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1
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Butt FA, De Simone A, Di Talia S, Poss KD. In toto live imaging of Erk signaling dynamics in developing zebrafish hepatocytes. Dev Biol 2025; 523:43-50. [PMID: 40228782 PMCID: PMC12068954 DOI: 10.1016/j.ydbio.2025.04.009] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2024] [Revised: 04/08/2025] [Accepted: 04/11/2025] [Indexed: 04/16/2025]
Abstract
Regional and tissue-wide regulation of signaling pathways orchestrates cellular proliferation and differentiation during organ development. In this study, we established an imaging platform for longitudinal analysis of liver development in live developing zebrafish. We generated hepatocyte-specific transgenic lines for kinase translocation reporters of extracellular signal-regulated kinase (Erk) and c-Jun N-terminal kinase (Jnk) signaling, and with these we captured signaling dynamics that govern rapid expansion of hepatocytes toward creation of the functioning liver at single-cell resolution. Our findings reveal Erk signaling fluctuations as the liver develops and introduce methodology for investigating cell-type specific signaling dynamics during organ morphogenesis.
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Affiliation(s)
- Faraz Ahmed Butt
- Duke Regeneration Center and Department of Cell Biology, Duke University Medical Center, Durham, NC, 27710, USA
| | - Alessandro De Simone
- Department of Genetics and Evolution, University of Geneva, 1211, Geneva, Switzerland
| | - Stefano Di Talia
- Duke Regeneration Center and Department of Cell Biology, Duke University Medical Center, Durham, NC, 27710, USA; Duke Center for Quantitative Living Systems, Duke University Medical Center, Durham, NC, 27710, USA
| | - Kenneth D Poss
- Duke Regeneration Center and Department of Cell Biology, Duke University Medical Center, Durham, NC, 27710, USA; Morgridge Institute for Research, Madison, WI, 53715, USA; Department of Cell and Regenerative Biology, University of Wisconsin, Madison, WI, 53705, USA.
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2
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Cao P, Jaeschke H, Ni HM, Ding WX. The Ways to Die: Cell Death in Liver Pathophysiology. Semin Liver Dis 2025. [PMID: 40199509 DOI: 10.1055/a-2576-4332] [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: 04/10/2025]
Abstract
Liver diseases are closely associated with various cell death mechanisms, including apoptosis, necroptosis, autophagy, pyroptosis, and ferroptosis. Each process contributes uniquely to the pathophysiology of liver injury and repair. Importantly, these mechanisms are not limited to hepatocytes; they also significantly involve nonparenchymal cells. This review examines the molecular pathways and regulatory mechanisms underlying these forms of cell death in hepatocytes, emphasizing their roles in several liver diseases, such as ischemia-reperfusion injury, metabolic dysfunction-associated steatotic liver disease, drug-induced liver injury, and alcohol-associated liver disease. Recent insights into ferroptosis and pyroptosis may reveal novel therapeutic targets for managing liver diseases. This review aims to provide a comprehensive overview of these cell death mechanisms in the context of liver diseases, detailing their molecular signaling pathways and implications for potential treatment strategies.
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Affiliation(s)
- Peng Cao
- Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City, Kansas
| | - Hartmut Jaeschke
- Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City, Kansas
| | - Hong-Min Ni
- Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City, Kansas
| | - Wen-Xing Ding
- Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City, Kansas
- Division of Gastroenterology, Hepatology and Mobility, Department of Internal Medicine, University of Kansas Medical Center, Kansas City, Kansas
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3
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Jin Y, Yuan H, Liu Y, Zhu Y, Wang Y, Liang X, Gao W, Ren Z, Ji X, Wu D. Role of hydrogen sulfide in health and disease. MedComm (Beijing) 2024; 5:e661. [PMID: 39156767 PMCID: PMC11329756 DOI: 10.1002/mco2.661] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2023] [Revised: 06/24/2024] [Accepted: 06/26/2024] [Indexed: 08/20/2024] Open
Abstract
In the past, hydrogen sulfide (H2S) was recognized as a toxic and dangerous gas; in recent years, with increased research, we have discovered that H2S can act as an endogenous regulatory transmitter. In mammals, H2S-catalyzing enzymes, such as cystathionine-β-synthase, cystathionine-γ-lyase, and 3-mercaptopyruvate sulfurtransferase, are differentially expressed in a variety of tissues and affect a variety of biological functions, such as transcriptional and posttranslational modification of genes, activation of signaling pathways in the cell, and metabolic processes in tissues, by producing H2S. Various preclinical studies have shown that H2S affects physiological and pathological processes in the body. However, a detailed systematic summary of these roles in health and disease is lacking. Therefore, this review provides a thorough overview of the physiological roles of H2S in different systems and the diseases associated with disorders of H2S metabolism, such as ischemia-reperfusion injury, hypertension, neurodegenerative diseases, inflammatory bowel disease, and cancer. Meanwhile, this paper also introduces H2S donors and novel release modes, as well as the latest preclinical experimental results, aiming to provide researchers with new ideas to discover new diagnostic targets and therapeutic options.
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Affiliation(s)
- Yu‐Qing Jin
- Henan International Joint Laboratory for Nuclear Protein RegulationSchool of Basic Medical Sciences, School of StomatologyHenan UniversityKaifengHenanChina
| | - Hang Yuan
- Henan International Joint Laboratory for Nuclear Protein RegulationSchool of Basic Medical Sciences, School of StomatologyHenan UniversityKaifengHenanChina
| | - Ya‐Fang Liu
- Henan International Joint Laboratory for Nuclear Protein RegulationSchool of Basic Medical Sciences, School of StomatologyHenan UniversityKaifengHenanChina
| | - Yi‐Wen Zhu
- School of Clinical MedicineHenan UniversityKaifengHenanChina
| | - Yan Wang
- Henan International Joint Laboratory for Nuclear Protein RegulationSchool of Basic Medical Sciences, School of StomatologyHenan UniversityKaifengHenanChina
| | - Xiao‐Yi Liang
- Henan International Joint Laboratory for Nuclear Protein RegulationSchool of Basic Medical Sciences, School of StomatologyHenan UniversityKaifengHenanChina
| | - Wei Gao
- Henan International Joint Laboratory for Nuclear Protein RegulationSchool of Basic Medical Sciences, School of StomatologyHenan UniversityKaifengHenanChina
| | - Zhi‐Guang Ren
- Henan International Joint Laboratory for Nuclear Protein RegulationSchool of Basic Medical Sciences, School of StomatologyHenan UniversityKaifengHenanChina
| | - Xin‐Ying Ji
- Henan International Joint Laboratory for Nuclear Protein RegulationSchool of Basic Medical Sciences, School of StomatologyHenan UniversityKaifengHenanChina
- Faculty of Basic Medical SubjectsShu‐Qing Medical College of ZhengzhouZhengzhouHenanChina
| | - Dong‐Dong Wu
- Henan International Joint Laboratory for Nuclear Protein RegulationSchool of Basic Medical Sciences, School of StomatologyHenan UniversityKaifengHenanChina
- School of StomatologyHenan UniversityKaifengHenanChina
- Department of StomatologyHuaihe Hospital of Henan UniversityKaifengHenanChina
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Wang Z, Ge W, Zhong X, Tong S, Zheng S, Xu X, Wang K. Inhibition of cysteine-serine-rich nuclear protein 1 ameliorates ischemia-reperfusion injury during liver transplantation in an MAPK-dependent manner. MOLECULAR BIOMEDICINE 2024; 5:22. [PMID: 38902590 PMCID: PMC11189853 DOI: 10.1186/s43556-024-00185-z] [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: 02/23/2024] [Accepted: 04/29/2024] [Indexed: 06/22/2024] Open
Abstract
Hepatic ischemia-reperfusion injury (HIRI) is a critical pathophysiological process during liver transplantation (LT). Multiple genes and signal pathways are dysregulated during HIRI. This study aims to identify genes as potential therapeutic targets for ameliorating HIRI. Datasets containing samples from the human donor liver (GSE151648) and mouse HIRI model (GSE117066) were analyzed to determine differentially expressed genes (DEGs). The selected DEGs were confirmed by real-time PCR and western blot in the hepatocyte hypoxia-reoxygenation (HR) model, mouse HIRI model, and human liver samples after transplantation. Genetic inhibition was used to further clarify the underlying mechanism of the gene in vitro and in vivo. Among the DEGs, CSRNP1 was significantly upregulated (|log FC|= 2.08, P < 0.001), and was positively correlated with the MAPK signal pathway (R = 0.67, P < 0.001). CSRNP1 inhibition by siRNA significantly suppressed apoptosis in the AML-12 cell line after HR (mean Annexin+ ratio = 60.62% vs 42.47%, P = 0.0019), but the protective effect was eliminated with an additional MAPK activator. Knocking down CSRNP1 gene expression by intravenous injection of AAV-shRNA markedly reduced liver injury in mouse HIRI model (ALT: AAV-NC vs AAV-shCsrnp1 = 26,673.5 ± 2761.2 vs 3839.7 ± 1432.8, P < 0.001; AST: AAV-NC vs AAV-shCsrnp1 = 8640.5 ± 1450.3 vs 1786.8 ± 518.3, P < 0.001). Liver-targeted delivery of siRNA by nanoparticles effectively inhibited intra-hepatic genetic expression of Csrnp1 and alleviated IRI by reducing tissue inflammation and hepatocyte apoptosis. Furthermore, CSRNP1 inhibition was associated with reduced activation of the MAPK pathway both in vitro and in vivo. In conclusion, our results demonstrated that CSRNP1 could be a potential therapeutic target to ameliorate HIRI in an MAPK-dependent manner.
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Affiliation(s)
- Zhoucheng Wang
- NHC Key Laboratory of Combined Multi-organ Transplantation, Hangzhou, 310003, Zhejiang, China
- Zhejiang University School of Medicine, Hangzhou, 310058, Zhejiang, China
| | - Wenwen Ge
- NHC Key Laboratory of Combined Multi-organ Transplantation, Hangzhou, 310003, Zhejiang, China
- Zhejiang University School of Medicine, Hangzhou, 310058, Zhejiang, China
| | - Xinyang Zhong
- NHC Key Laboratory of Combined Multi-organ Transplantation, Hangzhou, 310003, Zhejiang, China
- Zhejiang University School of Medicine, Hangzhou, 310058, Zhejiang, China
| | - Shizheng Tong
- The Fourth School of Clinical Medicine, Zhejiang Chinese Medical University, Hangzhou, 310053, Zhejiang, China
| | - Shusen Zheng
- NHC Key Laboratory of Combined Multi-organ Transplantation, Hangzhou, 310003, Zhejiang, China
- Department of Hepatobiliary and Pancreatic Surgery, Shulan Hospital of Hangzhou, Hangzhou, 310022, Zhejiang, China
| | - Xiao Xu
- NHC Key Laboratory of Combined Multi-organ Transplantation, Hangzhou, 310003, Zhejiang, China.
- Department of Hepatobiliary & Pancreatic Surgery and Minimally Invasive Surgery, Zhejiang Provincial People's Hospital (Affiliated People's Hospital), Hangzhou Medical College, Hangzhou, 310024, Zhejiang, China.
- Institute of Translational Medicine, Zhejiang University, Hangzhou, 310000, Zhejiang, China.
| | - Kai Wang
- Department of Hepatobiliary & Pancreatic Surgery and Minimally Invasive Surgery, Zhejiang Provincial People's Hospital (Affiliated People's Hospital), Hangzhou Medical College, Hangzhou, 310024, Zhejiang, China.
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5
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Groiss S, Viertler C, Kap M, Bernhardt G, Mischinger HJ, Sieuwerts A, Verhoef C, Riegman P, Kruhøffer M, Svec D, Sjöback SR, Becker KF, Zatloukal K. Inter-patient heterogeneity in the hepatic ischemia-reperfusion injury transcriptome: Implications for research and diagnostics. N Biotechnol 2024; 79:20-29. [PMID: 38072306 DOI: 10.1016/j.nbt.2023.12.001] [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: 09/14/2023] [Accepted: 12/07/2023] [Indexed: 01/16/2024]
Abstract
Cellular responses induced by surgical procedure or ischemia-reperfusion injury (IRI) may severely alter transcriptome profiles and complicate molecular diagnostics. To investigate this effect, we characterized such pre-analytical effects in 143 non-malignant liver samples obtained from 30 patients at different time points of ischemia during surgery from two individual cohorts treated either with the Pringle manoeuvre or total vascular exclusion. Transcriptomics profiles were analyzed by Affymetrix microarrays and expression of selected mRNAs was validated by RT-PCR. We found 179 mutually deregulated genes which point to elevated cytokine signaling with NFκB as a dominant pathway in ischemia responses. In contrast to ischemia, reperfusion induced pro-apoptotic and pro-inflammatory cascades involving TNF, NFκB and MAPK pathways. FOS and JUN were down-regulated in steatosis compared to their up-regulation in normal livers. Surprisingly, molecular signatures of underlying primary and secondary cancers were present in non-tumor tissue. The reported inter-patient variability might reflect differences in individual stress responses and impact of underlying disease conditions. Furthermore, we provide a set of 230 pre-analytically highly robust genes identified from histologically normal livers (<2% covariation across both cohorts) that might serve as reference genes and could be particularly suited for future diagnostic applications.
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Affiliation(s)
- Silvia Groiss
- Diagnostic & Research Institute of Pathology, Medical University of Graz, 8010 Graz, Austria
| | - Christian Viertler
- Diagnostic & Research Institute of Pathology, Medical University of Graz, 8010 Graz, Austria
| | - Marcel Kap
- Pathology Department, Erasmus University Medical Center, 3015CN Rotterdam, the Netherlands
| | - Gerwin Bernhardt
- Division of General Surgery, Department of Surgery, Medical University of Graz, 8010 Graz, Austria; Department of Orthopedics and Trauma Surgery, Medical University of Graz, 8010 Graz, Austria
| | - Hans-Jörg Mischinger
- Division of General Surgery, Department of Surgery, Medical University of Graz, 8010 Graz, Austria
| | - Anieta Sieuwerts
- Department of Medical Oncology, Erasmus MC Cancer Institute and Cancer Genomics Netherlands, Erasmus University Medical Center, 3015CN Rotterdam, the Netherlands
| | - Cees Verhoef
- Department of Surgical Oncology, Erasmus MC Cancer Institute, Erasmus University Medical Center, 3015CN Rotterdam, the Netherlands
| | - Peter Riegman
- Pathology Department, Erasmus University Medical Center, 3015CN Rotterdam, the Netherlands
| | | | - David Svec
- Laboratory of Gene Expression, Institute of Biotechnology CAS, 252 50 Vestec, Czech Republic
| | | | | | - Kurt Zatloukal
- Diagnostic & Research Institute of Pathology, Medical University of Graz, 8010 Graz, Austria.
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Deng Y, Luo H. The protective effects of phosphoserine aminotransferase 1 (PSAT1) against hepatic ischemia-reperfusion injury. J Cell Commun Signal 2023; 17:851-862. [PMID: 36745318 PMCID: PMC10409687 DOI: 10.1007/s12079-023-00727-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2022] [Accepted: 01/23/2023] [Indexed: 02/07/2023] Open
Abstract
Hepatic ischemia-reperfusion (I/R) injury is a severe clinical syndrome, causing a profound medical and socioeconomic burden worldwide. This study aimed to explore underlying biomarkers and treatment targets in the progression of hepatic I/R injury. We screened gene expression profiles of the hepatic I/R injury from the Gene Expression Omnibus (GEO) database, downloaded expression profiles data (GSE117066). Differentially expressed genes (DEGs) were identified through cluster of the PPI network, and enrichment pathways were conducted based on gene ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG) database. The bioinformatics analysis was used to identify biomarkers that alleviate hepatic I/R injury. Finally, the effects of hub gene were investigated by in vitro and in vivo experiments. A total of 162 DEGs (76 up-regulated and 86 down-regulated genes) were extracted between sham and I/R, and 248 DEGs (118 up-regulated and 130 down-regulated genes) were extracted between I/R and ischemic postconditioning (IPO). The cluster of the PPI network and maximal clique centrality (MCC) method of the common DEGs were performed to identify the phosphoserine aminotransferase 1 (PSAT1) as the potential gene for hepatic I/R injury. Then, the H-E, TUNEL and PCNA staining were indicated that the hepatic injury score was highest in I/R 6 h. The expression level of apoptosis-related proteins was consistent with the pathological results. Both gain- and loss-of-function assays demonstrated that hepatic I/R injury was alleviated by PSAT1. PSAT1 may play crucial roles in hepatic I/R injury and thus serves as a hub biomarker for hepatic I/R injury prognosis and individual-based treatment.
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Affiliation(s)
- Yinzhi Deng
- Department of Gastroenterology, Renmin Hospital of Wuhan University, Wuhan, 430060, Hubei Province, People's Republic of China
| | - Hesheng Luo
- Department of Gastroenterology, Renmin Hospital of Wuhan University, Wuhan, 430060, Hubei Province, People's Republic of China.
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7
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Hu H, Cheng X, Li F, Guan Z, Xu J, Wu D, Gao Y, Zhan X, Wang P, Zhou H, Rao Z, Cheng F. Defective efferocytosis by aged macrophages promotes STING signaling mediated inflammatory liver injury. Cell Death Discov 2023; 9:236. [PMID: 37422464 DOI: 10.1038/s41420-023-01497-9] [Citation(s) in RCA: 34] [Impact Index Per Article: 17.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2023] [Revised: 05/06/2023] [Accepted: 06/16/2023] [Indexed: 07/10/2023] Open
Abstract
Aged livers have shown aggravated liver ischemia and reperfusion (IR) injury. Timely efferocytosis of apoptotic cells is a key mechanism for avoiding excessive inflammation and tissue injury. Here, we investigated the alteration of efferocytosis by aged macrophages and its role in regulating macrophage STING (stimulator of interferon genes) signaling and liver IR injury. Aged and young mice were subjected to liver partial IR model. Liver injury and inflammation were measured. Efferocytosis by aged macrophages and the underlying regulatory mechanism were analyzed as well. Aged macrophages exhibited impaired efferocytosis with decreased MerTK (c-mer proto-oncogene tyrosine kinase) activation, which was reversed by treatment of the MerTK CRISPR activation plasmid. Increased MerTK cleavage by ADAM17 (a disintegrin and metalloproteinase 17) due to enhanced ROS (reactive oxygen species) levels contributed to defective efferocytosis by aged macrophages. MerTK activation by suppressing ADAM17 or ROS improved aged macrophage efferocytosis, leading to reduced inflammatory liver injury. Moreover, increased apoptotic hepatocytes, DNA accumulation, and macrophage STING activation were observed in aged ischemic livers. Improvement in efferocytosis by aged macrophages via MerTK activation suppressed STING activation and inflammatory liver injury. Our study demonstrates that aging suppresses MerTK- mediated macrophage efferocytosis to promote macrophage STING activation and inflammatory liver IR injury, suggesting a new mechanism and potential therapy to promote inflammation resolution and efferocytosis in aged livers.
