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1.
J Stroke Cerebrovasc Dis ; 29(10): 105029, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32912542

RESUMO

BACKGROUND: We investigated whether exogenous lysophosphatidic acid (LPA), a phospholipid extracellular signaling molecule, would increase infarct size and blood-brain barrier (BBB) disruption during the early stage of cerebral ischemia-reperfusion, and whether it works through Akt-mTOR-S6K1 intracellular signaling. MATERIAL AND METHODS: Rats were given either vehicle or LPA 1 mg/kg iv three times during reperfusion after one hour of middle cerebral artery (MCA) occlusion. In another group, prior to administration of LPA, 30 mg/kg of PF-4708671, an S6K1 inhibitor, was injected. After one hour of MCA occlusion and two hours of reperfusion the transfer coefficient (Ki) of 14C-α-aminoisobutyric acid and the volume of 3H-dextran distribution were determined to measure the degree of BBB disruption. At the same time, the size of infarct was determined and western blot analysis was performed to determine the levels of phosphorylated Akt (p-Akt) and phosphorylated S6 (pS6). RESULTS: LPA increased the Ki in the ischemic-reperfused cortex (+43%) when compared with Control rats and PF-4708671 pretreatment prevented the increase of Ki by LPA. LPA increased the percentage of cortical infarct out of total cortical area (+36%) and PF-4708671 pretreatment prevented the increase of the infarct size. Exogenous LPA did not significantly change the levels of p-Akt as well as pS6 in the ischemic-reperfused cortex. CONCLUSION: Our data demonstrate that the increase in BBB disruption could be one of the reasons of the increased infarct size by LPA. S6K1 may not be the major target of LPA. A decrease of LPA during early cerebral ischemia-reperfusion might be beneficial for neuronal survival.


Assuntos
Barreira Hematoencefálica/efeitos dos fármacos , Permeabilidade Capilar/efeitos dos fármacos , Córtex Cerebral/efeitos dos fármacos , Infarto da Artéria Cerebral Média/terapia , Lisofosfolipídeos/toxicidade , Traumatismo por Reperfusão/induzido quimicamente , Reperfusão , Animais , Barreira Hematoencefálica/fisiopatologia , Córtex Cerebral/enzimologia , Córtex Cerebral/patologia , Modelos Animais de Doenças , Infarto da Artéria Cerebral Média/enzimologia , Infarto da Artéria Cerebral Média/patologia , Infarto da Artéria Cerebral Média/fisiopatologia , Masculino , Fosforilação , Proteínas Proto-Oncogênicas c-akt/metabolismo , Ratos Endogâmicos F344 , Traumatismo por Reperfusão/enzimologia , Traumatismo por Reperfusão/patologia , Traumatismo por Reperfusão/fisiopatologia , Proteínas Quinases S6 Ribossômicas/metabolismo
2.
J Stroke Cerebrovasc Dis ; 29(9): 105041, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32807453

RESUMO

BACKGROUND AND PURPOSE: Ischemia-reperfusion injuries (IRIs) can aggravate the condition of some patients with acute occlusion of major intracranial artery (AOMIA) who received endovascular thrombectomy. Here, we provided data confirming the association of Repressor Element-1 Silencing Transcription factor (REST) with the long-term neuroprotective effect of the middle cerebral artery occlusion (MCAO) rats underwent Gradual Flow Restoration (GFR). METHODS: Long term neuroprotective effects of GFR intervention were evaluated on MCAO rats model after 3d and 7d reperfusion. The neurological deficit score and TTC staining were performed to evaluate the degree of brain damage in GFR and other interventions at different time. Differentially expressed genes related to cerebral ischemia reperfusion injury (CIRI) were initially screened and identified using GSE32529 microarray analysis. REST protein expression in rat brain cortex infarction was detected by Western blot analysis. RESULTS: MCAO rats intervened with GFR exhibited reduced neurological deficit (P < 0.05) and alleviated brain infarction volume (P < 0.01). The REST gene with up-regulated expression and its downstream genes with down-regulated expression were screened by Microarray analysis. The brain cortex infarction in MCAO rats produced high levels of REST expression. The GFR intervention inhibited REST expression, and alleviated brain injury on MCAO rats. CONCLUSION: Our results demonstrated that GFR intervention plays a long-term neuroprotective role and reduces brain edema and damage at reperfusion, possibly by inhibiting REST expression.


Assuntos
Edema Encefálico/prevenção & controle , Córtex Cerebral/metabolismo , Circulação Cerebrovascular , Infarto da Artéria Cerebral Média/terapia , Traumatismo por Reperfusão/prevenção & controle , Reperfusão/métodos , Proteínas Repressoras/metabolismo , Animais , Edema Encefálico/metabolismo , Edema Encefálico/patologia , Edema Encefálico/fisiopatologia , Córtex Cerebral/patologia , Córtex Cerebral/fisiopatologia , Modelos Animais de Doenças , Infarto da Artéria Cerebral Média/metabolismo , Infarto da Artéria Cerebral Média/fisiopatologia , Masculino , Ratos Sprague-Dawley , Reperfusão/efeitos adversos , Traumatismo por Reperfusão/metabolismo , Traumatismo por Reperfusão/patologia , Traumatismo por Reperfusão/fisiopatologia , Proteínas Repressoras/genética , Transdução de Sinais , Fatores de Tempo , Regulação para Cima
3.
J Stroke Cerebrovasc Dis ; 29(9): 105055, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32807461

