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1.
Gene ; 741: 144562, 2020 May 30.
Artigo em Inglês | MEDLINE | ID: mdl-32169629

RESUMO

Renal Ischemia/Reperfusion (rI/R)-induced acute lung injury (ALI) is a major problem in rI/R. The objective of the current study was to explore the defensive roles of propofol (Pro), an intravenous anesthetic, on rI/R-induced ALI through mitogen-activated protein kinase (MAPK) signaling. Rats were divided into Sham, Pro (10 mg/kg), rI/R, rI/R + Pro (5 mg/kg), and rI/R + Pro (10 mg/kg) groups. Rats were treated with Pro at 1 h after rI/R treatment. Serum and lung tissues at 24 h after rI/R were collected to evaluate morphological changes and the expression of myeloperoxidase (MPO), inflammatory cytokines, and crucial proteins in the MAPK pathway. Pro attenuated the production of mediators, resulting in reduced levels of autophagy and apoptosis by restricting the MAPK pathway in rI/R-induced ALI model. Pro represses rI/R-induced pulmonary autophagy and apoptosis by decreasing the production of inflammatory molecules, and the effects of Pro are involved in the inhibition of the MAPK pathway.


Assuntos
Lesão Renal Aguda/tratamento farmacológico , Lesão Pulmonar Aguda/tratamento farmacológico , Propofol/farmacologia , Traumatismo por Reperfusão/tratamento farmacológico , Lesão Renal Aguda/complicações , Lesão Renal Aguda/genética , Lesão Renal Aguda/patologia , Lesão Pulmonar Aguda/etiologia , Lesão Pulmonar Aguda/genética , Animais , Apoptose/efeitos dos fármacos , Autofagia/efeitos dos fármacos , Modelos Animais de Doenças , Humanos , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Ratos , Traumatismo por Reperfusão/complicações , Traumatismo por Reperfusão/genética , Traumatismo por Reperfusão/patologia
2.
Acta Cir Bras ; 34(12): e201901203, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32049184

RESUMO

PURPOSE: Composite flaps used in reconstructive surgery may intra- and postoperatively suffer from hypoperfusion and/or ischemia-reperfusion influencing wound healing. We aimed to follow-up the effect of ischemia on adipocutaneous flaps' wound healing and microcirculation. METHODS: In anesthetized rats groin flaps were formed bilaterally. In Control group the flaps were repositioned and sutured back. In Ischemia-Reperfusion (I/R) group before repositioning and suturing the flap pedicles were clamped for 60 minutes. Laser Doppler (LD) fluxmetry and temperature probes were applied on the cranial, central and caudal flap regions before/after preparation and ischemia, re-suturing, and on the 1st-3rd-5th-7th-14th postoperative days, before the final examinations and biopsies for histology. RESULTS: Flaps' skin temperature quickly recovered after repositioning. LD values were lower in the I/R group, reaching a significant level by the 3rd postoperative day, and remained lowered till the 14th day. The magnitude of alterations differed in the flap regions. Histologically normal wound healing process was seen, except for some I/R flaps, where hypertrophized mammary glands were found. CONCLUSIONS: Short-term ischemia could influence flap microcirculation and wound healing, and may result in hypertrophized mammary glands. Laser Doppler could be used to evaluate intra- and postoperative microcirculatory changes and may have significance in predicting complications.


Assuntos
Procedimentos Cirúrgicos Dermatológicos/efeitos adversos , Microcirculação/fisiologia , Retalho Miocutâneo/irrigação sanguínea , Traumatismo por Reperfusão/complicações , Pele/irrigação sanguínea , Cicatrização/fisiologia , Animais , Biópsia , Temperatura Corporal , Modelos Animais de Doenças , Fluxometria por Laser-Doppler , Masculino , Retalho Miocutâneo/patologia , Período Pós-Operatório , Ratos , Valores de Referência , Traumatismo por Reperfusão/patologia , Reprodutibilidade dos Testes , Pele/patologia , Fatores de Tempo , Resultado do Tratamento
3.
PLoS One ; 15(1): e0227780, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31945113

RESUMO

The engraftment of human stem cell-derived cardiomyocytes (hSC-CMs) is a promising treatment for remuscularizing the heart wall post-infarction, but it is plagued by low survival of transplanted cells. We hypothesize that this low survival rate is due to continued ischemia within the infarct, and that increasing the vascularization of the scar will ameliorate the ischemia and improve hSC-CM survival and engraftment. An adenovirus expressing the vascular growth factor Sonic Hedgehog (Shh) was injected into the infarcted myocardium of rats immediately after ischemia/reperfusion, four days prior to hSC-CM injection. By two weeks post-cell injection, Shh treatment had successfully increased capillary density outside the scar, but not within the scar. In addition, there was no change in vessel size or percent vascular volume when compared to cell injection alone. Micro-computed tomography revealed that Shh failed to increase the number and size of larger vessels. It also had no effect on graft size or heart function when compared to cell engraftment alone. Our data suggests that, when combined with the engraftment of hSC-CMs, expression of Shh within the infarct scar and surrounding myocardium is unable to increase vascularization of the infarct scar, and it does not improve survival or function of hSC-CM grafts.