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Affiliation(s)
- Haoran Hu
- Hepatobiliary Center, The First Affiliated Hospital of Nanjing Medical University; Key Laboratory of Liver Transplantation, Research Unit of Liver Transplantation and Transplant Immunology, Chinese Academy of Medical Sciences; NHC Key Laboratory of Living Donor Liver Transplantation (Nanjing Medical University), 210029, Nanjing, Jiangsu Province, China
| | - Xuyu Cheng
- Department of Breast Surgery, The First Affiliated Hospital of Nanjing Medical University, 210029, Nanjing, Jiangsu Province, China
| | - Fei Li
- Department of Anesthesiology, The First Affiliated Hospital of Nanjing Medical University, 210029, Nanjing, Jiangsu Province, China
| | - Zhu Guan
- Department of Anesthesiology, The First Affiliated Hospital of Nanjing Medical University, 210029, Nanjing, Jiangsu Province, China
| | - Jian Xu
- Hepatobiliary Center, The First Affiliated Hospital of Nanjing Medical University; Key Laboratory of Liver Transplantation, Research Unit of Liver Transplantation and Transplant Immunology, Chinese Academy of Medical Sciences; NHC Key Laboratory of Living Donor Liver Transplantation (Nanjing Medical University), 210029, Nanjing, Jiangsu Province, China
| | - Dongming Wu
- Hepatobiliary Center, The First Affiliated Hospital of Nanjing Medical University; Key Laboratory of Liver Transplantation, Research Unit of Liver Transplantation and Transplant Immunology, Chinese Academy of Medical Sciences; NHC Key Laboratory of Living Donor Liver Transplantation (Nanjing Medical University), 210029, Nanjing, Jiangsu Province, China
| | - Yiyun Gao
- Hepatobiliary Center, The First Affiliated Hospital of Nanjing Medical University; Key Laboratory of Liver Transplantation, Research Unit of Liver Transplantation and Transplant Immunology, Chinese Academy of Medical Sciences; NHC Key Laboratory of Living Donor Liver Transplantation (Nanjing Medical University), 210029, Nanjing, Jiangsu Province, China
| | - Xinyu Zhan
- Hepatobiliary Center, The First Affiliated Hospital of Nanjing Medical University; Key Laboratory of Liver Transplantation, Research Unit of Liver Transplantation and Transplant Immunology, Chinese Academy of Medical Sciences; NHC Key Laboratory of Living Donor Liver Transplantation (Nanjing Medical University), 210029, Nanjing, Jiangsu Province, China
| | - Ping Wang
- Hepatobiliary Center, The First Affiliated Hospital of Nanjing Medical University; Key Laboratory of Liver Transplantation, Research Unit of Liver Transplantation and Transplant Immunology, Chinese Academy of Medical Sciences; NHC Key Laboratory of Living Donor Liver Transplantation (Nanjing Medical University), 210029, Nanjing, Jiangsu Province, China
| | - Haoming Zhou
- Hepatobiliary Center, The First Affiliated Hospital of Nanjing Medical University; Key Laboratory of Liver Transplantation, Research Unit of Liver Transplantation and Transplant Immunology, Chinese Academy of Medical Sciences; NHC Key Laboratory of Living Donor Liver Transplantation (Nanjing Medical University), 210029, Nanjing, Jiangsu Province, China.
| | - Zhuqing Rao
- Department of Anesthesiology, The First Affiliated Hospital of Nanjing Medical University, 210029, Nanjing, Jiangsu Province, China.
| | - Feng Cheng
- Hepatobiliary Center, The First Affiliated Hospital of Nanjing Medical University; Key Laboratory of Liver Transplantation, Research Unit of Liver Transplantation and Transplant Immunology, Chinese Academy of Medical Sciences; NHC Key Laboratory of Living Donor Liver Transplantation (Nanjing Medical University), 210029, Nanjing, Jiangsu Province, China.
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8
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Sakamoto S, Bochimoto H, Shibata K, Zin NKM, Fukai M, Nakamura K, Ishikawa T, Fujiyoshi M, Shimamura T, Taketomi A. Exploration of Optimal pH in Hypothermic Machine Perfusion for Rat Liver Grafts Retrieved after Circulatory Death. J Clin Med 2023; 12:jcm12113845. [PMID: 37298042 DOI: 10.3390/jcm12113845] [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: 03/24/2023] [Revised: 06/01/2023] [Accepted: 06/02/2023] [Indexed: 06/12/2023] Open
Abstract
Ex vivo hypothermic machine perfusion (HMP) is a strategy for controlling ischemia-reperfusion injury in donation after circulatory death (DCD) liver transplantation. The pH of blood increases with a decrease in temperature and water dissociation, leading to a decrease in [H+]. This study aimed to verify the optimal pH of HMP for DCD livers. Rat livers were retrieved 30 min post-cardiac arrest and subjected to 3-h cold storage (CS) in UW solution (CS group) or HMP with UW-gluconate solution (machine perfusion [MP] group) of pH 7.4 (original), 7.6, 7.8, and 8.0 (MP-pH 7.6, 7.8, 8.0 groups, respectively) at 7-10 °C. The livers were subjected to normothermic perfusion to simulate reperfusion after HMP. All HMP groups showed greater graft protection compared to the CS group due to the lower levels of liver enzymes in the former. The MP-pH 7.8 group showed significant protection, evidenced by bile production, diminished tissue injury, and reduced flavin mononucleotide leakage, and further analysis by scanning electron microscopy revealed a well-preserved structure of the mitochondrial cristae. Therefore, the optimum pH of 7.8 enhanced the protective effect of HMP by preserving the structure and function of the mitochondria, leading to reduced reperfusion injury in the DCD liver.
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Affiliation(s)
- Sodai Sakamoto
- Department of Gastroenterological Surgery 1, Hokkaido University Graduate School of Medicine, Sapporo 060-0815, Japan
| | - Hiroki Bochimoto
- Department of Cell Physiology, The Jikei University School of Medicine, Tokyo 105-8461, Japan
| | - Kengo Shibata
- Gastroenterological Surgery 1, Hokkaido University Hospital, Sapporo 060-8648, Japan
| | - Nur Khatijah Mohd Zin
- Department of Cell Physiology, The Jikei University School of Medicine, Tokyo 105-8461, Japan
| | - Moto Fukai
- Department of Gastroenterological Surgery 1, Hokkaido University Graduate School of Medicine, Sapporo 060-0815, Japan
| | - Kosei Nakamura
- Department of Gastroenterological Surgery 1, Hokkaido University Graduate School of Medicine, Sapporo 060-0815, Japan
| | - Takahisa Ishikawa
- Department of Gastroenterological Surgery 1, Hokkaido University Graduate School of Medicine, Sapporo 060-0815, Japan
| | - Masato Fujiyoshi
- Department of Gastroenterological Surgery 1, Hokkaido University Graduate School of Medicine, Sapporo 060-0815, Japan
| | - Tsuyoshi Shimamura
- Division of Organ Transplantation, Hokkaido University Hospital, Sapporo 060-8648, Japan
| | - Akinobu Taketomi
- Department of Gastroenterological Surgery 1, Hokkaido University Graduate School of Medicine, Sapporo 060-0815, Japan
- Gastroenterological Surgery 1, Hokkaido University Hospital, Sapporo 060-8648, Japan
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9
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Mao B, Yuan W, Wu F, Yan Y, Wang B. Autophagy in hepatic ischemia-reperfusion injury. Cell Death Discov 2023; 9:115. [PMID: 37019879 PMCID: PMC10076300 DOI: 10.1038/s41420-023-01387-0] [Citation(s) in RCA: 21] [Impact Index Per Article: 10.5] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2023] [Revised: 02/23/2023] [Accepted: 02/27/2023] [Indexed: 04/07/2023] Open
Abstract
Hepatic ischemia-reperfusion injury (HIRI) is a major complication of liver resection or liver transplantation that can seriously affect patient's prognosis. There is currently no definitive and effective treatment strategy for HIRI. Autophagy is an intracellular self-digestion pathway initiated to remove damaged organelles and proteins, which maintains cell survival, differentiation, and homeostasis. Recent studies have shown that autophagy is involved in the regulation of HIRI. Numerous drugs and treatments can change the outcome of HIRI by controlling the pathways of autophagy. This review mainly discusses the occurrence and development of autophagy, the selection of experimental models for HIRI, and the specific regulatory pathways of autophagy in HIRI. Autophagy has considerable potential in the treatment of HIRI.
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Affiliation(s)
- Benliang Mao
- College of Clinical Medicine, Guizhou Medical University, Guiyang, China
| | - Wei Yuan
- Department of General Surgery, Guangzhou Red Cross Hospital affiliated to Jinan University, Guangzhou, China
| | - Fan Wu
- Department of General Surgery, Guangzhou Red Cross Hospital affiliated to Jinan University, Guangzhou, China
| | - Yong Yan
- Department of General Surgery, Guangzhou Red Cross Hospital affiliated to Jinan University, Guangzhou, China
| | - Bailin Wang
- College of Clinical Medicine, Guizhou Medical University, Guiyang, China.
- Department of General Surgery, Guangzhou Red Cross Hospital affiliated to Jinan University, Guangzhou, China.
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10
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Zhang J, Wang T, Bi J, Ke M, Ren Y, Wang M, Du Z, Liu W, Hu L, Zhang X, Liu X, Wang B, Wu Z, Lv Y, Meng L, Wu R. Overexpression of HSF2 binding protein suppresses endoplasmic reticulum stress via regulating subcellular localization of CDC73 in hepatocytes. Cell Biosci 2023; 13:64. [PMID: 36964632 PMCID: PMC10039577 DOI: 10.1186/s13578-023-01010-w] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2022] [Accepted: 03/07/2023] [Indexed: 03/26/2023] Open
Abstract
BACKGROUND Endoplasmic reticulum (ER) stress plays an important role in the occurrence and development of various liver diseases. However, there are no effective prevention and treatment strategies. We aimed to determine the role of heat shock factor 2 binding protein (HSF2BP) in ER stress. METHODS HSF2BP expression in mice and cultured hepatocytes was measured during ER stress induced by tunicamycin, and its importance in ER stress was evaluated in hepatocyte-specific HSF2BP transgenic (TG) and knockout (KO) mice. The effects and mechanisms of HSF2BP on ER stress were further probed in hepatic ischemia-reperfusion (I/R) injury. RESULTS HSF2BP expression was significantly upregulated during tunicamycin-induced ER stress in mice and cultured hepatocytes. Liver injury and ER stress were reduced in HSF2BP overexpressing mice after treating with tunicamycin, but were aggravated in HSF2BP knockout mice compared to the controls. In hepatic I/R injury, HSF2BP expression was significantly upregulated, and HSF2BP overexpressing mice had reduced liver injury and inflammation. These improvements were associated with ER stress inhibition. However, these results were reversed in hepatocyte-specific HSF2BP knockout mice. HSF2BP overexpression increased cytoplasmic CDC73 levels and inhibited the JNK signaling pathway. CDC73 knockdown using siRNA eliminated the protection exerted by HSF2BP overexpression in hypoxia/reoxygenation (H/R)-induced ER stress in hepatocytes. CONCLUSION HSF2BP is a previously uncharacterized regulatory factor in ER stress-likely acts by regulating CDC73 subcellular localization. The feasibility of HSF2BP-targeted treatment in ER stress-related liver disease deserves future research.
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Affiliation(s)
- Jia Zhang
- National Local Joint Engineering Research Center for Precision Surgery & Regenerative Medicine, Shaanxi Provincial Center for Regenerative Medicine and Surgical Engineering, Center for Regenerative and Reconstructive Medicine, Med-X Institute, First Affiliated Hospital of Xi'an Jiaotong University, 124, 76 West Yanta Road, Xi'an, Shaanxi, 710061, China
- Department of Gastroenterology, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, China
| | - Tao Wang
- National Local Joint Engineering Research Center for Precision Surgery & Regenerative Medicine, Shaanxi Provincial Center for Regenerative Medicine and Surgical Engineering, Center for Regenerative and Reconstructive Medicine, Med-X Institute, First Affiliated Hospital of Xi'an Jiaotong University, 124, 76 West Yanta Road, Xi'an, Shaanxi, 710061, China
- Department of Hepatobiliary Surgery, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, China
| | - Jianbin Bi
- National Local Joint Engineering Research Center for Precision Surgery & Regenerative Medicine, Shaanxi Provincial Center for Regenerative Medicine and Surgical Engineering, Center for Regenerative and Reconstructive Medicine, Med-X Institute, First Affiliated Hospital of Xi'an Jiaotong University, 124, 76 West Yanta Road, Xi'an, Shaanxi, 710061, China
- Department of Oncology, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, China
| | - Mengyun Ke
- National Local Joint Engineering Research Center for Precision Surgery & Regenerative Medicine, Shaanxi Provincial Center for Regenerative Medicine and Surgical Engineering, Center for Regenerative and Reconstructive Medicine, Med-X Institute, First Affiliated Hospital of Xi'an Jiaotong University, 124, 76 West Yanta Road, Xi'an, Shaanxi, 710061, China
| | - Yifan Ren
- National Local Joint Engineering Research Center for Precision Surgery & Regenerative Medicine, Shaanxi Provincial Center for Regenerative Medicine and Surgical Engineering, Center for Regenerative and Reconstructive Medicine, Med-X Institute, First Affiliated Hospital of Xi'an Jiaotong University, 124, 76 West Yanta Road, Xi'an, Shaanxi, 710061, China
- Department of General Surgery, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, China
| | - Mengzhou Wang
- National Local Joint Engineering Research Center for Precision Surgery & Regenerative Medicine, Shaanxi Provincial Center for Regenerative Medicine and Surgical Engineering, Center for Regenerative and Reconstructive Medicine, Med-X Institute, First Affiliated Hospital of Xi'an Jiaotong University, 124, 76 West Yanta Road, Xi'an, Shaanxi, 710061, China
- Department of Hepatobiliary Surgery, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, China
| | - Zhaoqing Du
- National Local Joint Engineering Research Center for Precision Surgery & Regenerative Medicine, Shaanxi Provincial Center for Regenerative Medicine and Surgical Engineering, Center for Regenerative and Reconstructive Medicine, Med-X Institute, First Affiliated Hospital of Xi'an Jiaotong University, 124, 76 West Yanta Road, Xi'an, Shaanxi, 710061, China
- Department of Hepatobiliary Surgery, Shaanxi Provincial People's Hospital, Xi'an, Shaanxi, China
| | - Wuming Liu
- National Local Joint Engineering Research Center for Precision Surgery & Regenerative Medicine, Shaanxi Provincial Center for Regenerative Medicine and Surgical Engineering, Center for Regenerative and Reconstructive Medicine, Med-X Institute, First Affiliated Hospital of Xi'an Jiaotong University, 124, 76 West Yanta Road, Xi'an, Shaanxi, 710061, China
- Department of Hepatobiliary Surgery, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, China
| | - Liangshuo Hu
- Department of Hepatobiliary Surgery, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, China
| | - Xiaogang Zhang
- Department of Hepatobiliary Surgery, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, China
| | - Xuemin Liu
- Department of Hepatobiliary Surgery, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, China
| | - Bo Wang
- Department of Hepatobiliary Surgery, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, China
| | - Zheng Wu
- Department of Hepatobiliary Surgery, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, China
| | - Yi Lv
- National Local Joint Engineering Research Center for Precision Surgery & Regenerative Medicine, Shaanxi Provincial Center for Regenerative Medicine and Surgical Engineering, Center for Regenerative and Reconstructive Medicine, Med-X Institute, First Affiliated Hospital of Xi'an Jiaotong University, 124, 76 West Yanta Road, Xi'an, Shaanxi, 710061, China
- Department of Hepatobiliary Surgery, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, China
| | - Lingzhong Meng
- Anesthesiology and Perioperative Medicine, Mayo Clinic College of Medicine, Rochester, MN, USA
| | - Rongqian Wu
- National Local Joint Engineering Research Center for Precision Surgery & Regenerative Medicine, Shaanxi Provincial Center for Regenerative Medicine and Surgical Engineering, Center for Regenerative and Reconstructive Medicine, Med-X Institute, First Affiliated Hospital of Xi'an Jiaotong University, 124, 76 West Yanta Road, Xi'an, Shaanxi, 710061, China.
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11
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Yu B, Zhang Y, Wang T, Guo J, Kong C, Chen Z, Ma X, Qiu T. MAPK Signaling Pathways in Hepatic Ischemia/Reperfusion Injury. J Inflamm Res 2023; 16:1405-1418. [PMID: 37012971 PMCID: PMC10065871 DOI: 10.2147/jir.s396604] [Citation(s) in RCA: 24] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2022] [Accepted: 03/16/2023] [Indexed: 03/29/2023] Open
Abstract
The mitogen-activated protein kinase signaling pathway can be activated by a variety of growth factors, cytokines, and hormones, and mediates numerous intracellular signals related to cellular activities, including cell proliferation, motility, and differentiation. It has been widely studied in the occurrence and development of inflammation and tumor. Hepatic ischemia-reperfusion injury (HIRI) is a common pathophysiological phenomenon that occurs in surgical procedures such as lobectomy and liver transplantation, which is characterized by severe inflammatory reaction after ischemia and reperfusion. In this review, we mainly discuss the role of p38, ERK1/2, JNK in MAPK family and TAK1 and ASK1 in MAPKKK family in HIRI, and try to find an effective treatment for HIRI.
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Affiliation(s)
- Bo Yu
- Department of Organ Transplantation, Renmin Hospital of Wuhan University, Wuhan, Hubei Province, People’s Republic of China
| | - Yalong Zhang
- Department of Organ Transplantation, Renmin Hospital of Wuhan University, Wuhan, Hubei Province, People’s Republic of China
| | - Tianyu Wang
- Department of Organ Transplantation, Renmin Hospital of Wuhan University, Wuhan, Hubei Province, People’s Republic of China
| | - Jiayu Guo
- Department of Organ Transplantation, Renmin Hospital of Wuhan University, Wuhan, Hubei Province, People’s Republic of China
| | - Chenyang Kong
- Department of Organ Transplantation, Renmin Hospital of Wuhan University, Wuhan, Hubei Province, People’s Republic of China
| | - Zhongbao Chen
- Department of Organ Transplantation, Renmin Hospital of Wuhan University, Wuhan, Hubei Province, People’s Republic of China
| | - Xiaoxiong Ma
- Department of Organ Transplantation, Renmin Hospital of Wuhan University, Wuhan, Hubei Province, People’s Republic of China
| | - Tao Qiu
- Department of Organ Transplantation, Renmin Hospital of Wuhan University, Wuhan, Hubei Province, People’s Republic of China
- Correspondence: Tao Qiu, Department of Organ Transplantation, Renmin Hospital of Wuhan University, Wuhan, Hubei Province, People’s Republic of China, Tel +86-13995632367, Email
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12
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Luteolin Pretreatment Attenuates Hepatic Ischemia-Reperfusion Injury in Mice by Inhibiting Inflammation, Autophagy, and Apoptosis via the ERK/PPARα Pathway. PPAR Res 2022; 2022:8161946. [PMID: 35966821 PMCID: PMC9366205 DOI: 10.1155/2022/8161946] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2022] [Revised: 06/25/2022] [Accepted: 07/16/2022] [Indexed: 11/18/2022] Open
Abstract
Hepatic ischemia-reperfusion (IR) injury is a clinically significant process that frequently occurs in liver transplantation, partial hepatectomy, and hemorrhagic shock. The aim of this study was to explore the effectiveness of luteolin in hepatic IR injury and the underlying mechanism. BALB/c mice were randomly divided into six groups, including normal controls (NC), luteolin (50 mg/kg), sham procedure, IR+25 mg/kg luteolin, and IR+50 mg/kg luteolin group. Serum and tissue samples were collected at 6 and 24 h after reperfusion to assay liver enzymes, inflammatory factors, expression of proteins associated with apoptosis and autophagy, and factors associated with the extracellular signal-regulated kinase/peroxisome proliferator-activated receptor alpha (ERK/PPARα) pathway. Luteolin preconditioning decreased hepatocyte injury caused by ischemia-reperfusion, downregulated inflammatory factors, and inhibited apoptosis and autophagy. Luteolin also inhibited ERK phosphorylation and activated PPARα.
