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Tian C, Wang A, Kuang Y. Remote ischemic conditioning in experimental hepatic ischemia‑reperfusion: A systematic review and meta‑analysis. Biomed Rep 2025; 22:49. [PMID: 39882337 PMCID: PMC11775642 DOI: 10.3892/br.2025.1927] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2024] [Accepted: 12/20/2024] [Indexed: 01/31/2025] Open
Abstract
Remote ischemic conditioning (RIC), including pre-conditioning (RIPC, before the ischemic event), per-conditioning (RIPerC, during the ischemic event), and post-conditioning (RIPostC, after the ischemic event), protects the liver in animal hepatic ischemia-reperfusion injuries models. However, several questions regarding the optimal timing of intervention and administration protocols remain unanswered. Therefore, the preclinical evidence on RIC in the HIRI models was systematically reviewed and meta-analyzed in the present review to provide constructive and helpful information for future works. In the present review, 39 articles were identified by searching the PubMed, OVID, Web of Science and Embase databases spanned from database inception to July 2024. According to the preferred reporting items for systematic reviews and meta-analyses guidelines, data were extracted independently by two researchers. The primary outcomes evaluated in this study were those directly related to liver injury, such as alanine transaminase (ALT), aspartate transaminase (AST) and liver histopathology. The risk of bias was assessed using the risk of bias tool of the SYstematic Review Centre for Laboratory animal Experimentation (SYRCLE). The findings were expressed as standardized mean difference (SMD) and analyzed using random-effects models. Egger's test was used to evaluate the publication bias. RIC significantly reduced the changes in ALT, AST and liver histopathology (all P<0.00001). These effects had two peaks, with the first peak of RIPerC/RIPostC occurring earlier, regardless of models and species. RIPerC/RIPostC exerted significant effects on changes in ALT and AST [ALT SMD (95% confidence interval (CI]): RIPC -1.97 (-2.40, -1.55) vs. -2.78 (-3.77, -1.78); P=0.142; AST SMD (95%CI): RIPC -1.45 (-1.90, -0.99) vs. -2.13 (-2.91, -1.34); P=0.142], and RIPC had a greater effect on liver histopathology change [SMD (95%CI): RIPC -2.68 (-3.67, -1.69) vs. -1.58 (-2.24, -0.92); P=0.070]; however, no interactions were observed between the two groups in the meta-regression analysis. RIC is the most effective in experimental HIRI, using a 10-25-min dose. These outcomes suggest that RIC may be a promising strategy for treating HIRI; however, future studies using repeated doses in animal models with comorbidities will present novel ideas for its therapeutic application. The protocol of present study was registered with PROSPERO (CRD42023482725).
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Affiliation(s)
- Chun Tian
- Department of Anesthesiology, Yongchuan Hospital of Chongqing Medical University, Chongqing 402160, P.R. China
| | - Aihua Wang
- Department of Science and Education, Yongchuan District People's Hospital of Chongqing, Chongqing 400010, P.R. China
| | - Yonghong Kuang
- Department of Science and Education, Yongchuan District People's Hospital of Chongqing, Chongqing 400010, P.R. China
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Lin L, Sun C, Ye Y, Zhu P, Pan K, Chen L. Transcriptome analysis revealed that ischemic post-conditioning suppressed the expression of inflammatory genes in lung ischemia-reperfusion injury. Front Genet 2024; 15:1425420. [PMID: 39655220 PMCID: PMC11625726 DOI: 10.3389/fgene.2024.1425420] [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: 05/17/2024] [Accepted: 11/11/2024] [Indexed: 12/12/2024] Open
Abstract
Introduction Ischemic post-conditioning (I-post C) is a recognized therapeutic strategy for lung ischemia/reperfusion injury (LIRI). However, the specific mechanisms underlying the lung protection conferred by I-post C remain unclear. This study aimed to investigate the protective mechanisms and potential molecular regulatory networks of I-post C on lung tissue. Methods Transcriptome analysis was performed on rat lung tissues obtained from Sham, ischemia-reperfusion (IR), and I-post C groups using RNA-seq to identify differentially expressed genes (DEGs). Subsequently, gene ontology (GO) analysis, Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis, and gene set enrichment analysis (GSEA) were conducted to elucidate significantly enriched pathways in the IR and I-post C groups. Additionally, protein-protein interaction (PPI) network analysis was carried out to examine associations among the DEGs. Pathological changes in lung tissues were assessed using hematoxylin-eosin (H&E) staining. The expression levels of CXCL1 and CXCL6 in the IR and I-post C groups were evaluated through immunofluorescence and Western blotting. Results Our results showed that I-post C significantly attenuated both pulmonary edema and inflammatory cell infiltration. Transcriptome analysis identified 38 DEGs in the I-post C group compared to the IR group, comprising 21 upregulated and 17 downregulated genes. Among these, seven inflammation-related DEGs exhibited co-expression patterns with the Sham and IR groups, with notable downregulation of Cxcl1 and Cxcl6. GO analysis primarily linked these DEGs to neutrophil activation, chemotaxis, cytokine activity, and CCR chemokine receptor binding. KEGG analysis revealed enriched pathways, including the IL-17, TNF, and NF-κB signaling pathways. GSEA indicated downregulation of neutrophil chemotaxis and the IL-17 signaling pathway, correlating with reduced expression of Cxcl1 and Cxcl6. Validation of Cxcl1 and Cxcl6 mRNA expression via immunofluorescence and Western blotting supported the RNA-seq findings. Furthermore, a PPI network was constructed to elucidate interactions among the 29 DEGs. Conclusions Through RNA-Seq analysis, we concluded that I-post C may reduce inflammation and suppress the IL-17 signaling pathway, thereby protecting against lung damage caused by LIRI, potentially involving neutrophil extracellular traps.
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Affiliation(s)
- Liangen Lin
- Department of Emergency, Wenzhou People’s Hospital, The Third Affiliated to Shanghai University, Wenzhou, Zhejiang, China
| | - Congcong Sun
- Department of Scientific Research Center, Wenzhou People’s Hospital, The Third Affiliated to Shanghai University, Wenzhou, Zhejiang, China
| | - Yuanwen Ye
- Department of Emergency, Wenzhou People’s Hospital, The Third Affiliated to Shanghai University, Wenzhou, Zhejiang, China
| | - Peng Zhu
- Department of Emergency, Wenzhou People’s Hospital, The Third Affiliated to Shanghai University, Wenzhou, Zhejiang, China
| | - Keyue Pan
- Department of Emergency, Wenzhou People’s Hospital, The Third Affiliated to Shanghai University, Wenzhou, Zhejiang, China
| | - Linglong Chen
- Department of Emergency, Wenzhou People’s Hospital, The Third Affiliated to Shanghai University, Wenzhou, Zhejiang, China
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Zhang M, Liu Q, Meng H, Duan H, Liu X, Wu J, Gao F, Wang S, Tan R, Yuan J. Ischemia-reperfusion injury: molecular mechanisms and therapeutic targets. Signal Transduct Target Ther 2024; 9:12. [PMID: 38185705 PMCID: PMC10772178 DOI: 10.1038/s41392-023-01688-x] [Citation(s) in RCA: 157] [Impact Index Per Article: 157.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2023] [Revised: 08/29/2023] [Accepted: 10/18/2023] [Indexed: 01/09/2024] Open
Abstract
Ischemia-reperfusion (I/R) injury paradoxically occurs during reperfusion following ischemia, exacerbating the initial tissue damage. The limited understanding of the intricate mechanisms underlying I/R injury hinders the development of effective therapeutic interventions. The Wnt signaling pathway exhibits extensive crosstalk with various other pathways, forming a network system of signaling pathways involved in I/R injury. This review article elucidates the underlying mechanisms involved in Wnt signaling, as well as the complex interplay between Wnt and other pathways, including Notch, phosphatidylinositol 3-kinase/protein kinase B, transforming growth factor-β, nuclear factor kappa, bone morphogenetic protein, N-methyl-D-aspartic acid receptor-Ca2+-Activin A, Hippo-Yes-associated protein, toll-like receptor 4/toll-interleukine-1 receptor domain-containing adapter-inducing interferon-β, and hepatocyte growth factor/mesenchymal-epithelial transition factor. In particular, we delve into their respective contributions to key pathological processes, including apoptosis, the inflammatory response, oxidative stress, extracellular matrix remodeling, angiogenesis, cell hypertrophy, fibrosis, ferroptosis, neurogenesis, and blood-brain barrier damage during I/R injury. Our comprehensive analysis of the mechanisms involved in Wnt signaling during I/R reveals that activation of the canonical Wnt pathway promotes organ recovery, while activation of the non-canonical Wnt pathways exacerbates injury. Moreover, we explore novel therapeutic approaches based on these mechanistic findings, incorporating evidence from animal experiments, current standards, and clinical trials. The objective of this review is to provide deeper insights into the roles of Wnt and its crosstalk signaling pathways in I/R-mediated processes and organ dysfunction, to facilitate the development of innovative therapeutic agents for I/R injury.
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Affiliation(s)
- Meng Zhang
- The Collaborative Innovation Center, Jining Medical University, Jining, Shandong, 272067, China
| | - Qian Liu
- Clinical Medical College, Jining Medical University, Jining, Shandong, 272067, China
| | - Hui Meng
- Clinical Medical College, Jining Medical University, Jining, Shandong, 272067, China
| | - Hongxia Duan
- Clinical Medical College, Jining Medical University, Jining, Shandong, 272067, China
| | - Xin Liu
- Second Clinical Medical College, Jining Medical University, Jining, Shandong, 272067, China
| | - Jian Wu
- Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital and Institutes of Biomedical Sciences, Fudan University, Shanghai, China
| | - Fei Gao
- The Collaborative Innovation Center, Jining Medical University, Jining, Shandong, 272067, China
- Institute of Zoology, Chinese Academy of Sciences, Beijing, China
| | - Shijun Wang
- Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital and Institutes of Biomedical Sciences, Fudan University, Shanghai, China.
| | - Rubin Tan
- Department of Physiology, Basic medical school, Xuzhou Medical University, Xuzhou, 221004, China.
| | - Jinxiang Yuan
- The Collaborative Innovation Center, Jining Medical University, Jining, Shandong, 272067, China.