RESUMO

BACKGROUND: To investigate the value of plasma high mobility group box protein 1 (HMGB1) in evaluating the prognosis of cerebral ischemia-reperfusion injury (CIRI) in ischemic stroke patients. METHODS: 132 ischemic stroke patients were recruited. Before and after thrombolytic therapy at 2 h, 6 h, 12 h, 24 h, and 36 h, the Glasgow Coma Scale (GCS) and National Institutes of Health Stroke Scale (NIHSS) were recorded. The Modified Rankin scale (mRS) was used to assess the prognosis at 3 months. RESULTS: The NIHSS score, GCS score and plasma HMGB1 level peaked at 6 h after thrombolytic therapy, and plasma HMGB1 level was positively correlated with infarct volume and NIHSS score, and negatively correlated with GCS score. Plasma HMGB1 level at 6 h had the highest value in identifying patients with poor unfavorable functional outcome after 3 months, with a sensitivity of 86.8% and a specificity of 74.0%. Logistic regression results showed that plasma HMGB1 had a strong association with unfavorable functional outcome [odds ratio (OR) =1.621, P<0.001]. After adjusting for infarct volume and NIHSS score did not attenuate the association (OR=1.381, P=0.005). Finally, we found that plasma HMGB1 at 6 h had the highest value in identifying patients with non-survival after 3 months (χ2=28.655, P<0.001). Logistic regression results showed that plasma HMGB1 had a strong association with non-survival (OR=2.315, P<0.001). After adjusting for infarct volume and NIHSS score did not attenuate the association (OR=2.013, P<0.001). CONCLUSION: Plasma HMGB1 exerts a good predictive value for CIRI in ischemic stroke patients, and its increased expression is correlated with worse prognosis.


Assuntos
Isquemia Encefálica/tratamento farmacológico , Fibrinolíticos/efeitos adversos , Proteína HMGB1/sangue , Traumatismo por Reperfusão/sangue , Acidente Vascular Cerebral/tratamento farmacológico , Terapia Trombolítica/efeitos adversos , Ativador de Plasminogênio Tecidual/efeitos adversos , Administração Intravenosa , Idoso , Idoso de 80 Anos ou mais , Biomarcadores/sangue , Isquemia Encefálica/sangue , Isquemia Encefálica/diagnóstico , Isquemia Encefálica/fisiopatologia , Avaliação da Deficiência , Feminino , Fibrinolíticos/administração & dosagem , Humanos , Masculino , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Recuperação de Função Fisiológica , Traumatismo por Reperfusão/induzido quimicamente , Traumatismo por Reperfusão/diagnóstico , Traumatismo por Reperfusão/fisiopatologia , Fatores de Risco , Acidente Vascular Cerebral/sangue , Acidente Vascular Cerebral/diagnóstico , Acidente Vascular Cerebral/fisiopatologia , Fatores de Tempo , Ativador de Plasminogênio Tecidual/administração & dosagem , Resultado do Tratamento
4.
Life Sci ; 256: 118016, 2020 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-32603817

RESUMO

AIMS: Ischemia/reperfusion (I/R) is one of the most important causes of acute kidney injury (AKI), a clinical syndrome with kidney dysfunction and high mortality rates. New diagnostic biomarkers need to be defined to better illuminate the pathophysiology of AKI. For the first time, we aim to investigate the protective effects of Curcumin which is known for its antioxidant and anti-inflammatory properties and 12/15 lipoxygenase inhibitor LOXblock-1 on I/R induced AKI by modulating inflammatory processes, oxidative stress, apoptosis and semaphorin-plexin pathway. MAIN METHODS: The rats were divided into five groups, with eight animals per group: Sham, I/R, I/R + DMSO (1%, i.p.), I/R + Curcumin (100 mg/kg, i.p.), I/R + LOXblock-1 (2 µg/kg, i.p.). KEY FINDINGS: The renal function biomarkers (BUN, CREA and UA) in serum were significantly increased in the I/R group. The inflammatory (TNF-α, IL-6 and MCP-1), apoptotic (CYCS and CASP3) and oxidative stress parameters (MDA, MPO, TAS and TOS) measured by ELISA were significantly increased in the I/R group. In histopathological analysis, it was observed that I/R caused serious damage to kidney tissue. SEMA3A was found to increase both serum level and mRNA expression in I/R group. It was observed that curcumin and LOXblock-1 reduce inflammatory processes, oxidative stress and apoptosis via the semaphorin-plexin pathway by both measurements and histopathological analysis. Curcumin was proved more effective than LOXblock-1 with its antioxidant feature in I/R injury. SIGNIFICANCE: The current study reveals the protective effects of Curcumin and LOXblock-1 on acute kidney injury by suppressing SEMA3A as a new biomarker.


Assuntos
Lesão Renal Aguda/prevenção & controle , Derivados de Benzeno/farmacologia , Curcumina/farmacologia , Inflamação/prevenção & controle , Traumatismo por Reperfusão/tratamento farmacológico , Animais , Anti-Inflamatórios não Esteroides/administração & dosagem , Anti-Inflamatórios não Esteroides/farmacologia , Apoptose/efeitos dos fármacos , Derivados de Benzeno/administração & dosagem , Moléculas de Adesão Celular/metabolismo , Curcumina/administração & dosagem , Inibidores de Lipoxigenase/administração & dosagem , Inibidores de Lipoxigenase/farmacologia , Proteínas do Tecido Nervoso/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Ratos , Ratos Wistar , Traumatismo por Reperfusão/fisiopatologia , Semaforina-3A/sangue , Semaforinas/metabolismo
5.
PLoS One ; 15(7): e0236444, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32702055

RESUMO

Cortical spreading depolarization (SD) waves negatively affect neuronal survival and outcome after ischemic stroke. We here aimed to investigate the effects of vagus nerve stimulation (VNS) on SDs in a rat model of focal ischemia. To this end, we delivered non-invasive VNS (nVNS) or invasive VNS (iVNS) during permanent middle cerebral artery occlusion (MCAO), and found that both interventions significantly reduced the frequency of SDs in the cortical peri-infarct area compared to sham VNS, without affecting relative blood flow changes, blood pressure, heart rate or breathing rate. In separate groups of rats subjected to transient MCAO, we found that cortical stroke volume was reduced 72 h after transient MCAO, whereas stroke volume in the basal ganglia remained unchanged. In rats treated with nVNS, motor outcome was improved 2 days after transient MCAO, but was similar to sham VNS animals 3 days after ischemia. We postulate that VNS may be a safe and efficient intervention to reduce the clinical burden of SD waves in stroke and other conditions.


