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Berezin AA, Obradovic Z, Berezina TA, Boxhammer E, Lichtenauer M, Berezin AE. Cardiac Hepatopathy: New Perspectives on Old Problems through a Prism of Endogenous Metabolic Regulations by Hepatokines. Antioxidants (Basel) 2023; 12:516. [PMID: 36830074 PMCID: PMC9951884 DOI: 10.3390/antiox12020516] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2023] [Revised: 02/12/2023] [Accepted: 02/16/2023] [Indexed: 02/22/2023] Open
Abstract
Cardiac hepatopathy refers to acute or chronic liver damage caused by cardiac dysfunction in the absence of any other possible causative reasons of liver injury. There is a large number of evidence of the fact that cardiac hepatopathy is associated with poor clinical outcomes in patients with acute or actually decompensated heart failure (HF). However, the currently dominated pathophysiological background does not explain a role of metabolic regulative proteins secreted by hepatocytes in progression of HF, including adverse cardiac remodeling, kidney injury, skeletal muscle dysfunction, osteopenia, sarcopenia and cardiac cachexia. The aim of this narrative review was to accumulate knowledge of hepatokines (adropin; fetuin-A, selenoprotein P, fibroblast growth factor-21, and alpha-1-microglobulin) as adaptive regulators of metabolic homeostasis in patients with HF. It is suggested that hepatokines play a crucial, causative role in inter-organ interactions and mediate tissue protective effects counteracting oxidative stress, inflammation, mitochondrial dysfunction, apoptosis and necrosis. The discriminative potencies of hepatokines for HF and damage of target organs in patients with known HF is under on-going scientific discussion and requires more investigations in the future.
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Affiliation(s)
- Alexander A. Berezin
- Internal Medicine Department, Zaporozhye Medical Academy of Postgraduate Education, 69000 Zaporozhye, Ukraine
- Klinik Barmelweid, Department of Psychosomatic Medicine and Psychotherapy, 5017 Barmelweid, Switzerland
| | - Zeljko Obradovic
- Klinik Barmelweid, Department of Psychosomatic Medicine and Psychotherapy, 5017 Barmelweid, Switzerland
| | - Tetiana A. Berezina
- Department of Internal Medicine & Nephrology, VitaCenter, 69000 Zaporozhye, Ukraine
| | - Elke Boxhammer
- Department of Internal Medicine II, Division of Cardiology, Paracelsus Medical University Salzburg, 5020 Salzburg, Austria
| | - Michael Lichtenauer
- Department of Internal Medicine II, Division of Cardiology, Paracelsus Medical University Salzburg, 5020 Salzburg, Austria
| | - Alexander E. Berezin
- Department of Internal Medicine II, Division of Cardiology, Paracelsus Medical University Salzburg, 5020 Salzburg, Austria
- Internal Medicine Department, Zaporozhye State Medical University, 69035 Zaporozhye, Ukraine
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Jin LM, Liu YX, Cheng J, Zhou L, Xie HY, Feng XW, Li H, Shen Y, Xu X, Zheng SS. The effect of SphK1/S1P signaling pathway on hepatic sinus microcirculation in rats with hepatic ischemia-reperfusion injury. Hepatobiliary Pancreat Dis Int 2022; 21:94-98. [PMID: 34233851 DOI: 10.1016/j.hbpd.2021.06.003] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/31/2020] [Accepted: 06/18/2021] [Indexed: 02/05/2023]
Affiliation(s)
- Li-Ming Jin
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China; NHC Key Laboratory of Combined Multi-organ Transplantation, Hangzhou 310003, China; Department of General Surgery, Hepatobiliary and Pancreatic Surgery and Minimally Invasive Surgery, Zhejiang Provincial People's Hospital, Affiliated People's Hospital of Hangzhou Medical College, Hangzhou 310014, China
| | - Yuan-Xing Liu
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China; NHC Key Laboratory of Combined Multi-organ Transplantation, Hangzhou 310003, China
| | - Jian Cheng
- Department of General Surgery, Hepatobiliary and Pancreatic Surgery and Minimally Invasive Surgery, Zhejiang Provincial People's Hospital, Affiliated People's Hospital of Hangzhou Medical College, Hangzhou 310014, China
| | - Lin Zhou
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China; NHC Key Laboratory of Combined Multi-organ Transplantation, Hangzhou 310003, China
| | - Hai-Yang Xie
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China; NHC Key Laboratory of Combined Multi-organ Transplantation, Hangzhou 310003, China
| | - Xiao-Wen Feng
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China; NHC Key Laboratory of Combined Multi-organ Transplantation, Hangzhou 310003, China
| | - Hui Li
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China; NHC Key Laboratory of Combined Multi-organ Transplantation, Hangzhou 310003, China
| | - Yan Shen
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China; NHC Key Laboratory of Combined Multi-organ Transplantation, Hangzhou 310003, China
| | - Xiao Xu
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China; NHC Key Laboratory of Combined Multi-organ Transplantation, Hangzhou 310003, China
| | - Shu-Sen Zheng
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China; NHC Key Laboratory of Combined Multi-organ Transplantation, Hangzhou 310003, China.