Assuntos
Proteínas Hedgehog/metabolismo , Células-Tronco Embrionárias Humanas/metabolismo , Infarto do Miocárdio/terapia , Miócitos Cardíacos/transplante , Adenoviridae/genética , Animais , Diferenciação Celular , Vasos Coronários/diagnóstico por imagem , Modelos Animais de Doenças , Vetores Genéticos/genética , Coração/diagnóstico por imagem , Proteínas Hedgehog/genética , Humanos , Masculino , Infarto do Miocárdio/diagnóstico por imagem , Infarto do Miocárdio/etiologia , Infarto do Miocárdio/mortalidade , Miocárdio/citologia , Miócitos Cardíacos/metabolismo , Neovascularização Fisiológica , Ratos , Proteínas Recombinantes/genética , Proteínas Recombinantes/metabolismo , Traumatismo por Reperfusão/complicações , Taxa de Sobrevida , Transfecção , Resultado do Tratamento , Regulação para Cima , Microtomografia por Raio-X
4.
Life Sci ; 246: 117327, 2020 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-31954161

RESUMO

Cytochrome P450 (CYP) epoxygenases can metabolize arachidonic acids to epoxyeicosatrienoic acids (EETs), which play a protective role in the renal system, but their involvement in ischemia/reperfusion (I/R)-induced acute kidney injury remains unknown. Here, using a rat model, we demonstrated that forced CYP2J2 expression attenuated I/R-induced renal dysfunction and protected histological integrity. We showed that CYP2J2 significantly decreased I/R-induced upregulation of blood urea nitrogen and serum creatinine and enhanced autophagy during I/R treatment. In addition, we determined the protective effect of CYP2J2 against I/R-caused apoptosis. We demonstrated that CYP2J2 overexpression attenuated the downregulation of SIRT1 and FoxO3a by I/R-induced injury. Moreover, exogenous 11,12-EET addition obviously promoted I/R-induced autophagic flux and suppressed I/R-induced apoptosis through SIRT1-FoxO3a signaling activation. Our data indicate that CYP2J2-produced EETs improve I/R-caused kidney injury by activating the SIRT1-FoxO3a signaling pathway, which protects from renal I/R injury.


Assuntos
Lesão Renal Aguda/etiologia , Sistema Enzimático do Citocromo P-450/metabolismo , Eicosanoides/metabolismo , Proteína Forkhead Box O3/metabolismo , Traumatismo por Reperfusão/complicações , Transdução de Sinais , Sirtuína 1/metabolismo , Lesão Renal Aguda/metabolismo , Lesão Renal Aguda/patologia , Animais , Nitrogênio da Ureia Sanguínea , Creatinina/sangue , Rim/patologia , Masculino , Ratos , Ratos Sprague-Dawley , Traumatismo por Reperfusão/metabolismo
5.
J Surg Res ; 246: 170-181, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31590030

RESUMO

BACKGROUND: Electroacupuncture has been reported to protect the body from organ damages, but its mechanisms remain to be explored. This research was designed to investigate the function of electroacupuncture in lung injury resulted from hind limb ischemia-reperfusion (LIR) and whether p38 mitogen-activated protein kinase (p38 MAPK)-mediated nuclear factor erythroid-2-related factor-2 (Nrf2)/heme oxygenase (HO)-1 pathway contributes to the protective effect of electroacupuncture on LIR-originated lung damage. MATERIALS AND METHODS: Rabbits were subjected to occluding femoral artery for 2 h. Then they received reperfusion for 4 h to establish lung injury model. Electroacupuncture stimulation was performed bilaterally at Feishu and Zusanli acupoints for 15 min once a day for 5 d before the experiment and throughout the hind LIR model performing in the experimental day. Blood samples and lung tissues were collected to examine the role of electroacupuncture treatment in inflammatory response, oxidative stress, and lung injury. Both the protein expression and the messenger RNA level of Nrf2 and HO-1 were detected. RESULTS: The results showed that electroacupuncture treatment remarkably alleviated lung injury, decreased inflammatory cytokines secretion, attenuated lung oxidative stress, increased the amount of Nrf2 and HO-1, and increased the ratio of phospho-p38 MAPK to p38 MAPK after LIR. However, the protective effects exerted by electroacupuncture were reversed to some extent by the preconditioning with SB203580, a p38 MAPK-specific inhibitor. CONCLUSIONS: These results suggested that electroacupuncture could attenuate lung injury in rabbits subjected to LIR by inhibition of proinflammatory cytokine response and oxidative stress through activating p38 MAPK-mediated Nrf2/HO-1 pathway.


Assuntos
Lesão Pulmonar Aguda/prevenção & controle , Eletroacupuntura , Extremidades/irrigação sanguínea , Sistema de Sinalização das MAP Quinases/imunologia , Traumatismo por Reperfusão/complicações , Lesão Pulmonar Aguda/imunologia , Lesão Pulmonar Aguda/patologia , Animais , Modelos Animais de Doenças , Artéria Femoral/cirurgia , Heme Oxigenase-1/metabolismo , Humanos , Imidazóis/farmacologia , Mediadores da Inflamação/imunologia , Mediadores da Inflamação/metabolismo , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Masculino , Fator 2 Relacionado a NF-E2/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Estresse Oxidativo/imunologia , Piridinas/farmacologia , Coelhos , Traumatismo por Reperfusão/imunologia , Traumatismo por Reperfusão/terapia , Resultado do Tratamento , Proteínas Quinases p38 Ativadas por Mitógeno/antagonistas & inibidores , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo
6.
Life Sci ; 241: 117170, 2020 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-31838137

RESUMO

AIMS: In this study, we investigate the effect and underlying mechanism of hyperbaric oxygen (HBO) treatment on a model of repeated cerebral ischemia-reperfusion injury (IR). MAIN METHODS: Eighty rats were randomly separated into sham, vehicle, hyperbaric air (HBA; 0.25 MPa, 60 min), and HBO (0.25 MPa, 60 min) groups. Repeated cerebral IR was induced by ligating the right and left bilateral common carotid arteries for 10 min and then allowing reperfusion for 10 min. This pattern was repeated three times. The neuroprotective effects of HBO were assessed by animal behavior, neuron morphology, inflammatory markers, intracellular calcium ion content, and autophagy-related protein and gene expression. KEY FINDINGS: Our result showed that HBO improved learning and memory in the navigation trail and probe trail of the Morris water maze, and these findings were supported by the observation data from 2,3,5-Triphenyltet-razolium chloride staining, Nissl staining, and electron microscopic. Importantly, we found that HBO reduced excessive autophagy in the prefrontal cortex, which was evidenced by activating of the mammalian target of the rapamycin (mTOR) and 4E-BP1, as well as suppression of LC3II and ATG5. Moreover, HBO significantly inhibited the cerebral IR-induced inflammatory reaction. Furthermore, HBO treatment modulated autophagy pathway-related factors, including producing a decrease in the intracellular calcium ion concentration and p53 level; meanwhile, the levels of BDNF and p-Akt were increased. SIGNIFICANCE: Our results indicated that HBO protected against IR-induced neuron injury by attenuating autophagy, inflammation, and calcium overload. These results provide a new mechanism and laboratory evidence for clinical treatment of VD.