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13
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Tang SP, Mao XL, Chen YH, Yan LL, Ye LP, Li SW. Reactive Oxygen Species Induce Fatty Liver and Ischemia-Reperfusion Injury by Promoting Inflammation and Cell Death. Front Immunol 2022; 13:870239. [PMID: 35572532 PMCID: PMC9098816 DOI: 10.3389/fimmu.2022.870239] [Citation(s) in RCA: 52] [Impact Index Per Article: 17.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2022] [Accepted: 04/07/2022] [Indexed: 01/24/2023] Open
Abstract
Liver transplantation is the ultimate method for treating end-stage liver disease. With the increasing prevalence of obesity, the number of patients with non-alcoholic fatty liver, a common cause of chronic liver disease, is on the rise and may become the main cause of liver transplantation in the future. With the increasing gap between the number of donor livers and patients waiting for liver transplantation and the increasing prevalence of non-alcoholic fatty liver, the proportion of steatosis livers among non-standard donor organs is also increasing. Ischemia-reperfusion injury has historically been the focus of attention in the liver transplantation process, and severe ischemia-reperfusion injury leads to adverse outcomes of liver transplantation. Studies have shown that the production of reactive oxygen species and subsequent oxidative stress play a key role in the pathogenesis of hepatic ischemia and reperfusion injury and non-alcoholic fatty liver. Furthermore, the sensitivity of fatty liver transplantation to ischemia-reperfusion injury has been suggested to be related to the production of reactive oxygen species (ROS) and oxidative stress. In ischemia-reperfusion injury, Kupffer cell and macrophage activation along with mitochondrial damage and the xanthine/xanthine oxidase system promote marked reactive oxygen species production and the inflammatory response and apoptosis, resulting in liver tissue injury. The increased levels of ROS and lipid peroxidation products, vicious circle of ROS and oxidative stress along with mitochondrial dysfunction promoted the progress of non-alcoholic fatty liver. In contrast to the non-fatty liver, a non-alcoholic fatty liver produces more reactive oxygen species and suffers more serious oxidative stress when subjected to ischemia-reperfusion injury. We herein review the effects of reactive oxygen species on ischemia-reperfusion injury and non-alcoholic fatty liver injury as well as highlight several treatment approaches.
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Affiliation(s)
- Shen-ping Tang
- Taizhou Hospital of Zhejiang Province Affiliated to Wenzhou Medical University, Linhai, China
| | - Xin-li Mao
- Key Laboratory of Minimally Invasive Techniques & Rapid Rehabilitation of Digestive System Tumor of Zhejiang Province, Taizhou Hospital Affiliated to Wenzhou Medical University, Linhai, China
- Department of Gastroenterology, Taizhou Hospital of Zhejiang Province affiliated to Wenzhou Medical University, Linhai, China
- Institute of Digestive Disease, Taizhou Hospital of Zhejiang Province Affiliated to Wenzhou Medical University, Linhai, China
| | - Ya-hong Chen
- Health Management Center, Taizhou Hospital of Zhejiang Province Affiliated to Wenzhou Medical University, Linhai, China
| | - Ling-ling Yan
- Department of Gastroenterology, Taizhou Hospital of Zhejiang Province affiliated to Wenzhou Medical University, Linhai, China
| | - Li-ping Ye
- Taizhou Hospital of Zhejiang Province Affiliated to Wenzhou Medical University, Linhai, China
- Key Laboratory of Minimally Invasive Techniques & Rapid Rehabilitation of Digestive System Tumor of Zhejiang Province, Taizhou Hospital Affiliated to Wenzhou Medical University, Linhai, China
- Department of Gastroenterology, Taizhou Hospital of Zhejiang Province affiliated to Wenzhou Medical University, Linhai, China
- Institute of Digestive Disease, Taizhou Hospital of Zhejiang Province Affiliated to Wenzhou Medical University, Linhai, China
| | - Shao-wei Li
- Key Laboratory of Minimally Invasive Techniques & Rapid Rehabilitation of Digestive System Tumor of Zhejiang Province, Taizhou Hospital Affiliated to Wenzhou Medical University, Linhai, China
- Department of Gastroenterology, Taizhou Hospital of Zhejiang Province affiliated to Wenzhou Medical University, Linhai, China
- Institute of Digestive Disease, Taizhou Hospital of Zhejiang Province Affiliated to Wenzhou Medical University, Linhai, China
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14
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Smith AO, Jonassen JA, Preval KM, Davis RJ, Pazour GJ. c-Jun N-terminal kinase (JNK) signaling contributes to cystic burden in polycystic kidney disease. PLoS Genet 2021; 17:e1009711. [PMID: 34962918 PMCID: PMC8746764 DOI: 10.1371/journal.pgen.1009711] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2021] [Revised: 01/10/2022] [Accepted: 12/11/2021] [Indexed: 11/18/2022] Open
Abstract
Polycystic kidney disease is an inherited degenerative disease in which the uriniferous tubules are replaced by expanding fluid-filled cysts that ultimately destroy organ function. Autosomal dominant polycystic kidney disease (ADPKD) is the most common form, afflicting approximately 1 in 1,000 people. It primarily is caused by mutations in the transmembrane proteins polycystin-1 (Pkd1) and polycystin-2 (Pkd2). The most proximal effects of Pkd mutations leading to cyst formation are not known, but pro-proliferative signaling must be involved for the tubule epithelial cells to increase in number over time. The c-Jun N-terminal kinase (JNK) pathway promotes proliferation and is activated in acute and chronic kidney diseases. Using a mouse model of cystic kidney disease caused by Pkd2 loss, we observe JNK activation in cystic kidneys and observe increased nuclear phospho c-Jun in cystic epithelium. Genetic removal of Jnk1 and Jnk2 suppresses the nuclear accumulation of phospho c-Jun, reduces proliferation and reduces the severity of cystic disease. While Jnk1 and Jnk2 are thought to have largely overlapping functions, we find that Jnk1 loss is nearly as effective as the double loss of Jnk1 and Jnk2. Jnk pathway inhibitors are in development for neurodegeneration, cancer, and fibrotic diseases. Our work suggests that the JNK pathway should be explored as a therapeutic target for ADPKD. Autosomal dominant polycystic kidney disease is a leading cause of end stage renal disease requiring dialysis or kidney transplant. During disease development, the cells lining the kidney tubules proliferate. This proliferation transforms normally small diameter tubules into fluid-filled cysts that enlarge with time, eventually destroying all kidney function. Despite decades of research, polycystic kidney disease remains incurable. Furthermore, the precise signaling events involved in cyst initiation and growth remain unclear. The c-Jun N-terminal kinase (JNK), is a major pathway regulating cellular proliferation and differentiation but its importance to polycystic kidney disease was not known. We show that JNK activity is elevated in cystic kidneys and that reducing JNK activity decreases cyst growth pointing to JNK inhibition as a therapeutic strategy for treating polycystic kidney disease.
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Affiliation(s)
- Abigail O. Smith
- Program in Molecular Medicine, University of Massachusetts Chan Medical School, Biotech II, Worcester, Massachusetts, United States of America
| | - Julie A. Jonassen
- Department of Microbiology and Physiological Systems, University of Massachusetts Chan Medical School, Worcester Massachusetts, United States of America
| | - Kenley M. Preval
- Program in Molecular Medicine, University of Massachusetts Chan Medical School, Biotech II, Worcester, Massachusetts, United States of America
| | - Roger J. Davis
- Program in Molecular Medicine, University of Massachusetts Chan Medical School, Biotech II, Worcester, Massachusetts, United States of America
| | - Gregory J. Pazour
- Program in Molecular Medicine, University of Massachusetts Chan Medical School, Biotech II, Worcester, Massachusetts, United States of America
- * E-mail:
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15
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Melin N, Sánchez-Taltavull D, Fahrner R, Keogh A, Dosch M, Büchi I, Zimmer Y, Medová M, Beldi G, Aebersold DM, Candinas D, Stroka D. Synergistic effect of the TLR5 agonist CBLB502 and its downstream effector IL-22 against liver injury. Cell Death Dis 2021; 12:366. [PMID: 33824326 PMCID: PMC8024273 DOI: 10.1038/s41419-021-03654-3] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2020] [Revised: 03/09/2021] [Accepted: 03/10/2021] [Indexed: 01/07/2023]
Abstract
The toll-like receptor 5 (TLR5) agonist, CBLB502/Entolimod, is a peptide derived from bacterial flagellin and has been shown to protect against radiation-induced tissue damage in animal models. Here we investigated the protective mechanism of CBLB502 in the liver using models of ischemia-reperfusion injury and concanavalin A (ConA) induced immuno-hepatitis. We report that pretreatment of mice with CBLB502 provoked a concomitant activation of NF-κB and STAT3 signaling in the liver and reduced hepatic damage in both models. To understand the underlying mechanism, we screened for cytokines in the serum of CBLB502 treated animals and detected high levels of IL-22. There was no transcriptional upregulation of IL-22 in the liver, rather it was found in extrahepatic tissues, mainly the colon, mesenteric lymph nodes (MLN), and spleen. RNA-seq analysis on isolated hepatocytes demonstrated that the concomitant activation of NF-κB signaling by CBLB502 and STAT3 signaling by IL-22 produced a synergistic cytoprotective transcriptional signature. In IL-22 knockout mice, the loss of IL-22 resulted in a decrease of hepatic STAT3 activation, a reduction in the cytoprotective signature, and a loss of hepatoprotection following ischemia-reperfusion-induced liver injury. Taken together, these findings suggest that CBLB502 protects the liver by increasing hepatocyte resistance to acute liver injury through the cooperation of TLR5-NF-κB and IL-22-STAT3 signaling pathways.
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Affiliation(s)
- Nicolas Melin
- Department for BioMedical Research, Inselspital, Bern University Hospital, University of Bern, 3008, Bern, Switzerland
- Visceral Surgery and Medicine, Inselspital, Bern University Hospital, University of Bern, 3008, Bern, Switzerland
| | - Daniel Sánchez-Taltavull
- Department for BioMedical Research, Inselspital, Bern University Hospital, University of Bern, 3008, Bern, Switzerland
- Visceral Surgery and Medicine, Inselspital, Bern University Hospital, University of Bern, 3008, Bern, Switzerland
| | - René Fahrner
- Department for BioMedical Research, Inselspital, Bern University Hospital, University of Bern, 3008, Bern, Switzerland
- Visceral Surgery and Medicine, Inselspital, Bern University Hospital, University of Bern, 3008, Bern, Switzerland
- Department of General, Visceral and Vascular Surgery, Bürgerspital Solothurn, 4500, Solothurn, Switzerland
| | - Adrian Keogh
- Department for BioMedical Research, Inselspital, Bern University Hospital, University of Bern, 3008, Bern, Switzerland
- Visceral Surgery and Medicine, Inselspital, Bern University Hospital, University of Bern, 3008, Bern, Switzerland
| | - Michel Dosch
- Department for BioMedical Research, Inselspital, Bern University Hospital, University of Bern, 3008, Bern, Switzerland
- Visceral Surgery and Medicine, Inselspital, Bern University Hospital, University of Bern, 3008, Bern, Switzerland
| | - Isabel Büchi
- Department for BioMedical Research, Inselspital, Bern University Hospital, University of Bern, 3008, Bern, Switzerland
- Visceral Surgery and Medicine, Inselspital, Bern University Hospital, University of Bern, 3008, Bern, Switzerland
| | - Yitzhak Zimmer
- Department for BioMedical Research, Inselspital, Bern University Hospital, University of Bern, 3008, Bern, Switzerland
- Department of Radiation Oncology, Inselspital, Bern University Hospital, University of Bern, 3010, Bern, Switzerland
| | - Michaela Medová
- Department for BioMedical Research, Inselspital, Bern University Hospital, University of Bern, 3008, Bern, Switzerland
- Department of Radiation Oncology, Inselspital, Bern University Hospital, University of Bern, 3010, Bern, Switzerland
| | - Guido Beldi
- Department for BioMedical Research, Inselspital, Bern University Hospital, University of Bern, 3008, Bern, Switzerland
- Visceral Surgery and Medicine, Inselspital, Bern University Hospital, University of Bern, 3008, Bern, Switzerland
| | - Daniel M Aebersold
- Department for BioMedical Research, Inselspital, Bern University Hospital, University of Bern, 3008, Bern, Switzerland
- Department of Radiation Oncology, Inselspital, Bern University Hospital, University of Bern, 3010, Bern, Switzerland
| | - Daniel Candinas
- Department for BioMedical Research, Inselspital, Bern University Hospital, University of Bern, 3008, Bern, Switzerland
- Visceral Surgery and Medicine, Inselspital, Bern University Hospital, University of Bern, 3008, Bern, Switzerland
| | - Deborah Stroka
- Department for BioMedical Research, Inselspital, Bern University Hospital, University of Bern, 3008, Bern, Switzerland.
- Visceral Surgery and Medicine, Inselspital, Bern University Hospital, University of Bern, 3008, Bern, Switzerland.
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16
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Garg R, Kumariya S, Katekar R, Verma S, Goand UK, Gayen JR. JNK signaling pathway in metabolic disorders: An emerging therapeutic target. Eur J Pharmacol 2021; 901:174079. [PMID: 33812885 DOI: 10.1016/j.ejphar.2021.174079] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2020] [Revised: 03/18/2021] [Accepted: 03/25/2021] [Indexed: 02/08/2023]
Abstract
Metabolic Syndrome is a multifactorial disease associated with increased risk of cardiovascular disorders, type 2 diabetes mellitus, fatty liver disease, etc. Various stress stimuli such as reactive oxygen species, endoplasmic reticulum stress, mitochondrial dysfunction, increased cytokines, or free fatty acids are known to aggravate progressive development of hyperglycemia and hyperlipidemia. Although the exact mechanism contributing to altered metabolism is unclear. Evidence suggests stress kinase role to be a crucial one in metabolic syndrome. Stress kinase, c-jun N-terminal kinase activation (JNK) is involved in various metabolic manifestations including obesity, insulin resistance, fatty liver disease as well as cardiometabolic disorders. It emerged as a foremost mediator in regulating metabolism in the liver, skeletal muscle, adipose tissue as well as pancreatic β cells. It has three isoforms each having a unique and tissue-specific role in altered metabolism. Current findings based on genetic manipulation or chemical inhibition studies identified JNK isoforms to play a central role in the regulation of whole-body metabolism, suggesting it to be a novel therapeutic target. Hence, it is imperative to elucidate its role in metabolic syndrome onset and progression. The purpose of this review is to elucidate in vitro and in vivo implications of JNK signaling along with the therapeutic strategy to inhibit specific isoform. Since metabolic syndrome is an array of diseases and complex pathway, carefully examining each tissue will be important for specific treatment strategies.
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Affiliation(s)
- Richa Garg
- Pharmaceutics & Pharmacokinetics, CSIR-Central Drug Research Institute, Jankipuram Extension, Lucknow, 226031, India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, 201002, India
| | - Sanjana Kumariya
- Pharmaceutics & Pharmacokinetics, CSIR-Central Drug Research Institute, Jankipuram Extension, Lucknow, 226031, India
| | - Roshan Katekar
- Pharmaceutics & Pharmacokinetics, CSIR-Central Drug Research Institute, Jankipuram Extension, Lucknow, 226031, India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, 201002, India
| | - Saurabh Verma
- Pharmaceutics & Pharmacokinetics, CSIR-Central Drug Research Institute, Jankipuram Extension, Lucknow, 226031, India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, 201002, India
| | - Umesh K Goand
- Pharmaceutics & Pharmacokinetics, CSIR-Central Drug Research Institute, Jankipuram Extension, Lucknow, 226031, India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, 201002, India
| | - Jiaur R Gayen
- Pharmaceutics & Pharmacokinetics, CSIR-Central Drug Research Institute, Jankipuram Extension, Lucknow, 226031, India; Pharmacology Division, CSIR-Central Drug Research Institute, Jankipuram Extension, Lucknow, 226031, India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, 201002, India.
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17
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Hu C, Zhao L, Zhang F, Li L. Melatonin and its protective role in attenuating warm or cold hepatic ischaemia/reperfusion injury. Cell Prolif 2021; 54:e13021. [PMID: 33751704 PMCID: PMC8016647 DOI: 10.1111/cpr.13021] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2020] [Revised: 01/27/2021] [Accepted: 02/21/2021] [Indexed: 12/26/2022] Open
Abstract
Although the liver is the only organ with regenerative capacity, various injury factors induce irreversible liver dysfunction and end‐stage liver disease. Liver resection and liver transplantation (LT) are effective treatments for individuals with liver failure, liver cirrhosis and liver cancers. The remnant or transplanted liver tissues will undergo hepatic ischaemia/reperfusion (IR), which leads to oxidative stress, inflammation, immune injury and liver damage. Moreover, systemic ischaemia induced by trauma, stroke, myocardial ischaemia, haemorrhagic shock and other injury factors also induces liver ischaemia/reperfusion injury (IRI) in individuals. Hepatic IRI can be divided into warm IRI, which is induced by liver surgery and systemic ischaemia, and cold IRI, which is induced by LT. Multiple studies have shown that melatonin (MT) acts as an endogenous free radical scavenger with antioxidant capacity and is also able to attenuate hepatic IRI via its anti‐inflammatory and antiapoptotic capacities. In this review, we discuss the potential mechanisms and current strategies of MT administration in liver surgery for protecting against warm or cold hepatic IRI. We highlight strategies to improve the efficacy and safety of MT for attenuating hepatic IRI in different conditions. After the potential mechanisms underlying the interactions between MT and other important cellular processes during hepatic IR are clarified, more opportunities will be available to use MT to treat liver diseases in the future.