Assuntos
Isquemia Encefálica/terapia , Infarto/terapia , Acidente Vascular Cerebral/terapia , Estimulação do Nervo Vago/métodos , Animais , Pressão Sanguínea , Isquemia Encefálica/fisiopatologia , Modelos Animais de Doenças , Frequência Cardíaca/fisiologia , Humanos , Infarto/fisiopatologia , Infarto da Artéria Cerebral Média/fisiopatologia , Infarto da Artéria Cerebral Média/terapia , Ratos , Traumatismo por Reperfusão/fisiopatologia , Traumatismo por Reperfusão/terapia , Acidente Vascular Cerebral/fisiopatologia , Estimulação do Nervo Vago/efeitos adversos
6.
J Stroke Cerebrovasc Dis ; 29(8): 104977, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32689608

RESUMO

BACKGROUND: Ischemic stroke is a severe neurological disorder that affected millions of people worldwide. Neuro-inflammation and apoptosis play an essential role in the pathogenesis of neuronal death during ischemic stroke. Alpha-pinene is a bicyclic terpenoid with anti-inflammatory and anti-apoptotic activities. Accordingly, the main purpose of this study was to assess the protective effect of α-pinene in ischemic stroke. MATERIALS AND METHODS: To induce ischemic stroke in male Wistar rats, the middle cerebral artery was occluded for 60 min followed by 24 h reperfusion. Alpha-pinene was injected intraperitoneally at the beginning of reperfusion. A day after reperfusion, the neurological deficits, volume of infarct area, and blood-brain barrier (BBB) permeability were evaluated. The mRNA expression of inflammatory cytokines as well as pro- and anti-apoptotic genes was assessed by using reverse transcription-polymerase chain reaction. The protein levels of inflammatory cytokines were also measured by ELISA method. RESULTS: The results showed that α-pinene (50 and 100 mg/kg) significantly improved sensorimotor function and decreased the volume of infarct area in the brain. The high permeability of BBB was also alleviated by α-pinene (50 and 100 mg/kg) in ischemic areas. Besides, α-pinene (100 mg/kg) attenuated neuro-inflammation through decreasing both the gene and protein expression of TNF-α and IL-1ß in the hippocampus, cortex, and striatum. Besides, α-pinene (100 mg/kg) suppressed apoptosis via downregulation of the pro-apoptotic Bax mRNA expression with a concomitant upregulation of anti-apoptotic Bcl-2 gene expression. CONCLUSIONS: Overall, it was concluded that α-pinene exerts neuroprotective effect during ischemic stroke through attenuating neuroinflammation and inhibition of apoptosis.


Assuntos
Anti-Inflamatórios/farmacologia , Apoptose/efeitos dos fármacos , Monoterpenos Bicíclicos/farmacologia , Encéfalo/efeitos dos fármacos , Citocinas/metabolismo , Infarto da Artéria Cerebral Média/tratamento farmacológico , Mediadores da Inflamação/metabolismo , Fármacos Neuroprotetores/farmacologia , Traumatismo por Reperfusão/prevenção & controle , Animais , Comportamento Animal/efeitos dos fármacos , Barreira Hematoencefálica/efeitos dos fármacos , Barreira Hematoencefálica/metabolismo , Encéfalo/metabolismo , Encéfalo/patologia , Encéfalo/fisiopatologia , Permeabilidade Capilar/efeitos dos fármacos , Citocinas/genética , Modelos Animais de Doenças , Infarto da Artéria Cerebral Média/metabolismo , Infarto da Artéria Cerebral Média/patologia , Infarto da Artéria Cerebral Média/fisiopatologia , Masculino , Proteínas Proto-Oncogênicas c-bcl-2/genética , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Ratos Wistar , Traumatismo por Reperfusão/metabolismo , Traumatismo por Reperfusão/patologia , Traumatismo por Reperfusão/fisiopatologia , Transdução de Sinais , Proteína X Associada a bcl-2/genética , Proteína X Associada a bcl-2/metabolismo
7.
Chem Biol Interact ; 327: 109187, 2020 Aug 25.
Artigo em Inglês | MEDLINE | ID: mdl-32610055

RESUMO

Hepatic ischemia-reperfusion injury (IRI) is not only one of the pathophysiological process involving the liver, but also a complex systemic process affecting multiple tissues and organs. IRI after liver transplant occurs due to in major resections and occlusion of vessels, or during the perioperative period, leads to acute liver failure which shows the dynamic process that involves two interrelated phases of local ischemic insult and inflammation-mediated reperfusion injury and has an impact on morbidity and mortality. The renin-angiotensin-aldosterone system (RAAS) is activated locally in the injured cells by the occurrence of I/R, which plays an essential role in the fate of the damaged tissue. However, a preclinical study explores the protective role of RAAS inhibitor in acute liver injury in a model of inflammation caused by ischemia and reperfusion. In-addition to RAAS blockers in monotherapy does not effectively block the complete pathway. Thus, the present study is designed to explore the effect of combined folic acid with RAAS blockers in combination, produce a synergistic effect. Moreover, in this review, we will describe the understanding of the possible incidence of downregulatory molecular mechanisms associated with renin-angiotensin-aldosterone system and the significance & outcome of the combination of folic acid and RAAS blockers in liver injury due to ischemia/reperfusion.