Assuntos
Autofagia , Isquemia Encefálica/complicações , Disfunção Cognitiva/prevenção & controle , Modelos Animais de Doenças , Oxigenação Hiperbárica/métodos , Fármacos Neuroprotetores , Traumatismo por Reperfusão/complicações , Animais , Comportamento Animal , Disfunção Cognitiva/etiologia , Disfunção Cognitiva/patologia , Feminino , Masculino , Camundongos , Ratos , Ratos Sprague-Dawley
7.
Proc Natl Acad Sci U S A ; 117(1): 698-707, 2020 01 07.
Artigo em Inglês | MEDLINE | ID: mdl-31848242

RESUMO

Group III/IV muscle afferents transduce nociceptive signals and modulate exercise pressor reflexes (EPRs). However, the mechanisms governing afferent responsiveness to dually modulate these processes are not well characterized. We and others have shown that ischemic injury can induce both nociception-related behaviors and exacerbated EPRs in the same mice. This correlated with primary muscle afferent sensitization and increased expression of glial cell line-derived neurotrophic factor (GDNF) in injured muscle and increased expression of GDNF family receptor α1 (GFRα1) in dorsal root ganglia (DRG). Here, we report that increased GDNF/GFRα1 signaling to sensory neurons from ischemia/reperfusion-affected muscle directly modulated nociceptive-like behaviors and increased exercise-mediated reflexes and group III/IV muscle afferent sensitization. This appeared to have taken effect through increased cyclic adenosine monophosphate (cAMP) response element binding (CREB)/CREB binding protein-mediated expression of the purinergic receptor P2X5 in the DRGs. Muscle GDNF signaling to neurons may, therefore, play an important dual role in nociception and sympathetic reflexes and could provide a therapeutic target for treating complications from ischemic injuries.


Assuntos
Fator Neurotrófico Derivado de Linhagem de Célula Glial/metabolismo , Mialgia/etiologia , Nociceptividade/fisiologia , Reflexo/fisiologia , Traumatismo por Reperfusão/patologia , Animais , Proteína de Ligação a CREB/metabolismo , Sistema Cardiovascular/inervação , AMP Cíclico/metabolismo , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/metabolismo , Modelos Animais de Doenças , Exercício Físico/fisiologia , Gânglios Espinais/metabolismo , Receptores de Fator Neurotrófico Derivado de Linhagem de Célula Glial/metabolismo , Frequência Cardíaca/fisiologia , Humanos , Masculino , Camundongos , Músculo Esquelético/irrigação sanguínea , Músculo Esquelético/inervação , Músculo Esquelético/metabolismo , Mialgia/patologia , Neurônios Aferentes/fisiologia , Receptores Purinérgicos P2X5/metabolismo , Traumatismo por Reperfusão/complicações , Transdução de Sinais/fisiologia
8.
Life Sci ; 242: 117217, 2020 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-31884094

RESUMO

AIM: Kidney ischemia reperfusion (IR) injury is an important health problem resulting in acute kidney failure. The oxidative stress and inflammatory process are the underlying mechanisms of IR injury. It has been purposed in this study to research the possible protective effects of fraxin on kidney injury induced by IR. MATERIAL AND METHODS: 32 Sprague Dawley male rats were divided into 4 groups. The groups were organized as follows; sham, IR, IR + fraxin 10 mg/kg, and IR + 50 mg/kg fraxin groups. Some oxidant, antioxidant and inflammatory parameters were evaluated in kidney tissues removed at the end of our experimental study. KEY FINDINGS: It was detected that the oxidant and proinflammatory markers increased and antioxidant parameters decreased in IR group but the results significantly reversed in treatment groups compared to IR group. And also, 8-OHdG, NF-κB, HAVCR1 immunopositivities were at severe levels and these results attenuated in IR fraxin + 10 mg/kg, and IR + fraxin 50 mg/kg groups. SIGNIFICANCE: These presented results have shown that fraxin performed protective effects against kidney injury induced by IR.


Assuntos
Lesão Renal Aguda/prevenção & controle , Antioxidantes/uso terapêutico , Cumarínicos/uso terapêutico , Traumatismo por Reperfusão/prevenção & controle , Lesão Renal Aguda/etiologia , Lesão Renal Aguda/patologia , Animais , Modelos Animais de Doenças , Rim/efeitos dos fármacos , Rim/patologia , Masculino , Malondialdeído/metabolismo , Peroxidase/metabolismo , Ratos , Ratos Sprague-Dawley , Traumatismo por Reperfusão/complicações , Traumatismo por Reperfusão/patologia , Superóxido Dismutase/metabolismo
9.
Exp Oncol ; 41(4): 328-334, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31868333