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Baranova K, Nalivaeva N, Rybnikova E. Neuroadaptive Biochemical Mechanisms of Remote Ischemic Conditioning. Int J Mol Sci 2023; 24:17032. [PMID: 38069355 PMCID: PMC10707673 DOI: 10.3390/ijms242317032] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2023] [Revised: 11/24/2023] [Accepted: 11/27/2023] [Indexed: 12/18/2023] Open
Abstract
This review summarizes the currently known biochemical neuroadaptive mechanisms of remote ischemic conditioning. In particular, it focuses on the significance of the pro-adaptive effects of remote ischemic conditioning which allow for the prevention of the neurological and cognitive impairments associated with hippocampal dysregulation after brain damage. The neuroimmunohumoral pathway transmitting a conditioning stimulus, as well as the molecular basis of the early and delayed phases of neuroprotection, including anti-apoptotic, anti-oxidant, and anti-inflammatory components, are also outlined. Based on the close interplay between the effects of ischemia, especially those mediated by interaction of hypoxia-inducible factors (HIFs) and steroid hormones, the involvement of the hypothalamic-pituitary-adrenocortical system in remote ischemic conditioning is also discussed.
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Affiliation(s)
| | | | - Elena Rybnikova
- I. P. Pavlov Institute of Physiology, Russian Academy of Sciences, 199034 Saint Petersburg, Russia; (K.B.); (N.N.)
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Guo R, Zheng P, Zhu S, Zeng Z, Li Z, Yang Y. Comprehensive analysis and identification of prognostic biomarkers and immunotherapeutic targets in the NADPH oxidase family (and its regulatory subunits) in pancreatic ductal adenocarcinoma. Clin Transl Oncol 2023; 25:3460-3470. [PMID: 37222951 DOI: 10.1007/s12094-023-03211-8] [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: 02/09/2023] [Accepted: 04/29/2023] [Indexed: 05/25/2023]
Abstract
PURPOSE This study aimed to evaluate the role of NADPH in pancreatic ductal adenocarcinoma using bioinformatic analyses and experimental validations. METHODS We compared the expression levels, performed GO and KEGG analysis of NADPH oxidase family and its regulatory subunits, and determined the survival of patients with pancreatic ductal adenocarcinoma by GEPIA, David and KM plotter. The relationship between their expression with immune infiltration levels, phagocytotic/NK cell immune checkpoints, recruitment-related molecules were detected by Timer 2.0 and TISIDB, respectively. Subsequently, their correlation with NK cell infiltration level was verified by immunohistochemistry. RESULTS The expression of some members of the NADPH oxidase family and its regulatory subunits was significantly increased in pancreatic ductal adenocarcinoma tissues compared to that in normal tissues and was positively correlated with natural killer (NK) cell infiltration. Furthermore, the NADPH oxidase family and its regulatory subunits were associated with survival and immune status in patients with pancreatic ductal adenocarcinoma, including chemokines, immune checkpoints, and immune infiltration levels of NK cells, monocytes, and myeloid-derived suppressor cells. CONCLUSIONS These results suggest the NADPH oxidase family and its regulatory subunits might serve as indicators for predicting the responsiveness to immunotherapy and outcome of patients with pancreatic ductal adenocarcinoma, providing a new perspective or strategy for immunotherapy in pancreatic ductal adenocarcinoma.
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Affiliation(s)
- Ruiqi Guo
- Department of Pathology, College of Basic Medicine, Chongqing Medical University, Chongqing, China
- Molecular Medicine Diagnostic and Testing Center, Chongqing Medical University, Chongqing, China
- Department of Pathology, the First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Panchun Zheng
- Department of Pathology, College of Basic Medicine, Chongqing Medical University, Chongqing, China
- Molecular Medicine Diagnostic and Testing Center, Chongqing Medical University, Chongqing, China
- Department of Pathology, the First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Shasha Zhu
- The Center for Clinical Molecular Medical Detection, the First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Zhen Zeng
- Department of Pathology, Chongqing University Cancer Hospital, Chongqing, China
| | - Zhenyu Li
- Department of Pathology, Chongqing University Cancer Hospital, Chongqing, China.
| | - Yaying Yang
- Department of Pathology, College of Basic Medicine, Chongqing Medical University, Chongqing, China.
- Molecular Medicine Diagnostic and Testing Center, Chongqing Medical University, Chongqing, China.
- Department of Pathology, the First Affiliated Hospital of Chongqing Medical University, Chongqing, China.
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Li JH, Jia JJ, He N, Zhou XL, Qiao YB, Xie HY, Zhou L, Zheng SS. Exosome is involved in liver graft protection after remote ischemia reperfusion conditioning. Hepatobiliary Pancreat Dis Int 2023; 22:498-503. [PMID: 35534341 DOI: 10.1016/j.hbpd.2022.04.004] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/28/2021] [Accepted: 04/11/2022] [Indexed: 02/05/2023]
Abstract
BACKGROUND Remote ischemic perconditioning (RIPerC) has been demonstrated to protect grafts from hepatic ischemia-reperfusion injury (IRI). This study investigated the role of exosomes in RIPerC of liver grafts in rats. METHODS Twenty-five rats (including 10 donors) were randomly divided into five groups (n = 5 each group): five rats were used as sham-operated controls (Sham), ten rats were for orthotopic liver transplantation (OLT, 5 donors and 5 recipients) and ten rats were for OLT + RIPerC (5 donors and 5 recipients). Liver architecture and function were evaluated. RESULTS Compared to the OLT group, the OLT + RIPerC group exhibited significantly improved liver graft histopathology and liver function (P < 0.05). Furthermore, the number of exosomes and the level of P-Akt were increased in the OLT + RIPerC group. CONCLUSIONS RIPerC effectively improves graft architecture and function, and this protective effect may be related to the increased number of exosomes. The upregulation of P-Akt may be involved in underlying mechanisms.
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Affiliation(s)
- Jian-Hui Li
- Department of Hepatobiliary and Pancreatic Surgery, Department of Liver Transplantation, Shulan (Hangzhou) Hospital, Zhejiang Shuren University School of Medicine, Hangzhou 310022, China; NHC Key Laboratory of Combined Multi-organ Transplantation, Hangzhou 310022, China
| | - Jun-Jun Jia
- Division of Hepatobiliary Pancreatic Surgery, First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China
| | - Ning He
- Division of Hepatobiliary Pancreatic Surgery, First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China
| | - Xue-Lian Zhou
- Department of Endocrinology, Children's Hospital, Zhejiang University School of Medicine, Hangzhou 310052, China
| | - Yin-Biao Qiao
- Division of Hepatobiliary Pancreatic Surgery, First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China
| | - Hai-Yang Xie
- NHC Key Laboratory of Combined Multi-organ Transplantation, Hangzhou 310022, China
| | - Lin Zhou
- NHC Key Laboratory of Combined Multi-organ Transplantation, Hangzhou 310022, China
| | - Shu-Sen Zheng
- Department of Hepatobiliary and Pancreatic Surgery, Department of Liver Transplantation, Shulan (Hangzhou) Hospital, Zhejiang Shuren University School of Medicine, Hangzhou 310022, China; NHC Key Laboratory of Combined Multi-organ Transplantation, Hangzhou 310022, China; Division of Hepatobiliary Pancreatic Surgery, First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China.
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Li J, Chang WT, Qin G, Wojcik KR, Li CQ, Hsu CW, Han M, Zhu X, Vanden Hoek TL, Shao ZH. Baicalein Preconditioning Cardioprotection Involves Pro-Oxidant Signaling and Activation of Pyruvate Dehydrogenase. THE AMERICAN JOURNAL OF CHINESE MEDICINE 2022; 50:1255-1267. [PMID: 35748215 DOI: 10.1142/s0192415x22500513] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/15/2023]
Abstract
Preconditioning has a powerful protective potential against myocardial ischemia-reperfusion injury (I/R). Our prior work demonstrated that baicalein, a flavonoid derived from the root of Scatellaria baicalensis Georgi (also known as Huangqin), confers this preconditioning protection. This study further explored the mechanisms of baicalein preconditioning (BC-PC) in mouse cardiomyocytes. Cells were treated with baicalein (10 μM) for a brief period of time (10 min) prior to simulated ischemia 90 min/reperfusion for 180 min. Baicalein triggered an induction of a small amount of mitochondrial reactive oxygen species (ROS) prior to the initiation of ischemia, assessed by 6-carboxy-2', 7'-dichlorodihydrofluorescein diacetate (6-carboxy-H2DCFDA). It also significantly increased cell viability measured by propidium iodide (PI) and lactate dehydrogenase and preserved mitochondrial membrane potential assessed by TMRM fluorescence intensity. Myxothiazol, a mitochondrial electron transport chain complex III inhibitor, partially blocked ROS generation induced by BC-PC and reduced cell viability. BC-PC increased phosphorylation of Akt (Thr308 and Ser473) and eNOS Ser1177, and nitric oxide (NO) production measured using 4,5-diaminofluorescein diacetate (DAF-2 DA, 1 μM). Akt inhibitor API-2 abolished Akt phosphorylation and reduced DAF-2 production and cell viability. In addition, BC-PC decreased phosphorylation of pyruvate dehydrogenase (PDH) reflecting upregulated PDH activity, and increased ATP production at 30 min during reperfusion. Taken together, baicalein preconditioning-induced cardioprotection involves pro-oxidant generation, activates survival signaling Akt/eNOS/NO, and improves metabolic recovery after I/R injury. Our work provides new perspectives on the effect of baicalein on cardiac preconditioning against I/R injury.