Assuntos
Ácido Fólico/uso terapêutico , Hepatopatias/tratamento farmacológico , Sistema Renina-Angiotensina/efeitos dos fármacos , Traumatismo por Reperfusão/tratamento farmacológico , Animais , Sinergismo Farmacológico , Homocisteína/metabolismo , Humanos , Hepatopatias/fisiopatologia , Traumatismo por Reperfusão/fisiopatologia , Ácido Úrico/metabolismo
8.
J Cardiothorac Surg ; 15(1): 134, 2020 Jun 10.
Artigo em Inglês | MEDLINE | ID: mdl-32522213

RESUMO

BACKGROUND: In a rabbit model of cardiopulmonary bypass (CPB) and cardioplegic arrest, we previously showed that hyperoxic myocardial reperfusion was associated with increased left ventricular (LV) systolic dysfunction and myocardial injury compared with normoxic reperfusion. The aim of this study was to evaluate in our experimental model the impact of post-CPB reperfusion conditions on other organs potentially vulnerable to ischemic injury such as the brain and kidney. METHODS: After 60 min of CPB, aortic cross-clamp, and cold cardioplegic arrest, rabbits were reperfused under hyperoxic or normoxic conditions for 120 min. Left ventricular systolic contractility (LV + dP/dt) and diastolic relaxation (LV -dP/dt) were continuously recorded, and end-organ injury was assessed by measuring circulating biomarkers specific for kidney (cystatin C and creatinine) and brain injury [S100B and neuron specific enolase (NSE)]. At completion of the protocol, kidney and brain tissues were harvested for measuring oxidant stress (OS), inflammation and apoptosis. RESULTS: Following aortic cross-clamp removal, rabbits exposed to normoxic reperfusion demonstrated preserved LV systolic and diastolic function compared with hyperoxic reperfusion (LV + dP/dt: 70 ± 14% of pre-CPB vs. 36 ± 21%, p = 0.018; LV -dP/dt: 72 ± 36% of pre-CPB vs. 33 ± 20%, p = 0.023). Similarly, CPB increased plasma creatinine, S100B and NSE that were significantly attenuated by normoxic reperfusion compared with hyperoxic reperfusion (creatinine: 4.0 ± 0.5 vs. 7.1 ± 0.8 mg/dL, p = 0.004; S100B: 4.0 ± 0.8 vs. 6.7 ± 1.0 ng/mL, p = 0.047; NSE: 57.7 ± 6.8 vs. 101.3 ± 16.1 pg/mL, p = 0.040). Furthermore, both kidney and brain tissues showed increased mRNA expression and activation of pathways for OS, inflammation, and apoptosis, that were reduced under normoxic compared with hyperoxic conditions. CONCLUSIONS: Normoxic reperfusion ameliorates cardiac, renal and neural injury compared with hyperoxic reperfusion in an in vivo animal model of CPB and cardioplegic arrest. This protective effect of normoxic reperfusion may be due to a reduction in signaling pathways for OS, inflammation, and apoptosis.


Assuntos
Isquemia Encefálica/sangue , Ponte Cardiopulmonar/efeitos adversos , Parada Cardíaca Induzida/efeitos adversos , Nefropatias/sangue , Oxigênio/administração & dosagem , Traumatismo por Reperfusão/sangue , Animais , Apoptose , Biomarcadores/sangue , Encéfalo/fisiopatologia , Isquemia Encefálica/etiologia , Isquemia Encefálica/fisiopatologia , Creatinina/sangue , Cistatina C/sangue , Inflamação/metabolismo , Rim/fisiopatologia , Nefropatias/etiologia , Nefropatias/fisiopatologia , Masculino , Estresse Oxidativo/genética , Fosfopiruvato Hidratase/sangue , RNA Mensageiro/metabolismo , Coelhos , Traumatismo por Reperfusão/etiologia , Traumatismo por Reperfusão/fisiopatologia , Subunidade beta da Proteína Ligante de Cálcio S100/sangue , Função Ventricular Esquerda
9.
Life Sci ; 256: 117864, 2020 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-32474021

RESUMO

As a major risk factor of acute kidney injury, renal ischemia/reperfusion (I/R) has a high mortality rate. Myeloid differentiation protein 2 (MD-2) is a secretory glycoprotein that plays an important role in inflammation. Our study aimed to explore the roles of MD-2 in I/R-induced inflammation and oxidative stress in vivo and in vitro. For the in vivo studies, male C57BL/6 mice were randomly divided into four groups: 1) sham, 2) I/R, 3) negative control for siRNA (siNC) and I/R treatment, or 4) MD-2 siRNA (siMD-2) and I/R. Levels of blood urea nitrogen and creatinine in the plasma were tested, and hematoxylin and eosin staining was performed at 24 h after I/R injury. The inflammatory cytokines TNF-α, IL-6, and MCP-1 were measured using ELISA and Real-time qPCR (RT-qPCR). Malondialdehyde (MDA) content and superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GPx) activity were estimated. For the in vitro studies, HK-2 cells were transfected with siMD-2 and then exposed to hypoxia/reoxygenation (H/R). Inflammatory cytokine expression and oxidative stress then were evaluated. We found decreased levels of blood urea nitrogen and creatinine levels after MD-2 silencing. MD-2 deficiency improved histological damage. MD-2 downregulation attenuated levels of inflammatory cytokines. Inhibition of MD-2 resulted in reduced MDA content and increased SOD, CAT, and GPx activity. Loss of function of MD-2 inhibited the H/R-induced production and expression of inflammatory cytokines. MD-2 silencing reduced MDA content after H/R, and MD-2 suppression enhanced SOD, CAT, and GPx activity. MD-2 deficiency also blocked H/R-mediated activation of the TLR4/TRAF6/NF-κB pathway, and pyrrolidinedithiocarbamate (PDTC) pretreatment strengthened the anti-inflammatory and antioxidant damage effects of MD-2 silencing. Taken together, our study revealed that MD-2 deficiency ameliorated renal I/R-induced inflammation and oxidative stress via inhibition of TLR4/TRAF6/NF-κB pathway.