RESUMO

BACKGROUND: Interaction between tumor cells and tumor microenvironment is critical for homeostasis of normal cells and tumor growth. Tumor cell - stroma interaction represents the potent factor able to initiate cancer and affect tumor progression and disease outcome. The tumors vary by their origin and microenvironment (proportion of stromal cells, their composition and activation state). The surgical stress and tumor microenvironment may potentiate acute hepatic failure in the patients with metastatic colorectal cancer (mCRC). Pathological effect of ischemia-reperfusion (I/R) consists in the increased generation of superoxide radicals (SR) and nitrogen oxide (NO) affecting the postresectional regeneration of liver tissue. Redox state of hepatic tissue in I/R setting upon resection of metastases may trigger the aggressiveness of residual cancer cells and regeneration or degradation of hepatic tissue. The aim of the study was to analyze redox state of hepatic tissue following surgery with Pringle maneuver (PM) in the patients with mCRC. MATERIALS AND METHODS: mCRC samples from 145 patients treated at National Cancer Institute, Ministry of Health of Ukraine, were analyzed. The patients obtained chemotherapy according to the approved international and national standards as well as clinical protocols. Two groups of patients were delineated according to the duration of the interruption of blood inflow due to PM, namely ≤ 45 min and > 45 min. The activity of FeS proteins in the electron transport chain (ETC) in mitochondria and lactoferrin (LF) level in the tissues were assessed by EPR (77К). The rates of SR and NO generation were determined with spin traps. The activity of matrix metalloproteinase (MMP)-2 and -9 was measured by gelatin zymography using SDS-polyacrylamide gel electrophoresis. RESULTS: In tissue of liver resected in the setting of > 45 min ischemia, ETC function in mitochondria was impaired (decreased activity of FeS protein of N-2 ETC complex I due to interaction with NO). This results in the hypoxia state and glycolysis with uncontrolled SR generation. In addition, the efficiency of detoxification system in hepatocytes is reduced substantially with increase in semiquinone and LF levels as well as MMP-2 and -9 activity as compared with liver without metastatic lesions that was not affected by I/R. CONCLUSIONS: The ischemic injury of liver in the setting of metastasis resection results from cell response to interruption of blood flow followed by reperfusion. The key factor in the genesis of reperfusion damage is uncontrolled increase of the levels of SR and their metabolites - reactive oxygen species as well as the increased MMP activity. Also, liver tissue affected by I/R contains high levels of xanthine oxidase metabolizing hypoxanthine and monoamine oxidase deaminizing biogenic amines. Both processes are the sources of SR.


Assuntos
Neoplasias Colorretais/patologia , Neoplasias Hepáticas/secundário , Neoplasias Hepáticas/cirurgia , Fígado/cirurgia , Estresse Oxidativo , Traumatismo por Reperfusão/metabolismo , Idoso , Neoplasias Colorretais/complicações , Neoplasias Colorretais/metabolismo , Feminino , Humanos , Fígado/metabolismo , Fígado/patologia , Neoplasias Hepáticas/complicações , Masculino , Oxirredução , Espécies Reativas de Oxigênio/metabolismo , Traumatismo por Reperfusão/complicações , Traumatismo por Reperfusão/patologia
10.
Rev. esp. anestesiol. reanim ; 66(7): 370-380, ago.-sept. 2019. tab, graf
Artigo em Espanhol | IBECS | ID: ibc-187550

RESUMO

Introducción: Los paradigmas de la hemofiltración para manejar pacientes críticos con una respuesta inflamatoria desregulada (RID) evalúan la función renal para su inicio, adaptación y finalización. Presentamos la Hiperfiltración Venosa Continua (Protocolo CONVEHY), en el cual una membrana de adsorción inespecífica (AN69-ST-heparina anclada) se utiliza con citrato como líquido anticoagulante y de sustitución. El protocolo CONVEHY utiliza herramientas fácilmente disponibles para lograr objetivos renales y no renales, guiándose por las respuestas fisiopatológicas. Objetivos: Comparar la respuesta a la membrana AN69-ST-HA cuando se utilizó heparina (He, n = 5: protocolo estándar) o citrato (Ci, n = 6: protocolo CONVEHY) para evaluar si fuera factible un estudio mayor sobre los beneficios de este protocolo. Materiales y métodos: En un estudio retrospectivo, se evaluaron los beneficios del protocolo CONVEHY en pacientes con RID en una unidad de cuidados críticos quirúrgicos (UCCq), evaluando las puntuaciones SOFA (He 11 +/- 2,35; Ci 11 +/- 3,63; p = 0,54) y APACHE II (He 28,60 +/- 9,40; Ci 24 +/- 8,46; p = 0,93). Resultados: Hospitalización (He 35,2 +/- 16,3 noches; Ci 9 +/- 2,53; p = 0,004), hospitalización tras el alta de UCCq (He 40,25 +/- 21,82; Ci 13,2 +/- 4,09; p = 0,063), pacientes hospitalizados > 20 días (He 80%; Ci 0%; p = 0,048), días con ventilación mecánica (He 16 +/- 5,66; Ci 4 +/- 1,72; p = 0,004) y la mortalidad predicha (55,39 +/- 26,13%) frente a la real en ambos grupos (9,1%; p = 0,004). Conclusiones: El protocolo CONVEHY mejora las respuestas clínicas de los pacientes con una RID, destacando el valor potencial de realizar estudios más grandes y confirmatorios