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Affiliation(s)
- Jing Li
- Department of Emergency Medicine, Center for Advanced Resuscitation Medicine, University of Illinois, Chicago, IL, USA
| | - Wei-Tien Chang
- Department of Emergency Medicine, National Taiwan University Hospital and College of Medicine, Taipei, Taiwan
| | - Gina Qin
- Department of Emergency Medicine, Center for Advanced Resuscitation Medicine, University of Illinois, Chicago, IL, USA
| | - Kimberly R Wojcik
- Department of Emergency Medicine, Center for Advanced Resuscitation Medicine, University of Illinois, Chicago, IL, USA
| | - Chang-Qing Li
- Department of Emergency Medicine, Center for Advanced Resuscitation Medicine, University of Illinois, Chicago, IL, USA
| | - Chin-Wang Hsu
- Department of Emergency, School of Medicine, College of Medicine, Wan Fang Hospital, Taipei Medical University, Taipei, Taiwan
- Emergency Department, Department of Emergency and Critical Medicine, Wan Fang Hospital, Taipei Medical University, Taipei, Taiwan
| | - Mei Han
- Department of Emergency Medicine, Center for Advanced Resuscitation Medicine, University of Illinois, Chicago, IL, USA
| | - Xiangdong Zhu
- Department of Emergency Medicine, Center for Advanced Resuscitation Medicine, University of Illinois, Chicago, IL, USA
| | - Terry L Vanden Hoek
- Department of Emergency Medicine, Center for Advanced Resuscitation Medicine, University of Illinois, Chicago, IL, USA
| | - Zuo-Hui Shao
- Department of Emergency Medicine, Center for Advanced Resuscitation Medicine, University of Illinois, Chicago, IL, USA
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Therapeutic Targets for Regulating Oxidative Damage Induced by Ischemia-Reperfusion Injury: A Study from a Pharmacological Perspective. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2022; 2022:8624318. [PMID: 35450409 PMCID: PMC9017553 DOI: 10.1155/2022/8624318] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/05/2021] [Revised: 02/28/2022] [Accepted: 03/15/2022] [Indexed: 12/22/2022]
Abstract
Ischemia-reperfusion (I-R) injury is damage caused by restoring blood flow into ischemic tissues or organs. This complex and characteristic lesion accelerates cell death induced by signaling pathways such as apoptosis, necrosis, and even ferroptosis. In addition to the direct association between I-R and the release of reactive oxygen species and reactive nitrogen species, it is involved in developing mitochondrial oxidative damage. Thus, its mechanism plays a critical role via reactive species scavenging, calcium overload modulation, electron transport chain blocking, mitochondrial permeability transition pore activation, or noncoding RNA transcription. Other receptors and molecules reduce tissue and organ damage caused by this pathology and other related diseases. These molecular targets have been gradually discovered and have essential roles in I-R resolution. Therefore, the current study is aimed at highlighting the importance of these discoveries. In this review, we inquire about the oxidative damage receptors that are relevant to reducing the damage induced by oxidative stress associated with I-R. Several complications on surgical techniques and pathology interventions do not mitigate the damage caused by I-R. Nevertheless, these therapies developed using alternative targets could work as coadjuvants in tissue transplants or I-R-related pathologies
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Teixeira da Silva R, Machado IF, Teodoro JS, Panisello-Roselló A, Roselló-Catafau J, Rolo AP, Palmeira CM. PEG35 as a Preconditioning Agent against Hypoxia/Reoxygenation Injury. Int J Mol Sci 2022; 23:1156. [PMID: 35163080 PMCID: PMC8834864 DOI: 10.3390/ijms23031156] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2021] [Revised: 01/18/2022] [Accepted: 01/19/2022] [Indexed: 12/22/2022] Open
Abstract
Pharmacological conditioning is a protective strategy against ischemia/reperfusion injury, which occurs during liver resection and transplantation. Polyethylene glycols have shown multiple benefits in cell and organ preservation, including antioxidant capacity, edema prevention and membrane stabilization. Recently, polyethylene glycol 35 kDa (PEG35) preconditioning resulted in decreased hepatic injury and protected the mitochondria in a rat model of cold ischemia. Thus, the study aimed to decipher the mechanisms underlying PEG35 preconditioning-induced protection against ischemia/reperfusion injury. A hypoxia/reoxygenation model using HepG2 cells was established to evaluate the effects of PEG35 preconditioning. Several parameters were assessed, including cell viability, mitochondrial membrane potential, ROS production, ATP levels, protein content and gene expression to investigate autophagy, mitochondrial biogenesis and dynamics. PEG35 preconditioning preserved the mitochondrial function by decreasing the excessive production of ROS and subsequent ATP depletion, as well as by recovering the membrane potential. Furthermore, PEG35 increased levels of autophagy-related proteins and the expression of genes involved in mitochondrial biogenesis and fusion. In conclusion, PEG35 preconditioning effectively ameliorates hepatic hypoxia/reoxygenation injury through the enhancement of autophagy and mitochondrial quality control. Therefore, PEG35 could be useful as a potential pharmacological tool for attenuating hepatic ischemia/reperfusion injury in clinical practice.
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Affiliation(s)
- Rui Teixeira da Silva
- Department of Life Sciences, University of Coimbra, 3000-456 Coimbra, Portugal; (J.S.T.); (A.P.R.); (C.M.P.)
- Center for Neurosciences and Cell Biology, University of Coimbra, 3004-504 Coimbra, Portugal;
- Experimental Pathology Department, Institute of Biomedical Research of Barcelona (IIBB), CSIC-IDIBAPS, 08036 Barcelona, Spain; (A.P.-R.); (J.R.-C.)
| | - Ivo F. Machado
- Center for Neurosciences and Cell Biology, University of Coimbra, 3004-504 Coimbra, Portugal;
- IIIUC—Institute of Interdisciplinary Research, University of Coimbra, 3030-789 Coimbra, Portugal
| | - João S. Teodoro
- Department of Life Sciences, University of Coimbra, 3000-456 Coimbra, Portugal; (J.S.T.); (A.P.R.); (C.M.P.)
- Center for Neurosciences and Cell Biology, University of Coimbra, 3004-504 Coimbra, Portugal;
| | - Arnau Panisello-Roselló
- Experimental Pathology Department, Institute of Biomedical Research of Barcelona (IIBB), CSIC-IDIBAPS, 08036 Barcelona, Spain; (A.P.-R.); (J.R.-C.)
| | - Joan Roselló-Catafau
- Experimental Pathology Department, Institute of Biomedical Research of Barcelona (IIBB), CSIC-IDIBAPS, 08036 Barcelona, Spain; (A.P.-R.); (J.R.-C.)
| | - Anabela P. Rolo
- Department of Life Sciences, University of Coimbra, 3000-456 Coimbra, Portugal; (J.S.T.); (A.P.R.); (C.M.P.)
- Center for Neurosciences and Cell Biology, University of Coimbra, 3004-504 Coimbra, Portugal;
| | - Carlos M. Palmeira
- Department of Life Sciences, University of Coimbra, 3000-456 Coimbra, Portugal; (J.S.T.); (A.P.R.); (C.M.P.)
- Center for Neurosciences and Cell Biology, University of Coimbra, 3004-504 Coimbra, Portugal;
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Lyu PW, Xu XD, Zong K, Qiu XG. Overexpression of DUOX2 mediates doxorubicin resistance and predicts prognosis of pancreatic cancer. Gland Surg 2022; 11:115-124. [PMID: 35242674 PMCID: PMC8825507 DOI: 10.21037/gs-21-776] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/24/2021] [Accepted: 01/11/2022] [Indexed: 01/27/2024]
Abstract
BACKGROUND Dysregulation of the nicotinamide adenine dinucleotide phosphate (NADPH) oxidase (NOX) family is frequently observed in cancers and associated with their development and progression. However, the expression, role, and clinical significance of the NOX family members in pancreatic cancer remain unexplored. METHODS The expression levels of the 7 NOX family genes were analyzed in Gene Expression Omnibus (GEO) datasets. The messenger RNA (mRNA) expression and gene alterations were explored using The Cancer Genome Atlas (TCGA) data portal. Clinical significance analyses of the NOX family genes were conducted among pancreatic cancer patients. The expression and prognostic value of dual oxidase 2 (DUOX2) were then validated by reverse transcription-quantitative polymerase chain reaction (RT-qPCR) and immunohistochemistry (IHC) in an independent validation cohort. The function of DUOX2 was analyzed by gene set enrichment analysis (GSEA) and its effect on the chemosensitivity of pancreatic cancer cells was detected by Cell Counting Kit-8 (CCK-8) assay. RESULTS Results showed that NOX1, NOX2 (CYBB), NOX4, DUOX1, and DUOX2 were upregulated, while NOX3 and NOX5 were downregulated in pancreatic cancer tissues compared with nontumor tissues. Genomic alteration analysis demonstrated that deregulation of NOX family genes was partially caused by genomic alterations. Survival analyses showed that only DUOX2 was associated with overall survival (OS) and relapse-free survival (RFS) of pancreatic cancer patients. The DUOX2 gene was observed to be markedly overexpressed in pancreatic cancer. In the GSEA results for pancreatic cancer patients, DUOX2 was significantly associated with oxidoreductase activity acting on nicotinamide adenine dinucleotide hydrogen (NADH) or NADPH and uridine 5'-diphospho-glucuronosyltansferase (UDP) glycosyltransferase activity. Knockdown of DUOX2 in pancreatic cancer cells increased their sensitivity to doxorubicin. CONCLUSIONS Overexpression of DUOX2 is correlated with prognosis and recurrence in pancreatic cancer patients and acts as a good marker for pancreatic cancer course prediction; furthermore, DUOX2 might be a therapeutic target for pancreatic cancer patients.