Assuntos
Inflamação/patologia , Antígeno 96 de Linfócito/metabolismo , Estresse Oxidativo/genética , Traumatismo por Reperfusão/fisiopatologia , Lesão Renal Aguda/etiologia , Lesão Renal Aguda/genética , Animais , Linhagem Celular , Inativação Gênica , Humanos , Inflamação/genética , Antígeno 96 de Linfócito/genética , Masculino , Camundongos , Camundongos Endogâmicos C57BL , NF-kappa B/metabolismo , RNA Interferente Pequeno/administração & dosagem , Fator 6 Associado a Receptor de TNF/metabolismo , Receptor 4 Toll-Like/metabolismo
10.
Life Sci ; 256: 117860, 2020 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-32534037

RESUMO

Optimal tissue oxygenation is essential for its normal function. Suboptimal oxygenation or ischemia contributes to increased mortalities during various pathological conditions such as stroke, acute kidney injury (AKI), cardiac failure. Despite the rapid progression of renal tissue injury, the mechanism underlying renal ischemia/reperfusion injury (IRI) remains highly unclear. Experimental in vitro and in vivo models epitomizing the fundamental process is critical to the research of the pathogenesis of IRI and the development of plausible therapeutics. In this review, we describe the in vitro and in vivo models of IRI, ranges from proximal tubular cell lines to surgery-based animal models like clamping of both renal pedicles (bilateral IRI), clamping of one renal pedicle (unilateral IRI), clamping of one/or both renal arteries/or vein, or unilateral IRI with contralateral nephrectomy (uIRIx). Also, advanced technologies like three-dimensional kidney organoids, kidney-on-a-chip are explained. This review provides thoughtful information for establishing reliable and pertinent models for studying IRI-associated acute renal pathologies.


Assuntos
Nefropatias/fisiopatologia , Rim/fisiopatologia , Traumatismo por Reperfusão/fisiopatologia , Lesão Renal Aguda/fisiopatologia , Animais , Modelos Animais de Doenças , Progressão da Doença , Humanos , Rim/irrigação sanguínea , Oxigênio/metabolismo , Artéria Renal/metabolismo , Reprodutibilidade dos Testes
11.
Am J Physiol Gastrointest Liver Physiol ; 319(1): G43-G50, 2020 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-32508156

RESUMO

Liver transplantation is the standard treatment for end-stage liver disease. However, due to the ongoing disparity between supply and demand for optimal donor organs, there is increasing usage of extended criteria donor organs, including steatotic liver grafts. To mitigate the increased risks associated with extended criteria donor livers, ex situ oxygenated machine perfusion (MP) has received increasing attention in recent years as an emerging platform for dynamic preservation, reconditioning, and viability assessment to increase organ utilization. MP can be applied at different temperatures. During hypothermic MP (4-12°C), liver metabolism is reduced, while oxygenation restores the intracellular levels of adenosine triphosphate. The liver is quickly "recharged" to support metabolism when at normothermia (35-37°C) and to ameliorate the detrimental effects of ischemia/reperfusion injury during transplantation. During normothermia, MP can be applied to assess hepatocellular and cholangiocellular viability. MP at hyperthermic (>38°C) temperatures (HyMP), however, remains relatively understudied. The liver is an important component in the regulation of core body temperature and, as such, displays significant physiological and metabolic changes in response to different temperatures. Hyperthermia may promote vasodilation, increase aerobic metabolism and induce production of protective molecules such as heat shock proteins. Therefore, HyMP could provide an attractive reconditioning strategy for steatotic livers. In this review, we describe current literature on the physiological and metabolic effects of the liver at hyperthermia for human, rodents, and pigs and provide a rationale for using therapeutic HyMP during isolated liver machine perfusion to recondition extended criteria donor livers, including steatotic livers, before transplantation.


Assuntos
Fígado Gorduroso/metabolismo , Hipertermia Induzida , Fígado/cirurgia , Traumatismo por Reperfusão/fisiopatologia , Temperatura , Animais , Humanos , Hipertermia Induzida/métodos , Fígado/metabolismo , Transplante de Fígado/métodos
12.
Am J Physiol Renal Physiol ; 319(2): F149-F154, 2020 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-32567347

RESUMO

Ischemia-reperfusion injury of the kidney is caused by the sudden and temporary obstruction of blood flow to the organ. Renal ischemia-reperfusion injury is associated with high morbidity and mortality, but effective therapies are lacking. Sexual dimorphism in renal injury has been acknowledged since the 1940s, and the possible role of sex hormones has been intensively investigated in the past decades. Clinical and experimental data demonstrate sexual differences in renal anatomy, physiology, and susceptibility to renal diseases including but not limited to ischemia-reperfusion injury. Some data suggest the protective role of female sex hormones, whereas others highlight the detrimental effect of male hormones in renal ischemia-reperfusion injury. Although the important role of sex hormones is evident, the exact underlying mechanisms remain to be elucidated. This review focuses on collecting the current knowledge about sexual dimorphism of renal ischemia-reperfusion injury, with emphasis on molecular mechanisms and potential novel therapeutic strategies.


