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Jin M, Li X, Yan F, Chen W, Jiang L, Zhang X. The effects of low-color-temperature dual-primary-color light-emitting diodes on three kinds of retinal cells. JOURNAL OF PHOTOCHEMISTRY AND PHOTOBIOLOGY B-BIOLOGY 2020; 214:112099. [PMID: 33285486 DOI: 10.1016/j.jphotobiol.2020.112099] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/23/2020] [Revised: 10/03/2020] [Accepted: 11/23/2020] [Indexed: 12/20/2022]
Abstract
Long-term illumination of the retina with blue-light-excited phosphor-converted light-emitting diodes (LEDs) may result in decreased retinal function, even if the levels of blue light emitted are low. New low-color-temperature dual-primary-color LEDs have been developed that are composed of only two LED chips: a red chip and a yellow chip. These LEDs are expected to become a new type of healthy lighting source because they do not emit blue light, they lack phosphor, and they solve the problem of low efficiency encountered with phosphor-converted low-color-temperature LEDs. Many studies have indicated that these new low-color-temperature LEDs are likely to have therapeutic effects. However, the biological safety of these LEDs needs to be explored before the therapeutic effects are explored. Therefore, this experiment was conducted to investigate the effects of the new low-color-temperature LEDs and fluorescent white LEDs on three types of retinal cells. We observed that the viability and numbers of retinal cells decreased gradually with increasing LED color temperature. The new low-color-temperature LEDs caused less death and adverse effects on proliferation than the fluorescent white LEDs. After irradiation with high-color-temperature LEDs, the expression of Zonula Occludens-1 (ZO-1) was decreased and discontinuous in ARPE-19 cells; the stress protein hemeoxygenase-1 (HO-1) was upregulated in R28 cells; and glial fibrillary acidic protein (GFAP) and vimentin were upregulated in rMC-1 cells. We therefore conclude that the new white LEDs cause almost no damage to retinal cells and reduce the potential human health risks of chronic exposure to fluorescent white LEDs.
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Affiliation(s)
- Ming Jin
- Affiliated Eye Hospital of Nanchang University, Jiangxi Research Institute of Ophthalmology and Visual Science, Jiangxi Clinical Research Center for Ophthalmic Disease, 463 Bayi Road, Nanchang, Jiangxi 330006, China
| | - Xiongfeng Li
- Affiliated Eye Hospital of Nanchang University, Jiangxi Research Institute of Ophthalmology and Visual Science, Jiangxi Clinical Research Center for Ophthalmic Disease, 463 Bayi Road, Nanchang, Jiangxi 330006, China
| | - Feng Yan
- Affiliated Eye Hospital of Nanchang University, Jiangxi Research Institute of Ophthalmology and Visual Science, Jiangxi Clinical Research Center for Ophthalmic Disease, 463 Bayi Road, Nanchang, Jiangxi 330006, China
| | - Weixin Chen
- Affiliated Eye Hospital of Nanchang University, Jiangxi Research Institute of Ophthalmology and Visual Science, Jiangxi Clinical Research Center for Ophthalmic Disease, 463 Bayi Road, Nanchang, Jiangxi 330006, China
| | - Lei Jiang
- Queen Mary School of Nanchang University, 461 Bayi Road, Nanchang, Jiangxi 330046, China
| | - Xu Zhang
- Affiliated Eye Hospital of Nanchang University, Jiangxi Research Institute of Ophthalmology and Visual Science, Jiangxi Clinical Research Center for Ophthalmic Disease, 463 Bayi Road, Nanchang, Jiangxi 330006, China.
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Hydrogen Gas Attenuates Hypoxic-Ischemic Brain Injury via Regulation of the MAPK/HO-1/PGC-1a Pathway in Neonatal Rats. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2020; 2020:6978784. [PMID: 32104537 PMCID: PMC7040418 DOI: 10.1155/2020/6978784] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/11/2019] [Revised: 12/09/2019] [Accepted: 12/31/2019] [Indexed: 12/24/2022]
Abstract
Neonatal hypoxic-ischemic encephalopathy (HIE) is a leading cause of death in neonates with no effective treatments. Recent advancements in hydrogen (H2) gas offer a promising therapeutic approach for ischemia reperfusion injury; however, the impact of this approach for HIE remains a subject of debate. We assessed the therapeutic effects of H2 gas on HIE and the underlying molecular mechanisms in a rat model of neonatal hypoxic-ischemic brain injury (HIBI). H2 inhalation significantly attenuated neuronal injury and effectively improved early neurological outcomes in neonatal HIBI rats as well as learning and memory in adults. This protective effect was associated with initiation time and duration of sustained H2 inhalation. Furthermore, H2 inhalation reduced the expression of Bcl-2-associated X protein (BAX) and caspase-3 while promoting the expression of Bcl-2, nuclear factor erythroid-2-related factor 2, and heme oxygenase-1 (HO-1). H2 activated extracellular signal-regulated kinase and c-Jun N-terminal protein kinase and dephosphorylated p38 mitogen-activated protein kinase (MAPK) in oxygen-glucose deprivation/reperfusion (OGD/R) nerve growth factor-differentiated PC12 cells. Inhibitors of MAPKs blocked H2-induced HO-1 expression. HO-1 small interfering RNA decreased the expression of peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α) and sirtuin 1 (SIRT1) and reversed the protectivity of H2 against OGD/R-induced cell death. These findings suggest that H2 augments cellular antioxidant defense capacity through activation of MAPK signaling pathways, leading to HO-1 expression and subsequent upregulation of PGC-1α and SIRT-1 expression. Thus, upregulation protects NGF-differentiated PC12 cells from OGD/R-induced oxidative cytotoxicity. In conclusion, H2 inhalation exerted protective effects on neonatal rats with HIBI. Early initiation and prolonged H2 inhalation had better protective effects on HIBI. These effects of H2 may be related to antioxidant, antiapoptotic, and anti-inflammatory responses. HO-1 plays an important role in H2-mediated protection through the MAPK/HO-1/PGC-1α pathway. Our results support further assessment of H2 as a potential therapeutic for neurological conditions in which oxidative stress and apoptosis are implicated.
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Pagano D, Oliva E, Khouzam S, Tuzzolino F, Cintorino D, Li Petri S, di Francesco F, Ricotta C, Bonsignore P, Tropea A, Calamia S, Costanzo F, Luca A, Gruttadauria S. The addition of simvastatin administration to cold storage solution of explanted whole liver grafts for facing ischemia/reperfusion injury in an area with a low rate of deceased donation: a monocentric randomized controlled double-blinded phase 2 study. BMC Surg 2018; 18:122. [PMID: 30587165 PMCID: PMC6307270 DOI: 10.1186/s12893-018-0455-7] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2018] [Accepted: 12/07/2018] [Indexed: 01/09/2023] Open
Abstract
BACKGROUND Liver transplantation is the best treatment for end-stage liver disease. The interruption of the blood supply to the donor liver during cold storage damages the liver, affecting how well the liver will function after transplant. The drug Simvastatin may help to protect donor livers against this damage and improve outcomes for transplant recipients. The aim of this study is to evaluate the benefits of treating the donor liver with Simvastatin compared with the standard transplant procedure. PATIENT AND METHODS We propose a prospective, double-blinded, randomized phase 2 study of 2 parallel groups of eligible adult patients. We will compare 3-month, 6-month, and 12-month graft survival after LT, in order to identify a significant relation between the two homogenous groups of LT patients. The two groups only differ by the Simvastatin or placebo administration regimen while following the same procedure, with identical surgical instruments, and medical and nursing skilled staff. To reach these goals, we determined that we needed to recruit 106 patients. This sample size achieves 90% power to detect a difference of 14.6% between the two groups survival using a one-sided binomial test. DISCUSSION This trial is designed to confirm the effectiveness of Simvastatin to protect healthy and steatotic livers undergoing cold storage and warm reperfusion before transplantation and to evaluate if the addition of Simvastatin translates into improved graft outcomes. TRIAL REGISTRATION ISRCTN27083228 .
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Affiliation(s)
- Duilio Pagano
- Department for the Treatment and Study of Abdominal Diseases and Abdominal Transplantation, IRCCS-ISMETT (Istituto di Ricovero e Cura a Carattere Scientifico - Istituto Mediterraneo per i Trapianti e Terapie ad alta specializzazione), UPMC (University of Pittsburgh Medical Center) Italy, Via E. Tricomi 5, 90127 Palermo, Italy
| | | | - Simone Khouzam
- Sidney Kimmel Medical College - Thomas Jefferson University, Philadelphia, PA USA
| | | | - Davide Cintorino
- Department for the Treatment and Study of Abdominal Diseases and Abdominal Transplantation, IRCCS-ISMETT (Istituto di Ricovero e Cura a Carattere Scientifico - Istituto Mediterraneo per i Trapianti e Terapie ad alta specializzazione), UPMC (University of Pittsburgh Medical Center) Italy, Via E. Tricomi 5, 90127 Palermo, Italy
| | - Sergio Li Petri
- Department for the Treatment and Study of Abdominal Diseases and Abdominal Transplantation, IRCCS-ISMETT (Istituto di Ricovero e Cura a Carattere Scientifico - Istituto Mediterraneo per i Trapianti e Terapie ad alta specializzazione), UPMC (University of Pittsburgh Medical Center) Italy, Via E. Tricomi 5, 90127 Palermo, Italy
| | - Fabrizio di Francesco
- Department for the Treatment and Study of Abdominal Diseases and Abdominal Transplantation, IRCCS-ISMETT (Istituto di Ricovero e Cura a Carattere Scientifico - Istituto Mediterraneo per i Trapianti e Terapie ad alta specializzazione), UPMC (University of Pittsburgh Medical Center) Italy, Via E. Tricomi 5, 90127 Palermo, Italy
| | - Calogero Ricotta
- Department for the Treatment and Study of Abdominal Diseases and Abdominal Transplantation, IRCCS-ISMETT (Istituto di Ricovero e Cura a Carattere Scientifico - Istituto Mediterraneo per i Trapianti e Terapie ad alta specializzazione), UPMC (University of Pittsburgh Medical Center) Italy, Via E. Tricomi 5, 90127 Palermo, Italy
| | - Pasquale Bonsignore
- Department for the Treatment and Study of Abdominal Diseases and Abdominal Transplantation, IRCCS-ISMETT (Istituto di Ricovero e Cura a Carattere Scientifico - Istituto Mediterraneo per i Trapianti e Terapie ad alta specializzazione), UPMC (University of Pittsburgh Medical Center) Italy, Via E. Tricomi 5, 90127 Palermo, Italy
| | - Alessandro Tropea
- Department for the Treatment and Study of Abdominal Diseases and Abdominal Transplantation, IRCCS-ISMETT (Istituto di Ricovero e Cura a Carattere Scientifico - Istituto Mediterraneo per i Trapianti e Terapie ad alta specializzazione), UPMC (University of Pittsburgh Medical Center) Italy, Via E. Tricomi 5, 90127 Palermo, Italy
| | - Sergio Calamia
- Department for the Treatment and Study of Abdominal Diseases and Abdominal Transplantation, IRCCS-ISMETT (Istituto di Ricovero e Cura a Carattere Scientifico - Istituto Mediterraneo per i Trapianti e Terapie ad alta specializzazione), UPMC (University of Pittsburgh Medical Center) Italy, Via E. Tricomi 5, 90127 Palermo, Italy
| | - Federico Costanzo
- Department for the Treatment and Study of Abdominal Diseases and Abdominal Transplantation, IRCCS-ISMETT (Istituto di Ricovero e Cura a Carattere Scientifico - Istituto Mediterraneo per i Trapianti e Terapie ad alta specializzazione), UPMC (University of Pittsburgh Medical Center) Italy, Via E. Tricomi 5, 90127 Palermo, Italy
| | - Angelo Luca
- Department of Diagnostic and Therapeutic Services, IRCCS-ISMETT, UPMC Italy, Palermo, Italy
| | - Salvatore Gruttadauria
- Department for the Treatment and Study of Abdominal Diseases and Abdominal Transplantation, IRCCS-ISMETT (Istituto di Ricovero e Cura a Carattere Scientifico - Istituto Mediterraneo per i Trapianti e Terapie ad alta specializzazione), UPMC (University of Pittsburgh Medical Center) Italy, Via E. Tricomi 5, 90127 Palermo, Italy
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Qu S, Yuan B, Zhang H, Huang H, Zeng Z, Yang S, Ling J, Jin L, Wu P. Heme Oxygenase 1 Attenuates Hypoxia-Reoxygenation Injury in Mice Liver Sinusoidal Endothelial Cells. Transplantation 2018; 102:426-432. [PMID: 29189483 DOI: 10.1097/tp.0000000000002028] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
BACKGROUND Heme oxygenase 1 (HO-1), a heat shock protein, can be involved in the resolution of inflammation by modulating cytokine expression and apoptotic cell death. Based on recent evidence that liver sinusoidal endothelial cells (LSECs) is the critical target in early period of liver ischemia-reperfusion injury (IRI), this study aims to clarify whether overexpression of HO-1 gene provides a protective effect on mice LSECs. METHODS LSECs were transfected with adenovirus vectors encoding mice HO-1 gene (Ad-HO-1) or green fluorescent protein. Controls were not infected with any vector. LSECs were then treated with hypoxic or normoxic culture. We used low serum culture medium and hypoxia-reoxygenation (H-R) conditions to cause IRI in vitro. The transfection efficiency of HO-1 gene in LSECs, after 48 hours of transfection, and the effect of HO-1 on the model of H-R injury in LSECs were observed. RESULTS Transfection of LSECs with Ad-HO-1 was at an optimal dose (multiplicity of infection = 80) to markedly express HO-1 mRNA and protein. Groups of overexpressed HO-1 showed lower levels of inflammatory factor mediators IL-6 and TNF-α. Survival rate of the cells after H-R injury was higher and attributed to overexpressed HO-1. In contrast, the control adenovirus expressing the enhanced green fluorescent protein failed to induce HO-1 expression and stimulated cell apoptosis. HO-1 expression was downregulated in all H-R groups compared with normoxia groups, which may be related to the disruption of the LSEC structure. CONCLUSIONS Upregulation of HO-1 can attenuate H-R injury in LSECs by inhibiting proinflammatory cytokine release and diminishing apoptotic cell death.
