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1
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Rao JS, Ivkov R, Sharma A. Nanoparticle-Based Interventions for Liver Transplantation. Int J Mol Sci 2023; 24:7496. [PMID: 37108659 PMCID: PMC10144867 DOI: 10.3390/ijms24087496] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2023] [Revised: 03/29/2023] [Accepted: 04/13/2023] [Indexed: 04/29/2023] Open
Abstract
Liver transplantation is the only treatment for hepatic insufficiency as a result of acute and chronic liver injuries/pathologies that fail to recover. Unfortunately, there remains an enormous and growing gap between organ supply and demand. Although recipients on the liver transplantation waitlist have significantly higher mortality, livers are often not allocated because they are (i) classified as extended criteria or marginal livers and (ii) subjected to longer cold preservation time (>6 h) with a direct correlation of poor outcomes with longer cold ischemia. Downregulating the recipient's innate immune response to successfully tolerate a graft having longer cold ischemia times or ischemia-reperfusion injury through induction of immune tolerance in the graft and the host would significantly improve organ utilization and post-transplant outcomes. Broadly, technologies proposed for development aim to extend the life of the transplanted liver through post-transplant or recipient conditioning. In this review, we focus on the potential benefits of nanotechnology to provide unique pre-transplant grafting and recipient conditioning of extended criteria donor livers using immune tolerance induction and hyperthermic pre-conditioning.
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Affiliation(s)
- Joseph Sushil Rao
- Division of Solid Organ Transplantation, Department of Surgery, University of Minnesota, Minneapolis, MN 55455, USA
- Schulze Diabetes Institute, Department of Surgery, University of Minnesota, Minneapolis, MN 55455, USA
| | - Robert Ivkov
- Department of Radiation Oncology and Molecular Radiation Sciences, Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA
- Department of Oncology, Sydney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA
- Department of Mechanical Engineering, Whiting School of Engineering, Johns Hopkins University, Baltimore, MD 21218, USA
- Department of Materials Science and Engineering, Whiting School of Engineering, Johns Hopkins University, Baltimore, MD 21218, USA
| | - Anirudh Sharma
- Department of Radiation Oncology and Molecular Radiation Sciences, Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA
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2
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Rao JS, Pruett TL. Immunology of the transplanted cryopreserved kidney. Cryobiology 2023; 110:1-7. [PMID: 36640932 DOI: 10.1016/j.cryobiol.2023.01.003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2022] [Revised: 12/28/2022] [Accepted: 01/10/2023] [Indexed: 01/13/2023]
Abstract
Transplantation has substituted dysfunctional organs with healthy organs from donors to significantly lower morbidity and mortality associated with end-stage organ disease. Since the advent of transplantation, the promise of functional replacement has attracted an exponential mismatch between organ supply and demand. Theoretical proposals to counter the increasing needs have either been to create a source through genetic engineering of porcine donors for xenotransplantation (with more potent immunosuppression protocols) or recreate one's organ in a pig using interspecies blastocyst complementation for exogenic organ transplantation (without immunosuppression). Another promising avenue has been organ banking through cryopreservation for transplantation. Although ice free preservation and acceptable early function following rewarming is critical for success in transplantation, the immunological response that predominantly defines short- and long-term graft survival has failed to captivate attention to date. It is well sorted that thermal and metabolic stress incurred at 4 °C during recovery and reperfusion of organs for clinical transplantation has varying impact on graft survival. Considering the magnitude of cellular imbalance and injury at sub-zero/ultralow temperatures in addition to the chemical toxicity of cryoprotective agents (CPA), it is essential to assess and address the immunological response associated following transplantation to maximize the success of cryopreservation.
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Affiliation(s)
- Joseph Sushil Rao
- Division of Solid Organ Transplantation, Department of Surgery, University of Minnesota, Minneapolis, MN, USA; Schulze Diabetes Institute, Department of Surgery, University of Minnesota, Minneapolis, MN, USA.
| | - Timothy L Pruett
- Division of Solid Organ Transplantation, Department of Surgery, University of Minnesota, Minneapolis, MN, USA.
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Verhaar N, de Buhr N, von Köckritz-Blickwede M, Hewicker-Trautwein M, Pfarrer C, Mazzuoli-Weber G, Schulte H, Kästner S. Ischaemic postconditioning reduces apoptosis in experimental jejunal ischaemia in horses. BMC Vet Res 2021; 17:175. [PMID: 33902575 PMCID: PMC8077964 DOI: 10.1186/s12917-021-02877-y] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2021] [Accepted: 04/12/2021] [Indexed: 03/06/2023] Open
Abstract
BACKGROUND Ischaemic postconditioning (IPoC) refers to brief periods of reocclusion of blood supply following an ischaemic event. This has been shown to ameliorate ischaemia reperfusion injury in different tissues, and it may represent a feasible therapeutic strategy for ischaemia reperfusion injury following strangulating small intestinal lesions in horses. The objective of this study was to assess the degree cell death, inflammation, oxidative stress, and heat shock response in an equine experimental jejunal ischaemia model with and without IPoC. METHODS In this randomized, controlled, experimental in vivo study, 14 horses were evenly assigned to a control group and a group subjected to IPoC. Under general anaesthesia, segmental ischaemia with arterial and venous occlusion was induced in 1.5 m jejunum. Following ischaemia, the mesenteric vessels were repeatedly re-occluded in group IPoC only. Full thickness intestinal samples and blood samples were taken at the end of the pre-ischaemia period, after ischaemia, and after 120 min of reperfusion. Immunohistochemical staining or enzymatic assays were performed to determine the selected variables. RESULTS The mucosal cleaved-caspase-3 and TUNEL cell counts were significantly increased after reperfusion in the control group only. The cleaved-caspase-3 cell count was significantly lower in group IPoC after reperfusion compared to the control group. After reperfusion, the tissue myeloperoxidase activity and the calprotectin positive cell counts in the mucosa were increased in both groups, and only group IPoC showed a significant increase in the serosa. Tissue malondialdehyde and superoxide dismutase as well as blood lactate levels showed significant progression during ischaemia or reperfusion. The nuclear immunoreactivity of Heat shock protein-70 increased significantly during reperfusion. None of these variables differed between the groups. The neuronal cell counts in the myenteric plexus ganglia were not affected by the ischaemia model. CONCLUSIONS A reduced apoptotic cell count was found in the group subjected to IPoC. None of the other tested variables were significantly affected by IPoC. Therefore, the clinical relevance and possible protective mechanism of IPoC in equine intestinal ischaemia remains unclear. Further research on the mechanism of action and its effect in clinical cases of strangulating colic is needed.
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Affiliation(s)
- Nicole Verhaar
- Clinic for Horses, University of Veterinary Medicine Hannover, Hannover, Germany.
| | - Nicole de Buhr
- Department of Biochemistry, University of Veterinary Medicine Hannover, Hannover, Germany
- Research Center for Emerging Infections and Zoonoses, University of Veterinary Medicine Hannover, Hannover, Germany
| | - Maren von Köckritz-Blickwede
- Department of Biochemistry, University of Veterinary Medicine Hannover, Hannover, Germany
- Research Center for Emerging Infections and Zoonoses, University of Veterinary Medicine Hannover, Hannover, Germany
| | | | - Christiane Pfarrer
- Institute for Anatomy, University of Veterinary Medicine Hannover, Hannover, Germany
| | - Gemma Mazzuoli-Weber
- Institute for Physiology and Cell Biology, University of Veterinary Medicine Hannover, Hannover, Germany
| | - Henri Schulte
- Institute of Functional and Applied Anatomy, Hannover Medical School, Hannover, Germany
| | - Sabine Kästner
- Clinic for Horses, University of Veterinary Medicine Hannover, Hannover, Germany
- Small Animal Clinic, University of Veterinary Medicine Hannover, Hannover, Germany
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Faghir-Ghanesefat H, Keshavarz-Bahaghighat H, Rajai N, Mokhtari T, Bahramnejad E, Kazemi Roodsari S, Dehpour AR. The Possible Role of Nitric Oxide Pathway in Pentylenetetrazole Preconditioning Against Seizure in Mice. J Mol Neurosci 2019; 67:477-483. [PMID: 30627955 DOI: 10.1007/s12031-018-1256-2] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2018] [Accepted: 12/28/2018] [Indexed: 11/24/2022]
Abstract
Preconditioning is defined as an induction of adaptive response in organs against lethal stimulation provoked by subsequent mild sublethal stress. Several chemical agents have been demonstrated to cause brain tolerance through preconditioning. The aim of the present study is to test the hypothesis that preconditioning with pentylenetetrazole (PTZ) may have protective effect against seizure induced by i.v. infusion of PTZ. Mice were preconditioned by low-dose administration of PTZ (25 mg/kg) for 5 consecutive days, and the threshold of seizure elicited by i.v. infusion of PTZ was measured. To investigate the possible role of nitric oxide, NOS inhibitor enzymes, including L-NG-nitro-L-arginine methyl ester hydrochloride (L-NAME) (10 mg/kg), aminoguanidine (AG) (50 mg/kg), 7-nitroindazole (7-NI) (15 mg/kg), and L-arginine (L-arg) (60 mg/kg), were administered concomitantly with PTZ in both acute and chronic phases. Determination of seizure threshold revealed significant enhancement after preconditioning with low dose of PTZ. While the protective effect of PTZ preconditioning was enhanced after the administration of L-arg, it was reversed following administration of L-NAME and 7NI, suggesting the involvement of nitric oxide pathway as an underlying mechanism of PTZ-induced preconditioning. Preconditioning with PTZ led to brain tolerance and adaptive response in animal model of PTZ-induced seizure. This effect is in part due to the involvement of nitric oxide pathway.
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Affiliation(s)
- Hedyeh Faghir-Ghanesefat
- Department of Pharmacology, School of Medicine, Tehran University of Medical Sciences, P.O. Box 13145-784, Tehran, Iran.,Experimental Medicine Research Center, Tehran University of Medical Sciences, Tehran, Iran
| | - Hedieh Keshavarz-Bahaghighat
- Department of Pharmacology, School of Medicine, Tehran University of Medical Sciences, P.O. Box 13145-784, Tehran, Iran.,Experimental Medicine Research Center, Tehran University of Medical Sciences, Tehran, Iran
| | - Nazanin Rajai
- Department of Pharmacology, School of Medicine, Tehran University of Medical Sciences, P.O. Box 13145-784, Tehran, Iran.,Experimental Medicine Research Center, Tehran University of Medical Sciences, Tehran, Iran
| | - Tahmineh Mokhtari
- Nervous System Stem Cells Research Center, Semnan University of Medical Sciences, Semnan, Iran.,Department of Anatomy, School of Medicine, Semnan University of Medical Sciences, Semnan, Iran
| | - Erfan Bahramnejad
- Department of Pharmacology, School of Medicine, Tehran University of Medical Sciences, P.O. Box 13145-784, Tehran, Iran.,Experimental Medicine Research Center, Tehran University of Medical Sciences, Tehran, Iran
| | - Soheil Kazemi Roodsari
- Department of Pharmacology, School of Medicine, Tehran University of Medical Sciences, P.O. Box 13145-784, Tehran, Iran.,Experimental Medicine Research Center, Tehran University of Medical Sciences, Tehran, Iran
| | - Ahmad Reza Dehpour
- Department of Pharmacology, School of Medicine, Tehran University of Medical Sciences, P.O. Box 13145-784, Tehran, Iran. .,Experimental Medicine Research Center, Tehran University of Medical Sciences, Tehran, Iran.
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Ingles J, Simpson A, Kyathanahalli C, Anamthathmakula P, Hassan S, Jeyasuria P, Condon JC. Preconditioning the uterine unfolded protein response maintains non-apoptotic Caspase 3-dependent quiescence during pregnancy. Cell Death Dis 2018; 9:933. [PMID: 30224704 PMCID: PMC6141493 DOI: 10.1038/s41419-018-1000-4] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2018] [Revised: 07/24/2018] [Accepted: 07/27/2018] [Indexed: 02/06/2023]
Abstract
The prevention of apoptotic caspase 3 activation through biological preconditioning, mediated through the modulation of the unfolded protein response has been demonstrated to ameliorate multiple pathophysiologies. The maintenance of non-apoptotic caspase 3 activity by the unfolded protein response within the pregnant uterus has previously been proven to be critical in inhibiting uterine myocyte contractility during pregnancy. Here we report that the pregnant uterus utilizes an unfolded protein response-preconditioning paradigm to conserve myometrial caspase 3 in a non-apoptotic state in order to effectively inhibit uterine contractility thereby preventing the onset of preterm labor. In the absence of appropriate endogenous preconditioning during pregnancy, uterine caspase 3 is transformed from a non-apoptotic to an apoptotic phenotype. Apoptotic caspase 3 activation results in the precocious triggering of local uterine inflammatory signaling and prostaglandin production, consequently resulting in an increased incidence of preterm birth. These findings represent a paradigm shift in our understanding of how preconditioning promotes the maintenance of uterine non-apoptotic caspase 3 action during pregnancy preventing the onset of premature uterine contraction and therefore defining the timing of the onset of labor.
