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1.
Acta Cir Bras ; 34(8): e201900805, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31618405

RESUMO

PURPOSE: To investigate the effect of sevoflurane preconditioning on ischemia/reperfusion (I/R)-induced pulmonary/hepatic injury. METHODS: Fifty-one Wistar rats were randomly grouped into sham, I/R, and sevoflurane groups. After reperfusion, the structural change of the lung was measured by Smith score, the wet and dry weights (W/D) were determined, malondialdehyde (MDA) myeloperoxidase (MPO) content was determined colorimetrically and by fluorescence, respectively, and matrix metalloprotein-9 (MMP-9) mRNA was quantified by RT-PCR. Biopsy and morphological analyses were performed on liver tissue, activities of aspartate aminotransferase (AST) and alanine aminotransferase (ALT) were determined, and tumor necrosis factor-alpha (TNF-α) level was determined. RESULTS: The sham group showed no changes in tissue structure. Structural lesions in the sevoflurane and I/R groups were mild and severe, respectively. Smith score, W/D, MDA, MPO, and MMP mRNA showed the same trend, and were increased in the I/R group and recovered in the sevoflurane group, compared with the sham group (both P<0.05). AST and ALT were significantly increased compared to the sham group (AST: 655±52.06 vs . 29±9.30 U/L; ALT: 693±75.56 vs . 37±6.71 U/L; P<0.05). In the sevoflurane group, AST and ALT levels were significantly decreased (464±47.71 and 516±78.84 U/L; P<0.001). TNF-α presented similar results. CONCLUSION: The protection of lung and liver by sevoflurane may be mediated by inhibited leukocyte recruitment and MMP-9 secretion.


Assuntos
Anestésicos Inalatórios/uso terapêutico , Precondicionamento Isquêmico/métodos , Fígado/irrigação sanguínea , Pulmão/irrigação sanguínea , Traumatismo por Reperfusão/prevenção & controle , Sevoflurano/uso terapêutico , Alanina Transaminase/sangue , Animais , Aspartato Aminotransferases/sangue , Modelos Animais de Doenças , Isquemia/prevenção & controle , Fígado/efeitos dos fármacos , Fígado/patologia , Pulmão/efeitos dos fármacos , Pulmão/patologia , Masculino , Malondialdeído/análise , Peroxidase/análise , Ratos , Ratos Wistar , Traumatismo por Reperfusão/tratamento farmacológico , Fator de Necrose Tumoral alfa/sangue
2.
Rev Assoc Med Bras (1992) ; 65(9): 1193-1200, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31618337

RESUMO

OBJECTIVES: This study was conducted to reveal the possible protective effects of ticagrelor and enoxaparin pretreatment against ischemia-reperfusion (IR)-induced injury on the lung tissue of a rat model. METHODS: Wistar albino rats were randomly divided into 4 groups as follows: group-1 (control-sham), group-2 (control-saline+IR), group-3 (ticagrelor+IR), group-4 (enoxaparin+IR). Before the ischemic period, saline, ticagrelor, and enoxaparin were administered to the 2nd-4th groups, respectively. In these groups, IR injury was induced by clamping the aorta infrarenally for 2 h, followed by 4 h of reperfusion except group-1. After the rats were euthanized, the lungs were processed for histological examinations. Paraffin sections were stained with Haematoxylin&Eosin (H&E) for light microscopic observation. Apoptosis was evaluated by caspase-3 immunoreactivity. Data were statistically analyzed using the SPSS software. RESULTS: In the lung sections stained with H&E, a normal histological structure was observed in group-1, whereas disorganized epithelial cells, hemorrhage, and inflammatory cell infiltration were seen in the alveolar wall in group-2. The histologic structure of the treatment groups was better than that of group-2. Caspase-3(+) apoptotic cells were noticeable in sections of group-2 and were lower in the treatment groups. In group-4, caspase-3 immunostaining was lower than in group-3. In group-2, apoptotic cells were significantly higher than in the other groups (p<0.001). CONCLUSION: Based on the histological results, we suggested that both therapies ameliorated the detrimental effects of IR. Caspase-3 immunohistochemistry results also revealed that pre-treatment with enoxaparin gave better results in an IR-induced rat injury model. In further studies, other parameters such as ROS and inflammatory gene expressions should be evaluated for accurate results.


Assuntos
Aorta Abdominal/cirurgia , Enoxaparina/farmacologia , Pulmão/efeitos dos fármacos , Substâncias Protetoras/farmacologia , Traumatismo por Reperfusão/prevenção & controle , Ticagrelor/farmacologia , Animais , Apoptose/efeitos dos fármacos , Caspase 3/metabolismo , Modelos Animais de Doenças , Pulmão/patologia , Lesão Pulmonar/prevenção & controle , Masculino , Distribuição Aleatória , Ratos Wistar , Traumatismo por Reperfusão/patologia
3.
Xi Bao Yu Fen Zi Mian Yi Xue Za Zhi ; 35(7): 601-605, 2019 Jul.
Artigo em Chinês | MEDLINE | ID: mdl-31537244

RESUMO

Objective To determine whether regulatory T cells (Tregs) are involved in sevoflurane preconditioning-induced brain protection against cerebral ischemia/reperfusion injury. Methods C57BL/6 mice were preconditioned with sevoflurane and then subjected to the middle cerebral artery occlusion modeling. The brain infarct volume and neurological score were assessed at 48 hours after cerebral reperfusion. Meanwhile, the proportion of Tregs in the spleen was analyzed by flow cytometry. Then, CD25 neutralizing antibody was administrated by intraperitoneal injection, following with the analysis of cerebral ischemia/reperfusion injury and the proportion of Tregs in the spleen after sevoflurane preconditioning. Results Compared with a control group, sevoflurane preconditioning markedly mitigated the cerebral ischemia/reperfusion injury in the mice including the infarct volume and neurological score. In the meantime, sevoflurane preconditioning significantly increased the proportion of Tregs in the spleen at 48 hours after cerebral reperfusion. Compared with the isotype antibody group, the CD25 neutralizing antibody reversed the increase of Tregs induced by sevoflurane preconditioning at 48 hours after reperfusion, which was also associated with the reversal of sevoflurane preconditioning-induced protectetion against cerebral ischemia/reperfusion injury. Conclusion Tregs are involved in sevoflurane preconditioning-induced cerebral protection against ischemia/reperfusion injury.