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Affiliation(s)
- Chenxia Hu
- State Key Laboratory for the Diagnosis and Treatment of Infectious Diseases, Collaborative Innovation Center for the Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China.,National Clinical Research Center for Infectious Diseases, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Lingfei Zhao
- Key Laboratory of Kidney Disease Prevention and Control Technology, Kidney Disease Center, Institute of Nephrology, First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China
| | - Fen Zhang
- State Key Laboratory for the Diagnosis and Treatment of Infectious Diseases, Collaborative Innovation Center for the Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China.,National Clinical Research Center for Infectious Diseases, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Lanjuan Li
- State Key Laboratory for the Diagnosis and Treatment of Infectious Diseases, Collaborative Innovation Center for the Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China.,National Clinical Research Center for Infectious Diseases, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
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18
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Zhang Y, Pan Q, Cheng Y, Liu Y. Effects of SP600125 and hypothermic machine perfusion on livers donated after cardiac death in a pig allograft transplantation model. Eur J Med Res 2021; 26:15. [PMID: 33546770 PMCID: PMC7863371 DOI: 10.1186/s40001-020-00472-9] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2019] [Accepted: 12/14/2020] [Indexed: 12/12/2022] Open
Abstract
BACKGROUND Hypothermic machine perfusion (HMP) improves the quality of donor livers for transplantation, both in animal models and in clinical practice. Treatment with SP600125, an inhibitor of c-Jun N-terminal kinase (JNK), can suppress the JNK signaling pathway to alleviate donor liver ischemia-reperfusion injury (IRI). We performed the present study with the objective of exploring the protective effects exerted by a combination of HMP and SP600125 on liver xenograft viability for donation after cardiac death (DCD) in a porcine model. METHODS 54 adult BAMA mini-pigs were randomly assigned to 5 groups, including sham, cold storage for 4 h (CS 4 h), CS 4 h + SP600125, CS 2 h + HMP 2 h, and CS 2 h + HMP 2 h + SP600125 groups. Donor livers in the CS 4 h and CS 4 h + SP600125 groups were conventionally cold preserved for 4 h, whereas donor livers in the CS 2 h + HMP 2 h and CS 2 h + HMP 2 h + SP600125 groups were cold preserved for 2 h and then treated with HMP for 2 h. The preservation and perfusion solutions contained SP600125 (20 µM). Follow-up was conducted for 5 days after liver transplantation to compare the surgical outcomes by means of serological examination, pathological results, and survival rate. RESULTS The most satisfactory outcome after liver transplantation was observed in the CS 2 h + HMP 2 h + SP600125 group, which presented with minimal damage of donor livers during 5 days' follow-up. Additionally, serological examination, pathological results, and survival rate concurred in showing better results in the CS 2 h + HMP 2 h ± SP600125 group than in the CS 4 h ± SP600125 group. CONCLUSION HMP in combination with SP600125 has hepatoprotective properties and improves the quality and viability of porcine livers collected after DCD, thus improving prognosis after liver transplantation.
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Affiliation(s)
- Yijie Zhang
- Department of Organ Transplantation and Hepatobiliary, The First Affiliated Hospital of China Medical University, No. 155, Nanjing Street, Shenyang, 110001, Liaoning, People's Republic of China.,The Key Laboratory of Organ Transplantation of Liaoning Province, The First Affiliated Hospital of China Medical University, No. 155, Nanjing Street, Shenyang, 110001, Liaoning, People's Republic of China
| | - Qi Pan
- Department of Organ Transplantation and Hepatobiliary, The First Affiliated Hospital of China Medical University, No. 155, Nanjing Street, Shenyang, 110001, Liaoning, People's Republic of China.,The Key Laboratory of Organ Transplantation of Liaoning Province, The First Affiliated Hospital of China Medical University, No. 155, Nanjing Street, Shenyang, 110001, Liaoning, People's Republic of China
| | - Ying Cheng
- Department of Organ Transplantation and Hepatobiliary, The First Affiliated Hospital of China Medical University, No. 155, Nanjing Street, Shenyang, 110001, Liaoning, People's Republic of China.,The Key Laboratory of Organ Transplantation of Liaoning Province, The First Affiliated Hospital of China Medical University, No. 155, Nanjing Street, Shenyang, 110001, Liaoning, People's Republic of China
| | - Yongfeng Liu
- Department of Organ Transplantation and Hepatobiliary, The First Affiliated Hospital of China Medical University, No. 155, Nanjing Street, Shenyang, 110001, Liaoning, People's Republic of China. .,The Key Laboratory of Organ Transplantation of Liaoning Province, The First Affiliated Hospital of China Medical University, No. 155, Nanjing Street, Shenyang, 110001, Liaoning, People's Republic of China.
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Li S, Zhu Z, Xue M, Pan X, Tong G, Yi X, Fan J, Li Y, Li W, Dong Y, Shen E, Gong W, Wang X, Yu Y, Maeng YJ, Li X, Lee KY, Jin L, Cong W. The protective effects of fibroblast growth factor 10 against hepatic ischemia-reperfusion injury in mice. Redox Biol 2021; 40:101859. [PMID: 33445067 PMCID: PMC7806526 DOI: 10.1016/j.redox.2021.101859] [Citation(s) in RCA: 34] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2020] [Revised: 01/02/2021] [Accepted: 01/04/2021] [Indexed: 02/07/2023] Open
Abstract
Hepatic ischemia-reperfusion injury (IRI) is a major complication of liver surgery and transplantation. IRI leads to hepatic parenchymal cell death, resulting in liver failure, and lacks effective therapeutic approaches. Fibroblast growth factor 10 (FGF10) is a paracrine factor which is well-characterized with respect to its pro-proliferative effects during embryonic liver development and liver regeneration, but its role in hepatic IRI remains unknown. In this study, we investigated the role of FGF10 in liver IRI and identified signaling pathways regulated by FGF10. In a mouse model of warm liver IRI, FGF10 was highly expressed during the reperfusion phase. In vitro experiments demonstrated that FGF10 was primarily secreted by hepatic stellate cells and acted on hepatocytes. The role of FGF10 in liver IRI was further examined using adeno-associated virus-mediated gene silencing and overexpression. Overexpression of FGF10 alleviated liver dysfunction, reduced necrosis and inflammation, and protected hepatocytes from apoptosis in the early acute injury phase of IRI. Furthermore, in the late phase of IRI, FGF10 overexpression also promoted hepatocyte proliferation. Meanwhile, gene silencing of FGF10 had the opposite effect. Further studies revealed that overexpression of FGF10 activated nuclear factor-erythroid 2-related factor 2 (NRF2) and decreased oxidative stress, mainly through activation of the phosphatidylinositol-3-kinase/AKT pathway, and the protective effects of FGF10 overexpression were largely abrogated in NRF2 knockout mice. These results demonstrate the protective effects of FGF10 in liver IRI, and reveal the important role of NRF2 in FGF10-mediated hepatic protection during IRI.
FGF10 is markedly upregulated in the early phase of liver IRI. FGF10 overexpression exerts great potential in ameliorating hepatic IRI. FGF10 knockdown significantly aggravates hepatic IRI. FGF10 overexpression activates PI3K/AKT-NRF2 signaling and thus ameliorates hepatic IRI. NRF2 knockout abrogates the protective effects of FGF10 overexpression during liver IRI.
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Affiliation(s)
- Santie Li
- School of Pharmaceutical Science, Wenzhou Medical University, Wenzhou, PR China; College of Pharmacy and Research Institute of Drug Development, Chonnam National University, Gwangju, Republic of Korea
| | - Zhongxin Zhu
- School of Pharmaceutical Science, Wenzhou Medical University, Wenzhou, PR China
| | - Mei Xue
- Central Laboratory, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, PR China
| | - Xuebo Pan
- School of Pharmaceutical Science, Wenzhou Medical University, Wenzhou, PR China
| | - Gaozan Tong
- School of Pharmaceutical Science, Wenzhou Medical University, Wenzhou, PR China
| | - Xinchu Yi
- School of Pharmaceutical Science, Wenzhou Medical University, Wenzhou, PR China
| | - Junfu Fan
- School of Pharmaceutical Science, Wenzhou Medical University, Wenzhou, PR China
| | - Yuankuan Li
- School of Pharmaceutical Science, Wenzhou Medical University, Wenzhou, PR China
| | - Wanqian Li
- School of Pharmaceutical Science, Wenzhou Medical University, Wenzhou, PR China
| | - Yetong Dong
- School of Pharmaceutical Science, Wenzhou Medical University, Wenzhou, PR China
| | - Enzhao Shen
- School of Pharmaceutical Science, Wenzhou Medical University, Wenzhou, PR China
| | - Wenjie Gong
- School of Pharmaceutical Science, Wenzhou Medical University, Wenzhou, PR China
| | - Xuejiao Wang
- School of Pharmaceutical Science, Wenzhou Medical University, Wenzhou, PR China
| | - Ying Yu
- School of Pharmaceutical Science, Wenzhou Medical University, Wenzhou, PR China
| | - Yoo Jae Maeng
- School of Pharmaceutical Science, Wenzhou Medical University, Wenzhou, PR China
| | - Xiaokun Li
- School of Pharmaceutical Science, Wenzhou Medical University, Wenzhou, PR China
| | - Kwang Youl Lee
- College of Pharmacy and Research Institute of Drug Development, Chonnam National University, Gwangju, Republic of Korea.
| | - Litai Jin
- School of Pharmaceutical Science, Wenzhou Medical University, Wenzhou, PR China.
| | - Weitao Cong
- School of Pharmaceutical Science, Wenzhou Medical University, Wenzhou, PR China.
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20
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Karaosmanoğlu O. P38-β/SAPK-inhibiting and apoptosis-inducing activities of (E)-4-chloro-2-((3-ethoxy-2-hydroxybenzylidene) amino)phenol. Hum Exp Toxicol 2020; 39:1374-1389. [PMID: 32394730 DOI: 10.1177/0960327120924112] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
The present study has three purposes; first evaluating cytotoxicity of (E)-4-chloro-2-((3-ethoxy-2-hydroxybenzylidene)amino)phenol (ACES), second deciphering ACES-mediated cellular death mechanism, and third estimating ACES-mediated alterations in the expressions of mitogen-activated protein kinase (MAPK) pathway-related genes. Neutral red uptake assay, cell cycle analysis, mitochondrial membrane potential (MMP), reactive oxygen species (ROS) measurements, caspase 3/7 and 9 activations, and quantitative reverse transcription-polymerase chain reaction (qRT-PCR) were implemented. IC50 values of ACES-treated five cells were around 4-6 µg/mL. However, Caco-2 and Huh-7 cells were found to be twofold resistant and fivefold sensitive with IC50 values of 11 µg/mL and 0.93 µg/mL, respectively. In this study, it was initially reported that ACES exhibits selective cytotoxicity to Huh-7 cells. In addition, ACES induced apoptosis by nuclear fragmentation, MMP disruption, and intracellular ROS elevation in MCF-7 cells. qRT-PCR experiment indicated the expressions of 30 genes including ATF2, CREB1, MYC, NFATC4 (NFAT3), CCNA1, CCNB1, CCND2, CDK2, CDKN1A (p21CIP1), CDKN1C (p57KIP2), CDKN2A (p16INK4a), CDKN2B (p15INK4b), DLK1, NRAS, CDC42, PAK1, MAP4K1 (HPK1), MAP3K3 (MEKK3), MAP2K3 (MEK3), MAP2K6 (MEK6), MOS, MAPK1 (ERK2), MAPK8 (JNK1), MAPK10 (JNK3), MAPK11 (p38-β), LAMTOR3 (MP1), MAPK8IP2 (JIP-1), PRDX6 (AOP2), COL1A1, and HSPA5 (Grp78) were downregulated at least 1.5-fold. Moreover, ACES effectively inhibited expressions of genes that code for elements of p38-β/stress-activated protein kinase (SAPK) pathway. ACES has the potential to be used for the reversal of trastuzumab resistance in breast cancer patients by inhibiting p38/SAPK pathway in MCF-7 cells. Therefore, with the selective cytotoxic, apoptosis-inducing, and p38-β/SAPK-inhibiting activities, ACES can be utilized for developing a novel anticancer drug.
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Affiliation(s)
- O Karaosmanoğlu
- Department of Biology, Kamil Özdağ Faculty of Science, Karamanoğlu Mehmetbey University, Karaman, Turkey
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21
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Fadel F, Al-Kandari N, Khashab F, Al-Saleh F, Al-Maghrebi M. JNK inhibition alleviates oxidative DNA damage, germ cell apoptosis, and mitochondrial dysfunction in testicular ischemia reperfusion injury. Acta Biochim Biophys Sin (Shanghai) 2020; 52:891-900. [PMID: 32662511 DOI: 10.1093/abbs/gmaa074] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/26/2019] [Indexed: 01/05/2023] Open
Abstract
The aim of this study is to determine whether the c-Jun N-terminal kinase (JNK) signaling is a regulator of oxidative DNA damage, germ cell apoptosis (GCA), and mitochondrial dysfunction during testicular ischemia reperfusion injury (tIRI) using the JNK inhibitor SP600125. Male Sprague Dawley rats (n = 36) were equally divided into three groups: sham, tIRI only, and tIRI + SP600125 (15 mg/kg). Testicular ischemia was induced for 1 h followed by 4 h of reperfusion prior to animal sacrifice. Spermatogenesis was evaluated by light microscopy, while expression of oxidative stress and GCA-related mRNAs and proteins were evaluated by real-time polymerase chain reaction and colorimetric assays, respectively. Expressions of JNK, p53, and survivin were detected by immunofluorescence (IF) staining. Indicators of mitochondrial dysfunction were examined by western blot analysis and colorimetric assay. In comparison to sham, the tIRI testes showed a significant increase in lipid and protein oxidation products. Oxidative DNA damage was reflected by a significant increase in the number of DNA strand breaks, increased concentration of 8-OHdG, and elevated poly (ADP-ribose) polymerase activity. Spermatogenic damage was associated with the activation of caspase 3 and elevated Bax to Bcl2 ratio. This was also accompanied by a significantly heightened IF expression of the phosphorylated forms of JNK and p53 paralled with the suppression of survivin. Mitochondrial dysfunction was reflected by NAD+ depletion, overexpression of uncoupling protein 2, and increased level of cytochrome c. Such tIRI-induced modulations were all attenuated by SP600125 treatment prior to reperfusion. In conclusion, JNK signaling regulates oxidative DNA damage, GCA, and mitochondrial dysfunction through activation of p53 and suppression of survivin during tIRI.
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Affiliation(s)
- Fatemah Fadel
- Department of Biochemistry, Faculty of Medicine, Kuwait University, Jabriyah 13110, Kuwait
| | - Nora Al-Kandari
- Department of Biochemistry, Faculty of Medicine, Kuwait University, Jabriyah 13110, Kuwait
| | - Farah Khashab
- Department of Biochemistry, Faculty of Medicine, Kuwait University, Jabriyah 13110, Kuwait
| | - Farah Al-Saleh
- Department of Biochemistry, Faculty of Medicine, Kuwait University, Jabriyah 13110, Kuwait
| | - May Al-Maghrebi
- Department of Biochemistry, Faculty of Medicine, Kuwait University, Jabriyah 13110, Kuwait
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22
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Guo W, Fang H, Cao S, Chen S, Li J, Shi J, Tang H, Zhang Y, Wen P, Zhang J, Wang Z, Shi X, Pang C, Yang H, Hu B, Zhang S. Six-Transmembrane Epithelial Antigen of the Prostate 3 Deficiency in Hepatocytes Protects the Liver Against Ischemia-Reperfusion Injury by Suppressing Transforming Growth Factor-β-Activated Kinase 1. Hepatology 2020; 71:1037-1054. [PMID: 31393024 PMCID: PMC7155030 DOI: 10.1002/hep.30882] [Citation(s) in RCA: 50] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/29/2019] [Accepted: 07/24/2019] [Indexed: 12/17/2022]
Abstract
BACKGROUND AND AIMS Hepatic ischemia-reperfusion (I/R) injury remains a major challenge affecting the morbidity and mortality of liver transplantation. Effective strategies to improve liver function after hepatic I/R injury are limited. Six-transmembrane epithelial antigen of the prostate 3 (Steap3), a key regulator of iron uptake, was reported to be involved in immunity and apoptotic processes in various cell types. However, the role of Steap3 in hepatic I/R-induced liver damage remains largely unclear. APPROACH AND RESULTS In the present study, we found that Steap3 expression was significantly up-regulated in liver tissue from mice subjected to hepatic I/R surgery and primary hepatocytes challenged with hypoxia/reoxygenation insult. Subsequently, global Steap3 knockout (Steap3-KO) mice, hepatocyte-specific Steap3 transgenic (Steap3-HTG) mice, and their corresponding controls were subjected to partial hepatic warm I/R injury. Hepatic histology, the inflammatory response, and apoptosis were monitored to assess liver damage. The molecular mechanisms of Steap3 function were explored in vivo and in vitro. The results demonstrated that, compared with control mice, Steap3-KO mice exhibited alleviated liver damage after hepatic I/R injury, as shown by smaller necrotic areas, lower serum transaminase levels, decreased apoptosis rates, and reduced inflammatory cell infiltration, whereas Steap3-HTG mice had the opposite phenotype. Further molecular experiments showed that Steap3 deficiency could inhibit transforming growth factor-β-activated kinase 1 (TAK1) activation and downstream c-Jun N-terminal kinase (JNK) and p38 signaling during hepatic I/R injury. CONCLUSIONS Steap3 is a mediator of hepatic I/R injury that functions by regulating inflammatory responses as well as apoptosis through TAK1-dependent activation of the JNK/p38 pathways. Targeting hepatocytes, Steap3 may be a promising approach to protect the liver against I/R injury.