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Affiliation(s)
- Judith Ingles
- Department of Physiology, School of Medicine, Wayne State University, Detroit, MI, USA
| | - Arren Simpson
- Department of Biology, University of Detroit Mercy, Detroit, MI, USA
| | | | | | - Sonia Hassan
- Department of Physiology, School of Medicine, Wayne State University, Detroit, MI, USA.,Department of Obstetrics and Gynecology, Wayne State University, Detroit, MI, USA.,Perinatal Research Initiative in support of the Perinatology Research Branch, Division of Obstetrics and Maternal-Fetal Medicine, Division of Intramural Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, U. S. Department of Health and Human Services, Bethesda and Detroit, MD and MI, USA
| | - Pancharatnam Jeyasuria
- Department of Physiology, School of Medicine, Wayne State University, Detroit, MI, USA.,Department of Obstetrics and Gynecology, Wayne State University, Detroit, MI, USA.,Perinatal Research Initiative in support of the Perinatology Research Branch, Division of Obstetrics and Maternal-Fetal Medicine, Division of Intramural Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, U. S. Department of Health and Human Services, Bethesda and Detroit, MD and MI, USA
| | - Jennifer C Condon
- Department of Physiology, School of Medicine, Wayne State University, Detroit, MI, USA. .,Department of Obstetrics and Gynecology, Wayne State University, Detroit, MI, USA. .,Perinatal Research Initiative in support of the Perinatology Research Branch, Division of Obstetrics and Maternal-Fetal Medicine, Division of Intramural Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, U. S. Department of Health and Human Services, Bethesda and Detroit, MD and MI, USA.
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Remote Ischemic Preconditioning Is Efficient in Reducing Hepatic Ischemia-Reperfusion Injury in a Growing Rat Model and Does Not Promote Histologic Lesions in Distant Organs. Transplant Proc 2018; 50:3840-3844. [PMID: 30385044 DOI: 10.1016/j.transproceed.2018.04.034] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2018] [Revised: 03/30/2018] [Accepted: 04/12/2018] [Indexed: 12/19/2022]
Abstract
OBJECTIVE Ischemic preconditioning (IPC) was developed to diminish ischemia-reperfusion injury (IRI). There are two main ways of performing it: direct ischemic-preconditioning (DIP) and remote ischemic-preconditioning (RIP). The objectives of this study were to investigate local and systemic effects of DIP and RIP in liver IRI. METHODS Thirty-two weaning rats (50-70 g body weight; 21 days old) were divided into 4 groups: control (C); ischemia followed by reperfusion (IR); DIP followed by ischemia and reperfusion; and RIP followed by ischemia and reperfusion. In the IR group, the vascular pedicles of medial and left lateral liver lobes were clamped for 60 minutes and then unclamped. In the DIP group, a 10-minute cycle of ischemia followed by a 10-minute reperfusion of the same lobes was performed before 60 minutes of ischemia. In the RIP group, three 5-minute cycles of clamping and unclamping of the femoral vessels were performed before liver ischemia. The animals were euthanized 24 hours after the surgical procedures. RESULTS The serum levels of liver enzymes were significantly lower in the RIP group compared to the control and IR groups and to the DIP group. The scores of histologic hepatic lesions were significantly lower in RIP animals than those of IR animals (P = .002) and similar to the C group animals. The Bax/BCl-xl relation was lower in the DIP group than that in the RIP group (P = .045) and no differences were observed in histologic analyses of kidney, lung, intestine, and heart. CONCLUSION In young animals, the beneficial effects of RIP are more evident than those of DIP.
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Tashiro S, Miyake H, Rokutan K. Role of geranylgeranylacetone as non-toxic HSP70 inducer in liver surgery: clinical application. JOURNAL OF HEPATO-BILIARY-PANCREATIC SCIENCES 2018; 25:269-274. [DOI: 10.1002/jhbp.549] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/11/2022]
Affiliation(s)
- Seiki Tashiro
- Department of Surgery; Taoka Hospital; Tokushima Japan
- School of Medicine; Tokushima University Graduate School; Tokushima Japan
| | - Hidenori Miyake
- School of Medicine; Tokushima University Graduate School; Tokushima Japan
- Department of Surgery; Tokushima Municipal Hospital; Tokushima Japan
| | - Kazuhito Rokutan
- Department of Pathophysiology; Institute of Biomedical Sciences; Tokushima University Graduate School; Tokushima Japan
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Abstract
OPINION STATEMENT Preconditioning is the premise that controlled preemptive exposure to sub-lethal doses of a stressor and can condition an organism or organ to later withstand a lethal dose. This process relies on marshaling endogenous survival resources that have evolved as part of an organism's evolutionary struggle to overcome at times harsh environmental conditions. This preconditioning response occurs through activation of myriad complex mechanisms that run the gamut from alterations in gene expression to the de novo synthesis and post-translational modification of proteins, and it may occur across exposure to a wide variety of stressors (i.e., ischemia, hypoxia, hypothermia, drugs). This review will focus on preconditioning in relation to an ischemic stressor (ischemic preconditioning) and how this process may be harnessed as a protective method to ameliorate targeted acute neurologic diseases especially. There has been considerable eagerness to translate ischemic preconditioning to the bedside, and to that end there have been recent trials examining its efficacy in various clinical settings. However, some of these trials have reached diverging conclusions with a protective effect seen in studies targeting acute kidney injury solely while no benefit was seen in larger trials targeting combined endpoints including cardio-, neuro-, and renoprotection in a cohort of patients undergoing cardiac surgery. While an extensive body of pre-clinical research offers ischemic preconditioning as a robust and highly faithful protective phenomenon, its clinical utility remains unproven. This current state may be due to persisting gaps in our understanding of how best to harness its power. This review will provide an overview of the biological mechanisms proposed to underlie ischemic preconditioning, explore initial disease targets, examine the challenges we must overcome to optimally engage this system, and report findings of recent clinical trials.
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Affiliation(s)
- Maranatha Ayodele
- Department of Neurology, University of Miami, Miller School of Medicine, 1120 NW 14th Street, CRB 1353, Miami, FL, 33136, USA.
| | - Sebastian Koch
- Department of Neurology, University of Miami, Miller School of Medicine, 1120 NW 14th Street, CRB 1365, Miami, FL, 33136, USA
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Abstract
A broad definition of preconditioning is "the preparation for a subsequent action." Mounting evidence demonstrates that novel remote preconditioning paradigms, in which protective stimuli experienced locally can capacitate systemic tolerance and enhanced cell viability upon exposure to ensuing cellular insults, have been largely successful in the field of cardiovascular ischemia/reperfusion injury. To ensure successful protective preconditioning, some models (including the uterus) have been demonstrated to activate the unfolded protein response (UPR), which is a cellular stress response controlled at the level of the endoplasmic reticulum. However, in the context of remote preconditioning, activation of these intracellular molecular pathways must result in the extracellular transmission of adaptive signals to remote targets. In our recently published manuscript, we have described the activation of the UPR in the pregnant uterine myocyte to be associated with increased uterine myocyte quiescence and normal gestational length. We hypothesize that ubiquitous uterine gestational stresses experienced in every pregnancy, which have been demonstrated in other systems to activate the UPR, may induce a robust paracrine dissemination of a uterine secretome, for example, glucose-regulated protein 78, with preconditioning-like properties. Furthermore, we speculate that the gestational stress-induced uterine secretome acts to promote both local and systemic tolerance to the ensuing gestational insults, allowing for the maintenance of uterine quiescence. In this context, preterm labor may be the result of a pregnant uterus experiencing a stress it cannot accommodate or when it is unable to host an appropriate UPR resulting in insufficient preconditioning and a diminished local and systemic capacity to tolerate pregnancy-dependent increases in normal gestational stress. This is highly attractive from a clinical viewpoint as we ultimately aim to identify local and systemic adaptations that may serve as preconditioning stimuli for use as a strategy to restore appropriate preconditioning profiles to prolong uterine quiescence in pregnancy.
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Affiliation(s)
- Judith Ingles
- 1 Department of Physiology, Wayne State University Perinatal Initiative, School of Medicine, Wayne State University, Detroit, MI, USA.,2 Department of Obstetrics and Gynecology, Wayne State University Perinatal Initiative, School of Medicine, Wayne State University, Detroit, MI, USA
| | - Chandrashekara N Kyathanahalli
- 1 Department of Physiology, Wayne State University Perinatal Initiative, School of Medicine, Wayne State University, Detroit, MI, USA.,2 Department of Obstetrics and Gynecology, Wayne State University Perinatal Initiative, School of Medicine, Wayne State University, Detroit, MI, USA
| | - Pancharatnam Jeyasuria
- 1 Department of Physiology, Wayne State University Perinatal Initiative, School of Medicine, Wayne State University, Detroit, MI, USA.,2 Department of Obstetrics and Gynecology, Wayne State University Perinatal Initiative, School of Medicine, Wayne State University, Detroit, MI, USA.,3 Perinatal Research Initiative Wayne State University School of Medicine, Wane State University, Detroit, MI, USA
| | - Jennifer C Condon
- 1 Department of Physiology, Wayne State University Perinatal Initiative, School of Medicine, Wayne State University, Detroit, MI, USA.,2 Department of Obstetrics and Gynecology, Wayne State University Perinatal Initiative, School of Medicine, Wayne State University, Detroit, MI, USA.,3 Perinatal Research Initiative Wayne State University School of Medicine, Wane State University, Detroit, MI, USA
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Nair A, Khan S, Omar S, Pei XQ, McNeill K, Chowienczyk P, Webb AJ. Remote ischaemic preconditioning suppresses endogenous plasma nitrite during ischaemia-reperfusion: a randomized controlled crossover pilot study. Br J Clin Pharmacol 2017; 83:1416-1423. [PMID: 28074482 DOI: 10.1111/bcp.13231] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2016] [Revised: 11/23/2016] [Accepted: 12/18/2016] [Indexed: 01/16/2023] Open
Abstract
AIM The aim of this article is to test the hypothesis that remote ischaemic preconditioning (RIPC) increases circulating endogenous local and systemic plasma (nitrite) during RIPC and ischaemia-reperfusion (IR) as a potential protective mechanism against ischaemia-reperfusion injury (IRI). METHODS Six healthy male volunteers (mean age 29.5 ± 7.6 years) were randomized in a crossover study to initially receive either RIPC (4 × 5 min cycles) to the left arm, or no RIPC (control), both followed by an ischaemia-reperfusion (IR) sequence (20 min cuff inflation to 200 mmHg, 20 min reperfusion) to the right arm. The volunteers returned at least 7 days later for the alternate intervention. The primary outcome was the effect of RIPC vs. control on local and systemic plasma (nitrite). RESULTS RIPC did not significantly change plasma (nitrite) in either the left or the right arm during the RIPC sequence. However, compared to control, RIPC decreased plasma (nitrite) during the subsequent IR sequence by ~26% (from 118 ± 9 to 87 ± 5 nmol l-1 ) locally in the left arm (P = 0.008) overall, with an independent effect of -58.70 nmol l-1 (95% confidence intervals -116.1 to -1.33) at 15 min reperfusion, and by ~24% (from 109 ± 9 to 83 ± 7 nmol l-1 ) systemically in the right arm (P = 0.03). CONCLUSIONS RIPC had no effect on plasma (nitrite) during the RIPC sequence, but instead decreased plasma (nitrite) by ~25% during IR. This would likely counteract the protective mechanisms of RIPC, and contribute to RIPC's lack of efficacy, as observed in recent clinical trials. A combined approach of RIPC with nitrite administration may be required.