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Affiliation(s)
- Siming Qu
- Organ Transplantation Center, the First Affiliated Hospital of Kunming Medical University, Kunming, Yunnan Province, China
| | - Bo Yuan
- Organ Transplantation Center, the First Affiliated Hospital of Kunming Medical University, Kunming, Yunnan Province, China
| | - Hongbin Zhang
- Organ Transplantation Center, the First Affiliated Hospital of Kunming Medical University, Kunming, Yunnan Province, China
| | - Hanfei Huang
- Organ Transplantation Center, the First Affiliated Hospital of Kunming Medical University, Kunming, Yunnan Province, China
| | - Zhong Zeng
- Organ Transplantation Center, the First Affiliated Hospital of Kunming Medical University, Kunming, Yunnan Province, China
| | - Shikun Yang
- Organ Transplantation Center, the First Affiliated Hospital of Kunming Medical University, Kunming, Yunnan Province, China
| | - Jie Ling
- Organ Transplantation Center, the First Affiliated Hospital of Kunming Medical University, Kunming, Yunnan Province, China
| | - Li Jin
- Organ Transplantation Center, the First Affiliated Hospital of Kunming Medical University, Kunming, Yunnan Province, China
| | - Pu Wu
- Organ Transplantation Center, the First Affiliated Hospital of Kunming Medical University, Kunming, Yunnan Province, China
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Afroz F, Kist A, Hua J, Zhou Y, Sokoya EM, Padbury R, Nieuwenhuijs V, Barritt G. Rapamycin induces the expression of heme oxygenase-1 and peroxyredoxin-1 in normal hepatocytes but not in tumorigenic liver cells. Exp Mol Pathol 2018; 105:334-344. [PMID: 30290159 DOI: 10.1016/j.yexmp.2018.09.006] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2018] [Revised: 08/27/2018] [Accepted: 09/28/2018] [Indexed: 12/14/2022]
Abstract
Rapamycin (sirolimus) is employed as an immunosuppressant following liver transplant, to inhibit the re-growth of cancer cells following liver resection for hepatocellular carcinoma (HCC), and for the treatment of advanced HCC. Rapamycin also induces the expression of antioxidant enzymes in the liver, suggesting that pretreatment with the drug could provide a potential strategy to reduce ischemia reperfusion injury following liver surgery. The aim of this study was to further investigate the actions of rapamycin in inducing expression of the antioxidant enzymes heme oxygenase-1 (HO-1) and peroxiredoxin-1 (Prx-1) in normal liver and in tumorigenic liver cells. A rat model of segmental hepatic ischemia and reperfusion, cultured freshly-isolated rat hepatocytes, and tumorigenic H4IIE rat liver cells in culture were employed. Expression of HO-1 and Prx-1 was measured using quantitative PCR and western blot. Rapamycin pre-treatment of normal liver in vivo or normal hepatocytes in vitro led to a substantial induction of mRNA encoding HO-1 and Prx-1. The dose-response curve for the action of rapamycin on mRNA expression was biphasic, showing an increase in expression at 0 - 0.1 μM rapamycin but a decrease from maximum at concentrations greater than 0.1 μM. By contrast, in H4IIE cells, rapamycin inhibited the expression of HO-1 and Prx-1 mRNA. Oltipraz, an established activator of transcription factor Nrf2, caused a large induction of HO-1 and Prx-1 mRNA. The dose response curve for the inhibition by rapamycin of HO-1 and Prx-4 mRNA expression, determined in the presence of oltipraz, was monophasic with half maximal inhibition at about 0.01 μM. It is concluded that, at concentrations comparable to those used clinically, pre-treatment of the liver with rapamycin induces the expression of HO-1 and Prx-1. However, the actions of rapamycin on the expression of these two antioxidant enzymes in normal hepatocytes are complex and, in tumorigenic liver cells, differ from those in normal hepatocytes. Further studies are warranted to evaluate preconditioning the livers of patients subject to liver resection or liver transplant with rapamycin as a viable strategy to reduce IR injury following liver surgery.
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Affiliation(s)
- Farhana Afroz
- Discipline of Medical Biochemistry, College of Medicine and Public Health, Flinders University, Adelaide, South Australia, Australia
| | - Alwyn Kist
- Discipline of Medical Biochemistry, College of Medicine and Public Health, Flinders University, Adelaide, South Australia, Australia
| | - Jin Hua
- Discipline of Medical Biochemistry, College of Medicine and Public Health, Flinders University, Adelaide, South Australia, Australia
| | - Yabin Zhou
- Discipline of Medical Biochemistry, College of Medicine and Public Health, Flinders University, Adelaide, South Australia, Australia
| | - Elke M Sokoya
- Discipline of Human Physiology, College of Medicine and Public Health, Flinders University, Adelaide, South Australia, Australia
| | - Robert Padbury
- The HPB and Liver Transplant Unit, Flinders Medical Centre and College of Medicine and Public Health, Flinders University, Adelaide, South Australia, Australia
| | | | - Greg Barritt
- Discipline of Medical Biochemistry, College of Medicine and Public Health, Flinders University, Adelaide, South Australia, Australia.
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Ryu JH, Park JW, Hwang JY, Park SJ, Kim JH, Sohn HM, Han SH. The attenuation of neurological injury from the use of simvastatin after spinal cord ischemia-reperfusion injury in rats. BMC Anesthesiol 2018; 18:31. [PMID: 29587636 PMCID: PMC5869785 DOI: 10.1186/s12871-018-0496-6] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2017] [Accepted: 03/20/2018] [Indexed: 02/05/2023] Open
Abstract
Background Spinal cord ischemic injury remains a serious complication of open surgical and endovascular aortic procedures. Simvastatin has been reported to be associated with neuroprotective effect after spinal cord ischemia-reperfusion (IR) injury. The aim of this study was to determine the therapeutic efficacy of starting simvastatin after spinal cord IR injury in a rat model. Methods In adult Sprague-Dawley rats, spinal cord ischemia was induced using a balloon-tipped catheter placed in the descending thoracic aorta. The animals were then randomly divided into 4 groups: group A (control); group B (0.5 mg/kg simvastatin); group C (1 mg/kg simvastatin); and group D (10 mg/kg simvastatin). Simvastatin was administered orally upon reperfusion for 5 days. Neurological function of the hind limbs was evaluated for 7 days after reperfusion and recorded using a motor deficit score (MDS) (0: normal, 5: complete paraplegia). The number of normal motor neurons within the anterior horns of the spinal cord was counted after final MDS evaluation. Then, the spinal cord was harvested for histopathological examination. Results Group D showed a significantly lower MDS than the other groups at post-reperfusion day 1 and this trend was sustained throughout the study period. Additionally, a greater number of normal motor neurons was observed in group D than in other groups (group D 21.2 [3.2] vs. group A: 15.8 [4.2]; group B 15.4 [3.4]; and group C 15.5 [3.7]; P = 0.002). Conclusions The results of the current study suggest that 10 mg/kg can significantly improve neurologic outcome by attenuating neurologic injury and restoring normal motor neurons after spinal cord IR injury.
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Affiliation(s)
- Jung-Hee Ryu
- Department of Anesthesiology and Pain Medicine, Seoul National University College of Medicine, Seoul, South Korea.,Department of Anesthesiology and Pain Medicine, Seoul National University Bundang Hospital, Seong-nam, South Korea
| | - Jin-Woo Park
- Department of Anesthesiology and Pain Medicine, Seoul National University College of Medicine, Seoul, South Korea.,Department of Anesthesiology and Pain Medicine, Seoul National University Bundang Hospital, Seong-nam, South Korea
| | - Jin-Young Hwang
- Department of Anesthesiology and Pain Medicine, Seoul National University College of Medicine, Seoul, South Korea.,Department of Anesthesiology and Pain Medicine, SNU-SMG hospital, Seoul, South Korea
| | - Seong-Joo Park
- Department of Anesthesiology and Pain Medicine, Seoul National University College of Medicine, Seoul, South Korea.,Department of Anesthesiology and Pain Medicine, Seoul National University Bundang Hospital, Seong-nam, South Korea
| | - Jin-Hee Kim
- Department of Anesthesiology and Pain Medicine, Seoul National University College of Medicine, Seoul, South Korea.,Department of Anesthesiology and Pain Medicine, Seoul National University Bundang Hospital, Seong-nam, South Korea
| | - Hye-Min Sohn
- Department of Anesthesiology and Pain Medicine, Seoul National University College of Medicine, Seoul, South Korea.,Department of Anesthesiology and Pain Medicine, Seoul National University Bundang Hospital, Seong-nam, South Korea
| | - Sung Hee Han
- Department of Anesthesiology and Pain Medicine, Seoul National University College of Medicine, Seoul, South Korea. .,Department of Anesthesiology and Pain Medicine, Seoul National University Bundang Hospital, Seong-nam, South Korea.
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Pretreatment Donors after Circulatory Death with Simvastatin Alleviates Liver Ischemia Reperfusion Injury through a KLF2-Dependent Mechanism in Rat. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2017; 2017:3861914. [PMID: 29348789 PMCID: PMC5733890 DOI: 10.1155/2017/3861914] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/28/2017] [Accepted: 07/24/2017] [Indexed: 12/15/2022]
Abstract
Objective Severe hepatic ischemia reperfusion injury (IRI) can result in poor short- and long-term graft outcome after transplantation. The way to improve the viability of livers from donors after circulatory death (DCD) is currently limited. The aim of the present study was to explore the protective effect of simvastatin on DCD livers and investigate the underlying mechanism. Methods 24 male rats randomly received simvastatin or its vehicle. 30 min later, rat livers were exposed to warm ischemia in situ for 30 min. Livers were removed and cold-stored in UW solution for 24 h, subsequently reperfused for 60 min with an isolated perfused rat liver system. Liver injury was evaluated during and after warm reperfusion. Results Pretreatment of DCD donors with simvastatin significantly decreased IRI liver enzyme release, increased bile output and ATP, and ameliorated hepatic pathological changes. Simvastatin maintained the expression of KLF2 and its protective target genes (eNOS, TM, and HO-1), reduced oxidative stress, inhibited innate immune responses and inflammation, and increased the expression of Bcl-2/Bax to suppress hepatocyte apoptosis compared to DCD control group. Conclusion Pretreatment of DCD donors with simvastatin improves DCD livers' functional recovery probably through a KLF2-dependent mechanism. These data suggest that simvastatin may provide a potential benefit for clinical DCD liver transplantation.
