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Ding N, Xiao H, Zhen L, Li H, Zhang Z, Ge J. Imp7 siRNA nanoparticles protect against mechanical ventilation-associated liver injury by inhibiting HMGB1 production and NETs formation. Biochim Biophys Acta Mol Basis Dis 2024; 1870:167085. [PMID: 38369216 DOI: 10.1016/j.bbadis.2024.167085] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2023] [Revised: 01/16/2024] [Accepted: 02/15/2024] [Indexed: 02/20/2024]
Abstract
Mechanical ventilation (MV) has the potential to induce extra-pulmonary organ damage by adversely affecting the lungs and promoting the secretion of inflammatory cytokines. High-mobility group box 1 protein (HMGB1) is a pro-inflammatory mediator in ventilator-induced lung injury (VILI), but its effect on MV-associated liver injury and the mechanisms are poorly understood. In the present study, mice were subjected to high-volume MV (20 ml/kg) to induce VILI. MV-induced HMGB1 prompted neutrophil extracellular traps (NETs) formation and PANoptosis within the liver. Inhibiting NETs formation by DNase I or PAD4 inhibitor, or by HMGB1 neutralizing ameliorated the liver injury. HMGB1 activated neutrophils to form NETs through TLR4/MyD88/TRAF6 pathway. Importantly, Importin7 siRNA nanoparticles inhibited HMGB1 release and protected against MV-associated liver injury. These data provide evidence of MV-induced HMGB1 prompted NETs formation and PANoptosis in the liver via the TLR4/MyD88/TRAF6 pathway. HMGB1 is a potential therapeutic target for MV-associated liver injury.
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Affiliation(s)
- Ning Ding
- Department of Anesthesiology, Shandong Provincial Third Hospital, Cheeloo College of Medicine, Shandong University, Jinan 250031, China; Shandong Provincial Key Medical and Health Laboratory of Intensive Care Rehabilitation, Shandong Provincial Third Hospital, Cheeloo College of Medicine, Shandong University, Jinan 250031, China.
| | - Hui Xiao
- Shandong Provincial Key Medical and Health Laboratory of Intensive Care Rehabilitation, Shandong Provincial Third Hospital, Cheeloo College of Medicine, Shandong University, Jinan 250031, China
| | - Lixiao Zhen
- Shandong Provincial Key Medical and Health Laboratory of Intensive Care Rehabilitation, Shandong Provincial Third Hospital, Cheeloo College of Medicine, Shandong University, Jinan 250031, China
| | - Huiqing Li
- Department of Anesthesiology, Shandong Provincial Third Hospital, Cheeloo College of Medicine, Shandong University, Jinan 250031, China; Shandong Provincial Key Medical and Health Laboratory of Intensive Care Rehabilitation, Shandong Provincial Third Hospital, Cheeloo College of Medicine, Shandong University, Jinan 250031, China
| | - Zengzhen Zhang
- Department of Anesthesiology, Shandong Provincial Third Hospital, Cheeloo College of Medicine, Shandong University, Jinan 250031, China; Shandong Provincial Key Medical and Health Laboratory of Intensive Care Rehabilitation, Shandong Provincial Third Hospital, Cheeloo College of Medicine, Shandong University, Jinan 250031, China
| | - Junke Ge
- Shandong Provincial Key Medical and Health Laboratory of Intensive Care Rehabilitation, Shandong Provincial Third Hospital, Cheeloo College of Medicine, Shandong University, Jinan 250031, China; Department of Intensive Care Medicine, Shandong Provincial Third Hospital, Cheeloo College of Medicine, Shandong University, Jinan 250031, China
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Späth MR, Hoyer-Allo KJR, Seufert L, Höhne M, Lucas C, Bock T, Isermann L, Brodesser S, Lackmann JW, Kiefer K, Koehler FC, Bohl K, Ignarski M, Schiller P, Johnsen M, Kubacki T, Grundmann F, Benzing T, Trifunovic A, Krüger M, Schermer B, Burst V, Müller RU. Organ Protection by Caloric Restriction Depends on Activation of the De Novo NAD+ Synthesis Pathway. J Am Soc Nephrol 2023; 34:772-792. [PMID: 36758124 PMCID: PMC10125653 DOI: 10.1681/asn.0000000000000087] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2022] [Accepted: 01/10/2023] [Indexed: 02/11/2023] Open
Abstract
SIGNIFICANCE STATEMENT AKI is a major clinical complication leading to high mortality, but intensive research over the past decades has not led to targeted preventive or therapeutic measures. In rodent models, caloric restriction (CR) and transient hypoxia significantly prevent AKI and a recent comparative transcriptome analysis of murine kidneys identified kynureninase (KYNU) as a shared downstream target. The present work shows that KYNU strongly contributes to CR-mediated protection as a key player in the de novo nicotinamide adenine dinucleotide biosynthesis pathway. Importantly, the link between CR and NAD+ biosynthesis could be recapitulated in a human cohort. BACKGROUND Clinical practice lacks strategies to treat AKI. Interestingly, preconditioning by hypoxia and caloric restriction (CR) is highly protective in rodent AKI models. However, the underlying molecular mechanisms of this process are unknown. METHODS Kynureninase (KYNU) knockout mice were generated by Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR) and comparative transcriptome, proteome and metabolite analyses of murine kidneys pre- and post-ischemia-reperfusion injury in the context of CR or ad libitum diet were performed. In addition, acetyl-lysin enrichment and mass spectrometry were used to assess protein acetylation. RESULTS We identified KYNU as a downstream target of CR and show that KYNU strongly contributes to the protective effect of CR. The KYNU-dependent de novo nicotinamide adenine dinucleotide (NAD+) biosynthesis pathway is necessary for CR-associated maintenance of NAD+ levels. This finding is associated with reduced protein acetylation in CR-treated animals, specifically affecting enzymes in energy metabolism. Importantly, the effect of CR on de novo NAD+ biosynthesis pathway metabolites can be recapitulated in humans. CONCLUSIONS CR induces the de novo NAD+ synthesis pathway in the context of IRI and is essential for its full nephroprotective potential. Differential protein acetylation may be the molecular mechanism underlying the relationship of NAD+, CR, and nephroprotection.
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Affiliation(s)
- Martin R. Späth
- Department II of Internal Medicine and Center for Molecular Medicine Cologne, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany
- CECAD, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany
| | - K. Johanna R. Hoyer-Allo
- Department II of Internal Medicine and Center for Molecular Medicine Cologne, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany
- CECAD, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany
| | - Lisa Seufert
- Department II of Internal Medicine and Center for Molecular Medicine Cologne, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany
- CECAD, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany
| | - Martin Höhne
- Department II of Internal Medicine and Center for Molecular Medicine Cologne, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany
| | - Christina Lucas
- CECAD, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany
| | - Theresa Bock
- CECAD, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany
- Institute of Genetics, University of Cologne, Cologne, Germany
| | - Lea Isermann
- CECAD, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany
- Medical Faculty, Institute for Mitochondrial Diseases and Aging, University of Cologne, Cologne, Germany
- Center for Molecular Medicine (CMMC), University of Cologne, Cologne, Germany
| | - Susanne Brodesser
- CECAD, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany
| | - Jan-Wilm Lackmann
- CECAD, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany
| | - Katharina Kiefer
- Department II of Internal Medicine and Center for Molecular Medicine Cologne, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany
- CECAD, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany
| | - Felix C. Koehler
- Department II of Internal Medicine and Center for Molecular Medicine Cologne, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany
- CECAD, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany
| | - Katrin Bohl
- Department II of Internal Medicine and Center for Molecular Medicine Cologne, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany
- CECAD, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany
| | - Michael Ignarski
- Department II of Internal Medicine and Center for Molecular Medicine Cologne, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany
- CECAD, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany
| | - Petra Schiller
- Institute of Medical Statistics and Computational Biology, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany
| | - Marc Johnsen
- Department II of Internal Medicine and Center for Molecular Medicine Cologne, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany
- CECAD, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany
| | - Torsten Kubacki
- Department II of Internal Medicine and Center for Molecular Medicine Cologne, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany
- CECAD, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany
| | - Franziska Grundmann
- Department II of Internal Medicine and Center for Molecular Medicine Cologne, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany
| | - Thomas Benzing
- Department II of Internal Medicine and Center for Molecular Medicine Cologne, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany
- CECAD, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany
| | - Aleksandra Trifunovic
- CECAD, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany
- Medical Faculty, Institute for Mitochondrial Diseases and Aging, University of Cologne, Cologne, Germany
- Center for Molecular Medicine (CMMC), University of Cologne, Cologne, Germany
| | - Marcus Krüger
- CECAD, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany
- Institute of Genetics, University of Cologne, Cologne, Germany
- Center for Molecular Medicine (CMMC), University of Cologne, Cologne, Germany
| | - Bernhard Schermer
- Department II of Internal Medicine and Center for Molecular Medicine Cologne, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany
- CECAD, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany
| | - Volker Burst
- Department II of Internal Medicine and Center for Molecular Medicine Cologne, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany
- Emergency Department, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany
| | - Roman-Ulrich Müller
- Department II of Internal Medicine and Center for Molecular Medicine Cologne, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany
- CECAD, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany
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Huang J, Wang Z, Zhang X, Gou Y, Li J, Guan S, Zhang H. Lipidomics Study of Sepsis-Induced Liver and Lung Injury under Anti-HMGB1 Intervention. J Proteome Res 2023. [DOI: 10.1021/acs.jproteome.2c00851] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 04/03/2023]
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Chen Z, Wang Z, Liu D, Zhao X, Ning S, Liu X, Wang G, Zhang F, Luo F, Yao J, Tian X. Critical role of caveolin-1 in intestinal ischemia reperfusion by inhibiting protein kinase C βII. Free Radic Biol Med 2023; 194:62-70. [PMID: 36410585 DOI: 10.1016/j.freeradbiomed.2022.11.030] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/18/2022] [Revised: 10/24/2022] [Accepted: 11/17/2022] [Indexed: 11/19/2022]
Abstract
Intestinal ischemia reperfusion (I/R) is a common clinical pathological process. We previously reported that pharmacological inhibition of protein kinase C (PKC) βII with a specific inhibitor attenuated gut I/R injury. However, the endogenous regulatory mechanism of PKCβII inactivation is still unclear. Here, we explored the critical role of caveolin-1 (Cav1) in protecting against intestinal I/R injury by regulating PKCβII inactivation. PKCβII translocated to caveolae and bound with Cav1 after intestinal I/R. Cav1 was highly expressed in the intestine of mice with I/R and IEC-6 cells stimulated with hypoxia/reoxygenation (H/R). Cav1-knockout (KO) mice suffered from worse intestinal injury after I/R than wild-type (WT) mice and showed extremely low survival due to exacerbated systemic inflammatory response syndrome (SIRS) and remote organ (lung and liver) injury. Cav1 deficiency resulted in excessive PKCβII activation and increased oxidative stress and apoptosis after intestinal I/R. Full-length Cav1 scaffolding domain peptide (CSP) suppressed excessive PKCβII activation and protected the gut against oxidative stress and apoptosis due to I/R injury. In summary, Cav1 could regulate PKCβII endogenous inactivation to alleviate intestinal I/R injury. This finding may represent a novel therapeutic strategy for the prevention and treatment of intestinal I/R injury.
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Affiliation(s)
- Zhao Chen
- Department of General Surgery, Second Affiliated Hospital, Dalian Medical University, 116023, Dalian, China
| | - Zhecheng Wang
- Department of Pharmacology, Dalian Medical University, 116044, Dalian, China
| | - Deshun Liu
- Department of General Surgery, Second Affiliated Hospital, Dalian Medical University, 116023, Dalian, China
| | - Xuzi Zhao
- Department of General Surgery, Second Affiliated Hospital, Dalian Medical University, 116023, Dalian, China
| | - Shili Ning
- Department of General Surgery, Second Affiliated Hospital, Dalian Medical University, 116023, Dalian, China
| | - Xingming Liu
- Department of General Surgery, Second Affiliated Hospital, Dalian Medical University, 116023, Dalian, China
| | - Guangzhi Wang
- Department of General Surgery, Second Affiliated Hospital, Dalian Medical University, 116023, Dalian, China
| | - Feng Zhang
- Department of General Surgery, Second Affiliated Hospital, Dalian Medical University, 116023, Dalian, China
| | - Fuwen Luo
- Department of General Surgery, Second Affiliated Hospital, Dalian Medical University, 116023, Dalian, China
| | - Jihong Yao
- Department of Pharmacology, Dalian Medical University, 116044, Dalian, China
| | - Xiaofeng Tian
- Department of General Surgery, Second Affiliated Hospital, Dalian Medical University, 116023, Dalian, China.
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de Oliveira T, Gonçalves G. Ovarian hormones influence immune response to liver ischemia-reperfusion. Braz J Med Biol Res 2023; 56:e12650. [PMID: 36946841 PMCID: PMC10021499 DOI: 10.1590/1414-431x2023e12650] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2022] [Accepted: 02/07/2023] [Indexed: 03/22/2023] Open
Abstract
Liver injury occurs after ischemia and reperfusion (IR), as seen in transplant settings. Sex hormones have been implicated in many pathophysiological mechanisms in females and this could lead to liver protection under inflammatory reperfusion conditions where an excessive immune response occurs. Despite such assumptions, this fact needs to be further investigated. To address this, female and male C57BL/6J mice (8-12 weeks old) were studied. Bilateral ovariectomy (OVX) was performed in females to decrease estradiol levels. IR was performed, and after two weeks, all animals underwent a sham control operation or IR with euthanasia at the following time points after reperfusion: 6, 12, 24, and 48 h. IR triggered an inflammatory process in the liver with recruitment of neutrophils into the parenchyma of male mice. The female sham mice were protected against liver IR presenting no alteration of aminotransferase (ALT) levels compared to males. OVX caused loss of protection, increasing hepatic injury as represented by increased ALT levels and myeloperoxidase (MPO) activity. Female sham mice showed increased Akt phosphorylation and activation, while males showed reduced Akt activation. Estradiol pretreatment recovered ALT levels after IR injury, which was associated with decreased liver injury.