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Affiliation(s)
- Peng-Wei Lyu
- Department of Breast Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Xiao-Dong Xu
- Department of Breast Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Ke Zong
- Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Xin-Guang Qiu
- Department of Thyroid Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
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11
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Guo W, Ren C, Zhang B, Zhao W, Gao Y, Yu W, Ji X. Chronic Limb Remote Ischemic Conditioning may have an Antihypertensive Effect in Patients with Hypertension. Aging Dis 2021; 12:2069-2079. [PMID: 34881086 PMCID: PMC8612623 DOI: 10.14336/ad.2021.0604] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2021] [Accepted: 06/06/2021] [Indexed: 12/14/2022] Open
Abstract
Hypertension is the leading preventable risk factor for all-cause morbidity and mortality worldwide. Despite antihypertensive medications have been available for decades, a big challenge we are facing is to increase the blood pressure (BP) control rate among the population. Therefore, it is necessary to search for new antihypertensive means to reduce the burden of disease caused by hypertension. Limb remote ischemic conditioning (LRIC) can trigger endogenous protective effects through transient and repeated ischemia on the limb to protect specific organs and tissues including the brain, heart, and kidney. The mechanisms of LRIC involve the regulation of the autonomic nervous system, releasing humoral factors, improvement of vascular endothelial function, and modulation of immune/inflammatory responses. These underlying mechanisms of LRIC may restrain the pathogenesis of hypertension through multiple pathways theoretically, leading to a potential decline in BP. Several existing studies have explored the impact of LRIC on BP, however, controversial findings were reported. To explore the potential antihypertensive effect of LRIC and the underlying mechanisms, we systematically reviewed the relevant articles to provide an insight into the novel therapy of hypertension.
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Affiliation(s)
- Wenting Guo
- 1Department of Neurology, Xuanwu Hospital, Capital Medical University, Beijing, China
| | - Changhong Ren
- 2Beijing Key Laboratory of Hypoxia Conditioning Translational Medicine, Xuanwu Hospital, Capital Medical, Beijing, China.,3Beijing Municipal Geriatric Medical Research Center, Beijing, China
| | - Bowei Zhang
- 1Department of Neurology, Xuanwu Hospital, Capital Medical University, Beijing, China
| | - Wenbo Zhao
- 1Department of Neurology, Xuanwu Hospital, Capital Medical University, Beijing, China.,2Beijing Key Laboratory of Hypoxia Conditioning Translational Medicine, Xuanwu Hospital, Capital Medical, Beijing, China
| | - Yu Gao
- 5Department of Neurology, The Affiliated Hospital of Qingdao University, Qingdao, Shandong, China
| | - Wantong Yu
- 1Department of Neurology, Xuanwu Hospital, Capital Medical University, Beijing, China
| | - Xunming Ji
- 1Department of Neurology, Xuanwu Hospital, Capital Medical University, Beijing, China.,2Beijing Key Laboratory of Hypoxia Conditioning Translational Medicine, Xuanwu Hospital, Capital Medical, Beijing, China.,4Department of Neurosurgery, Xuanwu Hospital, Capital Medical University, Beijing, China
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12
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Hassan MI, Ali FE, Shalkami AGS. Role of TLR-4/IL-6/TNF-α, COX-II and eNOS/iNOS pathways in the impact of carvedilol against hepatic ischemia reperfusion injury. Hum Exp Toxicol 2021; 40:1362-1373. [PMID: 33655798 DOI: 10.1177/0960327121999442] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/07/2023]
Abstract
AIM Hepatic ischemia/reperfusion (I/R) injury is a syndrome involved in allograft dysfunction. This work aimed to elucidate carvedilol (CAR) role in hepatic I/R injury. METHODS Male rats were allocated to Sham group, CAR group, I/R group and CAR plus I/R group. Rats subjected to hepatic ischemia for 30 minutes then reperfused for 60 minutes. Oxidative stress markers, inflammatory cytokines and nitric oxide synthases were measured in hepatic tissues. RESULTS Hepatocyte injury following I/R was confirmed by a marked increase in liver enzymes. Also, hepatic I/R increased the contents of malondialdehyde however decreased glutathione contents and activities of antioxidant enzymes. Furthermore, hepatic I/R caused elevation of toll-like receptor-4 (TLR-4) expression and inflammatory mediators levels such as tumor necrosis factor-α, interleukin-6 and cyclooxygenase-II. Hepatic I/R caused down-regulation of endothelial nitric oxide synthase and upregulation of inducible nitric oxide synthase expressions. CAR treatment before hepatic I/R resulted in the restoration of liver enzymes. Administration of CAR caused a significant correction of oxidative stress and inflammation markers as well as modulates the expression of endothelial and inducible nitric oxide synthase. CONCLUSIONS CAR protects liver from I/R injury through reduction of the oxidative stress and inflammation, and modulates endothelial and inducible nitric oxide synthase expressions.
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Affiliation(s)
- Mohamed Ia Hassan
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, 195495Al-Azhar University, Assiut, Egypt
| | - Fares Em Ali
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, 195495Al-Azhar University, Assiut, Egypt
| | - Abdel-Gawad S Shalkami
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, 195495Al-Azhar University, Assiut, Egypt
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13
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Drysch M, Schmidt SV, Becerikli M, Reinkemeier F, Dittfeld S, Wagner JM, Dadras M, Sogorski A, von Glinski M, Lehnhardt M, Behr B, Wallner C. Myostatin Deficiency Protects C2C12 Cells from Oxidative Stress by Inhibiting Intrinsic Activation of Apoptosis. Cells 2021; 10:cells10071680. [PMID: 34359850 PMCID: PMC8305813 DOI: 10.3390/cells10071680] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2021] [Revised: 06/28/2021] [Accepted: 06/29/2021] [Indexed: 01/09/2023] Open
Abstract
Ischemia reperfusion (IR) injury remains an important topic in clinical medicine. While a multitude of prophylactic and therapeutic strategies have been proposed, recent studies have illuminated protective effects of myostatin inhibition. This study aims to elaborate on the intracellular pathways involved in myostatin signaling and to explore key proteins that convey protective effects in IR injury. We used CRISPR/Cas9 gene editing to introduce a myostatin (Mstn) deletion into a C2C12 cell line. In subsequent experiments, we evaluated overall cell death, activation of apoptotic pathways, ROS generation, lipid peroxidation, intracellular signaling via mitogen-activated protein kinases (MAPKs), cell migration, and cell proliferation under hypoxic conditions followed by reoxygenation to simulate an IR situation in vitro (hypoxia reoxygenation). It was found that mitogen-activated protein kinase kinase 3/6, also known as MAPK/ERK Kinase 3/6 (MEK3/6), and subsequent p38 MAPK activation were blunted in C2C12-Mstn−/− cells in response to hypoxia reoxygenation (HR). Similarly, c-Jun N-terminal kinase (JNK) activation was negated. We also found the intrinsic activation of apoptosis to be more important in comparison with the extrinsic activation. Additionally, intercepting myostatin signaling mitigated apoptosis activation. Ultimately, this research validated protective effects of myostatin inhibition in HR and identified potential mediators worth further investigation. Intercepting myostatin signaling did not inhibit ROS generation overall but mitigated cellular injury. In particular, intrinsic activation of apoptosis origination from mitochondria was alleviated. This was presumably mediated by decreased activation of p38 caused by the diminished kinase activity increase of MEK3/6. Overall, this work provides important insights into HR signaling in C2C12-Mstn−/− cells and could serve as basis for further research.
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14
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The Protective Effect of Aspirin Eugenol Ester on Oxidative Stress to PC12 Cells Stimulated with H 2O 2 through Regulating PI3K/Akt Signal Pathway. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2021; 2021:5527475. [PMID: 34257805 PMCID: PMC8249132 DOI: 10.1155/2021/5527475] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/20/2021] [Accepted: 05/28/2021] [Indexed: 02/07/2023]
Abstract
Aspirin eugenol ester (AEE) is a new pharmaceutical compound esterified by aspirin and eugenol, which has anti-inflammatory, antioxidant, and other pharmacological activities. This study is aimed at identifying the protective effect of AEE against H2O2-induced apoptosis in rat adrenal pheochromocytoma PC12 cells and the possible mechanisms. The results of cell viability assay showed that AEE could increase the viability of PC12 cells stimulated by H2O2, while AEE alone had no significant effect on the viability of PC12 cells. Compared with the control group, the activities of superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GSH-Px) were significantly decreased, and the content of malondialdehyde (MDA) was significantly increased in the H2O2 group. By AEE pretreatment, the level of MDA was reduced and the levels of SOD, CAT, and GSH-Px were increased in H2O2-stimulated PC12 cells. In addition, AEE could reduce the apoptosis of PC12 cells induced by H2O2 via reducing superoxide anion, intracellular ROS, and mitochondrial ROS (mtROS) and increasing the levels of mitochondrial membrane potential (ΔΨm). Furthermore, the results of western blotting showed that compared with the control group, the expression of p-PI3K, p-Akt, and Bcl-2 was significantly decreased, while the expression of Caspase-3 and Bax was significantly increased in the H2O2 group. In the AEE group, AEE pretreatment could upregulate the expression of p-PI3K, p-Akt, and Bcl-2 and downregulate the expression of Caspase-3 and Bax in PC12 cells stimulated with H2O2. The silencing of PI3K with shRNA and its inhibitor-LY294002 could abrogate the protective effect of AEE in PC12 cells. Therefore, AEE has a protective effect on H2O2-induced PC12 cells by regulating the PI3K/Akt signal pathway to inhibit oxidative stress.
