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Huang Q, Wang Y, Zhang Z, Wu M, Liu J, Chen J, Li J, Yao Y, Guo C, Zhao D, Qi W, Li X. Organ dysfunction induced by hemorrhagic shock: From mechanisms to therapeutic medicines. Pharmacol Res 2025; 216:107755. [PMID: 40315969 DOI: 10.1016/j.phrs.2025.107755] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/10/2025] [Revised: 04/03/2025] [Accepted: 04/27/2025] [Indexed: 05/04/2025]
Abstract
Hemorrhagic shock (HS) leads to organ dysfunction, which increases the incidence of unfavorable outcomes in patients. However, adjuvant drug therapy for HS has not been widely accepted, and the benefits of vasopressors are generally considered to have insufficient evidence. Energy homeostasis disruption and excessive immune system activation are the main mechanisms underlying HS-induced organ dysfunction. Recent reports on HS animal models and clinical trials have revealed potential drugs that target the immune response, oxidative damage, and energy homeostasis in HS, providing new insights for the treatment of HS-induced organ dysfunction. In this review, we first discuss the pathophysiology of organ dysfunction involved in HS injury and then systematically review potential drugs that regulate immunity, the inflammatory response, oxidative damage, energy homeostasis, and cell death. We also review the available drugs with clinical evidence of HS-induced organ dysfunction efficacy. Treatment strategies combined with an improved understanding of the organ injury mechanisms of HS may help identify and develop targeted therapeutic modalities that mitigate severe organ dysfunction and reduce mortality caused by HS injury.
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Affiliation(s)
- Qingxia Huang
- Research Center of Traditional Chinese Medicine, College of Traditional Chinese Medicine, Changchun University of Chinese Medicine, Changchun, Jilin 130021, China; Northeast Asia Research Institute of Traditional Chinese Medicine, Key Laboratory of Active Substances and Biological Mechanisms of Ginseng Efficacy, Ministry of Education, Jilin Provincial Key Laboratory of Bio-Macromolecules of Chinese Medicine, Changchun University of Chinese Medicine, Changchun, Jilin 130117, China
| | - Yisa Wang
- Northeast Asia Research Institute of Traditional Chinese Medicine, Key Laboratory of Active Substances and Biological Mechanisms of Ginseng Efficacy, Ministry of Education, Jilin Provincial Key Laboratory of Bio-Macromolecules of Chinese Medicine, Changchun University of Chinese Medicine, Changchun, Jilin 130117, China
| | - Zepeng Zhang
- Research Center of Traditional Chinese Medicine, College of Traditional Chinese Medicine, Changchun University of Chinese Medicine, Changchun, Jilin 130021, China; Northeast Asia Research Institute of Traditional Chinese Medicine, Key Laboratory of Active Substances and Biological Mechanisms of Ginseng Efficacy, Ministry of Education, Jilin Provincial Key Laboratory of Bio-Macromolecules of Chinese Medicine, Changchun University of Chinese Medicine, Changchun, Jilin 130117, China
| | - Mingxia Wu
- Northeast Asia Research Institute of Traditional Chinese Medicine, Key Laboratory of Active Substances and Biological Mechanisms of Ginseng Efficacy, Ministry of Education, Jilin Provincial Key Laboratory of Bio-Macromolecules of Chinese Medicine, Changchun University of Chinese Medicine, Changchun, Jilin 130117, China
| | - Jiaqi Liu
- Northeast Asia Research Institute of Traditional Chinese Medicine, Key Laboratory of Active Substances and Biological Mechanisms of Ginseng Efficacy, Ministry of Education, Jilin Provincial Key Laboratory of Bio-Macromolecules of Chinese Medicine, Changchun University of Chinese Medicine, Changchun, Jilin 130117, China
| | - Jinjin Chen
- Northeast Asia Research Institute of Traditional Chinese Medicine, Key Laboratory of Active Substances and Biological Mechanisms of Ginseng Efficacy, Ministry of Education, Jilin Provincial Key Laboratory of Bio-Macromolecules of Chinese Medicine, Changchun University of Chinese Medicine, Changchun, Jilin 130117, China
| | - Jing Li
- Northeast Asia Research Institute of Traditional Chinese Medicine, Key Laboratory of Active Substances and Biological Mechanisms of Ginseng Efficacy, Ministry of Education, Jilin Provincial Key Laboratory of Bio-Macromolecules of Chinese Medicine, Changchun University of Chinese Medicine, Changchun, Jilin 130117, China
| | - Yao Yao
- Northeast Asia Research Institute of Traditional Chinese Medicine, Key Laboratory of Active Substances and Biological Mechanisms of Ginseng Efficacy, Ministry of Education, Jilin Provincial Key Laboratory of Bio-Macromolecules of Chinese Medicine, Changchun University of Chinese Medicine, Changchun, Jilin 130117, China
| | - Chen Guo
- Northeast Asia Research Institute of Traditional Chinese Medicine, Key Laboratory of Active Substances and Biological Mechanisms of Ginseng Efficacy, Ministry of Education, Jilin Provincial Key Laboratory of Bio-Macromolecules of Chinese Medicine, Changchun University of Chinese Medicine, Changchun, Jilin 130117, China
| | - Daqing Zhao
- Northeast Asia Research Institute of Traditional Chinese Medicine, Key Laboratory of Active Substances and Biological Mechanisms of Ginseng Efficacy, Ministry of Education, Jilin Provincial Key Laboratory of Bio-Macromolecules of Chinese Medicine, Changchun University of Chinese Medicine, Changchun, Jilin 130117, China
| | - Wenxiu Qi
- Northeast Asia Research Institute of Traditional Chinese Medicine, Key Laboratory of Active Substances and Biological Mechanisms of Ginseng Efficacy, Ministry of Education, Jilin Provincial Key Laboratory of Bio-Macromolecules of Chinese Medicine, Changchun University of Chinese Medicine, Changchun, Jilin 130117, China.
| | - Xiangyan Li
- Northeast Asia Research Institute of Traditional Chinese Medicine, Key Laboratory of Active Substances and Biological Mechanisms of Ginseng Efficacy, Ministry of Education, Jilin Provincial Key Laboratory of Bio-Macromolecules of Chinese Medicine, Changchun University of Chinese Medicine, Changchun, Jilin 130117, China.
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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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Hofmann J, Pühringer M, Steinkellner S, Holl AS, Meszaros AT, Schneeberger S, Troppmair J, Hautz T. Novel, Innovative Models to Study Ischemia/Reperfusion-Related Redox Damage in Organ Transplantation. Antioxidants (Basel) 2022; 12:antiox12010031. [PMID: 36670893 PMCID: PMC9855021 DOI: 10.3390/antiox12010031] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2022] [Revised: 12/20/2022] [Accepted: 12/22/2022] [Indexed: 12/28/2022] Open
Abstract
The implementation of ex vivo organ machine perfusion (MP) into clinical routine undoubtedly helped to increase the donor pool. It enables not just organ assessment, but potentially regeneration and treatment of marginal organs in the future. During organ procurement, redox-stress triggered ischemia-reperfusion injury (IRI) is inevitable, which in addition to pre-existing damage negatively affects such organs. Ex vivo MP enables to study IRI-associated tissue damage and its underlying mechanisms in a near to physiological setting. However, research using whole organs is limited and associated with high costs. Here, in vitro models well suited for early stage research or for studying particular disease mechanisms come into play. While cell lines convince with simplicity, they do not exert all organ-specific functions. Tissue slice cultures retain the three-dimensional anatomical architecture and cells remain within their naïve tissue-matrix configuration. Organoids may provide an even closer modelling of physiologic organ function and spatial orientation. In this review, we discuss the role of oxidative stress during ex vivo MP and the suitability of currently available in vitro models to further study the underlying mechanisms and to pretest potential treatment strategies.
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Abbasian N, Ghaderi-Najafabadi M, Watson E, Brown J, Yu Si L, Bursnall D, Pawluczyk I, Seymour AM, Bevington A. Hepatic cysteine sulphinic acid decarboxylase depletion and defective taurine metabolism in a rat partial nephrectomy model of chronic kidney disease. BMC Nephrol 2021; 22:250. [PMID: 34225671 PMCID: PMC8256558 DOI: 10.1186/s12882-021-02442-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2021] [Accepted: 06/04/2021] [Indexed: 11/17/2022] Open
Abstract
BACKGROUND Taurine depletion occurs in patients with end-stage chronic kidney disease (CKD). In contrast, in the absence of CKD, plasma taurine is reported to increase following dietary L-glutamine supplementation. This study tested the hypothesis that taurine biosynthesis decreases in a rat CKD model, but is rectified by L-glutamine supplementation. METHODS CKD was induced by partial nephrectomy in male Sprague-Dawley rats, followed 2 weeks later by 2 weeks of 12% w/w L-glutamine supplemented diet (designated NxT) or control diet (NxC). Sham-operated control rats (S) received control diet. RESULTS Taurine concentration in plasma, liver and skeletal muscle was not depleted, but steady-state urinary taurine excretion (a measure of whole-body taurine biosynthesis) was strongly suppressed (28.3 ± 8.7 in NxC rats versus 78.5 ± 7.6 μmol/24 h in S, P < 0.05), accompanied by reduced taurine clearance (NxC 0.14 ± 0.05 versus 0.70 ± 0.11 ml/min/Kg body weight in S, P < 0.05). Hepatic expression of mRNAs encoding key enzymes of taurine biosynthesis (cysteine sulphinic acid decarboxylase (CSAD) and cysteine dioxygenase (CDO)) showed no statistically significant response to CKD (mean relative expression of CSAD and CDO in NxC versus S was 0.91 ± 0.18 and 0.87 ± 0.14 respectively). Expression of CDO protein was also unaffected. However, CSAD protein decreased strongly in NxC livers (45.0 ± 16.8% of that in S livers, P < 0.005). L-glutamine supplementation failed to rectify taurine biosynthesis or CSAD protein expression, but worsened CKD (proteinuria in NxT 12.5 ± 1.2 versus 6.7 ± 1.5 mg/24 h in NxC, P < 0.05). CONCLUSION In CKD, hepatic CSAD is depleted and taurine biosynthesis impaired. This is important in view of taurine's reported protective effect against cardio-vascular disease - the leading cause of death in human CKD.
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Affiliation(s)
- Nima Abbasian
- Department of Respiratory Sciences, University of Leicester, Leicester, LE1 7RH, UK.
- School of Life and Medical Sciences, University of Hertfordshire, Hertfordshire, UK.
| | | | - Emma Watson
- Department of Cardiovascular Sciences, University of Leicester, Leicester, UK
| | - Jeremy Brown
- Department of Cardiovascular Sciences, University of Leicester, Leicester, UK
| | - Li Yu Si
- Department of Respiratory Sciences, University of Leicester, Leicester, LE1 7RH, UK
| | - Debbie Bursnall
- Division of Biomedical Services, University of Leicester, Leicester, UK
| | - Izabella Pawluczyk
- Department of Cardiovascular Sciences, University of Leicester, Leicester, UK
| | | | - Alan Bevington
- Department of Respiratory Sciences, University of Leicester, Leicester, LE1 7RH, UK.
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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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Li L, Li Y, Miao C, Liu Y, Liu R. Coriolus versicolor polysaccharides (CVP) regulates neuronal apoptosis in cerebral ischemia-reperfusion injury via the p38MAPK signaling pathway. ANNALS OF TRANSLATIONAL MEDICINE 2020; 8:1168. [PMID: 33241017 PMCID: PMC7576014 DOI: 10.21037/atm-20-5759] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 12/04/2022]
Abstract
Background This study aims to investigate the regulation of herbal polysaccharide, Coriolus versicolor polysaccharides (CVP), on neuronal apoptosis in a rat cerebral ischemia-reperfusion injury (CIRI) model. We also intend to explore the mechanisms and effectiveness of CVP in the treatment of neuronal apoptosis in CIRI rats, including neurological function, cerebral infarction volume, inflammatory factors, and the p38 mitogen-activated protein kinase (p38MAPK) signaling pathway as well as its downstream protein cleaved-Caspase-3. Methods A CIRI model was established in rats using the Longa method of middle cerebral artery occlusion. Neurological function scores and cerebral infarction volumes were measured in CIRI rats. Annexin V-fluorescein isothiocyanate (FITC) were used to measure neuronal apoptosis in CIRI rats. The levels of interleukin-1β (IL-1β) and tumor necrosis factor-α (TNF-α) in CIRI rats were determined using enzyme-linked immunosorbent assay (ELISA). A western blot assay was used to measure the protein expression levels of p38MAPK, phospho-p38MAPK (p-p38MAPK), Bcl-2, Bax and cleaved-Caspase-3 in brain tissue of CIRI rats. Results CVP can effectively improve the neurological function of rats after 6, 12, 24, and 48 h of CIRI. It can also improve the behavioral test, reduce the cerebral infarction volume and inhibit the apoptosis of nerve cells in CIRI rats. The protein expression levels of p-p38MAPK and cleaved-Caspase-3 exhibited a decreasing trend following CVP administration. Conclusions CVP can significantly reduce the pathological characteristics of CIRI in rats and inhibit the apoptosis of nerve cells around the lesions. The mechanism of its effectiveness is related to inhibiting the activation of the p38MAPK signaling pathway.