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Affiliation(s)
- Ashok Nair
- King's College London British Heart Foundation Centre, Cardiovascular Division, Department of Clinical Pharmacology, St. Thomas' Hospital, London, SE1 7EH, UK.,Biomedical Research Centre, Guy's & St. Thomas' NHS Foundation Trust, London, UK.,Department of Anaesthetics, Guy's & St. Thomas' NHS Foundation Trust, London, UK
| | - Sitara Khan
- King's College London British Heart Foundation Centre, Cardiovascular Division, Department of Clinical Pharmacology, St. Thomas' Hospital, London, SE1 7EH, UK.,Biomedical Research Centre, Guy's & St. Thomas' NHS Foundation Trust, London, UK
| | - Sami Omar
- King's College London British Heart Foundation Centre, Cardiovascular Division, Department of Clinical Pharmacology, St. Thomas' Hospital, London, SE1 7EH, UK.,Biomedical Research Centre, Guy's & St. Thomas' NHS Foundation Trust, London, UK
| | - Xiao-Qing Pei
- King's College London British Heart Foundation Centre, Cardiovascular Division, Department of Clinical Pharmacology, St. Thomas' Hospital, London, SE1 7EH, UK.,Biomedical Research Centre, Guy's & St. Thomas' NHS Foundation Trust, London, UK.,Ultrasound Department, Sun Yat-Sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, 510060, People's Republic of China
| | - Karen McNeill
- King's College London British Heart Foundation Centre, Cardiovascular Division, Department of Clinical Pharmacology, St. Thomas' Hospital, London, SE1 7EH, UK.,Biomedical Research Centre, Guy's & St. Thomas' NHS Foundation Trust, London, UK
| | - Phil Chowienczyk
- King's College London British Heart Foundation Centre, Cardiovascular Division, Department of Clinical Pharmacology, St. Thomas' Hospital, London, SE1 7EH, UK.,Biomedical Research Centre, Guy's & St. Thomas' NHS Foundation Trust, London, UK
| | - Andrew James Webb
- King's College London British Heart Foundation Centre, Cardiovascular Division, Department of Clinical Pharmacology, St. Thomas' Hospital, London, SE1 7EH, UK.,Biomedical Research Centre, Guy's & St. Thomas' NHS Foundation Trust, London, UK
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11
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Li S, Hafeez A, Noorulla F, Geng X, Shao G, Ren C, Lu G, Zhao H, Ding Y, Ji X. Preconditioning in neuroprotection: From hypoxia to ischemia. Prog Neurobiol 2017; 157:79-91. [PMID: 28110083 DOI: 10.1016/j.pneurobio.2017.01.001] [Citation(s) in RCA: 154] [Impact Index Per Article: 19.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2015] [Revised: 01/08/2017] [Accepted: 01/13/2017] [Indexed: 01/05/2023]
Abstract
Sublethal hypoxic or ischemic events can improve the tolerance of tissues, organs, and even organisms from subsequent lethal injury caused by hypoxia or ischemia. This phenomenon has been termed hypoxic or ischemic preconditioning (HPC or IPC) and is well established in the heart and the brain. This review aims to discuss HPC and IPC with respect to their historical development and advancements in our understanding of the neurochemical basis for their neuroprotective role. Through decades of collaborative research and studies of HPC and IPC in other organ systems, our understanding of HPC and IPC-induced neuroprotection has expanded to include: early- (phosphorylation targets, transporter regulation, interfering RNA) and late- (regulation of genes like EPO, VEGF, and iNOS) phase changes, regulators of programmed cell death, members of metabolic pathways, receptor modulators, and many other novel targets. The rapid acceleration in our understanding of HPC and IPC will help facilitate transition into the clinical setting.
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Affiliation(s)
- Sijie Li
- Beijing Key Laboratory of Hypoxic Conditioning Translational Medicine, Xuan Wu Hospital, Capital Medical University, Beijing, China; National Clinical Research Center for Geriatric Disorders, Beijing, China
| | - Adam Hafeez
- Department of Neurological Surgery, Wayne State University School of Medicine, Detroit, MI, USA
| | - Fatima Noorulla
- Department of Neurological Surgery, Wayne State University School of Medicine, Detroit, MI, USA
| | - Xiaokun Geng
- Department of Neurological Surgery, Wayne State University School of Medicine, Detroit, MI, USA; Department of Neurology, Luhe Hospital, Capital Medical University, Beijing, China
| | - Guo Shao
- Beijing Key Laboratory of Hypoxic Conditioning Translational Medicine, Xuan Wu Hospital, Capital Medical University, Beijing, China
| | - Changhong Ren
- Beijing Key Laboratory of Hypoxic Conditioning Translational Medicine, Xuan Wu Hospital, Capital Medical University, Beijing, China
| | - Guowei Lu
- Beijing Key Laboratory of Hypoxic Conditioning Translational Medicine, Xuan Wu Hospital, Capital Medical University, Beijing, China
| | - Heng Zhao
- Department of Neurosurgery, Stanford University, CA, USA
| | - Yuchuan Ding
- Beijing Key Laboratory of Hypoxic Conditioning Translational Medicine, Xuan Wu Hospital, Capital Medical University, Beijing, China; Department of Neurological Surgery, Wayne State University School of Medicine, Detroit, MI, USA
| | - Xunming Ji
- Beijing Key Laboratory of Hypoxic Conditioning Translational Medicine, Xuan Wu Hospital, Capital Medical University, Beijing, China; National Clinical Research Center for Geriatric Disorders, Beijing, China.
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Abstract
Ischemic disorders, such as myocardial infarction, stroke, and peripheral vascular disease, are the most common causes of debilitating disease and death in westernized cultures. The extent of tissue injury relates directly to the extent of blood flow reduction and to the length of the ischemic period, which influence the levels to which cellular ATP and intracellular pH are reduced. By impairing ATPase-dependent ion transport, ischemia causes intracellular and mitochondrial calcium levels to increase (calcium overload). Cell volume regulatory mechanisms are also disrupted by the lack of ATP, which can induce lysis of organelle and plasma membranes. Reperfusion, although required to salvage oxygen-starved tissues, produces paradoxical tissue responses that fuel the production of reactive oxygen species (oxygen paradox), sequestration of proinflammatory immunocytes in ischemic tissues, endoplasmic reticulum stress, and development of postischemic capillary no-reflow, which amplify tissue injury. These pathologic events culminate in opening of mitochondrial permeability transition pores as a common end-effector of ischemia/reperfusion (I/R)-induced cell lysis and death. Emerging concepts include the influence of the intestinal microbiome, fetal programming, epigenetic changes, and microparticles in the pathogenesis of I/R. The overall goal of this review is to describe these and other mechanisms that contribute to I/R injury. Because so many different deleterious events participate in I/R, it is clear that therapeutic approaches will be effective only when multiple pathologic processes are targeted. In addition, the translational significance of I/R research will be enhanced by much wider use of animal models that incorporate the complicating effects of risk factors for cardiovascular disease. © 2017 American Physiological Society. Compr Physiol 7:113-170, 2017.
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Affiliation(s)
- Theodore Kalogeris
- Department of Medical Pharmacology and Physiology, University of Missouri School of Medicine, Columbia, Missouri, USA
| | - Christopher P. Baines
- Department of Medical Pharmacology and Physiology, University of Missouri School of Medicine, Columbia, Missouri, USA
- Dalton Cardiovascular Research Center, University of Missouri, Columbia, Missouri, USA
- Department of Biomedical Sciences, University of Missouri College of Veterinary Medicine, Columbia, Missouri, USA
| | - Maike Krenz
- Department of Medical Pharmacology and Physiology, University of Missouri School of Medicine, Columbia, Missouri, USA
- Dalton Cardiovascular Research Center, University of Missouri, Columbia, Missouri, USA
| | - Ronald J. Korthuis
- Department of Medical Pharmacology and Physiology, University of Missouri School of Medicine, Columbia, Missouri, USA
- Dalton Cardiovascular Research Center, University of Missouri, Columbia, Missouri, USA
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Ueno K, Samura M, Nakamura T, Tanaka Y, Takeuchi Y, Kawamura D, Takahashi M, Hosoyama T, Morikage N, Hamano K. Increased plasma VEGF levels following ischemic preconditioning are associated with downregulation of miRNA-762 and miR-3072-5p. Sci Rep 2016; 6:36758. [PMID: 27905554 PMCID: PMC5131337 DOI: 10.1038/srep36758] [Citation(s) in RCA: 30] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2016] [Accepted: 10/21/2016] [Indexed: 12/16/2022] Open
Abstract
Ischemic preconditioning (IPC) has protective effects against ischemia-perfusion injury of organs. In the present study, we investigated the associated mechanisms after performing remote IPC (rIPC) of lower limbs by clamping abdominal aorta in mice. Subsequent experiments showed decreased damage and paralysis of lower limbs following spinal cord injury (SCI). Concomitantly, plasma vascular endothelial growth factor (VEGF) levels were increased 24 h after rIPC compared with those in sham-operated animals. In subsequent microRNA analyses, thirteen microRNAs were downregulated in exosomes 24 h after rIPC. Further studies of femoral CD34-positive bone marrow (BM) cells confirmed downregulation of these seven microRNAs 24 h after rIPC compared with those in sham-operated controls. Subsequent algorithm-based database searches suggested that two of the seven microRNAs bind to the 3′ UTR of VEGF mRNA, and following transfection into CD34-positive BM cells, anti-miR-762, and anti-miR-3072-5p inhibitors led to increased VEGF concentrations. The present data suggest that rIPC transiently increases plasma VEGF levels by downregulating miR-762 and miR-3072-5p in CD34-positive BM cells, leading to protection against organ ischemia.
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Affiliation(s)
- Koji Ueno
- Department of Surgery and Clinical Sciences, Yamaguchi University Graduate School of Medicine, Ube, Japan.,Center for Regenerative Medicine, Yamaguchi University Graduate School of Medicine, Ube, Japan
| | - Makoto Samura
- Department of Surgery and Clinical Sciences, Yamaguchi University Graduate School of Medicine, Ube, Japan
| | - Tamami Nakamura
- Department of Surgery and Clinical Sciences, Yamaguchi University Graduate School of Medicine, Ube, Japan
| | - Yuya Tanaka
- Department of Surgery and Clinical Sciences, Yamaguchi University Graduate School of Medicine, Ube, Japan
| | - Yuriko Takeuchi
- Department of Surgery and Clinical Sciences, Yamaguchi University Graduate School of Medicine, Ube, Japan
| | - Daichi Kawamura
- Department of Surgery and Clinical Sciences, Yamaguchi University Graduate School of Medicine, Ube, Japan
| | - Masaya Takahashi
- Department of Surgery and Clinical Sciences, Yamaguchi University Graduate School of Medicine, Ube, Japan
| | - Tohru Hosoyama
- Department of Surgery and Clinical Sciences, Yamaguchi University Graduate School of Medicine, Ube, Japan.,Center for Regenerative Medicine, Yamaguchi University Graduate School of Medicine, Ube, Japan
| | - Noriyasu Morikage
- Department of Surgery and Clinical Sciences, Yamaguchi University Graduate School of Medicine, Ube, Japan
| | - Kimikazu Hamano
- Department of Surgery and Clinical Sciences, Yamaguchi University Graduate School of Medicine, Ube, Japan
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14
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Kuramochi M, Izawa T, Pervin M, Bondoc A, Kuwamura M, Yamate J. The kinetics of damage-associated molecular patterns (DAMPs) and toll-like receptors during thioacetamide-induced acute liver injury in rats. ACTA ACUST UNITED AC 2016; 68:471-7. [PMID: 27522298 DOI: 10.1016/j.etp.2016.06.005] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2016] [Revised: 06/09/2016] [Accepted: 06/21/2016] [Indexed: 12/18/2022]
Abstract
Drug-induced liver injury (DILI) is a common problem in human medicine and it is a major reason to withdraw marketed drugs. However, the mechanism of DILI is still less known. Damage-associated molecular patterns (DAMPs), such as high-mobility group boxes (HMGBs), S100 proteins and heat shock proteins (HSPs), are released from injured or necrotic cells, bind to toll-like receptors (TLRs) and modulate inflammatory reactions. Here we investigated the kinetics of DAMPs, TLRs and MHC class II in a rat model of DILI with thioacetamide (TAA). After TAA administration, extensive necrosis was observed on days 1 and 2, followed by infiltration of inflammatory cells on day 3. The levels of serum liver enzymes also peaked on day 1. Expression of HMGB-1, -2 and S100A4 peaked on day 2. TLR-4 was up-regulated on day 3. The number of MHC class II-positive macrophages increased until day 2. These results suggest that HMGB-1, -2 and S100A4 are associated with hepatocellular necrosis and that DAMPs may activate TLR-4 and MHC class II during TAA-induced liver injury. Our data would contribute to the elucidation of the mechanism of DILI.