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Affiliation(s)
- Wen‐Zhi Guo
- Department of Hepatobiliary and Pancreatic SurgeryThe First Affiliated Hospital of Zhengzhou UniversityZhengzhouHenan ProvinceChina,Henan Key Laboratory of Digestive Organ TransplantationZhengzhouHenan ProvinceChina,Open and Key Laboratory of Hepatobiliary & Pancreatic Surgery and Digestive Organ Transplantation at Henan UniversitiesZhengzhouHenan ProvinceChina
| | - Hong‐Bo Fang
- Department of Hepatobiliary and Pancreatic SurgeryThe First Affiliated Hospital of Zhengzhou UniversityZhengzhouHenan ProvinceChina,Henan Key Laboratory of Digestive Organ TransplantationZhengzhouHenan ProvinceChina,Open and Key Laboratory of Hepatobiliary & Pancreatic Surgery and Digestive Organ Transplantation at Henan UniversitiesZhengzhouHenan ProvinceChina
| | - Sheng‐Li Cao
- Department of Hepatobiliary and Pancreatic SurgeryThe First Affiliated Hospital of Zhengzhou UniversityZhengzhouHenan ProvinceChina,Henan Key Laboratory of Digestive Organ TransplantationZhengzhouHenan ProvinceChina,Open and Key Laboratory of Hepatobiliary & Pancreatic Surgery and Digestive Organ Transplantation at Henan UniversitiesZhengzhouHenan ProvinceChina
| | - San‐Yang Chen
- Department of Hepatobiliary and Pancreatic SurgeryThe First Affiliated Hospital of Zhengzhou UniversityZhengzhouHenan ProvinceChina,Henan Key Laboratory of Digestive Organ TransplantationZhengzhouHenan ProvinceChina,Open and Key Laboratory of Hepatobiliary & Pancreatic Surgery and Digestive Organ Transplantation at Henan UniversitiesZhengzhouHenan ProvinceChina
| | - Jie Li
- Department of Hepatobiliary and Pancreatic SurgeryThe First Affiliated Hospital of Zhengzhou UniversityZhengzhouHenan ProvinceChina,Henan Key Laboratory of Digestive Organ TransplantationZhengzhouHenan ProvinceChina,Open and Key Laboratory of Hepatobiliary & Pancreatic Surgery and Digestive Organ Transplantation at Henan UniversitiesZhengzhouHenan ProvinceChina
| | - Ji‐Hua Shi
- Department of Hepatobiliary and Pancreatic SurgeryThe First Affiliated Hospital of Zhengzhou UniversityZhengzhouHenan ProvinceChina,Henan Key Laboratory of Digestive Organ TransplantationZhengzhouHenan ProvinceChina,Open and Key Laboratory of Hepatobiliary & Pancreatic Surgery and Digestive Organ Transplantation at Henan UniversitiesZhengzhouHenan ProvinceChina
| | - Hong‐Wei Tang
- Henan Key Laboratory of Digestive Organ TransplantationZhengzhouHenan ProvinceChina,Open and Key Laboratory of Hepatobiliary & Pancreatic Surgery and Digestive Organ Transplantation at Henan UniversitiesZhengzhouHenan ProvinceChina
| | - Yi Zhang
- Department of SurgeryThe First Affiliated Hospital of Zhengzhou UniversityZhengzhouHenan ProvinceChina
| | - Pei‐Hao Wen
- Department of Hepatobiliary and Pancreatic SurgeryThe First Affiliated Hospital of Zhengzhou UniversityZhengzhouHenan ProvinceChina,Henan Key Laboratory of Digestive Organ TransplantationZhengzhouHenan ProvinceChina,Open and Key Laboratory of Hepatobiliary & Pancreatic Surgery and Digestive Organ Transplantation at Henan UniversitiesZhengzhouHenan ProvinceChina
| | - Jia‐Kai Zhang
- Department of Hepatobiliary and Pancreatic SurgeryThe First Affiliated Hospital of Zhengzhou UniversityZhengzhouHenan ProvinceChina,Henan Key Laboratory of Digestive Organ TransplantationZhengzhouHenan ProvinceChina,Open and Key Laboratory of Hepatobiliary & Pancreatic Surgery and Digestive Organ Transplantation at Henan UniversitiesZhengzhouHenan ProvinceChina
| | - Zhi‐Hui Wang
- Department of Hepatobiliary and Pancreatic SurgeryThe First Affiliated Hospital of Zhengzhou UniversityZhengzhouHenan ProvinceChina,Henan Key Laboratory of Digestive Organ TransplantationZhengzhouHenan ProvinceChina,Open and Key Laboratory of Hepatobiliary & Pancreatic Surgery and Digestive Organ Transplantation at Henan UniversitiesZhengzhouHenan ProvinceChina
| | - Xiao‐Yi Shi
- Department of Hepatobiliary and Pancreatic SurgeryThe First Affiliated Hospital of Zhengzhou UniversityZhengzhouHenan ProvinceChina,Henan Key Laboratory of Digestive Organ TransplantationZhengzhouHenan ProvinceChina,Open and Key Laboratory of Hepatobiliary & Pancreatic Surgery and Digestive Organ Transplantation at Henan UniversitiesZhengzhouHenan ProvinceChina
| | - Chun Pang
- Department of Hepatobiliary and Pancreatic SurgeryThe First Affiliated Hospital of Zhengzhou UniversityZhengzhouHenan ProvinceChina,Henan Key Laboratory of Digestive Organ TransplantationZhengzhouHenan ProvinceChina,Open and Key Laboratory of Hepatobiliary & Pancreatic Surgery and Digestive Organ Transplantation at Henan UniversitiesZhengzhouHenan ProvinceChina
| | - Han Yang
- Department of Hepatobiliary and Pancreatic SurgeryThe First Affiliated Hospital of Zhengzhou UniversityZhengzhouHenan ProvinceChina,Henan Key Laboratory of Digestive Organ TransplantationZhengzhouHenan ProvinceChina,Open and Key Laboratory of Hepatobiliary & Pancreatic Surgery and Digestive Organ Transplantation at Henan UniversitiesZhengzhouHenan ProvinceChina
| | - Bo‐Wen Hu
- Department of Hepatobiliary and Pancreatic SurgeryThe First Affiliated Hospital of Zhengzhou UniversityZhengzhouHenan ProvinceChina,Henan Key Laboratory of Digestive Organ TransplantationZhengzhouHenan ProvinceChina,Open and Key Laboratory of Hepatobiliary & Pancreatic Surgery and Digestive Organ Transplantation at Henan UniversitiesZhengzhouHenan ProvinceChina
| | - Shui‐Jun Zhang
- Department of Hepatobiliary and Pancreatic SurgeryThe First Affiliated Hospital of Zhengzhou UniversityZhengzhouHenan ProvinceChina,Henan Key Laboratory of Digestive Organ TransplantationZhengzhouHenan ProvinceChina,Open and Key Laboratory of Hepatobiliary & Pancreatic Surgery and Digestive Organ Transplantation at Henan UniversitiesZhengzhouHenan ProvinceChina
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Chen W, Zheng D, Mou T, Pu J, Dai J, Huang Z, Luo Y, Zhang Y, Wu Z. Tle1 attenuates hepatic ischemia/reperfusion injury by suppressing NOD2/NF-κB signaling. Biosci Biotechnol Biochem 2020; 84:1176-1182. [PMID: 32114961 DOI: 10.1080/09168451.2020.1735928] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
Liver damage induced by ischemia/reperfusion (I/R) remains a primary issue in multiple hepatic surgeries. Innate immune-mediated inflammatory responses during the reperfusion stage aggravate the injury. Nevertheless, the detailed mechanism of hepatic I/R has not been fully clarified yet. Our research focuses on the role of Transducin-like enhancer of split-1 (Tle1) in the liver I/R injury and the relation between Tle1 and Nucleotide-binding oligomerization domain 2 (NOD2). To answer these questions, we constructed mouse models of I/R and cell models of hypoxia/reoxygenation (H/R). We found decreased Tle1 accompanied by increased NOD2 during reperfusion. Mice pro-injected with Tle1-siRNA emerged aggravated liver dysfunction. Repression of Tle1 had a significant impact on NOD2 and downstream NF-κB signaling in vitro. However, alteration of NOD2 failed to affect the expression of Tle1. To conclude, our study demonstrates that Tle1 shelters the liver from I/R injury through suppression of NOD2-dependent NF-κB activation and subsequent inflammatory responses.
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Affiliation(s)
- Wei Chen
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Daofeng Zheng
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Tong Mou
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Junliang Pu
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Jiangwen Dai
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Zuotian Huang
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Yunhai Luo
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Yuke Zhang
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Zhongjun Wu
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
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Inhibition of Frizzled-2 by small interfering RNA protects rat hepatic BRL-3A cells against cytotoxicity and apoptosis induced by Hypoxia/Reoxygenation. GASTROENTEROLOGIA Y HEPATOLOGIA 2020; 43:107-116. [PMID: 31964521 DOI: 10.1016/j.gastrohep.2019.02.006] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/03/2018] [Revised: 02/12/2019] [Accepted: 02/22/2019] [Indexed: 01/30/2023]
Abstract
Frizzled-2 plays an important role in maintaining normal hepatic cell functionality. This study aimed to investigate the role of inhibition of Frizzled-2 in protecting rat liver BRL-3A cells from Hypoxia/Reoxygenation (H/R). In vitro H/R hepatic cell model was established by culturing BRL-3A cells under H/R condition. Frizzled-2 siRNA was transfected into BRL-3A cells to inhibit Frizzled-2 signaling. Wnt5a and Frizzled-2 were significantly increased in BRL-3A cells upon H/R treatment. H/R treatment induced cell cytotoxicity, the early apoptosis rate and the intracellular Ca2+ level in BRL-3A cells while silencing frizzled-2 gene decreased the H/R induced cell cytotoxicity, apoptosis and intracellular Ca2+ level. In vivo mice study further showed the up-regulation of Frizzled-2/Wnt 5 pathway and cleaved Caspase-3 expression in liver tissues under ischemia and reperfusion injury (IRI). In summary, inhibition of Frizzled-2 by its siRNA may protects BRL-3A cells by attenuating the H/R induced cell cytotoxicity and apoptosis.
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Identification of Key Transcription Factors AP-1 and AP-1-Dependent miRNAs Forming a Co-Regulatory Network Controlling PTEN in Liver Ischemia/Reperfusion Injury. BIOMED RESEARCH INTERNATIONAL 2019; 2019:8962682. [PMID: 31781649 PMCID: PMC6875376 DOI: 10.1155/2019/8962682] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/08/2019] [Revised: 07/07/2019] [Accepted: 07/18/2019] [Indexed: 11/18/2022]
Abstract
Liver ischemia/reperfusion (I/R) injury is a complex and common clinical disease with limited therapeutic options. The aim of our study was to discover the candidate target genes in liver I/R injury and to further elucidate the potential regulatory mechanisms, especially the ones involving transcription factors and miRNAs. The analysis of mouse data set GSE10657 from Gene Expression Omnibus database (GEO) revealed 203 differentially expressed genes (DEGs) including 19 transcription factors (TFs). Functional and pathway enrichment analyses were conducted to explore their biological functions. We further obtained the targets of TFs and miRNAs, to form our TF-mRNA/TF-miRNA-mRNA co-regulatory network. In our network, we found that the important subunits of activator protein 1 (AP-1) including JUN, FOS and ATF3, were hub genes in liver I/R injury. AP-1 target genes were activated in our mouse models. AP-1 could transcriptionally activate phosphatase and tensin homolog (PTEN) while AP-1-dependent miRNAs countered this effect. In conclusion, this study suggested that AP-1, together with AP-1-dependent miRNAs formed a co-regulatory network enabling AP-1 target genes to be tightly controlled, which will complete the mechanism of liver ischemia/reperfusion injury and provide direction for finding potential therapeutic targets.
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26
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Sun Q, He Q, Xu J, Liu Q, Lu Y, Zhang Z, Xu X, Sun B. Guanine nucleotide-binding protein G(i)α2 aggravates hepatic ischemia-reperfusion injury in mice by regulating MLK3 signaling. FASEB J 2019; 33:7049-7060. [PMID: 30840837 DOI: 10.1096/fj.201802462r] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2023]
Abstract
Hepatic ischemia-reperfusion (I/R) injury is a major challenge in liver resection and transplantation surgeries. Previous studies have revealed that guanine nucleotide-binding protein G(i)α2 (GNAI2) was involved in the progression of myocardial and cerebral I/R injury, but the role and function of GNAI2 in hepatic I/R have not been elucidated. The hepatocyte-specific GNAI2 knockout (GNAI2hep-/-) mice were generated and subjected to hepatic I/R injury. Primary hepatocytes isolated from GNAI2hep-/- and GNAI2flox/flox mice were cultured and challenged to hypoxia-reoxygenation insult. The specific function of GNAI2 in I/R-triggered hepatic injury and the underlying molecular mechanism were explored by various phenotypic analyses and molecular biology methods. In this study, we demonstrated that hepatic GNAI2 expression was significantly increased in liver transplantation patients and wild-type mice after hepatic I/R. Interestingly, hepatocyte-specific GNAI2 deficiency attenuated I/R-induced liver damage, inflammation cytokine expression, macrophage/neutrophil infiltration, and hepatocyte apoptosis in vivo and in vitro. Mechanistically, up-regulation of GNAI2 phosphorylates mixed-lineage protein kinase 3 (MLK3) through direct binding, which exacerbated hepatic I/R damage via MAPK and NF-κB pathway activation. Furthermore, blocking MLK3 signaling reversed GNAI2-mediated hepatic I/R injury. Our study firstly identifies GNAI2 as a promising target for prevention of hepatic I/R-induced injury and related liver diseases.-Sun, Q., He, Q., Xu, J., Liu, Q., Lu, Y., Zhang, Z., Xu, X., Sun, B. Guanine nucleotide-binding protein G(i)α2 aggravates hepatic ischemia-reperfusion injury in mice by regulating MLK3 signaling.
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Affiliation(s)
- Qikai Sun
- The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
- Department of Hepatobiliary Surgery, Nanjing Drum Tower Hospital, Clinical College of Nanjing Medical University, Nanjing, China; and
- Department of Hepatobiliary Surgery, The Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing, China
| | - Qifeng He
- The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
- Department of Hepatobiliary Surgery, Nanjing Drum Tower Hospital, Clinical College of Nanjing Medical University, Nanjing, China; and
- Department of Hepatobiliary Surgery, The Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing, China
| | - Jianbo Xu
- The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
- Department of Hepatobiliary Surgery, Nanjing Drum Tower Hospital, Clinical College of Nanjing Medical University, Nanjing, China; and
- Department of Hepatobiliary Surgery, The Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing, China
| | - Qiaoyu Liu
- Department of Hepatobiliary Surgery, Nanjing Drum Tower Hospital, Clinical College of Nanjing Medical University, Nanjing, China; and
- Department of Hepatobiliary Surgery, The Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing, China
| | - Yijun Lu
- The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
- Department of Hepatobiliary Surgery, Nanjing Drum Tower Hospital, Clinical College of Nanjing Medical University, Nanjing, China; and
- Department of Hepatobiliary Surgery, The Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing, China
| | - Zechuan Zhang
- The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
- Department of Hepatobiliary Surgery, Nanjing Drum Tower Hospital, Clinical College of Nanjing Medical University, Nanjing, China; and
- Department of Hepatobiliary Surgery, The Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing, China
| | - Xiaoliang Xu
- Department of Hepatobiliary Surgery, Nanjing Drum Tower Hospital, Clinical College of Nanjing Medical University, Nanjing, China; and
- Department of Hepatobiliary Surgery, The Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing, China
| | - Beicheng Sun
- The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
- Department of Hepatobiliary Surgery, Nanjing Drum Tower Hospital, Clinical College of Nanjing Medical University, Nanjing, China; and
- Department of Hepatobiliary Surgery, The Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing, China
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Jiménez-Castro MB, Cornide-Petronio ME, Gracia-Sancho J, Casillas-Ramírez A, Peralta C. Mitogen Activated Protein Kinases in Steatotic and Non-Steatotic Livers Submitted to Ischemia-Reperfusion. Int J Mol Sci 2019; 20:1785. [PMID: 30974915 PMCID: PMC6479363 DOI: 10.3390/ijms20071785] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2019] [Revised: 04/03/2019] [Accepted: 04/09/2019] [Indexed: 12/12/2022] Open
Abstract
: We analyzed the participation of mitogen-activated protein kinases (MAPKs), namely p38, JNK and ERK 1/2 in steatotic and non-steatotic livers undergoing ischemia-reperfusion (I-R), an unresolved problem in clinical practice. Hepatic steatosis is a major risk factor in liver surgery because these types of liver tolerate poorly to I-R injury. Also, a further increase in the prevalence of steatosis in liver surgery is to be expected. The possible therapies based on MAPK regulation aimed at reducing hepatic I-R injury will be discussed. Moreover, we reviewed the relevance of MAPK in ischemic preconditioning (PC) and evaluated whether MAPK regulators could mimic its benefits. Clinical studies indicated that this surgical strategy could be appropriate for liver surgery in both steatotic and non-steatotic livers undergoing I-R. The data presented herein suggest that further investigations are required to elucidate more extensively the mechanisms by which these kinases work in hepatic I-R. Also, further researchers based in the development of drugs that regulate MAPKs selectively are required before such approaches can be translated into clinical liver surgery.
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Affiliation(s)
| | | | - Jordi Gracia-Sancho
- Liver Vascular Biology Research Group, Barcelona Hepatic Hemodynamic Laboratory IDIBAPS, 08036 Barcelona, Spain.
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), 08036 Barcelona, Spain.
| | - Araní Casillas-Ramírez
- Hospital Regional de Alta Especialidad de Ciudad Vitoria, Ciudad Victoria 87087, Mexico.
- Facultad de Medicina e ingeniería en Sistemas Computacionales de Matamoros, Universidad Autónoma de Tamaulipas, Matamoros 87300, México.
| | - Carmen Peralta
- Institut d'Investigacions Biomèdiques August Pi I Sunyer (IDIBAPS), Barcelona 08036, Spain.
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), 08036 Barcelona, Spain.
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Ke H, Zhang X, Cheng L, Fan Y, Xiao S, Ma Y, Feng G. Bioinformatic analysis to explore key genes associated with brain ischemia–reperfusion injury in rats. Int J Neurosci 2019; 129:945-954. [PMID: 30889366 DOI: 10.1080/00207454.2019.1595615] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/18/2023]
Affiliation(s)
- Hong Ke
- Department of Neurology, The Fourth People’s Hospital of Jinan, Jinan, Shandong, China
| | - Xiaoli Zhang
- Department of Nephrology, The Fourth People's Hospital of Jinan, Jinan, Shandong, China
| | - Lin Cheng
- Department of Emergency, Shandong Provincial Third Hospital, Jinan, Shandong, China
| | - Yanxia Fan
- Department of Neurology, The Fourth People’s Hospital of Jinan, Jinan, Shandong, China
| | - Shuping Xiao
- Department of Neurology, The Fourth People’s Hospital of Jinan, Jinan, Shandong, China
| | - Yingwen Ma
- Department of Neurology, The Fourth People’s Hospital of Jinan, Jinan, Shandong, China
| | - Guangkun Feng
- Department of Neurology, The Fourth People’s Hospital of Jinan, Jinan, Shandong, China
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Indispensable role of β-arrestin2 in the protection of remifentanil preconditioning against hepatic ischemic reperfusion injury. Sci Rep 2019; 9:2087. [PMID: 30765766 PMCID: PMC6376065 DOI: 10.1038/s41598-018-38456-9] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2016] [Accepted: 12/20/2018] [Indexed: 12/16/2022] Open
Abstract
Our previous study demonstrated that remifentanil, an opioid agonist, conferred profound liver protection during hepatic ischemia reperfusion injury (HIRI), in which Toll-like receptors (TLRs) played a crucial role in mediating the inflammatory responses. β-arrestin2, a well-known mu opioid receptor desensitizer, is also a negatively regulator of Toll-like receptor 4 (TLR4)-mediated inflammatory reactions in a mitogen-activated protein kinase (MAPK)-dependent manner. Using the rodent models of hepatic ischemia reperfusion injury both in wild type and TLR4 knockout (TLR4 KO) mice, we found that remifentanil preconditioning could inhibit the expression of TLR4 and reduce the inflammatory response induced by HIRI in wild type but not in TLR4 KO mice. For the in-vitro study, LPS was used to treat RAW264.7 macrophage cells to mimic the inflammatory response induced by HIRI. Remifentanil increased β-arrestin2 expression both in vivo and in vitro, while after silencing β-arrestin2 RNA, the effect of remifentanil in reducing cell death and apoptosis, as well as decreasing phosphorylation of ERK and JNK were abolished in RAW264.7 cells. These data suggested that remifentanil could ameliorate mice HIRI through upregulating β-arrestin2 expression, which may function as a key molecule in bridging opioid receptor and TLR4 pathway.