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Affiliation(s)
- Lei Li
- Department of Neurology, Xinxiang Central Hospital, Xinxiang, China
| | - Yan Li
- Clinical Medical College of Tianjin Medical University, Tianjin, China
| | - Cheng Miao
- Department of Neurology, Xinxiang Central Hospital, Xinxiang, China
| | - Yi Liu
- Department of Neurology, Xinxiang Central Hospital, Xinxiang, China
| | - Rui Liu
- Department of Neurology, Xinxiang Central Hospital, Xinxiang, China
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Transient Expression of Reck Under Hepatic Ischemia/Reperfusion Conditions Is Associated with Mapk Signaling Pathways. Biomolecules 2020; 10:biom10050747. [PMID: 32403397 PMCID: PMC7277810 DOI: 10.3390/biom10050747] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2020] [Revised: 05/04/2020] [Accepted: 05/07/2020] [Indexed: 12/14/2022] Open
Abstract
In this study, we demonstrated the involvement of matrix metalloproteinases (MMPs) in hepatic ischemia/reperfusion (I/R) injury. Our aim is to evaluate the impact of reperfusion on I/R-related changes in RECK, an MMP modulator, and mitogen-activated protein kinase (MAPKs) pathways (ERK, p38, and JNK). Male Wistar rats were either subjected to 60 min partial-hepatic ischemia or sham-operated. After a 60 min or 120 min reperfusion, liver samples were collected for analysis of MMP-2 and MMP-9 by zymography and RECK, TIMP-1, and TIMP-2 content, MAPKs activation (ERK1/2, JNK1/2, and p38), as well as iNOS and eNOS by Western blot. Serum enzymes AST, ALT, and alkaline-phosphatase were quantified. A transitory decrease in hepatic RECK and TIMPs was associated with a transitory increase in both MMP-2 and MMP-9 activity and a robust activation of ERK1/2, JNK1/2, and p38 were detected at 60 min reperfusion. Hepatic expression of iNOS was maximally upregulated at 120 min reperfusion. An increase in eNOS was detected at 120 min reperfusion. I/R evoked significant hepatic injury in a time-dependent manner. These findings provide new insights into the underlying molecular mechanisms of reperfusion in inducing hepatic injury: a transitory decrease in RECK and TIMPs and increases in both MAPK and MMP activity suggest their role as triggering factors of the organ dysfunction.
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Propofol post-conditioning lessens renal ischemia/reperfusion-induced acute lung injury associated with autophagy and apoptosis through MAPK signals in rats. Gene 2020; 741:144562. [PMID: 32169629 DOI: 10.1016/j.gene.2020.144562] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2019] [Accepted: 03/08/2020] [Indexed: 12/14/2022]
Abstract
Renal Ischemia/Reperfusion (rI/R)-induced acute lung injury (ALI) is a major problem in rI/R. The objective of the current study was to explore the defensive roles of propofol (Pro), an intravenous anesthetic, on rI/R-induced ALI through mitogen-activated protein kinase (MAPK) signaling. Rats were divided into Sham, Pro (10 mg/kg), rI/R, rI/R + Pro (5 mg/kg), and rI/R + Pro (10 mg/kg) groups. Rats were treated with Pro at 1 h after rI/R treatment. Serum and lung tissues at 24 h after rI/R were collected to evaluate morphological changes and the expression of myeloperoxidase (MPO), inflammatory cytokines, and crucial proteins in the MAPK pathway. Pro attenuated the production of mediators, resulting in reduced levels of autophagy and apoptosis by restricting the MAPK pathway in rI/R-induced ALI model. Pro represses rI/R-induced pulmonary autophagy and apoptosis by decreasing the production of inflammatory molecules, and the effects of Pro are involved in the inhibition of the MAPK pathway.
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Oliva J. Therapeutic Properties of Mesenchymal Stem Cell on Organ Ischemia-Reperfusion Injury. Int J Mol Sci 2019; 20:ijms20215511. [PMID: 31694240 PMCID: PMC6862572 DOI: 10.3390/ijms20215511] [Citation(s) in RCA: 34] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2019] [Revised: 10/29/2019] [Accepted: 11/02/2019] [Indexed: 12/13/2022] Open
Abstract
The shortage of donor organs is a major global concern. Organ failure requires the transplantation of functional organs. Donor’s organs are preserved for variable periods of warm and cold ischemia time, which requires placing them into a preservation device. Ischemia and reperfusion damage the organs, due to the lack of oxygen during the ischemia step, as well as the oxidative stress during the reperfusion step. Different methodologies are developed to prevent or to diminish the level of injuries. Preservation solutions were first developed to maximize cold static preservation, which includes the addition of several chemical compounds. The next chapter of organ preservation comes with the perfusion machine, where mechanical devices provide continuous flow and oxygenation ex vivo to the organs being preserved. In the addition of inhibitors of mitogen-activated protein kinase and inhibitors of the proteasome, mesenchymal stem cells began being used 13 years ago to prevent or diminish the organ’s injuries. Mesenchymal stem cells (e.g., bone marrow stem cells, adipose derived stem cells and umbilical cord stem cells) have proven to be powerful tools in repairing damaged organs. This review will focus upon the use of some bone marrow stem cells, adipose-derived stem cells and umbilical cord stem cells on preventing or decreasing the injuries due to ischemia-reperfusion.
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Affiliation(s)
- Joan Oliva
- Emmaus Medical, Inc., 21250 Hawthorne Blvd, Suite 800, Torrance, CA 90503, USA
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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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Wang JJ, Zhu JD, Zhang XH, Long TT, Ge G, Yu Y. Neuroprotective effect of Notch pathway inhibitor DAPT against focal cerebral ischemia/reperfusion 3 hours before model establishment. Neural Regen Res 2019; 14:452-461. [PMID: 30539813 PMCID: PMC6334612 DOI: 10.4103/1673-5374.245469] [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] [Subscribe] [Scholar Register] [Received: 05/28/2018] [Accepted: 08/15/2018] [Indexed: 12/22/2022] Open
Abstract
As an inhibitor of the Notch signaling pathway, N-[N-(3,5-difluorohenacetyl)-l-alanyl]-S-phenylglycine tert-butyl ester (DAPT) may protect brain tissue from serious ischemic injury. This study aimed to explore neuroprotection by DAPT after cerebral ischemia/reperfusion (I/R) injury. DAPT was intraperitoneally injected 3 hours before the establishment of a focal cerebral I/R model in the right middle cerebral artery of obstructed mice. Longa scores were used to assess neurological changes of mice. Nissl staining and TdT-mediated dUTP-biotin nick-end labeling staining were used to examine neuronal damage and cell apoptosis in the right prefrontal cortex, while immunofluorescence staining was used to detect glial fibrillary acidic protein- and Notch1-positive cells. Protein expression levels of Hes1 and Hes5 were detected by western blot assay in the right prefrontal cortex. Our results demonstrated that DAPT significantly improved neurobehavioral scores and relieved neuronal morphological damage. DAPT decreased the number of glial fibrillary acidic protein- and Notch1-positive cells in the right prefrontal cortex, while also reducing the number of apoptotic cells and decreasing interleukin-6 and tumor necrosis factor-α contents, and simultaneously downregulating Hes1 and Hes5 protein expression. These findings verify that DAPT alleviates pathological lesions and strengthens the anti-inflammatory response after cerebral I/R injury. Thus, DAPT might be developed as an effective drug for the prevention of cerebral I/R injury.
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Affiliation(s)
- Jun-Jie Wang
- Department of Anatomy, School of Basic Medicine, Guizhou Medical University, Guian New District, Guizhou Province, China
| | - Jun-De Zhu
- Department of Anatomy, School of Basic Medicine, Guizhou Medical University, Guian New District, Guizhou Province, China
| | - Xian-Hu Zhang
- Department of Anatomy, School of Basic Medicine, Guizhou Medical University, Guian New District, Guizhou Province, China
| | - Ting-Ting Long
- Department of Anatomy, School of Basic Medicine, Guizhou Medical University, Guian New District, Guizhou Province, China
| | - Guo Ge
- Department of Anatomy, School of Basic Medicine, Guizhou Medical University, Guian New District, Guizhou Province, China
| | - Yan Yu
- Department of Anatomy, School of Basic Medicine, Guizhou Medical University, Guian New District, Guizhou Province, China
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Regional Ischemic Preconditioning Has Clinical Value in Cirrhotic HCC Through MAPK Pathways. J Gastrointest Surg 2019; 23:1767-1777. [PMID: 30542823 PMCID: PMC6702190 DOI: 10.1007/s11605-018-3960-1] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/24/2018] [Accepted: 08/29/2018] [Indexed: 01/31/2023]
Abstract
BACKGROUND This study assessed the clinical value of regional ischemic preconditioning (RIP) and the role of the mitogen-activated protein kinase (MAPK) pathways in the protective mechanism of RIP in cirrhotic hepatocellular carcinoma (HCC) patients undergoing hepatectomy. METHODS Liver resection was performed with hemi-hepatic vascular inflow occlusion (HHV) under RIP (RIP group) or with HHV alone (HHV group). Clinical data, surgical outcomes, and the levels of phosphorylated MAPKs before occlusion and 30 min after reperfusion were estimated. RESULTS HHV under RIP was associated with less intraoperative blood loss (300 vs. 400 ml; P = 0.042), postoperative plasma transfused (400 vs. 800 ml; P = 0.019), and a higher level of prothrombin activity at postoperative days 3, 5, and 7 compared to HHV alone. The level of phosphorylated ERK protein was significantly increased and the levels of phosphorylated p38 and JNK proteins were significantly decreased 30 min after reperfusion compared to HHV group in the RIP group. CONCLUSIONS HHV under RIP may have clinical value in cirrhotic HCC patients requiring resection and the protective mechanism of RIP may be associated with changes in the protein phosphorylation level of MAPK pathways.
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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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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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15
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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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Xu Y, Yao J, Zou C, Zhang H, Zhang S, Liu J, Ma G, Jiang P, Zhang W. Asiatic acid protects against hepatic ischemia/reperfusion injury by inactivation of Kupffer cells via PPARγ/NLRP3 inflammasome signaling pathway. Oncotarget 2017; 8:86339-86355. [PMID: 29156799 PMCID: PMC5689689 DOI: 10.18632/oncotarget.21151] [Citation(s) in RCA: 38] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2016] [Accepted: 08/21/2017] [Indexed: 01/17/2023] Open
Abstract
Hepatic ischemia/reperfusion (I/R) contributes to major complications in clinical practice affecting perioperative morbidity and mortality. Recent evidence suggests the key role of nucleotide-binding oligomerization domain-like receptor (NLR) family pyrin domain-containing 3 (NLRP3) inflammaosme activation on the pathogenesis of I/R injury. Asiatic acid (AA) is a pentacyclic triterpene derivative presented with versatile activities, including antioxidant, anti-inflammation and hepatoprotective effects. This study was designed to determine whether AA had potential hepatoprotective benefits against hepatic I/R injury, as well as to unveil the underlying mechanisms involved in the putative effects. Mice subjected to warm hepatic I/R, and Kupffer cells (KCs) or RAW264.7 cells challenged with lipopolysaccharide (LPS)/H2O2, were pretreated with AA. Administration of AA significantly attenuated hepatic histopathological damage, global inflammatory level, apoptotic signaling level, as well as NLRP3 inflammasome activation. These effects were correlated with increased expression of peroxisome proliferator-activated receptor gamma (PPARγ). Conversely, pharmacological inhibition of PPARγ by GW9662 abolished the protective effects of AA on hepatic I/R injury and in turn aggravated NLRP3 inflammasome activation. Activation of NLRP3 inflammasome was most significant in nonparenchymal cells (NPCs). Depletion of KCs by gadolinium chloride (GdCl3) further attenuated the detrimental effects of GW9662 on hepatic I/R as well as NLRP3 activation. In vitro, AA concentration-dependently inhibited LPS/H2O2-induced NLRP3 inflammaosome activation in KCs and RAW264.7 cells. Either GW9662 or genetic knockdown of PPARγ abolished the AA-mediated inactivation of NLRP3 inflammasome. Mechanistically, AA attenuated I/R or LPS/H2O2-induced ROS production and phosphorylation level of JNK, p38 MAPK and IκBα but not ERK, a mechanism dependent on PPARγ. Finally, AA blocked the deleterious effects of LPS/H2O2-induced macrophage activation on hepatocyte viability in vitro, and improved survival in a lethal hepatic I/R injury model in vivo. Collectively, these data suggest that AA is effective in mitigating hepatic I/R injury through attenuation of KCs activation via PPARγ/NLRP3 inflammasome signaling pathway.