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Red Yeast Rice Protects Circulating Bone Marrow-Derived Proangiogenic Cells against High-Glucose-Induced Senescence and Oxidative Stress: The Role of Heme Oxygenase-1. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2017; 2017:3831750. [PMID: 28555162 PMCID: PMC5438855 DOI: 10.1155/2017/3831750] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/13/2017] [Revised: 03/28/2017] [Accepted: 04/02/2017] [Indexed: 12/22/2022]
Abstract
The inflammation and oxidative stress of bone marrow-derived proangiogenic cells (PACs), also named endothelial progenitor cells, triggered by hyperglycemia contributes significantly to vascular dysfunction. There is supporting evidence that the consumption of red yeast rice (RYR; Monascus purpureus-fermented rice) reduces the vascular complications of diabetes; however, the underlying mechanism remains unclear. This study aimed to elucidate the effects of RYR extract in PACs, focusing particularly on the role of a potent antioxidative enzyme, heme oxygenase-1 (HO-1). We found that treatment with RYR extract induced nuclear factor erythroid-2-related factor nuclear translocation and HO-1 mRNA and protein levels in PACs. RYR extract inhibited high-glucose-induced (30 mM) PAC senescence and the development of reactive oxygen species (ROS) in a dose-dependent manner. The HO-1 inducer cobalt protoporphyrin IX also decreased high-glucose-induced cell senescence and oxidative stress, whereas the HO-1 enzyme inhibitor zinc protoporphyrin IX and HO-1 small interfering RNA significantly reversed RYR extract-caused inhibition of senescence and reduction of oxidative stress in high-glucose-treated PACs. These results suggest that RYR extract serves as alternative and complementary medicine in the treatment of these diseases, by inducing HO-1, thereby decreasing the vascular complications of diabetes.
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A multidrug cocktail approach attenuates ischemic-type biliary lesions in liver transplantation from non-heart-beating donors. Med Hypotheses 2016; 91:47-52. [DOI: 10.1016/j.mehy.2016.04.013] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2015] [Revised: 12/20/2015] [Accepted: 04/08/2016] [Indexed: 02/06/2023]
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Effects of preoperative statin on liver reperfusion injury in major hepatic resection: a pilot study. Updates Surg 2016; 68:191-7. [DOI: 10.1007/s13304-016-0370-3] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2016] [Accepted: 05/04/2016] [Indexed: 10/21/2022]
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Hide D, Ortega-Ribera M, Garcia-Pagan JC, Peralta C, Bosch J, Gracia-Sancho J. Effects of warm ischemia and reperfusion on the liver microcirculatory phenotype of rats: underlying mechanisms and pharmacological therapy. Sci Rep 2016; 6:22107. [PMID: 26905693 PMCID: PMC4764954 DOI: 10.1038/srep22107] [Citation(s) in RCA: 28] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2015] [Accepted: 02/08/2016] [Indexed: 02/08/2023] Open
Abstract
Warm ischemia and reperfusion (WIR) causes hepatic damage and may lead to liver failure, however the mechanisms involved are largely unknown. Here we have characterized the microcirculatory status and endothelial phenotype of livers undergoing WIR, and evaluated the use of simvastatin in WIR injury prevention. Male Wistar rats received simvastatin, or vehicle, 30 min before undergoing 60 min of partial warm ischemia (70%) followed by 2 h or 24 h of reperfusion. Hepatic and systemic hemodynamics, liver injury (AST, ALT, LDH), endothelial function (vasodilatation in response to acetylcholine), KLF2 and nitric oxide pathways, oxidative stress, inflammation (neutrophil and macrophage infiltration) and cell death were evaluated. Profound microcirculatory dysfunction occurred rapidly following WIR. This was evidenced by down-regulation of the KLF2 vasoprotective pathway, impaired vasodilatory capability and endothelial activation, altogether leading to increased hepatic vascular resistance and liver inflammation, with significant leukocyte infiltration, oxidative stress and cell death. Simvastatin preserved the hepatic endothelial phenotype, and blunted the detrimental effects of WIR on liver hemodynamics and organ integrity. In conclusion, WIR-induced injury to liver sinusoidal endothelial cells is mitigated by pre-treatment with Simvastatin probably through a KLF2-dependent mechanism.
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Affiliation(s)
- Diana Hide
- Barcelona Hepatic Hemodynamic Lab. IDIBAPS Biomedical Research Institute – Hospital Clinic de Barcelona – CIBEREHD. Barcelona, Spain
| | - Martí Ortega-Ribera
- Barcelona Hepatic Hemodynamic Lab. IDIBAPS Biomedical Research Institute – Hospital Clinic de Barcelona – CIBEREHD. Barcelona, Spain
| | - Juan-Carlos Garcia-Pagan
- Barcelona Hepatic Hemodynamic Lab. IDIBAPS Biomedical Research Institute – Hospital Clinic de Barcelona – CIBEREHD. Barcelona, Spain
| | | | - Jaime Bosch
- Barcelona Hepatic Hemodynamic Lab. IDIBAPS Biomedical Research Institute – Hospital Clinic de Barcelona – CIBEREHD. Barcelona, Spain
| | - Jordi Gracia-Sancho
- Barcelona Hepatic Hemodynamic Lab. IDIBAPS Biomedical Research Institute – Hospital Clinic de Barcelona – CIBEREHD. Barcelona, Spain
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Liu L, Shang Y, Li M, Han X, Wang J, Wang J. Curcumin ameliorates asthmatic airway inflammation by activating nuclear factor-E2-related factor 2/haem oxygenase (HO)-1 signalling pathway. Clin Exp Pharmacol Physiol 2016; 42:520-9. [PMID: 25739561 DOI: 10.1111/1440-1681.12384] [Citation(s) in RCA: 60] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2015] [Revised: 02/26/2015] [Accepted: 02/26/2015] [Indexed: 12/27/2022]
Abstract
Previous studies have shown that curcumin alleviates asthma in vivo. However, the relationship between curcumin and the nuclear factor-E2-related factor 2 (Nrf2)/haem oxygenase (HO)-1 pathway in asthma treatment remains unknown. The aim of the present study was to investigate the mechanisms of curcumin involved in the amelioration of airway inflammation in a mouse asthma model. Curcumin was administrated to asthmatic mice, and bronchoalveolar lavage fluid was collected. Inflammatory cell infiltration was measured by Giemsa staining. Immunoglobulin E production in bronchoalveolar lavage fluid was measured by enzyme-linked immunosorbent assay. Histological analyses were evaluated with haematoxylin-eosin and periodic acid-Schiff staining. Airway hyperresponsiveness was examined by whole-body plethysmography. Nuclear factor-E2-related factor 2, HO-1, nuclear factor-κB and inhibitory κB/p-inhibitory κB levels in lung tissues were detected by western blot, and Nrf2 activity was measured by electrophoretic mobility shift assay. Tumour necrosis factor-α, interleukin (IL)-1β, and IL-6 levels in the small interfering RNA-transfected cells were detected by enzyme-linked immunosorbent assay. Curcumin treatment significantly reduced immunoglobulin E production, attenuated inflammatory cell accumulation and goblet cell hyperplasia, and ameliorated mucus secretion and airway hyperresponsiveness. Nuclear factor-E2-related factor 2 and HO-1 levels in lung tissues were significantly increased. Meanwhile, Nrf2 activity was enhanced. Nuclear factor-κB and p-inhibitory κB levels were elevated in the lung tissue of ovalbumin-challenged mice. Both were restored to normal levels after curcumin treatment. Haem oxygenase-1 and nuclear Nrf2 levels were enhanced in dose- and time-dependent manners in curcumin-treated RAW264.7 cells. Curcumin blocked lipopolysaccharide-upregulated expression of tumour necrosis factor-α, IL-1β, and IL-6. After the cells were transfected with HO-1 or Nrf2 small interfering RNA, lipopolysaccharide-induced pro-inflammation cytokine expression was significantly restored. In summary, curcumin might alleviate airway inflammation in asthma through the Nrf2/HO-1 pathway, potentially making it an effective drug in asthma treatment.
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Affiliation(s)
- Liyun Liu
- Department of Pediatrics, Shengjing Hospital of China Medical University, Shenyang, China
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Kocak FE, Kucuk A, Ozyigit F, Tosun M, Kocak C, Kocak A, Ekici MF, Yaylak F, Genc O. Protective effects of simvastatin administered in the experimental hepatic ischemia-reperfusion injury rat model. J Surg Res 2015; 199:393-401. [DOI: 10.1016/j.jss.2015.06.009] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2015] [Revised: 06/01/2015] [Accepted: 06/05/2015] [Indexed: 11/26/2022]
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Chen M, Suzuki A, Borlak J, Andrade RJ, Lucena MI. Drug-induced liver injury: Interactions between drug properties and host factors. J Hepatol 2015; 63:503-14. [PMID: 25912521 DOI: 10.1016/j.jhep.2015.04.016] [Citation(s) in RCA: 262] [Impact Index Per Article: 26.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/06/2015] [Revised: 04/01/2015] [Accepted: 04/07/2015] [Indexed: 12/13/2022]
Abstract
Idiosyncratic drug-induced liver injury (DILI) is a common cause for drug withdrawal from the market and although infrequent, DILI can result in serious clinical outcomes including acute liver failure and the need for liver transplantation. Eliminating the iatrogenic "harm" caused by a therapeutic intent is a priority in patient care. However, identifying culprit drugs and individuals at risk for DILI remains challenging. Apart from genetic factors predisposing individuals at risk, the role of the drugs' physicochemical and toxicological properties and their interactions with host and environmental factors need to be considered. The influence of these factors on mechanisms involved in DILI is multi-layered. In this review, we summarize current knowledge on 1) drug properties associated with hepatotoxicity, 2) host factors considered to modify an individuals' risk for DILI and clinical phenotypes, and 3) drug-host interactions. We aim at clarifying knowledge gaps needed to be filled in as to improve risk stratification in patient care. We therefore broadly discuss relevant areas of future research. Emerging insight will stimulate new investigational approaches to facilitate the discovery of clinical DILI risk modifiers in the context of disease complexity and associated interactions with drug properties, and hence will be able to move towards safety personalized medicine.
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Affiliation(s)
- Minjun Chen
- Division of Bioinformatics and Biostatistics, National Center for Toxicological Research, US Food and Drug Administration, Jefferson, AR, United States
| | - Ayako Suzuki
- Gastroenterology, Central Arkansas Veterans Healthcare System, Little Rock, AR, United States; Department of Medicine, University of Arkansas for Medical Sciences, Little Rock, AR, United States
| | - Jürgen Borlak
- Center of Pharmacology and Toxicology, Hannover Medical School, Hannover, Germany
| | - Raúl J Andrade
- Unidad de Gestión Clínica de Enfermedades Digestivas, Servicio de Farmacología Clínica, Instituto de Investigación Biomédica de Málaga (IBIMA), Hospital Universitario Virgen de la Victoria, Universidad de Málaga, Málaga, Spain; Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Madrid, Spain.
| | - M Isabel Lucena
- Unidad de Gestión Clínica de Enfermedades Digestivas, Servicio de Farmacología Clínica, Instituto de Investigación Biomédica de Málaga (IBIMA), Hospital Universitario Virgen de la Victoria, Universidad de Málaga, Málaga, Spain; Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Madrid, Spain
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15
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Liang GB, Luo GH, Bao DS, Chen AJ, Zhuang YX, Guo YN, Wang X, Wang YL, Chen ZP, Lu YP, Li YP. Impact of immunosuppressive agents on the expression of indoleamine 2,3-dioxygenase, heme oxygenase-1 and interleukin-7 in mesangial cells. Mol Med Rep 2015; 12:2577-83. [PMID: 25936769 PMCID: PMC4464319 DOI: 10.3892/mmr.2015.3713] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2014] [Accepted: 12/12/2014] [Indexed: 02/05/2023] Open
Abstract
Chronic allograft nephropathy (CAN) is a major cause of graft loss following kidney transplantation and may result from the interactions of various immune and non-immune factors. The aim of the present study was to establish an in vitro model of glomerular mesangial cell injury in order to examine the gene expression levels of indoleamine 2,3-dioxygenase (IDO), heme oxygenase-1 (HO-1) and interleukin-7 (IL-7) in mesangial cells during the healing process as well as to investigate the effects of various immunosuppressants on the expression of these genes. The HBZY-1 glomerular mesangial cell line was pre-treated in vitro with cytochalasin B for 2 h to induce reversible damage. Following the pre-treatment, the HBZY-1 cells were divided into five groups: Blank control group, cyclosporine A (CsA) group, tacrolimus (Tac) group, mycophenolate mofetil (MMF) group and rapamycin (RAPA) group. After treating the mesangial cells with each immunosuppressive drug for 6, 12 or 24 h, the mRNA and protein expression levels of IDO, HO-1 and IL-7 were examined using reverse transcription quantitative polymerase chain reaction (RT-qPCR), western blot and immunohistochemical analyses. The results showed that expression levels of HO-1 were significantly upregulated in response to treatment with CsA, FK506, RAPA and MMF, whereas the expression levels of IL-7 were markedly downregulated by treatment with the above immunosuppressants. CsA, FK506 and MMF significantly enhanced the expression levels of IDO, whereas RAPA exhibited no apparent effect on IDO. The present study may contribute to the understanding of the pathogenesis of CAN and provide novel strategies for the prevention and treatment of CAN.