Assuntos
Isquemia Encefálica/prevenção & controle , Precondicionamento Isquêmico , Traumatismo por Reperfusão/prevenção & controle , Sevoflurano/farmacologia , Linfócitos T Reguladores/citologia , Animais , Encéfalo/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos C57BL
4.
Acta Cir Bras ; 34(7): e201900707, 2019 Sep 16.
Artigo em Inglês | MEDLINE | ID: mdl-31531528

RESUMO

PURPOSE: To evaluate the effects of splenic ischemic preconditioning (sIPC) on oxidative stress induced by hepatic ischemia-reperfusion in rats. METHODS: Fifteen male Wistar rats were equally divided into 3 groups: SHAM, IRI and sIPC. Animals from IRI group were subjected to 45 minutes of partial liver ischemia (70%). In the sIPC group, splenic artery was clamped in 2 cycles of 5 min of ischemia and 5 min of reperfusion (20 min total) prior to hepatic ischemia. SHAM group underwent the same surgical procedures as in the remaining groups, but no liver ischemia or sIPC were induced. After 1h, hepatic and splenic tissue samples were harvested for TBARS, CAT, GPx and GSH-Rd measurement. RESULTS: sIPC treatment significantly decreased both hepatic and splenic levels of TBARS when compared to IRI group (p<0.01). Furthermore, the hepatic and splenic activities of CAT, GPx and GSH- Rd were significantly higher in sIPC group than in IRI group. CONCLUSION: sIPC was able to attenuate hepatic and splenic IRI-induced oxidative stress.


Assuntos
Precondicionamento Isquêmico/métodos , Hepatopatias/prevenção & controle , Fígado/irrigação sanguínea , Estresse Oxidativo/fisiologia , Traumatismo por Reperfusão/prevenção & controle , Animais , Modelos Animais de Doenças , Fígado/fisiologia , Hepatopatias/fisiopatologia , Masculino , Distribuição Aleatória , Ratos , Ratos Wistar , Traumatismo por Reperfusão/fisiopatologia
5.
Br J Anaesth ; 123(5): 584-591, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31521337

RESUMO

BACKGROUND: The REnal Protection Against Ischaemia-Reperfusion in transplantation (REPAIR) RCT examined whether remote ischaemic preconditioning (RIPC) improved renal function after living-donor kidney transplantation. The primary endpoint, glomerular filtration rate (GFR), quantified by iohexol at 12 months, suggested that RIPC may confer longer-term benefit. Here, we present yearly follow-up data of estimated GFR for up to 5 yr after transplantation. METHODS: In this double-blind, factorial RCT, we enrolled 406 adult live donor kidney transplant donor-recipient pairs in 15 European transplant centres. RIPC was performed before induction of anaesthesia. RIPC consisted of four 5 min inflations of a BP cuff on the upper arm to 40 mm Hg above systolic BP separated by 5 min periods of cuff deflation. For sham RIPC, cuff inflation to 40 mm Hg was undertaken. Pairs were randomised to sham RIPC, early RIPC only (immediately pre-surgery), late RIPC only (24 h pre-surgery), or dual RIPC (early and late RIPC). The pre-specified secondary outcome of estimated GFR (eGFR) was calculated from serum creatinine measurements, using the Chronic Kidney Disease Epidemiology Collaboration equation. Predefined safety outcomes were mortality and graft loss. RESULTS: There was a sustained improvement in eGFR after early RIPC, compared with control from 3 months to 5 yr (adjusted mean difference: 4.71 ml min-1 (1.73 m)-2 [95% confidence interval, CI: 1.54-7.89]; P=0.004). Mortality and graft loss were similar between groups (RIPC: 20/205 [9.8%] vs control 24/201 [11.9%]; hazard ratio: 0.79 [95% CI: 0.43-1.43]). CONCLUSIONS: RIPC safely improves long-term kidney function after living-donor renal transplantation when administered before induction of anaesthesia. CLINICAL TRIAL REGISTRATION: ISRCTN30083294.


Assuntos
Precondicionamento Isquêmico/métodos , Transplante de Rim , Traumatismo por Reperfusão/prevenção & controle , Adolescente , Adulto , Idoso , Aloenxertos , Método Duplo-Cego , Europa (Continente) , Feminino , Seguimentos , Taxa de Filtração Glomerular/fisiologia , Humanos , Rim/fisiologia , Rim/cirurgia , Doadores Vivos , Masculino , Pessoa de Meia-Idade , Tempo , Resultado do Tratamento , Adulto Jovem
6.
Chem Biol Interact ; 310: 108738, 2019 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-31283913

RESUMO

Ischemic stroke and reperfusion injury are a common and serve medical situation in the elderly population. H2S is a gas neuromodulator which also possesses anti-oxidant and anti-inflammatory properties, and is found to play neuroprotective effect in neurodegenerative diseases. This study investigated the effect of endogenous and exogenous H2S in a mouse model of ischemic stroke. 129P2-Cbstm1Unc/J mice with heterozygous mutants in H2S generating enzyme cystathionine ß-synthase were used to study the effect of endogenous H2S. H2S donor NaHS was used as exogenous H2S. Animals were pretreated with H2S and then subjected to middle cerebral artery occlusion surgery. Behavioral outcome was evaluated by novel object recognition test. Inflammatory cytokines were measured using ELISA. Western blot was used to detect the activation of NF-κB. Aged 129P2-Cbstm1Unc/J mice showed exaggerated inflammation and more severe cognitive impairment after ischemia, while exogenous H2S treatment inhibited inflammation and attenuated behavioral impairment. The anti-inflammatory effect of H2S was mediated by inhibiting NF-κB. Our findings suggest that both endogenous and exogenous H2S are involved in the neuroprotection against ischemia/reperfusion-induced cerebral injury.