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15
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Stankiewicz R, Grąt M. Direct, remote and combined ischemic conditioning in liver surgery. World J Hepatol 2021; 13:533-542. [PMID: 34131468 PMCID: PMC8173344 DOI: 10.4254/wjh.v13.i5.533] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/17/2021] [Revised: 03/28/2021] [Accepted: 05/07/2021] [Indexed: 02/06/2023] Open
Abstract
Liver ischemia-reperfusion injury is a major cause of postoperative liver dysfunction, morbidity and mortality following liver resection and transplantation. Ischemic conditioning has been shown to ameliorate ischemia-reperfusion injury in small animal models. It can be applied directly or remotely when cycles of ischemia and reperfusion are applied to a distant site or organ. Considering timing of the procedure, different protocols are available. Ischemic preconditioning refers to that performed before the duration of ischemia of the target organ. Ischemic perconditioning is performed over the duration of ischemia of the target organ. Ischemic postconditioning applies brief episodes of ischemia at the onset of reperfusion following a prolonged ischemia. Animal studies pointed towards suppressing cytokine release, enhancing the production of hepatoprotective adenosine and reducing liver apoptotic response as the potential mechanisms responsible for the protective effect of direct tissue conditioning. Interactions between neural, humoral and systemic pathways all lead to the protective effect of remote ischemic preconditioning. Despite promising animal studies, none of the aforementioned protocols proved to be clinically effective in liver surgery with the exception of morbidity reduction in cirrhotic patients undergoing liver resection. Further human clinical trials with application of novel conditioning protocols and combination of methods are warranted before implementation of ischemic conditioning in day-to-day clinical practice.
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Affiliation(s)
- Rafał Stankiewicz
- Department of General, Transplant and Liver Surgery, Medical University of Warsaw, Warsaw 02-097, Poland.
| | - Michał Grąt
- Department of General, Transplant and Liver Surgery, Medical University of Warsaw, Warsaw 02-097, Poland
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16
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Ma H, Yang B, Yu L, Gao Y, Ye X, Liu Y, Li Z, Li H, Li E. Sevoflurane protects the liver from ischemia-reperfusion injury by regulating Nrf2/HO-1 pathway. Eur J Pharmacol 2021; 898:173932. [PMID: 33631180 DOI: 10.1016/j.ejphar.2021.173932] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/04/2020] [Revised: 01/27/2021] [Accepted: 01/29/2021] [Indexed: 02/06/2023]
Abstract
We aimed to investigate the role and mechanism of sevoflurane (SEV) preconditioning in liver ischemia-reperfusion (I/R) injury. In vivo, rats were randomly divided into Sham group, I/R rat model group, I/R + SEV group and SEV group. In vitro, hypoxia-reoxygenation (H/R) cell model were established. Hematoxylin-Eosin (H&E) and TUNEL assay were used to evaluate the degree of tissue damage and detect apoptosis in rats, respectively. HO-1, nuclear Nrf2 and cytosolic Nrf2 expressions were detected by immunohistochemical staining, Western blot analysis and quantitative real-time PCR (qRT-PCR), respectively. Contents of Lactate dehydrogenase (LDH), malondialdehyde (MDA), and reactive oxygen species (ROS) were determined by corresponding kits. Inflammatory factor levels, cell viability, apoptosis were detected by enzyme-linked immunosorbent assay (ELISA), MTT assay, and flow cytometry, respectively.In the I/R group, liver damage was severe, apoptosis-positive cells were increased, HO-1 and nuclear Nrf2 expressions were increased, and cytosolic Nrf2 expression was decreased. After SEV pretreatment, the degree of liver injury and apoptosis in rats were significantly reduced, HO-1 and nuclear Nrf2 expressions were increased significantly, and cytosolic Nrf2 expression was decreased. 4% SEV had the best mitigating effect on H/R-induced liver cell damage, as evidenced by reduced contents of LDH and MDA, decreased inflammatory factors, a lowered apoptosis rate, inhibited ROS production, effectively promoted Nrf2 nucleation, and activated Nrf/HO-1 pathway. ML385 pretreatment significantly inhibited the effect of SEV on hepatocytes.Sevoflurane protects the liver from ischemia-reperfusion injury by regulating the Nrf2/HO-1 pathway.
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Affiliation(s)
- Hongyan Ma
- Department of Anesthesiology, The First Affiliated Hospital of Harbin Medical University, No.23, Youzheng Street, Nangang District, Harbin, Heilongjiang, 150001, China
| | - Baoyi Yang
- Department of Neursurgery, First Affiliated Hospital, Heilongjiang University of Chinese Medicine, No.26, Heping Road, Dongli District, Harbin, Heilongjiang, 150040, China
| | - Lu Yu
- Department of Anesthesiology, The First Affiliated Hospital of Harbin Medical University, No.23, Youzheng Street, Nangang District, Harbin, Heilongjiang, 150001, China
| | - Yang Gao
- Department of Anesthesiology, The First Affiliated Hospital of Harbin Medical University, No.23, Youzheng Street, Nangang District, Harbin, Heilongjiang, 150001, China
| | - Xiangmei Ye
- Laboratory of Hemooncology, The First Affiliated Hospital of Harbin Medical University, No.23, Youzheng Street, Nangang District, Harbin, Heilongjiang, 150001, China
| | - Ying Liu
- Department of Anesthesiology, The First Affiliated Hospital of Harbin Medical University, No.23, Youzheng Street, Nangang District, Harbin, Heilongjiang, 150001, China
| | - Zhengtian Li
- Department of Tumor Endoscopic Surgery, The First Affiliated Hospital of Harbin Medical University, No.23, Youzheng Street, Nangang District, Harbin, Heilongjiang, 150001, China
| | - Hulun Li
- Department of Neurobiology, Harbin Medical University, No.194, Xuefu Road, Harbin, Heilongjiang, 150001, China
| | - Enyou Li
- Department of Anesthesiology, The First Affiliated Hospital of Harbin Medical University, No.23, Youzheng Street, Nangang District, Harbin, Heilongjiang, 150001, China.
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17
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Hemorheological and Microcirculatory Factors in Liver Ischemia-Reperfusion Injury-An Update on Pathophysiology, Molecular Mechanisms and Protective Strategies. Int J Mol Sci 2021; 22:ijms22041864. [PMID: 33668478 PMCID: PMC7918617 DOI: 10.3390/ijms22041864] [Citation(s) in RCA: 26] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2021] [Revised: 02/10/2021] [Accepted: 02/11/2021] [Indexed: 02/08/2023] Open
Abstract
Hepatic ischemia-reperfusion injury (IRI) is a multifactorial phenomenon which has been associated with adverse clinical outcomes. IRI related tissue damage is characterized by various chronological events depending on the experimental model or clinical setting. Despite the fact that IRI research has been in the spotlight of scientific interest for over three decades with a significant and continuous increase in publication activity over the years and the large number of pharmacological and surgical therapeutic attempts introduced, not many of these strategies have made their way into everyday clinical practice. Furthermore, the pathomechanism of hepatic IRI has not been fully elucidated yet. In the complex process of the IRI, flow properties of blood are not neglectable. Hemorheological factors play an important role in determining tissue perfusion and orchestrating mechanical shear stress-dependent endothelial functions. Antioxidant and anti-inflammatory agents, ischemic conditioning protocols, dynamic organ preservation techniques may improve rheological properties of the post-reperfusion hepatic blood flow and target endothelial cells, exerting a potent protection against hepatic IRI. In this review paper we give a comprehensive overview of microcirculatory, rheological and molecular–pathophysiological aspects of hepatic circulation in the context of IRI and hepatoprotective approaches.
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18
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Shen Y, Shen X, Cheng Y, Liu Y. Myricitrin pretreatment ameliorates mouse liver ischemia reperfusion injury. Int Immunopharmacol 2020; 89:107005. [PMID: 33045574 DOI: 10.1016/j.intimp.2020.107005] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2020] [Revised: 08/27/2020] [Accepted: 09/10/2020] [Indexed: 02/06/2023]
Abstract
BACKGROUND Myricitrin has been reported to exert protective effects on liver diseases, but the protective effects of myricitrin against liver ischemia reperfusion (I/R) injury and the underlying mechanisms remain unexplored. This study aimed to investigate the effects of myricitrin on liver I/R injury and elucidate the underlying mechanisms. METHODS Mice were pretreated with myricitrin before liver I/R injury modeling. The mice were pretreated with either myricitrin or vehicle prior to liver ischemia. Some mice were further pretreated with the PI3K inhibitor LY294002. Liver tissues and blood samples were collected after 6 h of reperfusion. The degree of liver damage was determined by the serum levels of alanine aminotransferase (ALT), aspartate transaminase (AST), and lactic dehydrogenase (LDH) and histological examinations. The tumour necrosis factor-α (TNF-α), interleukin--1β (IL-1β), IL-4 and IL-10 expression levels were assessed by qRT-PCR and enzyme-linked immunosorbent assays (ELISAs). Serum superoxide dismutase (SOD) activity, catalase (CAT) activity, and contents of malondialdehyde (MDA), glutathione (GSH) and nitric oxide (NO) contents were measured. Western blotting and caspase-3 activity were conducted to determine the effect of myricitrin on apoptosis. The expression levels of proliferation related genes (Cyclin D1 and Cyclin E1) were determined by qRT-PCR and western-blotting. The expression of p-Akt, p-mTOR and p-eNOS in liver tissue were investigated by western-blotting. RESULTS Myricitrin not only significantly decreased the ALT, AST and LDH levels but also reduced the necrotic areas in the liver tissue compared with liver I/R injury group. In addition, myricitrin pretreatment alleviated liver injury by inhibiting the inflammatory response and suppressing oxidative stress. Western blotting and caspase-3 activity revealed that myricitrin inhibited liver I/R induced-apoptosis. Myricitrin promoted hepatocyte proliferation following liver I/R injury by upregulating the expression levels of Cyclin D1 and Cyclin E1. Further experiments indicated that the myricitrin pretreatment increased nitric oxide (NO) production by activating the PI3K/Akt signaling pathway. However, myricitrin triggered the hepatocyte proliferation and NO synthase activation was blocked by LY294002. CONCLUSION These results demonstrate that myricitrin alleviates liver I/R injury by suppressing oxidative stress, the inflammatory response, and apoptosis, improving liver proliferation and upregulating p-eNOS expression.