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Zhang P, Ming Y, Cheng K, Niu Y, Ye Q. Gene Expression Profiling in Ischemic Postconditioning to Alleviate Mouse Liver Ischemia/Reperfusion Injury. Int J Med Sci 2019; 16:343-354. [PMID: 30745817 PMCID: PMC6367534 DOI: 10.7150/ijms.29393] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/21/2018] [Accepted: 12/17/2018] [Indexed: 12/16/2022] Open
Abstract
Ischemic postconditioning (IPO) attenuates hepatic ischemia/reperfusion (I/R) injury. However, little is known about the underlying biological pathophysiology, which could be, at least in part, informed by exploring the transcriptomic changes using next-generation RNA sequencing (RNA-Seq). In this study, 18 mice (C57BL/6) were involved and randomly assigned to three groups: normal (n=6), I/R (n=6, subjected to 70% hepatic I/R), and IR+IPO (n=6, applying IPO to mice with I/R injury). We randomly selected 3 mice per group and extracted their liver tissues for next-generation RNA-Seq. We performed a bioinformatics analysis for two comparisons: normal vs. I/R and I/R vs. IR+IPO. From the analysis, 2416 differentially expressed genes (DEGs) were identified (p < 0.05 and fold change ≥ 1.5). Gene ontology (GO) analysis revealed that these genes were mainly related to cellular metabolic processes, nucleic acids and protein binding processes. The enriched Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways for the DEGs were the mitogen-activated protein kinase (MAPK), IL-17 signalling pathway, regulating pluripotency of stem cells, and insulin resistance pathway. Validation of 12 selected DEGs by qRT-PCR showed that Cyr61, Atf3, Nr4a1, Gdf15, Osgin1, Egr1, Epha2, Dusp1, Dusp6, Gadd45a and Gadd45b were significantly amplified. Finally, a protein-protein interaction (PPI) network constructed to determine interactions of these 11 DEGs. In summary, by exploring gene expression profiling in regard to hepatic I/R and IPO using next-generation RNA-Seq, we suggested a few progression-related genes and pathways, providing some clues for future experimental research.
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Affiliation(s)
- Pengpeng Zhang
- Department of Transplant Surgery, The Third Xiangya Hospital of Central South University, Changsha 410013, China
| | - Yingzi Ming
- Department of Transplant Surgery, The Third Xiangya Hospital of Central South University, Changsha 410013, China
| | - Ke Cheng
- Department of Transplant Surgery, The Third Xiangya Hospital of Central South University, Changsha 410013, China
| | - Ying Niu
- Department of Transplant Surgery, The Third Xiangya Hospital of Central South University, Changsha 410013, China
| | - Qifa Ye
- Department of Transplant Surgery, The Third Xiangya Hospital of Central South University, Changsha 410013, China.,Zhongnan Hospital of Wuhan University, Institute of Hepatobiliary Diseases of Wuhan University, Transplant Center of Wuhan University, Hubei Key Laboratory of Medical Technology on Transplantation, Wuhan, Hubei 430071, China
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Ren F, Mu N, Gao M, Sun J, Zhang C, Sun X, Li L, Li J, Liu T, Tse G, Dong M. Role of JNK signalling pathway and platelet‑lymphocyte aggregates in myocardial ischemia‑reperfusion injury and the cardioprotective effect of ischemic postconditioning in rats. Mol Med Rep 2018; 18:5237-5242. [PMID: 30320401 DOI: 10.3892/mmr.2018.9545] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2018] [Accepted: 08/30/2018] [Indexed: 11/06/2022] Open
Abstract
In myocardial ischemia‑reperfusion injury (MIRI), increased activity of the c‑Jun N‑terminal kinase (JNK) pathway and the activation of platelets that leads to the formation of platelet‑leukocyte aggregates (PLAs) have been observed. It was hypothesized that ischemic postconditioning in MIRI exerts cardioprotective effects by altering JNK activity, which in turn leads to reduced PLA levels. A total of 60 rats were randomly divided into 6 groups (n=10 for each group): i) Control; ii) ischemia‑reperfusion injury alone; iii) ischemia‑reperfusion with postconditioning (PostC group), iv) treatment with the JNK inhibitor‑SP600125; v) postC and treatment with anisomycin; and vi) treatment with the JNK activator‑anisomycin. Subsequently, the levels of PLA, infarct size, myocardial injury markers (creatinine kinase‑muscle/brain and troponin I) and were measured. Western blotting was used to determine the protein expression of phosphorylated‑JNK. MIRI led to increased myocardial infarct size that was associated with raised troponin I and creatine kinase‑muscle/brain. At different time points of MIRI, the level of PLA gradually increased. Compared with the injury‑reperfusion group, the level of PLA in the PostC and Inhibitor‑JNK groups was significantly reduced at 60 min and 3 h following reperfusion. MIRI was able to increase the expression of phosphorylated JNK. These effects were significantly reduced by ischemic postC or by treatment with SP600125. By contrast, the addition of anisomycin attenuated these protective effects. JNK is a critical mediator of MIRI. Ischemic postC can reduce the level of PLA during reperfusion by inhibiting the phosphorylation of JNK MAPK, thereby reducing MIRI. Pharmacological inhibition and activation of JNK can improve and reduce cardioprotective effects, respectively. These results explained the mechanism of the cardioprotection of postC and provided novel insight and target for the therapeutic strategy of MIRI.
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Affiliation(s)
- Faxin Ren
- Department of Cardiology, The Affiliated Yantai Yuhuangding Hospital of Qingdao University, Yantai, Shandong 264000, P.R. China
| | - Nan Mu
- Department of Gynaecology, The Affiliated Yantai Yuhuangding Hospital of Qingdao University, Yantai, Shandong 264000, P.R. China
| | - Mingxiao Gao
- Department of Cardiology, The Affiliated Yantai Yuhuangding Hospital of Qingdao University, Yantai, Shandong 264000, P.R. China
| | - Jing Sun
- Department of Cardiology, The Affiliated Yantai Yuhuangding Hospital of Qingdao University, Yantai, Shandong 264000, P.R. China
| | - Chuanhuan Zhang
- Department of Cardiology, The Affiliated Yantai Yuhuangding Hospital of Qingdao University, Yantai, Shandong 264000, P.R. China
| | - Xiaojian Sun
- Department of Cardiology, The Affiliated Yantai Yuhuangding Hospital of Qingdao University, Yantai, Shandong 264000, P.R. China
| | - Liudong Li
- Department of Cardiology, The Affiliated Yantai Yuhuangding Hospital of Qingdao University, Yantai, Shandong 264000, P.R. China
| | - Jun Li
- Department of Cardiology, The Affiliated Yantai Yuhuangding Hospital of Qingdao University, Yantai, Shandong 264000, P.R. China
| | - Tong Liu
- Tianjin Key Laboratory of Ionic‑Molecular Function of Cardiovascular Disease, Department of Cardiology, Tianjin Institute of Cardiology, Second Hospital of Tianjin Medical University, Tianjin 300211, P.R. China
| | - Gary Tse
- Li Ka Shing Institute of Health Sciences, Faculty of Medicine, Chinese University of Hong Kong, Hong Kong, SAR, P.R. China
| | - Mei Dong
- Department of Cardiology, The Affiliated Yantai Yuhuangding Hospital of Qingdao University, Yantai, Shandong 264000, P.R. China
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Deng J, Feng J, Liu T, Lu X, Wang W, Liu N, Lv Y, Liu Q, Guo C, Zhou Y. Beraprost sodium preconditioning prevents inflammation, apoptosis, and autophagy during hepatic ischemia-reperfusion injury in mice via the P38 and JNK pathways. Drug Des Devel Ther 2018; 12:4067-4082. [PMID: 30568428 PMCID: PMC6276616 DOI: 10.2147/dddt.s182292] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/07/2023] Open
Abstract
OBJECTIVE The goal of this study was to determine the effects of beraprost sodium (BPS) preconditioning on hepatic ischemia-reperfusion (IR) injury and its underlying mechanisms of action. MATERIALS AND METHODS Mice were randomly divided into sham, IR, IR+BPS (50 µg/kg), and IR+BPS (100 µg/kg) groups. Saline or BPS was given to the mice by daily gavage for 1 week before the hepatic IR model was established. Liver tissues and orbital blood were collected at 2, 8, and 24 hours after reperfusion for the determination of liver enzymes, inflammatory mediators, apoptosis- and autophagy-related proteins, key proteins in P38 and c-Jun N-terminal kinase (JNK) cascades, and evaluation of liver histopathology. RESULTS BPS preconditioning effectively reduced serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels, improved pathological damage, ameliorated production of tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β), and affected expressions of Bax, Bcl-2, Caspase-3, Caspase-8, and Caspase-9, microtubule-associated protein 1 light chain 3 (LC3), Beclin-1, and P62. The protective effects of BPS preconditioning were associated with reduced P38 and JNK phosphorylation. CONCLUSION BPS preconditioning ameliorated hepatic IR injury by suppressing inflammation, apoptosis, and autophagy, partially via inhibiting activation of the P38 and JNK cascades.
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Affiliation(s)
- Jingfan Deng
- Department of Gastroenterology, Shanghai Tenth People’s Hospital, Tongji University School of Medicine, Shanghai 200072, People’s Republic of China, ;
| | - Jiao Feng
- Department of Gastroenterology, Shanghai Tenth People’s Hospital, Tongji University School of Medicine, Shanghai 200072, People’s Republic of China, ;
| | - Tong Liu
- Department of Gastroenterology, Shanghai Tenth People’s Hospital, Tongji University School of Medicine, Shanghai 200072, People’s Republic of China, ;
| | - Xiya Lu
- Department of Gastroenterology, Shanghai Tenth People’s Hospital, Tongji University School of Medicine, Shanghai 200072, People’s Republic of China, ;
| | - Wenwen Wang
- Department of Gastroenterology, Shanghai Tenth People’s Hospital, Tongji University School of Medicine, Shanghai 200072, People’s Republic of China, ;
| | - Ning Liu
- Department of Gastroenterology, Shanghai Tenth People’s Hospital, School of Clinical Medicine of Nanjing Medical University, Shanghai 200072, People’s Republic of China
| | - Yang Lv
- Department of Gastroenterology, Shanghai Tenth People’s Hospital, Tongji University School of Medicine, Shanghai 200072, People’s Republic of China, ;
| | - Qing Liu
- Department of Gastroenterology, Shanghai Tenth People’s Hospital, Tongji University School of Medicine, Shanghai 200072, People’s Republic of China, ;
| | - Chuanyong Guo
- Department of Gastroenterology, Shanghai Tenth People’s Hospital, Tongji University School of Medicine, Shanghai 200072, People’s Republic of China, ; ,Correspondence: Chuanyong Guo; Yingqun Zhou, Department of Gastroenterology, Shanghai Tenth People’s Hospital, Tongji University School of Medicine, Number 301, Middle Yanchang Road, Jing’an, Shanghai 200072, People’s Republic of China, Tel +86 21 6630 2535; +86 21 3605 0414, Fax +86 21 6630 3983, Email ;
| | - Yingqun Zhou
- Department of Gastroenterology, Shanghai Tenth People’s Hospital, Tongji University School of Medicine, Shanghai 200072, People’s Republic of China, ; ,Correspondence: Chuanyong Guo; Yingqun Zhou, Department of Gastroenterology, Shanghai Tenth People’s Hospital, Tongji University School of Medicine, Number 301, Middle Yanchang Road, Jing’an, Shanghai 200072, People’s Republic of China, Tel +86 21 6630 2535; +86 21 3605 0414, Fax +86 21 6630 3983, Email ;
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Suh SW, Choi YS, Hong SA, Kang H, Lee D, Kim HR. Preoperative erythropoietin treatment improves survival following major hepatic resection in a cirrhotic rat model. Clin Res Hepatol Gastroenterol 2018; 42:347-352. [PMID: 29580765 DOI: 10.1016/j.clinre.2017.12.001] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/01/2017] [Revised: 12/06/2017] [Accepted: 12/06/2017] [Indexed: 02/04/2023]
Abstract
AIM Major hepatic resection of a cirrhotic liver may result in a fatal clinical course. Preoperative erythropoietin (EPO) treatment has been shown to have protective properties and to stimulate liver regeneration. This study aims to investigate the effect of preoperative EPO on survival following major hepatic resection in a cirrhotic rat model. METHODS Cirrhotic liver was induced by intraperitoneal injection of thioacetamide (200mg/kg/mL) in 72 Lewis rats. Each 36 rats received EPO (1IU/g, every second day, 5 times preoperatively) or saline (control) and major hepatectomy (removal of the left and half of the median lobe) was performed. Biochemical and immunohistochemical parameters, cytokines and overall survival were compared following surgery. RESULTS Rats that received preoperative EPO had decreased hepatic aspartate aminotransferase, alanine aminotransferase and interleukin (IL)-1β expression, 48hours following surgery. They had increased hepatocyte growth factor and vascular endothelial growth factor expression at 1hour, increased IL-6 expression at 24, 48 and 120hours and increased Ki-67, 120hours following surgery. Overall, survival was significantly improved among EPO-treated rats (P=0.034). CONCLUSION Preoperative EPO treatment has a protective effect and stimulates liver regeneration, leading to improved overall survival following major hepatectomy in a cirrhotic rat model.
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Affiliation(s)
- Suk-Won Suh
- Department of Surgery, College of Medicine, Chung-Ang University, 224-1, Heuk Seok-Dong, Dongjak-Ku, Seoul, 156-755, South Korea
| | - Yoo Shin Choi
- Department of Surgery, College of Medicine, Chung-Ang University, 224-1, Heuk Seok-Dong, Dongjak-Ku, Seoul, 156-755, South Korea.
| | - Soon Auck Hong
- Department of Pathology, College of Medicine, Soonchunhyang University, Chungnam, South Korea
| | - Hyun Kang
- Department of Anesthesiology and Pain Medicine, College of Medicine, Chung-Ang University, Seoul, South Korea
| | - Donghyun Lee
- Department of Biomedical Engineering, School of Integrative Engineering, Chung-Ang University, Seoul, 156-756, South Korea
| | - Hye Ryoun Kim
- Department of Laboratory Medicine, College of Medicine, Chung-Ang University, Seoul, South Korea
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Sun YW, Qiu HC, Ou MC, Chen RL, Liang G. Saponins isolated from Schizocapsa plantaginea inhibit human hepatocellular carcinoma cell growth in vivo and in vitro via mitogen-activated protein kinase signaling. Chin J Nat Med 2018; 16:29-40. [PMID: 29425588 DOI: 10.1016/s1875-5364(18)30027-x] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2017] [Indexed: 12/21/2022]
Abstract
The underground cane of Schizocapsa plantaginea (Hance) has long been used by Chinese ethnic minority as a constituent of anti-cancer formulae. Saponins are abundant secondary metabolic products located in the underground cane of this plant. The potential therapeutic effects of total saponins isolated from Schizocapsa plantaginea (Hance) (SSPH) on human hepatocellular carcinoma (HCC) were tested in vitro in human liver cancer cell lines, SMMC-7721 and Bel-7404. Apoptosis and cell cycle arrest were determined using flow cytometry, caspase activation was determined by ELISA, and PARP, cleaved PARP, mitogen-activated protein kinase (MAPK) expression and phosphorylation were measured using Western blotting analysis. In vivo anti-HCC effects of SSPH were verified in nude mouse xenograft model. SSPH exerted markedly inhibitory effect on HCC cell proliferation in time- and concentration-dependent manner. Moreover, SSPH significantly induced apoptosis through caspase-dependent signaling and arrested cell cycle at G2/M phase. These anti-proliferation effects of SSPH were associated with up-regulated phosphorylation of extracellular signal-regulated kinase-1/2 (Erk1/2) and c-jun-NH2-kinase-1/2 (JNK1/2) and reduced phosphorylation of p38MAPK. Furthermore, inhibitors of ERK, UO126, and JNK, SP600125 inhibited the anti-proliferation effects by SSPH, suggesting that Erk and JNK were the effector molecules in SSPH induced anti-proliferative action. During in vivo experiments, SSPH was found to inhibit xenograft tumor growth in nude mice, with a similar mechanism in vitro. Our study confirmed that SSPH exerted antagonistic effects on human liver cancer cells both in vitro and in vivo. Molecular mechanisms underlying SSPH action might be closely associated with MAPK signaling pathways. These results indicated that SSPH has potential therapeutic effects on HCC.
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Affiliation(s)
- Yue-Wen Sun
- College of Pharmacy, Guangxi Medical University, Nanning 530022, China
| | - Han-Chen Qiu
- College of Pharmacy, Guangxi Medical University, Nanning 530022, China
| | - Ming-Chun Ou
- College of Pharmacy, Guangxi Medical University, Nanning 530022, China
| | - Run-Li Chen
- College of Pharmacy, Guangxi Medical University, Nanning 530022, China
| | - Gang Liang
- College of Pharmacy, Guangxi Medical University, Nanning 530022, China.
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Wang W, Xiao Q, Hu XY, Liu ZZ, Zhang XJ, Xia ZP, Ye QF, Niu Y. Mild Hypothermia Pretreatment Attenuates Liver Ischemia Reperfusion Injury Through Inhibiting c-Jun NH2-terminal Kinase Phosphorylation in Rats. Transplant Proc 2018; 50:259-266. [PMID: 29407320 DOI: 10.1016/j.transproceed.2017.12.019] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/23/2017] [Revised: 11/22/2017] [Accepted: 12/12/2017] [Indexed: 02/07/2023]
Abstract
BACKGROUND Mild hypothermia is known to be protected against ischemia reperfusion (IR) injury. But the exact mechanisms of protection have not yet been fully understood and its usage has been limited. Mild hypothermia pretreatment (MHP) is used to investigate the mechanisms of the protective effects against liver IR injury. METHODS Anesthetized male Sprague-Dawley rats were randomly divided into five groups including the normal group (N), sham group (S), MHP group, normothermia pretreatment (NP) + IR group, and the MHP + IR group. In the pretreatment groups, mild hypothermia (32.2 ± 0.3°C) and normothermia (37 ± 0.5°C) pretreatment were applied for 2 hours, respectively. Then the IR groups suffered partial (70%) hepatic ischemia for 1 hour and reperfusion for 6 hours. At last, hepatic injury, apoptosis, and protein expression were assessed. RESULTS Levels of serum alanine transaminase, hepatic injury, hepatocyte apoptosis, and c-Jun N-terminal kinase (JNK) phosphorylation were significantly higher in the IR groups. But when compared to NP, all these changes induced by IR were markedly attenuated by MHP. Serum alanine transaminase levels were 383.4 ± 13.1U/L in the MHP + IR group and 951.3 ± 39.4 U/L in the NP + IR group. The histologic score of liver injury in the MHP + IR group was 4.83 ± 1.17, whereas in the NP + IR group it was 10.5 ± 1.05. The proportion of apoptotic cells in the MHP + IR group was 11.58 ± 0.60, but in the NP + IR group, it was 44.95 ± 1.61. The phosphorylation of JNK was also significantly reduced in the MHP + IR group. All these differences are statistically significant (P < .05). CONCLUSIONS MHP could markedly reduce liver IR injury, and these protective effects may be mainly exerted via inhibition of JNK phosphorylation.