Assuntos
Sulfeto de Hidrogênio/uso terapêutico , Precondicionamento Isquêmico/métodos , Fármacos Neuroprotetores/farmacologia , Traumatismo por Reperfusão/tratamento farmacológico , Animais , Comportamento Animal/efeitos dos fármacos , Disfunção Cognitiva/tratamento farmacológico , Citocinas/metabolismo , Sulfeto de Hidrogênio/farmacologia , Infarto da Artéria Cerebral Média/complicações , Inflamação/tratamento farmacológico , Camundongos , NF-kappa B/metabolismo , Traumatismo por Reperfusão/prevenção & controle
7.
Transplant Proc ; 51(5): 1549-1554, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31155190

RESUMO

OBJECTIVE: This study aimed to evaluate the effect of hepatic preconditioning with laser light in the presence of methylene blue (MB) in the liver ischemia-reperfusion injury process. METHOD: Forty male Wistar rats were divided into 8 experimental groups (n = 5). Saline (.5 mL) or MB (15 mg/kg) was injected intravenously (inferior vena cava). After 2 minutes, 660 nm laser light was applied at a dose of 112.5 DE. Fifteen minutes after the application of saline or MB, 1 hour partial ischemia followed by 15 minutes of reperfusion was applied when the rats were sacrificed. The mitochondrial function parameters (O2 consumption rates in states 3 and 4 and the respiratory control ratio), osmotic swelling, and determination of malondialdehyde were evaluated. Hepatic function was studied using the serum determination of the alanine aminotransferase and aspartate aminotransferase enzymes. RESULTS AND CONCLUSIONS: MB therapy alone showed the capacity of preserving the rate of oxygen consumption in the mitochondrial respiratory state of the group submitted to ischemia compared to the sham group. However, when combined with low-intensity laser therapy, it failed to replicate the relevant protective effects in relation to oxidative phosphorylation or the mitochondrial membrane ischemia/reperfusion injury. Whether or not MB was combined with laser treatment, it was shown to be efficient in reducing oxidative stress. In relation to alanine aminotransferase enzymes, whether or not laser treatment was combined with MB had a protective effect on the hepatic lesion, whereas in relation to aspartate aminotransferase enzymes only laser treatment was able to provide this protection.


Assuntos
Inibidores Enzimáticos/farmacologia , Lasers , Fígado/efeitos dos fármacos , Fígado/efeitos da radiação , Azul de Metileno/farmacologia , Traumatismo por Reperfusão/prevenção & controle , Animais , Masculino , Estresse Oxidativo/efeitos dos fármacos , Estresse Oxidativo/efeitos da radiação , Consumo de Oxigênio/efeitos dos fármacos , Consumo de Oxigênio/efeitos da radiação , Ratos , Ratos Wistar
8.
Life Sci ; 231: 116533, 2019 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-31173783

RESUMO

AIM: The aim of this study was to investigate the protective effect of chronic intermittent hypobaric hypoxia (CIHH) against skeletal muscle ischemia-reperfusion (IR) injury and to determine the underlying mechanism. MAIN METHODS: C57BL/6 mice were randomly divided into 3 groups: skeletal muscle IR injury group (IR), CIHH pretreatment following IR group (IR + CIHH), and sham operation group (Sham). The skeletal muscle IR injury model was induced by the unilateral application of a tourniquet on a hind limb for 3 h and then releasing it for 24 h. CIHH pretreatment simulating a 5000-m altitude was applied 6 h per day for 28 days. The functional and morphological performance of IR-injured gastrocnemius muscle was evaluated using contraction force, H&E staining, and transmission electron microscopy. IR injury-induced CD68+ macrophage infiltration was assessed by immunofluorescence. TNFα levels in serum and muscle were measured by ELISA and western blotting, respectively. Apoptosis was examined by TUNEL staining and Cleaved Caspase-3 protein expression. KEY FINDINGS: Acute IR injury resulted in reduced contraction tension, morphological destruction, macrophage infiltration, increased TNFα levels, and apoptosis in gastrocnemius muscle. CIHH pretreatment significantly ameliorated contraction function and morphological performance in IR-injured skeletal muscle. In addition, CIHH pretreatment resulted in marked decreases in CD68+ macrophage infiltration, TNFα levels, and apoptosis. SIGNIFICANCE: These data demonstrated that CIHH has a protective effect against acute IR injury in skeletal muscle via inhibition of inflammation and apoptosis.


Assuntos
Hipóxia/patologia , Músculo Esquelético/irrigação sanguínea , Traumatismo por Reperfusão/prevenção & controle , Animais , Apoptose/efeitos dos fármacos , Hipóxia/metabolismo , Inflamação/metabolismo , Inflamação/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Músculo Esquelético/metabolismo , Músculo Esquelético/patologia , Traumatismo por Reperfusão/metabolismo , Traumatismo por Reperfusão/patologia , Fator de Necrose Tumoral alfa/metabolismo
9.
Gen Physiol Biophys ; 38(3): 245-251, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-31184311

RESUMO

We have established that the continuous cold exposure (CCE, 4°C, 4 weeks) causes cold adaptation, increases systolic blood pressure, exerts infarct-limiting effect during coronary artery occlusion (45 min) and reperfusion (2 h). The CCE increases adrenal weight, heart weight and triiodothyronine (T3) level but does not change thymus, spleen weight, serum cortisol, corticosterone and thyroxin (T4) levels. The long-term (4°C, 8 h/day, 4 weeks) intermittent cold exposure (LICE) induces adaptation to the cold and increases T4 level. The brief (4°C, 1.5 h/day, 4 weeks) intermittent cold exposure (BICE) also evokes adaptation to the cold but had no effect on the blood pressure, the cardiac tolerance to ischemia/reperfusion, and does not change thymus, spleen weight, serum cortisol, corticosterone, T3 and T4 levels.