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Affiliation(s)
- Mizuki Kuramochi
- Veterinary Pathology, Osaka Prefecture University, 1-58 Rinku-Ourai-Kita, Izumisano City, Osaka 598-8531, Japan
| | - Takeshi Izawa
- Veterinary Pathology, Osaka Prefecture University, 1-58 Rinku-Ourai-Kita, Izumisano City, Osaka 598-8531, Japan
| | - Munmun Pervin
- Veterinary Pathology, Osaka Prefecture University, 1-58 Rinku-Ourai-Kita, Izumisano City, Osaka 598-8531, Japan
| | - Alexandra Bondoc
- Veterinary Pathology, Osaka Prefecture University, 1-58 Rinku-Ourai-Kita, Izumisano City, Osaka 598-8531, Japan
| | - Mitsuru Kuwamura
- Veterinary Pathology, Osaka Prefecture University, 1-58 Rinku-Ourai-Kita, Izumisano City, Osaka 598-8531, Japan
| | - Jyoji Yamate
- Veterinary Pathology, Osaka Prefecture University, 1-58 Rinku-Ourai-Kita, Izumisano City, Osaka 598-8531, Japan.
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Kierulf-Lassen C, Nieuwenhuijs-Moeke GJ, Krogstrup NV, Oltean M, Jespersen B, Dor FJMF. Molecular Mechanisms of Renal Ischemic Conditioning Strategies. Eur Surg Res 2015; 55:151-83. [PMID: 26330099 DOI: 10.1159/000437352] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2015] [Accepted: 07/02/2015] [Indexed: 11/19/2022]
Abstract
Ischemia-reperfusion injury is the leading cause of acute kidney injury in a variety of clinical settings such as renal transplantation and hypovolemic and/or septic shock. Strategies to reduce ischemia-reperfusion injury are obviously clinically relevant. Ischemic conditioning is an inherent part of the renal defense mechanism against ischemia and can be triggered by short periods of intermittent ischemia and reperfusion. Understanding the signaling transduction pathways of renal ischemic conditioning can promote further clinical translation and pharmacological advancements in this era. This review summarizes research on the molecular mechanisms underlying both local and remote ischemic pre-, per- and postconditioning of the kidney. The different types of conditioning strategies in the kidney recruit similar powerful pro-survival mechanisms. Likewise, renal ischemic conditioning mobilizes many of the same protective signaling pathways as in other organs, but differences are recognized.
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Nogueira MA, Coelho AMM, Sampietre SN, Patzina RA, Pinheiro da Silva F, D'Albuquerque LAC, Machado MCC. Beneficial effects of adenosine triphosphate-sensitive K + channel opener on liver ischemia/reperfusion injury. World J Gastroenterol 2014; 20:15319-15326. [PMID: 25386080 PMCID: PMC4223265 DOI: 10.3748/wjg.v20.i41.15319] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/28/2014] [Revised: 05/28/2014] [Accepted: 07/11/2014] [Indexed: 02/06/2023] Open
Abstract
AIM: To investigate the effect of diazoxide administration on liver ischemia/reperfusion injury.
METHODS: Wistar male rats underwent partial liver ischemia performed by clamping the pedicle from the medium and left anterior lateral segments for 1 h under mechanical ventilation. They were divided into 3 groups: Control Group, rats submitted to liver manipulation, Saline Group, rats received saline, and Diazoxide Group, rats received intravenous injection diazoxide (3.5 mg/kg) 15 min before liver reperfusion. 4 h and 24 h after reperfusion, blood was collected for determination of aspartate transaminase (AST), alanine transaminase (ALT), tumor necrosis factor (TNF-α), interleukin-6 (IL-6), interleukin-10 (IL-10), nitrite/nitrate, creatinine and tumor growth factor-β1 (TGF-β1). Liver tissues were assembled for mitochondrial oxidation and phosphorylation, malondialdehyde (MDA) content, and histologic analysis. Pulmonary vascular permeability and myeloperoxidase (MPO) were also determined.
RESULTS: Four hours after reperfusion the diazoxide group presented with significant reduction of AST (2009 ± 257 U/L vs 3523 ± 424 U/L, P = 0.005); ALT (1794 ± 295 U/L vs 3316 ± 413 U/L, P = 0.005); TNF-α (17 ± 9 pg/mL vs 152 ± 43 pg/mL, P = 0.013; IL-6 (62 ± 18 pg/mL vs 281 ± 92 pg/mL); IL-10 (40 ± 9 pg/mL vs 78 ± 10 pg/mL P = 0.03), and nitrite/nitrate (3.8 ± 0.9 μmol/L vs 10.2 ± 2.4 μmol/L, P = 0.025) when compared to the saline group. A significant reduction in liver mitochondrial dysfunction was observed in the diazoxide group compared to the saline group (P < 0.05). No differences in liver MDA content, serum creatinine, pulmonary vascular permeability and MPO activity were observed between groups. Twenty four hours after reperfusion the diazoxide group showed a reduction of AST (495 ± 78 U/L vs 978 ± 192 U/L, P = 0.032); ALT (335 ± 59 U/L vs 742 ± 182 U/L, P = 0.048), and TGF-β1 (11 ± 1 ng/mL vs 17 ± 0.5 ng/mL, P = 0.004) serum levels when compared to the saline group. The control group did not present alterations when compared to the diazoxide and saline groups.
CONCLUSION: Diazoxide maintains liver mitochondrial function, increases liver tolerance to ischemia/reperfusion injury, and reduces the systemic inflammatory response. These effects require further evaluation for using in a clinical setting.
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17
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Balzan SMP, Gava VG, Rieger A, Pra D, Trombini L, Zenkner FF, Horta JA, Azambuja G, Schopf L, Souza PLD. Ischemic versus pharmacologic hepatic preconditioning. J Surg Res 2014; 191:134-9. [DOI: 10.1016/j.jss.2014.03.073] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2013] [Revised: 03/02/2014] [Accepted: 03/25/2014] [Indexed: 01/26/2023]
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Wang X, Yuan B, Dong W, Yang B, Yang Y, Lin X, Gong G. Induction of heat-shock protein 70 expression by geranylgeranylacetone shows cytoprotective effects in cardiomyocytes of mice under humid heat stress. PLoS One 2014; 9:e93536. [PMID: 24695789 PMCID: PMC3973581 DOI: 10.1371/journal.pone.0093536] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2013] [Accepted: 03/04/2014] [Indexed: 11/23/2022] Open
Abstract
Background Increasing evidence has revealed that humid heat stress (HHS) causes considerable damage to human health. The cardiovascular system has been suggested to be the primary target of heat stress, which results in serious cardiovascular diseases. However, there is still a lack of effective approaches for the prevention and treatment of cardiovascular diseases induced by HHS. Objective Heat-shock proteins (Hsps), especially Hsp70, are reported to provide effective cytoprotection under various stress stimuli. In the present study, we evaluated the cytoprotective effect of geranylgeranylacetone (GGA), which was previously been reported to induce Hsp70 expression in cardiomyocytes under HHS. Methods and Principal Findings Using a mouse model of HHS, we showed that the pretreatment of GGA enhanced Hsp70 expression under HHS, as examined by quantitative real-time polymerase chain reaction (qRT-PCR) and Western blot. We then examined the effect of GGA pretreatment on the cardiomyocyte apoptosis induced by HHS using terminal-deoxynucleoitidyl transferase mediated nick end labeling (TUNEL) staining, and found that GGA pretreatment inhibited mitochondria-mediated apoptosis. GGA pretreatment could reverse the effect of HHS on cell apoptosis by increasing expression of Bcl-2, decreasing cytochrome c in cytosol, and increasing cytochrome c in mitochondria. However, GGA pretreatment had no effect on the oxidative stress induced by HHS as determined by levels of superoxide dismutase (SOD), malondialdehyde (MDA), and glutathione (GSH). Conclusion We have demonstrated that GGA pretreatment suppressed HHS-induced apoptosis of cardiomyocytes through the induction of Hsp70 overexpression.
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Affiliation(s)
- Xiaowu Wang
- Center of Cardiovascular Surgery, Guangzhou General Hospital of Guangzhou Military Command, Guangzhou, China
| | - Binbin Yuan
- Center of Cardiovascular Surgery, Guangzhou General Hospital of Guangzhou Military Command, Guangzhou, China
| | - Wenpeng Dong
- Center of Cardiovascular Surgery, Guangzhou General Hospital of Guangzhou Military Command, Guangzhou, China
| | - Bo Yang
- Center of Cardiovascular Surgery, Guangzhou General Hospital of Guangzhou Military Command, Guangzhou, China
| | - Yongchao Yang
- Center of Cardiovascular Surgery, Guangzhou General Hospital of Guangzhou Military Command, Guangzhou, China
| | - Xi Lin
- Center of Cardiovascular Surgery, Guangzhou General Hospital of Guangzhou Military Command, Guangzhou, China
| | - Gu Gong
- Department of Anesthesiology, General Hospital of Chengdu Military Command, Chengdu, China
- * E-mail:
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Targeting toll-like receptors 4 intracellular domain to prevent ischemic liver disease: an innovative approach or just a futuristic dream? Crit Care Med 2014; 42:487-8. [PMID: 24434465 DOI: 10.1097/ccm.0000000000000005] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
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Pantazi E, Zaouali MA, Bejaoui M, Serafin A, Folch-Puy E, Petegnief V, De Vera N, Ben Abdennebi H, Rimola A, Roselló-Catafau J. Silent information regulator 1 protects the liver against ischemia-reperfusion injury: implications in steatotic liver ischemic preconditioning. Transpl Int 2014; 27:493-503. [PMID: 24472096 DOI: 10.1111/tri.12276] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2013] [Revised: 07/27/2013] [Accepted: 01/23/2014] [Indexed: 12/30/2022]
Abstract
Ischemia-reperfusion (IR) injury is an important problem in liver surgery especially when steatosis is present. Ischemic preconditioning (PC) is the only surgical strategy that has been applied in patients with steatotic livers undergoing warm ischemia. Silent information regulator 1 (SIRT1) is a histone deacetylase that regulates various cellular processes. This study evaluates the SIRT1 implication in PC in fatty livers. Homozygous (Ob) Zucker rats were subjected to IR and IR + PC. An additional group treated with sirtinol or EX527 (SIRT1 inhibitors) before PC was also realized. Liver injury and oxidative stress were evaluated. SIRT1 protein levels and activity, as well as other parameters involved in PC protective mechanisms (adenosine monophosphate protein kinase, eNOS, HSP70, MAP kinases, apoptosis), were also measured. We demonstrated that the protective effect of PC was due in part to SIRT1 induction, as SIRT1 inhibition resulted in increased liver injury and abolished the beneficial mechanisms of PC. In this study, we report for the first time that SIRT1 is involved in the protective mechanisms induced by hepatic PC in steatotic livers.
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Affiliation(s)
- Eirini Pantazi
- Experimental Hepatic Ischemia-Reperfusion Unit, Institute of Biomedical Research of Barcelona, IIBB-CSIC, Barcelona, Catalonia, Spain; Networked Biomedical Research Center of Hepatic and Digestive Diseases (CiberEHD), Barcelona, Catalonia, Spain
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21
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Koch S. Preconditioning the human brain: practical considerations for proving cerebral protection. Transl Stroke Res 2013; 1:161-9. [PMID: 24323521 DOI: 10.1007/s12975-010-0025-5] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022]
Abstract
Ischemic preconditioning has evolved as one of the most powerful strategies for cerebral protection in laboratory models of ischemia. Translating the success of laboratory studies to human cerebral protection will necessitate an approximation of laboratory conditions. This would require a practical, easily implemented method of preconditioning and clinical settings in which cerebral ischemia is anticipated, thereby allowing cerebral preconditioning prior to ischemia onset. Remote limb ischemic preconditioning is readily instituted and used in several ongoing cardiac studies for ischemic myocardial protection. It is a potentially promising intervention for brain protection as well. Suitable clinical settings, in which a preliminary study of ischemic preconditioning in neurological disorders appears feasible, include carotid endarterectomy or stenting, cardiac surgery, and subarachnoid hemorrhage with the accompanying risk of vasospasm. These are settings, in which there is substantial risk of brain ischemia, which occurs over a short and predictable period, allowing for preconditioning to be implemented prior to ischemia onset.