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Affiliation(s)
- T.H.C. de Oliveira
- Departamento de Fisiologia e Biofísica, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Belo Horizonte, MG, Brasil
- Faculdade Ciências Médicas de Minas Gerais, Belo Horizonte, MG, Brasil
| | - G.K.N. Gonçalves
- Departamento de Fisiologia e Biofísica, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Belo Horizonte, MG, Brasil
- Faculdade Ciências Médicas de Minas Gerais, Belo Horizonte, MG, Brasil
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Hamed MA, Akhigbe RE, Aremu AO, Odetayo AF. Zinc normalizes hepatic lipid handling via modulation of ADA/XO/UA pathway and caspase 3 signaling in highly active antiretroviral therapy-treated Wistar rats. Chem Biol Interact 2022; 368:110233. [PMID: 36309141 DOI: 10.1016/j.cbi.2022.110233] [Citation(s) in RCA: 24] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2022] [Revised: 10/17/2022] [Accepted: 10/21/2022] [Indexed: 11/23/2022]
Abstract
BACKGROUND Although highly active antiretroviral therapy (HAART) is effective in the management of HIV, it has been reported to induce hepatic injury and non-alcoholic fatty liver (NAFLD). However, there is a lack of data on the roles of the adenosine deaminase (ADA)/xanthine oxidase (XO)/uric acid (UA) pathway and caspase 3 signaling in HAART-induced NAFLD. Also, whether or not zinc confers protection against HAART-induced NAFLD is not known. AIM This study evaluated the involvement of the ADA/XO/UA pathway and caspase 3 signaling in HAART-induced hepatic lipid accumulation. It also evaluated the possible protective effect of zinc in HAART-induced hepatic lipid accumulation and injury. METHODS Thirty two male Wistar rats (n = 8/group) were assigned into four groups namely; vehicle-treated (p.o), zinc-treated (3 mg/kg/day of elemental zinc; p.o), HAART-treated (a cocktail of 52.9 mg/kg of Efavirenz, 26.48 mg/kg of Lamivudine, and 26.48 mg/kg of Tenofovir; p.o), and HAART + zinc-treated groups. The treatment lasted for 8 weeks. RESULTS HAART administration led to increased body weight and hepatic weight, but unaltered hepatic organo-somatic index. HAART exposure also resulted in impaired glucose homeostasis, evidenced by increased fasting blood glucose, hyperinsulinemia, and insulin resistance (IR), increased plasma and hepatic cholesterol and triglycerides, and impaired hepatic function as depicted by elevated hepatic injury markers and reduced glycogen synthase activity and glycogen content. These findings were accompanied by increased plasma and hepatic ADA and XO activities, UA and malondialdehyde levels, inflammatory markers, and caspase 3 activities. However, HAART suppressed plasma and hepatic antioxidant defenses. Furthermore, HAART distorted hepatic histoarchitecture and reduced hepatic sinusoidal diameter. Co-administration of zinc with HAART normalized HAART-induced alterations. CONCLUSIONS These findings showed that downregulation of the ADA/XO/UA pathway and caspase 3 signalings may rescue the liver from HAART-induced lipid accumulation and injury.
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Affiliation(s)
- M A Hamed
- Department of Medical Laboratory Sciences, Afe Babalola University, Ado-Ekiti, Ekiti State, Nigeria; The Brainwill Laboratory, Osogbo, Osun State, Nigeria; Reproductive Biology and Toxicology Research Laboratory, Oasis of Grace Hospital, Osogbo, Osun State, Nigeria
| | - R E Akhigbe
- Reproductive Biology and Toxicology Research Laboratory, Oasis of Grace Hospital, Osogbo, Osun State, Nigeria; Department of Physiology, Ladoke Akintola University of Technology, Ogbomoso, Oyo State, Nigeria.
| | - A O Aremu
- Reproductive Biology and Toxicology Research Laboratory, Oasis of Grace Hospital, Osogbo, Osun State, Nigeria; Department of Morbid Anatomy, Obafemi Awolowo University Teaching Hospital Complex (OAUTHC), Ile Ife, Osun State, Nigeria
| | - A F Odetayo
- Reproductive Biology and Toxicology Research Laboratory, Oasis of Grace Hospital, Osogbo, Osun State, Nigeria; Department of Physiology, University of Ilorin, Ilorin, Kwara State, Nigeria
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Nakatake R, Schulz M, Kalvelage C, Benstoem C, Tolba RH. Effects of iNOS in Hepatic Warm Ischaemia and Reperfusion Models in Mice and Rats: A Systematic Review and Meta-Analysis. Int J Mol Sci 2022; 23:ijms231911916. [PMID: 36233220 PMCID: PMC9569681 DOI: 10.3390/ijms231911916] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2022] [Revised: 09/26/2022] [Accepted: 09/26/2022] [Indexed: 12/09/2022] Open
Abstract
Warm ischaemia is usually induced by the Pringle manoeuver (PM) during hepatectomy. Currently, there is no widely accepted standard protocol to minimise ischaemia-related injury, so reducing ischaemia-reperfusion damage is an active area of research. This systematic review and meta-analysis focused on inducible nitric oxide synthase (iNOS) as an early inflammatory response to hepatic ischaemia reperfusion injury (HIRI) in mouse- and rat-liver models. A systematic search of studies was performed within three databases. Studies meeting the inclusion criteria were subjected to qualitative and quantitative synthesis of results. We performed a meta-analysis of studies grouped by different HIRI models and ischaemia times. Additionally, we investigated a possible correlation of endothelial nitric oxide synthase (eNOS) and nitric oxide (NO) regulation with iNOS expression. Of 124 included studies, 49 were eligible for the meta-analysis, revealing that iNOS was upregulated in almost all HIRIs. We were able to show an increase of iNOS regardless of ischemia or reperfusion time. Additionally, we found no direct associations of eNOS or NO with iNOS. A sex gap of primarily male experimental animals used was observed, leading to a higher risk of outcomes not being translatable to humans of all sexes.
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Affiliation(s)
- Richi Nakatake
- Institute for Laboratory Animal Science and Experimental Surgery, RWTH Aachen University, 52074 Aachen, Germany
- Department of Surgery, Kansai Medical University, 2-5-1 Shinmachi, Hirakata, Osaka 573-1010, Japan
| | - Mareike Schulz
- Institute for Laboratory Animal Science and Experimental Surgery, RWTH Aachen University, 52074 Aachen, Germany
| | - Christina Kalvelage
- Department of Intensive Care Medicine, Medical Faculty, RWTH Aachen University, 52074 Aachen, Germany
| | - Carina Benstoem
- Department of Intensive Care Medicine, Medical Faculty, RWTH Aachen University, 52074 Aachen, Germany
| | - René H. Tolba
- Institute for Laboratory Animal Science and Experimental Surgery, RWTH Aachen University, 52074 Aachen, Germany
- Correspondence:
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Afolabi OA, Akhigbe TM, Akhigbe RE, Alabi BA, Gbolagun OT, Taiwo ME, Fakeye OO, Yusuf EO. Methanolic Moringa oleifera leaf extract protects against epithelial barrier damage and enteric bacterial translocation in intestinal I/R: Possible role of caspase 3. Front Pharmacol 2022; 13:989023. [PMID: 36210817 PMCID: PMC9546449 DOI: 10.3389/fphar.2022.989023] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2022] [Accepted: 09/05/2022] [Indexed: 11/25/2022] Open
Abstract
Background: Activation of caspase 3 has been implicated in the pathogenesis of I/R injury in various organs, but there is a paucity of data on its role in IIRI. Also, no reports were found on the beneficial role of methanolic Moringa oleifera leaf extract (MMOLE) in IIRI. This study investigated the involvement of caspase 3 in IIRI, and the impact of MMOLE in IIRI. Methods: Male Wistar rats were randomized into five groups; the sham-operated group that was sham-operated and received 0.5 ml of distilled water for 7 days prior to sham surgery, and the IIRI, febuxostat (FEB) +IIRI, low dose MMOLE (LDMO)+IIRI, and high dose MMOLE (HDMO)+IIRI groups that underwent I/R and also received 0.5 ml of distilled water, 10 mg/kg of febuxostat, 200 mg/kg of MMOLE, and 400 mg/kg of MMOLE respectively for 7 days prior to I/R. Markers of hepatic function, oxidative stress, and inflammation as well as enteric bacterial translocation and histoarchitecture integrity of intestinal and hepatic tissues were evaluated. The bioactive components of MMOLE were also determined by GC-MS. Results: As revealed by GC-MS, the active bioactive components of MMOLE were thiosemicarbazone, hydrazine, 1,3-dioxolane, octanoic acid, 1,3-benzenediamine, 9-octadecenoic acid, oleic acid, nonadecanoic acid, 3-undecanone, phosphonic acid, and cyclopentanecarboxylic acid. MMOLE alleviated IIRI-induced rise in intestinal and hepatic injury markers, malondialdehyde, TNF-α, IL-6, and myeloperoxidase activities. MMOLE improved IIRI-induced suppression of reduced glutathione, thiol and non-thiol proteins, and superoxide dismutase, catalase and glutathione peroxidase activities. These were associated with suppression of IIRI-induced caspase 3 activity and bacterial translocation. Histopathological evaluation revealed that MMOLE attenuated IIRI-induced alterations in intestinal and hepatic histoarchitecture integrity. MMOLE also militated against increased absolute and relative intestinal and hepatic weight, intestinal and hepatic injuries, epithelial mucosal barrier dysfunction, and enteric bacterial translocation associated with IIRI by downregulating oxidative stress-mediated activation of caspase 3. Conclusion: IIRI is associated with a rise in caspase 3 activity. Also, MMOLE confers protection against IIRI, possibly due to its constituent bioactive molecules, especially hydrazine, 9-octadecenoic acid, 1,3-dioxolane, oleic acid, and nonadecanoic acid.
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Affiliation(s)
- O A. Afolabi
- Department of Physiology, Ladoke Akintola University of Technology, Ogbomoso, Oyo, Nigeria
| | - T M. Akhigbe
- Department of Agronomy, Osun State University, Osogbo, Osun, Nigeria
- Reproductive Biology and Toxicology Research Laboratory, Oasis of Grace Hospital, Osogbo, Osun, Nigeria
| | - R E. Akhigbe
- Department of Physiology, Ladoke Akintola University of Technology, Ogbomoso, Oyo, Nigeria
- Reproductive Biology and Toxicology Research Laboratory, Oasis of Grace Hospital, Osogbo, Osun, Nigeria
| | - B A. Alabi
- Department of Pharmacology, Bowen University, Ogbomoso, Nigeria
| | - O T. Gbolagun
- Department of Physiology, Ladoke Akintola University of Technology, Ogbomoso, Oyo, Nigeria
| | - M E. Taiwo
- Department of Physiology, Ladoke Akintola University of Technology, Ogbomoso, Oyo, Nigeria
| | - O O. Fakeye
- Department of Physiology, Ladoke Akintola University of Technology, Ogbomoso, Oyo, Nigeria
| | - E O. Yusuf
- Department of Physiology, Ladoke Akintola University of Technology, Ogbomoso, Oyo, Nigeria
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Afolabi AO, Akhigbe TM, Odetayo AF, Anyogu DC, Hamed MA, Akhigbe RE. Restoration of Hepatic and Intestinal Integrity by Phyllanthus amarus Is Dependent on Bax/Caspase 3 Modulation in Intestinal Ischemia-/Reperfusion-Induced Injury. Molecules 2022; 27:5073. [PMID: 36014309 PMCID: PMC9413108 DOI: 10.3390/molecules27165073] [Citation(s) in RCA: 20] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2022] [Revised: 05/25/2022] [Accepted: 05/27/2022] [Indexed: 11/30/2022] Open
Abstract
Ethnopharmacological relevance: Oxidative stress is a key player in intestinal ischemia/reperfusion (I/R) injury (IIRI) with a tendency to trigger systemic inflammatory response, resulting in progressive distal organ injury. To date, the role of Bax/caspase 3 signaling in IIRI has not been reported. Furthermore, the discovery of a safe and effective drug remains pertinent in improving the outcome of IIRI. Therefore, this study investigated the role of Bax/caspase 3 signaling in intestinal I/R-induced intestinal and hepatic injury. In addition, the protective effect and possible associated mechanism of action of methanolic Phyllanthus amarus leaf extract (PA) against intestinal I/R-induced intestinal and hepatic injury were evaluated. Materials and methods: Fifty male Wistar rats were randomized into five groups (n = 10). The sham-operated group was received 0.5 mL of distilled water for seven days prior to the sham surgery, while the IIRI, febuxostat (FEB) + IIRI, low-dose PA (LDPA) + IIRI, and high-dose PA (HDPA) + IIRI groups underwent the I/R procedure. In addition to the procedure, IIRI, FEB + IIRI, LDPA + IIRI, and HDPA + IIRI received 0.5 mL of distilled water, 10 mg/kg of febuxostat, 200 mg/kg of PA, and 400 mg/kg of PA, respectively, for seven days prior to the I/R procedure. Results: Administration of methanolic Phyllanthus amarus leaf extracts attenuated the intestinal I/R-induced rise in intestinal and hepatic injury markers, malondialdehyde, nitric oxide, TNF-α, IL-6, and myeloperoxidase activities. In addition, Phyllanthus amarus ameliorated I/R-induced suppression of reduced glutathione, thiol and non-thiol proteins, and superoxide dismutase, catalase, and glutathione peroxidase activities in intestinal and hepatic tissues. These were coupled with the suppression of I/R-induced bacterial translocation, downregulation of I/R-induced activation of Bax/caspase 3 signaling, and improvement of I/R-induced distortion of intestinal and hepatic histoarchitecture by Phyllanthus amarus. Conclusion: Methanolic Phyllanthus amarus leaf extract protects against intestinal and hepatic injuries associated with intestinal I/R by suppressing oxidative-stress-mediated activation of Bax/caspase 3 signaling. The beneficial effects of Phyllanthus amarus may be ascribed to its constituent bioactive molecules, especially tannins, anthocyanin, alkaloids, and phenolics.
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Affiliation(s)
- Ayobami Oladele Afolabi
- Department of Physiology, Ladoke Akintola University of Technology, Ogbomoso 210214, Oyo State, Nigeria
| | - Tunmise Maryanne Akhigbe
- Department of Agronomy, Osun State University, Osogbo 210001, Osun State, Nigeria
- Reproductive Biology and Toxicology Research Laboratory, Oasis of Grace Hospital, Osogbo 210001, Osun State, Nigeria or
| | - Adeyemi Fatai Odetayo
- Reproductive Biology and Toxicology Research Laboratory, Oasis of Grace Hospital, Osogbo 210001, Osun State, Nigeria or
- Department of Physiology, University of Ilorin, Ilorin 240003, Kwara State, Nigeria
| | - Davinson Chuka Anyogu
- Department of Veterinary Pathology and Microbiology, University of Nigeria, Nsukka 410001, Enugu State, Nigeria
| | - Moses Agbomhere Hamed
- Reproductive Biology and Toxicology Research Laboratory, Oasis of Grace Hospital, Osogbo 210001, Osun State, Nigeria or
- The Brainwill Laboratory, Osogbo 210001, Osun State, Nigeria
- Department of Medical Laboratory Science, College of Medicine and Health Sciences, Afe Babalola University, Ado Ekiti 360001, Ekiti State, Nigeria
| | - Roland Eghoghosoa Akhigbe
- Department of Physiology, Ladoke Akintola University of Technology, Ogbomoso 210214, Oyo State, Nigeria
- Reproductive Biology and Toxicology Research Laboratory, Oasis of Grace Hospital, Osogbo 210001, Osun State, Nigeria or
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10
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Caloric restriction reduces the pro-inflammatory eicosanoid 20- hydroxyeicosatetraenoic acid to protect from acute kidney injury. Kidney Int 2022; 102:560-576. [PMID: 35654224 DOI: 10.1016/j.kint.2022.04.033] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2021] [Revised: 04/13/2022] [Accepted: 04/22/2022] [Indexed: 11/22/2022]
Abstract
Acute kidney injury is a frequent complication in the clinical setting and associated with significant morbidity and mortality. Preconditioning with short-term caloric restriction is highly protective against kidney injury in rodent ischemia reperfusion injury models. However, the underlying mechanisms are unknown hampering clinical translation. Here, we examined the molecular basis of caloric restriction-mediated protection to elucidate the principles of kidney stress resistance. Analysis of an RNAseq dataset after caloric restriction identified Cyp4a12a, a cytochrome exclusively expressed in male mice, to be strongly downregulated after caloric restriction. Kidney ischemia reperfusion injury robustly induced acute kidney injury in male mice and this damage could be markedly attenuated by pretreatment with caloric restriction. In females, damage was significantly less pronounced and preconditioning with caloric restriction had only little effect. Tissue concentrations of the metabolic product of Cyp4a12a, 20-hydroxyeicosatetraenoic acid (20-HETE), were found to be significantly reduced by caloric restriction. Conversely, intraperitoneal supplementation of 20-HETE in preconditioned males partly abrogated the protective potential of caloric restriction. Interestingly, this effect was accompanied by a partial reversal of caloric restriction-induced changes in protein but not RNA expression pointing towards inflammation, endoplasmic reticulum stress and lipid metabolism. Thus, our findings provide an insight into the mechanisms underlying kidney protection by caloric restriction. Hence, understanding the mediators of preconditioning is an important pre-requisite for moving towards translation to the clinical setting.