Assuntos
Aclimatação/fisiologia , Temperatura Baixa , Glucocorticoides/sangue , Traumatismo por Reperfusão/prevenção & controle , Hormônios Tireóideos/sangue
10.
Food Chem Toxicol ; 131: 110591, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31212009

RESUMO

Kidney ischemia reperfusion injury (IRI) is an acute kidney injury associated with high number of mortality. We have examined the molecular mechanism and found that oxidative stress and hypoxia leads to induction of autophagy. In IRI induced autophagy, TFEB translocated to nucleus in response to IRI and induced a number of target genes of Coordinated Lysosomal Expression and Regulation (CLEAR) network. Real-time PCR analyses result showed IRI dependent increase in mRNA level to lysosomal hydrolases (Ctsa, Psap), lysosomal membranes (Lamp1), lysosomal acidification (Atp6ap1) non-lysosomal proteins involved in lysosomal biogenesis (M6pr, Nagpa) and autophagy (Becn1, VPS11). Overall, both lysosomal biogenesis and autophagy pathways were induced. Two key players of TFEB dependent proteins in autophagy, LAMP1 and BECN1 were verified by protein analyses. Pretreatment with urolithin A promoted autophagy and attenuated renal injury in kidney IRI and thus inverse relationship existed between TFEB-CLEAR pathway and kidney injury. Urolithin A also attenuated IRI induced pro-inflammatory cytokines TNFα, IL1ß, MIP1α and MIP2 mRNA and associated kidney injury. Overall, our results explored the understanding of autophagy and CLEAR network to kidney IRI and those insights may help to develop new therapeutic strategies to protect against IRI.


Assuntos
Lesão Renal Aguda/prevenção & controle , Autofagia/efeitos dos fármacos , Fatores de Transcrição de Zíper de Leucina e Hélice-Alça-Hélix Básicos/metabolismo , Cumarínicos/uso terapêutico , Substâncias Protetoras/uso terapêutico , Traumatismo por Reperfusão/prevenção & controle , Lesão Renal Aguda/fisiopatologia , Animais , Autofagia/fisiologia , Núcleo Celular/metabolismo , Citocinas/metabolismo , Inflamação/prevenção & controle , Rim/patologia , Rim/fisiopatologia , Lisossomos/metabolismo , Masculino , Camundongos Endogâmicos C57BL , RNA Mensageiro/genética , Traumatismo por Reperfusão/fisiopatologia
11.
Plast Reconstr Surg ; 144(1): 124-133, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31246814

RESUMO

BACKGROUND: Free jejunal flaps are among the most commonly used flaps for esophageal reconstruction. However, ischemia-reperfusion injury caused by warm ischemia seen during transfer limits their use. Iloprost, a prostacyclin analogue, has been shown to reduce ischemia-reperfusion injury in various organs. The authors investigated tissue damage in jejunal flaps with iloprost and ischemic preconditioning and compared the effectiveness of these two modalities. METHODS: Thirty-four Sprague-Dawley rats were randomized into five groups: sham, ischemia-reperfusion (control), ischemic preconditioning, iloprost, and ischemic preconditioning plus iloprost. All flaps, except those in the sham group, underwent ischemia for 60 minutes and reperfusion for 2 hours. Flap perfusion was assessed by laser Doppler perfusion monitoring. Histologic sections were scored using the Chiu scoring system. Superoxide dismutase and myeloperoxidase levels were measured spectrophotometrically. RESULTS: Animals that were administered iloprost and/or underwent ischemic preconditioning had better postischemic recovery of mesenteric perfusion (ischemic preconditioning, 78 percent; iloprost, 83 percent; ischemic preconditioning plus iloprost, 90 percent; versus ischemia-reperfusion, 50 percent; p < 0.05). All intervention groups showed improved histology of jejunal flaps following ischemia-reperfusion injury (ischemic preconditioning, 3; iloprost, 2.3; ischemic preconditioning plus iloprost, 3.2; versus ischemia-reperfusion, 4.7; p < 0.01, p < 0.001, and p < 0.05, respectively). Superoxide dismutase levels were higher in ischemic preconditioning, iloprost plus ischemic preconditioning, and iloprost groups (ischemic preconditioning, 2.7 ± 0.2; ischemic preconditioning plus iloprost, 2.5 ± 0.3; versus ischemia-reperfusion, 1.2 ± 0.1; p < 0.01; iloprost, 2.4 ± 1.1; versus ischemia-reperfusion, 1.2 ± 0.1; p < 0.05). Myeloperoxidase, a marker for neutrophil infiltration, was lower in the iloprost group (iloprost, 222 ± 5; versus ischemia-reperfusion, 291 ± 25; p < 0.05). CONCLUSIONS: This study showed that both iloprost and ischemic preconditioning reduced reperfusion injury in jejunal flaps. Based on histologic results, iloprost may be a novel treatment alternative to ischemic preconditioning.