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Affiliation(s)
- Sebastian Koch
- Department of Neurology, University of Miami, 1150 NW 14th Street, PAC, Suite#609, Miami, FL, 33136, USA,
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22
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Stiegler P, Sereinigg M, Puntschart A, Bradatsch A, Seifert-Held T, Wiederstein-Grasser I, Leber B, Stadelmeyer E, Dandachi N, Zelzer S, Iberer F, Stadlbauer V. Oxidative stress and apoptosis in a pig model of brain death (BD) and living donation (LD). J Transl Med 2013; 11:244. [PMID: 24088575 PMCID: PMC3850531 DOI: 10.1186/1479-5876-11-244] [Citation(s) in RCA: 31] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2013] [Accepted: 10/01/2013] [Indexed: 12/20/2022] Open
Abstract
Background As organ shortage is increasing, the acceptance of marginal donors increases, which might result in poor organ function and patient survival. Mostly, organ damage is caused during brain death (BD), cold ischemic time (CIT) or after reperfusion due to oxidative stress or the induction of apoptosis. The aim of this study was to study a panel of genes involved in oxidative stress and apoptosis and compare these findings with immunohistochemistry from a BD and living donation (LD) pig model and after cold ischemia time (CIT). Methods BD was induced in pigs; after 12 h organ retrieval was performed; heart, liver and kidney tissue specimens were collected in the BD (n = 6) and in a LD model (n = 6). PCR analysis for NFKB1, GSS, SOD2, PPAR-alpha, OXSR1, BAX, BCL2L1, and HSP 70.2 was performed and immunohistochemistry used to show apoptosis and nitrosative stress induced cell damage. Results In heart tissue of BD BAX, BCL2L1 and HSP 70.2 increased significantly after CIT. Only SOD2 was over-expressed after CIT in BD liver tissue. In kidney tissue, BCL2L1, NFKB, OXSR1, SOD2 and HSP 70.2 expression was significantly elevated in LD. Immunohistochemistry showed a significant increase in activated Caspase 3 and nitrotyrosine positive cells after CIT in BD in liver and in kidney tissue but not in heart tissue. Conclusion The up-regulation of protective and apoptotic genes seems to be divergent in the different organs in the BD and LD setting; however, immunohistochemistry revealed more apoptotic and nitrotyrosine positive cells in the BD setting in liver and kidney tissue whereas in heart tissue both BD and LD showed an increase.
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Affiliation(s)
- Philipp Stiegler
- Division of Surgery, Department of Transplantation Surgery, Medical University, Auenbruggerplatz 29, Graz 8036, Austria.
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Krenz M, Baines C, Kalogeris T, Korthuis R. Cell Survival Programs and Ischemia/Reperfusion: Hormesis, Preconditioning, and Cardioprotection. ACTA ACUST UNITED AC 2013. [DOI: 10.4199/c00090ed1v01y201309isp044] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
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Onody P, Stangl R, Fulop A, Rosero O, Garbaisz D, Turoczi Z, Lotz G, Rakonczay Z, Balla Z, Hegedus V, Harsanyi L, Szijarto A. Levosimendan: a cardiovascular drug to prevent liver ischemia-reperfusion injury? PLoS One 2013; 8:e73758. [PMID: 24040056 PMCID: PMC3770697 DOI: 10.1371/journal.pone.0073758] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2013] [Accepted: 07/22/2013] [Indexed: 01/19/2023] Open
Abstract
Introduction Temporary occlusion of the hepatoduodenal ligament leads to an ischemic-reperfusion (IR) injury in the liver. Levosimendan is a new positive inotropic drug, which induces preconditioning-like adaptive mechanisms due to opening of mitochondrial KATP channels. The aim of this study was to examine possible protective effects of levosimendan in a rat model of hepatic IR injury. Material and Methods Levosimendan was administered to male Wistar rats 1 hour (early pretreatment) or 24 hours (late pretreatment) before induction of 60-minute segmental liver ischemia. Microcirculation of the liver was monitored by laser Doppler flowmeter. After 24 hours of reperfusion, liver and blood samples were taken for histology, immuno- and enzyme-histochemistry (TUNEL; PARP; NADH-TR) as well as for laboratory tests. Furthermore, liver antioxidant status was assessed and HSP72 expression was measured. Results In both groups pretreated with levosimendan, significantly better hepatic microcirculation was observed compared to respective IR control groups. Similarly, histological damage was also reduced after levosimendan administration. This observation was supported by significantly lower activities of serum ALT (pearly = 0.02; plate = 0.005), AST (pearly = 0.02; plate = 0.004) and less DNA damage by TUNEL test (pearly = 0.05; plate = 0.034) and PAR positivity (pearly = 0.02; plate = 0.04). Levosimendan pretreatment resulted in significant improvement of liver redox homeostasis. Further, significantly better mitochondrial function was detected in animals receiving late pretreatment. Finally, HSP72 expression was increased by IR injury, but it was not affected by levosimendan pretreatment. Conclusion Levosimendan pretreatment can be hepatoprotective and it could be useful before extensive liver resection.
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Affiliation(s)
- Peter Onody
- 1 Department of Surgery, Semmelweis University, Budapest, Hungary
- * E-mail:
| | - Rita Stangl
- 1 Department of Surgery, Semmelweis University, Budapest, Hungary
| | - Andras Fulop
- 1 Department of Surgery, Semmelweis University, Budapest, Hungary
| | - Oliver Rosero
- 1 Department of Surgery, Semmelweis University, Budapest, Hungary
| | - David Garbaisz
- 1 Department of Surgery, Semmelweis University, Budapest, Hungary
| | - Zsolt Turoczi
- 1 Department of Surgery, Semmelweis University, Budapest, Hungary
| | - Gabor Lotz
- 2 Department of Pathology, Semmelweis University, Budapest, Hungary
| | - Zoltan Rakonczay
- First Department of Medicine, University of Szeged, Szeged, Hungary
| | - Zsolt Balla
- First Department of Medicine, University of Szeged, Szeged, Hungary
| | - Viktor Hegedus
- 1 Department of Surgery, Semmelweis University, Budapest, Hungary
| | - Laszlo Harsanyi
- 1 Department of Surgery, Semmelweis University, Budapest, Hungary
| | - Attila Szijarto
- 1 Department of Surgery, Semmelweis University, Budapest, Hungary
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Gultekin FA, Cakmak GK, Turkcu UO, Yurdakan G, Demir FEO, Comert M. Effects of Ozone Oxidative Preconditioning on Liver Regeneration after Partial Hepatectomy in Rats. J INVEST SURG 2013; 26:242-52. [DOI: 10.3109/08941939.2012.750698] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Affiliation(s)
- Fatma Ayca Gultekin
- Department of General Surgery, School of Medicine, Bulent Ecevit University, Kozlu, Zonguldak, Turkey
| | - Guldeniz Karadeniz Cakmak
- Department of General Surgery, School of Medicine, Bulent Ecevit University, Kozlu, Zonguldak, Turkey
| | | | - Gamze Yurdakan
- Department of Pathology, School of Medicine, Bulent Ecevit University, Kozlu, Zonguldak, Turkey
| | - F. Ebru Ofluoglu Demir
- Ahmet Erdogan Vocational School of Health Services, Bulent Ecevit University, Kozlu, Zonguldak, Turkey
| | - Mustafa Comert
- Department of General Surgery, School of Medicine, Bulent Ecevit University, Kozlu, Zonguldak, Turkey
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Czigány Z, Turóczi Z, Bulhardt O, Hegedüs V, Lotz G, Rakonczay Z, Balla Z, Harsányi L, Szijártó A. [Remote ischemic conditioning: short-term effects on rat liver ischemic-reperfusion injury]. Orv Hetil 2012; 153:1579-87. [PMID: 23022881 DOI: 10.1556/oh.2012.29469] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/19/2022]
Abstract
INTRODUCTION Several techniques have been developed to reduce ischemic-reperfusion injury. A novel method is the remote ischemic perconditioning, applied parallel with target organ ischemia. AIM The aim of the study was to determine the extent of liver ischemic-reperfusion injury via the application of this novel method. METHODS Male Wistar rats (n = 30, 10/group) were subjected to 60-minute partial liver ischemia and 60-minute reperfusion. Rats in the perconditioned group received conditioning treatment during the last 40 minutes of liver ischemia by infrarenal aortic clamping. Hepatic and lower limb microcirculation was monitored by laser Doppler flowmeter during reperfusion. After reperfusion, liver samples were taken for routine histological examination and redox-state assessment. Serum transaminase activities and liver tissue heat-shock protein-72 expression were measured. RESULTS Parameters of microcirculation showed significant (p<0.05) improvement in the perconditioned group in comparison with the control. Besides the significant improvement observed in the serum alanine amino-transferase activities, significantly milder tissue injury was detected histologically in the liver sections of the perconditioned group. Moreover, significant improvement was found in the redox-state parameters. CONCLUSION Perconditioning may be a reasonable possibility to reduce liver ischemic-reperfusion injury.
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Affiliation(s)
- Zoltán Czigány
- Semmelweis Egyetem, Általános Orvostudományi Kar I. Sebészeti Klinika Budapest
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Liu XR, Luo M, Yan F, Zhang CC, Li SJ, Zhao HP, Ji XM, Luo YM. Ischemic postconditioning diminishes matrix metalloproteinase 9 expression and attenuates loss of the extracellular matrix proteins in rats following middle cerebral artery occlusion and reperfusion. CNS Neurosci Ther 2012; 18:855-63. [PMID: 22925005 DOI: 10.1111/j.1755-5949.2012.00366.x] [Citation(s) in RCA: 30] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2012] [Revised: 06/27/2012] [Accepted: 07/01/2012] [Indexed: 11/27/2022] Open
Abstract
AIMS Ischemic postconditioning (IPostC) has been proved to have neuroprotective effects for cerebral ischemia, but the underlying mechanism remains elusive. This study aimed at validating the neuroprotective effects of IPostC and investigating whether the neuroprotection of IPostC is associated with matrix metalloproteinase 9 (MMP9) and the extracellular matrix proteins, laminin and fibronectin, following cerebral ischemia/reperfusion in rats. METHODS The rats in middle cerebral artery occlusion (MCAO) group underwent MCAO and reperfusion, and the animals in MCAO + IPostC group were treated by occluding bilateral common carotid arteries for 10 seconds and then reperfusing for 10 seconds for five episodes at the beginning of MCAO. Apoptosis was detected with terminal deoxynucleotidyl transferase dUTP nick end labeling staining. The expression of MMP9, laminin, and fibronectin was measured with immunofluorescence and enzyme-linked immunosorbent assay. RESULTS IPostC reduced brain edema and infarct volume and improved the neurological function. Furthermore, IPostC decreased cell apoptosis compared with the MCAO group. Compared to the MCAO group, IPostC treatment reduced MMP9 expression. Moreover, the results showed that the expression of laminin and fibronectin significantly increased in the MCAO + IPostC group compared to the MCAO group. CONCLUSION These findings indicated that diminishment of MMP9 expression and the attenuation of degradation of laminin and fibronectin may be involved in the protective mechanisms of postconditioning against cerebral ischemia/reperfusion injury.
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Affiliation(s)
- Xiang-Rong Liu
- Cerebrovascular Diseases Research Institute, Xuanwu Hospital of Capital Medical University, Key Laboratory of Neurodegenerative Diseases (Capital Medical University), Ministry of Education, Beijing, China
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Enhancement of liver regeneration by adenosine triphosphate-sensitive K⁺ channel opener (diazoxide) after partial hepatectomy. Transplantation 2012; 93:1094-100. [PMID: 22466787 DOI: 10.1097/tp.0b013e31824ef1d1] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022]
Abstract
BACKGROUND Enhancement of liver regeneration is a matter of importance after partial liver transplantation including small-for-size grafting. Mitochondrial adenosine triphosphate (ATP)-sensitive K⁺ (mitoKATP) channel plays an important role in mitochondrial bioenergetics, which is a prerequisite for liver regeneration. However, the ATP-sensitive K⁺ (KATP) channel in hepatocytes is incompletely understood. We investigated the KATP channel in hepatocytes and examined the effects of diazoxide, a potent KATP channel opener, on liver regeneration using a rat model. METHODS Using rat primary hepatocytes, expression and localization of KATP channel subunits, Kir6.x and sulfonylurea receptor (SUR)x, were studied by polymerase chain reaction, Western blotting, and immunostaining. To investigate the role of KATP channel openers in liver regeneration, we allocated rats into four groups: control (vehicle) (n=24), diazoxide (n=24), vehicle plus channel blocker (n=6), and diazoxide plus channel blocker (n=6) groups. After 70% partial hepatectomy, hepatic tissue ATP levels, liver-to-body weight ratio, and proliferation rate of hepatocytes were examined. RESULTS KATP channel subunits, Kir6.1 and SUR1, were detected on hepatic mitochondria. During liver regeneration, liver-to-body weight ratio, proliferation rate of hepatocytes, and the hepatic ATP level were significantly higher in the diazoxide group than the control group at 2 days after partial hepatectomy. These effects of diazoxide were neutralized by a KATP channel blocker. CONCLUSIONS We demonstrated the existence of a mitoKATP channel in hepatocytes composed of Kir6.1 and SUR1. Diazoxide could enhance liver regeneration by keeping a higher ATP content of the liver tissue. These results suggest that diazoxide will sustain the mitochondrial energetics through the mitoKATP channel opening.