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11
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Zhang YN, Chang ZN, Liu ZM, Wen SH, Zhan YQ, Lai HJ, Zhang HF, Guo Y, Zhang XY. Dexmedetomidine Alleviates Gut-Vascular Barrier Damage and Distant Hepatic Injury Following Intestinal Ischemia/Reperfusion Injury in Mice. Anesth Analg 2021; 134:419-431. [PMID: 34889823 DOI: 10.1213/ane.0000000000005810] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
BACKGROUND Intestinal ischemia/reperfusion (I/R) challenge often results in gut barrier dysfunction and induces distant organ injury. Dexmedetomidine has been shown to protect intestinal epithelial barrier against I/R attack. The present study aims to investigate the degree to which intestinal I/R attack will contribute to gut-vascular barrier (GVB) damage, and to examine the ability of dexmedetomidine to minimize GVB and liver injuries in mice. METHODS In vivo, intestinal ischemic challenge was induced in mice by clamping the superior mesenteric artery for 45 minutes. After clamping, the mice were subjected to reperfusion for either 2, 4, 6, or 12 hours. Intraperitoneal injection of dexmedetomidine 15, 20, or 25 μg·kg-1 was performed intermittently at the phase of reperfusion. For the in vitro experiments, the challenge of oxygen-glucose deprivation/reoxygenation (OGD/R) was established in cultured vascular endothelial cells, and dexmedetomidine (1 nM) was used to treat the cells for 24 hours. Moreover, in vivo and in vitro, SKL2001 (a specific agonist of β-catenin) or XAV939 (a specific inhibitor of β-catenin) was applied to determine the role of β-catenin in the impacts provided by dexmedetomidine. RESULTS The attack of intestinal I/R induced GVB damage. The greatest level of damage was observed at 4 hours after intestinal reperfusion. There was a significant increase in plasmalemma vesicle-associated protein-1 (PV1, a specific biomarker for endothelial permeability) expression (5.477 ± 0.718 vs 1.000 ± 0.149; P < .001), and increased translocation of intestinal macromolecules and bacteria to blood and liver tissues was detected (all P < .001). Liver damages were observed. There were significant increases in histopathological scores, serum parameters, and inflammatory factors (all P < .001). Dexmedetomidine 20 μg·kg-1 reduced PV1 expression (0.466 ± 0.072 vs 1.000 ± 0.098; P < .001) and subsequent liver damages (all P < .01). In vitro, dexmedetomidine significantly improved vascular endothelial cell survival (79.387 ± 6.447% vs 50.535 ± 1.766%; P < .001) and increased the productions of tight junction protein and adherent junction protein (all P < .01) following OGD/R. Importantly, in cultured cells and in mice, β-catenin expression significantly decreased (both P < .001) following challenge. Dexmedetomidine or SKL2001 upregulated β-catenin expression and produced protective effects (all P < .01). However, XAV939 completely eliminated the protective effects of dexmedetomidine on GVB (all P < .001). CONCLUSIONS The disruption of GVB occurred following intestinal I/R. Dexmedetomidine alleviated I/R-induced GVB impairment and subsequent liver damage.
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Affiliation(s)
| | - Ze-Nan Chang
- Critical Care Medicine, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Zi-Meng Liu
- Critical Care Medicine, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | | | | | - Han-Jin Lai
- Critical Care Medicine, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | | | - Yi Guo
- From the Departments of Anesthesiology
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12
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Cienfuegos-Pecina E, Moreno-Peña DP, Torres-González L, Rodríguez-Rodríguez DR, Garza-Villarreal D, Mendoza-Hernández OH, Flores-Cantú RA, Samaniego Sáenz BA, Alarcon-Galvan G, Muñoz-Espinosa LE, Ibarra-Rivera TR, Saucedo AL, Cordero-Pérez P. Treatment with sodium ( S)-2-hydroxyglutarate prevents liver injury in an ischemia-reperfusion model in female Wistar rats. PeerJ 2021; 9:e12426. [PMID: 34824916 PMCID: PMC8592047 DOI: 10.7717/peerj.12426] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2021] [Accepted: 10/11/2021] [Indexed: 12/24/2022] Open
Abstract
Background Ischemia-reperfusion (IR) injury is one of the leading causes of early graft dysfunction in liver transplantation. Techniques such as ischemic preconditioning protect the graft through the activation of the hypoxia-inducible factors (HIF), which are downregulated by the EGLN family of prolyl-4-hydroxylases, a potential biological target for the development of strategies based on pharmacological preconditioning. For that reason, this study aims to evaluate the effect of the EGLN inhibitor sodium (S)-2-hydroxyglutarate [(S)-2HG] on liver IR injury in Wistar rats. Methods Twenty-eight female Wistar rats were divided into the following groups: sham (SH, n = 7), non-toxicity (HGTox, n = 7, 25 mg/kg of (S)-2HG, twice per day for two days), IR (n = 7, total liver ischemia: 20 minutes, reperfusion: 60 minutes), and (S)-2HG+IR (HGIR, n = 7, 25 mg/kg of (S)-2HG, twice per day for two days, total liver ischemia as the IR group). Serum ALT, AST, LDH, ALP, glucose, and total bilirubin were assessed. The concentrations of IL-1β, IL-6, TNF, malondialdehyde, superoxide dismutase, and glutathione peroxidase were measured in liver tissue, as well as the expression of Hmox1, Vegfa, and Pdk1, determined by RT-qPCR. Sections of liver tissue were evaluated histologically, assessing the severity of necrosis, sinusoidal congestion, and cytoplasmatic vacuolization. Results The administration of (S)-2HG did not cause any alteration in the assessed biochemical markers compared to SH. Preconditioning with (S)-2HG significantly ameliorated IR injury in the HGIR group, decreasing the serum activities of ALT, AST, and LDH, and the tissue concentrations of IL-1β and IL-6 compared to the IR group. IR injury decreased serum glucose compared to SH. There were no differences in the other biomarkers assessed. The treatment with (S)-2HG tended to decrease the severity of hepatocyte necrosis and sinusoidal congestion compared to the IR group. The administration of (S)-2HG did not affect the expression of Hmox1 but decreased the expression of both Vegfa and Pdk1 compared to the SH group, suggesting that the HIF-1 pathway is not involved in its mechanism of hepatoprotection. In conclusion, (S)-2HG showed a hepatoprotective effect, decreasing the levels of liver injury and inflammation biomarkers, without evidence of the involvement of the HIF-1 pathway. No hepatotoxic effect was observed at the tested dose.
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Affiliation(s)
- Eduardo Cienfuegos-Pecina
- Universidad Autónoma de Nuevo León. Liver Unit, Department of Internal Medicine, University Hospital "Dr. José E. González", Monterrey, Nuevo León, Mexico.,Universidad Autónoma de Nuevo León. Blood Bank, Department of Clinical Pathology, University Hospital "Dr. José E. González", Monterrey, Nuevo León, Mexico
| | - Diana P Moreno-Peña
- Universidad Autónoma de Nuevo León. Liver Unit, Department of Internal Medicine, University Hospital "Dr. José E. González", Monterrey, Nuevo León, Mexico
| | - Liliana Torres-González
- Universidad Autónoma de Nuevo León. Liver Unit, Department of Internal Medicine, University Hospital "Dr. José E. González", Monterrey, Nuevo León, Mexico
| | - Diana Raquel Rodríguez-Rodríguez
- Universidad Autónoma de Nuevo León. Liver Unit, Department of Internal Medicine, University Hospital "Dr. José E. González", Monterrey, Nuevo León, Mexico
| | - Diana Garza-Villarreal
- Universidad Autónoma de Nuevo León. Liver Unit, Department of Internal Medicine, University Hospital "Dr. José E. González", Monterrey, Nuevo León, Mexico
| | - Oscar H Mendoza-Hernández
- Universidad Autónoma de Nuevo León. Liver Unit, Department of Internal Medicine, University Hospital "Dr. José E. González", Monterrey, Nuevo León, Mexico
| | - Raul Alejandro Flores-Cantú
- Universidad Autónoma de Nuevo León. Liver Unit, Department of Internal Medicine, University Hospital "Dr. José E. González", Monterrey, Nuevo León, Mexico
| | - Brenda Alejandra Samaniego Sáenz
- Universidad Autónoma de Nuevo León. Liver Unit, Department of Internal Medicine, University Hospital "Dr. José E. González", Monterrey, Nuevo León, Mexico
| | - Gabriela Alarcon-Galvan
- Universidad de Monterrey, Basic Science Department, School of Medicine, Monterrey, Nuevo León, Mexico
| | - Linda E Muñoz-Espinosa
- Universidad Autónoma de Nuevo León. Liver Unit, Department of Internal Medicine, University Hospital "Dr. José E. González", Monterrey, Nuevo León, Mexico
| | - Tannya R Ibarra-Rivera
- Universidad Autónoma de Nuevo León. Department of Analytical Chemistry, School of Medicine, Monterrey, Nuevo León, Mexico
| | - Alma L Saucedo
- Universidad Autónoma de Nuevo León. Department of Analytical Chemistry, School of Medicine, Monterrey, Nuevo León, Mexico
| | - Paula Cordero-Pérez
- Universidad Autónoma de Nuevo León. Liver Unit, Department of Internal Medicine, University Hospital "Dr. José E. González", Monterrey, Nuevo León, Mexico
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13
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Liu H, Li J, Jiang C, Yuan T, Ma H. Cellular communication network factor 1 (CCN1) knockdown exerts a protective effect for hepatic ischemia/reperfusion injury by deactivating the MEK/ERK pathway. Clin Res Hepatol Gastroenterol 2021; 45:101737. [PMID: 34144219 DOI: 10.1016/j.clinre.2021.101737] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/15/2021] [Revised: 05/21/2021] [Accepted: 05/26/2021] [Indexed: 02/06/2023]
Abstract
OBJECTIVE Hepatic ischemia/reperfusion injury (IRI) is an unsettled and intractable conundrum in clinical treatment after liver transplantation and resection. Cellular communication network factor 1 (CCN1) is upregulated in liver IRI and may play a key role in this process. The objective of this study is to investigate the regulatory mechanism of CCN1 in liver IRI, which may provide new insight into liver IRI clinical treatment. METHODS The hepatic ischemia/reperfusion model was established in male C57BL/6 mice by occlusion of vessels in the liver followed by reperfusion. The mice were transfected with two small interfering RNAs (siRNAs) against CCN1 for CCN1 knockdown. The hypoxia/reoxygenation (HR) model was established in vitro using mouse hepatic cells followed by transfection with a siRNA and treatment with an ERK activator TPA to confirm the effects of CCN1 on the MEK/ERK pathway in liver IRI. RESULTS In hepatic IRI, CCN1 was upregulated and its knockdown reduced alanine aminotransferase and aspartate transaminase levels, myeloperoxidase activity, and the levels of IL-6 and TNF-α. CCN1 downregulation alleviated inflammatory cell infiltration and apoptosis in the liver. The expressions of cleaved caspase-9, cleaved caspase-3, Bax, and CHOP were decreased with an increased Bcl-2 level after CCN1 knockdown. The phosphorylation and activation of proteins in ER stress and MEK/ERK pathway were inhibited by CCN1 knockdown. In vitro, the levels of proinflammatory cytokines, apoptosis-inducing proteins, and proteins in ER stress and MEK/ERK pathway, which were decreased by CCN1 knockdown in HR, were restored by TPA, confirming that the activation of ERK aggravated cell apoptosis after reoxygenation. CONCLUSION Overall, CCN1 knockdown may suppress the inflammation, apoptosis during hepatic IRI by reducing the MEK/ERK pathway activation, which may be a breakthrough point in clinical alleviation of hepatic IRI caused by liver transplantation and resection.
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Affiliation(s)
- Huanqiu Liu
- Department of Anesthesiology, The First Hospital of Jilin University, Changchun, Jilin 130021, China
| | - Ji Li
- Department of Anesthesiology, The First Hospital of Jilin University, Changchun, Jilin 130021, China
| | - Chengwei Jiang
- Department of Pathology, China-Japan Union Hospital of Jilin University, Changchun, Jilin 130033, China
| | - Tong Yuan
- Department of Anesthesiology, The First Hospital of Jilin University, Changchun, Jilin 130021, China.
| | - Haichun Ma
- Department of Anesthesiology, The First Hospital of Jilin University, Changchun, Jilin 130021, China.
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14
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Amiresmaili S, Shahrokhi N, Khaksari M, AsadiKaram G, Aflatoonian MR, Shirazpour S, Amirkhosravi L, Mortazaeizadeh A. The Hepatoprotective mechanisms of 17β-estradiol after traumatic brain injury in male rats: Classical and non-classical estrogen receptors. ECOTOXICOLOGY AND ENVIRONMENTAL SAFETY 2021; 213:111987. [PMID: 33582408 DOI: 10.1016/j.ecoenv.2021.111987] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/19/2020] [Revised: 01/23/2021] [Accepted: 01/25/2021] [Indexed: 06/12/2023]
Abstract
Protective effects of estrogen (E2) on traumatic brain injury (TBI) have been determined. In this study, the hepatoprotective effects of E2 after TBI through its receptors and oxidative stress regulation have been evaluated. Diffuse TBI induced by the Marmarou method in male rats. G15, PHTPP, MPP, and ICI182-780 as selective antagonists of E2 were injected before TBI. The results indicated that TBI induces a significant increase in liver enzymes [Alkaline phosphatase (ALP), Aspartate aminotransferase (AST), Alanine aminotransferase (ALT), Glutamyl transferase (GGT)], and oxidants levels [Malondialdehyde (MDA), Nitric oxide (NO)] and decreases in antioxidant biomarkers [Glutathione peroxidase (GPx) and Superoxide dismutase (SOD)] in the brain and liver, and plasma. We also found that E2 significantly preserved levels of these biomarkers and enzymatic activity. All antagonists inhibited the effects of E2 on increasing SOD and GPx. Also, the effects of E2 on brain MDA levels were inhibited by all antagonists, but in the liver, only ICI + G15 + E2 + TBI group was affected. The impacts of E2 on brain and liver and plasma NO levels were inhibited by all antagonists. The current findings demonstrated that E2 probably improved liver injury after TBI by modulating oxidative stress. Also, both classic (ERβ, ERα) and non-classic [G protein-coupled estrogen receptor (GPER)] receptors are affected in the protective effects of E2.