Introduction: Haemofiltration paradigms used to manage critically ill patients with a dysregulated inflammatory response (DIR) assess kidney function to monitor its onset, adaptation, and completion. A Continuous Venous Hyperfiltration (CONVEHY) protocol is presented, in which a non-specific adsorption membrane (AN69-ST-Heparin Grafted) is used with citrate as an anticoagulant and substitution fluid. CONVEHY uses tools readily available to achieve kidney related and non-related objectives, and it is guided by the monitoring of pathophysiological responses. Objectives: To compare the response to an AN69-ST-HG membrane when heparin (He, n=5: Standard protocol) or citrate (Ci, n=6: CONVEHY protocol) was used to evaluate whether a larger study into the benefits of this protocol would be feasible. Materials and methods: In a retrospective pilot study, the benefits of the CONVEHY protocol to manage patients with a DIR in a surgical critical care unit (CCUs) were assessed by evaluating the SOFA (Sequential Organ Failure Assessment) (He 11 +/- 2.35; Ci 11 +/- 3.63: p=0.54) and APACHE II (He 28.60 +/- 9.40; Ci 24 +/- 8.46: p=0.93) scores. Results: Nights in hospital (He 35.2 +/- 16.3 nights; Ci 9 +/- 2.53: p=0.004), hospital admission after discharge from the CCUs (He 40.25 +/- 21.82; Ci 13.2 +/- 4.09: p=0.063), patients hospitalised >20 days (He 80%; Ci 0%: p=0.048), days requiring mechanical ventilation (He 16 +/- 5.66; Ci 4 +/- 1.72: p=0.004), and the predicted (55.39 +/- 26.13%) versus real mortality in both groups (9.1%: p=0.004). Conclusions: The CONVEHY protocol improves the clinical responses of patients with DIR, highlighting the potential value of performing larger and confirmatory studies


Assuntos
Humanos , Síndrome de Resposta Inflamatória Sistêmica/terapia , Hemofiltração/métodos , Heparina/uso terapêutico , Ácido Cítrico/uso terapêutico , Filtros de Membrana/métodos , Anticoagulantes/uso terapêutico , Traumatismo por Reperfusão/complicações , Filtração Prévia/métodos
11.
Oxid Med Cell Longev ; 2019: 8407206, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31379990

RESUMO

Purpose: Oxidative stress induced by reduced blood circulation is a critical pathological damage to retinal ganglion cells (RGCs) in glaucoma. We previously showed that green tea extract (GTE) and its catechin constituents alleviate sodium iodate-induced retinal degeneration in rats. Here, we investigated the therapeutic effect of GTE on ischemia-induced RGC degeneration in rats. Methods: RGC degeneration was induced by ischemic reperfusion in adult Fischer F344 rats. Green tea extract (Theaphenon E) was intragastrically administered 4 times within 48 hours after ischemia. RGC survival, pupillary light reflex, expressions of cell apoptosis, oxidative stress, and inflammation-related proteins were studied. Results: Ischemic reperfusion significantly induced apoptotic RGCs, RGC loss, and larger constricted pupil area compared to the untreated normal rats. Expressions of activated caspase-3 and caspase-8, Sod2, and inflammation-related proteins as well as p38 phosphorylation were significantly upregulated in the ischemia-injured rats. Compared to the saline-fed ischemic rats, significantly higher number of surviving RGCs, less apoptotic RGCs, and smaller constricted pupil area were observed in the GTE-fed ischemic rats. GTE also reduced the increased protein expressions caused by ischemic injury but enhanced the Jak phosphorylation in the retina. Notably, green tea extract did not affect the survival of RGCs in the uninjured normal rats. Conclusions: In summary, GTE offers neuroprotection to RGCs under ischemic challenge, suggesting a potential therapeutic strategy for glaucoma and optic neuropathies.


Assuntos
Extratos Vegetais/química , Substâncias Protetoras/uso terapêutico , Degeneração Retiniana/prevenção & controle , Chá/química , Animais , Apoptose/efeitos dos fármacos , Caspase 3/metabolismo , Sobrevivência Celular/efeitos dos fármacos , Feminino , Estresse Oxidativo/efeitos dos fármacos , Substâncias Protetoras/química , Substâncias Protetoras/farmacologia , Ratos , Ratos Endogâmicos F344 , Traumatismo por Reperfusão/complicações , Traumatismo por Reperfusão/patologia , Degeneração Retiniana/etiologia , Degeneração Retiniana/metabolismo , Células Ganglionares da Retina/citologia , Células Ganglionares da Retina/metabolismo , Superóxido Dismutase/genética , Superóxido Dismutase/metabolismo , Chá/metabolismo , Proteínas Quinases p38 Ativadas por Mitógeno/genética , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo
12.
Exp Mol Pathol ; 110: 104292, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31377235

RESUMO

Intestinal ischemic-reperfusion (IR) injury has detrimental effects on both local and distant organs in the body. Betanin is known for its antioxidant properties, and it is found mostly in vegetables. Therefore, the aim of the present study was to test the hypothesis that betanin administration prior intestinal IR, may be beneficial in protecting jejunal mucosa and lung parenchyma against IR damage. Male specific pathogen-free Charles River Wistar rats were used (n = 42). Betanin (50 mg/kg) was administered intraperitoneally 30 min before ischemia of the superior mesenteric artery lasting 1 h, followed by 1, 4 and 24 h of reperfusion. Immunohistochemical as well as histomorphometrical analysis indicated a protective effect of betanin pretreatment on jejunal tissue. Regarding morphometrical analysis betanin significantly (p < 0.01) augments intestinal villus height after 24 of reperfusion comparing to early stages. Betanin application reduced number of mast cells population in early reperfusion periods (p < 0.05). The protective effect of betanin on lung parenchyma, was detected in late reperfusion period (24 h) with improvement of histopathological injury index and morphometric analysis (p < 0.001 for both). The improvement of histopathological injury index (p < 0.001) and morphometric analysis (p < 0.001) during the late reperfusion period, suggests a protective effect of betanin on lung parenchyma. Moreover, suppression of the inflammatory response was mirrored by the reduction of myeloperoxidase (MPO) positive cells within lung parenchyma after 1 and 4 h of reperfusion (p < 0.001). Especially, during the first 4 h of reperfusion after betanin administration, a reduction of 74% of the polymorphonuclear neutrophils infiltration (MPO positive cell population) and of a nearly 46% of active MCs was observed. Upon morphometric examination, the lung histological architecture after 24 h of reperfusion appeared to be almost 100% better following betanin treatment, with 25% thinner interalveolar septa and 20% larger alveolar surface for respiratory gas exchange. The results suggest that betanin pretreatment protects the jejunal mucosa and the lung parenchyma, as well as reduces the inflammatory cell density after intestinal IR injury.