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Jaeschke H, Woolbright BL. Current strategies to minimize hepatic ischemia-reperfusion injury by targeting reactive oxygen species. Transplant Rev (Orlando) 2012; 26:103-14. [PMID: 22459037 DOI: 10.1016/j.trre.2011.10.006] [Citation(s) in RCA: 222] [Impact Index Per Article: 17.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2011] [Accepted: 10/17/2011] [Indexed: 12/15/2022]
Abstract
Ischemia-reperfusion is a major component of injury in vascular occlusion both during liver surgery and during liver transplantation. The pathophysiology of hepatic ischemia-reperfusion includes a number of mechanisms including oxidant stress that contribute to various degrees to the overall organ damage. A large volume of recent research has focused on the use of antioxidants to ameliorate this injury, although results in experimental models have not translated well to the clinic. This review focuses on critical sources and mediators of oxidative stress during hepatic ischemia-reperfusion, the status of current antioxidant interventions, and emerging mechanisms of protection by preconditioning. While recent advances in regulation of antioxidant systems by Nrf2 provide interesting new potential therapeutic targets, an increased focus must be placed on more in-depth mechanistic investigations in hepatic ischemia-reperfusion injury and translational research in order to refine current strategies in disease management.
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Affiliation(s)
- Hartmut Jaeschke
- Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City, KS 66160, USA.
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Szijártó A, Czigány Z, Turóczi Z, Harsányi L. Remote ischemic perconditioning--a simple, low-risk method to decrease ischemic reperfusion injury: models, protocols and mechanistic background. A review. J Surg Res 2012; 178:797-806. [PMID: 22868050 DOI: 10.1016/j.jss.2012.06.067] [Citation(s) in RCA: 52] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2011] [Revised: 06/18/2012] [Accepted: 06/26/2012] [Indexed: 12/18/2022]
Abstract
Interruption of blood flow can cause ischemic reperfusion injury, which sometimes has a fatal outcome. Recognition of the phenomenon known as reperfusion injury has led to initial interventional approaches to lessen the degree of damage. A number of efficient pharmacologic agents and surgical techniques (e.g., local ischemic preconditioning and postconditioning) are available. A novel, alternative approach to target organ protection is remote ischemic conditioning triggered by brief repetitive ischemia and reperfusion periods in distant organs. Among the different surgical techniques is so-called remote ischemic perconditioning, a method that applies short periods of ischemic reperfusion to a distant organ delivered during target organ ischemia. Although ischemic reperfusion injury is reduced by this technique, the explanation for this phenomenon is still unclear, and approximately only a dozen reports on the topic have appeared in the literature. In our study, therefore, we investigated the connective mechanisms, signal transduction, and effector mechanisms behind remote perconditioning, with a review on molecular background and favorable effects. In addition, we summarize the various treatment protocols and models to promote future experimental and clinical research.
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Affiliation(s)
- Attila Szijártó
- First Department of Surgery, Semmelweis University, Budapest, Hungary.
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31
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Abstract
The process of lipid peroxidation is widespread in biology and is mediated through both enzymatic and non-enzymatic pathways. A significant proportion of the oxidized lipid products are electrophilic in nature, the RLS (reactive lipid species), and react with cellular nucleophiles such as the amino acids cysteine, lysine and histidine. Cell signalling by electrophiles appears to be limited to the modification of cysteine residues in proteins, whereas non-specific toxic effects involve modification of other nucleophiles. RLS have been found to participate in several physiological pathways including resolution of inflammation, cell death and induction of cellular antioxidants through the modification of specific signalling proteins. The covalent modification of proteins endows some unique features to this signalling mechanism which we have termed the ‘covalent advantage’. For example, covalent modification of signalling proteins allows for the accumulation of a signal over time. The activation of cell signalling pathways by electrophiles is hierarchical and depends on a complex interaction of factors such as the intrinsic chemical reactivity of the electrophile, the intracellular domain to which it is exposed and steric factors. This introduces the concept of electrophilic signalling domains in which the production of the lipid electrophile is in close proximity to the thiol-containing signalling protein. In addition, we propose that the role of glutathione and associated enzymes is to insulate the signalling domain from uncontrolled electrophilic stress. The persistence of the signal is in turn regulated by the proteasomal pathway which may itself be subject to redox regulation by RLS. Cell death mediated by RLS is associated with bioenergetic dysfunction, and the damaged proteins are probably removed by the lysosome-autophagy pathway.
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Waterson RE, Thompson CG, Mabe NW, Kaur K, Talbot JN, Neubig RR, Rorabaugh BR. Gα(i2)-mediated protection from ischaemic injury is modulated by endogenous RGS proteins in the mouse heart. Cardiovasc Res 2011; 91:45-52. [PMID: 21349876 PMCID: PMC3112020 DOI: 10.1093/cvr/cvr054] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/30/2010] [Revised: 01/31/2011] [Accepted: 02/18/2011] [Indexed: 01/01/2023] Open
Abstract
AIMS Regulator of G protein signalling (RGS) proteins act as molecular 'off switches' that terminate G protein signalling by catalyzing the hydrolysis of Gα-bound GTP to GDP. Many different Gα(i)-coupled receptors have been implicated in the cardioprotective effects of ischaemic preconditioning. However, the role of RGS proteins in modulating cardioprotection has not been previously investigated. We used mice that were homozygous (GS/GS) or heterozygous (GS/+) for a mutation in Gα(i2) rendering it RGS-insensitive (G184S) to determine whether interactions between endogenous RGS proteins and Gα(i2) modulate Gα(i)-mediated protection from ischaemic injury. METHODS AND RESULTS Langendorff-perfused mouse hearts were subjected to 30 min global ischaemia and 2 h reperfusion. Infarcts in GS/GS (14.5% of area at risk) and GS/+ (22.6% of AAR) hearts were significantly smaller than those of +/+ hearts (37.2% of AAR) and recovery of contractile function was significantly enhanced in GS/GS and GS/+ hearts compared with +/+ hearts. The cardioprotective phenotype was not reversed by wortmannin or U0126 but was reversed by 5-hydroxydecanoic acid and HMR 1098, indicating that RGS-insensitive Gα(i2) protects the heart through a mechanism that requires functional ATP-dependent potassium channels but does not require acute activation of extracellular-regulated kinase or Akt signalling pathways. CONCLUSIONS This is the first study to demonstrate that Gα(i2)-mediated cardioprotection is suppressed by RGS proteins. These data suggest that RGS proteins may provide novel therapeutic targets to protect the heart from ischaemic injury.
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Affiliation(s)
- Rachael E. Waterson
- Department of Pharmaceutical and Biomedical Sciences, Raabe College of Pharmacy, Ohio Northern University, 525 South Main Street, Ada, OH 45810, USA
| | - Corbin G. Thompson
- Department of Pharmaceutical and Biomedical Sciences, Raabe College of Pharmacy, Ohio Northern University, 525 South Main Street, Ada, OH 45810, USA
| | - Nathaniel W. Mabe
- Department of Pharmaceutical and Biomedical Sciences, Raabe College of Pharmacy, Ohio Northern University, 525 South Main Street, Ada, OH 45810, USA
| | - Kuljeet Kaur
- Department of Pharmacology, University of Michigan, Ann Arbor, MI 48109, USA
| | - Jeffery N. Talbot
- Department of Pharmaceutical and Biomedical Sciences, Raabe College of Pharmacy, Ohio Northern University, 525 South Main Street, Ada, OH 45810, USA
| | - Richard R. Neubig
- Department of Pharmacology, University of Michigan, Ann Arbor, MI 48109, USA
- Department of Internal Medicine, Division of Cardiovascular Medicine, University of Michigan, Ann Arbor, MI 48109, USA
| | - Boyd R. Rorabaugh
- Department of Pharmaceutical and Biomedical Sciences, Raabe College of Pharmacy, Ohio Northern University, 525 South Main Street, Ada, OH 45810, USA
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Abdennebi HB, Zaoualí MA, Alfany-Fernandez I, Tabka D, Roselló-Catafau J. How to protect liver graft with nitric oxide. World J Gastroenterol 2011; 17:2879-89. [PMID: 21734799 PMCID: PMC3129502 DOI: 10.3748/wjg.v17.i24.2879] [Citation(s) in RCA: 31] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/17/2010] [Revised: 01/18/2011] [Accepted: 01/25/2011] [Indexed: 02/06/2023] Open
Abstract
Organ preservation and ischemia reperfusion injury associated with liver transplantation play an important role in the induction of graft injury. One of the earliest events associated with the reperfusion injury is endothelial cell dysfunction. It is generally accepted that endothelial nitric oxide synthase (e-NOS) is cell-protective by mediating vasodilatation, whereas inducible nitric oxide synthase mediates liver graft injury after transplantation. We conducted a critical review of the literature evaluating the potential applications of regulating and promoting e-NOS activity in liver preservation and transplantation, showing the most current evidence to support the concept that enhanced bioavailability of NO derived from e-NOS is detrimental to ameliorate graft liver preservation, as well as preventing subsequent graft reperfusion injury. This review deals mainly with the beneficial effects of promoting “endogenous” pathways for NO generation, via e-NOS inducer drugs in cold preservation solution, surgical strategies such as ischemic preconditioning, and alternative “exogenous” pathways that focus on the enrichment of cold storage liquid with NO donors. Finally, we also provide a basic bench-to-bed side summary of the liver physiology and cell signalling mechanisms that account for explaining the e-NOS protective effects in liver preservation and transplantation.
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Koch S, Katsnelson M, Dong C, Perez-Pinzon M. Remote ischemic limb preconditioning after subarachnoid hemorrhage: a phase Ib study of safety and feasibility. Stroke 2011; 42:1387-91. [PMID: 21415404 DOI: 10.1161/strokeaha.110.605840] [Citation(s) in RCA: 117] [Impact Index Per Article: 8.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022]
Abstract
BACKGROUND AND PURPOSE Making a limb transiently ischemic has been shown to induce ischemic tolerance in a distant organ. This phenomenon is known as remote ischemic limb preconditioning. We conducted a Phase IB study of remote ischemic limb preconditioning to determine the safety and feasibility of increasing durations of limb ischemia in patients with subarachnoid hemorrhage. METHODS Patients with aneurysmal subarachnoid hemorrhage underwent limb preconditioning every 24 to 48 hours for 14 days. Limb preconditioning consisted of 3 5-minute inflations of a blood pressure cuff to 200 mm Hg around a limb followed by 5 minutes of reperfusion. In the lead-in phase, we preconditioned the upper extremities, but this proved impractical and we began preconditioning the leg in a similar manner. Ischemia times were then escalated to 7.5 and 10 minutes. After each session, a visual analog scale was obtained and the extremity examined for neurovascular complications. RESULTS A total of 33 patients completed the study. Mean age was 53±12 years and mean Hunt Hess score was 2.4±0.9. In the lead-in phase, an average of 7.7±2.4 preconditioning sessions was completed with mean visual analog scale 3.6±3.4. In the dose escalation phase, an average of 8.6±2.1 preconditioning sessions was done with mean visual analog scale 1.8±2.2 and 2.5±2.9 for the 7.5- and 10-minute cohorts, respectively. No session was prematurely terminated due to subject discomfort. No objective signs of neurovascular injury were observed. CONCLUSIONS We found limb preconditioning to be safe and well tolerated, even at ischemia times of 10 minutes, in critically ill patients with subarachnoid hemorrhage.
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Affiliation(s)
- Sebastian Koch
- Department of Neurology, University of Miami, Miller School of Medicine, 1150 NW 14th Street, Suite 609, Professional Arts Center, Miami, FL 33136, USA.