Assuntos
Retalhos de Tecido Biológico , Iloprosta/farmacologia , Precondicionamento Isquêmico/métodos , Jejuno/transplante , Inibidores da Agregação de Plaquetas/farmacologia , Traumatismo por Reperfusão/prevenção & controle , Animais , Antioxidantes/metabolismo , Biomarcadores/metabolismo , Modelos Animais de Doenças , Esôfago/cirurgia , Fluxometria por Laser-Doppler/métodos , Masculino , Infiltração de Neutrófilos/efeitos dos fármacos , Peroxidase/metabolismo , Distribuição Aleatória , Ratos Sprague-Dawley , Superóxido Dismutase/metabolismo
12.
Chem Biol Interact ; 308: 332-338, 2019 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-31170386

RESUMO

BACKGROUND: Sevoflurane (sevo) has been reported to be an effective neuroprotective agent in cerebral ischemia/reperfusion injury (CIRI). However, the precise molecular mechanism underlying sevo preconditioning in CIRI remains largely unknown. METHODS: A middle cerebral artery occlusion (MCAO) rat model and primary cortical neurons after oxygen-glucose deprivation and reoxygenation (OGDR) were used as the in vivo and in vitro models of CIRI. The expression profiles of miR-181a and X chromosome-linked inhibitor-of-apoptosis protein (XIAP) in the cerebral cortex of rats and in cortical neurons were examined by qRT-PCR and Western blot, respectively. The infarct volumes were measured by TTC staining and neurological deficits in rats was determined by Zea-Longa scoring criteria. The cell viability, lactate dehydrogenase (LDH) release and apoptotic rate were detected in cortical neurons by MTT assay, LDH analysis and flow cytometry. Western blot analysis was performed to assess the expression of apoptosis-related protein. Luciferase reporter assay was used to confirm the interaction between miR-181a and XIAP. RESULTS: miR-181a was upregulated and XIAP was downregulated in rats after MCAO. Sevo preconditioning attenuated miR-181a expression and promoted XIAP level in a rat model of CIRI. Sevo preconditioning ameliorated anti-miR-181a-mediated protective effects on cerebral ischemia in rat model of CIRI, presented as the decrease of infarct volume, neurological deficit and apoptosis. Moreover, sevo pretreatment abated miR-181a-induced cellular injury in primary cortical neurons after OGD, embodied by the increase of cell viability, the reduction of LDH release and the decline of apoptosis. Furthermore, miR-181a suppressed XIAP expression by binding to its 3'UTR in cortical neurons, and sevo-mediated increase on XIAP expression was counteracted by miR-181 overexpression in OGDR-treated neurons. CONCLUSION: Sevo preconditioning protected against CIRI in vitro and in vivo possibly by inhibiting miR-181a and facilitating XIAP.


Assuntos
MicroRNAs/metabolismo , Fármacos Neuroprotetores/uso terapêutico , Traumatismo por Reperfusão/prevenção & controle , Sevoflurano/uso terapêutico , Regiões 3' não Traduzidas , Animais , Antagomirs/metabolismo , Apoptose/efeitos dos fármacos , Sequência de Bases , Regulação para Baixo/efeitos dos fármacos , Infarto da Artéria Cerebral Média/complicações , Proteínas Inibidoras de Apoptose/química , Proteínas Inibidoras de Apoptose/genética , Proteínas Inibidoras de Apoptose/metabolismo , Masculino , MicroRNAs/antagonistas & inibidores , MicroRNAs/genética , Neurônios/citologia , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Fármacos Neuroprotetores/farmacologia , Ratos , Ratos Sprague-Dawley , Traumatismo por Reperfusão/etiologia , Alinhamento de Sequência , Sevoflurano/farmacologia
13.
Acta Cir Bras ; 34(5): e201900501, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31166464

RESUMO

PURPOSE: To analyze the effects of ischemic preconditioning (IPC) in the expression of apoptosis-related genes in rat small intestine subjected to ischemia and reperfusion. METHODS: Thirty anesthetized rats underwent laparotomy and were drive into five groups: control (CG); ischemia (IG); ischemia and reperfusion (IRG); IPC and ischemia (IG+IPC); IPC and ischemia and reperfusion (I/RG+IPC). Intestinal ischemia was performed by clamping the superior mesenteric artery for 60 minutes, whereas reperfusion lasted for 120 minutes. IPC was carried out by one cycle of 5 minutes of ischemia followed by 10 minutes of reperfusion prior to the prolonged 60-minutes-ischemia and 120-minutes-reperfusion. Thereafter, the rats were euthanized and samples of small intestine were processed for histology and gene expression. RESULTS: Histology of myenteric plexus showed a higher presence of neurons presenting pyknotic nuclei and condensed chromatin in the IG and IRG. IG+IPC and I/RG+IPC groups exhibited neurons with preserved volume and nuclei, along with significant up-regulation of the anti-apoptotic protein Bcl2l1 and down-regulation of pro-apoptotic genes. Moreover, Bax/Bcl2 ratio was lower in the groups subjected to IPC, indicating a protective effect of IPC against apoptosis. CONCLUSION: Ischemic preconditioning protect rat small intestine against ischemia/reperfusion injury, reducing morphologic lesions and apoptosis.


Assuntos
Proteínas Reguladoras de Apoptose/análise , Apoptose/genética , Precondicionamento Isquêmico/métodos , Jejuno/irrigação sanguínea , Jejuno/patologia , Traumatismo por Reperfusão/prevenção & controle , Animais , Proteínas Reguladoras de Apoptose/genética , Constrição , Regulação para Baixo , Células Endoteliais/patologia , Expressão Gênica , Masculino , Artéria Mesentérica Superior , Isquemia Mesentérica/genética , Isquemia Mesentérica/patologia , Distribuição Aleatória , Ratos Wistar , Reação em Cadeia da Polimerase em Tempo Real , Valores de Referência , Reprodutibilidade dos Testes
14.
BMC Genomics ; 20(1): 361, 2019 May 09.
Artigo em Inglês | MEDLINE | ID: mdl-31072368