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Affiliation(s)
- Guo-Biao Liang
- Department of Urology, Affiliated Hospital of Zunyi Medical College, Zunyi, Guizhou 563003, P.R. China
| | - Guang-Heng Luo
- Department of Urology, Guizhou Provincial People's Hospital, Guiyang, Guizhou 550005, P.R. China
| | - Ding-Su Bao
- Department of Urology, Affiliated Hospital of Zunyi Medical College, Zunyi, Guizhou 563003, P.R. China
| | - An-Jian Chen
- Department of Urology, Affiliated Hospital of Zunyi Medical College, Zunyi, Guizhou 563003, P.R. China
| | - Yong-Xiang Zhuang
- Department of Urology, Affiliated Hospital of Zunyi Medical College, Zunyi, Guizhou 563003, P.R. China
| | - Ya-Nan Guo
- Department of Urology, Affiliated Hospital of Zunyi Medical College, Zunyi, Guizhou 563003, P.R. China
| | - Xin Wang
- Department of Urology, Affiliated Hospital of Zunyi Medical College, Zunyi, Guizhou 563003, P.R. China
| | - Yuan-Liang Wang
- Department of Urology, Affiliated Hospital of Zunyi Medical College, Zunyi, Guizhou 563003, P.R. China
| | - Zong-Ping Chen
- Department of Urology, Affiliated Hospital of Zunyi Medical College, Zunyi, Guizhou 563003, P.R. China
| | - Yi-Ping Lu
- Department of Urology, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, P.R. China
| | - You-Ping Li
- Transplantation Immunology Laboratory, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, P.R. China
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Yang CH, Kao MC, Shih PC, Li KY, Tsai PS, Huang CJ. Simvastatin attenuates sepsis-induced blood-brain barrier integrity loss. J Surg Res 2015; 194:591-598. [DOI: 10.1016/j.jss.2014.11.030] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2014] [Revised: 11/13/2014] [Accepted: 11/20/2014] [Indexed: 01/04/2023]
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Muchova L, Vanova K, Suk J, Micuda S, Dolezelova E, Fuksa L, Cerny D, Farghali H, Zelenkova M, Lenicek M, Wong RJ, Vreman HJ, Vitek L. Protective effect of heme oxygenase induction in ethinylestradiol-induced cholestasis. J Cell Mol Med 2015; 19:924-33. [PMID: 25683492 PMCID: PMC4420596 DOI: 10.1111/jcmm.12401] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2014] [Accepted: 07/21/2014] [Indexed: 01/20/2023] Open
Abstract
Estrogen-induced cholestasis is characterized by impaired hepatic uptake and biliary bile acids secretion because of changes in hepatocyte transporter expression. The induction of heme oxygenase-1 (HMOX1), the inducible isozyme in heme catabolism, is mediated via the Bach1/Nrf2 pathway, and protects livers from toxic, oxidative and inflammatory insults. However, its role in cholestasis remains unknown. Here, we investigated the effects of HMOX1 induction by heme on ethinylestradiol-induced cholestasis and possible underlying mechanisms. Wistar rats were given ethinylestradiol (5 mg/kg s.c.) for 5 days. HMOX1 was induced by heme (15 μmol/kg i.p.) 24 hrs prior to ethinylestradiol. Serum cholestatic markers, hepatocyte and renal membrane transporter expression, and biliary and urinary bile acids excretion were quantified. Ethinylestradiol significantly increased cholestatic markers (P ≤ 0.01), decreased biliary bile acid excretion (39%, P = 0.01), down-regulated hepatocyte transporters (Ntcp/Oatp1b2/Oatp1a4/Mrp2, P ≤ 0.05), and up-regulated Mrp3 (348%, P ≤ 0.05). Heme pre-treatment normalized cholestatic markers, increased biliary bile acid excretion (167%, P ≤ 0.05) and up-regulated hepatocyte transporter expression. Moreover, heme induced Mrp3 expression in control (319%, P ≤ 0.05) and ethinylestradiol-treated rats (512%, P ≤ 0.05). In primary rat hepatocytes, Nrf2 silencing completely abolished heme-induced Mrp3 expression. Additionally, heme significantly increased urinary bile acid clearance via up-regulation (Mrp2/Mrp4) or down-regulation (Mrp3) of renal transporters (P ≤ 0.05). We conclude that HMOX1 induction by heme increases hepatocyte transporter expression, subsequently stimulating bile flow in cholestasis. Also, heme stimulates hepatic Mrp3 expression via a Nrf2-dependent mechanism. Bile acids transported by Mrp3 to the plasma are highly cleared into the urine, resulting in normal plasma bile acid levels. Thus, HMOX1 induction may be a potential therapeutic strategy for the treatment of ethinylestradiol-induced cholestasis.
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Affiliation(s)
- Lucie Muchova
- Institute of Medical Biochemistry and Laboratory Diagnostics, 1st Faculty of Medicine, Charles University in Prague, Prague, Czech Republic
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Bejaoui M, Pantazi E, Folch-Puy E, Baptista PM, García-Gil A, Adam R, Roselló-Catafau J. Emerging concepts in liver graft preservation. World J Gastroenterol 2015; 21:396-407. [PMID: 25593455 PMCID: PMC4292271 DOI: 10.3748/wjg.v21.i2.396] [Citation(s) in RCA: 56] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/28/2014] [Revised: 10/24/2014] [Accepted: 12/08/2014] [Indexed: 02/06/2023] Open
Abstract
The urgent need to expand the donor pool in order to attend to the growing demand for liver transplantation has obliged physicians to consider the use of suboptimal liver grafts and also to redefine the preservation strategies. This review examines the different methods of liver graft preservation, focusing on the latest advances in both static cold storage and machine perfusion (MP). The new strategies for static cold storage are mainly designed to increase the fatty liver graft preservation via the supplementation of commercial organ preservation solutions with additives. In this paper we stress the importance of carrying out effective graft washout after static cold preservation, and present a detailed discussion of the future perspectives for dynamic graft preservation using MP at different temperatures (hypothermia at 4 °C, normothermia at 37 °C and subnormothermia at 20 °C-25 °C). Finally, we highlight some emerging applications of regenerative medicine in liver graft preservation. In conclusion, this review discusses the "state of the art" and future perspectives in static and dynamic liver graft preservation in order to improve graft viability.
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Matsuo S, Saiki Y, Adachi O, Kawamoto S, Fukushige S, Horii A, Saiki Y. Single-dose rosuvastatin ameliorates lung ischemia-reperfusion injury via upregulation of endothelial nitric oxide synthase and inhibition of macrophage infiltration in rats with pulmonary hypertension. J Thorac Cardiovasc Surg 2014; 149:902-9. [PMID: 25454916 DOI: 10.1016/j.jtcvs.2014.10.030] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/07/2014] [Revised: 09/23/2014] [Accepted: 10/04/2014] [Indexed: 10/24/2022]
Abstract
OBJECTIVE Lung ischemia-reperfusion (IR) injury during cardiopulmonary surgery is associated with postoperative morbidity and mortality, particularly in patients with pulmonary hypertension (PH). Using a rat model for monocrotaline-induced PH, we investigated the protective effect of rosuvastatin against IR injury in lungs affected by PH and attempted to elucidate its mechanism of action. METHODS Male Sprague-Dawley monocrotaline-treated rats were divided into 4 groups (n = 8-9): sham, control + IR, statin + IR, and statin + mevalonolactone + IR. Lung ischemia was induced by left pulmonary artery occlusion (1 hour), followed by reperfusion (4 hours). Rosuvastatin (2 mg/kg) was injected 18 hours before reperfusion and mevalonolactone (1 mg/kg) was injected immediately before reperfusion. The arterial oxygen tension/inspired oxygen fraction ratio was used as a measure of lung oxygenation. Left lung tissue was analyzed for the wet-to-dry lung weight ratio and protein expression of endothelial nitric oxide synthase (eNOS) and phospho-eNOS. Macrophage recruitment was assessed by CD68 immunostaining. RESULTS Our results showed that rosuvastatin decreased IR lung injury (control + IR vs statin + IR) in terms of the arterial oxygen tension/inspired oxygen fraction ratio (272 ± 43 vs 442 ± 13), wet-to-dry ratio (5.7 ± 0.7 vs 4.8 ± 0.6), and macrophage infiltration (8.0 ± 0.6/field vs 4.0 ± 0.5/field) (P < .05 for all). eNOS and phospho-eNOS were downregulated by IR, which was blocked by rosuvastatin. Effects of rosuvastatin were blunted by mevalonolactone. CONCLUSIONS Single-dose rosuvastatin decreased IR injury in lungs affected by PH via 2 anti-inflammatory mechanisms: preserving eNOS function and inhibiting macrophage infiltration.
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Affiliation(s)
- Satoshi Matsuo
- Division of Cardiovascular Surgery, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Yuriko Saiki
- Department of Molecular Pathology, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Osamu Adachi
- Division of Cardiovascular Surgery, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Shunsuke Kawamoto
- Division of Cardiovascular Surgery, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Shinichi Fukushige
- Department of Molecular Pathology, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Akira Horii
- Department of Molecular Pathology, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Yoshikatsu Saiki
- Division of Cardiovascular Surgery, Tohoku University Graduate School of Medicine, Sendai, Japan.
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Camara-Lemarroy CR. Reply: Regarding the Article: Hepatic Ischemia/Reperfusion Injury Is Diminished by Atorvastatin in Wistar Rats. Arch Med Res 2014; 45:441-2. [DOI: 10.1016/j.arcmed.2014.06.003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2014] [Accepted: 06/04/2014] [Indexed: 10/25/2022]
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Himori N, Maruyama K, Yamamoto K, Yasuda M, Ryu M, Omodaka K, Shiga Y, Tanaka Y, Nakazawa T. Critical neuroprotective roles of heme oxygenase-1 induction against axonal injury-induced retinal ganglion cell death. J Neurosci Res 2014; 92:1134-42. [PMID: 24799032 DOI: 10.1002/jnr.23398] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2014] [Revised: 03/10/2014] [Accepted: 04/01/2014] [Indexed: 12/26/2022]
Abstract
Although axonal damage induces significant retinal ganglion cell (RGC) death, small numbers of RGCs are able to survive up to 7 days after optic nerve crush (NC) injury. To develop new treatments, we set out to identify patterns of change in the gene expression of axonal damage-resistant RGCs. To compensate for the low density of RGCs in the retina, we performed retrograde labeling of these cells with 4Di-10ASP in adult mice and 7 days after NC purified the RGCs with fluorescence-activated cell sorting. Gene expression in the cells was determined with a microarray, and the expression of Ho-1 was determined with quantitative PCR (qPCR). Changes in protein expression were assessed with immunohistochemistry and immunoblotting. Additionally, the density of Fluoro-gold-labeled RGCs was counted in retinas from mice pretreated with CoPP, a potent HO-1 inducer. The microarray and qPCR analyses showed increased expression of Ho-1 in the post-NC RGCs. Immunohistochemistry also showed that HO-1-positive cells were present in the ganglion cell layer (GCL), and cell counting showed that the proportion of HO-1-positive cells in the GCL rose significantly after NC. Seven days after NC, the number of RGCs in the CoPP-treated mice was significantly higher than in the control mice. Combined pretreatment with SnPP, an HO-1 inhibitor, suppressed the neuroprotective effect of CoPP. These results reflect changes in HO-1 activity to RGCs that are a key part of RGC survival. Upregulation of HO-1 signaling may therefore be a novel therapeutic strategy for glaucoma.