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Ren Y, Lin S, Liu W, Ding H. Hepatic Remote Ischemic Preconditioning (RIPC) Protects Heart Damages Induced by Ischemia Reperfusion Injury in Mice. Front Physiol 2021; 12:713564. [PMID: 34671267 PMCID: PMC8520907 DOI: 10.3389/fphys.2021.713564] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/10/2021] [Accepted: 08/27/2021] [Indexed: 11/13/2022] Open
Abstract
It has been convincingly demonstrated that remote ischemic preconditioning (RIPC) can make the myocardium resistant to the subsequent ischemia reperfusion injury (IRI), which causes severe damages by mainly generating cell death. However, the cardioprotective effects of the hepatic RIPC, which is the largest metabolic organ against I/R, have not been fully studied. The aim of our research is whether remote liver RIPC may provide cardioprotective effects against the I/R-induced injury. Here, we generated an I/R mice model in four groups to analyze the effect. The control group is the isolated hearts with 140-min perfusion. I/R group added ischemia in 30 min following 90-min reperfusion. The third group (sham) was subjected to the same procedure as the latter group. The animals in the fourth group selected as the treatment group, underwent a hepatic RIPC by three cycles of 5-min occlusion of the portal triad and then followed by induction of I/R in the isolated heart. The level of myocardial infarction and the preventive effects of RIPC were assessed by pathological characteristics, namely, infarct, enzyme releases, pressure, and cardiac mechanical activity. Subjected to I/R, the hepatic RIPC minimized the infarct size (17.7 ± 4.96 vs. 50.06 ± 5, p < 0.001) and improved the left ventricular-developed pressure (from 47.42 ± 6.27 to 91.62 ± 5.22 mmHg) and the mechanical activity. Release of phosphocreatine kinase-myocardial band (73.86 ± 1.95 vs. 25.93 ± 0.66 IUL-1) and lactate dehydrogenase (299.01 ± 10.7 vs. 152.3 ± 16.7 IUL-1) was also decreased in the RIPC-treated group. These results demonstrate the cardioprotective effects of the hepatic remote preconditioning against the injury caused by I/R in the isolated perfused hearts.
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Affiliation(s)
- Yanlong Ren
- Department of Cardiology, Beijing Anzhen Hospital, Beijing Lab for Cardiovascular Precision Medicine, Capital Medical University, Beijing, China
| | - Shujin Lin
- College of Biological Science and Engineering, Fuzhou University, Fuzhou, China
| | - Wenxian Liu
- Department of Cardiology, Beijing Anzhen Hospital, Beijing Lab for Cardiovascular Precision Medicine, Capital Medical University, Beijing, China
| | - Huiguo Ding
- Department of Gastroenterology and Hepatology, Beijing Youan Hospital, Capital Medical University, Beijing, China
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Wang X, Walkey CJ, Maretti-Mira AC, Wang L, Johnson DL, DeLeve LD. Susceptibility of Rat Steatotic Liver to Ischemia-Reperfusion Is Treatable With Liver-Selective Matrix Metalloproteinase Inhibition. Hepatology 2020; 72:1771-1785. [PMID: 32060938 PMCID: PMC7523533 DOI: 10.1002/hep.31179] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/25/2019] [Accepted: 01/23/2020] [Indexed: 12/31/2022]
Abstract
BACKGROUND AND AIMS This study examined whether enhanced susceptibility of steatotic liver to ischemia-reperfusion (I/R) injury is due to impaired recruitment of bone marrow (BM) progenitors of liver sinusoidal endothelial cells (LSECs, also called sinusoidal endothelial cell progenitor cells [sprocs]) with diminished repair of injured LSECs and whether restoring signaling to recruit BM sprocs reduces I/R injury. APPROACH AND RESULTS Hepatic vessels were clamped for 1 hour in rats fed a high-fat, high-fructose (HFHF) diet for 5, 10, or 15 weeks. Matrix metalloproteinase 9 (MMP-9) antisense oligonucleotides (ASO) or an MMP inhibitor were used to induce liver-selective MMP-9 inhibition. HFHF rats had mild, moderate, and severe steatosis, respectively, at 5, 10, and 15 weeks. I/R injury was enhanced in HFHF rats; this was accompanied by complete absence of hepatic vascular endothelial growth factor (VEGF)-stromal cell-derived factor 1 (sdf1) signaling, leading to lack of BM sproc recruitment. Liver-selective MMP-9 inhibition to protect against proteolytic cleavage of hepatic VEGF using either MMP-9 ASO or intraportal MMP inhibitor in 5-week and 10-week HFHF rats enhanced hepatic VEGF-sdf1 signaling, increased BM sproc recruitment, and reduced alanine aminotransferase (ALT) by 92% and 77% at 5 weeks and by 80% and 64% at 10 weeks of the HFHF diet, respectively. After I/R injury in 15-week HFHF rats, the MMP inhibitor reduced active MMP-9 expression by 97%, ameliorated histologic evidence of injury, and reduced ALT by 58%, which is comparable to control rats sustaining I/R injury. Rescue therapy with intraportal MMP inhibitor, given after ischemia, in the 5-week HFHF rat reduced ALT by 71% and reduced necrosis. CONCLUSIONS Lack of signaling to recruit BM sprocs that repair injured LSECs renders steatotic liver more susceptible to I/R injury. Liver-selective MMP-9 inhibition enhances VEGF-sdf1 signaling and recruitment of BM sprocs, which markedly protects against I/R injury, even in severely steatotic rats.
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Affiliation(s)
- Xiangdong Wang
- USC Division of Gastrointestinal and Liver Disease and the USC Research Center for Liver Disease, Keck Medicine of USC Los Angeles CA
| | - Christopher J. Walkey
- Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston TX
| | - Ana C. Maretti-Mira
- USC Division of Gastrointestinal and Liver Disease and the USC Research Center for Liver Disease, Keck Medicine of USC Los Angeles CA
| | - Lei Wang
- USC Division of Gastrointestinal and Liver Disease and the USC Research Center for Liver Disease, Keck Medicine of USC Los Angeles CA
| | - Deborah L. Johnson
- Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston TX
| | - Laurie D. DeLeve
- USC Division of Gastrointestinal and Liver Disease and the USC Research Center for Liver Disease, Keck Medicine of USC Los Angeles CA
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Gabiatti G, Grezzana-Filho TDJM, Cerski CTS, Bofill C, Valle S, Corso CO. Topical hepatic hypothermia associated with ischemic preconditioning. Histopathological and biochemical analysis of ischemia reperfusion damage in a 24 hour model 1. Acta Cir Bras 2018; 33:924-934. [PMID: 30484502 DOI: 10.1590/s0102-865020180100000007] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2018] [Accepted: 09/09/2018] [Indexed: 11/22/2022] Open
Abstract
PURPOSE To develop a new 24 hour extended liver ischemia and reperfusion (LIR) model analyzing the late biochemical and histopathological results of the isolated and combined application of recognized hepatoprotective mechanisms. In addition, we used a new stratification with zoning to classify the histological lesion. METHODS A modified animal model of severe hepatic damage produced through 90 minutes of segmental ischemia (70% of the organ) and posterior observation for 24 hours of reperfusion, submitted to ischemic preconditioning (IPC) and topical hypothermia (TH) at 26ºC, in isolation or in combination, during the procedure. Data from intraoperative biometric parameters, besides of late biochemical markers and histopathological findings, both at 24 hours evolution time, were compared with control (C) and normothermic ischemia (NI) groups. RESULTS All groups were homogeneous with respect to intraoperative physiological parameters. There were no losses once the model was stablished. Animals subjected to NI and IPC had worse biochemical (gamma-glutamyl transpeptidase, alkaline phosphatase, lactate dehydrogenase, aspartate aminotransferase, alanine aminotransferase, direct bilirubin, and total bilirubin) and histopathological scores (modified Suzuki score) compared to those of control groups and groups with isolated or associated TH (p < 0.05). CONCLUSION The new extended model demonstrates liver ischemia and reperfusion at 24 hour of evolution and, in this extreme scenario, only the groups subjected to topical hypothermia, combined with ischemic preconditioning or alone, had better outcomes than those subjected to only ischemic preconditioning and normothermic ischemia, reaching similar biochemical and histopathological scores to those of the control group.