Assuntos
Betacianinas/farmacologia , Inflamação/tratamento farmacológico , Jejuno/efeitos dos fármacos , Pulmão/efeitos dos fármacos , Traumatismo por Reperfusão/complicações , Animais , Betacianinas/administração & dosagem , Inflamação/etiologia , Jejuno/lesões , Jejuno/patologia , Pulmão/patologia , Masculino , Nutrição Parenteral , Ratos , Ratos Wistar
13.
Eur J Pharmacol ; 861: 172610, 2019 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-31425684

RESUMO

Echinocystic acid (EA) was found to possess antiviral, anti-inflammatory and antioxidation activities. A recent study showed the antiapoptotic effects of EA on acute myocardial infarction. In this study, we demonstrated the potential neuroprotective effects of EA on cerebral ischemia/reperfusion (I/R) injury in mice. Intraperitoneal injection of EA 1 h before ischemia significantly reduced the cerebral infarct volume and neurological deficit after 60 min of ischemia and 24 h of reperfusion. The neuroprotective effects of EA occurred in a dose-dependent manner. Then, we explored the mechanisms of neuroprotection by EA. This compound exerted antiapoptotic activity by upregulating the level of Bcl-2 and simultaneously downregulating the levels of cleaved caspase-3 and Bax. Furthermore, EA also possessed anti-inflammatory activity and prevented the excessive phosphorylation of NF-κB (p-P65) and the increase in IL-1ß and IL-6 levels. Finally, our data indicated that EA treatment decreased the level of phosphorylated JNK in vivo, and the JNK activator anisomycin (AN) reversed the neuroprotective effects of EA, indicating that the JNK pathway is involved in the antiapoptotic and anti-inflammatory mechanisms of EA. In summary, our findings suggest that EA provides neuroprotective effects through its antiapoptotic and anti-inflammatory activities by inhibiting the JNK signaling pathway in cerebral I/R injury. Due to its safety and lack of toxicity, EA is a potential candidate for the treatment of ischemic stroke in future clinical trials.


Assuntos
Infarto da Artéria Cerebral Média/complicações , Proteínas Quinases JNK Ativadas por Mitógeno/metabolismo , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Ácido Oleanólico/análogos & derivados , Traumatismo por Reperfusão/tratamento farmacológico , Traumatismo por Reperfusão/patologia , Animais , Apoptose/efeitos dos fármacos , Comportamento Animal/efeitos dos fármacos , Relação Dose-Resposta a Droga , Masculino , Camundongos , Camundongos Endogâmicos ICR , Ácido Oleanólico/farmacologia , Ácido Oleanólico/uso terapêutico , Fosforilação/efeitos dos fármacos , Traumatismo por Reperfusão/complicações , Traumatismo por Reperfusão/metabolismo , Fator de Transcrição RelA/metabolismo
14.
Mol Cell Biochem ; 460(1-2): 151-164, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31280436

RESUMO

Diallyl trisulfide (DATS) is distinguished as the most potent polysulfide isolated from garlic. The aim of our study was to investigate effects of oral administration of DATS on healthy and diabetic rats, with special attention on heart function. Rats were randomly divided into four groups: CTRL (healthy rats), DATS (healthy rats treated with DATS), DM (diabetic rats), DM + DATS (diabetic rats treated with DATS). DATS (40 mg/kg of body weight) was administered every other day for 3 weeks, at the end of which rats underwent echocardiography, glycemic measurement and redox status assessment. Isolated rat hearts were subjected to 30 min global ischemia and 60 min reperfusion, after which heart tissue was counterstain with hematoxylin and eosin and cardiac Troponin T staining (cTnT), while expression of Bax, B cell lymphoma 2 (Bcl-2), caspase-3, caspase-9 and superoxide dismutase-2 were examined in the left ventricle. DATS treatment significantly reduced blood glucose levels of diabetic rats, and improved cardiac function recovery, diminished oxidation status, attenuated cardiac remodeling and inhibited myocardial apoptosis in healthy and diabetic rats. DATS treatment causes promising cardioprotective effects on ex vivo-induced ischemia/reperfusion (I/R) injury in diabetic and healthy rat heart probably mediated by inhibited myocardial apoptosis. Moreover, appropriate DATS consumption may provide potential co-therapy or prevention of hyperglycemia and various cardiac complications in rats with DM.


Assuntos
Compostos Alílicos/uso terapêutico , Cardiotônicos/uso terapêutico , Diabetes Mellitus Experimental/complicações , Diabetes Mellitus Experimental/tratamento farmacológico , Traumatismo por Reperfusão/complicações , Traumatismo por Reperfusão/tratamento farmacológico , Sulfetos/uso terapêutico , Animais , Apoptose/efeitos dos fármacos , Biomarcadores/metabolismo , Cardiotônicos/farmacologia , Diabetes Mellitus Experimental/fisiopatologia , Masculino , Miocárdio/patologia , Estresse Oxidativo/efeitos dos fármacos , Ratos Wistar , Traumatismo por Reperfusão/fisiopatologia
15.
Mol Cell Biochem ; 460(1-2): 217-224, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31280437