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Affiliation(s)
- Yuntai Shen
- School of Clinical Medicine, Weifang Medical University, Weifang 266003, China
| | - Xiangrong Shen
- Department of Chinese Medicine, Zhucheng Shiqiaozi Hospital, Weifang 262208, China; Department of Chinese Medicine, The Affiliated Hospital of Qingdao University, Qingdao 260153, China
| | - Yao Cheng
- Department of Anesthesiology, Zhucheng People's Hospital, Weifang 262200, China
| | - Yulan Liu
- Department of Nursing, Zhucheng People's Hospital, Weifang 262200, China.
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19
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Yang L, Cao H, Sun D, Lin L, Zheng WP, Shen ZY, Song HL. Normothermic Machine Perfusion Combined with Bone Marrow Mesenchymal Stem Cells Improves the Oxidative Stress Response and Mitochondrial Function in Rat Donation After Circulatory Death Livers. Stem Cells Dev 2020; 29:835-852. [PMID: 32253985 PMCID: PMC7336881 DOI: 10.1089/scd.2019.0301] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Abstract
There is a need to improve the quality of donor liver from donation after circulatory death (DCD). The purpose of this study was to investigate the effects and mechanism of normothermic machine perfusion (NMP) combined with bone marrow mesenchymal stem cells (BMMSCs) on the oxidative stress and mitochondrial function in DCD livers. DCD livers were obtained, a rat NMP system was established, and BMMSCs were extracted and identified. The DCD livers were grouped by their preservation method: Normal, static cold storage (SCS), NMP (P), and NMP combined with BMMSCs (PB), and the preservation time was up to 8 h. An IAR20 cell oxidative stress injury model was established in vitro by simulating DCD oxidative stress injury and coculturing with BMMSCs for 6 h. Compared with SCS group, after 6 h in vitro, the PB and P groups had significantly improved liver function and liver histological damage, reduced hepatocyte apoptosis and oxidative stress, improved hepatocyte mitochondrial damage, and increased mitochondrial membrane potential. These indicators were significantly better in the PB group than in the P group. BMMSCs significantly inhibited reactive oxygen species release from the IAR20 cell oxidative stress model in vitro, ameliorated mitochondrial damage, and increased mitochondrial membrane potential level. BMMSCs also downregulated the JUN N-terminal kinase-nuclear factor kappa B (JNK-NF-κB) signaling pathway significantly in the IAR20 cell oxidative stress model and promoted AMP-activated protein kinase (AMPK) activation. We verified that NMP combined with BMMSCs also played the same role in the PB group. NMP combined with BMMSCs could improve liver quality by relieving oxidative stress injury and improving mitochondrial function in rat DCD livers. The mechanism of protective role might involve inhibiting the JNK-NF-κB pathway to reduce oxidative stress and promote AMPK activation, thereby reducing mitochondrial damage and increase mitochondrial function.
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Affiliation(s)
- Liu Yang
- Tianjin First Central Hospital Clinic Institute, Tianjin Medical University, Tianjin, People's Republic of China
| | - Huan Cao
- Tianjin First Central Hospital Clinic Institute, Tianjin Medical University, Tianjin, People's Republic of China.,Department of Organ Transplantation, Tianjin First Central Hospital, Tianjin, People's Republic of China
| | - Dong Sun
- Tianjin First Central Hospital Clinic Institute, Tianjin Medical University, Tianjin, People's Republic of China.,NHC Key Laboratory of Critical Care Medicine, Tianjin, People's Republic of China
| | - Ling Lin
- Tianjin First Central Hospital Clinic Institute, Tianjin Medical University, Tianjin, People's Republic of China.,Tianjin Clinical Research Center for Organ Transplantation, Tianjin, People's Republic of China
| | - Wei-Ping Zheng
- Department of Organ Transplantation, Tianjin First Central Hospital, Tianjin, People's Republic of China.,Key Laboratory of Transplant Medicine, Chinese Academy of Medical Sciences, Tianjin, People's Republic of China
| | - Zhong-Yang Shen
- Department of Organ Transplantation, Tianjin First Central Hospital, Tianjin, People's Republic of China.,Key Laboratory of Transplant Medicine, Chinese Academy of Medical Sciences, Tianjin, People's Republic of China
| | - Hong-Li Song
- Department of Organ Transplantation, Tianjin First Central Hospital, Tianjin, People's Republic of China.,Tianjin Key Laboratory of Organ Transplantation, Tianjin, People's Republic of China
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20
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CXCL16 silencing alleviates hepatic ischemia reperfusion injury during liver transplantation by inhibiting p38 phosphorylation. Pathol Res Pract 2020; 216:152913. [PMID: 32171552 DOI: 10.1016/j.prp.2020.152913] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/18/2019] [Revised: 02/17/2020] [Accepted: 03/01/2020] [Indexed: 02/08/2023]
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21
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Soares ROS, Losada DM, Jordani MC, Évora P, Castro-E-Silva O. Ischemia/Reperfusion Injury Revisited: An Overview of the Latest Pharmacological Strategies. Int J Mol Sci 2019; 20:ijms20205034. [PMID: 31614478 PMCID: PMC6834141 DOI: 10.3390/ijms20205034] [Citation(s) in RCA: 239] [Impact Index Per Article: 39.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2019] [Revised: 10/03/2019] [Accepted: 10/08/2019] [Indexed: 02/08/2023] Open
Abstract
Ischemia/reperfusion injury (IRI) permeates a variety of diseases and is a ubiquitous concern in every transplantation proceeding, from whole organs to modest grafts. Given its significance, efforts to evade the damaging effects of both ischemia and reperfusion are abundant in the literature and they consist of several strategies, such as applying pre-ischemic conditioning protocols, improving protection from preservation solutions, thus providing extended cold ischemia time and so on. In this review, we describe many of the latest pharmacological approaches that have been proven effective against IRI, while also revisiting well-established concepts and presenting recent pathophysiological findings in this ever-expanding field. A plethora of promising protocols has emerged in the last few years. They have been showing exciting results regarding protection against IRI by employing drugs that engage several strategies, such as modulating cell-surviving pathways, evading oxidative damage, physically protecting cell membrane integrity, and enhancing cell energetics.
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Affiliation(s)
| | - Daniele M Losada
- Department of Anatomic Pathology, Faculty of Medical Sciences, University of Campinas, 13083-970 Campinas, Brazil.
| | - Maria C Jordani
- Department of Surgery & Anatomy, Ribeirão Preto Medical School, University of São Paulo, 14049-900 Ribeirão Preto, Brazil.
| | - Paulo Évora
- Department of Surgery & Anatomy, Ribeirão Preto Medical School, University of São Paulo, 14049-900 Ribeirão Preto, Brazil.
- Department of Gastroenterology, São Paulo Medical School, University of São Paulo, 01246-903 São Paulo, Brazil.
| | - Orlando Castro-E-Silva
- Department of Surgery & Anatomy, Ribeirão Preto Medical School, University of São Paulo, 14049-900 Ribeirão Preto, Brazil.
- Department of Gastroenterology, São Paulo Medical School, University of São Paulo, 01246-903 São Paulo, Brazil.
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22
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Sedaghat Z, Fatemikia H, Tanha K, Zahiri M, Assadi M. Scintigraphic evaluation of remote pre-conditioning protection against unilateral renal ischemia/reperfusion injury in rats: a longitudinal study. Int Urol Nephrol 2019; 51:2083-2089. [PMID: 31407138 DOI: 10.1007/s11255-019-02258-3] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2019] [Accepted: 08/05/2019] [Indexed: 01/23/2023]
Abstract
PURPOSE To determine the role of remote perconditioning (RPeC) on renal function and histology in an animal model of unilateral renal ischemia and reperfusion (IR) injury. METHODS Rats were subjected to 60 min unilateral renal ischemia. RPeC protocol was the application of four cycles of 5 min IR of left femoral artery during renal ischemia. Assessments of histological changes and renal function were made 24 h, 1 week, or 3 weeks later. 99mTc-DMSA scan was performed using a small-animals SPECT system. RESULTS 24-h reperfusion decreased the 99mTc-DMSA uptake in the left kidney compared to the intact kidney of control animals. RPeC group has higher uptake compared to the IR group. After 1 week and 3 weeks, uptakes were gradually increased in both groups and no differences were observed. Severe morphological changes in the ischemic kidneys of both groups were observed after 24 h which attenuated after 1 week and 3 weeks. Moreover, no differences in creatinine and BUN levels between IR-treated and intact animals were observed. CONCLUSION These data suggest that RPeC exerts a partially transient improvement in the renal function in the first day after reperfusion. However, long-term follow-up study showed no beneficial effects of RPeC. Moreover, noninvasive 99mTc-DMSA scan revealed a suitable tool in the follow-up evaluation of recovery process in the unilateral renal IR injury models.