Assuntos
Lesão Renal Aguda/fisiopatologia , Rim/irrigação sanguínea , Rim/fisiopatologia , Traumatismo por Reperfusão/fisiopatologia , Caracteres Sexuais , Animais , Hormônios Esteroides Gonadais/metabolismo , Humanos
13.
Am J Physiol Regul Integr Comp Physiol ; 319(2): R133-R141, 2020 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-32459970

RESUMO

Ischemic stroke is one of the most frequent causes of injury in the central nervous system which may lead to multiorgan dysfunction, including in the lung. The aim of this study was to investigate whether brain ischemia/reperfusion with or without mechanical ventilation leads to lung injury. Male Sprague-Dawley rats were assigned to four groups: Sham, 1-h brain ischemia (MCAO)/24-h reperfusion (I/R), mechanical ventilation with moderate tidal volume (MTV), and I/R+MTV. The pulmonary capillary permeability (Kfc) was measured in the isolated perfused lung. Mean arterial blood pressure (MAP), heart rate (HR), blood-gas variables, histopathological parameters, lung glutathione peroxidase, and TNF-α were measured. Kfc in the I/R, MTV, and I/R+MTV groups were higher than that in the Sham group. In the I/R, MTV, and I/R+MTV groups, arterial partial pressures of oxygen and the arterial partial pressure of oxygen/fraction of inspired oxygen ratios were lower, whereas arterial partial pressures of carbon dioxide were higher than those in the Sham group. The histopathological score in the I/R group was more than that in the Sham group, and in the MTV and I/R+MTV groups were higher than those in the Sham and I/R groups. Furthermore, there were stepwise rises in TNF-α in the I/R, MTV, and I/R+MTV groups, respectively. There was no significant difference in MAP between groups. However, HR in the MTV group was higher than that in the Sham group. Brain ischemia/reperfusion leads to pulmonary capillary endothelial damage and the impairment of gas exchange in the alveolar-capillary barrier, which is exacerbated by mechanical ventilation with moderate tidal volume partially linked to inflammatory reactions.


Assuntos
Traumatismo por Reperfusão/fisiopatologia , Respiração Artificial/efeitos adversos , Volume de Ventilação Pulmonar/fisiologia , Lesão Pulmonar Induzida por Ventilação Mecânica/fisiopatologia , Animais , Pulmão/fisiopatologia , Masculino , Ratos , Ratos Sprague-Dawley , Traumatismo por Reperfusão/sangue , Fator de Necrose Tumoral alfa/sangue , Lesão Pulmonar Induzida por Ventilação Mecânica/sangue
14.
J Vasc Res ; 57(4): 178-184, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32434183

RESUMO

BACKGROUND: Lysophosphatidic acid (LPA) is a small phospholipid-signaling molecule, which can alter responses to stress in the central nervous system. OBJECTIVE: We hypothesized that exogenous LPA would increase the size of infarct and reduce microregional O2 supply/consumption balance after cerebral ischemia-reperfusion. METHODS: This was tested in isoflurane-anesthetized rats with middle cerebral artery blockade for 1 h and reperfusion for 2 h with or without LPA (1 mg/kg, at 30, 60, and 90 min after reperfusion). Regional cerebral blood flow was determined using a C14-iodoantipyrine autoradiographic technique. Regional small-vessel (20-60 µm in diameter) arterial and venous oxygen saturations were determined microspectrophotometrically. RESULTS: There were no significant hemodynamic or arterial blood gas differences between groups. The control ischemic-reperfused cortex had a similar O2 consumption to the contralateral cortex. However, microregional O2 supply/consumption balance was significantly reduced in the ischemic-reperfused cortex with many areas of low O2 saturation (43 of 80 veins with O2 saturation below 50%). LPA did not significantly alter cerebral blood flow, but it did significantly increase O2 extraction and consumption of the ischemic-reperfused region. It also significantly increased the number of small veins with low O2 saturations in the reperfused region (76 of 80 veins with O2 saturation below 50%). This was associated with a significantly increased cortical infarct size after LPA administration (11.4 ± 0.5% control vs. 16.4 ± 0.6% LPA). CONCLUSION: This suggests that LPA reduces cell survival and that it is associated with an increase in the number of small microregions with reduced local oxygen balance after cerebral ischemia-reperfusion.


Assuntos
Córtex Cerebral/irrigação sanguínea , Córtex Cerebral/efeitos dos fármacos , Circulação Cerebrovascular/efeitos dos fármacos , Infarto da Artéria Cerebral Média/patologia , Lisofosfolipídeos/toxicidade , Microcirculação/efeitos dos fármacos , Consumo de Oxigênio/efeitos dos fármacos , Oxigênio/sangue , Traumatismo por Reperfusão/patologia , Animais , Morte Celular/efeitos dos fármacos , Córtex Cerebral/patologia , Veias Cerebrais/efeitos dos fármacos , Veias Cerebrais/patologia , Veias Cerebrais/fisiopatologia , Modelos Animais de Doenças , Infarto da Artéria Cerebral Média/sangue , Infarto da Artéria Cerebral Média/fisiopatologia , Masculino , Ratos Endogâmicos F344 , Traumatismo por Reperfusão/sangue , Traumatismo por Reperfusão/fisiopatologia
15.
Life Sci ; 255: 117833, 2020 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-32450167

RESUMO

AIMS: This study aimed to evaluate the effect of oleuropein (OLE), the main phenolic compound present in olive leaves, on kidney ischemia-reperfusion injury (IRI) and to explore the underlying protective mechanism. MAIN METHODS: Rat kidneys were subjected to 60 min of bilateral warm ischemia followed by 120 min of reperfusion. OLE was administered orally 48 h, 24 h and 30 min prior to ischemia at doses of 10, 50 and 100 mg/kg body weight. The creatinine, urea, uric acid concentrations and lactate dehydrogenase (LDH) activity in plasma were evaluated. Oxidative stress and inflammation parameters were also assessed. Renal expression of AMP-activated protein kinase (p-AMPK), endothelial nitric oxide synthase (eNOS), mitogen-activated protein kinases (MAPK), inflammatory proteins and apoptotic proteins were evaluated using Western blot. KEY FINDINGS: Our results showed that OLE at 50 mg/kg reduced kidney IRI as revealed by a significant decrease of plasmatic creatinine, urea, uric acid concentrations and LDH activity. In parallel, OLE up-regulated antioxidant capacities. Moreover, OLE diminished the level of CRP and the expression of cyclooxygenase 2 (COX-2). Finally, OLE enhanced AMPK phosphorylation as well as eNOS expression whereas MAPK, and cleaved caspase-3 implicated in cellular apoptosis were attenuated in the ischemic kidneys. SIGNIFICANCE: In conclusion, this study shows that OLE could be used as therapeutic agent to reduce IRI through its anti-oxidative, anti-inflammatory and anti-apoptotic properties.