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Fudaba Y, Tashiro H, Ohdan H, Miyata Y, Shibata S, Shintaku S, Nishihara M, Asahara T, Ito H, Fukuda Y, Dohi K. Efficacy of HSP72 induction in rat liver by orally administered geranylgeranylacetone. Transpl Int 2011. [DOI: 10.1111/j.1432-2277.2000.tb02037.x] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
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Bhuiyan MIH, Kim YJ. Mechanisms and prospects of ischemic tolerance induced by cerebral preconditioning. Int Neurourol J 2010; 14:203-12. [PMID: 21253330 PMCID: PMC3021810 DOI: 10.5213/inj.2010.14.4.203] [Citation(s) in RCA: 26] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2010] [Accepted: 12/14/2010] [Indexed: 12/20/2022] Open
Abstract
In the brain, brief episodes of ischemia induce tolerance against a subsequent severe episode of ischemia. This phenomenon of endogenous neuroprotection is known as preconditioning-induced ischemic tolerance. The purpose of this review is to summarize the current state of knowledge about mechanisms and potential applications of cerebral preconditioning and ischemic tolerance. Articles related to the terms ischemic preconditioning and ischemic tolerance were systematically searched via MEDLINE/PubMed, and articles published in English related to the nervous system were selected and analyzed. The past two decades have provided interesting insights into the molecular mechanisms of this neuroprotective phenomenon. Although both rapid and delayed types of tolerance have been documented in experimental settings, the delayed type has been found to be more prominent in the case of neuronal ischemic tolerance. Many intracellular signaling pathways have been implicated regarding ischemic preconditioning. Most of these are associated with membrane receptors, kinase cascades, and transcription factors. Moreover, ischemic tolerance can be induced by exposing animals or cells to diverse types of endogenous and exogenous stimuli that are not necessarily hypoxic or ischemic in nature. These cross-tolerances raise the hope that, in the future, it will be possible to pharmacologically activate or mimic ischemic tolerance in the human brain. Another promising approach is remote preconditioning in which preconditioning of one organ or system leads to the protection of a different (remote) organ that is difficult to target, such as the brain. The preconditioning strategy and related interventions can confer neuroprotection in experimental ischemia, and, thus, have promise for practical applications in cases of vascular neurosurgery and endo-vascular therapy.
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Affiliation(s)
| | - Youn Jung Kim
- Kyung Hee University College of Nursing Science, Seoul, Korea
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Civelek B, Selcuk T, Bilgen E, Demirbag E, Celebioglu S. Intermittent ischaemia of skin flaps shortens time taken to divide pedicles: an experimental study in rats. ACTA ACUST UNITED AC 2010; 43:241-4. [PMID: 19863425 DOI: 10.3109/02844310903138906] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022]
Abstract
Ischaemic preconditioning increases the survival of flaps. Random-pattern McFarlane dorsal flaps were raised in 30 female Wistar rats, which were divided into three groups. An ischaemic conditioning protocol with clamping of the pedicle was used. No clamping was used in the control group, and the pedicle was clamped for 15 minutes in the second group and 20 minutes in the third group daily to see if the duration of ischaemia had any effects on the viability of the flaps. The pedicles were divided earlier in the clamped groups than in the control group. The size of necrotic areas of the flaps in the clamped groups was smaller than on the control group. Daily postoperative intermittent ischaemic conditioning in the pedicles of the flaps had a protective effect on their survival and led to earlier division of the pedicles.
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Affiliation(s)
- Birol Civelek
- Department of Plastic and Reconstructive Surgery, Diskapi Y. Beyazit Training and Research Hospital, Ankara, Turkey.
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Lappalainen Z, Lappalainen J, Oksala NKJ, Laaksonen DE, Khanna S, Sen CK, Atalay M. Exercise training and experimental diabetes modulate heat shock protein response in brain. Scand J Med Sci Sports 2010; 20:83-9. [PMID: 19017295 DOI: 10.1111/j.1600-0838.2008.00872.x] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/24/2022]
Abstract
In diabetes, defense systems against cellular stress are impaired. Heat shock proteins (HSPs) function primarily as molecular chaperones. Factors that raise tissue HSP levels may slow progression of diabetes and improve diabetic complications that also affect brain tissue. This study tested the effect of an 8-week exercise training on brain HSP response in rats with or without streptozotocin-induced diabetes (SID). In untrained animals, the HSP levels were not different between SID and non-diabetic groups. Endurance training, however, increased HSP72 and HSP90 protein in non-diabetic rats, whereas SID significantly decreased the effect of training on these HSPs. At the mRNA level, HSP60, HSP90 and GRP75 were increased due to training, whereas HSP72 mRNA was only increased in exercise-trained diabetic animals. Training or diabetes had no effect on protein carbonyl content, a marker of oxidative damage. Altogether, our findings suggest that endurance training increases HSP expression in the brain, and that experimental diabetes is associated with an incomplete HSP response at the protein level.
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Affiliation(s)
- Z Lappalainen
- Institute of Biomedicine, Physiology, University of Kuopio, and Institute of Clinical Medicine, Surgery, Kuopio University Hospital, Kuopio, Finland
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Andreani P, Hoti E, de la Serna S, degli Esposti D, Sebagh M, Lemoine A, Ichai P, Saliba F, Castaing D, Azoulay D. Ischaemic preconditioning of the graft in adult living related right lobe liver transplantation: impact on ischaemia-reperfusion injury and clinical relevance. HPB (Oxford) 2010; 12:439-46. [PMID: 20815852 PMCID: PMC3030752 DOI: 10.1111/j.1477-2574.2010.00194.x] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
BACKGROUND Ischaemic preconditioning (IPC) of the right liver graft in the donor has not been studied in adult-to-adult living related liver transplantation (LRLT). OBJECTIVE To assess the IPC effect of the graft on ischaemia reperfusion injury in the recipient and compare recipient and donor outcomes with and without preconditioned grafts. PATIENTS AND METHODS Alternate patients were transplanted with right lobe grafts that were (n = 22; Group (Precond)) or were not (n = 22; Group (Control)) subjected to IPC in the living donor. Liver ischaemia-reperfusion injury, liver/kidney function, morbidity/mortality rates and outcomes were compared. Univariate and multivariate analyses were performed to identify factors predictive of the aspartate aminotransferase (AST) peak and minimum prothrombin time. RESULTS Both groups had similar length of hospital stay, morbidity/mortality, primary non-function and acute rejection rates. Post-operative AST (P = 0.8) and alanine aminotransferase (ALT) peaks (P = 0.6) were similar in both groups (307 +/- 189 and 437 +/- 302 vs. 290 +/- 146 and 496 +/- 343, respectively). In univariate analysis, only pre-operative AST and warm ischemia time (WIT) were significantly associated with post-operative AST peak (in recipients). In multivariate analysis, the graft/recipient weight ratio (P = 0.003) and pre-operative bilirubin concentration (P = 0.004) were significantly predictive of minimum prothrombin time post-transplantation. CONCLUSIONS Graft IPC in the living related donor is not associated with any benefit for the recipient or the donor and its clinical value remains uncertain.
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Affiliation(s)
- Paola Andreani
- Centre Hépato-Biliaire, Département de Chirurgie Hépato-BiliaireIFR 89.9
| | - Emir Hoti
- Centre Hépato-Biliaire, Département de Chirurgie Hépato-BiliaireIFR 89.9
| | - Sofia de la Serna
- Centre Hépato-Biliaire, Département de Chirurgie Hépato-BiliaireIFR 89.9
| | | | - Mylène Sebagh
- Département d'Anatomopathologie, Hôpital Paul BrousseVillejuif, France
| | | | - Philippe Ichai
- Centre Hépato-Biliaire, Département de Chirurgie Hépato-BiliaireIFR 89.9
| | - Fauzi Saliba
- Centre Hépato-Biliaire, Département de Chirurgie Hépato-BiliaireIFR 89.9
| | - Denis Castaing
- Centre Hépato-Biliaire, Département de Chirurgie Hépato-BiliaireIFR 89.9
| | - Daniel Azoulay
- Centre Hépato-Biliaire, Département de Chirurgie Hépato-BiliaireIFR 89.9
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Abstract
The reader may be eager to examine in which diseases ozonetherapy can be proficiently used and she/he will be amazed by the versatility of this complementary approach (Table 9 1). The fact that the medical applications are numerous exposes the ozonetherapist to medical derision because superficial observers or sarcastic sceptics consider ozonetherapy as the modern panacea. This seems so because ozone, like oxygen, is a molecule able to act simultaneously on several blood components with different functions but, as we shall discuss, ozonetherapy is not a panacea. The ozone messengers ROS and LOPs can act either locally or systemically in practically all cells of an organism. In contrast to the dogma that “ozone is always toxic”, three decades of clinical experience, although mostly acquired in private clinics in millions of patients, have shown that ozone can act as a disinfectant, an oxygen donor, an immunomodulator, a paradoxical inducer of antioxidant enzymes, a metabolic enhancer, an inducer of endothelial nitric oxide synthase and possibly an activator of stem cells with consequent neovascularization and tissue reconstruction.
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Affiliation(s)
- Velio Bocci
- Department of Physiology, University of Siena, via A. Moro 2, 53100 Siena, Italy
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Is Ozone Really a “Wonder Drug”? OZONE 2010. [PMCID: PMC7498889 DOI: 10.1007/978-90-481-9234-2_8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 10/31/2022]
Abstract
Even if the reader has only browsed through the previous chapters, he ought to have received my feeling that ozone has an enormous therapeutic potential that, so far, has been either disregarded, if not obstructed by world medical authorities. Reasons for delaying the use of ozone are multiple: while quacks and inexpert ozonetherapists are at fault for poor work, other aspects such as commercial and pharmaceutical interests, prejudice, lack of knowledge and a myopic medical vision have done their best to block a substantial and rapid progress.
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Yeh CH, Hsu SP, Yang CC, Chien CT, Wang NP. Hypoxic preconditioning reinforces HIF-alpha-dependent HSP70 signaling to reduce ischemic renal failure-induced renal tubular apoptosis and autophagy. Life Sci 2009; 86:115-23. [PMID: 19962996 DOI: 10.1016/j.lfs.2009.11.022] [Citation(s) in RCA: 78] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2009] [Revised: 11/24/2009] [Accepted: 11/18/2009] [Indexed: 12/15/2022]
Abstract
AIMS Repetitive hypoxic preconditioning (RHP) may provide more efficient protection than single hypoxic preconditioning against renal ischemia/reperfusion-induced injury via hypoxia-induced factor 1alpha (HIF-1alpha)-dependent heat shock protein 70 (HSP70) pathways. MAIN METHODS Wistar rats were subjected to intermittent hypoxic exposure (15h/day), whereas controls were kept at sea level. We evaluated renal expression of HIF-1alpha, HSP70, the endoplasmic reticulum stress protein GRP78, caspase 12, Beclin-1, and poly-(ADP-ribose)-polymerase (PARP) with western blotting. Renal apoptosis determined by terminal transferase dUTP nick end labeling (TUNEL), Beclin-1-dependent autophagy, and monocyte/macrophage (ED-1) infiltration were evaluated by immunocytochemistry. Renal function was determined with blood urea nitrogen (BUN) and plasma creatinine levels. HIF-1alpha inhibitors and Deoxyribonucleotide (DNA) or Ribonucleotide (RNA) interference of HSP70 were used to evaluate their possible roles in this process. KEY FINDINGS Renal HIF-1alpha and HSP70 expression were enhanced by hypoxic preconditioning and inhibited by the HIF-1alpha inhibitor, YC-1, as well as phosphatidylinositol 3-kinase (PI3K)/Akt inhibitors. After the return to normoxia, renal HSP70 protein levels were maintained for one week in the RHP group, but they decayed after one day in the single hypoxic preconditioning group. Ischemia/reperfusion significantly increased renal TUNEL-apoptosis, Beclin-1-dependent autophagy, ED-1 infiltration, expression of GRP78, caspase 12, Beclin-1, PARP, and BUN and plasma creatinine levels in control rats. RHP significantly decreased all ischemia/reperfusion-enhanced parameters. Intraperitoneal pretreatment with YC-1 and quercetin (an inhibitor of HSP70 induction) eliminated RHP-induced protection. Anti-sense oligodeoxyribonucleotides or interference RNA targeting HSP70 abrogated the protection against hypoxia/reoxygenation-induced oxidative injury in RHP-treated proximal tubules. SIGNIFICANCE We demonstrate that RHP promotes HIF-1alpha-dependent HSP70 signaling to reduce renal ischemia/reperfusion injury.