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Affiliation(s)
- Sedigheh Amiresmaili
- Department of Physiology, Bam University of Medical Sciences, Bam, Iran; Physiology Research Center, Institute of Basic and Clinical Physiology Science, Kerman University of Medical Sciences, Kerman, Iran
| | - Nader Shahrokhi
- Neuroscience Research Center, Institute of Neuropharmacology, Kerman University of Medical Sciences, Kerman, Iran.
| | - Mohammad Khaksari
- Endocrinology and Metabolism Research Center, Institute of Basic and Clinical Physiology Science, Kerman University of Medical Sciences, Kerman, Iran
| | - Gholamreza AsadiKaram
- Physiology Research Center, Institute of Basic and Clinical Physiology Science, Kerman University of Medical Sciences, Kerman, Iran
| | | | - Sara Shirazpour
- Neuroscience Research Center, Institute of Neuropharmacology, Kerman University of Medical Sciences, Kerman, Iran
| | - Ladan Amirkhosravi
- Endocrinology and Metabolism Research Center, Institute of Basic and Clinical Physiology Science, Kerman University of Medical Sciences, Kerman, Iran
| | - Abbas Mortazaeizadeh
- Researcher, Pathology and Stem Cells Research Center, Kerman University of Medical Sciences, Kerman, Iran
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15
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Yang J, Meng M, Pan C, Qian L, Sun Y, Shi H, Shen Y, Dou W. Intravoxel Incoherent Motion and Dynamic Contrast-Enhanced Magnetic Resonance Imaging to Early Detect Tissue Injury and Microcirculation Alteration in Hepatic Injury Induced by Intestinal Ischemia-Reperfusion in a Rat Model. J Magn Reson Imaging 2021; 54:751-760. [PMID: 33749079 PMCID: PMC8451931 DOI: 10.1002/jmri.27604] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2020] [Revised: 02/26/2021] [Accepted: 03/03/2021] [Indexed: 12/21/2022] Open
Abstract
Background Intravoxel incoherent motion (IVIM) can provide quantitative information about water diffusion and perfusion that can be used to evaluate hepatic injury, but it has not been studied in hepatic injury induced by intestinal ischemia–reperfusion (IIR). Dynamic contrast‐enhanced (DCE) magnetic resonance imaging (MRI) can provide perfusion data, but it is unclear whether it can provide useful information for assessing hepatic injury induced by IIR. Purpose To examine whether IVIM and DCE‐MRI can detect early IIR‐induced hepatic changes, and to evaluate the relationship between IVIM and DCE‐derived parameters and biochemical indicators and histological scores. Study Type Prospective pre‐clinical study. Population Forty‐two male Sprague–Dawley rats. Field Strength/Sequence IVIM‐diffusion‐weighted imaging (DWI) using diffusion‐weighted echo‐planar imaging sequence and DCE‐MRI using fast spoiled gradient recalled‐based sequence at 3.0 T. Assessment All rats were randomly divided into the control group (Sham), the simple ischemia group, the ischemia–reperfusion (IR) group (IR1h, IR2h, IR3h, and IR4h) in a model of secondary hepatic injury caused by IIR, and IIR was induced by clamping the superior mesenteric artery for 60 minutes and then removing the vascular clamp. Advanced Workstation (AW) 4.6 was used to calculate the imaging parameters (apparent diffusion coefficient [ADC], true diffusion coefficient [D], perfusion‐related diffusion [D*] and volume fraction [f]) of IVIM. OmniKinetics (OK) software was used to calculate the DCE imaging parameters (Ktrans, Kep, and Ve). Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) were analyzed with an automatic biochemical analyzer. Superoxide dismutase (SOD) activity was assessed using the nitro‐blue tetrazolium method. Malondialdehyde (MDA) was determined by thiobarbituric acid colorimetry. Histopathology was performed with hematoxylin and eosin staining. Statistical Tests One‐way analysis of variance (ANOVA) and Bonferroni post‐hoc tests were used to analyze the imaging parameters and biochemical indicators among the different groups. Pearson correlation analysis was applied to determine the correlation between imaging parameters and biochemical indicators or histological score. Results ALT and MDA reached peak levels at IR4h, while SOD reached the minimum level at IR4h (all P < 0.05). ADC, D, D*, and f gradually decreased as reperfusion continued, and Ktrans and Ve gradually increased (all P < 0.05). The degrees of change for f and Ve were greater than those of other imaging parameters at IR1h (all P < 0.05). All groups showed good correlation between imaging parameters and SOD and MDA (r[ADC] = 0.615, −0.666, r[D] = 0.493, −0.612, r[D*] = 0.607, −0.647, r[f] = 0.637, −0.682, r[Ktrans] = −0.522, 0.500, r[Ve] = −0.590, 0.665, respectively; all P < 0.05). However, the IR groups showed poor or no correlation between the imaging parameters and SOD and MDA (P [Ktrans and MDA] = 0.050, P [D and SOD] = 0.125, P [the remaining imaging parameters] < 0.05). All groups showed a positive correlation between histological score and Ktrans and Ve (r = 0.775, 0.874, all P < 0.05), and a negative correlation between histological score and ADC, D, f, and D* (r = −0.739, −0.821, −0.868, −0.841, respectively; all P < 0.05). For the IR groups, there was a positive correlation between histological score and Ktrans and Ve (r = 0.747, 0.802, all P < 0.05), and a negative correlation between histological score and ADC, D, f, and D* (r = −0.567, −0.712, −0.715, −0.779, respectively; all P < 0.05). Data Conclusion The combined application of IVIM and DCE‐MRI has the potential to be used as an imaging tool for monitoring IIR‐induced hepatic histopathology. Level of Evidence 1 Technical Efficacy Stage 2
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Affiliation(s)
- Jiaxing Yang
- Department of RadiologyChangzhou Second People's HospitalChangzhouChina
- Graduate CollegeDalian Medical UniversityDalianChina
| | - Mingzhu Meng
- Department of RadiologyChangzhou Second People's HospitalChangzhouChina
| | - Changjie Pan
- Department of RadiologyChangzhou Second People's HospitalChangzhouChina
| | - Liulan Qian
- Department of Science and EducationChangzhou Second People's HospitalChangzhouChina
| | - Yangyang Sun
- Department of PathologyChangzhou Second People's HospitalChangzhouChina
| | - Haifeng Shi
- Department of RadiologyChangzhou Second People's HospitalChangzhouChina
| | - Yong Shen
- Department of Enhanced ApplicationGE Healthcare ChinaBeijingChina
| | - Weiqiang Dou
- Department of MR ResearchGE Healthcare ChinaBeijingChina
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Amiresmaili S, Khaksari M, Shahrokhi N, Abolhassani M. Evolution of TLR4 role in mediating the hepatoprotective effects of estradiol after traumatic brain injury in male rats. Biochem Pharmacol 2020; 178:114044. [PMID: 32445868 DOI: 10.1016/j.bcp.2020.114044] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2020] [Accepted: 05/18/2020] [Indexed: 02/08/2023]
Abstract
Several studies have shown that 17β-estradiol (E2) exerted beneficial effects on liver disease, and it has a protective impact on brain damage after traumatic brain injury (TBI). TBI-induced liver injury is associated with the activation of TLR4. However, it remains unknown whether E2 can modulate TBI-induced liver injury through TLR4. The objective of this study was to determine the role of TLR4 in hepatoprotective mechanisms of E2 after TBI. Diffuse TBI induced by the Marmarou model in male rats. TAK-242 as a selective antagonist of TLR4 (3 mg/kg) and E2 (33.3 μg/kg) were injected (i.p) respectively 30 min before and 30 min after TBI. The results showed that E2 and TAK-242 markedly inhibited TBI-induced liver injury, which was characterized by decreased aminotransferase activities, inhibition of the oxidative stress, and reduced levels of pro-inflammatory cytokines tumor necrosis factor-α (TNF-α) and IL-17 in the liver. We also found that TBI induced significant upregulation of TLR4 in the liver, with peak expression occurring 24 h after TBI, and that treatment with E2 significantly inhibited the upregulation of TLR4. Also, both classic [Estrogen receptors alpha (ERα) and beta (ERβ)] and non-classic (G protein-coupled estrogen receptor GPER) E2 receptors are involved in modulating the expression of TLR4. These results suggested that the hepatoprotective effects of estradiol after TBI may be mediated via the downregulation expression of TLR4.
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Affiliation(s)
- Sedigheh Amiresmaili
- Department of Physiology, Faculty of Medicine, Kerman University of Medical Sciences, Kerman, Iran; Department of Physiology, Bam University of Medical Sciences, Bam, Iran
| | - Mohammad Khaksari
- Neuroscince and Endocrinology and Metabolism Research Centers, Institute of Neuropharmacology, Kerman University of Medical Sciences, Kerman, Iran.
| | - Nader Shahrokhi
- Neuroscience Research Center, Institute of Neuropharmacology, Kerman University of Medical Sciences, Kerman, Iran
| | - Moslem Abolhassani
- Department of Clinical Biochemistry, School of Medicine, Kerman University of Medical Sciences, Kerman, Iran
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Zhang Y, Shi Y, Li Z, Sun L, Zhang M, Yu L, Wu S. BPA disrupts 17‑estradiol‑mediated hepatic protection against ischemia/reperfusion injury in rat liver by upregulating the Ang II/AT1R signaling pathway. Mol Med Rep 2020; 22:416-422. [PMID: 32319667 PMCID: PMC7248534 DOI: 10.3892/mmr.2020.11072] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2019] [Accepted: 03/23/2020] [Indexed: 12/17/2022] Open
Abstract
Bisphenol A (BPA), a xenoestrogen commonly used in plastics, may act as an endocrine disruptor, which indicates that BPA might be a public health risk. The present study aimed to investigate the effect of BPA on 17β-estradiol (E2)-mediated protection against liver ischemia/reperfusion (I/R) injury, and to identify the underlying mechanisms using a rat model. A total of 56 male Sprague Dawley rats were randomly divided into the following seven groups: i) Sham; ii) I/R; iii) Sham + BPA; iv) I/R + BPA; v) I/R + E2; vi) I/R + E2 + BPA; and vii) I/R + E2 + BPA + losartan [LOS; an angiotensin II (Ang II) type I receptor (ATIR) antagonist]. A rat model of hepatic I/R injury was established by inducing hepatic ischemia for 60 min followed by reperfusion for 24 h. When ischemia was induced, rats were treated with vehicle, E2, BPA or LOS. After 24 h of reperfusion, blood samples and hepatic tissues were collected for histopathological and biochemical examinations. The results suggested that 4 mg/kg BPA did not significantly alter the liver function, or Ang II and AT1R expression levels in the Sham and I/R groups. However, 4 mg/kg BPA inhibited E2-mediated hepatic protection by enhancing hepatic necrosis, and increasing the release of alanine transaminase, alkaline phosphatase and total bilirubin (P<0.05). Moreover, BPA increased serum and hepatic Ang II levels, as well as AT1R protein expression levels in the E2-treated rat model of liver I/R injury (P<0.05). LOS treatment reversed the negative effects of BPA on hepatic necrosis and liver serum marker levels, although it did not reverse BPA-mediated upregulation of serum and hepatic Ang II levels, or hepatic AT1R expression. Therefore, the present study suggested that BPA disrupted E2-mediated hepatic protection following I/R injury, but did not significantly affect healthy or I/R-injured livers; therefore, the mechanism underlying the effects of BPA may be associated with upregulation of the Ang II/AT1R signaling pathway.
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Affiliation(s)
- Yili Zhang
- Department of Radiology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi 710061, P.R. China
| | - Yu Shi
- Department of Medical Oncology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi 710061, P.R. China
| | - Zeyu Li
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi 710061, P.R. China
| | - Liankang Sun
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi 710061, P.R. China
| | - Mei Zhang
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi 710061, P.R. China
| | - Liang Yu
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi 710061, P.R. China
| | - Shengli Wu
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi 710061, P.R. China
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Wen S, Li X, Ling Y, Chen S, Deng Q, Yang L, Li Y, Shen J, Qiu Y, Zhan Y, Lai H, Zhang X, Ke Z, Huang W. HMGB1-associated necroptosis and Kupffer cells M1 polarization underlies remote liver injury induced by intestinal ischemia/reperfusion in rats. FASEB J 2020; 34:4384-4402. [PMID: 31961020 DOI: 10.1096/fj.201900817r] [Citation(s) in RCA: 62] [Impact Index Per Article: 12.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2019] [Revised: 10/07/2019] [Accepted: 01/13/2020] [Indexed: 12/11/2022]
Abstract
Reperfusion of the ischemic intestine often leads to drive distant organ injury, especially injuries associated with hepatocellular dysfunction. The precise molecular mechanisms and effective multiple organ protection strategies remain to be developed. In the current study, significant remote liver dysfunction was found after 6 hours of reperfusion according to increased histopathological scores, serum lactate dehydrogenase (LDH), alanine aminotransferase (ALT)/aspartate aminotransferase (AST) levels, as well as enhanced bacterial translocation in a rat intestinal ischemia/reperfusion (I/R) injury model. Moreover, receptor-interacting protein kinase 1/3 (RIP1/3) and phosphorylated-MLKL expressions in tissue were greatly elevated, indicating that necroptosis occurred and resulted in acute remote liver function impairment. Inhibiting the necroptotic pathway attenuated HMGB1 cytoplasm translocation and tissue damage. Meanwhile, macrophage-depletion study demonstrated that Kupffer cells (KCs) are responsible for liver damage. Blocking HMGB1 partially restored the liver function via suppressed hepatocyte necroptosis, tissue inflammation, hepatic KCs, and circulating macrophages M1 polarization. What's more, HMGB1 neutralization further protects against intestinal I/R-associated liver damage in microbiota-depleted rats. Therefore, intestinal I/R is likely associated with acute liver damage due to hepatocyte necroptosis, and which could be ameliorated by Nec-1 administration and HMGB1 inhibition with the neutralizing antibody and inhibitor. Necroptosis inhibition and HMGB1 neutralization/inhibition, may emerge as effective pharmacological therapies to minimize intestinal I/R-induced acute remote organ dysfunction.