Assuntos
Inflamação/prevenção & controle , Iridoides/farmacologia , Rim/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Traumatismo por Reperfusão/tratamento farmacológico , Animais , Anti-Inflamatórios/administração & dosagem , Anti-Inflamatórios/farmacologia , Antioxidantes/administração & dosagem , Antioxidantes/farmacologia , Apoptose/efeitos dos fármacos , Relação Dose-Resposta a Droga , Iridoides/administração & dosagem , Rim/patologia , Masculino , Ratos , Ratos Wistar , Traumatismo por Reperfusão/fisiopatologia , Fatores de Tempo
16.
Transplant Proc ; 52(5): 1556-1558, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32229046

RESUMO

BACKGROUND: The delayed graft function (DGF) in kidney transplantation (KT) is a risk factor for long-term poor graft survival. The pathogenesis is multifactorial but mainly related to an ischemia-reperfusion injury. However, the graft hemodynamics have been recently identified as a key aspect for early DGF risk assessment and potential therapeutic intervention. METHODS: A pilot study on 20 single kidney grafts from donor after brain death with intraoperative measurement of graft arterial flowmetry, 30 minutes after reperfusion. Exclusion criteria were grafts with multiple arteries or severe atherosclerosis of the recipient's external iliac artery. RESULTS: KT recipients with DGF (n = 4, 20%) were homogenous with controls (n = 16) in terms of cold ischemia time, donor age, recipients' hemodynamic parameters, renal artery, and recipients' external iliac artery diameters. Nonetheless, at transplant, the kidney grafts that developed DGF were characterized by a significantly higher renal artery resistive index (DGF vs no-DGF 0.96 ± 0.04 vs 0.77 ± 0.13, P = .02), as well as lower flow extraction rate (24.8% ± 11.8 vs 59.2% ± 21.1, P < .01). CONCLUSIONS: Intraoperative arterial graft flowmetry seems to be an effective tool to identify grafts at high risk of DGF.


Assuntos
Função Retardada do Enxerto/diagnóstico por imagem , Transplante de Rim/efeitos adversos , Monitorização Intraoperatória/estatística & dados numéricos , Reologia/estatística & dados numéricos , Ultrassonografia Doppler/estatística & dados numéricos , Adulto , Função Retardada do Enxerto/fisiopatologia , Feminino , Sobrevivência de Enxerto , Hemodinâmica , Humanos , Rim/irrigação sanguínea , Transplante de Rim/métodos , Masculino , Pessoa de Meia-Idade , Monitorização Intraoperatória/métodos , Projetos Piloto , Valor Preditivo dos Testes , Artéria Renal/fisiopatologia , Traumatismo por Reperfusão/diagnóstico por imagem , Traumatismo por Reperfusão/fisiopatologia , Estudos Retrospectivos , Reologia/métodos , Medição de Risco , Fatores de Risco , Transplantes/irrigação sanguínea , Ultrassonografia Doppler/métodos
17.
Zool Res ; 41(3): 220-230, 2020 May 18.
Artigo em Inglês | MEDLINE | ID: mdl-32314558

RESUMO

Ischemia/reperfusion (I/R) is a pathological process that occurs in numerous organs throughout the human body, and it is frequently associated with severe cellular damage and death. Recently it has emerged that ferroptosis, a new form of regulated cell death that is caused by iron-dependent lipid peroxidation, plays a significantly detrimental role in many I/R models. In this review, we aim to revise the pathological process of I/R and then explore the molecular pathogenesis of ferroptosis. Furthermore, we aim to evaluate the role that ferroptosis plays in I/R, providing evidence to support the targeting of ferroptosis in the I/R pathway may present as a therapeutic intervention to alleviate ischemia/reperfusion injury (IRI) associated cell damage and death.


Assuntos
Ferroptose , Traumatismo por Reperfusão/veterinária , Animais , Traumatismo por Reperfusão/fisiopatologia
18.
J Clin Invest ; 130(3): 1062-1072, 2020 03 02.
Artigo em Inglês | MEDLINE | ID: mdl-32118586

RESUMO

Sickle cell anemia is a unique disease dominated by hemolytic anemia and vaso-occlusive events. The latter trigger a version of ischemia/reperfusion (I/R) pathobiology that is singular in its origin, cyclicity, complexity, instability, perpetuity, and breadth of clinical consequences. Specific clinical features are probably attributable to local I/R injury (e.g., stroke syndromes) or remote organ injury (e.g., acute chest syndrome) or the systematization of inflammation (e.g., multifocal arteriopathy). Indeed, by fashioning an underlying template of endothelial dysfunction and vulnerability, the robust inflammatory systematization no doubt contributes to all sickle pathology. In this Review, we highlight I/R-targeting therapeutics shown to improve microvascular blood flow in sickle transgenic mice undergoing I/R, and we suggest how such insights might be translated into human therapeutic strategies.