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Affiliation(s)
- Ying Xu
- Department of Laboratory Center, Affiliated People's Hospital of Jiangsu University, Zhenjiang, China
| | - Jun Yao
- Department of Gastroenterology, Affiliated People's Hospital of Jiangsu University, Zhenjiang, China
| | - Chen Zou
- Department of General Surgery, Affiliated People's Hospital of Jiangsu University, Zhenjiang, China
| | - Heng Zhang
- Department of General Surgery, Affiliated People's Hospital of Jiangsu University, Zhenjiang, China
| | - Shouliang Zhang
- Department of General Surgery, Affiliated People's Hospital of Jiangsu University, Zhenjiang, China
| | - Jun Liu
- Department of General Surgery, Affiliated People's Hospital of Jiangsu University, Zhenjiang, China
| | - Gui Ma
- Department of General Surgery, Affiliated People's Hospital of Jiangsu University, Zhenjiang, China
| | - Pengcheng Jiang
- Department of General Surgery, Affiliated People's Hospital of Jiangsu University, Zhenjiang, China
| | - Wenbo Zhang
- Department of General Surgery, Affiliated People's Hospital of Jiangsu University, Zhenjiang, China
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Li Y, Xu B, Xu M, Chen D, Xiong Y, Lian M, Sun Y, Tang Z, Wang L, Jiang C, Lin Y. 6-Gingerol protects intestinal barrier from ischemia/reperfusion-induced damage via inhibition of p38 MAPK to NF-κB signalling. Pharmacol Res 2017; 119:137-148. [PMID: 28167239 DOI: 10.1016/j.phrs.2017.01.026] [Citation(s) in RCA: 95] [Impact Index Per Article: 11.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/10/2016] [Accepted: 01/25/2017] [Indexed: 01/08/2023]
Abstract
Intestinal ischemia reperfusion (I/R) injury caused by severe trauma, intestinal obstruction, and operation is one of the tough challenges in clinic. 6-Gingerol (6G), a main active ingredient of ginger, is found to have anti-microbial, anti-inflammatory, anti-oxidative, and anti-cancer activities. The present study was designed to characterize the potential protective effects of 6G on rat intestinal I/R injury and reveal the correlated mechanisms. Rat intestinal I/R model was established with clamping the superior mesenteric artery (SMA) and 6G was intragastrically administered for three consecutive days before I/R injury. Caco-2 and IEC-6 cells were incubated under hypoxia/reoxygenation (H/R) conditions to simulate I/R injury in vitro. The results showed that 6G significantly alleviated intestinal injury in I/R injured rats by reducing the generation of oxidative stress and inhibiting p38 MAPK signaling pathway. 6G significantly reduced MDA level and increased the levels of SOD, GSH, and GSH-Px in I/R injured intestinal tissues. 6G significantly decreased the production of proinflammatory cytokines including TNF-α, IL-1β, and IL-6, and inhibited the expression of inflammatory mediators iNOS/NO in I/R injured intestinal tissues. The impaired intestinal barrier function was restored by using 6G in I/R injured rats and in both Caco-2 and IEC-6 cells characterized by inhibiting p38 MAPK phosphorylation, nuclear translocation of NF-κB, and expression of myosin light chain kinase (MLCK) protein. 6G also reduced the generation of reactive oxygen species (ROS) in both Caco-2 and IEC-6 cells. In vitro transfection of p38 MAPK siRNA mitigated the impact of 6G on NF-κB and MLCK expression, and the results further corroborated the protective effects of 6G on intestinal I/R injury by repressing p38 MAPK signaling. In conclusion, the present study suggests that 6G exerts protective effects against I/R-induced intestinal mucosa injury by inhibiting the formation of ROS and p38 MAPK activation, providing novel insights into the mechanisms of this therapeutic candidate for the treatment of intestinal injury.
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Affiliation(s)
- Yanli Li
- Department of Pharmacology, Dalian Medical University, Dalian 116044, China
| | - Bin Xu
- Department of Pharmacology, Dalian Medical University, Dalian 116044, China
| | - Ming Xu
- Department of Pharmacology, Dalian Medical University, Dalian 116044, China
| | - Dapeng Chen
- Laboratory Animal Center, Dalian Medical University, Dalian 116044, China
| | - Yongjian Xiong
- Central Laboratory, The First Affiliated Hospital, Dalian Medical University, Dalian 116044, China
| | - Mengqiao Lian
- Department of Pharmacology, Dalian Medical University, Dalian 116044, China
| | - Yuchao Sun
- Department of Pharmacology, Dalian Medical University, Dalian 116044, China
| | - Zeyao Tang
- Department of Pharmacology, Dalian Medical University, Dalian 116044, China
| | - Li Wang
- Department of Pharmacology, Dalian Medical University, Dalian 116044, China
| | - Chunling Jiang
- Department of Physiology, Dalian Medical University, Dalian 116044, China
| | - Yuan Lin
- Department of Pharmacology, Dalian Medical University, Dalian 116044, China.
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Interferon regulatory factor-1 activates autophagy to aggravate hepatic ischemia-reperfusion injury via the P38/P62 pathway in mice. Sci Rep 2017; 7:43684. [PMID: 28266555 PMCID: PMC5339805 DOI: 10.1038/srep43684] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/11/2016] [Accepted: 01/30/2017] [Indexed: 01/07/2023] Open
Abstract
Increasing evidence has linked autophagy to a detrimental role in hepatic ischemia- reperfusion (IR) injury (IRI). Here we focus on the role of interferon regulatory factor-1 (IRF-1) in regulating autophagy to aggravate hepatic IRI. We found that IRF-1 was up-regulated during hepatic IRI and was associated with an activation of the autophagic signaling. This increased IRF-1 expression, which was allied with high autophagic activity, amplified liver damage to IR, an effect which was abrogated by IRF-1 depletion. Moreover, IRF-1 contributed to P38 induced autophagic and apoptotic cell death, that can play a key role in liver dysfunction. The levels of P62 mRNA and protein were increased when P38 was activated and decreased when P38 was inhibited by SB203580. We conclude that IRF-1 functioned as a trigger to activate autophagy via P38 activation and that P62 was required for this P38-mediated autophagy. IRF-1 appears to exert a pivotal role in hepatic IRI, by predisposing hepatocytes to activate an autophagic pathway. Such an effect promotes autophagic cell death through the P38/P62 pathway. The identification of this novel pathway, that links expression levels of IRF-1 with autophagy, may provide new insights for the generation of novel protective therapies directed against hepatic IRI.
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Abstract
Ischemic disorders, such as myocardial infarction, stroke, and peripheral vascular disease, are the most common causes of debilitating disease and death in westernized cultures. The extent of tissue injury relates directly to the extent of blood flow reduction and to the length of the ischemic period, which influence the levels to which cellular ATP and intracellular pH are reduced. By impairing ATPase-dependent ion transport, ischemia causes intracellular and mitochondrial calcium levels to increase (calcium overload). Cell volume regulatory mechanisms are also disrupted by the lack of ATP, which can induce lysis of organelle and plasma membranes. Reperfusion, although required to salvage oxygen-starved tissues, produces paradoxical tissue responses that fuel the production of reactive oxygen species (oxygen paradox), sequestration of proinflammatory immunocytes in ischemic tissues, endoplasmic reticulum stress, and development of postischemic capillary no-reflow, which amplify tissue injury. These pathologic events culminate in opening of mitochondrial permeability transition pores as a common end-effector of ischemia/reperfusion (I/R)-induced cell lysis and death. Emerging concepts include the influence of the intestinal microbiome, fetal programming, epigenetic changes, and microparticles in the pathogenesis of I/R. The overall goal of this review is to describe these and other mechanisms that contribute to I/R injury. Because so many different deleterious events participate in I/R, it is clear that therapeutic approaches will be effective only when multiple pathologic processes are targeted. In addition, the translational significance of I/R research will be enhanced by much wider use of animal models that incorporate the complicating effects of risk factors for cardiovascular disease. © 2017 American Physiological Society. Compr Physiol 7:113-170, 2017.
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Affiliation(s)
- Theodore Kalogeris
- Department of Medical Pharmacology and Physiology, University of Missouri School of Medicine, Columbia, Missouri, USA
| | - Christopher P. Baines
- Department of Medical Pharmacology and Physiology, University of Missouri School of Medicine, Columbia, Missouri, USA
- Dalton Cardiovascular Research Center, University of Missouri, Columbia, Missouri, USA
- Department of Biomedical Sciences, University of Missouri College of Veterinary Medicine, Columbia, Missouri, USA
| | - Maike Krenz
- Department of Medical Pharmacology and Physiology, University of Missouri School of Medicine, Columbia, Missouri, USA
- Dalton Cardiovascular Research Center, University of Missouri, Columbia, Missouri, USA
| | - Ronald J. Korthuis
- Department of Medical Pharmacology and Physiology, University of Missouri School of Medicine, Columbia, Missouri, USA
- Dalton Cardiovascular Research Center, University of Missouri, Columbia, Missouri, USA
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Kumar M, Sharma K, Bhoi S, Kumar M, Pol MM. Expression of p38 mitogen-activated protein kinases, glycogen synthase kinase, c-Jun NH2-terminal kinase, extracellular signal-regulated kinase signaling: Can it be used as molecular markers among trauma-hemorrhagic shock patients? J Emerg Trauma Shock 2016; 9:131-132. [PMID: 27904257 PMCID: PMC5113078 DOI: 10.4103/0974-2700.193346] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/04/2022] Open
Affiliation(s)
- Manoj Kumar
- Department of Emergency Medicine, JPNATC, AIIMS, New Delhi, India E-mail:
| | - Keshava Sharma
- Department of Emergency Medicine, JPNATC, AIIMS, New Delhi, India E-mail:
| | - Sanjeev Bhoi
- Department of Emergency Medicine, JPNATC, AIIMS, New Delhi, India E-mail:
| | - Mahendra Kumar
- Department of Emergency Medicine, AIIMS, New Delhi, India
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Ruess DA, Probst M, Marjanovic G, Wittel UA, Hopt UT, Keck T, Bausch D. HDACi Valproic Acid (VPA) and Suberoylanilide Hydroxamic Acid (SAHA) Delay but Fail to Protect against Warm Hepatic Ischemia-Reperfusion Injury. PLoS One 2016; 11:e0161233. [PMID: 27513861 PMCID: PMC4981462 DOI: 10.1371/journal.pone.0161233] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2016] [Accepted: 08/02/2016] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Histone deacetylases (HDAC) catalyze N-terminal deacetylation of lysine-residues on histones and multiple nuclear and cytoplasmic proteins. In various animal models, such as trauma/hemorrhagic shock, ischemic stroke or myocardial infarction, HDAC inhibitor (HDACi) application is cyto- and organoprotective and promotes survival. HDACi reduce stress signaling, cell death and inflammation. Hepatic ischemia-reperfusion (I/R) injury during major liver resection or transplantation increases morbidity and mortality. Assuming protective properties, the aim of this study was to investigate the effect of the HDACi VPA and SAHA on warm hepatic I/R. MATERIAL AND METHODS Male Wistar-Kyoto rats (age: 6-8 weeks) were randomized to VPA, SAHA, vehicle control (pre-) treatment or sham-groups and underwent partial no-flow liver ischemia for 90 minutes with subsequent reperfusion for 6, 12, 24 and 60 hours. Injury and regeneration was quantified by serum AST and ALT levels, by macroscopic aspect and (immuno-) histology. HDACi treatment efficiency, impact on MAPK/SAPK-activation and Hippo-YAP signaling was determined by Western blot. RESULTS Treatment with HDACi significantly enhanced hyperacetylation of Histone H3-K9 during I/R, indicative of adequate treatment efficiency. Liver injury, as measured by macroscopic aspect, serum transaminases and histology, was delayed, but not alleviated in VPA and SAHA treated animals. Importantly, tissue destruction was significantly more pronounced with VPA. SAPK-activation (p38 and JNK) was reduced by VPA and SAHA in the early (6h) reperfusion phase, but augmented later on (JNK, 24h). Regeneration appeared enhanced in SAHA and VPA treated animals and was dependent on Hippo-YAP signaling. CONCLUSIONS VPA and SAHA delay warm hepatic I/R injury at least in part through modulation of SAPK-activation. However, these HDACi fail to exert organoprotective effects, in this setting. For VPA, belated damage is even aggravated.