RESUMO

BACKGROUND: Blood flow restoration is a definitive therapy for salvaging the myocardium following ischemic injury. Nevertheless, the sudden restoration of blood flow to the ischemic myocardium can induce ischemia-reperfusion injury (IRI). RESULTS: Herein, we investigated the cardioprotective effect of remote ischemic postconditioning (RPostC) through our in vivo rat model of myocardial IRI. The study included three groups: the control group, the IRI group, and the IRI + RPostC group. Ischemia-reperfusion treatment led to an increase in the myocardial infarction area, which was inhibited by RPostC. In contrast to that in the control group, the myocardial apoptosis level was enhanced in the IRI group, whereas RPostC treatment decreased IRI-induced cellular apoptosis. Affymetrix Rat Gene 2.0 ST chip data identified a total of 265 upregulated genes and 267 downregulated genes between the IRI and IRI + RPostC groups. A group of differentially expressed noncoding RNAs (ncRNAs), such as MTA_TC0600002772.mm, MTA_TC1300002394.mm, U7 small nuclear RNA (Rnu7) and RGD7543256_1, were identified. Gene Ontology (GO) enrichment analysis indicated that the positive regulation of some molecular functions, such as GTPase activity, GTP binding, cyclic-nucleotide phosphodiesterase activity and cytokine activity, may contribute to the cardioprotective role of RPostC. Moreover, pathway enrichment analysis using the Kyoto Encyclopedia of Genes and Genomes (KEGG) suggested the potential implication of the TNF signaling pathway and Toll-like receptor signaling pathway. Global signal transduction network analysis, co-expression network analysis and quantitative real-time polymerase chain reaction analysis further identified several core genes, including Pdgfra, Stat1, Lifr and Stfa3. CONCLUSION: Remote ischemic postconditioning treatment can decrease IRI-mediated myocardial apoptosis by regulating multiple processes and pathways, such as GTPase activity, cytokine activity, and the TNF and Toll-like receptor signaling pathways. The potential role of the above ncRNAs and core genes in IRI-induced cardiac damage merits further study as well.


Assuntos
Apoptose , Perfilação da Expressão Gênica/métodos , Redes Reguladoras de Genes , Pós-Condicionamento Isquêmico/métodos , Traumatismo por Reperfusão/genética , Traumatismo por Reperfusão/prevenção & controle , Transdução de Sinais , Animais , Masculino , Ratos , Ratos Wistar
15.
Mol Med Rep ; 19(6): 4852-4862, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31059068

RESUMO

Cerebrovascular disease (CVD) is one of the leading causes of mortality worldwide. The role of cytochrome c oxidase subunit 6B1 (COX6B1) in the central nervous system remains unclear. The present study aimed to analyze the role of COX6B1 in rat hippocampal neurons extracted from fetal rats. The subcellular localization of the neuron­specific marker microtubule­associated protein 2 was detected by immunofluorescence assay. Cell viability was assessed using a cell counting kit, and the levels of apoptosis and cytosolic Ca2+ were analyzed by flow cytometry. The expression levels of the molecular factors downstream to COX6B1 were determined using reverse transcription­quantitative polymerase chain reaction and western blotting. Reoxygenation following oxygen­glucose deprivation (OGD) decreased cell viability and the expression levels of COX6B1 in a time­dependent manner, and 60 min of reoxygenation was identified as the optimal time period for establishing an ischemia/reperfusion (I/R) model. Overexpression of COX6B1 was demonstrated to reverse the viability of hippocampal neurons following I/R treatment. Specifically, COX6B1 overexpression decreased the cytosolic concentration of Ca2+ and suppressed neuronal apoptosis, which were increased following I/R treatment. Furthermore, overexpression of COX6B1 increased the protein expression levels of apoptosis regulator BCL­2 and mitochondrial cytochrome c (cyt c), and decreased the protein expression levels of apoptosis regulator BCL2­associated X and cytosolic cyt c in I/R model cells. Collectively, the present study results suggested that COX6B1 overexpression may reverse I/R­induced neuronal damage by increasing the viability of neurons, by decreasing the cytosolic levels of Ca2+ and by suppressing apoptosis. These results may facilitate the development of novel strategies for the prevention and treatment of CVD.


Assuntos
Complexo IV da Cadeia de Transporte de Elétrons/metabolismo , Complexo IV da Cadeia de Transporte de Elétrons/farmacologia , Neurônios/metabolismo , Traumatismo por Reperfusão/prevenção & controle , Lobo Temporal/metabolismo , Animais , Apoptose/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Transtornos Cerebrovasculares/prevenção & controle , Citocromos c/metabolismo , Complexo IV da Cadeia de Transporte de Elétrons/genética , Feminino , Glucose/metabolismo , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Neurônios/patologia , Oxigênio/metabolismo , Substâncias Protetoras/metabolismo , Substâncias Protetoras/farmacologia , Ratos , Ratos Sprague-Dawley , Lobo Temporal/patologia , Proteína bcl-X/metabolismo
16.
J Stroke Cerebrovasc Dis ; 28(7): 1832-1840, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31078389

RESUMO

GOAL: The present study aimed to examine whether Am80 (tamibarotene) protects the hippocampus against cerebral ischemia-reperfusion (I/R) injury and whether phosphoinositide-3-kinase/Akt (PI3K/Akt) pathway mediates this effect. MATERIALS AND METHODS: Rats were subjected to 90 minutes of middle cerebral artery occlusion followed by 24 hours of reperfusion. The animals were randomly divided into 7 groups: sham-operated group; I/R group; groups pretreated with 2 mg/kg, 6 mg/kg, and 10 mg/kg of Am80; Am80 (6 mg/kg) combined with the selective PI3K inhibitor wortmannin (0.6 mg/kg), and wortmannin (0.6 mg/kg) only group. After 24 hours of reperfusion, neurological deficits and infarct volume were measured. Pathological changes in hippocampal neurons were analyzed by transmission electron microscopy. Neuronal survival was examined by TUNEL staining. The expression of Bcl-2, Bax, and Akt, and Akt phosphorylation (p-Akt) were measured by Western blotting and quantitative real-time polymerase chain reaction. FINDINGS: The pretreatment with Am80 improved the neurologic deficit score, reduced infarct volume, and decreased the number of TUNEL-positive cells in the hippocampus. Moreover, Am80 pretreatment downregulated the expression of Bax, upregulated the expression of Bcl-2, and increased the level of p-Akt. Wortmannin abolished in part the increase in p-Act and the neuroprotective effect exerted on the ischemic by Am80 pretreatment. CONCLUSIONS: Our results documented that Am80 pretreatment protects ischemic hippocampus after cerebral I/R by regulating the expression of apoptosis-related proteins through the activation of the PI3K/Akt signaling pathway.


