti-Inflammatory and Immune Medicine, Hefei, Anhui Province, 230032, People's Republic of China
| | - Feng Xiao
- Institute of Clinical Pharmacology, Anhui Medical University, Key Laboratory of Anti-Inflammatory and Immune Medicine, Ministry of Education, Anhui Collaborative Innovation Center of Anti-Inflammatory and Immune Medicine, Hefei, Anhui Province, 230032, People's Republic of China
| | - Nan Li
- Institute of Clinical Pharmacology, Anhui Medical University, Key Laboratory of Anti-Inflammatory and Immune Medicine, Ministry of Education, Anhui Collaborative Innovation Center of Anti-Inflammatory and Immune Medicine, Hefei, Anhui Province, 230032, People's Republic of China
| | - Shan Shan
- Institute of Clinical Pharmacology, Anhui Medical University, Key Laboratory of Anti-Inflammatory and Immune Medicine, Ministry of Education, Anhui Collaborative Innovation Center of Anti-Inflammatory and Immune Medicine, Hefei, Anhui Province, 230032, People's Republic of China
| | - Meng Qi
- Institute of Clinical Pharmacology, Anhui Medical University, Key Laboratory of Anti-Inflammatory and Immune Medicine, Ministry of Education, Anhui Collaborative Innovation Center of Anti-Inflammatory and Immune Medicine, Hefei, Anhui Province, 230032, People's Republic of China
| | - Zi-Ying Wang
- Institute of Clinical Pharmacology, Anhui Medical University, Key Laboratory of Anti-Inflammatory and Immune Medicine, Ministry of Education, Anhui Collaborative Innovation Center of Anti-Inflammatory and Immune Medicine, Hefei, Anhui Province, 230032, People's Republic of China
| | - Sheng-Nan Zhang
- Institute of Clinical Pharmacology, Anhui Medical University, Key Laboratory of Anti-Inflammatory and Immune Medicine, Ministry of Education, Anhui Collaborative Innovation Center of Anti-Inflammatory and Immune Medicine, Hefei, Anhui Province, 230032, People's Republic of China
| | - Wei Wei
- Institute of Clinical Pharmacology, Anhui Medical University, Key Laboratory of Anti-Inflammatory and Immune Medicine, Ministry of Education, Anhui Collaborative Innovation Center of Anti-Inflammatory and Immune Medicine, Hefei, Anhui Province, 230032, People's Republic of China
| | - Wu-Yi Sun
- Institute of Clinical Pharmacology, Anhui Medical University, Key Laboratory of Anti-Inflammatory and Immune Medicine, Ministry of Education, Anhui Collaborative Innovation Center of Anti-Inflammatory and Immune Medicine, Hefei, Anhui Province, 230032, People's Republic of China
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Hou L, Zhang Z, Yang L, Chang N, Zhao X, Zhou X, Yang L, Li L. NLRP3 inflammasome priming and activation in cholestatic liver injury via the sphingosine 1-phosphate/S1P receptor 2/Gα (12/13)/MAPK signaling pathway. J Mol Med (Berl) 2021; 99:273-288. [PMID: 33388881 DOI: 10.1007/s00109-020-02032-4] [Citation(s) in RCA: 34] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2020] [Revised: 12/04/2020] [Accepted: 12/23/2020] [Indexed: 12/19/2022]
Abstract
NLRP3 inflammasome-driven inflammation represents a key trigger for hepatic fibrogenesis during cholestatic liver injury. However, whether sphingosine 1-phosphate (S1P) plays a role in NLRP3 inflammasome priming and activation remains unknown. Here, we found that the expression of NLRP3 in macrophages and NLRP3 inflammasome activation were significantly elevated in the liver injured by bile duct ligation (BDL). In vitro, S1P promoted the NLRP3 inflammasome priming and activation via S1P receptor 2 (S1PR2) in bone marrow-derived monocyte/macrophages (BMMs). Focusing on BMMs, the gene silencing of Gα12 or Gα13 by specific siRNA suppressed NLRP3 inflammasome priming and pro-inflammatory cytokine (IL-1β and IL-18) secretion, whereas Gα(i/o) and Gαq were not involved in this process. The MAPK signaling pathways (P38, ERK, and JNK) mediated NLRP3 inflammasome priming and IL-1β and IL-18 secretion, whereas blockage of PI3K, ROCK, and Rho family had no such effect. Moreover, JTE-013 (S1PR2 inhibitor) treatment markedly reduced NLRP3 inflammasome priming and activation in BDL-injured liver. Collectively, S1P promotes NLRP3 inflammasome priming and pro-inflammatory cytokines (IL-1β and IL-18) secretion via the S1PR2/Gα(12/13)/MAPK pathway, which may represent an effective therapeutic strategy for liver disease. KEY MESSAGE: • Hepatic NLRP3 expression was significantly elevated in BMMs of BDL-injured mouse liver. • S1P promoted NLRP3 inflammasome priming and activation in BMMs, depending on the S1PR2/Gα(12/13)/MAPK pathway. • Blockade of S1PR2 by JTE-013 reduced NLRP3 inflammasome priming and activation inflammasome in vivo.