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Affiliation(s)
- Noriko Himori
- Department of Ophthalmology, Tohoku University Graduate School of Medicine, Miyagi, Japan
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Cámara-Lemarroy CR, Guzmán-de la Garza FJ, Alarcón-Galván G, Cordero-Pérez P, Muñoz-Espinosa L, Torres-González L, Fernández-Garza NE. Hepatic ischemia/reperfusion injury is diminished by atorvastatin in Wistar rats. Arch Med Res 2014; 45:210-6. [PMID: 24726586 DOI: 10.1016/j.arcmed.2014.02.001] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2013] [Accepted: 01/30/2014] [Indexed: 01/09/2023]
Abstract
BACKGROUND AND AIMS Temporal occlusion of the hepatoduodenal ligament (HDL) is often used during liver surgeries in order to reduce blood loss, resulting in ischemia/reperfusion injury (I/R). The aim of the study was to investigate the effects of atorvastatin (ATOR) on hepatic I/R injury and on serum levels of tumor necrosis factor-alpha (TNF-α), endothelin-1 (ET-1), antithrombin III (ATIII) and intracellular adhesion molecule-1 (ICAM-1). METHODS Liver ischemia was induced in Wistar rats by clamping the HDL for 60 min, followed by either 60 or 180 min reperfusion. Rats received either vehicle or 10 mg/kg ATOR before hepatic I/R. Control group received sham surgery. Livers were examined for histological damage and serum AST, ALT, TNF-α, ET-1, ATIII and ICAM-1 concentrations were measured. RESULTS After I/R, AST and ALT were significantly elevated, ATIII levels were significantly depleted, both TNF-α and ICAM-1 levels increased and ET-1 was significantly elevated (at 180 min). ATOR pretreatment attenuated these alterations and diminished histological injury scores. CONCLUSIONS Our results show that ATOR protects the liver from I/R injury.
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Affiliation(s)
| | | | - Gabriela Alarcón-Galván
- Servicio de Anatomía Patológica y Citopatología, Hospital Universitario "José Eleuterio González," Monterrey, Nuevo León, Mexico
| | - Paula Cordero-Pérez
- Unidad de Hígado, Departamento de Medicina Interna, Universidad Autónoma de Nuevo León, School of Medicine, Monterrey, Nuevo León, Mexico
| | - Linda Muñoz-Espinosa
- Unidad de Hígado, Departamento de Medicina Interna, Universidad Autónoma de Nuevo León, School of Medicine, Monterrey, Nuevo León, Mexico
| | - Liliana Torres-González
- Unidad de Hígado, Departamento de Medicina Interna, Universidad Autónoma de Nuevo León, School of Medicine, Monterrey, Nuevo León, Mexico
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Barone E, Di Domenico F, Butterfield DA. Statins more than cholesterol lowering agents in Alzheimer disease: their pleiotropic functions as potential therapeutic targets. Biochem Pharmacol 2013; 88:605-16. [PMID: 24231510 DOI: 10.1016/j.bcp.2013.10.030] [Citation(s) in RCA: 56] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2013] [Revised: 10/22/2013] [Accepted: 10/28/2013] [Indexed: 02/05/2023]
Abstract
Alzheimer disease (AD) is a progressive neurodegenerative disorder characterized by severe cognitive impairment, inability to perform activities of daily living and mood changes. Statins, long known to be beneficial in conditions where dyslipidemia occurs by lowering serum cholesterol levels, also have been proposed for use in neurodegenerative conditions, including AD. However, it is not clear that the purported effectiveness of statins in neurodegenerative disorders is directly related to cholesterol-lowering effects of these agents; rather, the pleiotropic functions of statins likely play critical roles. The aim of this review is to provide an overview on the new discoveries about the effects of statin therapy on the oxidative and nitrosative stress levels as well as on the modulation of the heme oxygenase/biliverdin reductase (HO/BVR) system in the brain. We propose a novel mechanism of action for atorvastatin which, through the activation of HO/BVR-A system, may contribute to the neuroprotective effects thus suggesting a potential therapeutic role in AD and potentially accounting for the observation of decreased AD incidence with persons on statin.
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Affiliation(s)
- Eugenio Barone
- Department of Chemistry, Center of Membrane Sciences, and Sanders-Brown Center on Aging, University of Kentucky, Lexington, KY 40506-0055, USA
| | - Fabio Di Domenico
- Department of Biochemical Sciences, Sapienza University of Rome, Piazzale Aldo Moro 5, 00185 Rome, Italy
| | - D Allan Butterfield
- Department of Chemistry, Center of Membrane Sciences, and Sanders-Brown Center on Aging, University of Kentucky, Lexington, KY 40506-0055, USA.
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Gracia-Sancho J, García-Calderó H, Hide D, Marrone G, Guixé-Muntet S, Peralta C, García-Pagán JC, Abraldes JG, Bosch J. Simvastatin maintains function and viability of steatotic rat livers procured for transplantation. J Hepatol 2013; 58:1140-1146. [PMID: 23428876 DOI: 10.1016/j.jhep.2013.02.005] [Citation(s) in RCA: 52] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/24/2012] [Revised: 01/17/2013] [Accepted: 02/05/2013] [Indexed: 02/07/2023]
Abstract
BACKGROUND & AIMS Liver grafts obtained from healthy rat donors develop acute microcirculatory dysfunction due to cold-storage and warm-reperfusion injuries. These detrimental effects are avoided adding simvastatin to the cold-storage solution. Considering the importance of increasing organ donor pool for transplantation, we characterized whether simvastatin pretreatment can protect steatotic grafts from cold-storage and warm-reperfusion injuries. METHODS Rats fed with high-fat diet received a single dose of simvastatin, or its vehicle, 30 min before liver procurement. Grafts were then cold stored for 0 h (control group) or 16 h and warm reperfused. At the end of the reperfusion period, hepatic vascular resistance, endothelial function, nitric oxide pathway, cell death, oxidative stress, autophagy, and liver injury were evaluated. Hepatic vascular resistance and endothelial function were determined in a group of simvastatin-treated livers in the presence of the nitric oxide synthase inhibitor L-NNA. RESULTS Cold-stored rat steatotic livers exhibit increased hepatic vascular resistance and marked endothelial dysfunction, together with liver damage, oxidative stress, and low nitric oxide. Simvastatin markedly improved liver injury and prevented hepatic endothelial dysfunction. The beneficial effects of simvastatin were associated with cell death diminution, autophagy induction, and nitric oxide release. Statin-derived liver microcirculation protection was not observed when nitric oxide production was blunted. CONCLUSIONS Pretreatment of steatotic liver donors with simvastatin shortly before procurement of the liver graft strongly protects both parenchymal and endothelial components of the liver after warm reperfusion. Our data reinforce the use of statins to protect liver grafts undergoing transplantation.
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Affiliation(s)
- Jordi Gracia-Sancho
- Barcelona Hepatic Hemodynamic Laboratory, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Hospital Clínic de Barcelona, Centro de Investigación en Red en Enfermedades Hepáticas y Digestivas (CIBERehd), University of Barcelona, Spain.
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Tamura T, Kondo T, Ogawa K, Fukunaga K, Ohkohchi N. Protective effect of heme oxygenase-1 on hepatic ischemia-reperfusion injury through inhibition of platelet adhesion to the sinusoids. J Gastroenterol Hepatol 2013; 28:700-6. [PMID: 23215739 DOI: 10.1111/jgh.12075] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 10/29/2012] [Indexed: 12/14/2022]
Abstract
BACKGROUND AND AIM Heme oxygenase-1 (HO-1) acts as a protector against hepatic inflammatory injury. HO-1 catalyzes the conversion of heme protein to biliverdin, free iron, and carbon monoxide. Pro-inflammatory responses play critical roles in hepatic ischemia-reperfusion (I/R) injury, and carbon monoxide effectively downregulates I/R injury. The aim of this study was to evaluate the mechanism by which HO-1 reduces warm I/R injury. METHODS Sprague-Dawley rats were divided into two groups: the 20-min ischemia group (control group; n = 6) and the 20-min ischemia with cobalt protoporphyrin (CoPP group; n = 6). CoPP is an inducer of HO-1 in the sinusoids. Kupffer cells were labeled using the liposome entrapment method, and platelets were labeled with rhodamine-6G. The adherent platelets were observed for up to 120 min after reperfusion by intravital microscopy. RESULTS In the control group, the number of adherent platelets significantly increased than in the CoPP group. Terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling-positive cells were observed after 120 min of reperfusion in the control group. They were not observed in the CoPP group. In the CoPP group, serum alanine transaminase and interleukin-6 levels reduced after reperfusion. Moreover, the flow velocity of platelets in the hepatic sinusoid markedly increased. CONCLUSIONS This study suggests that HO-1 inhibits platelet adhesion to sinusoids. Such inhibition leads to the prevention of hepatic I/R injury.
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Affiliation(s)
- Takafumi Tamura
- Department of Surgery, Faculty of Medicine, Division of Clinical Medicine, University of Tsukuba, Tsukuba, Japan
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Nykänen AI, Tuuminen R, Lemström KB. Donor simvastatin treatment and cardiac allograft ischemia/reperfusion injury. Trends Cardiovasc Med 2013; 23:85-90. [PMID: 23295079 DOI: 10.1016/j.tcm.2012.09.005] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/30/2012] [Revised: 06/30/2012] [Accepted: 07/02/2012] [Indexed: 01/14/2023]
Abstract
Ischemia/reperfusion injury of a transplanted heart may result in serious early and late adverse effects such as primary graft dysfunction, increased allograft immunogenicity, and initiation of fibroproliferative cascades that compromise the survival of the recipient. Microvascular dysfunction has a central role in ischemia/reperfusion injury through increased vascular permeability, leukocyte adhesion and extravasation, thrombosis, vasoconstriction, and the no-reflow phenomenon. Here we review the involvement of microvascular endothelial cells and their surrounding pericytes in ischemia/reperfusion injury, and the pleiotropic, cholesterol-independent effects of statins on microvascular dysfunction. In addition, we delineate how the rapid vasculoprotective effects of statins could be used to protect cardiac allografts against ischemia/reperfusion injury by administering statins to the organ donor before graft removal and transplantation.
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Affiliation(s)
- Antti I Nykänen
- Transplantation Laboratory, Haartman Institute, P.O. Box 21 (Haartmaninkatu 3), FI-00014, University of Helsinki, Finland.
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Khalifian S, Broyles JM, Tuffaha SH, Alrakan M, Ibrahim Z, Sarhane KA. Immune mechanisms of ischemia-reperfusion injury in transplantation. ACTA ACUST UNITED AC 2013. [DOI: 10.4236/oji.2013.33020] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022]
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Nigro Neto C, Tardelli MA, Paulista PHD. Use of volatile anesthetics in extracorporeal circulation. Rev Bras Anestesiol 2012; 62:346-55. [PMID: 22656680 DOI: 10.1016/s0034-7094(12)70135-6] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2011] [Accepted: 08/03/2011] [Indexed: 11/26/2022] Open
Abstract
BACKGROUND AND OBJECTIVES The use of volatile anesthetics in cardiac surgery is not recent. Since the introduction of halothane in clinical practice, several cardiac surgery centers started to use these anesthetics constantly. CONTENT In the last years a great number of studies have shown that the volatile anesthetics have a protecting effect against myocardial ischemic dysfunction. Experimental evidences have shown that the halogenated anesthetics have cardioprotective effects that cannot be only explained by coronary flow alterations or by the balance between myocardium available and consumed oxygen. In addition to that, the use of volatile anesthetics during extracorporeal circulation (ECC) in cardiac surgery plays an important role. Recent studies have proven that these agents have cardioprotective properties and produce better results when the volatile anesthetic is used during the whole surgery procedure, including ECC. The use of halogenated anesthetics through calibrated vaporizers adapted to the ECC circuit via oxygenator membranes has become popular. Therefore, the professionals involved such as anesthesiologists and perfusionists should learn specifics in order to solve possible doubts.