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Affiliation(s)
- Zahra Sedaghat
- Physiology Department, School of Medicine, Bushehr University of Medical Sciences, Moallem Street, Bushehr, 7514633341, Iran.
| | - Hossein Fatemikia
- Physiology Department, School of Medicine, Bushehr University of Medical Sciences, Moallem Street, Bushehr, 7514633341, Iran
- Physiology Department, School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Kaveh Tanha
- Medical Physics and Biomedical Engineering Department, Tehran University of Medical Sciences, Tehran, Iran
- The Persian Gulf Nuclear Medicine Research Center, Bushehr University of Medical Sciences, Bushehr, Iran
| | - Maria Zahiri
- Department of Anatomical Sciences, School of Medicine, Bushehr University of Medical Sciences, Bushehr, Iran
| | - Majid Assadi
- The Persian Gulf Nuclear Medicine Research Center, Bushehr University of Medical Sciences, Bushehr, Iran
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Associations of Oxidative Stress and Postoperative Outcome in Liver Surgery with an Outlook to Future Potential Therapeutic Options. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2019; 2019:3950818. [PMID: 30906502 PMCID: PMC6393879 DOI: 10.1155/2019/3950818] [Citation(s) in RCA: 48] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/23/2018] [Accepted: 01/02/2019] [Indexed: 12/16/2022]
Abstract
Several types of surgical procedures have shown to elicit an inflammatory stress response, leading to substantial cytokine production and formation of oxygen-based or nitrogen-based free radicals. Chronic liver diseases including cancers are almost always characterized by increased oxidative stress, in which hepatic surgery is likely to potentiate at least in the short term and hereby furthermore impair the hepatic redox state. During liver resection, intermittent inflow occlusion is commonly applied to prevent excessive blood loss but resulting ischemia and reperfusion of the liver have been linked to increased oxidative stress, leading to impairment of cell functions and subsequent cell death. In the field of liver transplantation, ischemia/reperfusion injury has extensively been investigated in the last decades and has recently been in the scientific focus again due to increased use of marginal donor organs and new machine perfusion concepts. Therefore, given the intriguing role of oxidative stress in the pathogenesis of numerous diseases and in the perioperative setting, the interest for a therapeutic antioxidative agent has been present for several years. This review is aimed at giving an introduction to oxidative stress in surgical procedures in general and then examines the role of oxidative stress in liver surgery in particular, discussing both transplantation and resection. Results from studies in the animal and human settings are included. Finally, potential therapeutic agents that might be beneficial in reducing the burden of oxidative stress in hepatic diseases and during surgery are presented. While there is compelling evidence from animal models and a limited number of clinical studies showing that oxidative stress plays a major role in both liver resection and transplantation and several recent studies have suggested a potential for antioxidative treatment in chronic liver disease (e.g., steatosis), the search for effective antioxidants in the field of liver surgery is still ongoing.
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24
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Li DY, Liu WT, Wang GY, Shi XJ. Impact of combined ischemic preconditioning and remote ischemic perconditioning on ischemia-reperfusion injury after liver transplantation. Sci Rep 2018; 8:17979. [PMID: 30568237 PMCID: PMC6299280 DOI: 10.1038/s41598-018-36365-5] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2018] [Accepted: 11/19/2018] [Indexed: 12/15/2022] Open
Abstract
Ischemic preconditioning (IPC) and remote ischemic perconditioning (RIPer) confer protective effects against liver ischemia-reperfusion injury (IRI), but data about RIPer applying in liver transplantation is lacking. The study aimed to evaluate whether the combination of IPC and RIPer provides reinforced protective effects. C57BL/6 mice (160 pairs) were allocated into four groups: control, subjected to liver transplantation only; IPC, donor hilar was clamped for 10 min followed by 15 min of reperfusion; RIPer, three cycles of occlusion (5 min) and opening (5 min) of femoral vascular bundle were performed before reperfusion; IPC + RIPer, donors and recipients were subjected to IPC and RIPer respectively. Liver tissues were obtained for histological evaluation, TUNEL staining, malondialdehyde assays, GSH-Px assays, and NF-κB p65 protein and Bcl-2/Bax mRNA analyses. Blood samples were used to evaluate ALT, AST, TNF-α, NOx levels and flow cytometry. We found that protective efficacy of RIPer is less than IPC in terms of ALT, TNF-α, GSH-Px and NOx at 2 h postoperation, but almost equivalent at 24 h and 72 h postoperation. Except for Suzuki scores, ALT, Bcl-2/Bax mRNA ratio, other indices showed that combined treatment brought enhanced attenuation in IRI, compared with single treatment, through additive effects on antioxidation, anti-apoptosis, modulation of microcirculation disturbance, and inhibition of innate immune response. This study suggested a combined strategy that could enhance protection against IRI in clinical liver transplantation, otherwise, provided a hint that RIPer's mechanism might be partly or totally different from IPC in humoral pathway.
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Affiliation(s)
- Ding-Yang Li
- Department of Hepatobiliary & Pancreatic Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450000, Henan Province, China
| | - Wen-Tao Liu
- Department of Hepatobiliary & Pancreatic Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450000, Henan Province, China
| | - Guang-Yi Wang
- Department of Hepatobiliary & Pancreatic Surgery, The First Norman Bethune Hospital Affiliated to Jilin University, Changchun, 130021, Jilin Province, China
| | - Xiao-Ju Shi
- Department of Hepatobiliary & Pancreatic Surgery, The First Norman Bethune Hospital Affiliated to Jilin University, Changchun, 130021, Jilin Province, China.
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25
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Liu Y, Zhang W, Cheng Y, Miao C, Gong J, Wang M. Activation of PPARγ by Curcumin protects mice from ischemia/reperfusion injury induced by orthotopic liver transplantation via modulating polarization of Kupffer cells. Int Immunopharmacol 2018; 62:270-276. [PMID: 30036770 DOI: 10.1016/j.intimp.2018.07.013] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2018] [Revised: 06/18/2018] [Accepted: 07/13/2018] [Indexed: 02/07/2023]
Abstract
Curcumin shows protective effects on various diseases due to its anti-inflammatory and anti-oxidative functions; however, its effect on organ transplantation has not been fully elucidated. To understand its role in liver ischemia/reperfusion (I/R) injury, we studied its impact on orthotopic liver transplantation (OLT) and Kupffer cells (KCs) polarization and its underlying mechanisms. We first investigated the reactive oxygen species (ROS) accumulation and cytokines profile of KCs, intracellular ROS and the mRNA level of pro-inflammatory cytokines were downregulated while the mRNA level of anti-inflammatory cytokine was upregulated by the pretreatment of Curcumin; Then the liver injury was detected by histopathological examination and liver function. Pretreatment with Curcumin significantly alleviated liver injury while improving liver function and overall post-transplantation survival compared with the control groups. The Western blotting showed that Curcumin inhibited the function of KCs via down-regulating the nuclear factor κb (NF-κb) signaling pathway by activating peroxisome proliferator-activated receptor γ (PPARγ) and flow cytometry revealed that Curcumin suppressed pro-inflammatory phenotype (M1) of KCs while promoting its anti-inflammatory phenotype (M2) polarization. These results showed that Curcumin may exert positive effects on I/R injury after OLT through activating PPARγ by inhibiting the activation of NF-κb pathway and remodeling the polarization of KCs. This may reveal a potential therapy for I/R injury after liver transplantation.
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Affiliation(s)
- Yan Liu
- Department of Gastroenterology, The Fifth People's Hospital of Chengdu, Chengdu, 611130, PR China
| | - Wenfeng Zhang
- Department of Hepatobiliary Surgery and Chongqing Key Laboratory of Hepatobiliary Surgery, Second Affiliated Hospital of Chongqing Medical University, Chongqing, 400010, PR China
| | - Yao Cheng
- Department of Hepatobiliary Surgery and Chongqing Key Laboratory of Hepatobiliary Surgery, Second Affiliated Hospital of Chongqing Medical University, Chongqing, 400010, PR China
| | - Chunmu Miao
- Department of Hepatobiliary Surgery and Chongqing Key Laboratory of Hepatobiliary Surgery, Second Affiliated Hospital of Chongqing Medical University, Chongqing, 400010, PR China
| | - Jianping Gong
- Department of Hepatobiliary Surgery and Chongqing Key Laboratory of Hepatobiliary Surgery, Second Affiliated Hospital of Chongqing Medical University, Chongqing, 400010, PR China
| | - Menghao Wang
- Department of Hepatobiliary Surgery and Chongqing Key Laboratory of Hepatobiliary Surgery, Second Affiliated Hospital of Chongqing Medical University, Chongqing, 400010, PR China.
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26
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Orbach SM, Ehrich MF, Rajagopalan P. High-throughput toxicity testing of chemicals and mixtures in organotypic multi-cellular cultures of primary human hepatic cells. Toxicol In Vitro 2018; 51:83-94. [PMID: 29751030 DOI: 10.1016/j.tiv.2018.05.006] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2017] [Revised: 05/06/2018] [Accepted: 05/07/2018] [Indexed: 02/07/2023]
Abstract
High-throughput screening (HTS) of liver toxicants can bridge the gap in understanding adverse effects of chemicals on humans. Toxicity testing of mixtures is time consuming and expensive, since the number of possible combinations increases exponentially with the number of chemicals. The combination of organotypic culture models (OCMs) and HTS assays can lead to the rapidly evaluation of chemical toxicity in a cost and time-effective manner while prioritizing chemicals that warrant additional investigation. We describe the design, assembly and toxicant response of multi-cellular hepatic organotypic culture models comprised of primary human or rat cells assembled in 96-well plates (denoted as μOCMs). These models were assembled using automated procedures that did not affect hepatocyte function or viability, rendering them ideal for large-scale toxicity evaluations. Rat μOCMs were assembled to obtain insights into deviations from human toxicity. Four test chemicals (acetaminophen, ethanol, isoniazid, and perfluorooctanoic acid) were added to the μOCMs individually or in mixtures. HTS assays were utilized to measure cell death, apoptosis, glutathione depletion, mitochondrial membrane damage, and cytochrome P450 2E1 activity. The μOCMs exhibited increased toxicant sensitivity compared to hepatocyte sandwich cultures. Synergistic and non-synergistic interactions were observed when the toxicants were added as mixtures. Specifically, chemical interactions in the μOCMs were manifested by changes in apoptosis and decreased glutathione. The μOCMs accurately predicted hepatotoxicity for individual and mixtures of toxicants, demonstrating their potential for large-scale toxicity evaluations in the future.