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Affiliation(s)
- Lei Hou
- Department of Cell Biology, Municipal Laboratory for Liver Protection and Regulation of Regeneration, Capital Medical University, Beijing, 100069, China
| | - Zhi Zhang
- Department of Cell Biology, Municipal Laboratory for Liver Protection and Regulation of Regeneration, Capital Medical University, Beijing, 100069, China
| | - Le Yang
- Department of Cell Biology, Municipal Laboratory for Liver Protection and Regulation of Regeneration, Capital Medical University, Beijing, 100069, China
| | - Na Chang
- Department of Cell Biology, Municipal Laboratory for Liver Protection and Regulation of Regeneration, Capital Medical University, Beijing, 100069, China
| | - Xinhao Zhao
- Department of Cell Biology, Municipal Laboratory for Liver Protection and Regulation of Regeneration, Capital Medical University, Beijing, 100069, China
| | - Xuan Zhou
- Department of Cell Biology, Municipal Laboratory for Liver Protection and Regulation of Regeneration, Capital Medical University, Beijing, 100069, China
| | - Lin Yang
- Department of Cell Biology, Municipal Laboratory for Liver Protection and Regulation of Regeneration, Capital Medical University, Beijing, 100069, China
| | - Liying Li
- Department of Cell Biology, Municipal Laboratory for Liver Protection and Regulation of Regeneration, Capital Medical University, Beijing, 100069, China.
- , Beijing, China.
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De Smedt J, van Os EA, Talon I, Ghosh S, Toprakhisar B, Furtado Madeiro Da Costa R, Zaunz S, Vazquez MA, Boon R, Baatsen P, Smout A, Verhulst S, van Grunsven LA, Verfaillie CM. PU.1 drives specification of pluripotent stem cell-derived endothelial cells to LSEC-like cells. Cell Death Dis 2021; 12:84. [PMID: 33446637 PMCID: PMC7809369 DOI: 10.1038/s41419-020-03356-2] [Citation(s) in RCA: 24] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2020] [Revised: 12/02/2020] [Accepted: 12/07/2020] [Indexed: 12/25/2022]
Abstract
To date, there is no representative in vitro model for liver sinusoidal endothelial cells (LSECs), as primary LSECs dedifferentiate very fast in culture and no combination of cytokines or growth factors can induce an LSEC fate in (pluripotent stem cell (PSC)-derived) endothelial cells (ECs). Furthermore, the transcriptional programmes driving an LSEC fate have not yet been described. Here, we first present a computational workflow (CenTFinder) that can identify transcription factors (TFs) that are crucial for modulating pathways involved in cell lineage specification. Using CenTFinder, we identified several novel LSEC-specific protein markers, such as FCN2 and FCN3, which were validated by analysis of previously published single-cell RNAseq data. We also identified PU.1 (encoded by the SPI1 gene) as a major regulator of LSEC-specific immune functions. We show that SPI1 overexpression (combined with the general EC TF ETV2) in human PSCs induces ECs with an LSEC-like phenotype. The ETV2-SPI1-ECs display increased expression of LSEC markers, such as CD32B and MRC1, as well as several of the proposed novel markers. More importantly, ETV2-SPI1-ECs acquire LSEC functions, including uptake of FSA-FITC, as well as labelled IgG. In conclusion, we present the CenTFinder computational tool to identify key regulatory TFs within specific pathways, in this work pathways of lineage specification, and we demonstrate its use by the identification and validation of PU.1 as a master regulator for LSEC fating.