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Affiliation(s)
- Gémerson Gabiatti
- Fellow PhD degree, Postgraduate Program of Surgical Sciences, Universidade Federal do Rio Grande do Sul (UFRGS), Porto Alegre-RS, Brazil. Conception and design of the study, technical procedures, acquisition and analysis of data, manuscript writing
| | - Tomaz de Jesus Maria Grezzana-Filho
- PhD, Liver Transplantation Surgeon, Hospital de Clinicas de Porto Alegre (HCPA), Department of Surgery, UFRGS, Porto Alegre-RS, Brazil. Conception and design of the study, analysis of data, manuscript writing
| | - Carlos Thadeu Schmidt Cerski
- PhD, Associate Professor, Department of Pathology, UFRGS, Porto Alegre-RS, Brazil. Histopathological examinations
| | - Carlos Bofill
- Graduate student, Faculty of Medicine, UFRGS, Porto Alegre-RS, Brazil. Technical procedures, acquisition of data
| | - Stella Valle
- Coordinator, Laboratory of Veterinary Clinical Analysis (LACVet), Porto Alegre-RS, Brazil. Acquisition of data
| | - Carlos Otávio Corso
- PhD, Associate Professor, Postgraduate Program of Surgical Sciences, Department of Surgery, UFRGS, Porto Alegre-RS, Brazil. Manuscript writing, critical revision, final approval
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Karatzas T, Sikalias N, Mantas D, Papalois A, Alexiou K, Mountzalia L, Kouraklis G. Histopathological changes and onset of severe hepatic steatosis in rats fed a choline-free diet. Exp Ther Med 2018; 16:1735-1742. [PMID: 30186395 PMCID: PMC6122429 DOI: 10.3892/etm.2018.6385] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2018] [Accepted: 06/15/2018] [Indexed: 12/20/2022] Open
Abstract
Hepatic steatosis significantly increases morbidity and mortality associated with major liver surgery. Several rodent models of hepatic steatosis have been previously reported, which aimed to investigate the effect of various pharmaceutical agents and interventional procedures on the pathophysiology of steatotic liver. The aim of the present study was to investigate the time frame of severe hepatic steatosis in rats after they were fed a choline-free diet and any associated histopathological changes. The duration of feeding with a choline-free diet required to develop severe hepatic steatosis was investigated in Wistar rats. The severity of hepatic steatosis in liver specimens was evaluated at 8, 10, 12 and 14 weeks following the onset of the choline-free diet. Comparisons were made with rats receiving standardized laboratory food. Feeding rats for 12–13 weeks with a choline-free diet led to 66% fatty liver infiltration, which exceeded 68% after 14 weeks. Prior to 8 weeks, the fatty infiltration reached 43%, with a gradual increase revealing a stronger rate from 8–12 weeks and a gradual decline after 14 weeks. At 12–13 weeks the fatty infiltration was considered representative of severe hepatic steatosis. Macrovesicular fatty infiltration revealed a significant increase at a steady rate between 8 and 14 weeks, with evidence of the onset of lobular inflammation and steatohepatitis after 14 weeks of feeding with the choline-free diet. Microvesicular fatty infiltration demonstrated a lower growth rate between 8 and 12 weeks while maintaining a steady rate between 12 and 14 weeks. Mixed fatty infiltration maintained its steady rate of hepatic parenchyma from 8.8–9.5%. Rats fed with the standard laboratory diet did not demonstrate fatty infiltration >4.5%, so they did not develop hepatic steatosis. Developing an ideal model of hepatic steatosis is a particular challenge. The findings of the present study indicate that severe hepatic steatosis in rodents may lead to the development of steatohepatitis after feeding with a choline-free diet for at least 14 weeks. This model is of particular interest in experimental liver surgery and associated surgical maneuvers, and is easily reproducible.