Assuntos
Anemia Falciforme , Endotélio Vascular , Anemia Falciforme/genética , Anemia Falciforme/metabolismo , Anemia Falciforme/fisiopatologia , Animais , Modelos Animais de Doenças , Endotélio Vascular/metabolismo , Endotélio Vascular/fisiopatologia , Inflamação/classificação , Inflamação/genética , Inflamação/metabolismo , Inflamação/fisiopatologia , Camundongos , Camundongos Transgênicos , Traumatismo por Reperfusão/classificação , Traumatismo por Reperfusão/genética , Traumatismo por Reperfusão/metabolismo , Traumatismo por Reperfusão/fisiopatologia
19.
Oxid Med Cell Longev ; 2020: 3076131, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32190170

RESUMO

Objectives: Our previous study showed that aldose reductase (AR) played key roles in fatty liver ischemia-reperfusion (IR) injury by regulating inflammatory response and energy metabolism. Here, we aim to investigate the role and mechanism of AR in the regeneration of normal and fatty livers after liver surgery. Methods: The association of AR expression with liver regeneration was studied in the rat small-for-size liver transplantation model and the mice major hepatectomy and hepatic IR injury model with or without fatty change. The direct role and mechanism of AR in liver regeneration was explored in the AR knockout mouse model. Results: Delayed regeneration was detected in fatty liver after liver surgery in both rat and mouse models. Furthermore, the expression of AR was increased in liver after liver surgery, especially in fatty liver. In a functional study, the knockout of AR promoted liver regeneration at day 2 after major hepatectomy and IR injury. Compared to wild-type groups, the expressions of cyclins were increased in normal and fatty livers of AR knockout mice. AR inhibition increased the expressions of PPAR-α and PPAR-γ in both normal liver and fatty liver groups after major hepatectomy and IR injury. In addition, the knockout of AR promoted the expressions of SDHB, AMPK, SIRT1, and PGC1-α and PPAR. Conclusions: The knockout of AR promoted the regeneration of normal and fatty livers through regulating energy metabolism. AR may be a new potential therapeutic target to accelerate liver regeneration after surgery.


Assuntos
Aldeído Redutase/antagonistas & inibidores , Metabolismo Energético , Inibidores Enzimáticos/farmacologia , Regeneração Hepática/fisiologia , Trifosfato de Adenosina/metabolismo , Aldeído Redutase/metabolismo , Animais , Peso Corporal/efeitos dos fármacos , Ciclinas/metabolismo , Modelos Animais de Doenças , Metabolismo Energético/efeitos dos fármacos , Fígado Gorduroso/enzimologia , Fígado Gorduroso/patologia , Fígado Gorduroso/fisiopatologia , Hepatectomia , Fígado/patologia , Fígado/fisiopatologia , Fígado/cirurgia , Masculino , Camundongos Endogâmicos C57BL , Tamanho do Órgão/efeitos dos fármacos , Biogênese de Organelas , Ratos Sprague-Dawley , Traumatismo por Reperfusão/patologia , Traumatismo por Reperfusão/fisiopatologia , Regulação para Cima/efeitos dos fármacos
20.
Am J Physiol Renal Physiol ; 318(5): F1100-F1112, 2020 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-32116018

RESUMO

In the early proximal tubule, Na+-glucose cotransporter 2 (SGLT2) mediates the bulk of renal glucose reabsorption. Gene deletion in mice (Sglt2-/-) was used to determine the role of SGLT2 in acute kidney injury induced by bilateral ischemia-reperfusion (IR). In Sglt2-/- and littermate wild-type mice, plasma creatinine increased similarly on day 1 after IR. This was associated with an equal increase in both genotypes in the urinary kidney injury molecule-1-to-creatinine ratio, a tubular injury marker, and similarly reduced urine osmolality and increased plasma osmolality, indicating impaired urine concentration. In both IR groups, FITC-sinistrin glomerular filtration rate was equally reduced on day 14, and plasma creatinine was similarly and incompletely restored on day 23. In Sglt2-/- mice subjected to IR, fractional urinary glucose excretion was increased on day 1 but reduced and associated with normal renal Na+-glucose cotransporter 1 (Sglt1) mRNA expression on day 23, suggesting temporary SGLT1 suppression. In wild-type mice subjected to IR, renal Sglt1 mRNA was likewise normal on day 23, whereas Sglt2 mRNA was reduced by 57%. In both genotypes, IR equally reduced urine osmolality and renal mRNA expression of the Na+-K+-2Cl- cotransporter and renin on day 23, suggesting thick ascending limb dysfunction, and similarly increased renal mRNA expression of markers of injury, inflammation, oxidative stress, and fibrosis (kidney injury molecule-1, neutrophil gelatinase-associated lipocalin, monocyte chemoattractant protein-1, transforming growth factor-ß1, NADPH oxidase-2, and collagen type 1). This was associated with equal increases in kidney histological damage scores and similar degree of capillary loss in both genotypes. The data indicate that genetic deletion of SGLT2 did not protect the kidneys in the initial injury phase or the subsequent recovery phase in a mouse model of IR-induced acute kidney injury.


Assuntos
Lesão Renal Aguda/metabolismo , Glicemia/metabolismo , Rim/metabolismo , Traumatismo por Reperfusão/metabolismo , Transportador 2 de Glucose-Sódio/deficiência , Lesão Renal Aguda/genética , Lesão Renal Aguda/patologia , Lesão Renal Aguda/fisiopatologia , Animais , Biomarcadores/sangue , Modelos Animais de Doenças , Taxa de Filtração Glomerular , Rim/patologia , Camundongos Endogâmicos C57BL , Camundongos Knockout , Eliminação Renal , Reabsorção Renal , Traumatismo por Reperfusão/genética , Traumatismo por Reperfusão/patologia , Traumatismo por Reperfusão/fisiopatologia , Transportador 2 de Glucose-Sódio/genética , Fatores de Tempo
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