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Affiliation(s)
- Caetano Nigro Neto
- Anesthesiology, Universidade Federal de São Paulo (UNIFESP), Rua Peixoto Gomide 502/173B, SP, Brazil.
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Monitoring molecular changes induced by ischemia/reperfusion in human free muscle flap tissue samples. Ann Plast Surg 2012; 68:202-8. [PMID: 21508818 DOI: 10.1097/sap.0b013e3181f77ba5] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/14/2023]
Abstract
BACKGROUND Our current knowledge of the pathophysiological sequelae of ischemia or reperfusion (I/R) injury in free tissue transfer in reconstructive surgery is based on data obtained in animal experiments. In this study, we investigated the histologic and molecular changes after 11 free microsurgical muscle transfers in human muscle tissue. METHODS Biopsies of free muscle flap tissue were taken immediately before clipping of the pedicle and 5 days after ischemia and successful microanastomosis and restoration of the blood flow. Samples were analyzed histologically for edema formation and by immunohistochemistry for infiltration of inflammatory cells and angiogenesis. Expression levels of the inflammatory marker proteins interleukin-1β and tumor necrosis factor α and of complement component 3 as a major mediator of I/R injury were analyzed by real-time polymerase chain reaction. A TUNEL (terminal desoxynucleotidyl transferase-mediated-dUTP-nick-end-labeling) assay was used to assess apoptosis levels within the human muscle tissue. RESULTS I/R injury leads to a significant up-regulation of inflammatory parameters, infiltration of inflammatory cells, and angiogenesis. Increased complement component 3 deposition and apoptosis of cells were accompanied by interstitial edema as indication for a pronounced postischemic inflammatory reaction within the muscle tissue after free tissue transfer. CONCLUSIONS Our findings of molecular changes induced by I/R injury in human striated muscle tissue validate data obtained in animal models of I/R injury. The parameters and inflammatory patterns defined in this study will allow for the monitoring of the success of novel pharmaceutical strategies in the future and will help to transfer data obtained in animal work to the in vivo setting in human beings.
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Ajamieh H, Farrell G, Wong HJ, Yu J, Chu E, Chen J, Teoh N. Atorvastatin protects obese mice against hepatic ischemia-reperfusion injury by Toll-like receptor-4 suppression and endothelial nitric oxide synthase activation. J Gastroenterol Hepatol 2012; 27:1353-61. [PMID: 22432744 DOI: 10.1111/j.1440-1746.2012.07123.x] [Citation(s) in RCA: 31] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
BACKGROUND AND AIM Steatosis accentuates the severity of hepatic ischemia-reperfusion injury (IRI). 3-Hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors ("statins") protect the heart and brain against post-ischemic injury, without necessarily lowering serum cholesterol. We tested whether 10-day or 1-day atorvastatin administration protects livers with fatty change or non-alcoholic steatohepatitis (NASH) against IRI. METHODS Mice with dietary or genetic simple steatosis (SS) or NASH were subjected to 60 min of partial hepatic ischemia/24-h reperfusion, with/without atorvastatin administered with food (5 mg/kg body weight) for 10 days, or injected intravenously (5 mg/kg) 24 h before ischemia. Liver injury, Toll-like receptor-4 (TLR4), cytokines/chemokines, endothelial nitric oxide synthase (eNOS), activation and thromboxane B2 production were determined. RESULTS Atorvastatin conferred 70-90% hepatic protection against IRI in obese animals with SS or NASH, in which IRI was accentuated twofold to fivefold. IRI markedly upregulated TLR4 and activated nuclear factor-κB (NF-κB); atorvastatin abrogated these effects, as well as activating eNOS. Atorvastatin dampened the post-ischemic induction of thromboxane B2, macrophage inflammatory protein-1a, monocyte chemotactic protein-1, tumor necrosis factor-α, interleukin (IL)-12 p40, γ-interferon, IL-6, and adhesion molecules (vascular cell adhesion molecule-1, E-selectin, vascular endothelial-cadherin), and reduced macrophage and neutrophil recruitment. There was no reduction in serum cholesterol that could explain these effects, and hepatic cholesterol was normal in these mice. A single 24-h injection of atorvastatin conferred equivalent hepatoprotection. CONCLUSION Statins exert major hepatoprotection against IRI in lean, fatty, and NASH livers that is not due to cholesterol removal. Rather, statins downregulate TLR4 to prevent NF-κB activation, with resultant suppression of adhesion molecules, chemokines/cytokines, and thromboxane B2 production. Short-term statin treatment is an effective, readily-available preventive agent against hepatic IRI, irrespective of obesity and fatty liver disease.
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Affiliation(s)
- Hussam Ajamieh
- Gastroenterology and Hepatology Unit, Australian National University Medical School, the Canberra Hospital, Australian Capital Territory, Canberra, Australia
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Atorvastatin treatment in a dog preclinical model of Alzheimer's disease leads to up-regulation of haem oxygenase-1 and is associated with reduced oxidative stress in brain. Int J Neuropsychopharmacol 2012; 15:981-7. [PMID: 21767440 DOI: 10.1017/s1461145711001118] [Citation(s) in RCA: 56] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/22/2022] Open
Abstract
Alzheimer's disease (AD) is a neurodegenerative disorder characterized by progressive cognitive impairment and neuropathology. Only acetylcholinesterase inhibitors and the NMDA antagonist memantine are approved for AD treatment. Recent preclinical and epidemiological studies proposed statins as novel therapeutics for AD, but the mechanisms of action are still unknown. Here, we demonstrate that atorvastatin (80 mg/d for 14.5 months) treatment resulted in an up-regulation of the inducible isoform of haem oxygenase (HO-1), an enzyme with significant neuroprotective activity. Atorvastatin selectively increased HO-1 in the parietal cortex but not cerebellum. In contrast, HO-2 was increased in cerebellum but not parietal cortex. No changes were observed in HO-1 or HO-2 in the liver. Significant negative correlations between HO-1 and oxidative stress indices and positive correlations with glutathione levels in parietal cortex were found. HO-1 up-regulation significantly correlated with lower discrimination learning error scores in aged beagles. Reference to therapeutic applications of atorvastatin in AD is discussed.
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Sagiroglu T, Aksoy MB, Sagiroglu G, Tozkir H, Oguz S, Yalta T, Yagci MA, Sezer A. Effect of leptin and apelin preconditioning on hepatic ischemia reperfusion injury in rats. Indian J Surg 2012; 76:111-6. [PMID: 24891774 DOI: 10.1007/s12262-012-0676-4] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2011] [Accepted: 06/22/2012] [Indexed: 12/19/2022] Open
Abstract
Leptin and apelin are important adipocytokines involved in a variety of endocrine and paracrine functions. The aim of this study was to evaluate the effect of exogenous leptin and apelin preconditioning on hepatic ischemia reperfusion (I/R) injury in rats. Forty mice were assigned to four groups (n = 10): sham-operated control (sham), I/R injury, I/R + leptin (I/R + L), and I/R + apelin (I/R + A). Leptin 100 μg/kg/day and apelin 2 μg/kg/day were delivered intraperitoneally starting 3 days prior to surgical procedure in I/R + L and I/R + A groups, respectively. All I/R groups underwent 45 min of warm ischemia, followed by 30 min of reperfusion. Serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST), liver malondialdehyde (MDA) and glutathione (GSH), and liver histopathology were compared between groups. MDA was elevated in I/R, but stayed similar in I/R + L and I/R + A compared to sham. I/R + A had significantly lower MDA compared to I/R. GSH levels did not differ significantly between the groups. ALT and AST were elevated in all I/R groups, but significant reduction was observed in I/R + L and I/R + A compared to I/R. Liver histopathology was mostly mild in I/R + L and I/R + A, in contrast to severe injury observed in the I/R group. Leptin and apelin preconditioning significantly reduced hepatic I/R injury in rats.
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Affiliation(s)
- Tamer Sagiroglu
- Faculty of Medicine Department of General Surgery, Trakya University, Trakya Üniversitesi Tıp Fakültesi Genel Cerrahi, AD 22030 Edirne, Turkey
| | - Mustafa Burak Aksoy
- Faculty of Medicine Department of Emergency Service, Trakya University, Trakya Üniversitesi Tıp Fakültesi Acil Servis, AD 22030 Edirne, Turkey
| | - Gonul Sagiroglu
- Faculty of Medicine Department of Anesthesiology and Reanimation, Trakya University, TrakyaUniversities Tıp Fakültesi Genel Cerrahi, AD 22030 Edirne, Turkey
| | - Hilmi Tozkir
- Faculty of Medicine Department of Medical Genetics, Trakya University, Trakya Üniversitesi Tıp Fakültesi Tıbbi Biyoloji ve Genetik, AD 22100 Edirne, Turkey
| | - Serhat Oguz
- Faculty of Medicine Department of General Surgery, Trakya University, Trakya Üniversitesi Tıp Fakültesi Genel Cerrahi, AD 22030 Edirne, Turkey
| | - Tulin Yalta
- Faculty of Medicine Department of Pathology, Trakya University, Trakya Üniversitesi Tıp FakültesiPatoloji, AD 22030 Edirne, Turkey
| | - Mehmet A Yagci
- Hakkari State Hospital, Hakkari Devlet Hastanesi, Hakkari, Turkey
| | - Atakan Sezer
- Faculty of Medicine Department of General Surgery, Trakya University, Trakya Üniversitesi Tıp Fakültesi Genel Cerrahi, AD 22030 Edirne, Turkey
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Tympa A, Theodoraki K, Tsaroucha A, Arkadopoulos N, Vassiliou I, Smyrniotis V. Anesthetic Considerations in Hepatectomies under Hepatic Vascular Control. HPB SURGERY : A WORLD JOURNAL OF HEPATIC, PANCREATIC AND BILIARY SURGERY 2012; 2012:720754. [PMID: 22690040 PMCID: PMC3368350 DOI: 10.1155/2012/720754] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 01/09/2012] [Revised: 03/06/2012] [Accepted: 03/21/2012] [Indexed: 02/08/2023]
Abstract
Background. Hazards of liver surgery have been attenuated by the evolution in methods of hepatic vascular control and the anesthetic management. In this paper, the anesthetic considerations during hepatic vascular occlusion techniques were reviewed. Methods. A Medline literature search using the terms "anesthetic," "anesthesia," "liver," "hepatectomy," "inflow," "outflow occlusion," "Pringle," "hemodynamic," "air embolism," "blood loss," "transfusion," "ischemia-reperfusion," "preconditioning," was performed. Results. Task-orientated anesthetic management, according to the performed method of hepatic vascular occlusion, ameliorates the surgical outcome and improves the morbidity and mortality rates, following liver surgery. Conclusions. Hepatic vascular occlusion techniques share common anesthetic considerations in terms of preoperative assessment, monitoring, induction, and maintenance of anesthesia. On the other hand, the hemodynamic management, the prevention of vascular air embolism, blood transfusion, and liver injury are plausible when the anesthetic plan is scheduled according to the method of hepatic vascular occlusion performed.