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Affiliation(s)
- Theodore Karatzas
- Second Department of Propaedeutic Surgery, School of Medicine, National and Kapodistrian University of Athens, 'Laikon' General Hospital, 11527 Athens, Greece
| | - Nikolaos Sikalias
- Department of Surgery, Sismanogleion General Hospital, 15126 Athens, Greece
| | - Dimitrios Mantas
- Second Department of Propaedeutic Surgery, School of Medicine, National and Kapodistrian University of Athens, 'Laikon' General Hospital, 11527 Athens, Greece
| | | | | | | | - Gregory Kouraklis
- Second Department of Propaedeutic Surgery, School of Medicine, National and Kapodistrian University of Athens, 'Laikon' General Hospital, 11527 Athens, Greece
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Li JH, Jia JJ, Shen W, Chen SS, Jiang L, Xie HY, Zhou L, Zheng SS. Optimized postconditioning algorithm protects liver graft after liver transplantation in rats. Hepatobiliary Pancreat Dis Int 2018; 17:32-38. [PMID: 29428101 DOI: 10.1016/j.hbpd.2018.01.006] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/28/2016] [Accepted: 07/13/2017] [Indexed: 02/05/2023]
Abstract
BACKGROUND Ischemia reperfusion injury (IRI) causes postoperative complications and influences the outcome of the patients undergoing liver surgery and transplantation. Postconditioning (PostC) is a known manual conditioning to decrease the hepatic IRI. Here we aimed to optimize the applicable PostC protocols and investigate the potential protective mechanism. METHODS Thirty Sprague-Dawley rats were randomly divided into 3 groups: the sham group (n = 5), standard orthotopic liver transplantation group (OLT, n = 5), PostC group (OLT followed by clamping and re-opening the portal vein for different time intervals, n = 20). PostC group was then subdivided into 4 groups according to the different time intervals: (10 s × 3, 10 s × 6, 30 s × 3, 60 s × 3, n = 5 in each subgroup). Liver function, histopathology, malondialdehyde (MDA), myeloperoxidase (MPO), expressions of p-Akt and endoplasmic reticulum stress (ERS) related genes were evaluated. RESULTS Compared to the OLT group, the grafts subjected to PostC algorithm (without significant prolonging the total ischemic time) especially with short stimulus and more cycles (10 s × 6) showed significant alleviation of morphological damage and graft function. Besides, the production of reactive oxidative agents (MDA) and neutrophil infiltration (MPO) were significantly depressed by PostC algorithm. Most of ERS related genes were down-regulated by PostC (10 s × 6), especially ATF4, Casp12, hspa4, ATF6 and ELF2, while p-Akt was up-regulated. CONCLUSIONS PostC algorithm, especially 10 s × 6 algorithm, showed to be effective against rat liver graft IRI. These protective effects may be associated with its antioxidant, inhibition of ERS and activation of p-Akt expression of reperfusion injury salvage kinase pathway.
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Affiliation(s)
- Jian-Hui Li
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery First Affiliated Hospital, Zhejiang Univeristy School of Medicine, Hangzhou 310003, China; NHFPC Key Laboratory of Combined Multi-organ Transplantation, Hangzhou 310003, China
| | - Jun-Jun Jia
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery First Affiliated Hospital, Zhejiang Univeristy School of Medicine, Hangzhou 310003, China; NHFPC Key Laboratory of Combined Multi-organ Transplantation, Hangzhou 310003, China; Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Hangzhou, China
| | - Wen Shen
- Zhejiang Chinese Medical University, Hangzhou 310053, China
| | - Sha-Sha Chen
- Department of Anesthesia, First Affiliated Hospital, Zhejiang Univeristy School of Medicine, Hangzhou 310003, China
| | - Li Jiang
- NHFPC Key Laboratory of Combined Multi-organ Transplantation, Hangzhou 310003, China
| | - Hai-Yang Xie
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery First Affiliated Hospital, Zhejiang Univeristy School of Medicine, Hangzhou 310003, China; NHFPC Key Laboratory of Combined Multi-organ Transplantation, Hangzhou 310003, China; Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Hangzhou, China
| | - Lin Zhou
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery First Affiliated Hospital, Zhejiang Univeristy School of Medicine, Hangzhou 310003, China; NHFPC Key Laboratory of Combined Multi-organ Transplantation, Hangzhou 310003, China; Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Hangzhou, China
| | - Shu-Sen Zheng
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery First Affiliated Hospital, Zhejiang Univeristy School of Medicine, Hangzhou 310003, China; NHFPC Key Laboratory of Combined Multi-organ Transplantation, Hangzhou 310003, China; Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Hangzhou, China.
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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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Sikalias N, Karatzas T, Alexiou K, Mountzalia L, Demonakou M, Kostakis ID, Zacharioudaki A, Papalois A, Kouraklis G. Intermittent Ischemic Preconditioning Protects Against Hepatic Ischemia-Reperfusion Injury and Extensive Hepatectomy in Steatotic Rat Liver. J INVEST SURG 2017. [PMID: 28644700 DOI: 10.1080/08941939.2017.1334844] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
BACKGROUND Hepatic steatosis causes severe liver damage and has deleterious effects when associated with ischemia-reperfusion mechanisms. Ischemic preconditioning (IPC) protects lean liver against prolonged ischemia by improving micro-circulation and reducing lipid peroxidation. We investigated the effect of intermittent IPC on liver ischemia-reperfusion injury (IRI) and extensive hepatectomy in severe hepatic steatosis. METHODS Severe hepatic steatosis was performed by 12-14 weeks of choline-free diet in 108 Wistar rats. We induced 30-minute ischemia-reperfusion manipulations and extensive hepatectomy with or without prior IPC in steatotic livers and after 6 and 24 hours of reperfusion blood transaminases, and IL6, TNFα, NO and Lactate in blood and liver tissue were measured. RESULTS Steatotic rats subjected to hepatic ischemia-reperfusion alone after extensive hepatectomy, showed severe liver damage with significantly increased values of AST, ALT, TNFα and Lactate and significantly reduced IL6 and NO, while no one rat survived for more than 29 hours. On the contrary, steatotic rats subjected to intermittent IPC, 24 hours before ischemia-reperfusion, presented increased 30-day survival (67%), lower values of AST, ALT, TNFα and Lactate, and increased IL6 and NO levels. Simple and intermittent IPC manipulations, 1 hour before the IRI and extended hepatectomy, did not prolong survival more than 57 and 98 hours, respectively. Simple IPC, 24 hours before IRI and extended hepatectomy had the lowest possible survival (16.7%). CONCLUSIONS Hepatic steatosis and IRI after major liver surgery largely affect morbidity and mortality. Intermittent IPC, 24 hours before IRI and extensive hepatectomy, presents higher 30-day survival and improved liver function parameters.