Assuntos
Benzoatos/farmacologia , Hipocampo/efeitos dos fármacos , Infarto da Artéria Cerebral Média/prevenção & controle , Neurônios/efeitos dos fármacos , Fármacos Neuroprotetores/farmacologia , Fosfatidilinositol 3-Quinase/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Traumatismo por Reperfusão/prevenção & controle , Tetra-Hidronaftalenos/farmacologia , Animais , Apoptose/efeitos dos fármacos , Modelos Animais de Doenças , Hipocampo/enzimologia , Hipocampo/ultraestrutura , Infarto da Artéria Cerebral Média/enzimologia , Infarto da Artéria Cerebral Média/patologia , Masculino , Neurônios/enzimologia , Neurônios/ultraestrutura , Fosforilação , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Ratos Sprague-Dawley , Traumatismo por Reperfusão/enzimologia , Traumatismo por Reperfusão/patologia , Transdução de Sinais/efeitos dos fármacos , Proteína X Associada a bcl-2/metabolismo
17.
Gene ; 708: 14-20, 2019 Aug 05.
Artigo em Inglês | MEDLINE | ID: mdl-31082504

RESUMO

INTRODUCTION: Renal ischemia/reperfusion injury (IRI) remains one of the most diseases in clinic. The purpose of this study was to investigate the potential role and mechanism of propofol in protecting mice kidney from IRI. METHODS: Renal I/R model was established in C57/BL6 mice by clamping bilateral renal pedicles for 35 min. The mice were randomly divided into four groups: sham group, IR group, IR + Propofol group, and IR + Propofol+LY294002 group. Histological assessment of kidney was conducted by HE staining and the levels of serum creatinine (SCr) and blood urea nitrogen (BUN) of each group were measured. Expressions of inflammatory factors (IL-6, TNF-α) were detected by qRT-PCR and immunoblotting. The expression levels of cleaved Caspasse-3, PI3K, Akt, p-Akt, mTOR, and p-mTOR within renal tissue samples were measured by Western Blot. RESULTS: The levels BUN, Cr and morphological damage score increased significantly after renal IRI. However, such changes could be prevented by propofol. Besides, IRI reduced renal expressions of PI3K, p-Akt, p-mTOR, and increased the levels of IL-6, TNF-α,cl-caspase-3 in kidney, After propofol treatment, these changes were significantly alleviated, but the use of PI3K inhibitor LY294002 could reverse the effects of propofol. CONCLUSION: Propofol can protect renal IRI partially by reducing apoptosis and release of inflammatory cytokines, which is possibly involved in the modulation of the PI3K/AKT/mTOR signaling pathway. Our data suggested that propofol may play certain positive roles in protecting the kidney from IRI.


Assuntos
Lesão Renal Aguda/prevenção & controle , Propofol/farmacologia , Substâncias Protetoras/farmacologia , Traumatismo por Reperfusão/prevenção & controle , Transdução de Sinais/efeitos dos fármacos , Lesão Renal Aguda/etiologia , Animais , Apoptose/efeitos dos fármacos , Citocinas/imunologia , Citocinas/metabolismo , Modelos Animais de Doenças , Avaliação Pré-Clínica de Medicamentos , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Fosfatidilinositol 3-Quinases/metabolismo , Propofol/uso terapêutico , Substâncias Protetoras/uso terapêutico , Proteínas Proto-Oncogênicas c-akt/metabolismo , Traumatismo por Reperfusão/etiologia , Serina-Treonina Quinases TOR/metabolismo , Resultado do Tratamento
18.
Transplant Proc ; 51(4): 1268-1275, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-31101212

RESUMO

BACKGROUND: Ischemia reperfusion (I/R) injury remains one of the most challenging fields of organ transplantation. It is highly associated with the use of expanded criteria donors that might conclude to delayed graft function or early or late graft failure. OBJECTIVE: To investigate the metabolic, microcirculatory parameters, and histologic changes under the effect of N,N-dimethyltryptamine (DMT) in a renal I/R model in rats. METHOD: In 26 anesthetized rats both kidneys were exposed. In the control group (n = 6) no other intervention happened. In 20 other animals, the right renal vessels were ligated, and after 60 minutes the right kidney was removed. The left renal vessels were clamped for 60 minutes then released, followed by 120 minutes of reperfusion. In the I/R group (n = 10), there was no additive treatment, while in I/R + DMT group (n = 10) DMT was administered 15 minutes before ischemia. Blood samples were taken, laser Doppler measurement was performed, and both kidneys were evaluated histologically. RESULTS: Microcirculation (blood flux units [BFU]) diminished in all groups, but remarkably so in the I/R + DMT group. This group compensated better after the 30th minute of reperfusion. The control and I/R + DMT groups had similar BFUs after 120 minutes of reperfusion, but in the I/R group BFU was higher. Tubular necrosis developed in the I/R and I/R + DMT groups too; it was moderated under DMT effect, and severe without. Histologic injuries were less in I/R + DMT Group compared to non-treated animals. CONCLUSION: Histologic changes characteristic to I/R injuries were reversible and microcirculation recovered at the end of 120 minutes reperfusion under the administration of DMT. DMT can be used for renoprotection in kidney transplantation.