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Affiliation(s)
- Dietrich A. Ruess
- Department of Surgery, University Hospital Freiburg, Freiburg, Germany
- * E-mail:
| | - Moriz Probst
- Department of Surgery, University Hospital Freiburg, Freiburg, Germany
| | - Goran Marjanovic
- Department of Surgery, University Hospital Freiburg, Freiburg, Germany
| | - Uwe A. Wittel
- Department of Surgery, University Hospital Freiburg, Freiburg, Germany
| | - Ulrich T. Hopt
- Department of Surgery, University Hospital Freiburg, Freiburg, Germany
| | - Tobias Keck
- Department of Surgery, University Hospital Schleswig-Holstein, Campus Lübeck, Lübeck, Germany
| | - Dirk Bausch
- Department of Surgery, University Hospital Schleswig-Holstein, Campus Lübeck, Lübeck, Germany
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Su D, Ma J, Zhang Z, Tian Y, Shen B. Protective Effects of UCF-101 on Cerebral Ischemia-Reperfusion (CIR) is Depended on the MAPK/p38/ERK Signaling Pathway. Cell Mol Neurobiol 2016; 36:907-914. [PMID: 26429193 PMCID: PMC11482449 DOI: 10.1007/s10571-015-0275-6] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/23/2015] [Accepted: 09/24/2015] [Indexed: 10/23/2022]
Abstract
This study was aimed to investigate the treatment mechanisms of 5-[5-(2-nitrophenyl) furfuryliodine]-1,3-diphenyl-2-thiobarbituric acid (UCF-101) in cerebral ischemia-reperfusion (CIR) model rats. Total of 54 healthy male Wistar rats were randomly assigned into three groups, namely sham group, vehicle group, and UCF-101 group. The CIR-injured model was established by right middle cerebral artery occlusion and reperfusion. Neurological function was assessed by an investigator according to the Longa neurologic deficit scores. Meanwhile, the cerebral tissue morphology and apoptotic neurons were evaluated by H&E and TUNEL staining, respectively. Additionally, the expressions of caspase 3, p-p38, and p-ERK were detected by immunohistochemistry or/and Western blotting assays. As results, neurologic deficit and pathological damage were obviously enhanced and TUNEL positive neurons were significantly increased in CIR-injured rats, as compared with those in sham group. Furthermore, the expressions of caspase 3, p-p38, and p-ERK were also significantly increased in vehicle group than those in sham group (P < 0.05). However, UCF-101 treatment could markedly weaken the neurologic deficit with lower scores and improve pathological condition. After UCF-101 treatment, TUNEL positive neurons as well as the expression of caspase 3 were significantly decreased than those in vehicle group (P < 0.05). Besides, p-p38 was decreased while p-ERK was increased in UCF-101 group than those in vehicle group (P < 0.05). Therefore, we concluded that the protective effects of UCF-101 might be associated with apoptosis process and MAPK signaling pathway in the CIR-injured model.
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Affiliation(s)
- Danying Su
- Department of Neurology, The Fourth Affiliated Hospital of Harbin Medical University, 150000, Harbin, People's Republic of China
| | - Jing Ma
- Department of Anatomy, Harbin Medical University, 150000, Harbin, People's Republic of China.
| | - Zhuobo Zhang
- Department of Neurology, The Fourth Affiliated Hospital of Harbin Medical University, 150000, Harbin, People's Republic of China
| | - Ye Tian
- Department of Cardiology, The First Affiliated Hospital of Harbin Medical University, 150000, Harbin, People's Republic of China
| | - Baozhong Shen
- Department of Imaging, The Fourth Affiliated Hospital Harbin Medical University, No. 37 Yiyuan Str, Nangang District, 150001, Harbin, People's Republic of China.
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Yang X, Wang J, Dai J, Shao J, Ma J, Chen C, Ma S, He Q, Luo P, Yang B. Autophagy protects against dasatinib-induced hepatotoxicity via p38 signaling. Oncotarget 2016; 6:6203-17. [PMID: 25749037 PMCID: PMC4467432 DOI: 10.18632/oncotarget.3357] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2014] [Accepted: 01/14/2015] [Indexed: 01/01/2023] Open
Abstract
Liver dysfunction is a common side effect associated with the treatment of dasatinib and its mechanism is poorly understood. Autophagy has been thought to be a potent survival or death factor for liver dysfunction, which may shed the light on a novel strategy for the intervention of hepatotoxicity caused by dasatinib. In this study, we show for the first time that autophagy is induced, which is consistent with the formation of liver damage. Autophagy inhibition exacerbated dasatinib-induced liver failure, suggesting that autophagy acted as a self-defense mechanism to promote survival. Oxidative stress has been shown to be an important stimulus for autophagy and hepatotoxicity. Interestingly, dasatinib increased the activity of p38, which is a critical modulator of the oxidative stress related to liver injury and autophagy. p38 silencing significantly blocked LC3-II induction and p62 reduction by dasatinib, which was accompanied by increased caspase-3 and PARP cleavage, indicating that autophagy alleviated dasatinib-induced hepatotoxicity via p38 signaling. Finally, the p38 agonist isoproterenol hydrochloride (ISO) alleviated dasatinib-induced liver failure by enhancing autophagy without affecting the anticancer activity of dasatinib. Thus, this study revealed that p38-activated autophagy promoted survival during liver injury, which may provide novel approaches for managing the clinical applications of dasatinib.
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Affiliation(s)
- Xiaochun Yang
- Institute of Pharmacology & Toxicology, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, China
| | - Jincheng Wang
- Institute of Pharmacology & Toxicology, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, China
| | - Jiabin Dai
- Institute of Pharmacology & Toxicology, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, China
| | - Jinjin Shao
- Institute of Pharmacology & Toxicology, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, China
| | - Jian Ma
- Center for Drug Safety Evaluation and Research of Zhejiang University, Hangzhou, China
| | - Chao Chen
- Center for Drug Safety Evaluation and Research of Zhejiang University, Hangzhou, China
| | - Shenglin Ma
- Nanjing Medical University, Affiliated Hangzhou Hospital, Hangzhou First People's Hospital, Hangzhou, China
| | - Qiaojun He
- Institute of Pharmacology & Toxicology, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, China
| | - Peihua Luo
- Institute of Pharmacology & Toxicology, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, China
| | - Bo Yang
- Institute of Pharmacology & Toxicology, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, China
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Sun Y, Gao Y, Sun J, Liu X, Ma D, Ma C, Wang Y. Expression profile analysis based on DNA microarray for patients undergoing off-pump coronary artery bypass surgery. Exp Ther Med 2016; 11:864-872. [PMID: 26998004 PMCID: PMC4774345 DOI: 10.3892/etm.2016.3003] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2014] [Accepted: 12/03/2015] [Indexed: 12/24/2022] Open
Abstract
Off-pump coronary artery bypass (OPCAB) surgery is the most effective treatment for coronary heart disease. The aim of this study was to explore the effects of OPCAB on the basis of the associated molecular mechanisms. GSE12486 expression profiles downloaded from the Gene Expression Omnibus database (GEO) were analyzed to identify the differentially expressed genes (DEGs). Principal component analysis (PCA) was conducted based on the expression profiles of DEGs. Function and pathway enrichment of upregulated DEGs was performed, followed by protein-protein interaction (PPI) network construction. Gene Set Enrichment Analysis (GSEA) was used for miRNA enrichment analysis based on expression profiles and prediction of their association with the disease. Cytoscape was applied to construct miRNA regulatory networks of DEGs. In total 64 DEGs were identified, including 63 upregulated and 1 downregulated gene. The first principal component in the PCA analysis was able to distinguish between pre- and post-OPCAB samples. Upregulated DEGs mainly enriched 20 Gene Ontology terms, such as chemokine activity, and 5 pathways including the chemokine signaling pathway. The constructed PPI network contained 234 edges and 55 nodes, and 10 upregulated hub nodes, including FBJ murine osteosarcoma viral oncogene homolog (FOS), were screened. A total of 36 miRNAs, including MIR-224 and MIR-7, were screened by GSEA enrichment analysis. A miRNA regulatory network including 176 edges and 97 nodes was constructed, showing the regulatory relationships between miRNAs and DEGs. For example, early growth response 2 (EGR2) was regulated by 8 miRNAs including MIR-150, MIR-142-3P, MIR-367 and MIR-224. The identified DEGs might play important roles in patients pre- and post-OPCAB surgery via the regulation of associated genes.
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Affiliation(s)
- Yunpeng Sun
- Department of Cardiac Surgery, The First Hospital of Jilin University, Changchun, Jilin 130021, P.R. China
| | - Yongsheng Gao
- Department of Cardiac Surgery, The First Hospital of Jilin University, Changchun, Jilin 130021, P.R. China
| | - Jingnan Sun
- Cancer Center, The First Hospital of Jilin University, Changchun, Jilin 130021, P.R. China
| | - Xuguang Liu
- Department of Cardiac Surgery, The First Hospital of Jilin University, Changchun, Jilin 130021, P.R. China
| | - Dashi Ma
- Department of Cardiac Surgery, The First Hospital of Jilin University, Changchun, Jilin 130021, P.R. China
| | - Chunye Ma
- Department of Cardiac Surgery, The First Hospital of Jilin University, Changchun, Jilin 130021, P.R. China
| | - Yong Wang
- Department of Cardiac Surgery, The First Hospital of Jilin University, Changchun, Jilin 130021, P.R. China
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Bejaoui M, Pantazi E, De Luca V, Panisello A, Folch-Puy E, Serafin A, Capasso C, C T S, Rosselló-Catafau J. Acetazolamide protects steatotic liver grafts against cold ischemia reperfusion injury. J Pharmacol Exp Ther 2015; 355:191-198. [PMID: 26330538 DOI: 10.1124/jpet.115.225177] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2015] [Accepted: 08/26/2015] [Indexed: 08/29/2023] Open
Abstract
Ischemia reperfusion injury (IRI) is a primary concern in liver transplantation, especially when steatosis is present. Acetazolamide (AZ), a specific carbonic anhydrase (CA) inhibitor, has been suggested to protect against hypoxia. Here, we hypothesized that AZ administration could be efficient to protect fatty livers against cold IRI. Obese Zucker rat livers were preserved in Institut Georges Lopez-1 storage solution for 24 hours at 4°C and ex vivo perfused for 2 hours at 37°C. Alternatively, rats were also treated with intravenous injection of AZ (30 mg/kg) before liver recovery. Liver injury, hepatic function, and vascular resistance were determined. CA II protein levels and CA hydratase activity were assessed as well as other parameters involved in IRI (endothelial nitric oxide synthase, mitogen activated protein kinase family, hypoxic inducible factor 1 alpha, and erythropoietin). We demonstrated that AZ administration efficiently protects the steatotic liver against cold IRI. AZ protection was associated with better function, decreased vascular resistance, and activation of endothelial nitric oxide synthase. This was consistent with an effective mitogen activated protein kinase inactivation. Finally, no effect on the hypoxic inductible factor 1 alpha/erythropoietin pathway was observed. The present study demonstrated that AZ administration is a suitable pharmacological strategy for preserving fatty liver grafts against cold IRI.