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Affiliation(s)
- Aliki Tympa
- First Department of Anesthesiology, School of Medicine, University of Athens, Aretaieion Hospital, 76 Vassilisis Sofias Avenue, 11528 Athens, Greece
| | - Kassiani Theodoraki
- First Department of Anesthesiology, School of Medicine, University of Athens, Aretaieion Hospital, 76 Vassilisis Sofias Avenue, 11528 Athens, Greece
| | - Athanassia Tsaroucha
- First Department of Anesthesiology, School of Medicine, University of Athens, Aretaieion Hospital, 76 Vassilisis Sofias Avenue, 11528 Athens, Greece
| | - Nikolaos Arkadopoulos
- Fourth Department of Surgery, School of Medicine, University of Athens, Attikon Hospital, 1 Rimini Street, 12410 Chaidari, Greece
| | - Ioannis Vassiliou
- Second Department of Surgery, School of Medicine, University of Athens, Aretaieion Hospital, 76 Vassilisis Sofias Avenue, 11528 Athens, Greece
| | - Vassilios Smyrniotis
- Fourth Department of Surgery, School of Medicine, University of Athens, Attikon Hospital, 1 Rimini Street, 12410 Chaidari, Greece
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Yun N, Kim SH, Lee SM. Differential consequences of protein kinase C activation during early and late hepatic ischemic preconditioning. J Physiol Sci 2012; 62:199-209. [PMID: 22359070 PMCID: PMC10717168 DOI: 10.1007/s12576-012-0199-6] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2012] [Accepted: 02/03/2012] [Indexed: 01/17/2023]
Abstract
Activation of protein kinase C (PKC) has been implicated in the protection of ischemic preconditioning (IPC), but the exact role of PKC in early and late hepatic IPC is still unclear. The present study was conducted in order to investigate the differential role of PKC during early and late hepatic IPC. Rats were subjected to 90 min of partial hepatic ischemia followed by 3 (early IPC) and 24 h (late IPC) of reperfusion. IPC was induced by 10 min of ischemia following 10 min of reperfusion prior to sustained ischemia, and chelerythrine, a PKC inhibitor, was injected 10 min before IPC (5 mg/kg, i.v.). Chelerythrine abrogated the protection of early IPC, as indicated by increased serum aminotransferase activities and decreased hepatic glutathione content. While the IPC-treated group showed a few apoptotic cell deaths during both phases, chelerythrine attenuated these changes only at late IPC and limited IPC-induced inducible nitric oxide synthase (iNOS) and heme oxygenase-1 (HO-1) overexpression. Membrane translocation of PKC-δ and -ε during IPC was blocked by chelerythrine. Our results suggest that PKC might play a differential role in early and late IPC; activation of PKC-δ and -ε prevents necrosis in early IPC through preservation of redox state and prevents apoptosis in late IPC with iNOS and HO-1 induction. Therefore, PKC represents a promising target for hepatocyte tolerance to ischemic injury, and understanding the differential role of PKC in early and late IPC is important for clinical application of IPC.
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Affiliation(s)
- Nari Yun
- School of Pharmacy, Sungkyunkwan University, 300 Cheoncheon-dong, Jangan-gu, Suwon, Gyeonggi-do 440-746 Korea
| | - Sung-Hwa Kim
- School of Pharmacy, Sungkyunkwan University, 300 Cheoncheon-dong, Jangan-gu, Suwon, Gyeonggi-do 440-746 Korea
| | - Sun-Mee Lee
- School of Pharmacy, Sungkyunkwan University, 300 Cheoncheon-dong, Jangan-gu, Suwon, Gyeonggi-do 440-746 Korea
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Hwang J, Han JI, Han S. Effect of pretreatment with simvastatin on spinal cord ischemia-reperfusion injury in rats. J Cardiothorac Vasc Anesth 2012; 27:79-85. [PMID: 22445180 DOI: 10.1053/j.jvca.2012.01.025] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/03/2011] [Indexed: 11/11/2022]
Abstract
OBJECTIVE The aim of this study was to evaluate the pretreatment effect of simvastatin on spinal cord ischemia-reperfusion injury. DESIGN Prospective, interventional study. SETTING University research laboratory. PARTICIPANTS Forty-five male Sprague-Dawley rats. INTERVENTIONS Rats were treated with oral simvastatin, 10 mg/kg (simvastatin group; n = 15) or saline (control group; n = 15) for 5 days before ischemia. Spinal cord ischemia was induced using a balloon-tipped catheter placed in the proximal descending aorta in the control and simvastatin groups, but not in the sham group (n = 15). MEASUREMENTS AND MAIN RESULTS Neurologic function was assessed daily using the motor deficit index until 7 days after reperfusion. After the last neurologic evaluation, a histologic examination of the spinal cord was performed. At day 1 after reperfusion, the simvastatin group showed a significantly lower motor deficit index compared with the control group (2.0, 2.0-2.0, v 4.0, 3.5-5.0; p < 0.001). This trend was sustained at day 7 (2.0, 1.5-2.0, v 4.0, 3.0-4.0; p < 0.001). The simvastatin group displayed a significantly larger number of normal motor neurons compared with the control group (mean ± SD, 31.7 ± 6.1 v 20.4 ± 4.4; p < 0.001). However, compared with the sham group, the simvastatin group displayed fewer intact motor neurons (sham group, 38.5 ± 5.1; p = 0.005). CONCLUSIONS Pretreatment with simvastatin, 10 mg/kg, given orally for 5 days before the ischemia-reperfusion insult, improved the neurologic outcome and preserved more normal motor neurons compared with the control group in a rat model of spinal cord ischemia-reperfusion.
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Affiliation(s)
- Jinyoung Hwang
- Department of Anesthesiology and Pain Medicine, Seoul National University, Bundang Hospital, Seongnamsi, Gyeonggido, Korea
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Schaalan MF. Effects of pioglitazone and/or simvastatin on circulating TNFα and adiponectin levels in insulin resistance. J Immunotoxicol 2012; 9:201-9. [DOI: 10.3109/1547691x.2012.660998] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/14/2023] Open
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Ischemic Postconditioning Protects Liver From Ischemia-Reperfusion Injury by Modulating Mitochondrial Permeability Transition. Transplantation 2012; 93:265-71. [DOI: 10.1097/tp.0b013e31823ef335] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/27/2022]
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Barone E, Mancuso C, Di Domenico F, Sultana R, Murphy MP, Head E, Butterfield DA. Biliverdin reductase-A: a novel drug target for atorvastatin in a dog pre-clinical model of Alzheimer disease. J Neurochem 2011; 120:135-46. [PMID: 22004509 DOI: 10.1111/j.1471-4159.2011.07538.x] [Citation(s) in RCA: 54] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/20/2023]
Abstract
Biliverdin reductase-A (BVR-A) is a pleiotropic enzyme involved in cellular stress responses. It not only transforms biliverdin-IX alpha into the antioxidant bilirubin-IX alpha but through its serine/threonine/tyrosine kinase activity is able to modulate cell signaling networks. BVR-A's involvement in neurodegenerative disorders such as Alzheimer disease (AD) and amnestic mild cognitive impairment was previously described. Statins have been proposed to reduce risk of AD. In this study we evaluated the effect of atorvastatin treatment (80 mg/day for 14.5 months) on BVR-A in the parietal cortex, cerebellum and liver of a well characterized pre-clinical model of AD, the aged beagle. We found that atorvastatin significantly increased BVR-A protein levels, phosphorylation and activity only in parietal cortex. Additionally, we found significant negative correlations between BVR-A and oxidative stress indices, as well as discrimination learning error scores. Furthermore, BVR-A up-regulation and post-translational modifications significantly correlated with β-secretase protein levels in the brain, suggesting a possible role for BVR-A in Aβ formation.
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Affiliation(s)
- Eugenio Barone
- Department of Chemistry, Center of Membrane Sciences, and Sanders-Brown Center on Aging, University of Kentucky, Lexington, Kentucky 40506-0055, USA
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Liu Y, Sun XJ, Liu J, Kang ZM, Deng XM. Heme oxygenase-1 could mediate the protective effects of hyperbaric oxygen preconditioning against hepatic ischemia-reperfusion injury in rats. Clin Exp Pharmacol Physiol 2011; 38:675-82. [DOI: 10.1111/j.1440-1681.2011.05560.x] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/13/2023]
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von Heesen M, Seibert K, Hülser M, Scheuer C, Wagner M, Menger MD, Schilling MK, Moussavian MR. Multidrug donor preconditioning protects steatotic liver grafts against ischemia-reperfusion injury. Am J Surg 2011; 203:168-76. [PMID: 21782153 DOI: 10.1016/j.amjsurg.2011.01.026] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2010] [Revised: 01/20/2011] [Accepted: 01/20/2011] [Indexed: 12/18/2022]
Abstract
BACKGROUND Graft dysfunction of steatotic livers (SL) still remains a major challenge in liver transplantation. Different mechanisms are thought to be involved in the impaired tolerance of SL to ischemia-reperfusion injury. Thus, different pharmacologic strategies may need to be combined to effectively protect SL and to reduce graft dysfunction after transplantation. Therefore, we analyzed the effectiveness of a multidrug donor preconditioning (MDDP) procedure to protect SL from cold ischemia-reperfusion injury. METHODS Liver steatosis was induced by a high-carbohydrate, fat-free diet. A total of 24 Sprague-Dawley rats were divided into 3 groups (n = 8 each), including a control group with nonsteatotic livers (Con), a vehicle-treated SL group (SL-Con), and a SL group undergoing MDDP (SL-MDDP), including pentoxyphylline, glycine, deferoxamine, N-acetylcysteine, erythropoietin, melatonin, and simvastatin. MDDP was applied before liver perfusion with 4°C histidine-tryptophan-ketoglutarate (HTK) solution and organ harvest. After 24 hours of cold storage in HTK, postischemic reperfusion was performed in an isolated liver reperfusion model using 37°C Krebs-Henseleit bicarbonate buffer. RESULTS After 60 minutes of reperfusion, SL showed a significant reduction of bile flow as well as a marked increase of liver enzyme levels and apoptotic cell death compared with Con. This was associated with an increased malondialdehyde formation, interleukin-1 production, and leukocytic tissue infiltration. MDDP completely abolished the inflammatory response and was capable of significantly reducing parenchymal dysfunction and injury. CONCLUSIONS MDDP decreases SL injury after cold storage and reperfusion. The concept of MDDP as a simple and safe preoperative regime, thus may be of interest in clinical use, expanding the donor pool from marginal donors.
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Affiliation(s)
- Maximilian von Heesen
- Department of General, Vascular and Pediatric Surgery, University of Saarland, Homburg/Saar, Germany
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Llacuna L, Fernández A, Montfort CV, Matías N, Martínez L, Caballero F, Rimola A, Elena M, Morales A, Fernández-Checa JC, García-Ruiz C. Targeting cholesterol at different levels in the mevalonate pathway protects fatty liver against ischemia-reperfusion injury. J Hepatol 2011; 54:1002-10. [PMID: 21145825 DOI: 10.1016/j.jhep.2010.08.031] [Citation(s) in RCA: 50] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/07/2010] [Revised: 08/05/2010] [Accepted: 08/16/2010] [Indexed: 02/06/2023]
Abstract
BACKGROUND & AIMS Liver steatosis enhances ischemia/reperfusion (I/R) injury and is considered a primary factor in graft failure after liver transplantation. Although previous reports have shown a role for qualitative steatosis (macrovesicular vs. microvesicular) in hepatic I/R injury, no studies have compared side by side the specific contribution of individual lipids accumulating in fatty liver to I/R damage. METHODS We used nutritional and genetic models of micro and macrovesicular fatty livers exhibiting specific lipid profiles to assess their susceptibility to normothermic I/R injury. RESULTS Unlike choline-deficient (CD) diet-fed mice, characterized by predominant liver triglycerides/free fatty acids (TG/FFA) accumulation, mice fed a cholesterol-enriched (HC) diet, which exhibited enhanced hepatic cholesterol loading in mitochondria, were highly sensitive to I/R-induced liver injury. In vivo two-photon confocal imaging revealed enhanced mitochondrial depolarization and generation of reactive oxygen species following hepatic I/R in HC-fed but not in CD-fed mice, consistent with decreased mitochondrial GSH (mGSH) observed in HC-fed mice. Moreover, ob/ob mice, characterized by increased hepatic TG, FFA, and cholesterol levels, were as sensitive to I/R-mediated liver injury as mice fed the HC diet. Livers from ob/ob mice displayed increased StAR expression and mitochondrial cholesterol accumulation, resulting in mGSH depletion. Interestingly, atorvastatin therapy or squalene synthase inhibition in vivo attenuated StAR overexpression, mitochondrial cholesterol loading, and mGSH depletion, protecting ob/ob mice from I/R-mediated liver injury. CONCLUSIONS Cholesterol accumulation, particularly in mitochondria, sensitizes to hepatic I/R injury, and thus represents a novel target to prevent the enhanced damage of steatotic livers to I/R-mediated damage.