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Affiliation(s)
- Shihong Wen
- Department of Anesthesiology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Xiang Li
- Department of Anesthesiology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Yihong Ling
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, China.,Department of Pathology, Sun Yat-sen University Cancer Center, Guangzhou, China
| | - Shaoqian Chen
- Department of Medical Laboratory, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Qiwen Deng
- Department of Anesthesiology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Lu Yang
- Department of Anesthesiology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Ying Li
- State Key Laboratory of Applied Microbiology Southern China, Guangzhou, China.,Guangdong Institute of Microbiology, Guangdong Academy of Sciences, Guangzhou, China
| | - Jiantong Shen
- Department of Anesthesiology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Yuxin Qiu
- Department of Anesthesiology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Yaqing Zhan
- Department of Anesthesiology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Hanjin Lai
- Surgical Intensive Care Unit, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Xuyu Zhang
- Department of Anesthesiology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Zunfu Ke
- Department of Pathology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Wenqi Huang
- Department of Anesthesiology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
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Wang Z, Sun R, Wang G, Chen Z, Li Y, Zhao Y, Liu D, Zhao H, Zhang F, Yao J, Tian X. SIRT3-mediated deacetylation of PRDX3 alleviates mitochondrial oxidative damage and apoptosis induced by intestinal ischemia/reperfusion injury. Redox Biol 2019; 28:101343. [PMID: 31655428 PMCID: PMC6820261 DOI: 10.1016/j.redox.2019.101343] [Citation(s) in RCA: 153] [Impact Index Per Article: 25.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2019] [Revised: 10/06/2019] [Accepted: 10/11/2019] [Indexed: 12/11/2022] Open
Abstract
Background Hydrogen peroxide (H2O2)-induced mitochondrial oxidative damage is critical to intestinal ischemia/reperfusion (I/R) injury, and PRDX3 is an efficient H2O2 scavenger that protects cells from mitochondrial oxidative damage and apoptosis. However, the function of PRDX3 in intestinal I/R injury is unclear. The aim of this study was to investigate the precise mechanism underlying the involvement of PRDX3 in intestinal I/R injury. Methods An intestinal I/R model was established in mice with superior mesenteric artery occlusion, and Caco-2 cells were subjected to hypoxia/reoxygenation (H/R) for the in vivo simulation of I/R. Results PRDX3 expression was decreased during intestinal I/R injury, and PRDX3 overexpression significantly attenuated H/R-induced mitochondrial oxidative damage and apoptosis in Caco-2 cells. The level of acetylated PRDX3 was clearly increased both in vivo and in vitro. The inhibition of SIRTs by nicotinamide (NAM) increased the level of acetylated PRDX3 and impaired the antioxidative activity of PRDX3. Furthermore, NAM did not increase the acetylation of PRDX3 in sirtuin-3 (SIRT3)-knockdown Caco-2 cells. Importantly, PRDX3 acetylation was increased in mice lacking SIRT3, and this effect was accompanied by serious mitochondrial oxidative damage, apoptosis and remote organ damage after intestinal I/R injury. We screened potential sites of PRDX3 acetylation in the previously reported acetylproteome through immunoprecipitation (IP) experiments and found that SIRT3 deacetylates K253 on PRDX3 in Caco-2 cells. Furthermore, PRDX3 with the lysine residue K253 mutated to arginine (K253R) increased its dimerization in Caco-2 cells after subjected to 12 h hypoxia and followed 4 h reoxygenation. Caco-2 cells transfected with the K253R plasmid exhibited notably less mitochondrial damage and apoptosis, and transfection of the K253Q plasmid abolished the protective effect of PRDX3 overexpression. Analysis of ischemic intestines from clinical patients further verified the correlation between SIRT3 and PRDX3. Conclusions PRDX3 is a key protective factor for intestinal I/R injury, and SIRT3-mediated PRDX3 deacetylation can alleviate intestinal I/R-induced mitochondrial oxidative damage and apoptosis.
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Affiliation(s)
- Zhanyu Wang
- Department of Surgery, The Second Affiliated Hospital of Dalian Medical University, Dalian, 116023, China
| | - Ruimin Sun
- Department of Pharmacology, Dalian Medical University, Dalian, 116044, China
| | - Guangzhi Wang
- Department of Surgery, The Second Affiliated Hospital of Dalian Medical University, Dalian, 116023, China
| | - Zhao Chen
- Department of Surgery, The Second Affiliated Hospital of Dalian Medical University, Dalian, 116023, China
| | - Yang Li
- Department of Surgery, The Second Affiliated Hospital of Dalian Medical University, Dalian, 116023, China
| | - Yan Zhao
- Department of Pharmacology, Dalian Medical University, Dalian, 116044, China
| | - Deshun Liu
- Department of Surgery, The Second Affiliated Hospital of Dalian Medical University, Dalian, 116023, China
| | - Huanyu Zhao
- Department of Pharmacology, Dalian Medical University, Dalian, 116044, China
| | - Feng Zhang
- Department of Surgery, The Second Affiliated Hospital of Dalian Medical University, Dalian, 116023, China
| | - Jihong Yao
- Department of Pharmacology, Dalian Medical University, Dalian, 116044, China.
| | - Xiaofeng Tian
- Department of Surgery, The Second Affiliated Hospital of Dalian Medical University, Dalian, 116023, China.
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Females Are More Resistant to Ischemia-Reperfusion-induced Intestinal Injury Than Males. Ann Surg 2019; 272:1070-1079. [PMID: 30614877 DOI: 10.1097/sla.0000000000003167] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
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Abstract
Despite efforts in prevention and intensive care, trauma and subsequent sepsis are still associated with a high mortality rate. Traumatic injury remains the main cause of death in people younger than 45 years and is thus a source of immense social and economic burden. In recent years, the knowledge concerning gender medicine has continuously increased. A number of studies have reported gender dimorphism in terms of response to trauma, shock and sepsis. However, the advantageous outcome following trauma-hemorrhage in females is not due only to sex. Rather, it is due to the prevailing hormonal milieu of the victim. In this respect, various experimental and clinical studies have demonstrated beneficial effects of estrogen for the central nervous system, the cardiopulmonary system, the liver, the kidneys, the immune system, and for the overall survival of the host. Nonetheless, there remains a gap between the bench and the bedside. This is most likely because clinical studies have not accounted for the estrus cycle. This review attempts to provide an overview of the current level of knowledge and highlights the most important organ systems responding to trauma, shock and sepsis. There continues to be a need for clinical studies on the prevailing hormonal milieu following trauma, shock and sepsis.
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Affiliation(s)
- Florian Bösch
- Department of General, Visceral, and Transplant Surgery, Ludwig Maximilians-University Munich, 81377, Munich, Germany
| | - Martin K Angele
- Department of General, Visceral, and Transplant Surgery, Ludwig Maximilians-University Munich, 81377, Munich, Germany
| | - Irshad H Chaudry
- Center for Surgical Research and Department of Surgery, University of Alabama at Birmingham, Birmingham, AL, 35294, USA.
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22
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Li W, Li D, Sun L, Li Z, Yu L, Wu S. The protective effects of estrogen on hepatic ischemia-reperfusion injury in rats by downregulating the Ang II/AT1R pathway. Biochem Biophys Res Commun 2018; 503:2543-2548. [DOI: 10.1016/j.bbrc.2018.07.013] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2018] [Accepted: 07/04/2018] [Indexed: 12/27/2022]
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23
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Li Y, Ren Q, Zhu L, Li Y, Li J, Zhang Y, Zheng G, Han T, Sun S, Feng F. Involvement of methylation of MicroRNA-122, -125b and -106b in regulation of Cyclin G1, CAT-1 and STAT3 target genes in isoniazid-induced liver injury. BMC Pharmacol Toxicol 2018; 19:11. [PMID: 29554950 PMCID: PMC5859513 DOI: 10.1186/s40360-018-0201-x] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2017] [Accepted: 03/09/2018] [Indexed: 12/31/2022] Open
Abstract
Background This investigation aimed to evaluate the role of methylation in the regulation of microRNA (miR)-122, miR-125b and miR-106b gene expression and the expression of their target genes during isoniazid (INH)-induced liver injury. Methods Rats were given INH 50 mg kg− 1·d− 1 once per day for 3, 7, 10, 14, 21 and 28 days and were sacrificed. Samples of blood and liver were obtained. Results We analysed the methylation and expression levels of miR-122, miR-125b and miR-106b and their potential gene targets in livers. Liver tissue pathologies, histological scores and alanine aminotransferase (ALT) and aspartate aminotransferase (AST) activities changed, indicating the occurrence of liver injury. Relative expression levels of miR-122, miR-125b and miR-106b genes in the liver decreased after INH administration and correlated with the scores of liver pathology and serum AST and ALT activities, suggesting that miR-122, miR-125b and miR-106b are associated with INH-induced liver injury. The amount of methylated miR-122, miR-125b and miR-106b in the liver increased after INH administration and correlated with their expression levels, suggesting the role of methylation in regulating miRNA gene expression. Two miR-122 gene targets, cell cycle protein G1 (Cyclin G1) and cationic amino acid transporter-1 (CAT-1), also increased at the mRNA and protein levels, which suggests that lower levels of miR-122 contribute to the upregulation of Cyclin G1 and CAT-1 and might play a role in INH-induced liver injury. Signal transducer and activator of transcription 3 (STAT3) was a common target gene of miR-125b and miR-106b, and its expression levels of mRNA and protein increased after INH administration. The protein expression of phosphorylated (p)-STAT3 and the mRNA expression of RAR-related orphan receptor gamma (RORγt) regulated by p-STAT3 also increased. Meanwhile, the mRNA and protein expression of interleukin (IL)-17 regulated by RORγt, and the mRNA and protein expression of CXCL1 and MIP-2 regulated by IL-17 increased after INH administration. These results demonstrate that lower levels of hepatic miR-125b and miR-106b contribute to the upregulation of STAT3 in stimulating the secretion of inflammatory factors during INH-induced liver injury. Conclusions Our results suggested that DNA methylation probably regulates the expression of miRNA genes (miR-122, miR-125b, and miR-106b), affecting the expression of their gene targets (Cyclin G1, CAT-1, and STAT3) and participating in the process of INH-induced liver injury. Electronic supplementary material The online version of this article (10.1186/s40360-018-0201-x) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Yuhong Li
- Hebei Province Key Laboratory of Occupational Health and Safety for Coal Industry, School of Public Health, North China University of Science and Technology, No.21 Bohai Road, Tangshan, 063210, People's Republic of China
| | - Qi Ren
- Hebei Province Key Laboratory of Occupational Health and Safety for Coal Industry, School of Public Health, North China University of Science and Technology, No.21 Bohai Road, Tangshan, 063210, People's Republic of China
| | - Lingyan Zhu
- Hebei Province Key Laboratory of Occupational Health and Safety for Coal Industry, School of Public Health, North China University of Science and Technology, No.21 Bohai Road, Tangshan, 063210, People's Republic of China
| | - Yingshu Li
- Hebei Province Key Laboratory of Occupational Health and Safety for Coal Industry, School of Public Health, North China University of Science and Technology, No.21 Bohai Road, Tangshan, 063210, People's Republic of China
| | - Jinfeng Li
- Hebei Province Key Laboratory of Occupational Health and Safety for Coal Industry, School of Public Health, North China University of Science and Technology, No.21 Bohai Road, Tangshan, 063210, People's Republic of China
| | - Yiyang Zhang
- Hebei Province Key Laboratory of Occupational Health and Safety for Coal Industry, School of Public Health, North China University of Science and Technology, No.21 Bohai Road, Tangshan, 063210, People's Republic of China
| | - Guoying Zheng
- Hebei Province Key Laboratory of Occupational Health and Safety for Coal Industry, School of Public Health, North China University of Science and Technology, No.21 Bohai Road, Tangshan, 063210, People's Republic of China
| | - Tiesheng Han
- Hebei Province Key Laboratory of Occupational Health and Safety for Coal Industry, School of Public Health, North China University of Science and Technology, No.21 Bohai Road, Tangshan, 063210, People's Republic of China
| | - Shufeng Sun
- College of Nursing and Rehabilitation, North China University of Science and Technology, Tangshan, 063210, China
| | - Fumin Feng
- Hebei Province Key Laboratory of Occupational Health and Safety for Coal Industry, School of Public Health, North China University of Science and Technology, No.21 Bohai Road, Tangshan, 063210, People's Republic of China.
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Liu L, Yao J, Li Z, Zu G, Feng D, Li Y, Qasim W, Zhang S, Li T, Zeng H, Tian X. miR-381-3p knockdown improves intestinal epithelial proliferation and barrier function after intestinal ischemia/reperfusion injury by targeting nurr1. Cell Death Dis 2018. [PMID: 29540663 PMCID: PMC5852084 DOI: 10.1038/s41419-018-0450-z] [Citation(s) in RCA: 50] [Impact Index Per Article: 7.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/14/2023]
Abstract
Impairment in gut barrier function induced by intestinal ischemia/reperfusion (I/R) injury is associated with high morbidity and mortality. Intestinal barrier function requires the tight coordination of epithelial migration, proliferation and differentiation. We previously observed that nuclear receptor-related protein 1 (nurr1)-mediated proliferative pathway was impaired in intestinal I/R injury. Here, we aimed to assess the effect of nurr1 on intestinal barrier function and to evaluate microRNA (miRNA)-nurr1-mediated restoration of intestinal barrier function in intestinal I/R injury. We induced an in vivo intestinal I/R injury mouse model by clamping and then releasing the superior mesenteric artery. We also performed an in vitro study in which we exposed Caco-2 and IEC-6 cells to hypoxia/reoxygenation (H/R) conditions to stimulate intestinal I/R injury. Our results demonstrated that nurr1 regulated intestinal epithelial development and barrier function after intestinal I/R injury. miR-381-3p, which directly suppressed nurr1 translation, was identified by microarray and bioinformatics analysis. miR-381-3p inhibition enhanced intestinal epithelial proliferation and barrier function in vitro and in vivo and also attenuated remote organ injury and improved survival. Importantly, nurr1 played an indispensable role in the protective effect of miR-381-3p inhibition. Collectively, these findings show that miR-381-3p inhibition mitigates intestinal I/R injury by enhancing nurr1-mediated intestinal epithelial proliferation and barrier function. This discovery may lead to the development of therapeutic interventions for intestinal I/R injury.
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Affiliation(s)
- Liwei Liu
- Department of General Surgery, The Second Affiliated Hospital of Dalian Medical University, Dalian, 116023, China
| | - Jihong Yao
- Department of Pharmacology, Dalian Medical University, Dalian, 116044, China.
| | - Zhenlu Li
- Department of General Surgery, The Second Affiliated Hospital of Dalian Medical University, Dalian, 116023, China
| | - Guo Zu
- Department of General Surgery, The Second Affiliated Hospital of Dalian Medical University, Dalian, 116023, China
| | - Dongcheng Feng
- Department of General Surgery, The Second Affiliated Hospital of Dalian Medical University, Dalian, 116023, China
| | - Yang Li
- Department of General Surgery, The Second Affiliated Hospital of Dalian Medical University, Dalian, 116023, China
| | - Wasim Qasim
- Department of General Surgery, The Second Affiliated Hospital of Dalian Medical University, Dalian, 116023, China
| | - Su Zhang
- Department of General Surgery, The Second Affiliated Hospital of Dalian Medical University, Dalian, 116023, China
| | - Tong Li
- Department of General Surgery, The Second Affiliated Hospital of Dalian Medical University, Dalian, 116023, China
| | - Huizhi Zeng
- Department of General Surgery, The Second Affiliated Hospital of Dalian Medical University, Dalian, 116023, China
| | - Xiaofeng Tian
- Department of General Surgery, The Second Affiliated Hospital of Dalian Medical University, Dalian, 116023, China.
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Al-Tarrah K, Moiemen N, Lord JM. The influence of sex steroid hormones on the response to trauma and burn injury. BURNS & TRAUMA 2017; 5:29. [PMID: 28920065 PMCID: PMC5597997 DOI: 10.1186/s41038-017-0093-9] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/05/2016] [Accepted: 07/19/2017] [Indexed: 12/24/2022]
Abstract
Trauma and related sequelae result in disturbance of homeostatic mechanisms frequently leading to cellular dysfunction and ultimately organ and system failure. Regardless of the type and severity of injury, gender dimorphism in outcomes following trauma have been reported, with females having lower mortality than males, suggesting that sex steroid hormones (SSH) play an important role in the response of body systems to trauma. In addition, several clinical and experimental studies have demonstrated the effects of SSH on the clinical course and outcomes following injury. Animal studies have reported the ability of SSH to modulate immune, inflammatory, metabolic and organ responses following traumatic injury. This indicates that homeostatic mechanisms, via direct and indirect pathways, can be maintained by SSH at local and systemic levels and hence result in more favourable prognosis. Here, we discuss the role and mechanisms by which SSH modulates the response of the body to injury by maintaining various processes and organ functions. Such properties of sex hormones represent potential novel therapeutic strategies and further our understanding of current therapies used following injury such as oxandrolone in burn-injured patients.