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Affiliation(s)
- Nikolaos Sikalias
- a Department of Surgery , Sismanogleion General Hospital , Athens , Greece
| | - Theodore Karatzas
- b Second Department of Propedeutic Surgery , National and Kapodistrian University of Athens, School of Medicine , Athens , Greece
| | | | | | - Maria Demonakou
- c Department of Pathology , Sismanogleion General Hospital , Athens , Greece
| | - Ioannis D Kostakis
- b Second Department of Propedeutic Surgery , National and Kapodistrian University of Athens, School of Medicine , Athens , Greece
| | | | | | - Gregory Kouraklis
- b Second Department of Propedeutic Surgery , National and Kapodistrian University of Athens, School of Medicine , Athens , Greece
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Adachi M, Kisu I, Nagai T, Emoto K, Banno K, Umene K, Nogami Y, Tsuchiya H, Itagaki I, Kawamoto I, Nakagawa T, Ogasawara K, Aoki D. Evaluation of allowable time and histopathological changes in warm ischemia of the uterus in cynomolgus monkey as a model for uterus transplantation. Acta Obstet Gynecol Scand 2016; 95:991-8. [DOI: 10.1111/aogs.12943] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2016] [Accepted: 06/15/2016] [Indexed: 12/21/2022]
Affiliation(s)
- Masataka Adachi
- Department of Obstetrics and Gynecology; Keio University School of Medicine; Tokyo Japan
| | - Iori Kisu
- Department of Obstetrics and Gynecology; Keio University School of Medicine; Tokyo Japan
| | - Toshihiro Nagai
- Electron Microscope Laboratory; Keio University School of Medicine; Tokyo Japan
| | - Katsura Emoto
- Department of Pathology; Keio University School of Medicine; Tokyo Japan
| | - Kouji Banno
- Department of Obstetrics and Gynecology; Keio University School of Medicine; Tokyo Japan
| | - Kiyoko Umene
- Department of Obstetrics and Gynecology; Keio University School of Medicine; Tokyo Japan
| | - Yuya Nogami
- Department of Obstetrics and Gynecology; Keio University School of Medicine; Tokyo Japan
| | - Hideaki Tsuchiya
- Research Center for Animal Life Science; Shiga University of Medical Science; Shiga Japan
| | - Iori Itagaki
- Research Center for Animal Life Science; Shiga University of Medical Science; Shiga Japan
- The Corporation for Production and Research of Laboratory Primates; Ibaraki Japan
| | - Ikuo Kawamoto
- Research Center for Animal Life Science; Shiga University of Medical Science; Shiga Japan
| | - Takahiro Nakagawa
- Research Center for Animal Life Science; Shiga University of Medical Science; Shiga Japan
| | - Kazumasa Ogasawara
- Research Center for Animal Life Science; Shiga University of Medical Science; Shiga Japan
- Department of Pathology; Division of Pathology and Disease Regulation; Shiga University of Medical Science; Shiga Japan
| | - Daisuke Aoki
- Department of Obstetrics and Gynecology; Keio University School of Medicine; Tokyo Japan
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11
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Meng GX, Yuan Q, Wei LP, Meng H, Wang YJ. Protein kinase C-β inhibitor treatment attenuates hepatic ischemia and reperfusion injury in diabetic rats. Exp Ther Med 2015; 11:565-570. [PMID: 26893648 DOI: 10.3892/etm.2015.2927] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2014] [Accepted: 12/12/2014] [Indexed: 12/18/2022] Open
Abstract
Hepatic ischemia and reperfusion (I/R) injury plays an active role in hepatic resection and transplantation. While the effects of protein kinase C (PKC)-βII activation and the role of PKC-β inhibitors are well understood in myocardial I/R in diabetes, they remain unclear in liver I/R. The aim of this study was to explore the effect of PKC-β inhibition and the potential mechanism by which PKC-β inhibitor treatment protects against hepatic I/R injury in diabetic rats. Diabetic rats were established and randomized into two groups. These were an untreated group (n=10), which did not receive any treatment, and a treatment group (n=10), orally treated with ruboxistaurin at a dose of 5 mg/kg/day for 2 weeks. The rats from the two groups were subjected to hepatic I/R. Aspartate transaminase (AST) and lactate dehydrogenase (LDH) levels were measured by enzymatic methods at 1, 3 and 5 h after I/R. Tumor necrosis factor-α (TNF-α) and intercellular adhesion molecule 1 (ICAM-1) were examined by enzyme-linked immunosorbent assay at the same time-points. Nuclear factor-κB (NF-κB) p65 expression was analyzed by immunofluorescence and western blotting. Apoptosis of hepatic cells was examined by the western blot analysis of caspase 3 expression and by DNA ladder analysis. Pathological changes were examined using light and electron microscopy. Serum AST and LDH levels in the PKC-β inhibitor treatment group were diminished compared with those in the untreated group (P<0.01). Serum TNF-α and ICAM-1 (P<0.01) levels were also decreased at different time-points in the PKC-β inhibitor treatment group. The relative expression of NF-κB p65 and caspase 3 in the hepatic tissue was weakened in the PKC-β inhibitor treatment group compared with that in the untreated group (P<0.01). Pathological changes in hepatic tissue were attenuated by the PKC-β inhibitor. In conclusion, PKC-β inhibitor treatment protected against liver I/R injury in diabetic rats. The mechanisms probably involved the attenuation of microvascular injury, reduced transport of injury-associated factors and diminishment of the activation of NF-κB p65.