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Affiliation(s)
- Mohamed Bejaoui
- Experimental Hepatic Ischemia-Reperfusion Unit, Institute of Biomedical Research of Barcelona-Spanish National Research Council, Barcelona, Catalonia, Spain (M.B., E.P., A.P., E. F.-P., J. R.-C.); Institute of Bioscience and Bioresources, National Research Council, Napoli, Italy (V.D.L., C.C.); University of Florence, Neurofarba Department, Sesto Fiorentino, Firenze, Italy (S.C.T.); and Platform of Laboratory Animal Applied Research, Barcelona Science Park, Barcelona, Catalonia, Spain (A.S.)
| | - Eirini Pantazi
- Experimental Hepatic Ischemia-Reperfusion Unit, Institute of Biomedical Research of Barcelona-Spanish National Research Council, Barcelona, Catalonia, Spain (M.B., E.P., A.P., E. F.-P., J. R.-C.); Institute of Bioscience and Bioresources, National Research Council, Napoli, Italy (V.D.L., C.C.); University of Florence, Neurofarba Department, Sesto Fiorentino, Firenze, Italy (S.C.T.); and Platform of Laboratory Animal Applied Research, Barcelona Science Park, Barcelona, Catalonia, Spain (A.S.)
| | - Viviana De Luca
- Experimental Hepatic Ischemia-Reperfusion Unit, Institute of Biomedical Research of Barcelona-Spanish National Research Council, Barcelona, Catalonia, Spain (M.B., E.P., A.P., E. F.-P., J. R.-C.); Institute of Bioscience and Bioresources, National Research Council, Napoli, Italy (V.D.L., C.C.); University of Florence, Neurofarba Department, Sesto Fiorentino, Firenze, Italy (S.C.T.); and Platform of Laboratory Animal Applied Research, Barcelona Science Park, Barcelona, Catalonia, Spain (A.S.)
| | - Arnau Panisello
- Experimental Hepatic Ischemia-Reperfusion Unit, Institute of Biomedical Research of Barcelona-Spanish National Research Council, Barcelona, Catalonia, Spain (M.B., E.P., A.P., E. F.-P., J. R.-C.); Institute of Bioscience and Bioresources, National Research Council, Napoli, Italy (V.D.L., C.C.); University of Florence, Neurofarba Department, Sesto Fiorentino, Firenze, Italy (S.C.T.); and Platform of Laboratory Animal Applied Research, Barcelona Science Park, Barcelona, Catalonia, Spain (A.S.)
| | - Emma Folch-Puy
- Experimental Hepatic Ischemia-Reperfusion Unit, Institute of Biomedical Research of Barcelona-Spanish National Research Council, Barcelona, Catalonia, Spain (M.B., E.P., A.P., E. F.-P., J. R.-C.); Institute of Bioscience and Bioresources, National Research Council, Napoli, Italy (V.D.L., C.C.); University of Florence, Neurofarba Department, Sesto Fiorentino, Firenze, Italy (S.C.T.); and Platform of Laboratory Animal Applied Research, Barcelona Science Park, Barcelona, Catalonia, Spain (A.S.)
| | - Anna Serafin
- Experimental Hepatic Ischemia-Reperfusion Unit, Institute of Biomedical Research of Barcelona-Spanish National Research Council, Barcelona, Catalonia, Spain (M.B., E.P., A.P., E. F.-P., J. R.-C.); Institute of Bioscience and Bioresources, National Research Council, Napoli, Italy (V.D.L., C.C.); University of Florence, Neurofarba Department, Sesto Fiorentino, Firenze, Italy (S.C.T.); and Platform of Laboratory Animal Applied Research, Barcelona Science Park, Barcelona, Catalonia, Spain (A.S.)
| | - Clemente Capasso
- Experimental Hepatic Ischemia-Reperfusion Unit, Institute of Biomedical Research of Barcelona-Spanish National Research Council, Barcelona, Catalonia, Spain (M.B., E.P., A.P., E. F.-P., J. R.-C.); Institute of Bioscience and Bioresources, National Research Council, Napoli, Italy (V.D.L., C.C.); University of Florence, Neurofarba Department, Sesto Fiorentino, Firenze, Italy (S.C.T.); and Platform of Laboratory Animal Applied Research, Barcelona Science Park, Barcelona, Catalonia, Spain (A.S.)
| | - Supuran C T
- Experimental Hepatic Ischemia-Reperfusion Unit, Institute of Biomedical Research of Barcelona-Spanish National Research Council, Barcelona, Catalonia, Spain (M.B., E.P., A.P., E. F.-P., J. R.-C.); Institute of Bioscience and Bioresources, National Research Council, Napoli, Italy (V.D.L., C.C.); University of Florence, Neurofarba Department, Sesto Fiorentino, Firenze, Italy (S.C.T.); and Platform of Laboratory Animal Applied Research, Barcelona Science Park, Barcelona, Catalonia, Spain (A.S.)
| | - Joan Rosselló-Catafau
- Experimental Hepatic Ischemia-Reperfusion Unit, Institute of Biomedical Research of Barcelona-Spanish National Research Council, Barcelona, Catalonia, Spain (M.B., E.P., A.P., E. F.-P., J. R.-C.); Institute of Bioscience and Bioresources, National Research Council, Napoli, Italy (V.D.L., C.C.); University of Florence, Neurofarba Department, Sesto Fiorentino, Firenze, Italy (S.C.T.); and Platform of Laboratory Animal Applied Research, Barcelona Science Park, Barcelona, Catalonia, Spain (A.S.)
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26
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Bejaoui M, Pantazi E, De Luca V, Panisello A, Folch-Puy E, Hotter G, Capasso C, T. Supuran C, Rosselló-Catafau J. Carbonic Anhydrase Protects Fatty Liver Grafts against Ischemic Reperfusion Damage. PLoS One 2015; 10:e0134499. [PMID: 26225852 PMCID: PMC4520486 DOI: 10.1371/journal.pone.0134499] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2015] [Accepted: 07/09/2015] [Indexed: 01/11/2023] Open
Abstract
Carbonic anhydrases (CAs) are ubiquitous metalloenzymes that catalyze the reversible hydration of carbon dioxide to bicarbonate and a proton. CAs are involved in numerous physiological and pathological processes, including acid-base homeostasis, electrolyte balance, oxygen delivery to tissues and nitric oxide generation. Given that these processes are found to be dysregulated during ischemia reperfusion injury (IRI), and taking into account the high vulnerability of steatotic livers to preservation injury, we hypothesized a new role for CA as a pharmacological agent able to protect against ischemic damage. Two different aspects of the role of CA II in fatty liver grafts preservation were evaluated: 1) the effect of its addition to Institut Georges Lopez (IGL-1) storage solution after cold ischemia; 2) and after 24h of cold storage followed by two hours of normothermic ex-vivo perfusion. In all cases, liver injury, CA II protein concentration, CA II mRNA levels and CA II activity were determined. In case of the ex-vivo perfusion, we further assessed liver function (bile production, bromosulfophthalein clearance) and Western blot analysis of phosphorylated adenosine monophosphate activated protein kinase (AMPK), mitogen activated protein kinases family (MAPKs) and endoplasmic reticulum stress (ERS) parameters (GRP78, PERK, IRE, eIF2α and ATF6). We found that CA II was downregulated after cold ischemia. The addition of bovine CA II to IGL-1 preservation solution efficiently protected steatotic liver against cold IRI. In the case of reperfusion, CA II protection was associated with better function, AMPK activation and the prevention of ERS and MAPKs activation. Interestingly, CA II supplementation was not associated with enhanced CO2 hydration. The results suggest that CA II modulation may be a promising target for fatty liver graft preservation.
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Affiliation(s)
- Mohamed Bejaoui
- Department of Experimental Pathology, Institute of Biomedical Research of Barcelona-Spanish National Research Council (IIBB-CSIC), IDIBAPS, Barcelona, Spain
| | - Eirini Pantazi
- Department of Experimental Pathology, Institute of Biomedical Research of Barcelona-Spanish National Research Council (IIBB-CSIC), IDIBAPS, Barcelona, Spain
| | - Viviana De Luca
- Institute of Bioscience and Bioresources (IBBR), National Research Council, Napoli, Italy
| | - Arnau Panisello
- Department of Experimental Pathology, Institute of Biomedical Research of Barcelona-Spanish National Research Council (IIBB-CSIC), IDIBAPS, Barcelona, Spain
| | - Emma Folch-Puy
- Department of Experimental Pathology, Institute of Biomedical Research of Barcelona-Spanish National Research Council (IIBB-CSIC), IDIBAPS, Barcelona, Spain
| | - Georgina Hotter
- Department of Experimental Pathology, Institute of Biomedical Research of Barcelona-Spanish National Research Council (IIBB-CSIC), IDIBAPS, Barcelona, Spain
| | - Clemente Capasso
- Institute of Bioscience and Bioresources (IBBR), National Research Council, Napoli, Italy
| | | | - Joan Rosselló-Catafau
- Department of Experimental Pathology, Institute of Biomedical Research of Barcelona-Spanish National Research Council (IIBB-CSIC), IDIBAPS, Barcelona, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Barcelona, Spain
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27
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Pan ST, Qin Y, Zhou ZW, He ZX, Zhang X, Yang T, Yang YX, Wang D, Qiu JX, Zhou SF. Plumbagin induces G2/M arrest, apoptosis, and autophagy via p38 MAPK- and PI3K/Akt/mTOR-mediated pathways in human tongue squamous cell carcinoma cells. DRUG DESIGN DEVELOPMENT AND THERAPY 2015; 9:1601-26. [PMID: 25834400 PMCID: PMC4365758 DOI: 10.2147/dddt.s76057] [Citation(s) in RCA: 46] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 01/13/2023]
Abstract
Plumbagin (5-hydroxy-2-methyl-1,4-naphthoquinone; PLB), a naturally occurring naphthoquinone isolated from the roots of Plumbaginaceae plants, has been reported to possess anticancer activities in both in vitro and in vivo studies, but the effect of PLB on tongue squamous cell carcinoma (TSCC) is not fully understood. This study aimed to investigate the effects of PLB on cell cycle distribution, apoptosis, and autophagy, and the underlying mechanisms in the human TSCC cell line SCC25. The results have revealed that PLB exerted potent inducing effects on cell cycle arrest, apoptosis, and autophagy in SCC25 cells. PLB arrested SCC25 cells at the G2/M phase in a concentration- and time-dependent manner with a decrease in the expression level of cell division cycle protein 2 homolog (Cdc2) and cyclin B1 and increase in the expression level of p21 Waf1/Cip1, p27 Kip1, and p53 in SCC25 cells. PLB markedly induced apoptosis and autophagy in SCC25 cells. PLB decreased the expression of the anti-apoptotic proteins B-cell lymphoma 2 (Bcl-2) and B-cell lymphoma-extra large (Bcl-xl) while increasing the expression level of the pro-apoptotic protein Bcl-2-associated X protein (Bax) in SCC25 cells. Furthermore, PLB inhibited phosphatidylinositol 3 kinase (PI3K)/protein kinase B (Akt)/mammalian target of rapamycin (mTOR), glycogen synthase kinase 3β (GSK3β), and p38 mitogen-activated protein kinase (p38 MAPK) pathways as indicated by the alteration in the ratio of phosphorylation level over total protein expression level, contributing to the autophagy inducing effect. In addition, we found that wortmannin (a PI3K inhibitor) and SB202190 (a selective inhibitor of p38 MAPK) strikingly enhanced PLB-induced autophagy in SCC25 cells, suggesting the involvement of PI3K- and p38 MAPK-mediated signaling pathways. Moreover, PLB induced intracellular reactive oxygen species (ROS) generation and this effect was attenuated by l-glutathione (GSH) and n-acetyl-l-cysteine (NAC). Taken together, these results indicate that PLB promotes cellular apoptosis and autophagy in TSCC cells involving p38 MAPK- and PI3K/Akt/mTOR-mediated pathways with contribution from the GSK3β and ROS-mediated pathways.