Assuntos
Antioxidantes/farmacologia , Transplante de Rim/efeitos adversos , Rim/efeitos dos fármacos , N,N-Dimetiltriptamina/farmacologia , Traumatismo por Reperfusão/prevenção & controle , Animais , Modelos Animais de Doenças , Rim/patologia , Masculino , Ratos , Receptores sigma/agonistas
19.
Plast Reconstr Surg ; 143(6): 1657-1664, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-31136481

RESUMO

BACKGROUND: When frostbite thaws, reperfusion injury has a crucial impact on tissue injury, and production of free radicals induces further tissue damage. This study examined whether extract of Ginkgo biloba 761 could ameliorate frostbite injury as a free radical scavenger. METHODS: Seventy-five Fisher 344 rats were divided into five groups of 15, and frostbite injury was created in each animal by sandwiching the left hind foot between a frozen magnet (-78.5°C) and a room-temperature magnet. Group I received saline; groups II, III, and IV received extract of Ginkgo biloba 761 (200, 100, and 50 mg/kg, respectively); and group V received superoxide dismutase (12 mg/kg). All drugs were injected intraperitoneally three times at 24-hour intervals. The wound surface area was measured throughout the wound healing period. Wounds were also harvested at various times to count cells stained by monoclonal antibodies for 4-hydroxy-2-nonenal and 8-hydroxy-2'-deoxyguanosine. RESULTS: Compared to group I, the wound surface area was significantly smaller in groups II and III on days 1 and 3 after wound creation. Histologic examination revealed significantly more 4-hydroxy-2-nonenal-stained cells and 8-hydroxy-2'-deoxyguanosine-stained cells in group I compared to other groups on day 1. However, there was no difference in the total healing period among the groups. A higher dose test of extract of Ginkgo biloba 761 (300 mg/kg daily) induced animal death, probably because of toxicity. CONCLUSION: Extract of Ginkgo biloba 761 demonstrated a protective effect against frostbite in the present model and probably alleviated reperfusion injury by reducing tissue peroxidation.


Assuntos
Congelamento das Extremidades/prevenção & controle , Extratos Vegetais/administração & dosagem , Traumatismo por Reperfusão/tratamento farmacológico , Cicatrização/fisiologia , Administração Tópica , Animais , Biópsia por Agulha , Modelos Animais de Doenças , Feminino , Congelamento das Extremidades/tratamento farmacológico , Congelamento das Extremidades/patologia , Imuno-Histoquímica , Masculino , Distribuição Aleatória , Ratos , Ratos Endogâmicos F344 , Traumatismo por Reperfusão/prevenção & controle , Resultado do Tratamento
20.
Molecules ; 24(9)2019 May 03.
Artigo em Inglês | MEDLINE | ID: mdl-31058815

RESUMO

c-Jun N-terminal kinase (JNK) is activated by various brain insults and is implicated in neuronal injury triggered by reperfusion-induced oxidative stress. Some JNK inhibitors demonstrated neuroprotective potential in various models, including cerebral ischemia/reperfusion injury. The objective of the present work was to study the neuroprotective activity of a new specific JNK inhibitor, IQ-1S (11H-indeno[1,2-b]quinoxalin-11-one oxime sodium salt), in the model of global cerebral ischemia (GCI) in rats compared with citicoline (cytidine-5'-diphosphocholine), a drug approved for the treatment of acute ischemic stroke and to search for pleiotropic mechanisms of neuroprotective effects of IQ-1S. The experiments were performed in a rat model of ischemic stroke with three-vessel occlusion (model of 3VO) affecting the brachiocephalic artery, the left subclavian artery, and the left common carotid artery. After 7-min episode of GCI in rats, 25% of animals died, whereas survived animals had severe neurological deficit at days 1, 3, and 5 after GCI. At day 5 after GCI, we observing massive loss of pyramidal neurons in the hippocampal CA1 area, increase in lipid peroxidation products in the brain tissue, and decrease in local cerebral blood flow (LCBF) in the parietal cortex. Moreover, blood hyperviscosity syndrome and endothelial dysfunction were found after GCI. Administration of IQ-1S (intragastrically at a dose 50 mg/kg daily for 5 days) was associated with neuroprotective effect comparable with the effect of citicoline (intraperitoneal at a dose of 500 mg/kg, daily for 5 days).The neuroprotective effect was accompanied by a decrease in the number of animals with severe neurological deficit, an increase in the number of animals with moderate degree of neurological deficit compared with control GCI group, and an increase in the number of unaltered neurons in the hippocampal CA1 area along with a significant decrease in the number of neurons with irreversible morphological damage. In rats with IQ-1S administration, the LCBF was significantly higher (by 60%) compared with that in the GCI control. Treatment with IQ-1S also decreases blood viscosity and endothelial dysfunction. A concentration-dependent decrease (IC50 = 0.8 ± 0.3 µM) of tone in isolated carotid arterial rings constricted with phenylephrine was observed after IQ-1S application in vitro. We also found that IQ-1S decreased the intensity of the lipid peroxidation in the brain tissue in rats with GCI. 2.2-Diphenyl-1-picrylhydrazyl scavenging for IQ-1S in acetonitrile and acetone exceeded the corresponding values for ionol, a known antioxidant. Overall, these results suggest that the neuroprotective properties of IQ-1S may be mediated by improvement of cerebral microcirculation due to the enhanced vasorelaxation, beneficial effects on blood viscosity, attenuation of the endothelial dysfunction, and antioxidant/antiradical IQ-1S activity.


Assuntos
Isquemia Encefálica/prevenção & controle , Citidina Difosfato Colina/administração & dosagem , Fármacos Neuroprotetores/administração & dosagem , Oximas/administração & dosagem , Quinoxalinas/administração & dosagem , Traumatismo por Reperfusão/prevenção & controle , Animais , Isquemia Encefálica/metabolismo , Circulação Cerebrovascular , Citidina Difosfato Colina/farmacologia , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Humanos , Peroxidação de Lipídeos/efeitos dos fármacos , Masculino , Fármacos Neuroprotetores/farmacologia , Oximas/farmacologia , Quinoxalinas/farmacologia , Ratos , Ratos Wistar , Resultado do Tratamento
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