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Affiliation(s)
- K Al-Tarrah
- Institute of Inflammation and Ageing, Birmingham University Medical School, B15 2TT, Birmingham, UK.,Scar Free Foundation Centre for Burns Research, University Hospital Birmingham Foundation Trust, B15 2WB, Birmingham, UK
| | - N Moiemen
- Scar Free Foundation Centre for Burns Research, University Hospital Birmingham Foundation Trust, B15 2WB, Birmingham, UK
| | - J M Lord
- Institute of Inflammation and Ageing, Birmingham University Medical School, B15 2TT, Birmingham, UK
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Wang G, Yao J, Li Z, Zu G, Feng D, Shan W, Li Y, Hu Y, Zhao Y, Tian X. miR-34a-5p Inhibition Alleviates Intestinal Ischemia/Reperfusion-Induced Reactive Oxygen Species Accumulation and Apoptosis via Activation of SIRT1 Signaling. Antioxid Redox Signal 2016; 24:961-73. [PMID: 26935288 DOI: 10.1089/ars.2015.6492] [Citation(s) in RCA: 100] [Impact Index Per Article: 11.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
AIMS Reactive oxygen species (ROS) generation and massive epithelial apoptosis are critical in the pathogenesis of intestinal ischemia/reperfusion (I/R) injury. We previously found that the Sirtuin 1 (SIRT1)-mediated antioxidant pathway was impaired in the intestine after I/R. Here, we investigate the potential role of SIRT1-targeting microRNAs (miRNAs) in regulating ROS accumulation and apoptosis in intestinal I/R, and the important role SIRT1 involved in. RESULTS C57BL/6 mice were subjected to intestinal I/R induced by occlusion of the superior mesenteric artery followed by reperfusion. Caco-2 cells were incubated under hypoxia/reoxygenation condition to mimic I/R in vivo. We find that SIRT1 is gradually repressed during the early reperfusion, and that this repression results in intestinal ROS accumulation and apoptosis. Using bioinformatics analysis and real-time PCR, we demonstrate that miR-34a-5p and miR-495-3p are significantly increased among the 41 putative miRNAs that can target SIRT1. Inhibition of miR-34a-5p, but not miR-495-3p, attenuates intestinal I/R injury, as demonstrated by repressing p66shc upregulation, manganese superoxide dismutase repression, and the caspase-3 activation in vitro and in vivo; it further alleviates systemic injury, as demonstrated by reducing inflammatory cytokine release, attenuating lung and liver lesions, and improving survival. Interestingly, SIRT1 plays an indispensable role in the protection afforded by miR-34a-5p inhibition. INNOVATION This study provides the first evidence of miRNAs in regulating oxidative stress and apoptosis in intestinal I/R. CONCLUSION miR-34a-5p knockdown attenuates intestinal I/R injury through promoting SIRT1-mediated suppression of epithelial ROS accumulation and apoptosis. This may represent a novel prophylactic approach to intestinal I/R injury. Antioxid. Redox Signal. 24, 961-973.
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Affiliation(s)
- Guangzhi Wang
- 1 Department of General Surgery, The Second Hospital of Dalian Medical University , Dalian, China
| | - Jihong Yao
- 2 Department of Pharmacology, Dalian Medical University , Dalian, China
| | - Zhenlu Li
- 1 Department of General Surgery, The Second Hospital of Dalian Medical University , Dalian, China
| | - Guo Zu
- 1 Department of General Surgery, The Second Hospital of Dalian Medical University , Dalian, China
| | - Dongcheng Feng
- 1 Department of General Surgery, The Second Hospital of Dalian Medical University , Dalian, China
| | - Wen Shan
- 2 Department of Pharmacology, Dalian Medical University , Dalian, China
| | - Yang Li
- 1 Department of General Surgery, The Second Hospital of Dalian Medical University , Dalian, China
| | - Yan Hu
- 2 Department of Pharmacology, Dalian Medical University , Dalian, China
| | - Yongfu Zhao
- 1 Department of General Surgery, The Second Hospital of Dalian Medical University , Dalian, China
| | - Xiaofeng Tian
- 1 Department of General Surgery, The Second Hospital of Dalian Medical University , Dalian, China
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27
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Aufhauser DD, Wang Z, Murken DR, Bhatti TR, Wang Y, Ge G, Redfield RR, Abt PL, Wang L, Svoronos N, Thomasson A, Reese PP, Hancock WW, Levine MH. Improved renal ischemia tolerance in females influences kidney transplantation outcomes. J Clin Invest 2016; 126:1968-77. [PMID: 27088798 DOI: 10.1172/jci84712] [Citation(s) in RCA: 116] [Impact Index Per Article: 12.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2015] [Accepted: 02/05/2016] [Indexed: 01/25/2023] Open
Abstract
Experimentally, females show an improved ability to recover from ischemia-reperfusion injury (IRI) compared with males; however, this sex-dependent response is less established in humans. Here, we developed a series of murine renal ischemia and transplant models to investigate sex-specific effects on recovery after IRI. We found that IRI tolerance is profoundly increased in female mice compared with that observed in male mice and discovered an intermediate phenotype after neutering of either sex. Transplantation of adult kidneys from either sex into a recipient of the opposite sex followed by ischemia at a remote time resulted in ischemia recovery that reflected the sex of the recipient, not the donor, revealing that the host sex determines recovery. Likewise, renal IRI was exacerbated in female estrogen receptor α-KO mice, while female mice receiving supplemental estrogen before ischemia were protected. We examined data from the United Network for Organ Sharing (UNOS) to determine whether there is an association between sex and delayed graft function (DGF) in patients who received deceased donor renal transplants. A multivariable logistic regression analysis determined that there was a greater association with DGF in male recipients than in female recipients. Together, our results demonstrate that sex affects renal IRI tolerance in mice and humans and indicate that estrogen administration has potential as a therapeutic intervention to clinically improve ischemia tolerance.
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Mitochondrial Dysfunction and Autophagy in Hepatic Ischemia/Reperfusion Injury. BIOMED RESEARCH INTERNATIONAL 2015; 2015:183469. [PMID: 26770970 PMCID: PMC4684839 DOI: 10.1155/2015/183469] [Citation(s) in RCA: 93] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/29/2015] [Revised: 11/10/2015] [Accepted: 11/11/2015] [Indexed: 12/26/2022]
Abstract
Ischemia/reperfusion (I/R) injury remains a major complication of liver resection, transplantation, and hemorrhagic shock. Although the mechanisms that contribute to hepatic I/R are complex and diverse involving the interaction of cell injury in hepatocytes, immune cells, and endothelium, mitochondrial dysfunction is a cardinal event culminating in hepatic reperfusion injury. Mitochondrial autophagy, so-called mitophagy, is a key cellular process that regulates mitochondrial homeostasis and eliminates damaged mitochondria in a timely manner. Growing evidence accumulates that I/R injury is attributed to defective mitophagy. This review aims to summarize the current understanding of autophagy and its role in hepatic I/R injury and highlight the various therapeutic approaches that have been studied to ameliorate injury.
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Guo Y, Hu B, Huang H, Tsung A, Gaikwad NW, Xu M, Jiang M, Ren S, Fan J, Billiar TR, Huang M, Xie W. Estrogen Sulfotransferase Is an Oxidative Stress-responsive Gene That Gender-specifically Affects Liver Ischemia/Reperfusion Injury. J Biol Chem 2015; 290:14754-64. [PMID: 25922074 DOI: 10.1074/jbc.m115.642124] [Citation(s) in RCA: 32] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2015] [Indexed: 01/08/2023] Open
Abstract
Estrogen sulfotransferase (EST) regulates estrogen homeostasis by sulfonating and deactivating estrogens. Liver ischemia and reperfusion (I/R) involves both hypoxia during the ischemic phase and oxidative damage during the reperfusion phase. In this report, we showed that the expression of EST was markedly induced by I/R. Mechanistically, oxidative stress-induced activation of Nrf2 was responsible for the EST induction, which was abolished in Nrf2(-/-) mice. EST is a direct transcriptional target of Nrf2. In female mice, the I/R-responsive induction of EST compromised estrogen activity. EST ablation attenuated I/R injury as a result of decreased estrogen deprivation, whereas this benefit was abolished upon ovariectomy. The effect of EST ablation was sex-specific because the EST(-/-) males showed heightened I/R injury. Reciprocally, both estrogens and EST regulate the expression and activity of Nrf2. Estrogen deprivation by ovariectomy abolished the I/R-responsive Nrf2 accumulation, whereas the compromised estrogen deprivation in EST(-/-) mice was associated with increased Nrf2 accumulation. Our results suggested a novel I/R-responsive feedback mechanism to limit the activity of Nrf2 in which Nrf2 induces the expression of EST, which subsequently increases estrogen deactivation and limits the estrogen-responsive activation of Nrf2. Inhibition of EST, at least in females, may represent an effective approach to manage hepatic I/R injury.
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Affiliation(s)
- Yan Guo
- From the Center for Pharmacogenetics and Department of Pharmaceutical Sciences, the Department of Pathology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China 200025
| | - Bingfang Hu
- From the Center for Pharmacogenetics and Department of Pharmaceutical Sciences, the Institute of Clinical Pharmacology, Sun Yat-Sen University, Guangzhou, China 510275
| | | | | | - Nilesh W Gaikwad
- the Department of Nutrition and Department of Environmental Toxicology, University of California, Davis, California 95616, and
| | - Meishu Xu
- From the Center for Pharmacogenetics and Department of Pharmaceutical Sciences
| | - Mengxi Jiang
- From the Center for Pharmacogenetics and Department of Pharmaceutical Sciences
| | - Songrong Ren
- From the Center for Pharmacogenetics and Department of Pharmaceutical Sciences
| | - Jie Fan
- Surgical Research, Veterans Affairs Pittsburgh Healthcare System, Pittsburgh, Pennsylvania 15240
| | | | - Min Huang
- the Institute of Clinical Pharmacology, Sun Yat-Sen University, Guangzhou, China 510275
| | - Wen Xie
- From the Center for Pharmacogenetics and Department of Pharmaceutical Sciences, Department of Pharmacology and Chemical Biology, University of Pittsburgh, Pittsburgh, Pennsylvania 15261,
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Wang G, Chen Z, Zhang F, Jing H, Xu W, Ning S, Li Z, Liu K, Yao J, Tian X. Blockade of PKCβ protects against remote organ injury induced by intestinal ischemia and reperfusion via a p66shc-mediated mitochondrial apoptotic pathway. Apoptosis 2014; 19:1342-1353. [PMID: 24930012 DOI: 10.1007/s10495-014-1008-x] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/05/2023]
Abstract
Intestinal ischemia-reperfusion (I/R) is a serious clinical dilemma with high morbidity and mortality. Remote organ damage, especially acute lung injury and liver injury are common complications that contribute to the high mortality rate. We previously demonstrated that activation of PKCβII is specifically involved in the primary injury of intestinal I/R. Considering the tissue-specific features of PKC activation, we hypothesized that some kind of PKC isoform may play important roles in the progression of secondary injury in the remote organ. Mice were studied in in vivo model of intestinal I/R. The activation of PKC isoforms were screened in the lung and liver. Interestingly, we found that PKCβII was also activated exclusively in the lung and liver after intestinal I/R. PKCβII suppression by a specific inhibitor, LY333531, significantly attenuated I/R-induced histologic damage, inflammatory cell infiltration, oxidative stress, and apoptosis in these organs, and also alleviated systemic inflammation. In addition, LY333531 markedly restrained p66shc activation, mitochondrial translocation, and binding to cytochrome-c. These resulted in the decrease of cytochrome-c release and caspase-3 cleavage, and an increase in glutathione and glutathione peroxidase. These data indicated that activated PKC isoform in the remote organ, specifically PKCβII, is the same as that in the intestine after intestinal I/R. PKCβII suppression protects against remote organ injury, which may be partially attributed to the p66shc-cytochrome-c axis. Combined with our previous study, the development of a specific inhibitor for prophylaxis against intestinal I/R is promising, to prevent multiple organ injury.
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Affiliation(s)
- Guangzhi Wang
- Department of General Surgery, The Second Hospital of Dalian Medical University, Dalian, 116023, China
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Fan Z, Jing H, Yao J, Li Y, Hu X, Shao H, Shen G, Pan J, Luo F, Tian X. The protective effects of curcumin on experimental acute liver lesion induced by intestinal ischemia-reperfusion through inhibiting the pathway of NF-κB in a rat model. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2014; 2014:191624. [PMID: 25215173 PMCID: PMC4158106 DOI: 10.1155/2014/191624] [Citation(s) in RCA: 32] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/03/2014] [Revised: 07/29/2014] [Accepted: 08/01/2014] [Indexed: 02/05/2023]
Abstract
OBJECTIVE In this study, we investigated the protective effect and mechanism of curcumin on a rat model of intestinal ischemia/reperfusion (I/R), which induces an acute liver lesion. METHODS Curcumin was injected into rats in the curcumin groups through left femoral vein. The same volume of vehicle (0.9% normal saline) was injected into sham and I/R groups. Blood and liver tissue were gathered for serological and histopathological determination. RESULTS Intestinal I/R led to severe liver injury manifested as a significant increase in serum AST and ALT levels; all of those were reduced by treatment with curcumin. Simultaneously, the activity of SOD in liver decreased after intestinal I/R, which was increased by curcumin treatment. On the other hand, curcumin reduced MPO activity of liver tissue, as well as serum IL-6 and TNF-α levels observably. This is in parallel with the decreased level of liver intercellular cell adhesion molecule-1 (ICAM-1) and nuclear factor-κB (NF-κB) expression. CONCLUSION Our findings suggest that curcumin treatment attenuates liver lesion induced by intestinal I/R, attributable to the antioxidative and anti-inflammatory effect via inhibition of the NF-κB pathway.