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Affiliation(s)
- Jonathan De Smedt
- Department of Development and Regeneration, Stem Cell Institute, KU Leuven, Leuven, Belgium.
| | - Elise Anne van Os
- Liver Cell Biology research group, Vrije Universiteit Brussel (VUB), Brussels, Belgium
| | - Irene Talon
- Department of Development and Regeneration, Stem Cell Institute, KU Leuven, Leuven, Belgium
| | - Sreya Ghosh
- Department of Development and Regeneration, Stem Cell Institute, KU Leuven, Leuven, Belgium
| | - Burak Toprakhisar
- Department of Development and Regeneration, Stem Cell Institute, KU Leuven, Leuven, Belgium
| | | | - Samantha Zaunz
- Department of Development and Regeneration, Stem Cell Institute, KU Leuven, Leuven, Belgium
| | - Marta Aguirre Vazquez
- Department of Development and Regeneration, Stem Cell Institute, KU Leuven, Leuven, Belgium
| | - Ruben Boon
- The Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, MA, 02114, USA.,The Broad Institute of Harvard and MIT, Cambridge, MA, 02142, USA
| | - Pieter Baatsen
- Electron Microscopy Platform of VIB Bio Imaging Core at KU Leuven and VIB-KU Leuven Center for Brain & Disease Research, Leuven, Belgium
| | - Ayla Smout
- Liver Cell Biology research group, Vrije Universiteit Brussel (VUB), Brussels, Belgium
| | - Stefaan Verhulst
- Liver Cell Biology research group, Vrije Universiteit Brussel (VUB), Brussels, Belgium
| | - Leo A van Grunsven
- Liver Cell Biology research group, Vrije Universiteit Brussel (VUB), Brussels, Belgium
| | - Catherine M Verfaillie
- Department of Development and Regeneration, Stem Cell Institute, KU Leuven, Leuven, Belgium.
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Shiri A, Sarvari J, Firoozi Ghahestani S, Gholijani N, Tamaddon AM, Rastegari M, Moattari A, Hosseini SY. The Inflammatory and Fibrotic Patterns of Hepatic Stellate Cells Following Coagulation Factors (VII or X)-Shielded Adenovirus Infection. Curr Microbiol 2021; 78:718-726. [PMID: 33410956 DOI: 10.1007/s00284-020-02297-5] [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: 03/07/2020] [Accepted: 11/13/2020] [Indexed: 12/13/2022]
Abstract
The role of coagulation factors on the inflammatory effect of adenovirus (Ad) is an unresolved question that was considered herein. Adenovirus-36(Ad36) and adenovector-5-GFP(Ad5-GFP) were prepared; then, they were loaded with VII or FX factors. The size/charge parameters and transduction efficiency were evaluated using fluorescent microscopy and Zetasizer, respectively. The Ad36-coagulation factor complexes were added on the stellate cells, LX-2. Thereafter, the expression levels of inflammatory and fibrotic genes including PKR, IL-1β, TNF-α, TIMP-1, collagen, and TGF-β were measured by qPCR and ELISA assays. The loading of FVII or FX factors not only increased the size/charge of Ad5-GFP but also enhanced the transduction rate up to 60% and 75%, respectively, compared to the controls (45%). The PKR expression analysis showed an upregulation following treatment with all Ad36 forms (P = 0.0152). The IL-1β and TNF-α cytokines analyses demonstrated that the Ad36-FVII complex elicited the highest inflammatory response (P = 0.05). Similarly, the fibrosis-related expression analysis revealed a more inductive role of FVII when loaded on Ad36, compared to the FX factor. The findings suggested that adenovirus elicited the innate inflammatory and activation state in the hepatic stellate cell. In addition, adenovirus shielded by FVII exhibited more innate inflammation as well as activation of the stellate cells than the FX-loaded virus.