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Affiliation(s)
- Laura Llacuna
- Liver Unit and Centro de Investigaciones Biomédicas Esther Koplowitz, IMDiM, Hospital Clínic i Provincial and CIBEREHD, IDIBAPS, Spain
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Ischemia/reperfusion injury in liver resection: a review of preconditioning methods. Surg Today 2011; 41:620-9. [PMID: 21533932 DOI: 10.1007/s00595-010-4444-4] [Citation(s) in RCA: 41] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2010] [Accepted: 10/18/2010] [Indexed: 02/06/2023]
Abstract
Ischemic preconditioning is one of the therapeutic interventions aiming at preventing ischemia/reperfusion-related injury. Numerous experimental studies and a few clinical series have shown that during liver resections, ischemic preconditioning is a promising strategy for optimizing the postoperative outcome. Moreover, various types of pharmacological intervention as well as different types of preconditioning, such as remote preconditioning, the use of heat shock, and hyperbaric oxygen, have been developed to attenuate the functional impairment accompanying ischemia/reperfusion injury. This review summarizes the various forms of preconditioning, thus suggesting that close cooperation between surgeons and anesthesiologists paves the way to apply novel strategies to improve the outcome of liver resection.
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von Heesen M, Hülser M, Seibert K, Scheuer C, Dold S, Kollmar O, Wagner M, Menger MD, Schilling MK, Moussavian MR. Split-liver procedure and inflammatory response: improvement by pharmacological preconditioning. J Surg Res 2011; 168:e125-35. [PMID: 21435665 DOI: 10.1016/j.jss.2011.01.036] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2010] [Revised: 01/17/2011] [Accepted: 01/19/2011] [Indexed: 01/10/2023]
Abstract
BACKGROUND Final outcome of split-liver (SL) transplantation is impaired due to an increased rate of vascular complications and primary non-function. Herein, we hypothesized that an in situ split-liver procedure induces an inflammatory response and a deterioration of graft quality. We further studied whether graft quality can be improved by pharmacologic preconditioning. MATERIAL AND METHODS SL-procedure was performed in rats. One group (SL-HPP; n = 8) was pretreated according to a defined protocol [Homburg preconditioning protocol (HPP)], including pentoxyphylline, glycine, deferoxamine, N-acetylcysteine, erythropoietin, melatonin, and simvastatin. A second SL group (SL-Con; n = 8) received NaCl. Untreated non-SL served as controls (Sham; n = 8). Cytokines release, leukocyte invasion, endothelial activation and liver morphology were studied directly after liver harvest and after 8 h cold storage. Lung tissue was studied to determine remote injury. RESULTS The SL-procedure induced an increase of TNF-α concentration, intercellular-adhesion-molecule 1 (ICAM-1) expression, leukocytic-tissue infiltration and vacuolization. This was associated with an increased number of apoptotic hepatocytes. HPP reduced TNF-α release, ICAM-1 expression, the number of infiltrated leukocytes, as well as hepatocellular vacuolization and apoptosis. In lung tissue, the SL-procedure caused an increased IL-1 and IL-6 concentration and leukocyte infiltration. CONCLUSIONS HPP was capable of abrogating cytokine-mediated leukocytic response. Pharmacologic preconditioning of liver donors prevents the SL procedure-mediated inflammatory response, resulting in an improved graft quality.
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Affiliation(s)
- Maximilian von Heesen
- Department of General, Vascular and Pediatric Surgery, University of Saarland, Homburg/Saar, Germany
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Abstract
Warm hepatic ischemia-reperfusion injury is a significant medical problem in many clinical conditions such as liver transplantation, hepatic surgery for tumor excision, trauma and hepatic failure after hemorrhagic shock. Partial or, mostly, total interruption of hepatic blood flow is often necessary when liver surgery is performed. This interruption of blood flow is termed "warm ischemia" and upon revascularization, when molecular oxygen is reintroduced, the organ undergoes a process called "reperfusion injury" that causes deterioration of organ function. Ischemia reperfusion results in cellular damage and tissue injury associated with a complex series of events. Pathophysiological mechanisms leading to tissue injury following ischemia-reperfusion will be discussed and therapies targeted to reduce liver damage will be summarized within this review.
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Affiliation(s)
- Serdar Dogan
- Department of Biochemistry, Akdeniz University School of Medicine, Antalya, Turkey
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Abstract
BACKGROUND Vascular occlusion to prevent haemorrhage during liver resection causes ischaemia-reperfusion (IR) injury. Insights into the mechanisms of IR injury gathered from experimental models have contributed to the development of therapeutic approaches, some of which have already been tested in randomized clinical trials. METHODS The review was based on a PubMed search using the terms 'ischemia AND hepatectomy', 'ischemia AND liver', 'hepatectomy AND drug treatment', 'liver AND intermittent clamping' and 'liver AND ischemic preconditioning'; only randomized controlled trials (RCTs) were included. RESULTS Twelve RCTs reported on ischaemic preconditioning and intermittent clamping. Both strategies seem to confer protection and allow extension of ischaemia time. Fourteen RCTs evaluating pharmacological interventions, including antioxidants, anti-inflammatory drugs, vasodilators, pharmacological preconditioning and glucose infusion, were identified. CONCLUSION Several strategies to prevent hepatic IR have been developed, but few have been incorporated into clinical practice. Although some pharmacological strategies showed promising results with improved clinical outcome there is not sufficient evidence to recommend them.
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Affiliation(s)
- R Bahde
- Surgical Research, Department of General and Visceral Surgery, Muenster University Hospital, Waldeyer Strasse 1, D-48149 Muenster, Germany
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Abstract
Statins are established in the prevention and therapy of chronic cardiovascular diseases because of inhibition of HMG-CoA (3-hydroxy-3-methylglutaryl-coenzyme A), thus lowering blood cholesterol levels. However, their cholesterol-independent effects include regulation of Rho/Rho-kinases (ROCK) and eNOS, proteins centrally involved in various models of acute inflammation. Therefore, we tested the hypothesis that simvastatin confers protection after rat hemorrhage/resuscitation (H/R) and wanted to elucidate the mechanisms involved. Fifty-two female Lewis rats (180-250 g) were pretreated with simvastatin 5 mg/kg per day or vehicle for 6 days (i.p.). Then, rats were hemorrhaged to a mean arterial pressure of 30 +/- 2 mmHg for 60 min and resuscitated. Control group underwent surgical procedures without H/R. Two hours after resuscitation, tissues were harvested. Mortality was assessed 72 h after H/R. Simvastatin pretreatment increased survival after H/R from 20% to 80%. Serum alanine aminotransferase after H/R increased 2.2-fold in vehicle as compared with simvastatin-treated rats. Histopathological analysis revealed decreased hepatic necrosis in simvastatin-treated rats after H/R. Hepatic oxidative (4-hydroxynonenal) and nitrosative (3-nitrotyrosine) stress, inflammatory markers (serum IL-6 and hepatic infiltration with polymorphonuclear leukocytes), and actin cytoskeleton rearrangements were decreased after simvastatin pretreatment compared with vehicle-treated rats after H/R. Simvastatin increased eNOS and heme oxygenase 1 expression and eNOS activation. Expression of Rho/Rho-kinase and myosin phosphatase targeting subunit, Thr-MYPT1, a marker for Rho-kinase activity, decreased after simvastatin treatment compared with vehicle-treated rats after H/R. Simvastatin pretreatment exerts beneficial effects in this model of acute inflammation by supporting protective mechanisms that are important for hepatic microcirculation after H/R.
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Flow cessation triggers endothelial dysfunction during organ cold storage conditions: strategies for pharmacologic intervention. Transplantation 2010; 90:142-9. [PMID: 20606606 DOI: 10.1097/tp.0b013e3181e228db] [Citation(s) in RCA: 88] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/19/2022]
Abstract
BACKGROUND Vascular pathologies constitute a major cause of graft rejection after organ transplantation. Recent studies have documented an improvement in transplant outcome when organs are preserved through pulsatile perfusion; however, the underlying mechanisms of these observations are poorly characterized. We hypothesized that the temporary absence of flow occurring in the context of organ cold storage conditions disrupts endothelial vasoprotective programs, and that this consequence of stasis may be a target for pharmacological modulation. METHODS The expression of the transcription factor Kruppel-like factor 2 (KLF2) and its vasoprotective target genes were assessed during cold storage conditions in cultured human endothelial cells and murine aortic segments. In addition, we evaluated the effect of simvastatin used as a supplement in a cold preservation solution on the expression of vasoprotective genes, and on endothelial activation and apoptosis. RESULTS The expression of endothelial KLF2 and its vasoprotective transcriptional targets were rapidly lost during cold preservation in vitro and ex vivo. Importantly, simvastatin treatment blocked the decay of KLF2, sustaining a vasoprotective phenotype, and preventing endothelial activation and apoptosis. CONCLUSIONS Flow stasis leads to acute endothelial dysfunction and apoptosis in the context of cold storage conditions. Supplementation of organ preservation solutions with pharmacologic agents that restore endothelial vasoprotective programs, by upregulating KLF2, may represent a significant advancement of current organ preservation techniques.
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Yang S, Shih HJ, Chow YC, Wang TY, Tsai PS, Huang CJ. Simvastatin Attenuates Testicular Injury Induced by Torsion-Detorsion. J Urol 2010; 184:750-6. [PMID: 20639051 DOI: 10.1016/j.juro.2010.03.103] [Citation(s) in RCA: 14] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2009] [Indexed: 10/19/2022]
Affiliation(s)
- Stone Yang
- Department of Urology, Mackay Memorial Hospital, Taipei, Taiwan, Republic of China
- Mackay Medicine, Management and Nursing College, Taipei Medical University, Taipei, Taiwan, Republic of China
| | - Hung-Jen Shih
- Department of Urology, Changhua Christian Hospital, Changhua, Taiwan, Republic of China
| | - Yung-Chiong Chow
- Department of Urology, Mackay Memorial Hospital, Taipei, Taiwan, Republic of China
| | - Tao-Yeuan Wang
- Department of Pathology, Mackay Memorial Hospital, Taipei, Taiwan, Republic of China
| | - Pei-Shan Tsai
- Graduate Institute of Nursing, Taipei Medical University, Taipei, Taiwan, Republic of China
| | - Chun-Jen Huang
- Department of Pharmacology, Taipei Medical University, Taipei, Taiwan, Republic of China
- Department of Anesthesiology, Buddhist Tzu Chi General Hospital, Taipei Branch, Taipei, Taiwan, Republic of China
- School of Medicine, Tzu Chi University, Hualien, Taiwan, Republic of China
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Multidrug donor preconditioning prevents cold liver preservation and reperfusion injury. Langenbecks Arch Surg 2010; 396:231-41. [PMID: 20582598 DOI: 10.1007/s00423-010-0668-4] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2010] [Accepted: 06/10/2010] [Indexed: 12/23/2022]
Abstract
PURPOSE Primary graft dysfunction still represents a major challenge in liver transplantation. We herein studied in an isolated rat liver perfusion model whether a multidrug donor preconditioning (MDDP) can not only reduce but also completely prevent cold ischemia-reperfusion injury. METHODS MDDP included curcumin, simvastatin, N-acetylcysteine, erythropoietin, pentoxyphylline, melatonin, glycine, and methylprednisolone. Postischemic reperfusion was performed after 24 h cold storage in histidine-tryptophan-ketoglutarate solution with 37°C Krebs Henseleit bicarbonate buffer. RESULTS Cold hepatic ischemia-reperfusion resulted in a massive K(+) release, protein loss, and aspartate aminotransferase, alanine aminotransferase, and lactate dehydrogenase elevation. This was associated with increased malondialdehyde formation, enhanced tumor necrosis factor-alpha and interleukin-6 production, pronounced leukocytic tissue infiltration, and apoptotic cell death. CONCLUSIONS MDDP abolished the inflammation response and was capable of completely preventing the manifestation of parenchymal injury. Thus, MDDP potentiates the protective effects reported after single-drug donor preconditioning and may therefore be an interesting approach to improve the outcome in clinical liver transplantation.
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