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Affiliation(s)
- Guang-Xing Meng
- Department of Hepatobiliary Surgery, Tianjin Hepatobiliary Research Institute, Tianjin Third Central Hospital, Tianjin 300170, P.R. China
| | - Qiang Yuan
- Department of Hepatobiliary Surgery, Tianjin Hepatobiliary Research Institute, Tianjin Third Central Hospital, Tianjin 300170, P.R. China
| | - Li-Ping Wei
- Department of Cardiology, Tianjin Union Medicine Center, Tianjin 300121, P.R. China
| | - Hua Meng
- Department of Gastrointestinal Surgery, Beijing Friendship Hospital, Capital Medical University, Beijing 100050, P.R. China
| | - Yi-Jun Wang
- Department of Hepatobiliary Surgery, Tianjin Hepatobiliary Research Institute, Tianjin Third Central Hospital, Tianjin 300170, P.R. China
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12
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Lee JC, Tae HJ, Chen BH, Cho JH, Kim IH, Ahn JH, Park JH, Shin BN, Lee HY, Cho YS, Cho JH, Hong S, Choi SY, Won MH, Park CW. Failure in neuroprotection of remote limb ischemic postconditioning in the hippocampus of a gerbil model of transient cerebral ischemia. J Neurol Sci 2015; 358:377-84. [DOI: 10.1016/j.jns.2015.09.371] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2015] [Revised: 09/05/2015] [Accepted: 09/27/2015] [Indexed: 10/23/2022]
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13
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Giri S, Acikgöz A, Bader A. Isolation and Expansion of Hepatic Stem-like Cells from a Healthy Rat Liver and their Efficient Hepatic Differentiation of under Well-defined Vivo Hepatic like Microenvironment in a Multiwell Bioreactor. J Clin Exp Hepatol 2015; 5:107-22. [PMID: 26155038 PMCID: PMC4491607 DOI: 10.1016/j.jceh.2015.03.003] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/04/2015] [Accepted: 03/20/2015] [Indexed: 02/08/2023] Open
Abstract
BACKGROUND Currently, undifferentiated cells are found in all tissue and term as local stem cells which are quiescent in nature and less in number under normal healthy conditions but activate upon injury and repair the tissue or organs via automated activating mechanism. Due to very scanty presence of local resident somatic local stem cells in healthy organs, isolation and expansion of these adult stems is an immense challenge for medical research and cell based therapy. Particularly organ like liver, there is an ongoing controversy about existence of liver stem cells. METHODS Herein, Hepatic stem cells population was identified during culture of primary hepatocyte cells upon immediate isolation of primary hepatocyte cells. These liver stem cells has been expanded extensively and differentiated into primary hepatocytes under defined culture conditions in a nanostructured self assembling peptides modular bioreactor that mimic the state of art of liver microenvironment and compared with Matrigel as a positive control. Nanostructured self assembling peptides were used a defined extracellular matrix and Matrigel was used for undefined extracellular matrix. Proliferation of hepatic stem cells was investigated by two strategies. First strategy is to provide high concentration of hepatocyte growth factor (HGF) and second strategy is to evaluate the role of recombinant human erythropoietin (rHuEPO) in presence of trauma/ischemia cytokines (IL-6, TNF-α). Expansion to hepatic differentiation is observed by morphological analysis and was evaluated for the expression of hepatocyte-specific genes using RT-PCR and biochemical methods. RESULTS Hepatocyte-specific genes are well expressed at final stage (day 21) of differentiation period. The differentiated hepatocytes exhibited functional hepatic characteristics such as albumin secretion, urea secretion and cytochrome P450 expression. Additionally, immunofluorescence analysis revealed that hepatic stem cells derived hepatocytes exhibited mature hepatocyte markers (albumin, CK-19, CPY3A1, alpha 1-antitrypsin). Expansion and hepatic differentiation was efficiently in nanostructured self assembling peptides without such batch to batch variation while there was much variation in Matrigel coated bioreactor. In conclusion, the results of the study suggest that the nanostructured self assembling peptides coated bioreactor supports expansion as well as hepatic differentiation of liver stem cells which is superior than Matrigel. CONCLUSION This defined microenvironment conditions in bioreactor module can be useful for research involving bioartificial liver system, stem cell research and engineered liver tissue which could contribute to regenerative cell therapies or drug discovery and development.
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Key Words
- A1AT, Alpha 1-antitrypsin
- AFP, α-fetoprotein
- CK 7, Cytokeratin 7
- CK-19, Cytokeratin 19
- CPY3A1, Cytochrome P450 3A 1
- EROD, Ethoxyresorufin O-deethylase
- GaIN, D-galactosamine
- HGF, Hepatocyte growth factor
- IL-6, Interleukin 6
- MROD, Methoxyresorufin O-demethylase
- Matrigel
- PROD, Pentoxyresorufin O-depentylase
- TNF-α, Tumor necrosis factor alpha
- Thy1, Thy-1 cell surface antigen
- bioreactor
- defined culture conditions
- hepatic stem cells
- nanostructured self assembling peptides
- rHuEPO, Recombinant human erythropoietin
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Affiliation(s)
- Shibashish Giri
- Department of Cell Techniques and Applied Stem Cell Biology, Center for Biotechnology and Biomedicine (BBZ), University of Leipzig, Deutscher Platz 5, 04103 Leipzig, Germany,Address for correspondence: Shibashish Giri, Department of Cell Techniques and Applied Stem Cell Biology, Center for Biotechnology and Biomedicine, Medical faculty, University of Leipzig, Deutscher Platz 5, D-04103 Leipzig, Germany.