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Affiliation(s)
- Chung-Hsin Yeh
- Division of Urology, Shin Kong Wu Ho-Su Memorial Hospital, Taipei, Taiwan
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Bocci V, Borrelli E, Travagli V, Zanardi I. The ozone paradox: ozone is a strong oxidant as well as a medical drug. Med Res Rev 2009; 29:646-82. [PMID: 19260079 DOI: 10.1002/med.20150] [Citation(s) in RCA: 202] [Impact Index Per Article: 12.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
After five decades characterized by empiricism and several pitfalls, some of the basic mechanisms of action of ozone in pulmonary toxicology and in medicine have been clarified. The present knowledge allows to understand the prolonged inhalation of ozone can be very deleterious first for the lungs and successively for the whole organism. On the other hand, a small ozone dose well calibrated against the potent antioxidant capacity of blood can trigger several useful biochemical mechanisms and reactivate the antioxidant system. In detail, firstly ex vivo and second during the infusion of ozonated blood into the donor, the ozone therapy approach involves blood cells and the endothelium, which by transferring the ozone messengers to billions of cells will generate a therapeutic effect. Thus, in spite of a common prejudice, single ozone doses can be therapeutically used in selected human diseases without any toxicity or side effects. Moreover, the versatility and amplitude of beneficial effect of ozone applications have become evident in orthopedics, cutaneous, and mucosal infections as well as in dentistry.
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Affiliation(s)
- Velio Bocci
- Department of Physiology, University of Siena, Siena, Italy.
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Goebel U, Mecklenburg A, Siepe M, Roesslein M, Schwer CI, Pahl HL, Priebe HJ, Schlensak C, Loop T. Protective effects of inhaled carbon monoxide in pig lungs during cardiopulmonary bypass are mediated via an induction of the heat shock response. Br J Anaesth 2009; 103:173-84. [PMID: 19403594 DOI: 10.1093/bja/aep087] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/14/2023] Open
Abstract
BACKGROUND Cardiopulmonary bypass (CPB) may cause acute lung injury leading to increased morbidity and mortality after cardiac surgery. Preconditioning by inhaled carbon monoxide reduces pulmonary inflammation during CPB. We hypothesized that inhaled carbon monoxide mediates its anti-inflammatory and cytoprotective effects during CPB via induction of pulmonary heat shock proteins (Hsps). METHODS Pigs were randomized either to a control group, to standard CPB, to carbon monoxide+CPB, or to quercetin (a flavonoid and unspecific inhibitor of the heat shock response)+control, to quercetin+CPB, and to quercetin+carbon monoxide+CPB. In the carbon monoxide groups, lungs were ventilated with 250 ppm carbon monoxide in addition to standard ventilation before CPB. At various time points, lung biopsies were obtained and pulmonary Hsp and cytokine concentrations determined. RESULTS Haemodynamic parameters were largely unaffected by CPB, carbon monoxide inhalation, or administration of quercetin. Compared with standard CPB, carbon monoxide inhalation significantly increased the pulmonary expression of the Hsps 70 [27 (SD 3) vs 69 (10) ng ml(-1) at 120 min post-CPB, P<0.05] and 90 [0.3 (0.03) vs 0.52 (0.05) after 120 min CPB, P<0.05], induced the DNA binding of heat shock factor-1, reduced interleukin-6 protein expression [936 (75) vs 320 (138) at 120 min post-CPB, P<0.001], and decreased CPB-associated lung injury (assessed by lung biopsy). These carbon monoxide-mediated effects were inhibited by quercetin. CONCLUSIONS As quercetin, a Hsp inhibitor, reversed carbon monoxide-mediated pulmonary effects, we conclude that the anti-inflammatory and protective effects of preconditioning by inhaled carbon monoxide during CPB in pigs are mediated by an activation of the heat shock response.
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Affiliation(s)
- U Goebel
- Department of Anaesthesia and Critical Care Medicine, University Medical Center, Hugstetterstrasse 55, D-79106 Freiburg im Breisgau, Germany
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Mechanism of liver regeneration after liver resection and portal vein embolization (ligation) is different? ACTA ACUST UNITED AC 2009; 16:292-9. [PMID: 19333540 DOI: 10.1007/s00534-009-0058-x] [Citation(s) in RCA: 27] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2008] [Accepted: 11/09/2008] [Indexed: 12/22/2022]
Abstract
Whether or not liver regeneration after portal branch embolization (PE) (ligation, PVL) in the non-embolized (ligated) lobe is by the same mechanism as regeneration in the remnant lobe after liver resection has been reviewed. Portal vein branch embolization and heat shock protein are then discussed. Tumor growth accelerated in the remnant liver after hepatectomy. In contrast, PE or PVL resulted in marked contralateral hepatic hypertrophy and significant reduction of tumor growth in the non-embolized (non-ligated) lobes. Follistatin administration significantly increased liver regeneration after hepatectomy in rats. In contrast, regeneration of non-ligated lobes after PVL was not accelerated by exogenous follistatin. Tumor growth also was not accelerated. The liver regeneration rate peaked at 48-72 h in the nonligated lobe after PVL, a delay of 24 h compared with the remnant liver after hepatectomy. In the postoperative early stage, the expression of activin betaA, betaC, and betaE mRNAs was stronger in PVL than in hepatectomy. At 72 h the expression of activin receptor type IIA mRNA reached a peak in hepatectomy, but was significantly lower in PVL. Thus, regulation of activin signaling through receptors is one of the factors determining liver regeneration after hepatectomy and PVL. These serial experimental results imply that the mechanism of liver regeneration after portal branch ligation (embolization) is different from that after hepatectomy. Heat shock protein was induced in the liver experimentally by intermittent ischemic preconditioning and could play some beneficial role in the recovery of liver function after hepatectomy, even in cirrhotic patients. When heat shock protein following right portal vein embolization in both the embolized and non-embolized hepatic lobes was investigated in clinical cases, a two to fourfold increase in HSP70 was induced in the non-embolized lobe compared with the embolized lobe. Oral administration of geranylgeranylacetone (a non-toxic HSP inducer) suppressed inflammatory responses and improved survival after 95% hepatectomy by induction of HSP70 in rats.
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Desai KK, Dikdan GS, Shareef A, Koneru B. Ischemic preconditioning of the liver: a few perspectives from the bench to bedside translation. Liver Transpl 2008; 14:1569-77. [PMID: 18975290 DOI: 10.1002/lt.21630] [Citation(s) in RCA: 35] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Utilization of ischemic preconditioning to ameliorate ischemia/reperfusion injury has been extensively studied in various organs and species for the past two decades. While hepatic ischemic preconditioning in animals has been largely beneficial, translational efforts in the two clinical contexts--liver resection and decreased donor liver transplantation--have yielded mixed results. This review is intended to critically examine the translational data and identify some potential reasons for the disparate clinical results, and highlight some issues for further studies.
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Affiliation(s)
- Kunj K Desai
- Department of Surgery, University of Medicine and Dentistry-New Jersey Medical School, Newark, NJ, USA
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Abstract
PURPOSE OF REVIEW Ischemic preconditioning that consists of a short period of hepatic inflow occlusion followed by reperfusion has the potential to increase tolerance to a subsequent prolonged ischemic insult. This review outlines current insight into ischemic preconditioning for hepatic ischemia and reperfusion injury in experimental and clinical settings. RECENT FINDINGS Experimental evidence suggests that interleukin-6 signaling and increased phosphorylation of STAT3 (signal transducer and activator of transcription-3) are involved in the protective effects of ischemic preconditioning. The benefit of ischemic preconditioning is restricted, however, by old liver and prolonged ischemic time (>60 min). To overcome this, ascorbic acid or glucose administration combined with ischemic preconditioning potentially can maintain the integrity of hepatic mitochondrial function through signal transduction pathways. The influence of ischemic preconditioning on hepatic regeneration varies with partial hepatectomy or small-for-size liver graft models, and remains controversial. Clinically, ischemic preconditioning in deceased donors protects against ischemia and reperfusion injury, as demonstrated by lowered liver enzyme levels, reduced incidence of primary nonfunction, and increased hepatic hypoxia-induced factor-1alpha concentrations. SUMMARY Enhanced understanding of the mechanisms of organ tolerance induced by ischemic preconditioning would strengthen the significance of this potential therapeutic strategy in liver transplantation.
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Ischemic preconditioning prevents free radical production and mitochondrial depolarization in small-for-size rat liver grafts. Transplantation 2008; 85:1322-31. [PMID: 18475191 DOI: 10.1097/tp.0b013e31816de302] [Citation(s) in RCA: 32] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
BACKGROUND Ischemic preconditioning (IP) renders tissues more tolerant to subsequent longer episodes of ischemia. This study tested whether IP attenuates injury of small-for-size liver grafts by preventing free radical production and mitochondrial dysfunction. METHODS IP was induced by clamping the portal vein and hepatic artery for 9 min. Livers were harvested 5 min after releasing the clamp. Mitochondrial polarization and cell death were assessed by intravital confocal/multiphoton microscopy of rhodamine 123 (Rh123) and propidium iodide. Free radicals were trapped with alpha-(4-pyridyl 1-oxide)-N-tert-butylnitrone and measured using electron spin resonance. RESULTS After quarter-size liver transplantation, alanine aminotransferase, serum bilirubin, necrosis, and apoptosis all increased. IP blocked these increases by more than 58%. 5-Bromo-2'-deoxyuridine labeling and increases of graft weight were only approximately 3% and 0.2% in quarter-size grafts without IP, respectively, but increased to 32% and 60% in ischemic-preconditioned grafts, indicating better liver regeneration. Eighteen hours after implantation, viable cells with depolarized mitochondria in quarter-size grafts were 15 per high power field, and dead cells were less than 1 per high power field, indicating that depolarization preceded necrosis. A free radical adduct signal was detected in bile from quarter-size grafts. IP decreased this free radical formation and prevented mitochondrial depolarization. IP did not increase heat shock proteins 10, 27, 32, 60, 70, 72, 75 and Cu/Zn-superoxide dismutase (SOD) but increased heat shock protein-90, a chaperone that facilitates protein import into mitochondria, and mitochondrial Mn-SOD. CONCLUSION Taken together, IP decreases injury and improves regeneration of small-for-size liver grafts, possibly by increasing mitochondrial Mn-SOD, thus protecting against free radical production and mitochondrial dysfunction.
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Husain S, Potter DE. The opioidergic system: potential roles and therapeutic indications in the eye. J Ocul Pharmacol Ther 2008; 24:117-40. [PMID: 18355128 DOI: 10.1089/jop.2007.0112] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Affiliation(s)
- Shahid Husain
- Department of Ophthalmology, Storm Eye Institute, Hewitt Laboratory of the Ola B Williams Glaucoma Center, Medical University of South Carolina, Charleston, SC 29425, USA.
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Dembiński A, Warzecha Z, Ceranowicz P, Warzecha AM, Pawlik WW, Dembiński M, Rembiasz K, Sendur P, Kuśnierz-Cabala B, Tomaszewska R, Chowaniec E, Konturek PC. Dual, time-dependent deleterious and protective effect of anandamide on the course of cerulein-induced acute pancreatitis. Role of sensory nerves. Eur J Pharmacol 2008; 591:284-92. [PMID: 18593574 DOI: 10.1016/j.ejphar.2008.06.059] [Citation(s) in RCA: 30] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2008] [Revised: 06/04/2008] [Accepted: 06/12/2008] [Indexed: 01/13/2023]
Abstract
Some recent studies indicate that cannabis may induce acute pancreatitis in humans and administration of anandamide increases the severity of acute pancreatitis; whereas another study exhibits some therapeutic effects in acute pancreatitis. Aim of the present study was to discover what is the reason for these opposite confusing results and to determine the role of sensory nerves in this effect. Acute pancreatitis was induced in rats by cerulein. Anandamide, an endogenous cannabinoid, was administered i.p. (1.5 micromol/kg) before or 2 h after cerulein administration. Stimulation of sensory nerves was performed by capsaicin (0.5 mg/kg s.c.). In rats treated with combination of anandamide plus capsaicin, capsaicin was given 10 min after each dose of anandamide. After the last injection of cerulein or 4 h later, the study was terminated. In our study we observed that stimulation of sensory nerves by capsaicin, before administration of cerulein, reduced the severity of acute pancreatitis. Anandamide, administered alone before cerulein, increased pancreatic damage in acute pancreatitis. Anandamide administered in combination with capsaicin, before cerulein, abolished the capsaicin-induced protective effect on the pancreas. Opposite effects were observed when capsaicin and anandamide were administered after injection of cerulein. Capsaicin increased the severity of acute pancreatitis, whereas anandamide reduced pancreatic damage and reversed the deleterious effect of capsaicin. We conclude that the effect of anandamide on the severity of acute pancreatitis depends on the phase of this disease. Administration of anandamide, before induction of pancreatitis, aggravates pancreatic damage; whereas anandamide administered after induction of pancreatitis, reduces the severity of acute pancreatitis. Sensory nerves are involved in the mechanism of this biphasic effect of anandamide.
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Affiliation(s)
- Artur Dembiński
- Department of Physiology, Jagiellonian University Medical College, Krakow, Poland.
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