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Affiliation(s)
- Sophia M Orbach
- Department of Chemical Engineering, Virginia Tech, Suite 245 Goodwin Hall, 635 Prices Fork Road, Blacksburg, VA 24061, USA.
| | - Marion F Ehrich
- Department of Biomedical Sciences and Pathobiology, Virginia-Maryland College of Veterinary Medicine, 205 Duck Pond Drive, Blacksburg, VA 24061, USA.
| | - Padmavathy Rajagopalan
- Department of Chemical Engineering, Virginia Tech, Suite 245 Goodwin Hall, 635 Prices Fork Road, Blacksburg, VA 24061, USA; ICTAS Center for Systems Biology of Engineered Tissue, Virginia Tech, 333 Kelly Hall, 325 Stanger Street, Blacksburg, VA 24061, USA; School of Biomedical Engineering and Sciences, Virginia Tech, 333 Kelly Hall, 325 Stanger Street, Blacksburg, VA 24061, USA.
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27
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Polyphenolic Compounds, Antioxidant, and Cardioprotective Effects of Pomace Extracts from Fetească Neagră Cultivar. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2018; 2018:8194721. [PMID: 29765504 PMCID: PMC5885407 DOI: 10.1155/2018/8194721] [Citation(s) in RCA: 41] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/06/2017] [Accepted: 01/31/2018] [Indexed: 12/17/2022]
Abstract
Grape pomace is a potential source of natural antioxidant agents. Phenolic compounds and antioxidant and cardioprotective properties of fresh and fermented pomace extracts obtained from Vitis vinifera L. red variety Fetească neagră grown in Romania in 2015 were investigated. Grape pomace extracts total phenolic index, total tannins, total anthocyanins, proanthocyanidins, flavan-3-ol monomers, stilbenes, and DPPH free radical scavenger were measured. The effect of a seven-day pretreatment with grape pomace extracts on the isoprenaline-induced infarct-like lesion in rats was assessed by ECG monitoring, serum levels of creatine kinase, aspartate transaminase, and alanine transaminase. Total serum oxidative status, total antioxidant response, oxidative stress index, malondialdehyde, total thiols, and nitric oxide have been also assessed. Higher phenolic content and antioxidant activity were found in fermented pomace extracts when compared to fresh pomace extracts. Pretreatment with grape pomace extracts significantly improved cardiac and oxidative stress parameters. In conclusion, Fetească neagră pomace extracts had a good in vitro antioxidant activity due to an important phenolic content. In vivo, the extracts had cardioprotective effects against isoprenaline-induced infarct-like lesion by reducing oxidative stress, fresh pomace extracts having a better effect.
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28
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Chen G, Thakkar M, Robinson C, Doré S. Limb Remote Ischemic Conditioning: Mechanisms, Anesthetics, and the Potential for Expanding Therapeutic Options. Front Neurol 2018; 9:40. [PMID: 29467715 PMCID: PMC5808199 DOI: 10.3389/fneur.2018.00040] [Citation(s) in RCA: 59] [Impact Index Per Article: 8.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2017] [Accepted: 01/17/2018] [Indexed: 12/23/2022] Open
Abstract
Novel and innovative approaches are essential in developing new treatments and improving clinical outcomes in patients with ischemic stroke. Remote ischemic conditioning (RIC) is a series of mechanical interruptions in blood flow of a distal organ, following end organ reperfusion, shown to significantly reduce infarct size through inhibition of oxidation and inflammation. Ischemia/reperfusion (I/R) is what ultimately leads to the irreversible brain damage and clinical picture seen in stroke patients. There have been several reports and reviews about the potential of RIC in acute ischemic stroke; however, the focus here is a comprehensive look at the differences in the three types of RIC (remote pre-, per-, and postconditioning). There are some limited uses of preconditioning in acute ischemic stroke due to the unpredictability of the ischemic event; however, it does provide the identification of biomarkers for clinical studies. Remote limb per- and postconditioning offer a more promising treatment during patient care as they can be harnessed during or after the initial ischemic insult. Though further research is needed, it is imperative to discuss the importance of preclinical data in understanding the methods and mechanisms involved in RIC. This understanding will facilitate translation to a clinically feasible paradigm for use in the hospital setting.
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Affiliation(s)
- Gangling Chen
- Department of Anesthesiology, Center for Translational Research in Neurodegenerative Disease, University of Florida, Gainesville, FL, United States.,Department of Pharmacology of Chinese Materia Medica, China Pharmaceutical University, Nanjing, China
| | - Mrugesh Thakkar
- Department of Anesthesiology, Center for Translational Research in Neurodegenerative Disease, University of Florida, Gainesville, FL, United States
| | - Christopher Robinson
- McKnight Brain Institute, University of Florida, Gainesville, FL, United States.,Department of Neurology, University of Florida, Gainesville, FL, United States
| | - Sylvain Doré
- Department of Anesthesiology, Center for Translational Research in Neurodegenerative Disease, University of Florida, Gainesville, FL, United States.,McKnight Brain Institute, University of Florida, Gainesville, FL, United States.,Department of Neurology, University of Florida, Gainesville, FL, United States.,Department of Psychiatry, University of Florida, Gainesville, FL, United States.,Department of Pharmaceutics, University of Florida, Gainesville, FL, United States.,Department of Psychology, University of Florida, Gainesville, FL, United States.,Department of Neuroscience, University of Florida, Gainesville, FL, United States
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29
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Liang RP, Jia JJ, Li JH, He N, Zhou YF, Jiang L, Bai T, Xie HY, Zhou L, Sun YL. Mitofusin-2 mediated mitochondrial Ca 2+ uptake 1/2 induced liver injury in rat remote ischemic perconditioning liver transplantation and alpha mouse liver-12 hypoxia cell line models. World J Gastroenterol 2017; 23:6995-7008. [PMID: 29097872 PMCID: PMC5658317 DOI: 10.3748/wjg.v23.i38.6995] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/28/2017] [Revised: 08/19/2017] [Accepted: 09/06/2017] [Indexed: 02/06/2023] Open
Abstract
AIM To investigate the protective mechanism of mitofusin-2 (Mfn2) in rat remote ischemic perconditioning (RIC) models and revalidate it in alpha mouse liver-12 (AML-12) hypoxia cell lines. METHODS Sprague-Dawley rats were divided into three groups (n = 6 each): sham, orthotopic liver transplantation and RIC. After operation, blood samples were collected to test alanine aminotransferase and aspartate aminotransferase. The liver lobes were harvested for histopathological examination, western blotting (WB) and quantitative real-time (qRT)-PCR. AML-12 cell lines were then subjected to normal culture, anoxic incubator tank culture (hypoxia) and anoxic incubator tank culture with Mfn2 knockdown (hypoxia + Si), and data of qRT-PCR, WB, mitochondrial membrane potential (ΔΨm), apoptosis, endoplasmic reticulum Ca2+ concentrations and mitochondrial Ca2+ concentrations were collected. RESULTS Both sham and normal culture groups showed no injury during the experiment. The RIC group showed amelioration of liver function compared with the orthotopic liver transplantation group (P < 0.05). qRT-PCR and WB confirmed that Mfn2-mitochondrial Ca2+ uptake 1/2 (MICUs) axis was changed (P < 0.005). In AML-12 cell lines, compared with the hypoxia group, the hypoxia + Si group attenuated the collapse of ΔΨm and apoptosis (P < 0.005). The endoplasmic reticulum Ca2+ decrease and mitochondrial Ca2+ overloading observed in the hypoxia group were also attenuated in the hypoxia + Si group (P < 0.005). Finally, qRT-PCR and WB confirmed the Mfn2-MICUs axis change in all the groups (P < 0.005). CONCLUSION Mfn2 participates in liver injury in rat RIC models and AML-12 hypoxia cell lines by regulating the MICUs pathway.
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Affiliation(s)
- Ruo-Peng Liang
- Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, Henan Province, China
- Institute of Hepatobiliary and Pancreatic Diseases, Zhengzhou University, Zhengzhou 450052, Henan Province, China
| | - Jun-Jun Jia
- Key Lab of Combined Multi-Organ Transplantation, Ministry of Public Health, Hangzhou 310003, Zhejiang Province, China
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, Zhejiang Province, China
- Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Hangzhou 310003, Zhejiang Province, China
| | - Jian-Hui Li
- Key Lab of Combined Multi-Organ Transplantation, Ministry of Public Health, Hangzhou 310003, Zhejiang Province, China
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, Zhejiang Province, China
- Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Hangzhou 310003, Zhejiang Province, China
| | - Ning He
- Key Lab of Combined Multi-Organ Transplantation, Ministry of Public Health, Hangzhou 310003, Zhejiang Province, China
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, Zhejiang Province, China
- Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Hangzhou 310003, Zhejiang Province, China
| | - Yan-Fei Zhou
- Key Lab of Combined Multi-Organ Transplantation, Ministry of Public Health, Hangzhou 310003, Zhejiang Province, China
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, Zhejiang Province, China
- Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Hangzhou 310003, Zhejiang Province, China
| | - Li Jiang
- Key Lab of Combined Multi-Organ Transplantation, Ministry of Public Health, Hangzhou 310003, Zhejiang Province, China
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, Zhejiang Province, China
- Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Hangzhou 310003, Zhejiang Province, China
| | - Tao Bai
- Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, Henan Province, China
- Institute of Hepatobiliary and Pancreatic Diseases, Zhengzhou University, Zhengzhou 450052, Henan Province, China
| | - Hai-Yang Xie
- Key Lab of Combined Multi-Organ Transplantation, Ministry of Public Health, Hangzhou 310003, Zhejiang Province, China
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, Zhejiang Province, China
- Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Hangzhou 310003, Zhejiang Province, China
| | - Lin Zhou
- Key Lab of Combined Multi-Organ Transplantation, Ministry of Public Health, Hangzhou 310003, Zhejiang Province, China
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, Zhejiang Province, China
- Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Hangzhou 310003, Zhejiang Province, China
| | - Yu-Ling Sun
- Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, Henan Province, China
- Institute of Hepatobiliary and Pancreatic Diseases, Zhengzhou University, Zhengzhou 450052, Henan Province, China
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