| | - Ali Acikgöz
- Department of Cell Techniques and Applied Stem Cell Biology, Center for Biotechnology and Biomedicine (BBZ), University of Leipzig, Deutscher Platz 5, 04103 Leipzig, Germany,Department of Gastroenterology and Hepatology, Klinikum St Georg, Delitzscher Straße, Leipzig, Germany
| | - Augustinus Bader
- Department of Cell Techniques and Applied Stem Cell Biology, Center for Biotechnology and Biomedicine (BBZ), University of Leipzig, Deutscher Platz 5, 04103 Leipzig, Germany
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14
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Jia J, Li J, Jiang L, Zhang J, Chen S, Wang L, Zhou Y, Xie H, Zhou L, Zheng S. Protective effect of remote limb ischemic perconditioning on the liver grafts of rats with a novel model. PLoS One 2015; 10:e0121972. [PMID: 25785455 PMCID: PMC4364967 DOI: 10.1371/journal.pone.0121972] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2014] [Accepted: 02/05/2015] [Indexed: 12/16/2022] Open
Abstract
Background Remote ischemic conditioning (RIC) is a known manual conditioning to decrease ischemic reperfusion injury (IRI) but not increase ischemic time. Here we tried to establish a rat RIC model of liver transplantation (LT), optimize the applicable protocols and investigate the protective mechanism. Methods The RIC model was developed by a standard tourniquet. Sprague-Dawley rats were assigned randomly to the sham operated control (N), standard rat liver transplantation (OLT) and RIC groups. According to the different protocols, RIC group was divided into 3 subgroups （10min×3, n = 6; 5min×3, n = 6; 1min×3, n = 6）respectively. Serum transaminases (ALT, AST), creatine kinase (CK), histopathologic changes, malondialdehyde (MDA), myeloperoxidase (MPO) and expressions of p-Akt were evaluated. Results Compared with the OLT group, the grafts subjected to RIC 5min*3 algorithm showed significant reduction of morphological damage and improved the graft function. Also, production of reactive oxygen species (MDA) and neutrophil accumulation (MPO) were markedly depressed and p-Akt was upregulated. Conclusion In conclusion, we successfully established a novel model of RIC in rat LT, the optimal RIC 5min*3 algorithm seemed to be more efficient to alleviate IRI of the liver graft in both functional and morphological categories, which due to its antioxidative, anti-inflammation activities and activating PI3K Akt pathway.
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Affiliation(s)
- Junjun Jia
- Key Laboratory of Combined Multi-organ Transplantation, Ministry of Public Health; Department of Hepatobiliary and Pancreatic Surgery, First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Jianhui Li
- Key Laboratory of Combined Multi-organ Transplantation, Ministry of Public Health; Department of Hepatobiliary and Pancreatic Surgery, First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Li Jiang
- Key Laboratory of Combined Multi-organ Transplantation, Ministry of Public Health; Department of Hepatobiliary and Pancreatic Surgery, First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Jing Zhang
- Key Laboratory of Combined Multi-organ Transplantation, Ministry of Public Health; Department of Hepatobiliary and Pancreatic Surgery, First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Shasha Chen
- Department of Anesthesia, First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Li Wang
- Key Laboratory of Combined Multi-organ Transplantation, Ministry of Public Health; Department of Hepatobiliary and Pancreatic Surgery, First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Yanfei Zhou
- Key Laboratory of Combined Multi-organ Transplantation, Ministry of Public Health; Department of Hepatobiliary and Pancreatic Surgery, First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Haiyang Xie
- Key Laboratory of Combined Multi-organ Transplantation, Ministry of Public Health; Department of Hepatobiliary and Pancreatic Surgery, First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Lin Zhou
- Key Laboratory of Combined Multi-organ Transplantation, Ministry of Public Health; Department of Hepatobiliary and Pancreatic Surgery, First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Shusen Zheng
- Key Laboratory of Combined Multi-organ Transplantation, Ministry of Public Health; Department of Hepatobiliary and Pancreatic Surgery, First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
- * E-mail:
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15
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Hemorrhagic preconditioning improves vascular reactivity after hemorrhagic shock by activation of PKCα and PKCε via the adenosine A1 receptor in rats. J Trauma Acute Care Surg 2013; 74:1266-74. [DOI: 10.1097/ta.0b013e31828dba35] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/27/2023]
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16
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Xu J, Lan D, Yang G, Li T, Liu L. Hemorrhagic preconditioning improves vascular reactivity after hemorrhagic shock by activation of PKC[alpha] and PKC[epsilon] via the adenosine A1 receptor in rats. J Trauma Acute Care Surg 2013. [DOI: 10.1097/01586154-201305000-00012] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
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17
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Li Q, Liu Y, Jiao J, Zhang C, Lou J. Assessment of effects of IR and IPC on activities of cytochrome P450 isozymes in rats by a five-drug cocktail approach. Drug Dev Ind Pharm 2013; 40:157-62. [PMID: 23339682 DOI: 10.3109/03639045.2012.752499] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/09/2023]
Abstract
BACKGROUND AND OBJECTIVE To evaluate the effects of ischemia and reperfusion (IR) and ischemic preconditioning (IPC) on the metabolic activities of cytochrome P450 (CYP) isozymes in rats by a five-drug cocktail approach. METHODS Cocktail approach was used to evaluate the influence of IR and IPC on the activities of CYP1A2, CYP2C9, CYP2E1, CYP2D6 and CYP3A4, which were reflected by the changes of pharmacokinetic parameters of five specific probe drugs: caffeine, chlorzoxazone, tolbutamide, metoprolol and midazolam, respectively. Rats were randomly divided into IR, IPC and sham groups, and then injected the mixture of five probe drugs. Blood samples were collected at a series of time-points and the concentrations of probe drugs in plasma were determined by a HPLC method with UV detection. The pharmacokinetic parameters were calculated by the software of DAS 2.0. RESULTS The parameters including t(1/2β), CLs, AUC, MRT and K10 exhibited a similar tendency for both IR and IPC groups. Compared with sham group, CLs and K10 of five probe drugs were significantly lower (p < 0.05), AUC and t(1/2β) of five or some probe drugs were significantly increased in IR and IPC groups (p < 0.05). Compared with IPC group, CLs of five probe drugs were decreased and AUC were significantly increased in the IR group (p < 0.05). CONCLUSION IR can variably decrease the activities of CYP isozymes in rats and this decrease can be attenuated by IPC.