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Affiliation(s)
- Shu-Ting Pan
- Department of Oral and Maxillofacial Surgery, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, People's Republic of China
| | - Yiru Qin
- Department of Pharmaceutical Sciences, College of Pharmacy, University of South Florida, Tampa, FL, USA
| | - Zhi-Wei Zhou
- Department of Pharmaceutical Sciences, College of Pharmacy, University of South Florida, Tampa, FL, USA ; Guizhou Provincial Key Laboratory for Regenerative Medicine, Stem Cell and Tissue Engineering Research Center and Sino-US Joint Laboratory for Medical Sciences, Guizhou Medical University, Guiyang, Guizhou, People's Republic of China
| | - Zhi-Xu He
- Guizhou Provincial Key Laboratory for Regenerative Medicine, Stem Cell and Tissue Engineering Research Center and Sino-US Joint Laboratory for Medical Sciences, Guizhou Medical University, Guiyang, Guizhou, People's Republic of China
| | - Xueji Zhang
- Research Center for Bioengineering and Sensing Technology, University of Science and Technology Beijing, Beijing, People's Republic of China
| | - Tianxin Yang
- Department of Internal Medicine, University of Utah and Salt Lake Veterans Affairs Medical Center, Salt Lake City, UT, USA
| | - Yin-Xue Yang
- Department of Colorectal Surgery, General Hospital of Ningxia Medical University, Yinchuan, Ningxia, People's Republic of China
| | - Dong Wang
- Cancer Center, Daping Hospital and Research Institute of Surgery, Third Military Medical University, Chongqing, People's Republic of China
| | - Jia-Xuan Qiu
- Department of Oral and Maxillofacial Surgery, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, People's Republic of China
| | - Shu-Feng Zhou
- Department of Pharmaceutical Sciences, College of Pharmacy, University of South Florida, Tampa, FL, USA
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Oxidative Stress in the Ischemic and Non-Ischemic Parts of the Rat Liver after Two-Thirds Ischemia/Reperfusion. Biosci Biotechnol Biochem 2014; 74:979-83. [DOI: 10.1271/bbb.90838] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/14/2023]
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Pantazi E, Zaouali MA, Bejaoui M, Serafin A, Folch-Puy E, Petegnief V, De Vera N, Ben Abdennebi H, Rimola A, Roselló-Catafau J. Silent information regulator 1 protects the liver against ischemia-reperfusion injury: implications in steatotic liver ischemic preconditioning. Transpl Int 2014; 27:493-503. [PMID: 24472096 DOI: 10.1111/tri.12276] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2013] [Revised: 07/27/2013] [Accepted: 01/23/2014] [Indexed: 12/30/2022]
Abstract
Ischemia-reperfusion (IR) injury is an important problem in liver surgery especially when steatosis is present. Ischemic preconditioning (PC) is the only surgical strategy that has been applied in patients with steatotic livers undergoing warm ischemia. Silent information regulator 1 (SIRT1) is a histone deacetylase that regulates various cellular processes. This study evaluates the SIRT1 implication in PC in fatty livers. Homozygous (Ob) Zucker rats were subjected to IR and IR + PC. An additional group treated with sirtinol or EX527 (SIRT1 inhibitors) before PC was also realized. Liver injury and oxidative stress were evaluated. SIRT1 protein levels and activity, as well as other parameters involved in PC protective mechanisms (adenosine monophosphate protein kinase, eNOS, HSP70, MAP kinases, apoptosis), were also measured. We demonstrated that the protective effect of PC was due in part to SIRT1 induction, as SIRT1 inhibition resulted in increased liver injury and abolished the beneficial mechanisms of PC. In this study, we report for the first time that SIRT1 is involved in the protective mechanisms induced by hepatic PC in steatotic livers.
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Affiliation(s)
- Eirini Pantazi
- Experimental Hepatic Ischemia-Reperfusion Unit, Institute of Biomedical Research of Barcelona, IIBB-CSIC, Barcelona, Catalonia, Spain; Networked Biomedical Research Center of Hepatic and Digestive Diseases (CiberEHD), Barcelona, Catalonia, Spain
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Beneficial effects of green tea catechin on massive hepatectomy model in rats. J Gastroenterol 2014; 49:692-701. [PMID: 23543313 DOI: 10.1007/s00535-013-0799-9] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/18/2012] [Accepted: 03/18/2013] [Indexed: 02/04/2023]
Abstract
BACKGROUND Green tea catechin, especially epigallocatechin gallate (EGCG), is a well-known scavenger of reactive oxygen species and it may also function as an antioxidant through modulation of transcriptional factors and enzyme activities. METHODS Green tea extract (GTE®) which contained numerous EGCG was used. Wistar rats were performed 90 % hepatectomy and classified into 2 groups with (GTEHx, n = 25) or without GTE treatment (Hx, n = 25) and sacrificed at 1, 3, 7 and 14 days after operations. All rats had free access to drinking water supplemented with or without GTE from the 7th pre-operative day. Liver regeneration, hepatic inducible nitric oxide synthase (iNOS), anti-oxidative enzymes [superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GSH-Px)] and inflammatory markers [cyclooxygenase-2 (COX-2), nuclear factor kappa B (NFκB), tumor necrosis factor-α (TNF-α)] were investigated. RESULTS The liver weight to body weight ratio (p < 0.01), proliferating cell nuclear antigen labeling index (p < 0.05) and phosphorylated extracellular signal-regulated kinase 1/2 (p < 0.05) at day 1 in the GTEHx group significantly increased compared to the Hx group. Hepatic iNOS levels at day 1 significantly decreased (p < 0.01) in the GTEHx group. Hepatic SOD, CAT and GSH-Px levels at day 1 significantly increased (SOD: p < 0.01, CAT and GSH-Px: p < 0.05) in the GTEHx group. In contrast, COX-2, NFκB and TNF-α levels at day 1 significantly decreased (COX-2: p < 0.01, NFκB and TNF-α: p < 0.05) in the GTEHx group. CONCLUSIONS GTE pretreatment stimulated liver regeneration and improved liver damage after massive hepatectomy through anti-oxidative and anti-inflammatory effects. Green tea catechin might have the potential to attenuate liver dysfunction in early stage after massive hepatectomy.
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Guan J, Li H, Lv T, Chen D, Yuan Y, Qu S. Bone Morphogenic Protein-7 Contributes to Cerebral Ischemic Preconditioning Induced-Ischemic Tolerance by Activating p38 Mitogen-Activated Protein Kinase Signaling Pathway. Inflammation 2014; 37:1289-96. [DOI: 10.1007/s10753-014-9856-7] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/04/2023]
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Yang J, Liang Y, Han H, Qin H. Identification of a miRNA signature in neutrophils after traumatic injury. Acta Biochim Biophys Sin (Shanghai) 2013; 45:938-45. [PMID: 24108763 DOI: 10.1093/abbs/gmt100] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022] Open
Abstract
Traumatic injury is the cause of significant mortality and morbidity. The molecular mechanisms underlying traumatic injury logically involve changes in gene expression that may be regulated through microRNAs (miRNAs). However, the association between miRNA deregulation and traumatic injury is largely unknown. The purpose of the present study is to address this issue. In this study, we used microarray profiling to evaluate the differential expressions of miRNAs in neutrophils obtained from patients with major trauma (injury severity scores >16), relative to healthy individuals. This neutrophilic miRNA signature was further validated using quantitative real-time reverse transcription-polymerase chain reaction (qRT-PCR). Genes and signaling pathways related to trauma-induced deregulated miRNAs were investigated in silico using the ontology-based and network mapping algorithms of Gene Ontology and Kyoto Encyclopedia of Genes or Genomes. Results showed that 13 miRNAs in neutrophils of major trauma patients were significantly and differentially expressed compared with the miRNA profiles of healthy controls. The results of qRT-PCR and in silico analysis revealed that miR-23a-5p, miR-30e-3p, miR-223-5p, miR-3945, miR-155-5p, and miR-150-5p were likely participants in the traumatic pathogenesis of these patients. In conclusion, neutrophils associated with traumatic injury were found to have a unique miRNA signature. Changes in signaling pathways due to deregulated miRNAs may be involved in the pathological processes of traumatic injury.
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Affiliation(s)
- Jun Yang
- Department of Surgery, Shanghai Jiao Tong University School of Medicine Affiliated Sixth People's Hospital, Shanghai 200233, China
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The novel guanylhydrazone CPSI-2364 ameliorates ischemia reperfusion injury after experimental small bowel transplantation. Transplantation 2013; 95:1315-23. [PMID: 23598944 DOI: 10.1097/tp.0b013e31828e72fa] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
BACKGROUND Resident macrophages within the tunica muscularis are known to play a crucial role in initiating severe inflammation in response to ischemia reperfusion injury after intestinal transplantation contributing to graft dysmotility, bacterial translocation, and possibly, acute rejection. The p38 mitogen-activated protein kinase is a key player in the signaling of proinflammatory cytokine synthesis in macrophages. Therefore, we investigated the effects of CPSI-2364, an apparent macrophage-specific inhibitor of the p38 mitogen-activated protein kinase pathway in an isogenic intestinal rat transplantation model. METHODS Recipient and donor animals were treated perioperatively with CPSI-2364 (1 mg/kg, intravenously) or vehicle solution. Nontransplanted animals served as control. Animals were killed 30 min, 3 hr, and 18 hr after reperfusion. RESULTS CPSI-2364 treatment resulted in significantly less leukocyte infiltration and significantly improved graft motor function (18 hr). Messenger RNA expression of proinflammatory cytokines (interleukin 6) and kinetic active mediators (NO) was reduced by CPSI-2364 in the early phase after transplantation. Histologic evaluation revealed the protective effects of CPSI-2364 treatment by a significantly less destruction of mucosal integrity at all time points. Perioperative treatment with CPSI-2364 improves graft motor function through impaired inflammatory responses to ischemia reperfusion injury by inhibition of proinflammatory cytokines and suppression of nitric oxide production in macrophages. CONCLUSIONS CPSI-2364 presents as a promising complementary pharmacological approach preventing postoperative dysmotility for clinical intestinal transplantation.
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Nace GW, Huang H, Klune JR, Eid RE, Rosborough BR, Korff S, Li S, Shapiro RA, Stolz DB, Sodhi CP, Hackam DJ, Geller DA, Billiar TR, Tsung A. Cellular-specific role of toll-like receptor 4 in hepatic ischemia-reperfusion injury in mice. Hepatology 2013; 58:374-87. [PMID: 23460269 PMCID: PMC3688695 DOI: 10.1002/hep.26346] [Citation(s) in RCA: 99] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/11/2012] [Accepted: 02/15/2013] [Indexed: 12/19/2022]
Abstract
UNLABELLED Ischemia-reperfusion (I/R) injury is a process whereby an initial hypoxic insult and subsequent return of blood flow leads to the propagation of innate immune responses and organ injury. The necessity of the pattern recognition receptor, Toll-like receptor (TLR)4, for this innate immune response has been previously shown. However, TLR4 is present on various cell types of the liver, both immune and nonimmune cells. Therefore, we sought to determine the role of TLR4 in individual cell populations, specifically, parenchymal hepatocytes (HCs), myeloid cells, including Kupffer cells, and dendritic cells (DCs) subsequent to hepatic I/R. When HC-specific (Alb-TLR4(-/-) ) and myeloid-cell-specific (Lyz-TLR4(-/-) ) TLR4 knockout (KO) mice were subjected to warm hepatic ischemia, there was significant protection in these mice, compared to wild type (WT). However, the protection afforded in these two strains was significantly less than global TLR4 KO (TLR4(-/-) ) mice. DC-specific TLR4(-/-) (CD11c-TLR4(-/-) ) mice had significantly increased hepatocellular damage, compared to WT mice. Circulating levels of high-mobility group box 1 (HMGB1) were significantly reduced in Alb-TLR4(-/-) mice, compared to WT, Lyz-TLR4(-/-) , CD11c-TLR4(-/-) mice and equivalent to global TLR4(-/-) mice, suggesting that TLR4-mediated HMGB1 release from HCs may be a source of HMGB1 after I/R. HCs exposed to hypoxia responded by rapidly phosphorylating the mitogen-activated protein kinases, c-Jun-N-terminal kinase (JNK) and p38, in a TLR4-dependent manner; inhibition of JNK decreased release of HMGB1 after both hypoxia in vitro and I/R in vivo. CONCLUSION These results provide insight into the individual cellular response of TLR4. The parenchymal HC is an active participant in sterile inflammatory response after I/R through TLR4-mediated activation of proinflammatory signaling and release of danger signals, such as HMGB1.