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Affiliation(s)
- Zhe Fan
- Department of General Surgery, The Third People's Hospital of Dalian, Dalian 116033, China
| | - Huirong Jing
- Department of General Surgery, The Second Hospital of Dalian Medical University, Dalian 116023, China
| | - Jihong Yao
- Department of Pharmacology, Dalian Medical University, Dalian 116044, China
| | - Yang Li
- Department of General Surgery, Liaoning Cancer Hospital and Institute, Shenyang 110042, China
| | - Xiaowei Hu
- Department of Pharmacology, Dalian Medical University, Dalian 116044, China
| | - Huizhu Shao
- Department of Pharmacology, Dalian Medical University, Dalian 116044, China
| | - Gang Shen
- Department of General Surgery, Children's Hospital of Dalian, Dalian 116000, China
| | - Jiyong Pan
- Department of General Surgery, The Third People's Hospital of Dalian, Dalian 116033, China
| | - Fuwen Luo
- Department of General Surgery, The Second Hospital of Dalian Medical University, Dalian 116023, China
| | - Xiaofeng Tian
- Department of General Surgery, The Second Hospital of Dalian Medical University, Dalian 116023, China
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Modulating the p66shc signaling pathway with protocatechuic acid protects the intestine from ischemia-reperfusion injury and alleviates secondary liver damage. ScientificWorldJournal 2014; 2014:387640. [PMID: 24757420 PMCID: PMC3976807 DOI: 10.1155/2014/387640] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2013] [Accepted: 02/16/2014] [Indexed: 01/23/2023] Open
Abstract
Intestinal ischemia-reperfusion (I/R) injury is a serious clinical pathophysiological process that may result in acute local intestine and remote liver injury. Protocatechuic acid (PCA), which has been widely studied as a polyphenolic compound, induces expression of antioxidative genes that combat oxidative stress and cell apoptosis. In this study, we investigated the effect of PCA pretreatment for protecting intestinal I/R-induced local intestine and remote liver injury in mice. Intestinal I/R was established by superior mesenteric artery occlusion for 45 min followed by reperfusion for 90 min. After the reperfusion period, PCA pretreatment markedly alleviated intestine and liver injury induced by intestinal I/R as indicated by histological alterations, decreases in serological damage parameters and nuclear factor-kappa B and phospho-foxo3a protein expression levels, and increases in glutathione, glutathione peroxidase, manganese superoxide dismutase protein expression, and Bcl-xL protein expression in the intestine and liver. These parameters were accompanied by PCA-induced adaptor protein p66shc suppression. These results suggest that PCA has a significant protective effect in the intestine and liver following injury induced by intestinal I/R. The protective effect of PCA may be attributed to the suppression of p66shc and the regulation of p66shc-related antioxidative and antiapoptotic factors.
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Hughes HD, Carroll JA, Burdick Sanchez NC, Richeson JT. Natural variations in the stress and acute phase responses of cattle. Innate Immun 2013; 20:888-96. [PMID: 24217218 DOI: 10.1177/1753425913508993] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Abstract
Activation of the innate immune system and acute phase response (APR) results in several responses that include fever, metabolic adaptations and changes in behavior. The APR can be modulated by many factors, with stress being the most common. An elevation of stress hormones for a short duration of time can be beneficial. However, elevation of stress hormones repeatedly or for an extended duration of time can be detrimental to the overall health and well-being of animals. The stress and APR responses can also be modulated by naturally-occurring variations, such as breed, gender, and temperament. These three natural variations modulate both of these responses, and can therefore modulate the ability of an animal to recover from a stressor or infection. Understanding that cattle have different immunological responses, based on naturally occurring variations such as these, may be the foundation of new studies on how to effectively manage cattle so that health is optimized and production is benefited.
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Affiliation(s)
- Heather D Hughes
- West Texas A&M University, Department of Agricultural Sciences, Canyon, TX, USA
| | | | | | - John T Richeson
- West Texas A&M University, Department of Agricultural Sciences, Canyon, TX, USA USDA-ARS, Livestock Issues Research Unit, Lubbock, TX, USA
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Alhan E, Cinel A, Türkyilmaz S, Erçin C, Kural B, Usta A. Effects of 17ß-Estradiol on the Acute Necrotizing Pancreatitis after Onset in Rats. EUR J INFLAMM 2013. [DOI: 10.1177/1721727x1301100311] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022] Open
Abstract
The aim of this study was to investigate the influence of 17ß-estradiol (E2) on acute necrotizing pancreatitis (ANP) induced by glycodeoxycholic acid in rats. Rats were divided into six groups as sham + saline, sham + single dose E2 (SDE2), sham + multiple dose E2 (MDE2), ANP + saline, ANP + SDE2, and ANP + MDE2. ANP in rats was induced by glycodeoxycholic acid. The extent of acinar cell injury, mortality, systemic cardiorespiratory variables, functional capillary density (FCD), renal/hepatic functions, and changes in some enzyme markers for pancreatic and lung tissue were investigated during ANP in rats. The induction of ANP resulted in a significant increase in the mortality rate, pancreatic necrosis, and serum activity of amylase, alanine aminotransferase (ALT), interleukin (IL)-6, lactate dehydrogenase (LDH) in bronchoalveolar lavage (BAL) fluid, serum concentration of urea, and tissue activity of myeloperoxidase (MPO) and malondialdehyde (MDA) in the pancreas and lung, and a significant decrease in concentrations of calcium, blood pressure, urine output, p02, and functional capillary density (FCD). The use of E2 did not alter these changes. E2 demonstrated no effect on the course of ANP in rats. Therefore, it has no value in the treatment during acute pancreatitis.
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Affiliation(s)
- E. Alhan
- Department of Surgery, Karadeniz Technical University, Trabzon, Turkey
| | - A. Cinel
- Department of Surgery, Karadeniz Technical University, Trabzon, Turkey
| | - S. Türkyilmaz
- Department of Surgery, Karadeniz Technical University, Trabzon, Turkey
| | - C. Erçin
- Department of Pathology, Kocaeli University, Kocaeli, Turkey
| | - B.V. Kural
- Department of Biochemistry, Karadeniz Technical University, Trabzon, Turkey
| | - A. Usta
- Department of Surgery, Karadeniz Technical University, Trabzon, Turkey
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Burra P, De Martin E, Gitto S, Villa E. Influence of age and gender before and after liver transplantation. Liver Transpl 2013; 19:122-34. [PMID: 23172830 DOI: 10.1002/lt.23574] [Citation(s) in RCA: 51] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/24/2012] [Accepted: 11/08/2012] [Indexed: 12/15/2022]
Abstract
Women constitute a particular group among patients with chronic liver disease and in the post-liver transplantation (LT) setting: they are set apart not only by traditional differences with respect to men (ie, body mass index, different etiologies of liver disease, and accessibility to transplantation) but also in increasingly evident ways related to hormonal changes that characterize first the fertile age and subsequently the postmenopausal period (eg, disease course variability and responses to therapy). The aim of this review is, therefore, to evaluate the role of the interplay of factors such as age, gender, and hormones in influencing the natural history of chronic liver disease before and after LT and their importance in determining outcomes after LT. As the population requiring LT ages and the mean age at transplantation increases, older females are being considered for transplantation. Older patients are at greater risk for nonalcoholic steatohepatitis, osteoporosis, and a worse response to antiviral therapy. Female gender per se is associated with a greater risk for osteoporosis because of metabolic changes after menopause, the bodily structure of females, and, in the population of patients with chronic liver disease, the greater prevalence of cholestatic and autoimmune liver diseases. With menopause, the fall of protective estrogen levels can lead to increased fibrosis progression, and this represents a negative turning point for women with chronic liver disease and especially for patients with hepatitis C. Therefore, the notion of gender as a binary female/male factor is now giving way to the awareness of more complex disease processes within the female gender that follow hormonal, social, and age patterns and need to be addressed directly and specifically.
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Affiliation(s)
- Patrizia Burra
- Multivisceral Transplant Unit, Department of Surgery, Oncology, and Gastroenterology, Padua University Hospital, Padua, Italy.
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Yang X, Qin L, Liu J, Tian L, Qian H. 17β-Estradiol protects the liver against cold ischemia/reperfusion injury through the Akt kinase pathway. J Surg Res 2012; 178:996-1002. [PMID: 22835949 DOI: 10.1016/j.jss.2012.07.007] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2012] [Revised: 06/22/2012] [Accepted: 07/03/2012] [Indexed: 10/28/2022]
Abstract
BACKGROUND Hepatic ischemia-reperfusion (IR) injury occurs during liver resection and transplantation. Recent studies have shown that 17β-estradiol (E2) can protect the heart and liver against warm IR. The present study focused on the cytoprotective effects of E2 on cold IR injury to the liver. MATERIALS AND METHODS Sprague-Dawley male rats were randomly divided into three groups: sham, IR, and IR plus E2. The model of rat orthotopic liver transplantation was used. The rats in the IR plus E2 group were intraperitoneally injected with E2 (100 μg/kg/d) for 7 d before surgery. The sham and IR group received the same quantity of saline. The donor livers were then orthotopically transplanted into rats after cold ischemia preservation for 4 h at 4°C lactated Ringer's solution. After 6 h reperfusion, liver function, bile flow volume, hepatocyte apoptosis, and activation of Akt, glycogen synthase kinase-3β, and Bcl-2-associated death promoter were assessed. The survival rate of the rats was also investigated. RESULTS The administration of E2 significantly prolonged the survival of liver grafts by improving liver function and decreasing hepatocyte apoptosis. Rats undergoing E2 demonstrated a greater level activation of Akt in the liver compared with the IR group. In addition, E2 also inhibited the activities of glycogen synthase kinase-3β, Bcl-2-associated death promoter, and caspase-3-induced by IR injury. CONCLUSIONS E2 pretreatment attenuated the hepatocellular damage caused by hepatic cold IR injury through the Akt pathway. Estrogen therapy might be important in clinical settings associated with cold IR injury during liver transplantation.
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Affiliation(s)
- Xiaohua Yang
- Department of General Surgery, The First Affiliated Hospital of Soochow University, Suzhou, China
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Baxi DB, Singh PK, Vachhrajani KD, Ramachandran AV. Melatonin supplementation in rat ameliorates ovariectomy-induced oxidative stress. Climacteric 2012; 16:274-83. [DOI: 10.3109/13697137.2012.682108] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022]
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The effects of estrogen on various organs: therapeutic approach for sepsis, trauma, and reperfusion injury. Part 2: liver, intestine, spleen, and kidney. J Anesth 2012; 26:892-9. [DOI: 10.1007/s00540-012-1426-2] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/27/2011] [Accepted: 05/24/2012] [Indexed: 11/26/2022]
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17β-estradiol attenuates reduced-size hepatic ischemia/reperfusion injury by inhibition apoptosis via mitochondrial pathway in rats. Shock 2012; 37:183-90. [PMID: 22089190 DOI: 10.1097/shk.0b013e31823f1918] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
The aim of this study was to investigate the effect of 17β-estradiol (E2) on hepatocyte apoptosis after reduced-size hepatic ischemia/reperfusion (I/R) injury and its mechanism. A rat model of reduced-size hepatic I/R injury was established. Sprague-Dawley rats were randomly allocated into sham, I/R, and E2 + I/R group. 17β-Estradiol (4 mg/kg) or the vehicle was administered i.p. 1 h before ischemia and immediately after operation. For each group, 10 rats were used to investigate the survival during a week after reperfusion. Blood samples and liver tissues were obtained in the remaining animals after 3, 6, 12, and 24 h of reperfusion to assess serum aspartate aminotransferase and alanine aminotransferase levels, liver tissue malondialdehyde concentration, superoxide dismutase activity, and histopathologic changes. Apoptosis ratio; expression of cytochrome c, Bcl-2, and Bax proteins; and enzymatic activities of caspase 9 and caspase 3 were performed in the samples at 12 h after reperfusion. The serum aspartate aminotransferase and alanine aminotransferase levels and tissue malondialdehyde concentration were increased in the I/R group, whereas the increase was significantly reduced by E2. The superoxide dismutase activity, depressed by I/R injury, was elevated back to normal levels by treatment with E2. Severe hepatic damage was observed by light microscopy in the I/R group, whereas administration of E2 resulted in tissue and cellular preservation. Furthermore, E2 inhibited hepatocellular apoptosis by upregulating the ratio of Bcl-2 and Bax expression, reduced cytosolic cytochrome c level, and decreased caspase 9 and caspase 3 activities. The 7-day survival rate was significantly higher in the E2 + I/R group than in the I/R group. These results indicated that E2 protects liver tissues from reduced-size hepatic I/R injury by suppressing mitochondrial apoptotic pathways.
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Shingu C, Hagiwara S, Iwasaka H, Matsumoto S, Koga H, Yokoi I, Noguchi T. EPCK1, a Vitamin C and E Analogue, Reduces Endotoxin-Induced Systemic Inflammation in Mice. J Surg Res 2011; 171:719-25. [DOI: 10.1016/j.jss.2010.03.040] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2009] [Revised: 02/16/2010] [Accepted: 03/17/2010] [Indexed: 01/25/2023]
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Remote ischemic preconditioning by hindlimb occlusion prevents liver ischemic/reperfusion injury. Ann Surg 2011; 254:178-80. [PMID: 21606831 DOI: 10.1097/sla.0b013e318221ff34] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/28/2022]
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Robert R, Ghazali DA, Favreau F, Mauco G, Hauet T, Goujon JM. Gender difference and sex hormone production in rodent renal ischemia reperfusion injury and repair. JOURNAL OF INFLAMMATION-LONDON 2011; 8:14. [PMID: 21658244 PMCID: PMC3127739 DOI: 10.1186/1476-9255-8-14] [Citation(s) in RCA: 30] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/05/2010] [Accepted: 06/09/2011] [Indexed: 01/29/2023]
Abstract
BACKGROUND Several lines of evidence suggest a protective effect of female sex hormones in several organs subjected to ischemia-reperfusion injury. The aim of the study was to investigate sex hormone production in male rats after a renal ischemia-reperfusion sequence and analyze the influence of gender differences on tissue remodelling during the recovery process. METHOD Age-matched sexually mature male and female rats were subjected to 60 min of renal unilateral ischemia by pedicle clamping with contralateral nephrectomy and followed for 1 or 5 days after reperfusion. Plasma creatinine, systemic testosterone, progesterone and estradiol levels were determined. Tubular injury, cell proliferation and inflammation, were evaluated as well as proliferating cell nuclear antigen, vimentin and translocator protein (TSPO) expressions by immunohistochemistry. RESULTS After 1 and 5 days of reperfusion, plasma creatinine was significantly higher in males than in females, supporting the high mortality in this group. After reperfusion, plasma testosterone levels decreased whereas estradiol significantly increased in male rats. Alterations of renal function, associated with tubular injury and inflammation persisted during the 5 days post-ischemia-reperfusion, and a significant improvement was observed in females at 5 days of reperfusion. Proliferating cell nuclear antigen and vimentin expression were upregulated in kidneys from males and attenuated in females, in parallel to injury development. TSPO expression was transiently increased in proximal tubules in male rats. CONCLUSIONS After ischemia, renal function recovery and tissue injury is gender-dependent. These differences are associated with a modulation of sex hormone production and a modification of tissue remodeling and proliferative cell processes.
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Affiliation(s)
- René Robert
- CHU Poitiers, Service de Réanimation Médicale Poitiers, F-86000, France.
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Zhou B, Zhang PJ, Tian T, Jin C, Li Y, Feng M, Liu XY, Jie L, Tao LD. Role of vascular endothelial growth factor in protection of intrahepatic cholangiocytes mediated by hypoxic preconditioning after liver transplantation in rats. Transplant Proc 2011; 42:2457-62. [PMID: 20832524 DOI: 10.1016/j.transproceed.2010.04.028] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2008] [Accepted: 04/21/2010] [Indexed: 12/26/2022]
Abstract
OBJECTIVE To investigate the effect on intrahepatic cholangiocytes mediated by hypoxic preconditioning (HP) after liver transplantation and the role of vascular endothelial growth factor (VEGF). MATERIALS AND METHODS This experiment was based on a model of rat orthotopic liver autotransplantation. Sprague-Dawley rats were randomly divided into 3 groups: normal control, autotransplantation (AT), and HP. The HP group was subjected to 8% oxygen atmosphere for 90 minutes before surgery. At 6, 12, 24, and 48 hours after autotransplantation, the rats were killed for testing .Serum total bilirubin, direct bilirubin, and alkaline phosphatase concentrations were determined. The microstructure of cholangiocytes and the ultramicrostructure of cholangioles were determined. Immunohistochemistry was used to detect the expression of VEGF and the proliferation rate of cholangiocytes. RESULTS Total bilirubin, direct bilirubin, and alkaline phosphatase concentrations in the AT group increased considerably more than in the HP group during the entire interval (P < .05). Light microscopy demonstrated that the microstructure of cholangiocytes in the AT group was damaged more seriously than in the HP group. At transmission electron microscopy, the ultramicrostructure of cholangioles was changed more obviously than in the HP group. The expression of VEGF on cholangiocytes and the proliferation rate of cholangiocytes were higher in the HP group than in the AT group over the entire experiment (P < .05). CONCLUSION Hypoxic preconditioning has a protective effect on cholangiocytes after liver autotransplantation. The mechanism may be related to HP-induced overexpression of VEGF on cholangiocytes.