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Affiliation(s)
- W Wang
- Zhongnan Hospital of Wuhan University, Institute of Hepatobiliary Diseases of Wuhan University, Transplant Center of Wuhan University, Hubei Key Laboratory of Medical Technology on Transplantation, Wuhan, China
| | - Q Xiao
- The Third Xiangya Hospital of Central South University, Research Center of National Health Ministry on Transplantation Medicine Engineering and Technology, Changsha, China
| | - X-Y Hu
- Zhongnan Hospital of Wuhan University, Institute of Hepatobiliary Diseases of Wuhan University, Transplant Center of Wuhan University, Hubei Key Laboratory of Medical Technology on Transplantation, Wuhan, China
| | - Z-Z Liu
- Zhongnan Hospital of Wuhan University, Institute of Hepatobiliary Diseases of Wuhan University, Transplant Center of Wuhan University, Hubei Key Laboratory of Medical Technology on Transplantation, Wuhan, China
| | - X-J Zhang
- Zhongnan Hospital of Wuhan University, Institute of Hepatobiliary Diseases of Wuhan University, Transplant Center of Wuhan University, Hubei Key Laboratory of Medical Technology on Transplantation, Wuhan, China
| | - Z-P Xia
- Zhongnan Hospital of Wuhan University, Institute of Hepatobiliary Diseases of Wuhan University, Transplant Center of Wuhan University, Hubei Key Laboratory of Medical Technology on Transplantation, Wuhan, China
| | - Q-F Ye
- Zhongnan Hospital of Wuhan University, Institute of Hepatobiliary Diseases of Wuhan University, Transplant Center of Wuhan University, Hubei Key Laboratory of Medical Technology on Transplantation, Wuhan, China; The Third Xiangya Hospital of Central South University, Research Center of National Health Ministry on Transplantation Medicine Engineering and Technology, Changsha, China.
| | - Y Niu
- The Third Xiangya Hospital of Central South University, Research Center of National Health Ministry on Transplantation Medicine Engineering and Technology, Changsha, China
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Ishikawa T, Shimada S, Fukai M, Kimura T, Umemoto K, Shibata K, Fujiyoshi M, Fujiyoshi S, Hayasaka T, Kawamura N, Kobayashi N, Shimamura T, Taketomi A. Post-reperfusion hydrogen gas treatment ameliorates ischemia reperfusion injury in rat livers from donors after cardiac death: a preliminary study. Surg Today 2018; 48:1081-1088. [PMID: 29980846 DOI: 10.1007/s00595-018-1693-0] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2018] [Accepted: 06/28/2018] [Indexed: 12/11/2022]
Abstract
BACKGROUND AND PURPOSE We reported previously that hydrogen gas (H2) reduced hepatic ischemia and reperfusion injury (IRI) after prolonged cold storage (CS) of livers retrieved from heart-beating donors. The present study was designed to assess whether H2 reduced hepatic IRI during donation of a cardiac death (DCD) graft with subsequent CS. METHODS Rat livers were harvested after 30-min cardiac arrest and stored for 4 h in University of Wisconsin solution. The graft was reperfused with oxygenated buffer, with or without H2 (H2 or NT groups, respectively), at 37° for 90 min on isolated perfused rat liver apparatus. RESULTS In the NT group, liver enzyme leakage, apoptosis, necrosis, energy depletion, redox status, impaired microcirculation, and bile production were indicative of severe IRI, whereas in the H2 group these impairments were significantly suppressed. The phosphorylation of cytoplasmic MKK4 and JNK were enhanced in the NT group and suppressed in the H2 group. NFkB-p65 and c-Fos in the nucleus were unexpectedly unchanged by IRI regardless of H2 treatment, indicating the absence of inflammation in this model. CONCLUSION H2 was observed to ameliorate IRI in the DCD liver by maintaining microcirculation, mitochondrial functions, and redox status, as well as suppressing the cytoplasmic MKK4-JNK-mediated cellular death pathway.
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Affiliation(s)
- Takahisa Ishikawa
- Department of Gastroenterological Surgery I, Graduate School of Medicine, Hokkaido University, N-15, W-7, Kita-Ku, Sapporo, 060-8638, Japan
| | - Shingo Shimada
- Department of Gastroenterological Surgery I, Graduate School of Medicine, Hokkaido University, N-15, W-7, Kita-Ku, Sapporo, 060-8638, Japan
| | - Moto Fukai
- Department of Gastroenterological Surgery I, Graduate School of Medicine, Hokkaido University, N-15, W-7, Kita-Ku, Sapporo, 060-8638, Japan.
| | - Taichi Kimura
- Laboratory of Cancer Research, Department of Pathology, Graduate School of Medicine, Hokkaido University, Sapporo, Japan
| | - Kouhei Umemoto
- Department of Gastroenterological Surgery I, Graduate School of Medicine, Hokkaido University, N-15, W-7, Kita-Ku, Sapporo, 060-8638, Japan
| | - Kengo Shibata
- Department of Gastroenterological Surgery I, Graduate School of Medicine, Hokkaido University, N-15, W-7, Kita-Ku, Sapporo, 060-8638, Japan
| | - Masato Fujiyoshi
- Department of Gastroenterological Surgery I, Graduate School of Medicine, Hokkaido University, N-15, W-7, Kita-Ku, Sapporo, 060-8638, Japan
| | - Sunao Fujiyoshi
- Department of Gastroenterological Surgery I, Graduate School of Medicine, Hokkaido University, N-15, W-7, Kita-Ku, Sapporo, 060-8638, Japan
| | - Takahiro Hayasaka
- Department of Gastroenterological Surgery I, Graduate School of Medicine, Hokkaido University, N-15, W-7, Kita-Ku, Sapporo, 060-8638, Japan
| | - Norio Kawamura
- Department of Transplant Surgery, Graduate School of Medicine, Hokkaido University, Sapporo, Japan
| | - Nozomi Kobayashi
- Department of Gastroenterological Surgery I, Graduate School of Medicine, Hokkaido University, N-15, W-7, Kita-Ku, Sapporo, 060-8638, Japan
| | - Tsuyoshi Shimamura
- Division of Organ Transplantation, Central Clinical Facilities, Hokkaido University Hospital, Sapporo, Japan
| | - Akinobu Taketomi
- Department of Gastroenterological Surgery I, Graduate School of Medicine, Hokkaido University, N-15, W-7, Kita-Ku, Sapporo, 060-8638, Japan
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Reviews of Interleukin-37: Functions, Receptors, and Roles in Diseases. BIOMED RESEARCH INTERNATIONAL 2018; 2018:3058640. [PMID: 29805973 PMCID: PMC5899839 DOI: 10.1155/2018/3058640] [Citation(s) in RCA: 66] [Impact Index Per Article: 9.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 11/20/2017] [Revised: 02/10/2018] [Accepted: 02/13/2018] [Indexed: 12/22/2022]
Abstract
Interleukin-37 (IL-37) is an IL-1 family cytokine discovered in recent years and has 5 different isoforms. As an immunosuppressive factor, IL-37 can suppress excessive immune response. IL-37 plays a role in protecting the body against endotoxin shock, ischemia-reperfusion injury, autoimmune diseases, and cardiovascular diseases. In addition, IL-37 has a potential antitumor effect. IL-37 and its receptors may serve as novel targets for the study, diagnosis, and treatment of immune-related diseases and tumors.
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Zhuang S, Hua X, He K, Zhou T, Zhang J, Wu H, Ma X, Xia Q, Zhang J. Inhibition of GSK‐3β induces AP‐1‐mediated osteopontin expression to promote cholestatic liver fibrosis. FASEB J 2018. [DOI: 10.1096/fj.201701137r] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/26/2023]
Affiliation(s)
- Shaoyong Zhuang
- Department of Liver SurgeryShanghai Jiao‐Tong UniversityShanghaiChina
- Liver Transplantation CenterShanghai Jiao‐Tong UniversityShanghaiChina
| | - Xiangwei Hua
- Division of Gastroenterology and HepatologyShanghai Institute of Digestive DiseaseRen Ji HospitalSchool of MedicineShanghai Jiao‐Tong UniversityShanghaiChina
| | - Kang He
- Department of Liver SurgeryShanghai Jiao‐Tong UniversityShanghaiChina
- Liver Transplantation CenterShanghai Jiao‐Tong UniversityShanghaiChina
| | - Tao Zhou
- Department of Liver SurgeryShanghai Jiao‐Tong UniversityShanghaiChina
- Liver Transplantation CenterShanghai Jiao‐Tong UniversityShanghaiChina
| | - Jiang Zhang
- Key Laboratory of Gastroenterology and HepatologyMinistry of HealthShanghai Jiao‐Tong UniversityShanghaiChina
| | - Haoyu Wu
- Department of Liver SurgeryShanghai Jiao‐Tong UniversityShanghaiChina
- Liver Transplantation CenterShanghai Jiao‐Tong UniversityShanghaiChina
| | - Xiong Ma
- Institute of Transplantation ScienceThe Affiliated Hospital of Qingdao UniversityShandongChina
- Department of Medicine IIUniversity of Munich‐Campus GrosshadernMunichGermany
| | - Qiang Xia
- Department of Liver SurgeryShanghai Jiao‐Tong UniversityShanghaiChina
- Liver Transplantation CenterShanghai Jiao‐Tong UniversityShanghaiChina
| | - Jianjun Zhang
- Department of Liver SurgeryShanghai Jiao‐Tong UniversityShanghaiChina
- Liver Transplantation CenterShanghai Jiao‐Tong UniversityShanghaiChina
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Zhang S, Jiang S, Wang H, Di W, Deng C, Jin Z, Yi W, Xiao X, Nie Y, Yang Y. SIRT6 protects against hepatic ischemia/reperfusion injury by inhibiting apoptosis and autophagy related cell death. Free Radic Biol Med 2018; 115:18-30. [PMID: 29129519 DOI: 10.1016/j.freeradbiomed.2017.11.005] [Citation(s) in RCA: 40] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/02/2017] [Revised: 11/05/2017] [Accepted: 11/07/2017] [Indexed: 12/22/2022]
Abstract
Silent information regulator 6 (SIRT6), a class III histone deacetylase, has been revealed to participate in multiple metabolic processes in the liver, and it plays important roles in protecting against ischemia/reperfusion (I/R) injury in multiple organs. In this study, we explored whether SIRT6 is protective against hepatic I/R injury and elucidated the underlying mechanisms. The expression of SIRT6 was significantly decreased during reperfusion compared with the control group. SIRT6-LKO mice exhibited significantly aggravated oxidative stress, mitochondrial dysfunction, inflammatory responses, mitogen-activated protein kinase (MAPK) signaling activation, and apoptosis and autophagy related hepatocyte death compared with control mice. In vitro studies in SIRT6-KO hepatocytes exhibited similar results. In contrast, SIRT6 upregulation alleviated liver damage during hepatic I/R injury. Our study demonstrated for the first time that SIRT6 upregulation effectively protects against hepatic I/R injury. The underlying mechanisms involve the maintenance of oxidative homeostasis and mitochondrial function, which subsequently inhibit the inflammatory responses and MAPK signaling, and finally attenuate apoptosis and autophagy related hepatocyte death. These results suggest that the activation of SIRT6 exerts multifaceted protective effects during hepatic I/R injury, which can provide a novel therapeutic target for hepatic I/R injury.
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Affiliation(s)
- Song Zhang
- State Key Laboratory of Cancer Biology, Department of Gastroenterology, Xijing Hospital, The Fourth Military Medical University, 127 Changle West Road, Xi'an 710032, China
| | - Shuai Jiang
- Key Laboratory of Resource Biology and Biotechnology in Western China, Ministry of Education. Faculty of Life Sciences, Northwest University, 229 Taibai North Road, Xi'an 710069, China; Department of Aerospace Medicine, The Fourth Military Medical University, Xi'an 710032, China
| | - Haiping Wang
- Key Laboratory of Ministry of Education for Medicinal Plant Resources and Natural Pharmaceutical Chemistry, College of Life Sciences, Shaanxi Normal University, 199 Changan South Road, Xi'an 710062, China
| | - Wencheng Di
- Department of Cardiology, Affiliated Drum Tower Hospital of Nanjing University Medical School, 321 Zhongshan Road, Nanjing, Jiangsu 210008, China
| | - Chao Deng
- Department of Cardiovascular Surgery, Xijing Hospital, The Fourth Military Medical University, 127 Changle West Road, Xi'an 710032, China
| | - Zhenxiao Jin
- Department of Cardiovascular Surgery, Xijing Hospital, The Fourth Military Medical University, 127 Changle West Road, Xi'an 710032, China
| | - Wei Yi
- Department of Cardiovascular Surgery, Xijing Hospital, The Fourth Military Medical University, 127 Changle West Road, Xi'an 710032, China
| | - Xiao Xiao
- State Key Laboratory of Cancer Biology, Department of Gastroenterology, Xijing Hospital, The Fourth Military Medical University, 127 Changle West Road, Xi'an 710032, China
| | - Yongzhan Nie
- State Key Laboratory of Cancer Biology, Department of Gastroenterology, Xijing Hospital, The Fourth Military Medical University, 127 Changle West Road, Xi'an 710032, China.
| | - Yang Yang
- Key Laboratory of Resource Biology and Biotechnology in Western China, Ministry of Education. Faculty of Life Sciences, Northwest University, 229 Taibai North Road, Xi'an 710069, China; Department of Biomedical Engineering, The Fourth Military Medical University, 169 Changle West Road, Xi'an 710032, China.
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Li H, Zhang X, Tan J, Sun L, Xu L, Jiang Y, Lou J, Shi X, Mi W. Propofol postconditioning protects H9c2 cells from hypoxia/reoxygenation injury by inducing autophagy via the SAPK/JNK pathway. Mol Med Rep 2018; 17:4573-4580. [PMID: 29328382 DOI: 10.3892/mmr.2018.8424] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2017] [Accepted: 09/06/2017] [Indexed: 11/06/2022] Open
Affiliation(s)
- Hao Li
- Anesthesia and Operation Center, Chinese PLA General Hospital, Beijing 100853, P.R. China
| | - Xuan Zhang
- Anesthesia and Operation Center, Chinese PLA General Hospital, Beijing 100853, P.R. China
| | - Jian Tan
- Department of Thoracic Surgery, PLA Army General Hospital, Beijing 100700, P.R. China
| | - Li Sun
- Anesthesia and Operation Center, Chinese PLA General Hospital, Beijing 100853, P.R. China
| | - Long‑He Xu
- Anesthesia and Operation Center, Chinese PLA General Hospital, Beijing 100853, P.R. China
| | - Yu‑Ge Jiang
- Anesthesia and Operation Center, Chinese PLA General Hospital, Beijing 100853, P.R. China
| | - Jing‑Sheng Lou
- Anesthesia and Operation Center, Chinese PLA General Hospital, Beijing 100853, P.R. China
| | - Xue‑Yin Shi
- Department of Anesthesiology, Changzheng Hospital, Second Military Medical University, Shanghai 200003, P.R. China
| | - Wei‑Dong Mi
- Anesthesia and Operation Center, Chinese PLA General Hospital, Beijing 100853, P.R. China
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41
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Cicenas J, Zalyte E, Rimkus A, Dapkus D, Noreika R, Urbonavicius S. JNK, p38, ERK, and SGK1 Inhibitors in Cancer. Cancers (Basel) 2017; 10:cancers10010001. [PMID: 29267206 PMCID: PMC5789351 DOI: 10.3390/cancers10010001] [Citation(s) in RCA: 68] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2017] [Revised: 12/14/2017] [Accepted: 12/19/2017] [Indexed: 12/11/2022] Open
Abstract
Mitogen-activated protein kinases (MAP kinases) are a family of kinases that regulates a range of biological processes implicated in the response to growth factors like latelet-derived growth factor (PDGF), epidermal growth factor (EGF), vascular endothelial growth factor (VEGF), and stress, such as ultraviolet irradiation, heat shock, and osmotic shock. The MAP kinase family consists of four major subfamilies of related proteins (extracellular regulated kinases 1/2 (ERK1/2), c-Jun N-terminal kinase (JNK), p38, and extracellular regulated kinase 5 (ERK5)) and regulates numerous cellular activities, such as apoptosis, gene expression, mitosis, differentiation, and immune responses. The deregulation of these kinases is shown to be involved in human diseases, such as cancer, immune diseases, inflammation, and neurodegenerative disorders. The awareness of the therapeutic potential of the inhibition of MAP kinases led to a thorough search for small-molecule inhibitors. Here, we discuss some of the most well-known MAP kinase inhibitors and their use in cancer research.
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Affiliation(s)
- Jonas Cicenas
- Department for Microbiology, Immunbiology und Genetics, Max F. Perutz Laboratories, University of Vienna, Vienna AT-1030, Austria.
- Proteomics Centre, Institute of Biochemistry, Vilnius University, 01513 Vilnius, Lithuania.
- MAP Kinase Resource, Bioinformatics, Melchiorstrasse 9, CH-3027 Bern, Switzerland.
| | - Egle Zalyte
- Proteomics Centre, Institute of Biochemistry, Vilnius University, 01513 Vilnius, Lithuania.
| | - Arnas Rimkus
- Faculty of Medicine, Vilnius University, 01513 Vilnius, Lithuania.
| | - Dalius Dapkus
- Department of Biology and Chemistry, Lithuanian University of Educational Sciences, 08106 Vilnius, Lithuania.
| | - Remigijus Noreika
- Department of Biology and Chemistry, Lithuanian University of Educational Sciences, 08106 Vilnius, Lithuania.
| | - Sigitas Urbonavicius
- Cardiovascular Research Centre, Viborg Hospital, Heibergs Alle 4, 8800 Viborg, Denmark.