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Affiliation(s)
- Gary W Nace
- Department of Surgery, University of Pittsburgh, Pittsburgh, PA 15213, USA
| | - Hai Huang
- Department of Surgery, University of Pittsburgh, Pittsburgh, PA 15213, USA
| | - John R Klune
- Department of Surgery, University of Pittsburgh, Pittsburgh, PA 15213, USA
| | - Raymond E Eid
- Department of Surgery, University of Pittsburgh, Pittsburgh, PA 15213, USA
| | - Brian R Rosborough
- Department of Surgery, University of Pittsburgh, Pittsburgh, PA 15213, USA
| | - Sebastian Korff
- Department of Surgery, University of Pittsburgh, Pittsburgh, PA 15213, USA,Department of Orthopedic and Trauma Surgery, University of Heidelberg, Heidelberg, Germany
| | - Shen Li
- Department of Surgery, University of Pittsburgh, Pittsburgh, PA 15213, USA
| | - Richard A Shapiro
- Department of Surgery, University of Pittsburgh, Pittsburgh, PA 15213, USA
| | - Donna B Stolz
- Department of Cell Biology, University of Pittsburgh, Pittsburgh, PA 15213, USA
| | - Chhinder P Sodhi
- Division of Pediatric Surgery, Department of Surgery, Children’s Hospital of Pittsburgh, University of Pittsburgh School of Medicine, Pittsburgh, PA 15224, USA
| | - David J Hackam
- Division of Pediatric Surgery, Department of Surgery, Children’s Hospital of Pittsburgh, University of Pittsburgh School of Medicine, Pittsburgh, PA 15224, USA
| | - David A Geller
- Department of Surgery, University of Pittsburgh, Pittsburgh, PA 15213, USA
| | - Timothy R Billiar
- Department of Surgery, University of Pittsburgh, Pittsburgh, PA 15213, USA
| | - Allan Tsung
- Department of Surgery, University of Pittsburgh, Pittsburgh, PA 15213, USA,Corresponding author: Allan Tsung, 3459 Fifth Avenue, UPMC Montefiore, 7 South, Pittsburgh, PA 15213-2582, Telephone: 412-692-2001, Fax: 412-692-2002
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The Fibrin-Derived Peptide Bβ15-42 Attenuates Liver Damage in a Rat Model of Liver Ischemia/Reperfusion Injury. Shock 2013; 39:397-403. [DOI: 10.1097/shk.0b013e31828c2b75] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
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Zheng S, Sugita S, Hirai S, Egashira Y. Protective effect of low molecular fraction of MGN-3, a modified arabinoxylan from rice bran, on acute liver injury by inhibition of NF-κB and JNK/MAPK expression. Int Immunopharmacol 2012; 14:764-9. [DOI: 10.1016/j.intimp.2012.10.012] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2012] [Revised: 07/30/2012] [Accepted: 10/12/2012] [Indexed: 12/22/2022]
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Yang YY, Huang YT, Lee TY, Chan CC, Yeh YC, Lee KC, Lin HC. Rho-kinase-dependent pathway mediates the hepatoprotective effects of sorafenib against ischemia/reperfusion liver injury in rats with nonalcoholic steatohepatitis. Liver Transpl 2012; 18:1371-83. [PMID: 22847887 DOI: 10.1002/lt.23520] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
During liver transplantation, nonalcoholic steatohepatitis (NASH) aggravates ischemia/reperfusion (IR) injury by activating various kinases and subsequently releasing cytokines and chemokines. Nonetheless, the effect of the multikinase inhibitor sorafenib on IR liver injury in rats with NASH has never been explored. Our study was designed to determine this effect and associated mechanisms in NASH rats. Sorafenib was acutely administered to NASH rats with IR liver injury that were or were not chronically pretreated with the Rho-kinase-specific inhibitor fasudil. Then, the following were evaluated: mean arterial pressure; hepatic blood flow and microcirculatory dysfunction; hepatic inflammation (serum alanine aminotransferase); necrosis; apoptosis; leukocyte infiltration; CD45 staining; caspase levels and DNA fragmentation; various serum and hepatic cytokines; and proteins and genes of the Raf/mitogen-activated protein-extracellular signal-regulated kinase kinase (MEK)/extracellular signal-regulated kinase (ERK), p38 mitogen-activated protein kinase, and apoptosis pathways. In NASH rats with IR liver injury, hepatic inflammation, necrosis, apoptosis, leukocyte infiltration, and microcirculatory dysfunction were significantly attenuated by the acute administration of sorafenib through the inhibition of the hepatic release of macrophage inflammatory protein 2, keratinocyte chemoattractant, granulocyte-monocyte colony-stimulating factor, and hepatic caspase-3 and caspase-9 as well as DNA fragmentation. Furthermore, there was decreased expression of p-Raf1 (where p indicates the phosphorylated form), p-MEK1/2, p-ERK1/2, p-Rho-kinase, B cell lymphoma 2-associated death promoter, and B cell lymphoma 2-associated X protein at the protein and messenger RNA levels. Notably, the aforementioned beneficial effects of sorafenib were significantly abolished by chronic pretreatment with the Rho-kinase-specific inhibitor fasudil. This study demonstrated that the multikinase inhibitor sorafenib protects NASH rats from IR injury by interfering with the inflammation, necrotic, and apoptotic responses causing leukocyte-dependent hepatic microcirculatory dysfunction. The hepatoprotective effects of sorafenib seem to work through the inhibition of the Rho-kinase-dependent Raf/MEK/ERK pathway, which is up-regulated during IR injury in the livers of NASH rats.
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Affiliation(s)
- Ying-Ying Yang
- Division of General Medicine, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan.
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Sakai N, Van Sweringen HL, Belizaire RM, Quillin RC, Schuster R, Blanchard J, Burns JM, Tevar AD, Edwards MJ, Lentsch AB. Interleukin-37 reduces liver inflammatory injury via effects on hepatocytes and non-parenchymal cells. J Gastroenterol Hepatol 2012; 27:1609-16. [PMID: 22646996 PMCID: PMC3448792 DOI: 10.1111/j.1440-1746.2012.07187.x] [Citation(s) in RCA: 108] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
BACKGROUND AND AIM The purpose of the present study was to determine the effects of interleukin-37 (IL-37) on liver cells and on liver inflammation induced by hepatic ischemia/reperfusion (I/R). METHODS Mice were subjected to I/R. Some mice received recombinant IL-37 (IL-37) at the time of reperfusion. Serum levels of alanine aminotransferase, and liver myeloperoxidase content were assessed. Serum and liver tumor necrosis factor-α (TNF-α), macrophage inflammatory protein-2 (MIP-2) and keratinocyte chemokine (KC) were also assessed. Hepatic reactive oxygen species (ROS) levels were assessed. For in vitro experiments, isolated hepatocytes and Kupffer cells were treated with IL-37 and inflammatory stimulants. Cytokine and chemokine production by these cells were assessed. Primary hepatocytes underwent induced cell injury and were treated with IL-37 concurrently. Hepatocyte cytotoxicity and Bcl-2 expression were determined. Isolated neutrophils were treated with TNF-α and IL-37 and neutrophil activation and respiratory burst were assessed. RESULTS IL-37 reduced hepatocyte injury and neutrophil accumulation in the liver after I/R. These effects were accompanied by reduced serum levels of TNF-α and MIP-2 and hepatic ROS levels. IL-37 significantly reduced MIP-2 and KC productions from lipopolysaccharide-stimulated hepatocytes and Kupffer cells. IL-37 significantly reduced cell death and increased Bcl-2 expression in hepatocytes. IL-37 significantly suppressed TNF-α-induced neutrophil activation. CONCLUSIONS IL-37 is protective against hepatic I/R injury. These effects are related to the ability of IL-37 to reduce proinflammatory cytokine and chemokine production by hepatocytes and Kupffer cells as well as having a direct protective effect on hepatocytes. In addition, IL-37 contributes to reduce liver injury through suppression of neutrophil activity.
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Affiliation(s)
- Nozomu Sakai
- Department of Surgery, University of Cincinnati, Cincinnati, Ohio, USA
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Ocuin LM, Zeng S, Cavnar MJ, Sorenson EC, Bamboat ZM, Greer JB, Kim TS, Popow R, DeMatteo RP. Nilotinib protects the murine liver from ischemia/reperfusion injury. J Hepatol 2012; 57:766-73. [PMID: 22641092 PMCID: PMC3437237 DOI: 10.1016/j.jhep.2012.05.012] [Citation(s) in RCA: 45] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/30/2012] [Revised: 05/15/2012] [Accepted: 05/19/2012] [Indexed: 12/13/2022]
Abstract
BACKGROUND & AIMS The mitogen-activated protein kinases (MAPKs), c-Jun N-terminal kinase (JNK), and p38, mediate liver ischemia/reperfusion (I/R) injury via cell death and inflammatory cytokine expression, respectively. Nilotinib is an orally available receptor tyrosine kinase inhibitor used for chronic myelogenous leukemia that also has in vitro activity against JNK and p38. In this study, we examine its therapeutic potential against hepatic I/R injury. METHODS The effects of nilotinib on liver I/R injury were tested using a murine model of warm, segmental liver I/R. Serum ALT was measured and livers were analyzed by histology, RT-PCR, Western blot, and flow cytometry. The in vitro effects of nilotinib on hepatocyte and non-parenchymal cell (NPC) MAPK activation and cytokine production were also tested. RESULTS Mice receiving nilotinib had markedly lower serum ALT levels and less histologic injury and apoptosis following liver I/R. Nilotinib did not inhibit its known receptor tyrosine kinases. Nilotinib lowered intrahepatic expression of IL-1β, IL-6, MCP-1, and MIP-2 and systemic levels of IL-6, MCP-1, and TNF. Nilotinib reduced NPC activation of p38 MAPK signaling and decreased the recruitment of inflammatory monocytes and their production of TNF. Nilotinib attenuated JNK phosphorylation and hepatocellular apoptosis. In vitro, nilotinib demonstrated direct inhibition of JNK activation in isolated hepatocytes cultured under hypoxic conditions, and blocked activation of p38 MAPK and cytokine production by stimulated NPCs. CONCLUSIONS Nilotinib lowers both liver JNK activation and NPC p38 MAPK activation and may be useful for ameliorating liver I/R injury in humans.
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Affiliation(s)
- Lee M Ocuin
- Hepatopancreatobiliary Service, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA
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40
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Yang QG, Liu SN. P38 MAPK signaling pathway and hepatic fibrosis. Shijie Huaren Xiaohua Zazhi 2012; 20:2231-2236. [DOI: 10.11569/wcjd.v20.i24.2231] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Mitogen-activated protein kinase (MAPK) cascade is one of eukaryotic cell-mediated extracellular signal responses to distinct environmental stresses. P38 MAPK is an important member of the MAPK family and plays an important role in a variety of physiological and pathological processes such as inflammation, cellular stress, apoptosis, cell cycle and growth. This article reviews the role of the P38 MAPK signaling pathway in the pathogenesis of hepatic fibrosis in terms of its structure composition, distribution and subtypes, activation pathways and function.
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41
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Masuda T, Iwashita Y, Hagiwara S, Ohta M, Inomata M, Noguchi T, Kitano S. WITHDRAWN: Alpha-lipoic acid derivate DHLHZn reduces hepatic ischemia/reperfusion injury by inhibition of pro-inflammatory signaling. J Surg Res 2012. [DOI: 10.1016/j.jss.2012.04.059] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/28/2022]
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42
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Lv KY, Yu XY, Bai YS, Zhu SH, Tang HT, Ben DF, Xiao SC, Wang GY, Ma B, Xia ZF. Role of inhibition of p38 mitogen-activated protein kinase in liver dysfunction after hemorrhagic shock and resuscitation. J Surg Res 2012; 178:827-32. [PMID: 22560853 DOI: 10.1016/j.jss.2012.04.006] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2012] [Revised: 03/14/2012] [Accepted: 04/04/2012] [Indexed: 10/28/2022]
Abstract
BACKGROUND The liver is one of the organs most frequently affected by trauma and hemorrhagic shock; the exact role of p38 mitogen-activated protein kinase (MAPK) activation in response to hepatic hemorrhagic shock/resuscitation (HS/R) remains unclear. MATERIALS AND METHODS C57Bl/6 mice were divided into four groups: sham-operated group, SB-only group, control group, and SB + HS/R group. Hepatocellular injury (aspartate aminotransferase [AST] and alanine aminotransferase [ALT]) and tumor necrosis factor (TNF-α) and interleukin (IL-1β) messenger ribonucleic acid (mRNA) expression in the liver were assessed 6 h after resuscitation, p38 MAPK activation in the liver was assessed at 30 min after resuscitation. RESULTS p38 MAPK activation was higher in the control group than other groups 30 min after resuscitation. p38 MAPK activation level in the SB + HS/R group did not change significantly compared with that of sham and SB-only groups, but was significantly lower than that in the control group. The TNF-α mRNA expression in the control group was significantly higher than that in the sham group. The TNF-α mRNA levels after HS/R in the SB + HS/R group were significantly lower than those in the control group and were roughly the same as those in the sham and SB-only groups. IL-1β mRNA expression showed similar changes in the four groups. Serum ALT and AST levels in the control group were significantly higher than those in the sham group. The increase in serum ALT and AST levels after HS/R in the SB + HS/R group was significantly less pronounced than that in the control group and markedly higher than that in the sham group. CONCLUSIONS p38 MAPK was phosphorylated during the HS/R process. Inhibiting the activation of p38 MAPK may attenuate HS/R injury to the liver.