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Affiliation(s)
- B Zhou
- Institute of General Surgical Research, Second Affiliated Hospital, Yangzhou University, China
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44
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Abu-Amara M, Yang SY, Quaglia A, Rowley P, Tapuria N, Seifalian AM, Fuller BJ, Davidson BR. Effect of remote ischemic preconditioning on liver ischemia/reperfusion injury using a new mouse model. Liver Transpl 2011; 17:70-82. [PMID: 21254347 DOI: 10.1002/lt.22204] [Citation(s) in RCA: 36] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Ischemic preconditioning of remote organs (RIPC) reduces liver ischemia/reperfusion (IR) injury in the rabbit and rat. Mice are the only species available with a large number of transgenic strains. This study describes development and validation of a mouse model of hindlimb RIPC that attenuates liver IR injury. Mice were allocated to 4 groups: (1) Sham surgery; (2) RIPC: 6 cycles of 4 × 4 minutes ischemia/reperfusion of hindlimb; (3) IR: 40 minutes lobar (70%) hepatic ischemia and 2 hours reperfusion; (4) RIPC+IR: RIPC followed by IR group procedures. Plasma liver aminotransferases and hepatic histopathological and transmission electron microscopy studies were performed at the end of the experiment. Hepatic microcirculatory blood flow was measured throughout the experiment. Postoperative complications and animal survival were evaluated. Hindlimb RIPC using a tourniquet resulted in limb paralysis. Hindlimb RIPC using direct clamping of the femoral vessels showed no side effects. Compared to liver IR alone, RIPC+IR reduced plasma aminotransferases (P < 0.05) and histopathological and ultrastructural features of injury. Hepatic microcirculatory blood flow was preserved in the RIPC+IR compared to IR group (P < 0.05). There was no mortality in any of the groups. By demonstrating a consistent improvement in these features of liver IR injury with antecedent hindlimb RIPC and by minimizing experimental confounding variables, we validated this mouse model. In conclusion, we describe a validated mouse model of hindlimb RIPC that reduces liver IR injury. With the availability of transgenic mice strains, this model should prove useful in unraveling the mechanisms of protection of hindlimb RIPC.
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Affiliation(s)
- Mahmoud Abu-Amara
- Division of Surgery and Interventional Science, University College London, United Kingdom
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Wang J, Qiao L, Li Y, Yang G. Ginsenoside Rb1 attenuates intestinal ischemia-reperfusion- induced liver injury by inhibiting NF-kappaB activation. Exp Mol Med 2009; 40:686-98. [PMID: 19116454 DOI: 10.3858/emm.2008.40.6.686] [Citation(s) in RCA: 47] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/27/2023] Open
Abstract
Intestinal ischemia-reperfusion (I/R) is an important event in the pathogenesis of multiple organ dysfunction syndrome (MODS). The aim of this study is to determine the effects of ginsenoside Rb1 on liver injury induced by intestinal I/R in rats. Adult male Wistar rats were randomly divided into four groups: (1) a control, sham-operated group (sham group); (2) an intestinal I/R group subjected to 1 h intestinal ischemia and 2 h reperfusion (I/R group); (3) a group treated with 20 mg/kg ginsenoside Rb1 before reperfusion (Rb1-20 group); and (4) a group treated with 40 mg/kg ginsenoside Rb1 before reperfusion (Rb1-40 group). Liver and intestinal histology was observed. Aspartate aminotransferase (AST), alanine aminotransferase (ALT) level in serum and malondialdehyde (MDA) level in intestinal tissues were measured. Myeloperoxidase (MPO), TNF-alpha, MDA level and immunohistochemical expression of NF-kgr;B and intracellular adhesion molecule-1 (ICAM-1) in liver tissues was assayed. In addition, a western blot analysis of liver NF-kappaB expression was performed. Results indicated intestinal I/R induced intestinal and liver injury, which was characterized by increase of AST and ALT in serum, MDA level in intestine, MPO, TNF-alpha and MDA level and ICAM-1 and NF-kappaB expression in the liver tissues. Ginsenoside Rb1 (20, 40 mg/kg) ameliorated liver injury, decreased MPO, TNF-alpha and MDA level, NF-kappaB and ICAM-1 expression in liver tissues. In conclusion, ginsenoside Rb1 ablated liver injury induced by intestinal I/R by inhibiting NF-kappaB activation.
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Affiliation(s)
- Jin Wang
- Department of Emergency Medicine, Tongji Hospital, Tongji Medicine College, Huazhong University of Science and Technology, 1095 Jiefang Avenue, Wuhan, Hubei 430030, P.R. China
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Kuntz CL, Hadjiliadis D, Ahya VN, Kotloff RM, Pochettino A, Lewis J, Christie JD. Risk factors for early primary graft dysfunction after lung transplantation: a registry study. Clin Transplant 2009; 23:819-30. [PMID: 19239481 DOI: 10.1111/j.1399-0012.2008.00951.x] [Citation(s) in RCA: 103] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/13/2023]
Abstract
BACKGROUND Primary graft dysfunction (PGD) is a leading cause of early morbidity and mortality in lung transplantation. We sought to identify risk factors for PGD using the United Network for Organ Sharing/International Society for Heart and Lung Transplant (UNOS/ISHLT) Registry. METHODS A total of 6984 lung transplants between 1994 and 2002 were available for analysis. Potential risk factors were tested for association with PGD and multivariable logistic regression was applied to adjust for confounding. RESULTS The overall incidence of PGD was 10.7% (95% CI 9.9-11.4). In multivariable analyses, factors independently associated with PGD were donor age >45 yr (p < 0.001); donor head trauma (p = 0.03); recipient body mass index >25 kg/m(2) (p = 0.005); recipient female gender (p = 0.001); use of Eurocollins preservation solution (p = 0.001); single lung transplant (p = 0.005); increased ischemic time (p < 0.001); and elevated recipient pulmonary artery systolic pressure at transplant (p < 0.001). Recipient transplant diagnosis was strongly associated with PGD, with primary or secondary pulmonary hypertension (p < 0.001 for both), and idiopathic (p < 0.001) or secondary pulmonary fibrosis (p = 0.011) as significant and independent risk factors for PGD. CONCLUSIONS Risk factors for PGD in the UNOS/ISHLT registry are consistent with prior smaller studies. Recipient, donor, and therapy variables are independently associated with PGD, as defined in a large registry.
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Affiliation(s)
- Catherine L Kuntz
- Division of Pulmonary and Critical Care Medicine, Department of Medicine, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA
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Ba ZF, Hsu JT, Chen J, Kan WH, Schwacha MG, Chaudry IH. Systematic analysis of the salutary effect of estrogen on cardiac performance after trauma-hemorrhage. Shock 2008; 30:585-589. [PMID: 18391854 DOI: 10.1097/shk.0b013e31816f1a45] [Citation(s) in RCA: 15] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/27/2022]
Abstract
Although 17beta-estradiol (estrogen) and estrogen receptor (ER) agonist administration after trauma-hemorrhage improves cardiac function, it remains unknown what the optimal estrogen or ER agonist dosage is to elicit this beneficial effect. To study this, the dose-dependent effects of estrogen, propylpyrazole triol (ER-alpha agonist), and diarylpropionitrile (DPN; ER-beta agonist) on heart performance (+dP/dt) were determined in sham rats and in experimental animals at the time of maximal bleedout (MBO) or at 2 h after trauma-hemorrhage. The results showed that estrogen and DPN induced dose-dependent increases in the maximal rate of left ventricular pressure increase (+dP/dt) in all groups, whereas propylpyrazole triol was ineffective at all doses. The maximal dose and the 50% effective dose of DPN were approximately 100-fold lower than those of estrogen. The half-life of estrogen in plasma was approximately 25 min in sham and MBO groups. A positive correlation between the estrogen-induced increase in +dP/dt and survival in MBO rats were observed. These results collectively suggest that the salutary effects of estrogen on cardiac performance are dose-dependent and mediated via ER-beta.
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Affiliation(s)
- Zheng F Ba
- Center for Surgical Research and Department of Surgery, University of Alabama at Birmingham, Birmingham, Alabama 35294-0019, USA
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Ba ZF, Chaudry IH. Role of estrogen receptor subtypes in estrogen-induced organ-specific vasorelaxation after trauma-hemorrhage. Am J Physiol Heart Circ Physiol 2008; 295:H2061-7. [PMID: 18805896 DOI: 10.1152/ajpheart.00707.2008] [Citation(s) in RCA: 16] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/26/2023]
Abstract
Although endothelin-1 (ET-1)-induced organ hypoperfusion after trauma-hemorrhage is improved by estrogen administration, it remains unclear whether estrogen receptor (ER) subtypes play any role in the attenuation of ET-1-induced vasoconstriction in any specific organ bed. To investigate this, isolated perfusion experiments in the heart, liver, small intestine, kidney, and lung were carried out in sham, at the time of maximum bleedout (MBO; i.e., 5-cm midline incision, with removal of 60% of circulating blood volume over 45 min to maintain a mean blood pressure of 40 mmHg), and 2 h after trauma-hemorrhage and resuscitation (T-H/R). Organ-specific ET-1-induced vasoconstriction was evaluated, and the effects of 17beta-estradiol (E2) and ER-specific agonists propylpyrazole triol (PPT; ERalpha agonist) and diarylpropionitrile (DPN; ERbeta agonist) were determined. ET-1 induced the greatest vasoconstriction in sham animals, with the strongest response in the kidneys, followed by the small intestine and liver. ET-1-induced responses were weakest in the heart and lungs. ET-1-induced vasoconstriction was evident at the time of MBO but was significantly decreased at 2 h after T-H/R. ERbeta plays an important role in cardiac performance, as evidenced by improved heart performance (+dP/dt) in the presence of DPN. DPN also induced a greater effect than PPT in the reduction of ET-1-induced vasoconstriction in the kidneys and lungs. In contrast, PPT attenuated ET-1-induced vasoconstriction in the liver, whereas both DPN and PPT were equally effective in the small intestine. The increased +dP/dt values induced by E2, DPN, or PPT were evident at the time of MBO but were significantly decreased at 2 h after T-H/R. These data indicate that the effects of ET-1 on vasoconstriction and the role of ER subtypes in estrogen-induced vasorelaxation are organ specific and temporally specific after trauma-hemorrhage.
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Affiliation(s)
- Zheng F Ba
- Center for Surgical Research, University of Alabama, 1670 Univ. Blvd., G094 Volker Hall, Birmingham, AL 35294-0019, USA
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van der Bilt JDW, Kranenburg O, Borren A, van Hillegersberg R, Borel Rinkes IHM. Ageing and hepatic steatosis exacerbate ischemia/reperfusion-accelerated outgrowth of colorectal micrometastases. Ann Surg Oncol 2008; 15:1392-8. [PMID: 18335279 DOI: 10.1245/s10434-007-9758-0] [Citation(s) in RCA: 30] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2007] [Revised: 10/14/2007] [Accepted: 10/15/2007] [Indexed: 02/06/2023]
Abstract
BACKGROUND Ischemia/reperfusion (I/R) injury is frequently encountered during hepatic surgery. We recently showed that I/R accelerates the outgrowth of pre-established colorectal micrometastases. The aim of this study was to assess the influence of ischemia time, gender, age, and liver steatosis on the accelerated outgrowth of colorectal metastases following I/R. METHODS Five days after tumor cell inoculation, mice were subjected to 20, 30 or 45 min of left lobar I/R. To assess the influence of age, gender, and liver steatosis on I/R-accelerated tumor growth, we compared old with young mice, male with female mice, and mice with healthy livers with mice with steatotic livers. Endpoints were extent of tissue necrosis and tumor growth. RESULTS With increasing ischemia times, tissue necrosis and I/R-accelerated tumor growth increased, with a significant stimulatory effect at 30 and 45 min of ischemia. I/R-stimulated outgrowth of micrometastases was further increased by 33% in aged mice and by 42% in steatotic livers and was associated with increased tissue necrosis. In female mice tissue necrosis had decreased by 47% and tumor growth was reduced in both control and clamped liver lobes. The stimulatory effect of I/R on metastasis outgrowth was similar in male and female mice. CONCLUSIONS I/R-accelerated outgrowth of colorectal micrometastases largely depends on the duration of the ischemic period, with a safe upper limit of 20 min in mice. The stimulatory effects of I/R on tumor growth are exacerbated in aged mice and in steatotic livers.
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Burkhardt M, Slotta JE, Garcia P, Seekamp A, Menger MD, Pohlemann T. The effect of estrogen on hepatic microcirculation after ischemia/reperfusion. Int J Colorectal Dis 2008; 23:113-9. [PMID: 17665206 DOI: 10.1007/s00384-007-0360-5] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 06/28/2007] [Indexed: 02/04/2023]
Abstract
BACKGROUND AND AIMS Gender dimorphism in clinical manifestation of sepsis, hemorrhage, and trauma is still under investigation. Several experimental studies have indicated a protective effect of estrogen. Nonetheless, the effect of gender on hepatic ischemia/reperfusion remains controversially discussed, and the influence of estrogen is still unclear. In the present study, we investigated whether hepatic ischemia/reperfusion (I/R) injury is gender-dependent and if hepatic microvascular reperfusion injury can be prevented by estrogen. MATERIALS AND METHODS Eight female and eight male Sprague-Dawley rats were subjected to 90 min left lobar ischemia followed by 60 min reperfusion. Additional six males were pretreated with 17beta-estradiol 24 h before I/R. Six female and six male rats served as nonischemic sham animals. By means of intravital microscopy, sinusoidal perfusion, leukocyte-endothelial cell interaction, and Kupffer cell activity were analyzed. Finally, arterial blood and liver tissue samples were taken for histomorphological analysis and liver enzyme determination. RESULTS After hepatic ischemia/reperfusion, animals revealed a significant gender-specific impairment of hepatic microcirculation, whereas Kupffer cell depression, sinusoidal perfusion failure, leukocyte-endothelial cell interaction within post sinusoidal venules, and parenchymal liver cell damage were more pronounced in male animals. Pretreatment with estrogen caused a normalization of Kupffer cell dysfunction and an amelioration of sinusoidal perfusion failure and venular leukocyte-endothelial cell interaction. However, estrogen did not protect from manifestation of post ischemic parenchymal cell damage. CONCLUSION Hepatic ischemia and reperfusion generate a gender-specific occurrence of microvascular injury, which seems to be partially mediated by estrogen. However, additional factors may contribute to the initial post ischemic parenchymal cell damage.
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Affiliation(s)
- M Burkhardt
- Department of Trauma, Hand and Reconstructive Surgery, Saarland University Hospital, Kirrberger Strasse, 66421 Homburg/Saar, Germany.
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