RESUMO

Resveratrol (RSV) is a natural polyphenolic compound having antioxidant effects. This study was designed to investigate the protective effects of resveratrol against oxidative stress in hepatic ischemia-reperfusion (I/R) injury in streptozotocin (STZ)-induced diabetic rats. STZ was injected intraperitonally (i.p.) to 18 Sprague-Dawley albino rats, which were divided into three groups, each having six rats. First group was non-treated diabetic group (D), second diabetic group was subjected to 30 min of hepatic ischemia followed by a 45-min reperfusion period (D + I/R), and third diabetic group was subjected to 30 min of hepatic ischemia followed by a 45-min reperfusion period and treated with 20 mg/kg/day oral RSV before 30 min I/R injury (D + I/R + RSV). At the end of the experimental period, animals were decapitated, and blood samples were collected to determine tissue tumor necrosis factor-α (TNF-α) levels. Liver and lung tissue samples were obtained for the evaluation of biochemical parameters including malondialdehyde (MDA) and glutathione (GSH) levels and histopathological examinations. Compared to control, I/R injury resulted in decreases in GSH levels and increases in MDA levels. Tissue TNF-α levels were also increased in the D + I/R group compared to D group. Treatment with RSV prevented the alterations on biochemical parameters and histopathological changes induced by I/R. We demonstrate that in diabetic rats, hepatic I/R injury is associated with an augmented inflammatory response and oxidative stress, while RSV pre-treatment significantly decreased these responses. Larger clinical studies are desirable to determine the exact role(s) of RSV on hepatic I/R injury among diabetic subjects.


Assuntos
Diabetes Mellitus Experimental/tratamento farmacológico , Fígado/patologia , Substâncias Protetoras/uso terapêutico , Traumatismo por Reperfusão/tratamento farmacológico , Resveratrol/uso terapêutico , Animais , Glicemia/metabolismo , Peso Corporal/efeitos dos fármacos , Diabetes Mellitus Experimental/complicações , Glutationa/metabolismo , Fígado/efeitos dos fármacos , Malondialdeído/metabolismo , Substâncias Protetoras/farmacologia , Ratos Sprague-Dawley , Traumatismo por Reperfusão/complicações , Resveratrol/farmacologia , Estreptozocina , Fator de Necrose Tumoral alfa/metabolismo
16.
Int J Mol Sci ; 20(13)2019 Jun 28.
Artigo em Inglês | MEDLINE | ID: mdl-31261724

RESUMO

Neurodegeneration caused with retinal ischemia or high intraocular pressure is irreversible in general. We have focused on the role of hypoxia-inducible factor (HIF) in retinal homeostasis and revealed that HIF inhibition may be effective against retinal neovascular and neurodegeneration. In this study, we performed in vitro screening of natural products and found halofuginone, which is a derivative of febrifugine extracted from hydrangea, as a novel HIF inhibitor. Administration of halofuginone showed a significant neuroprotective effect by inhibiting HIF-1α expression in a murine retinal ischemia-reperfusion model histologically and functionally. These results indicate that halofuginone can be a neuroprotective agent in ischemic retinal degenerative diseases.


Assuntos
Subunidade alfa do Fator 1 Induzível por Hipóxia/antagonistas & inibidores , Fármacos Neuroprotetores/uso terapêutico , Piperidinas/uso terapêutico , Quinazolinonas/uso terapêutico , Traumatismo por Reperfusão/tratamento farmacológico , Degeneração Retiniana/tratamento farmacológico , Células 3T3 , Animais , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Traumatismo por Reperfusão/complicações , Degeneração Retiniana/etiologia , Vasos Retinianos/patologia
17.
Nat Rev Neurol ; 15(8): 473-481, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31263257

RESUMO

Ischaemic stroke elicits a strong neuroinflammatory response, but the functional relevance and therapeutic potential of neuroinflammation has only recently become apparent. In acute experimental stroke, T cells contribute to ischaemia-reperfusion injury after recanalization in an antigen-independent manner. Surprisingly, the detrimental T cell effects are platelet-dependent. Glycoprotein (GP)Ib-mediated and GPVI-mediated platelet activation, but not GPIIb-IIIa-mediated platelet aggregation, is an important checkpoint that orchestrates thrombotic and pro-inflammatory pathways, and downstream activation of coagulation factor XII is a driving force of ischaemia-reperfusion injury in acute stroke. The evidence therefore suggests that T cells interact with platelets and facilitate further infarct development through a complex process that we refer to as thrombo-inflammation. Results of clinical trials of agents that target lymphocytes support this concept. However, in the majority of patients with ischaemic stroke, recanalization cannot be achieved and the contribution of T cells in the setting of the resultant permanent ischaemia and subacute stroke is less clear and more complex. In some settings, T cells still seem to aggravate neuronal damage late after the ischaemic insult, but stroke triggers systemic immunodepression, therefore further anti-inflammatory treatments would need to be used carefully in this context. Targeting stroke-related neuroinflammation could become an effective adjunct therapy to improve outcomes after ischaemic stroke, but this approach will require caution regarding the timing and avoidance of adverse effects.


Assuntos
Plaquetas/imunologia , Isquemia Encefálica/imunologia , Isquemia Encefálica/terapia , Encefalite/imunologia , Trombose Intracraniana/imunologia , Acidente Vascular Cerebral/imunologia , Acidente Vascular Cerebral/terapia , Linfócitos T/imunologia , Animais , Isquemia Encefálica/complicações , Encefalite/complicações , Humanos , Trombose Intracraniana/complicações , Microbiota/imunologia , Traumatismo por Reperfusão/complicações , Traumatismo por Reperfusão/imunologia , Traumatismo por Reperfusão/terapia , Acidente Vascular Cerebral/complicações
18.
Eur J Pharmacol ; 857: 172452, 2019 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-31202798

RESUMO

Enhancer of zeste homolog-2 (EZH2), a histone methyltransferase, has been recognized to play a pivotal role in regulating the immune response in various diseases. However, its role in the inflammatory response induced by ischaemic stroke remains to be further investigated. The aim of this study was to determine the role of EZH2 in microglia-associated inflammation in ischaemic stroke and to further detect the effects of the EZH2 inhibitor, 3-deazaadenosine A (DZNep), in ischaemic brain injury. Here, we found that both in vivo ischemic/reperfusion (I/R) injury and in vitro oxygen-glucose deprivation (OGD) treatment induced a marked upregulation of EZH2 in microglia. The administration of the EZH2 inhibitor DZNep improved behavioural performance and reduced the infarct volume in mice after experimental stroke. Furthermore, we showed that DZNep blocked pro-inflammatory (CD86+) microglial activation and triggered anti-inflammatory (CD206+) microglial polarization in experimental stroke. Pro-inflammatory cytokines such as IL-1ß, IL-6, TNF-α and CXCL10 were also significantly downregulated by DZNep. In addition, it was found that DZNep blocked the phosphorylation of signal transducer and activator of transcription 3 (STAT3) in microglia, which was increased by I/R injury and OGD. Collectively, we demonstrated that EZH2 is implicated in regulating microglial activation and exacerbates neurological deficits after ischaemic stroke, probably via activating STAT3, and that the EZH2 inhibitor DZNep can exert neuroprotective effects after ischaemic stroke.