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Chen X, Zhu X, Liu Y, Lv Q, Ma J. Silencing of phospholipase C gamma 2 promotes proliferation of rat hepatocytes in vitro. J Cell Biochem 2017; 119:4085-4096. [PMID: 29236324 DOI: 10.1002/jcb.26592] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2017] [Accepted: 12/07/2017] [Indexed: 11/10/2022]
Abstract
The management of hepatic failure is undoubtedly difficult, and poor results have led to the search for novel therapeutic approaches. Nowadays, anti-apoptotic gene therapy is considered as an ideal approach. It has been proved that phospholipase Cγ2 (PLCγ2) is involved in the apoptosis of immune cells and tumor cells; however, whether this gene is related to hepatocyte death is still unclear. This study examined the role of PLCγ2 by inhibiting its expression in rat hepatocytes with siRNA. We also further analyzed the cellular mechanism by which the expression inhibition of PLCγ2 induces cell death. Silencing PLCγ2 gene by adenovirus vector expressing PLCγ2-targeted siRNA caused the great decline in the number of G1- and G2/M phase cells, the significant increase in the number of S phase cells, and the obvious reduction in apoptosis index. In addition, silencing PLCγ2 gene relieved the rat hepatocyte damage, such as the cell shrinkage and chromatin condensation, nuclear fragmentation. Further analysis of Ad-PLCγ2 siRNA-transfected hepatocytes demonstrated that suppression of PLCγ2 gene expression could cause the caspase dependent cell death by inhibiting the signal pathway MEKK1/MKK4/JNK1/2/c-Jun. In conclusion, these findings suggest that interference with PLCγ2 expression could relieve the inhibitory effect of PLCγ2 on hepaocyte apoptosis, thus, promote proliferation through inactivating PKCδ-mediated JNK1/2 signaling pathway.
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Affiliation(s)
- Xiaoguang Chen
- Animal Science and Technology School, Henan University of Science and Technology, Luoyang, China
| | - Xuemin Zhu
- Animal Science and Technology School, Henan University of Science and Technology, Luoyang, China
| | - Yumei Liu
- Animal Science and Technology School, Henan University of Science and Technology, Luoyang, China
| | - Qiongxia Lv
- Animal Science and Technology School, Henan University of Science and Technology, Luoyang, China
| | - Jun Ma
- Animal Science and Technology School, Henan University of Science and Technology, Luoyang, China
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Okada M, Kuramoto K, Takeda H, Watarai H, Sakaki H, Seino S, Seino M, Suzuki S, Kitanaka C. The novel JNK inhibitor AS602801 inhibits cancer stem cells in vitro and in vivo. Oncotarget 2017; 7:27021-32. [PMID: 27027242 PMCID: PMC5053629 DOI: 10.18632/oncotarget.8395] [Citation(s) in RCA: 36] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/27/2015] [Accepted: 03/16/2016] [Indexed: 02/06/2023] Open
Abstract
A phase 2 clinical trial investigating the efficacy and safety of AS602801, a newly developed JNK inhibitor, in the treatment of inflammatory endometriosis is complete. We are now examining whether AS602801 acts against human cancer cells in vitro and in vivo. In vitro, AS602801 exhibited cytotoxicity against both serum-cultured non-stem cancer cells and cancer stem cells derived from human pancreatic cancer, non-small cell lung cancer, ovarian cancer and glioblastoma at concentrations that did not decrease the viability of normal human fibroblasts. AS602801 also inhibited the self-renewal and tumor-initiating capacity of cancer stem cells surviving AS602801 treatment. Cancer stem cells in established xenograft tumors were reduced by systemic administration of AS602801 at a dose and schedule that did not adversely affect the health of the tumor-bearing mice. These findings suggest AS602801 is a promising anti-cancer stem cell agent, and further investigation of the utility of AS602801 in the treatment of cancer seems warranted.
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Affiliation(s)
- Masashi Okada
- Department of Molecular Cancer Science, Yamagata University School of Medicine, Yamagata, Japan
| | - Kenta Kuramoto
- Department of Molecular Cancer Science, Yamagata University School of Medicine, Yamagata, Japan
| | - Hiroyuki Takeda
- Department of Molecular Cancer Science, Yamagata University School of Medicine, Yamagata, Japan.,Department of Clinical Oncology, Yamagata University School of Medicine, Yamagata, Japan
| | - Hikaru Watarai
- Department of Molecular Cancer Science, Yamagata University School of Medicine, Yamagata, Japan.,Second Department of Surgery, Yamagata University School of Medicine, Yamagata, Japan
| | - Hirotsugu Sakaki
- Department of Molecular Cancer Science, Yamagata University School of Medicine, Yamagata, Japan.,Department of Obstetrics and Gynecology, Yamagata University School of Medicine, Yamagata, Japan
| | - Shizuka Seino
- Department of Molecular Cancer Science, Yamagata University School of Medicine, Yamagata, Japan.,Research Institute for Promotion of Medical Sciences, Yamagata University Faculty of Medicine, Yamagata , Japan
| | - Manabu Seino
- Department of Molecular Cancer Science, Yamagata University School of Medicine, Yamagata, Japan.,Department of Obstetrics and Gynecology, Yamagata University School of Medicine, Yamagata, Japan
| | - Shuhei Suzuki
- Department of Molecular Cancer Science, Yamagata University School of Medicine, Yamagata, Japan.,Department of Clinical Oncology, Yamagata University School of Medicine, Yamagata, Japan
| | - Chifumi Kitanaka
- Department of Molecular Cancer Science, Yamagata University School of Medicine, Yamagata, Japan.,Research Institute for Promotion of Medical Sciences, Yamagata University Faculty of Medicine, Yamagata , Japan
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44
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Biochemical targets of drugs mitigating oxidative stress via redox-independent mechanisms. Biochem Soc Trans 2017; 45:1225-1252. [PMID: 29101309 DOI: 10.1042/bst20160473] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2017] [Revised: 09/24/2017] [Accepted: 09/26/2017] [Indexed: 12/13/2022]
Abstract
Acute or chronic oxidative stress plays an important role in many pathologies. Two opposite approaches are typically used to prevent the damage induced by reactive oxygen and nitrogen species (RONS), namely treatment either with antioxidants or with weak oxidants that up-regulate endogenous antioxidant mechanisms. This review discusses options for the third pharmacological approach, namely amelioration of oxidative stress by 'redox-inert' compounds, which do not inactivate RONS but either inhibit the basic mechanisms leading to their formation (i.e. inflammation) or help cells to cope with their toxic action. The present study describes biochemical targets of many drugs mitigating acute oxidative stress in animal models of ischemia-reperfusion injury or N-acetyl-p-aminophenol overdose. In addition to the pro-inflammatory molecules, the targets of mitigating drugs include protein kinases and transcription factors involved in regulation of energy metabolism and cell life/death balance, proteins regulating mitochondrial permeability transition, proteins involved in the endoplasmic reticulum stress and unfolded protein response, nuclear receptors such as peroxisome proliferator-activated receptors, and isoprenoid synthesis. The data may help in identification of oxidative stress mitigators that will be effective in human disease on top of the current standard of care.
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45
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Wang J, Tai G. Role of C-Jun N-terminal Kinase in Hepatocellular Carcinoma Development. Target Oncol 2017; 11:723-738. [PMID: 27392951 DOI: 10.1007/s11523-016-0446-5] [Citation(s) in RCA: 34] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Hepatocellular carcinoma (HCC) is among the most frequently occurring cancers and the leading causes of cancer mortality worldwide. Identification of the signaling pathways regulating liver carcinogenesis is critical for developing novel chemoprevention and targeted therapies. C-Jun N-terminal kinase (JNK) is a member of a larger group of serine/threonine (Ser/Thr) protein kinases known as the mitogen-activated protein kinase (MAPK) family. JNK is an important signaling component that converts external stimuli into a wide range of cellular responses, including cell proliferation, differentiation, survival, migration, invasion, and apoptosis, as well as the development of inflammation, fibrosis, cancer growth, and metabolic diseases. Because of the essential roles of JNK in these cellular functions, deregulated JNK is often found to contribute to the development of HCC. Recently, the functions and molecular mechanisms of JNK in HCC development have been addressed using mouse models and human HCC cell lines. Furthermore, recent studies demonstrate that the activation of JNK by oncogenes can promote the development of cancers by regulating the transforming growth factor (TGF)-β/Smad pathway, which makes the oncogenes/JNK/Smad signaling pathway an attractive target for cancer therapy. Additionally, JNK-targeted therapy has a broad potential for clinical applications. In summary, we are convinced that promising new avenues for the treatment of HCC by targeting JNK are on the horizon, which will undoubtedly lead to better, more effective, and faster therapies in the years to come.
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Affiliation(s)
- Juan Wang
- Department of Immunology, College of Basic Medical Sciences, Jilin University, 126 Xinmin Street, Jilin, Changchun, 130021, China
| | - Guixiang Tai
- Department of Immunology, College of Basic Medical Sciences, Jilin University, 126 Xinmin Street, Jilin, Changchun, 130021, China.
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McCurdy S, Liu CA, Yap J, Boisvert WA. Potential role of IL-37 in atherosclerosis. Cytokine 2017; 122:154169. [PMID: 28988706 DOI: 10.1016/j.cyto.2017.09.025] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/23/2017] [Revised: 09/13/2017] [Accepted: 09/22/2017] [Indexed: 12/31/2022]
Abstract
IL-37 is a member of the IL-1 family, but unlike most other members of this family of cytokines, it has wide-ranging anti-inflammatory properties. Initially shown to bind IL-18 binding protein and prevent IL-18-mediated inflammation, its known role has been expanded to include distinct pathways, both intracellular involving the transcription factor Smad3, and extracellular via binding to the orphan receptor IL-1R8. A number of recent publications investigating the role of IL-37 in atherosclerosis and ischemic heart disease have revealed promising therapeutic value of the cytokine. Although research concerning the role of IL-37 and its mechanism in atherosclerosis is relatively scant, there are a number of well-known atherosclerotic processes that this cytokine can mediate with the potential of modulating the disease progression itself. This review will probe in detail the effects of IL-37 on important pathological processes such as inflammation, dysregulated lipid metabolism, and apoptosis, by analyzing existing data as well as exploring the potential of this cytokine to influence these properties.
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Affiliation(s)
- Sara McCurdy
- Center for Cardiovascular Research, John A. Burns School of Medicine, University of Hawaii, Honolulu, HI, United States
| | - Chloe A Liu
- Center for Cardiovascular Research, John A. Burns School of Medicine, University of Hawaii, Honolulu, HI, United States
| | - Jonathan Yap
- Center for Cardiovascular Research, John A. Burns School of Medicine, University of Hawaii, Honolulu, HI, United States
| | - William A Boisvert
- Center for Cardiovascular Research, John A. Burns School of Medicine, University of Hawaii, Honolulu, HI, United States; Institute of Fundamental Medicine and Biology, Kazan Federal University, Kazan, Russia.
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Takahashi S, Tanaka N, Golla S, Fukami T, Krausz KW, Polunas MA, Weig BC, Masuo Y, Xie C, Jiang C, Gonzalez FJ. Editor's Highlight: Farnesoid X Receptor Protects Against Low-Dose Carbon Tetrachloride-Induced Liver Injury Through the Taurocholate-JNK Pathway. Toxicol Sci 2017; 158:334-346. [PMID: 28505368 PMCID: PMC5837376 DOI: 10.1093/toxsci/kfx094] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Hepatotoxicity is of major concern for humans exposed to industrial chemicals and drugs. Disruption of farnesoid X receptor (FXR), a master regulator of bile acid (BA) metabolism, enhanced the sensitivity to liver injury in mice after toxicant exposure, but the precise mechanism remains unclear. In this study, the interconnection between BA metabolism, FXR, and chemically induced hepatotoxicity was investigated using metabolomics, Fxr-null mice (Fxr-/-) and hepatocytes, and recombinant adenoviruses. A single low-dose intraperitoneal injection of carbon tetrachloride (CCl4), an inducer of acute hepatitis in mice, resulted in more severe hepatocyte damage and higher induction of pro-inflammatory mediators, such as chemokine (C-C motif) ligand 2 (Ccl2), in Fxr-/-. Serum metabolomics analysis revealed marked increases in circulating taurocholate (TCA) and tauro-β-muricholate (T-β-MCA) in these mice, and forced expression of bile salt export protein (BSEP) by recombinant adenovirus in Fxr-/- ameliorated CCl4-induced liver damage. Treatment of Fxr-null hepatocytes with TCA, but not T-β-MCA, significantly increased c-Jun-N-terminal kinase (JNK) activation and Ccl2 mRNA levels, and up-regulation of Ccl2 mRNA was attenuated by co-treatment with a JNK inhibitor SP600125, indicating that TCA directly amplifies hepatocyte inflammatory signaling mainly mediated by JNK under FXR-deficiency. Additionally, pretreatment with SP600125 or restoration of FXR expression in liver by use of recombinant adenovirus, attenuated CCl4-induced liver injury. Collectively, these results suggest that the TCA-JNK axis is likely associated with increased susceptibility to CCl4-induced acute liver injury in Fxr-/-, and provide clues to the mechanism by which FXR and its downstream gene targets, such as BSEP, protects against chemically induced hepatotoxicity.
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Affiliation(s)
- Shogo Takahashi
- Laboratory of Metabolism, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892
| | - Naoki Tanaka
- Laboratory of Metabolism, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892
- Department of Metabolic Regulation, Shinshu University Graduate School of Medicine, Matsumoto, Nagano 390-8621, Japan
| | - Srujana Golla
- Laboratory of Metabolism, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892
| | - Tatsuki Fukami
- Laboratory of Metabolism, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892
| | - Kristopher W. Krausz
- Laboratory of Metabolism, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892
| | | | - Blair C. Weig
- Department of Pharmacology and Toxicology, Environmental and Occupational Health Sciences Institute, Rutgers University, Piscataway, New Jersey 08854
| | - Yusuke Masuo
- Laboratory of Metabolism, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892
| | - Cen Xie
- Laboratory of Metabolism, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892
| | - Changtao Jiang
- Laboratory of Metabolism, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892
| | - Frank J. Gonzalez
- Laboratory of Metabolism, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892
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Induction of autophagy reduces ischemia/reperfusion injury in steatotic rat livers. J Surg Res 2017; 216:207-218. [PMID: 28807209 DOI: 10.1016/j.jss.2017.04.012] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2016] [Revised: 03/23/2017] [Accepted: 04/11/2017] [Indexed: 12/22/2022]
Abstract
BACKGROUND Steatotic livers are particularly vulnerable to ischemia/reperfusion injury (IRI). One of the reasons is an underlying impairment of autophagy. Autophagy is regulated by glycogen synthase kinase 3b (GSK3b) and extracellular signal-regulated kinases (ERK1/2) pathways. Both of them are target proteins of a cell-protective drug, lithium chloride. Lithium chloride treatment reduces IRI in many organs including liver. Therefore, we aimed to investigate the effect of lithium chloride treatment on autophagy induction in steatotic rat livers. We also wanted to evaluate the related cell-protective effects on the enhanced hepatic IRI. MATERIALS AND METHODS After inducing hepatic steatosis, rats were injected with lithium chloride or normal saline for 3 d before being subjected to 70% selective warm ischemia for 60 min. After reperfusion, rats were observed for 30 min, 6, 24, and 48 h. RESULTS Lithium chloride appeared to protect hepatocytes from IRI via its ability to induce autophagy by modulation of both GSK3b and ERK1/2 pathways. Hepatic damage was significantly decreased in the treatment group as indicated by a reduced inflammatory response, less apoptosis, less necrosis, and lower liver enzyme levels. CONCLUSIONS Simultaneous modulation of GSK3b and ERK1/2 pathways might be an interesting strategy to reduce IRI in steatotic livers with an impairment of autophagy.
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Inhalation of high concentrations of hydrogen ameliorates liver ischemia/reperfusion injury through A 2A receptor mediated PI3K-Akt pathway. Biochem Pharmacol 2017; 130:83-92. [DOI: 10.1016/j.bcp.2017.02.003] [Citation(s) in RCA: 35] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2016] [Accepted: 02/01/2017] [Indexed: 12/12/2022]
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Wang J, Koh H, Zhou L, Bae U, Lee H, Bang IH, Ka S, Oh S, Bae EJ, Park B. Sirtuin 2 aggravates postischemic liver injury by deacetylating mitogen-activated protein kinase phosphatase-1. Hepatology 2017; 65:225-236. [PMID: 27532371 PMCID: PMC5215544 DOI: 10.1002/hep.28777] [Citation(s) in RCA: 49] [Impact Index Per Article: 6.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/02/2016] [Accepted: 07/27/2016] [Indexed: 12/20/2022]
Abstract
UNLABELLED Sirtuin 2 (Sirt2) is known to negatively regulate anoxia-reoxygenation injury in myoblasts. Because protein levels of Sirt2 are increased in ischemia-reperfusion (I/R)-injured liver tissues, we examined whether Sirt2 is protective or detrimental against hepatic I/R injury. We overexpressed Sirt2 in the liver of C57BL/6 mice using a Sirt2 adenovirus. Wild-type and Sirt2 knockout mice were subjected to a partial (70%) hepatic ischemia for 45 minutes, followed by various periods of reperfusion. In another set of experiments, wild-type mice were pretreated intraperitoneally with AGK2, a Sirt2 inhibitor. Isolated hepatocytes and Kupffer cells from wild-type and Sirt2 knockout mice were subjected to hypoxia-reoxygenation injury to determine the in vitro effects of Sirt2. Mice subjected to I/R injury showed typical patterns of hepatocellular damage. Prior injection with Sirt2 adenovirus aggravated liver injury, as demonstrated by increases in serum aminotransferases, prothrombin time, proinflammatory cytokines, hepatocellular necrosis and apoptosis, and neutrophil infiltration relative to control virus-injected mice. Pretreatment with AGK2 resulted in significant improvements in serum aminotransferase levels and histopathologic findings. Similarly, experiments with Sirt2 knockout mice also revealed reduced hepatocellular injury. The molecular mechanism of Sirt2's involvement in this aggravation of hepatic I/R injury includes the deacetylation and inhibition of mitogen-activated protein kinase phosphatase-1 and consequent activation of mitogen-activated protein kinases. CONCLUSION Sirt2 is an aggravating factor during hepatic I/R injury. (Hepatology 2017;65:225-236).
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Affiliation(s)
- Jie Wang
- Department of BiochemistryChonbuk National University Medical SchoolJeonjuJeonbukRepublic of Korea
| | - Hyoung‐Won Koh
- Department of BiochemistryChonbuk National University Medical SchoolJeonjuJeonbukRepublic of Korea
| | - Lu Zhou
- Department of Sports MedicineTaishan Medical UniversityTaianShandongChina
| | - Ui‐Jin Bae
- Department of BiochemistryChonbuk National University Medical SchoolJeonjuJeonbukRepublic of Korea
| | - Hwa‐Suk Lee
- Department of BiochemistryChonbuk National University Medical SchoolJeonjuJeonbukRepublic of Korea
| | - In Hyuk Bang
- Department of BiochemistryChonbuk National University Medical SchoolJeonjuJeonbukRepublic of Korea
| | - Sun‐O Ka
- Department of BiochemistryChonbuk National University Medical SchoolJeonjuJeonbukRepublic of Korea
| | - Seon‐Hee Oh
- Department of Premedics, School of MedicineChosun UniversityGwangjuRepublic of Korea
| | - Eun Ju Bae
- College of PharmacyWoosuk UniversityWanjuJeonbukRepublic of Korea
| | - Byung‐Hyun Park
- Department of BiochemistryChonbuk National University Medical SchoolJeonjuJeonbukRepublic of Korea
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