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Affiliation(s)
- Alireza Shiri
- Department of Bacteriology and Virology, School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Jamal Sarvari
- Department of Bacteriology and Virology, School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran.,GastroenteroHepatology Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Saeed Firoozi Ghahestani
- Department of Bacteriology and Virology, School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Nasser Gholijani
- Autoimmunity Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Ali Mohammad Tamaddon
- Pharmaceutics Department, School of Pharmacy, Shiraz University of Medical Sciences, Shiraz, Iran.,Center for Nanotechnology in Drug Delivery, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Mahroo Rastegari
- Department of Bacteriology and Virology, School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Afagh Moattari
- Department of Bacteriology and Virology, School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran.
| | - Seyed Younes Hosseini
- Department of Bacteriology and Virology, School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran.
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Zhang L, Zeyu W, Liu B, Jang S, Zhang Z, Jiang Y. Pyroptosis in liver disease. REVISTA ESPANOLA DE ENFERMEDADES DIGESTIVAS 2020; 113:280-285. [PMID: 33233902 DOI: 10.17235/reed.2020.7034/2020] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/20/2022]
Abstract
Pyroptosis is an inflammatory cell death process that is dependent on caspase. Pyroptosis is a specific form of programmed cell death with the morphological characteristics of formation of pores on the cell membrane, cell swelling, and rupture of the plasma membrane. Recent studies have demonstrated that pyroptosis plays an important role in the occurrence and development of liver diseases. Here, we focus on the mechanisms of pyroptosis, as well as on the relationship between pyroptosis and liver diseases.
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Affiliation(s)
- Lijuan Zhang
- Gastroenterology, Wuxi Number Nine People's Hospital Affiliated to Soochow University
| | - Wang Zeyu
- Liver Cancer Center, Key Laboratory of Cancer Prevention and Therapy. Tianjin Medical University Cancer Institute and Hos
| | - Binghua Liu
- Gastroenterology, The Second Hospital of Tianjin Medical University
| | | | - Zhiguang Zhang
- Gastroenterology, The Second Hospital of Tianjin Medical University
| | - Yong Jiang
- Gastroenterology, The Second Hospital of Tianjin Medical University, CHINA
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45
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The Gut Microbiota: How Does It Influence the Development and Progression of Liver Diseases. Biomedicines 2020; 8:biomedicines8110501. [PMID: 33207562 PMCID: PMC7697996 DOI: 10.3390/biomedicines8110501] [Citation(s) in RCA: 23] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2020] [Revised: 11/06/2020] [Accepted: 11/13/2020] [Indexed: 02/07/2023] Open
Abstract
The gut–liver axis plays important roles in both the maintenance of a healthy liver and the pathogenesis of liver diseases, where the gut microbiota acts as a major determinant of this relationship. Gut bacteria-derived metabolites and cellular components are key molecules that affect the function of the liver and modulate the pathology of liver diseases. Accumulating evidence showed that gut microbiota produces a myriad of molecules, including lipopolysaccharide, lipoteichoic acid, peptidoglycan, and DNA, as well as short-chain fatty acids, bile acids, trimethylamine, and indole derivatives. The translocation of these components to the liver exerts beneficial or pathogenic effects by interacting with liver immune cells. This is a bidirectional relationship. Therefore, the existence of crosstalk between the gut and liver and its implications on host health and diseases are essential for the etiology and treatment of diseases. Several mechanisms have been proposed for the pathogenesis of liver diseases, but still, the mechanisms behind the pathogenic role of gut-derived components on liver pathogenesis remain elusive and not understandable. This review discusses the current progress on the gut microbiota and its components in terms of the progression of liver diseases, and in turn, how liver diseases indirectly affect the intestinal function and induce intestinal inflammation. Moreover, this paper highlights the current therapeutic and preventive strategies used to restore the gut microbiota composition and improve host health.