Assuntos
Proteína Potenciadora do Homólogo 2 de Zeste/antagonistas & inibidores , Infarto da Artéria Cerebral Média/patologia , Microglia/efeitos dos fármacos , Microglia/patologia , Fármacos Neuroprotetores/farmacologia , Tubercidina/farmacologia , Animais , Apoptose/efeitos dos fármacos , Modelos Animais de Doenças , Infarto da Artéria Cerebral Média/complicações , Infarto da Artéria Cerebral Média/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Traumatismo por Reperfusão/complicações , Fator de Transcrição STAT3/metabolismo , Regulação para Cima/efeitos dos fármacos
19.
Biomed Pharmacother ; 117: 108941, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31200256

RESUMO

Ischemic stroke represents a major cause of adult physical disability, which is triggered by cerebral artery occlusion induced blood flow blockage. MiR-874-3p has been reported to be down-regulated in the brain injury induced by ischemia-reperfusion (I/R), but the direct evidence associated with injury of I/R remains unknown. In this study, we found that miR-874-3p levels significantly decreased in rat I/R brain induced by middle cerebral artery occlusion/reperfusion (MCAO/R) and SH-SY5Y cells following oxygen-glucose deprivation and reperfusion (OGD/R) treatment. Upregulation of miR-874-3p reduced infarct volumes and cell apoptosis in the in vivo I/R stroke model using TTC and TUNEL staining, as well as increased proliferation and inhibited apoptosis in OGD/R induced SH-SY5Y cells by CCK-8, Edu staining and flow cytometry analysis. Mechanistically, bioinformatics analysis and luciferase reporter assay confirmed BCL-2-modifying factor (BMF) and Bcl-2 family protein Bcl-rambo (BCL2L13) were the direct targets of miR-874-3p. Furthermore, BMF or BCL2L13 knockdown also provided significant protection against OGD/R induced injury, while their overexpression reversed the protective effects of miR-874-3p on SH-SY5Y cells following OGD/R. In summary, our results suggest that miR-874-3p attenuated ischemic injury by negatively regulating BMF and BCL2L13, highlighting a novel therapeutic target for ischemic stroke.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Isquemia Encefálica/genética , MicroRNAs/genética , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Traumatismo por Reperfusão/genética , Regulação para Cima/genética , Regiões 3' não Traduzidas/genética , Proteínas Adaptadoras de Transdução de Sinal/genética , Animais , Apoptose/genética , Sequência de Bases , Isquemia Encefálica/complicações , Linhagem Celular Tumoral , Proliferação de Células , Regulação para Baixo/genética , Glucose/deficiência , Humanos , Masculino , MicroRNAs/metabolismo , Oxigênio , Proteínas Proto-Oncogênicas c-bcl-2/genética , Ratos , Traumatismo por Reperfusão/complicações
20.
Artif Cells Nanomed Biotechnol ; 47(1): 2431-2439, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31187646

RESUMO

Numerous differentially expressed long non-coding RNAs (lncRNAs) have been identified in cerebral ischemia-reperfusion (I/R) injury using RNA-Seq analysis. However, little is known about whether and how lncRNAs are involved in cerebral I/R injury. In this study, we investigated the function of the lncRNA Oprm1 in cerebral I/R injury and explored the underlying mechanism. An oxygen-glucose deprivation model in N2a cells was utilized to mimic cerebral I/R injury in vitro. Trypan blue staining, terminal deoxytransferase-mediated dUTP-biotin nick end labelling and caspase-3 were measured to evaluate apoptosis. Middle cerebral artery occlusion was performed in mice to evaluate the function of lncRNA Oprm1 in vivo. Real-time PCR and western blotting were used to measure the expression levels of lncRNA Opmr1, caspase-3, miR-155, GATA binding protein 3 (GATA3) and nuclear factor (NF)-κB. lncRNA Oprm1 was mainly located in the cytoplasm. Overexpression of lncRNA Oprm1 alleviated the apoptosis induced by oxygen-glucose deprivation and significantly reduced cleaved caspase-3 levels. Infarct size was distinctly decreased in the lncRNA Oprm1-overexpression group. The neurological score was also improved. Our findings showed that the lncRNA Oprm1/miR-155/GATA3 axis plays an important role in cerebral I/R injury. lncRNA Oprm1 may attenuate cerebral injury through the NF-κB pathway. lncRNA Oprm1 may serve as a potential target for new therapeutic interventions in patients with ischemic stroke.


Assuntos
Apoptose/genética , Fator de Transcrição GATA3/metabolismo , Infarto da Artéria Cerebral Média/complicações , MicroRNAs/genética , RNA Longo não Codificante/genética , Traumatismo por Reperfusão/genética , Traumatismo por Reperfusão/metabolismo , Animais , Linhagem Celular Tumoral , Expressão Gênica , Camundongos , Camundongos Endogâmicos C57BL , Traumatismo por Reperfusão/complicações , Traumatismo por Reperfusão/patologia , Transdução de Sinais/genética
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