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Affiliation(s)
- Kai-yang Lv
- Burn Center, Changhai Hospital, Second Military Medical University, No. 168 Changhai Road, Shanghai 200433, China
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Dukes F, Kanterakis S, Lee J, Pietrofesa R, Andersen ES, Arguiri E, Tyagi S, Showe L, Amrani Y, Christofidou-Solomidou M. Gene expression profiling of flaxseed in mouse lung tissues-modulation of toxicologically relevant genes. BMC COMPLEMENTARY AND ALTERNATIVE MEDICINE 2012; 12:47. [PMID: 22520446 PMCID: PMC3409040 DOI: 10.1186/1472-6882-12-47] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/20/2012] [Accepted: 04/20/2012] [Indexed: 01/19/2023]
Abstract
BACKGROUND Flaxseed (FS), a nutritional supplement consisting mainly of omega-3 fatty acids and lignan phenolics has potent anti-inflammatory, anti-fibrotic and antioxidant properties. The usefulness of flaxseed as an alternative and complimentary treatment option has been known since ancient times. We have shown that dietary FS supplementation ameliorates oxidative stress and inflammation in experimental models of acute and chronic lung injury in mice resulting from diverse toxicants. The development of lung tissue damage in response to direct or indirect oxidant stress is a complex process, associated with changes in expression levels of a number of genes. We therefore postulated that flaxseed might modulate gene expression of vital signaling pathways, thus interfering with the development of tissue injury. METHODS We evaluated gene expression in lungs of flaxseed-fed (10%FS) mice under unchallenged, control conditions. We reasoned that array technology would provide a powerful tool for studying the mechanisms behind this response and aid the evaluation of dietary flaxseed intervention with a focus on toxicologically relevant molecular gene targets. Gene expression levels in lung tissues were analyzed using a large-scale array whereby 28,800 genes were evaluated. RESULTS 3,713 genes (12.8%) were significantly (p < 0.05) differentially expressed, of which 2,088 had a >1.5-fold change. Genes affected by FS include those in protective pathways such as Phase I and Phase II. CONCLUSIONS The array studies have provided information on how FS modulates gene expression in lung and how they might be related to protective mechanisms. In addition, our study has confirmed that flaxseed is a nutritional supplement with potentially useful therapeutic applications in complementary and alternative (CAM) medicine especially in relation to treatment of lung disease.
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Bhogal RH, Weston CJ, Curbishley SM, Adams DH, Afford SC. Activation of CD40 with platelet derived CD154 promotes reactive oxygen species dependent death of human hepatocytes during hypoxia and reoxygenation. PLoS One 2012; 7:e30867. [PMID: 22295117 PMCID: PMC3266283 DOI: 10.1371/journal.pone.0030867] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2011] [Accepted: 12/29/2011] [Indexed: 01/21/2023] Open
Abstract
BACKGROUND Hypoxia and hypoxia-reoxygenation (H-R) are pathogenic factors in many liver diseases that lead to hepatocyte death as a result of reactive oxygen species (ROS) accumulation. The tumor necrosis factor super-family member CD154 can also induce hepatocyte apoptosis via activation of its receptor CD40 and induction of autocrine/paracrine Fas Ligand/CD178 but the relationship between CD40 activation, ROS generation and apoptosis is poorly understood. We hypothesised that CD40 activation and ROS accumulation act synergistically to drive human hepatocyte apoptosis. METHODS Human hepatocytes were isolated from liver tissue and exposed to an in vitro model of hypoxia and H-R in the presence or absence of CD154 and/or various inhibitors. Hepatocyte ROS production, apoptosis and necrosis were determined by labelling cells with 2',7'-dichlorofluorescin, Annexin-V and 7-AAD respectively in a three-colour reporter flow cytometry assay. RESULTS Exposure of human hepatocytes to recombinant CD154 or platelet-derived soluble CD154 augments ROS accumulation during H-R resulting in NADPH oxidase-dependent apoptosis and necrosis. The inhibition of c-Jun N-terminal Kinase and p38 attenuated CD154-mediated apoptosis but not necrosis. CONCLUSIONS CD154-mediated apoptosis of hepatocytes involves ROS generation that is amplified during hypoxia-reoxygenation. This finding provides a molecular mechanism to explain the role of platelets in hepatocyte death during ischemia-reperfusion injury.
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Affiliation(s)
- Ricky H Bhogal
- Centre for Liver Research, School of Infection and Immunity, Institute of Biomedical Research, The Medical School, The University of Birmingham, Edgbaston, Birmingham, United Kingdom.
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Sato H, Tanaka T, Tanaka N. The effect of p38 mitogen-activated protein kinase activation on inflammatory liver damage following hemorrhagic shock in rats. PLoS One 2012; 7:e30124. [PMID: 22253904 PMCID: PMC3253806 DOI: 10.1371/journal.pone.0030124] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2011] [Accepted: 12/14/2011] [Indexed: 12/26/2022] Open
Abstract
Hemorrhagic shock is a frequent cause of liver failure and often leads to a fatal outcome. Several studies have revealed that p38 MAPK is a key mediator in hemorrhagic damage of the primary organs through the activation of proinflammatory cytokines such as tumor necrosis factor (TNF)-α and interleukin (IL)-1β. However, the precise role of these factors in liver damage following hemorrhagic shock is unclear. In this study, we used FR167653, a specific inhibitor of p38 MAPK phosphorylation, to examine the role of p38 MAPK in liver damage occurring up to 5 hours after a hemorrhagic episode in a rat model. Activation of p38 MAPK in the liver as well as an increase in hepatic mRNA expression and serum concentrations of TNF-α and IL-1β occurred during the early phase after hemorrhage. Increased serum levels of hepatic enzymes, as well as histological damage and activated neutrophil accumulation in the liver, were observed in the late phase following hemorrhagic shock. FR167653 inhibited the inflammation-related hepatic injury following hemorrhagic shock. Bacterial lipopolysaccharide (LPS) derived from the gut appeared to have little effects on the hepatic damage. These results demonstrate that p38 MAPK activation is induced by hepatic ischemia during hemorrhagic shock and plays an important role both in the hepatic expression of proinflammatory cytokines and in the development of inflammation-related liver damage.
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Affiliation(s)
- Hiroaki Sato
- Department of Forensic Medicine, University of Occupational and Environmental Health, Japan, Yahata-Nishi, Kitakyushu, Japan.
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Ye P, Yang B, Wu XL, Jiang MD. P38 MAPK signaling pathway: biological functions, roles in the pathogenesis of liver fibrosis and common research methods. Shijie Huaren Xiaohua Zazhi 2011; 19:3353-3358. [DOI: 10.11569/wcjd.v19.i32.3353] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
The activation and proliferation of hepatic stellate cells (HSC) are the key events in hepatic fibrogenesis. Now the research about the mechanisms of action of HSC-related signal transduction has become a hot topic. This article reviews the biological functions of the p38 MAPK signaling pathway and its roles in the pathogenesis of liver fibrosis and summarizes common research methods for this signaling pathway.
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Iannelli A, de Sousa G, Zucchini N, Saint-Paul MC, Gugenheim J, Rahmani R. Anti-Apoptotic Pro-Survival Effect of Clotrimazole in a Normothermic Ischemia Reperfusion Injury Animal Model. J Surg Res 2011; 171:101-7. [DOI: 10.1016/j.jss.2010.03.035] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2009] [Revised: 02/19/2010] [Accepted: 03/11/2010] [Indexed: 10/19/2022]
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Nagaleekar VK, Sabio G, Aktan I, Chant A, Howe IW, Thornton TM, Benoit PJ, Davis RJ, Rincon M, Boyson JE. Translational control of NKT cell cytokine production by p38 MAPK. JOURNAL OF IMMUNOLOGY (BALTIMORE, MD. : 1950) 2011; 186:4140-6. [PMID: 21368234 PMCID: PMC3697841 DOI: 10.4049/jimmunol.1002614] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Indexed: 11/19/2022]
Abstract
NKT cells are known to rapidly produce a large amount of cytokines upon activation. Although a number of signaling pathways that regulate the development of NKT cells have been identified, the signaling pathways involved in the regulation of NKT cell cytokine production remain unclear. In this study, we show that the p38 MAPK pathway is dispensable for the development of NKT cells. However, NKT cell cytokine production and NKT-mediated liver damage are highly dependent on activation of this pathway. p38 MAPK does not substantially affect cytokine gene expression in NKT cells, but it regulates the synthesis of cytokines through the Mnk-eIF4E pathway. Thus, in addition to gene expression, translational regulation by p38 MAPK could be a novel mechanism that contributes to the overall production of cytokine by NKT cells.
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Affiliation(s)
- Viswas K. Nagaleekar
- Department of Medicine/Immunobiology, University of Vermont, Burlington VT 05405, USA
| | - Guadalupe Sabio
- Howard Hughes Medical Institute and Program in Molecular Medicine, University of Massachusetts Medical school, Worcester, MA 01605, USA
| | - Idil Aktan
- Department of Surgery, University of Vermont, Burlington VT 05405, USA
| | - Alan Chant
- Department of Surgery, University of Vermont, Burlington VT 05405, USA
| | - Isaac W. Howe
- Department of Surgery, University of Vermont, Burlington VT 05405, USA
| | - Tina M. Thornton
- Department of Medicine/Immunobiology, University of Vermont, Burlington VT 05405, USA
| | - Patrick J. Benoit
- Department of Surgery, University of Vermont, Burlington VT 05405, USA
| | - Roger J. Davis
- Howard Hughes Medical Institute and Program in Molecular Medicine, University of Massachusetts Medical school, Worcester, MA 01605, USA
| | - Mercedes Rincon
- Department of Medicine/Immunobiology, University of Vermont, Burlington VT 05405, USA
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Abstract
Warm hepatic ischemia-reperfusion injury is a significant medical problem in many clinical conditions such as liver transplantation, hepatic surgery for tumor excision, trauma and hepatic failure after hemorrhagic shock. Partial or, mostly, total interruption of hepatic blood flow is often necessary when liver surgery is performed. This interruption of blood flow is termed "warm ischemia" and upon revascularization, when molecular oxygen is reintroduced, the organ undergoes a process called "reperfusion injury" that causes deterioration of organ function. Ischemia reperfusion results in cellular damage and tissue injury associated with a complex series of events. Pathophysiological mechanisms leading to tissue injury following ischemia-reperfusion will be discussed and therapies targeted to reduce liver damage will be summarized within this review.
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Affiliation(s)
- Serdar Dogan
- Department of Biochemistry, Akdeniz University School of Medicine, Antalya, Turkey
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Liao YH, Qian NS, Zhang Y, Dou KF. Traumatic stress and hepatocyte apoptosis. Shijie Huaren Xiaohua Zazhi 2010; 18:1569-1576. [DOI: 10.11569/wcjd.v18.i15.1569] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Trauma can cause stress in organisms and may promote cell apoptosis and lead to pathological damage. A variety of factors are involved in this process. The mechanisms responsible for traumatic stress-induced apoptosis are complex and controversial, especially in non-nervous organs. The liver plays a key role in metabolism and is one of the target organs of severe stress. Stress-induced hyperglycemia, calcium overload, oxidative stress, ischemia/reperfusion, inflammatory response, and immunosuppression caused by traumatic stress may lead to hepatocyte apoptosis. Thus, it is of great significance to explore the relationship between traumatic stress and hepatocyte apoptosis.
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