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46
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Stimulation of soluble guanylate cyclase exerts antiinflammatory actions in the liver through a VASP/NF-κB/NLRP3 inflammasome circuit. Proc Natl Acad Sci U S A 2020; 117:28263-28274. [PMID: 33106416 PMCID: PMC7668051 DOI: 10.1073/pnas.2000466117] [Citation(s) in RCA: 38] [Impact Index Per Article: 7.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022] Open
Abstract
Fatty liver, which is an initial step in the development of more severe complications such as liver cirrhosis, is prevalent worldwide in our society. This study demonstrates that stimulation of soluble guanylate cyclase (sGC), an enzyme producing the second messenger cGMP, protects against the most common features of fatty liver, namely inflammation and fibrosis, in animal models of the disease. Our study also provides an explanation for this protection and describes how sGC stimulation blocks the inflammasome (a protein complex responsible for the production of the potent proinflammatory cytokine interleukin-1β) in liver macrophages. The results of this study support the investigation of sGC stimulators, which are already approved for treatment in other conditions, in patients with fatty liver disease. Soluble guanylate cyclase (sGC) catalyzes the conversion of guanosine triphosphate into cyclic guanosine-3′,5′-monophosphate, a key second messenger in cell signaling and tissue homeostasis. It was recently demonstrated that sGC stimulation is associated with a marked antiinflammatory effect in the liver of mice with experimental nonalcoholic steatohepatitis (NASH). Here, we investigated the mechanisms underlying the antiinflammatory effect of the sGC stimulator praliciguat (PRL) in the liver. Therapeutic administration of PRL exerted antiinflammatory and antifibrotic actions in mice with choline-deficient l-amino acid-defined high-fat diet-induced NASH. The PRL antiinflammatory effect was associated with lower F4/80- and CX3CR1-positive macrophage infiltration into the liver in parallel with lower Ly6CHigh- and higher Ly6CLow-expressing monocytes in peripheral circulation. The PRL antiinflammatory effect was also associated with suppression of hepatic levels of interleukin (IL)-1β, NLPR3 (NACHT, LRR, and PYD domain-containing protein 3), ASC (apoptosis-associated speck-like protein containing a caspase-recruitment domain), and active cleaved-caspase-1, which are components of the NLRP3 inflammasome. In Kupffer cells challenged with the classical inflammasome model of lipopolysaccharide plus adenosine triphosphate, PRL inhibited the priming (expression of Il1b and Nlrp3) and blocked the release of mature IL-1β. Mechanistically, PRL induced the protein kinase G (PKG)-mediated phosphorylation of the VASP (vasodilator-stimulated phosphoprotein) Ser239 residue which, in turn, reduced nuclear factor-κB (NF-κB) activity and Il1b and Nlrp3 gene transcription. PRL also reduced active cleaved-caspase-1 levels independent of pannexin-1 activity. These data indicate that sGC stimulation with PRL exerts antiinflammatory actions in the liver through mechanisms related to a PKG/VASP/NF-κB/NLRP3 inflammasome circuit.
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47
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Shatoor AS, Al Humayed S. The Protective Effect of Crataegus aronia Against High-Fat Diet-Induced Vascular Inflammation in Rats Entails Inhibition of the NLRP-3 Inflammasome Pathway. Cardiovasc Toxicol 2020; 20:82-99. [PMID: 31183600 DOI: 10.1007/s12012-019-09534-9] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/12/2023]
Abstract
This study investigated whether the whole-plant aqueous extract of Crataegus aronia (C. aronia) could protect against or alleviate high-fat diet (HFD)-induced aortic vascular inflammation in rats by inhibiting the NLRP-3 inflammasome pathway and examined some mechanisms of action with respect to its antioxidant and hypolipidemic effects. Adult male Wistar rats were divided into five groups (n = 6/each): standard diet (10% fat) fed to control rats, control + C. aronia (200 mg/kg), HFD (40% fat), HFD + C. aronia, and HFD post-treated with C. aronia. The HFD was fed for 8 weeks and C. aronia was administered orally for 4 weeks. In addition, isolated macrophages from control rats were pre-incubated with two doses of C. aronia (25 and 50 μg/mL) with or without lipopolysaccharide (LPS) stimulation. Only in HFD-fed rats, co- and post-C. aronia therapy lowered circulatory levels of LDL-C and ox-LDL-c and aortic protein levels of LOX-1 and CD36. C. aronia also inhibited the nuclear accumulation of NF-κB and lowered protein levels of NLRP-3, caspase-1, and mature IL-1β. In vitro, in the absence of ox-LDL-c, C. aronia led to reduced nuclear levels of NF-κB, ROS generation, and protein NLRP-3 levels, in both LPS-stimulated and unstimulated macrophages, in a dose-dependent manner. However, protein levels of LOX-1 were not affected by C. aronia in unstimulated cells. In conclusion, C. aronia inhibits the NLRP-3 inflammasome pathway, induced by HFD feeding in the aorta of rats, mainly by its hypolipidemic effect and in vitro, in LPS-stimulated macrophages, by its antioxidant effect.