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Affiliation(s)
- Qin Li
- Department of Pharmacology, College of Basic Medicine, Tianjin Medical University , No. 22 Qixiangtai Road, Tianjin , P.R. China
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18
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Choi KK, Cho JA, Kim SH, Lee SW, Min SO, Kim KS. Immediately transcripted genes in various hepatic ischemia models. JOURNAL OF THE KOREAN SURGICAL SOCIETY 2012; 83:298-306. [PMID: 23166889 PMCID: PMC3491232 DOI: 10.4174/jkss.2012.83.5.298] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/26/2012] [Revised: 09/15/2012] [Accepted: 10/04/2012] [Indexed: 11/30/2022]
Abstract
PURPOSE To elucidate the characteristic gene transcription profiles among various hepatic ischemia conditions, immediately transcribed genes and the degree of ischemic injury were compared among total ischemia (TI), intermittent clamping (IC), and ischemic preconditioning (IPC). METHODS Sprague-Dawley rats were equally divided into control (C, sham-operated), TI (ischemia for 90 minutes), IC (ischemia for 15 minutes and reperfusion for 5 minutes, repeated six times), and IPC (ischemia for 15 minutes, reperfusion for 5 minutes, and ischemia again for 90 minutes) groups. A cDNA microarray analysis was performed using hepatic tissues obtained by partial hepatectomy after occluding hepatic inflow. RESULTS THE CDNA MICROARRAY REVEALED THE FOLLOWING: interleukin (IL)-1β expression was 2-fold greater in the TI group than in the C group. In the IC group, IL-1α/β expression increased by 2.5-fold, and Na+/K+ ATPase β1 expression decreased by 2.4-fold. In the IPC group, interferon regulatory factor-1, osteoprotegerin, and retinoblastoma-1 expression increased by approximately 2-fold compared to that in the C group, but the expression of Na+/K+ ATPase β1 decreased 3-fold. CONCLUSION The current findings revealed characteristic gene expression profiles under various ischemic conditions. However, additional studies are needed to clarify the mechanism of protection against IPC.
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Affiliation(s)
- Kang Kook Choi
- Department of Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
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19
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Demirci BG, Cindoruk M, Yilmaz UT, Demirag MD, Gonul II, Demirci U, Gulbahar O, Dalgic A. Effects of everolimus on hepatic ischemia/reperfusion injury in an experimental rat model. Eur Surg 2012. [DOI: 10.1007/s10353-012-0152-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/27/2022]
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20
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Jin LM, Jin SF, Liu YX, Zhou L, Xie HY, Yan S, Xu X, Zheng SS. Ischemic preconditioning enhances hepatocyte proliferation in the early phase after ischemia under hemi-hepatectomy in rats. Hepatobiliary Pancreat Dis Int 2012; 11:521-6. [PMID: 23060398 DOI: 10.1016/s1499-3872(12)60217-3] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
BACKGROUND Ischemia/reperfusion (I/R) injury is an important barrier to liver surgery and transplantation because it impairs remnant liver/reduced-size-graft regeneration. Ischemic preconditioning (IPC), as an effective measure to overcome I/R injury, has been shown to enhance the regenerative capacity of hepatocytes. However, investigations have always focused on regeneration in the late phase after reperfusion. This study aimed to investigate whether IPC enhances hepatocyte proliferation in the early phase after reperfusion and possible underlying mechanisms. METHODS A total of 90 rats were divided into three groups: hemi-hepatectomy alone (PHx group), 60 minutes of ischemia plus hemi-hepatectomy (I/R group), and a cycle of 10 minutes of alternating I/R prior to 60 minutes of ischemia plus hemi-hepatectomy (IPC group). Each group was divided into five subgroups sacrificed after 0.5, 2, 6, 12 or 24 hours (n=6/subgroup). Subsequently, serum concentrations of alanine aminotransferase (ALT), aspartate aminotransferase (AST), tumor necrosis factor-alpha (TNF-alpha), and interleukin-6 (IL-6) were measured; caspase-3 and proliferating cell nuclear antigen (PCNA) proteins were also determined by Western blotting. Furthermore, PCNA was detected by immunohistochemistry to identify the expression site. RESULTS Serum ALT and AST levels after 2-24 hours of reperfusion in the PHx and IPC groups were remarkably decreased compared to the I/R group, and the serum TNF-alpha was relatively lower. A significant increase of serum IL-6 levels was found in the PHx and IPC groups compared with the I/R group at each time point. Furthermore, PCNA expression was remarkably increased in the IPC group after 6-12 hours of reperfusion, and in the earlier 0.5 and 6 hours time points after reperfusion have shown the massive PCNA-positive hepatocytes. At the same time, the expression of liver p-JNK was higher in the IPC group in the early phase after reperfusion than that of the I/R group and its expression was consistent with the PCNA. CONCLUSION IPC can initiate hepatocyte proliferation in the early phase after ischemia under hemi-hepatectomy, and may be associated with p-JNK expression and triggered by TNF-alpha/IL-6 signals.
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Affiliation(s)
- Li-Ming Jin
- Department of General Surgery, First Affiliated Hospital, Zhejiang Chinese Medical University, Hangzhou 310003, China
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Zhao H, Ren C, Chen X, Shen J. From rapid to delayed and remote postconditioning: the evolving concept of ischemic postconditioning in brain ischemia. Curr Drug Targets 2012; 13:173-87. [PMID: 22204317 DOI: 10.2174/138945012799201621] [Citation(s) in RCA: 89] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/01/2010] [Revised: 08/09/2011] [Accepted: 08/12/2011] [Indexed: 01/13/2023]
Abstract
Ischemic postconditioning is a concept originally defined to contrast with that of ischemic preconditioning. While both preconditioning and postconditioning confer a neuroprotective effect on brain ischemia, preconditioning is a sublethal insult performed in advance of brain ischemia, and postconditioning, which conventionally refers to a series of brief occlusions and reperfusions of the blood vessels, is conducted after ischemia/reperfusion. In this article, we first briefly review the history of preconditioning, including the experimentation that initially uncovered its neuroprotective effects and later revealed its underlying mechanisms-of-action. We then discuss how preconditioning research evolved into that of postconditioning--a concept that now represents a broad range of stimuli or triggers, including delayed postconditioning, pharmacological postconditioning, remote postconditioning--and its underlying protective mechanisms involving the Akt, MAPK, PKC and K(ATP) channel cell-signaling pathways. Because the concept of postconditioning is so closely associated with that of preconditioning, and both share some common protective mechanisms, we also discuss whether a combination of preconditioning and postconditioning offers greater protection than preconditioning or postconditioning alone.
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Affiliation(s)
- Heng Zhao
- Department of Neurosurgery, Stanford University School of Medicine, Stanford, CA 94305-5327, USA.
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