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Affiliation(s)
- Abdullah S Shatoor
- Department of Medicine, Cardiology Section, College of Medicine, King Khalid University, Abha, 61421, Saudi Arabia.
| | - Suliman Al Humayed
- Department of Medicine, College of Medicine, King Khalid University, Abha, 61421, Saudi Arabia
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Yan H, Zhong M, Yang J, Guo J, Yu J, Yang Y, Ma Z, Zhao B, Zhang Y, Wang J, Wu C, Dittmer U, Yang D, Lu M, Zhang E, Yan H. TLR5 activation in hepatocytes alleviates the functional suppression of intrahepatic CD8 + T cells. Immunology 2020; 161:325-344. [PMID: 32852795 DOI: 10.1111/imm.13251] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/21/2020] [Revised: 08/04/2020] [Accepted: 08/17/2020] [Indexed: 12/12/2022] Open
Abstract
The liver is an immune-privileged organ with a tolerogenic environment for maintaining liver homeostasis. This hepatic tolerance limits the intrahepatic CD8+ T-cell response for eliminating infections. The tolerant microenvironment in the liver is orchestrated by liver-specific immunoregulatory cells that can be functionally regulated by pathogen-associated molecular patterns (PAMPs). Here, we report that flagellin, a key PAMP of gut bacteria, modulates the intrahepatic CD8+ T-cell response by activating the TLR5 signalling pathway of hepatocytes. We found that mice treated with Salmonella-derived recombinant flagellin (SF) by hydrodynamic injection had a significantly elevated IFN-γ production by the intrahepatic lymphocytes in 7 days after injection. This was correlated with a reduced immune suppressive effect of primary mouse hepatocytes (PMHs) in comparison with that of PMHs from mock-injected control mice. In vitro co-culture of SF-treated PMHs with splenocytes revealed that hepatocyte-induced immune suppression is alleviated through activation of the TLR5 but not the NLRC4 signalling pathway, leading to improved activation and function of CD8+ T cells during anti-CD3 stimulation or antigen-specific activation. In an acute HBV replication mouse model established by co-administration of SF together with an HBV-replicating plasmid by hydrodynamic injection, SF significantly enhanced the intrahepatic HBV-specific CD8+ T-cell response against HBV surface antigen. Our results clearly showed that flagellin plays a role in modulating the intrahepatic CD8+ T-cell response by activating the TLR5 pathway in PMHs, which suggests a potential role for gut bacteria in regulating liver immunity.
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Affiliation(s)
- Hu Yan
- Mucosal Immunity Research Group, State Key Laboratory of Virology, Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan, China.,University of Chinese Academy of Sciences, Beijing, China
| | - Maohua Zhong
- Mucosal Immunity Research Group, State Key Laboratory of Virology, Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan, China
| | - Jingyi Yang
- Mucosal Immunity Research Group, State Key Laboratory of Virology, Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan, China
| | - Jiabao Guo
- Mucosal Immunity Research Group, State Key Laboratory of Virology, Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan, China.,University of Chinese Academy of Sciences, Beijing, China
| | - Jie Yu
- Mucosal Immunity Research Group, State Key Laboratory of Virology, Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan, China.,University of Chinese Academy of Sciences, Beijing, China
| | - Yi Yang
- Mucosal Immunity Research Group, State Key Laboratory of Virology, Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan, China.,University of Chinese Academy of Sciences, Beijing, China
| | - Zhiyong Ma
- Department of Infectious Diseases, Zhongnan Hospital of Wuhan University, Wuhan, China
| | - Bali Zhao
- Mucosal Immunity Research Group, State Key Laboratory of Virology, Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan, China.,University of Chinese Academy of Sciences, Beijing, China
| | - Yue Zhang
- Mucosal Immunity Research Group, State Key Laboratory of Virology, Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan, China.,University of Chinese Academy of Sciences, Beijing, China
| | - Junzhong Wang
- Department of Infectious Diseases, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Chunchen Wu
- State Key Laboratory of Virology, Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan, China
| | - Ulf Dittmer
- Institute for Virology, University Hospital Essen, University of Duisburg-Essen, Essen, Germany
| | - Dongliang Yang
- Department of Infectious Diseases, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Mengji Lu
- Institute for Virology, University Hospital Essen, University of Duisburg-Essen, Essen, Germany
| | - Ejuan Zhang
- Mucosal Immunity Research Group, State Key Laboratory of Virology, Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan, China
| | - Huimin Yan
- Mucosal Immunity Research Group, State Key Laboratory of Virology, Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan, China.,University of Chinese Academy of Sciences, Beijing, China
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49
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Wilkinson AL, Qurashi M, Shetty S. The Role of Sinusoidal Endothelial Cells in the Axis of Inflammation and Cancer Within the Liver. Front Physiol 2020; 11:990. [PMID: 32982772 PMCID: PMC7485256 DOI: 10.3389/fphys.2020.00990] [Citation(s) in RCA: 79] [Impact Index Per Article: 15.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/04/2020] [Accepted: 07/20/2020] [Indexed: 12/12/2022] Open
Abstract
Liver sinusoidal endothelial cells (LSEC) form a unique barrier between the liver sinusoids and the underlying parenchyma, and thus play a crucial role in maintaining metabolic and immune homeostasis, as well as actively contributing to disease pathophysiology. Whilst their endocytic and scavenging function is integral for nutrient exchange and clearance of waste products, their capillarisation and dysfunction precedes fibrogenesis. Furthermore, their ability to promote immune tolerance and recruit distinct immunosuppressive leukocyte subsets can allow persistence of chronic viral infections and facilitate tumour development. In this review, we present the immunological and barrier functions of LSEC, along with their role in orchestrating fibrotic processes which precede tumourigenesis. We also summarise the role of LSEC in modulating the tumour microenvironment, and promoting development of a pre-metastatic niche, which can drive formation of secondary liver tumours. Finally, we summarise closely inter-linked disease pathways which collectively perpetuate pathogenesis, highlighting LSEC as novel targets for therapeutic intervention.
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Affiliation(s)
| | | | - Shishir Shetty
- Centre for Liver and Gastrointestinal Research, Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, United Kingdom
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Gautheron J, Gores GJ, Rodrigues CMP. Lytic cell death in metabolic liver disease. J Hepatol 2020; 73:394-408. [PMID: 32298766 PMCID: PMC7371520 DOI: 10.1016/j.jhep.2020.04.001] [Citation(s) in RCA: 152] [Impact Index Per Article: 30.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/05/2020] [Revised: 03/02/2020] [Accepted: 04/01/2020] [Indexed: 12/11/2022]
Abstract
Regulated cell death is intrinsically associated with inflammatory liver disease and is pivotal in governing outcomes of metabolic liver disease. Different types of cell death may coexist as metabolic liver disease progresses to inflammation, fibrosis, and ultimately cirrhosis. In addition to apoptosis, lytic forms of hepatocellular death, such as necroptosis, pyroptosis and ferroptosis elicit strong inflammatory responses due to cell membrane permeabilisation and release of cellular components, contributing to the recruitment of immune cells and activation of hepatic stellate cells. The control of liver cell death is of fundamental importance and presents novel opportunities for potential therapeutic intervention. This review summarises the underlying mechanism of distinct lytic cell death modes and their commonalities, discusses their relevance to metabolic liver diseases of different aetiologies, and acknowledges the limitations of current knowledge in the field. We focus on the role of hepatocyte necroptosis, pyroptosis and ferroptosis in non-alcoholic fatty liver disease, alcohol-associated liver disease and other metabolic liver disorders, as well as potential therapeutic implications.
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Affiliation(s)
- Jérémie Gautheron
- Sorbonne Université, Inserm, Centre de Recherche Saint-Antoine (CRSA), Paris, France; Institute of Cardiometabolism and Nutrition (ICAN), Paris, France
| | - Gregory J Gores
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN, USA
| | - Cecília M P Rodrigues
- Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, Universidade de Lisboa, Lisbon, Portugal.
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