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1.
Zhongguo Ying Yong Sheng Li Xue Za Zhi ; 35(4): 300-303, 2019 Jul 28.
Artigo em Chinês | MEDLINE | ID: mdl-31701710

RESUMO

OBJECTIVE: To investigate the effects of 1,25-dihydroxyvitamin D3 (1,25-VitD3) supplementation on cerebral injury after ischemia/reperfusion (I/R) in mice with middle cerebral artery occlusion (MCAO). METHODS: Male C57BL6 mice were randomly divided into Sham group, Vehicle group and 1,25-VitD3 group, with 10 mice in each group. Vehicle group and 1,25-VitD3 group were given MCAO for 1 hour, and then killed after reperfusion for 24 hours. Mice in 1,25-VitD3 group were treated with 1,25-VitD3 at the dose of 100 ng/(kg·d) by injected intraperitoneally for 5 days before MCAO operation. Cerebral ischemic penumbra areas of each group were collected for TTC staining, RT-PCR, TTC staining and immunohistochemistry assay. The function defect of mice was evaluated by using neurological function score. RESULTS: Compared with the sham group, the volume of cerebral infarction in Vehicle group was increased significantly, and the expressions of IL-6, IL-1beta and Gp91phox in brain tissues were increased significantly (P<0.05); compared with Vehicle group, supplementation of 1,25-VitD3 reduced the volume of cerebral infarction by about 50% in I/R mice (P<0.05), and the expressions of IL-6, IL-1beta and Gp91phox in brain tissues of 1,25-VitD3 group were decreased significantly (P<0.05). The expression of Foxp3, a T-regulatory cell marker, was significantly increased in the brain of mice (P<0.05), while the expression of Rorc, a transcription factor, was significantly decreased (P<0.05), suggesting that Th17/gamma Delta T-cell response was reduced and the number of neutrophils in the brain injury site of mice was significantly reduced (P<0.05). CONCLUSION: Vitamin D could alleviate the development of cerebral infarction after arterial occlusion (MCAO) reperfusion, and its mechanism may be through regulating the inflammatory response in mouse brain I/R.


Assuntos
Infarto da Artéria Cerebral Média/tratamento farmacológico , Substâncias Protetoras/farmacologia , Traumatismo por Reperfusão/tratamento farmacológico , Vitamina D/farmacologia , Animais , Encéfalo , Citocinas/metabolismo , Inflamação , Masculino , Camundongos , Camundongos Endogâmicos C57BL , NADPH Oxidase 2/metabolismo , Distribuição Aleatória , Ratos Sprague-Dawley , Linfócitos T , Células Th17
2.
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
3.
Acta Cir Bras ; 34(8): e201900806, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31618406

RESUMO

PURPOSE: To assess Cyclosporine A (CsA) therapy at an intraperitoneal dose of 15 mg.kg -1 in a rodent model of non-septic renal ischemia. METHODS: Twenty male Wistar rats were randomized to receive CsA therapy or none therapy before undergoing 30 minutes of renal ischemia followed by reperfusion. Additionally, 10 rats were randomized to undergo the same surgical procedure of the aforementioned animals with neither ischemia nor CsA therapy. Twelve hours after kidney ischemia, the left kidneys were evaluated for histological injury according to Park's criteria. Serum creatinine (Cr), urea nitrogen (Ur) and sodium levels were obtained at different times of the experimental protocol. RESULTS: Rodents in the CsA group showed negative results (p<0.05) in serum variables (Cr: 0.41±0.05mg/dL vs . 4.17±1.25mg/dL; Ur: 40.90±3.98mg/dL vs . 187.70±22.93mg/dL) even the non CsA or control group (Cr: 0.35±0.07mg/dL vs . 3.80±1.20mg/dL; Ur: 40.10±4.70mg/dL vs . 184.50±49.80mg/dL). The negative results were also verified in histological evaluation, CsA group had 50% in the very severe grade of lesion, 10% in the severe and 40% in the moderate to severe whereas the control group had 90% in the very severe grade. CONCLUSION: CsA was incapable of preventing the deleterious effects of ischemia-reperfusion injury in rat kidneys.


Assuntos
Ciclosporina/farmacologia , Imunossupressores/farmacocinética , Rim/irrigação sanguínea , Traumatismo por Reperfusão/tratamento farmacológico , Animais , Creatinina/sangue , Modelos Animais de Doenças , Isquemia/prevenção & controle , Rim/efeitos dos fármacos , Masculino , Ratos , Ratos Wistar , Traumatismo por Reperfusão/patologia , Sódio/sangue , Ureia/sangue
4.
Medicine (Baltimore) ; 98(42): e17591, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31626131

RESUMO

BACKGROUND: Spinal cord ischemia-reperfusion injury (SCII) is a common complication of spinal surgery as well as thoracic and abdominal surgery. Acute cytotoxic edema is the key pathogenic alteration. Therefore, avoiding or decreasing cellular edema has become the major target for SCII treatment. METHODS: The antiedema activity of ginsenoside Rb1 on aquaporin (AQP) 4, nerve growth factor (NGF), and brain-derived neurotrophic factor expression was detected by western blot and real-time polymerase chain reaction under conditions of oxygen-glucose deprivation/reoxygenation (OGD/R) in a rat astrocyte model in vitro. In addition, the cellular membrane permeability of AQP4 overexpressing cells or AQP4 small interfering RNA-transfected cells was detected. RESULTS: Ginsenoside Rb1 significantly prevented OGD/R-induced AQP4 downregulation in rat astrocytes. In addition, ginsenoside Rb1 treatment or AQP4 overexpression in rat astrocytes significantly attenuated the OGD/R-induced increase of cellular membrane permeability. Moreover, ginsenoside Rb1 obviously prevented the OGD/R-induced decrease of NGF and BDNT expression in rat astrocytes. CONCLUSION: These findings demonstrate that ginsenoside Rb1 can relieve spinal cord edema and improve neurological function by increasing AQP4 expression.


Assuntos
Aquaporina 4/genética , Astrócitos/metabolismo , Regulação da Expressão Gênica no Desenvolvimento , Ginsenosídeos/farmacologia , Glucose/metabolismo , Oxigênio/metabolismo , Traumatismo por Reperfusão/genética , Animais , Animais Recém-Nascidos , Aquaporina 4/biossíntese , Astrócitos/efeitos dos fármacos , Astrócitos/patologia , Western Blotting , Células Cultivadas , Modelos Animais de Doenças , Ensaio de Imunoadsorção Enzimática , RNA/genética , Ratos , Ratos Sprague-Dawley , Traumatismo por Reperfusão/tratamento farmacológico , Traumatismo por Reperfusão/patologia , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Medula Espinal/metabolismo , Medula Espinal/patologia
5.
DNA Cell Biol ; 38(10): 1025-1029, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31532239

RESUMO

Neutrophil trafficking into damaged or infected tissues is essential for the initiation of inflammation, clearance of pathogens and damaged cells, and ultimately tissue repair. Neutrophil recruitment is highly dependent on the stepwise induction of adhesion molecules and promigratory chemokines and cytokines. A number of studies in animal models have shown the efficacy of cannabinoid receptor 2 (CB2) agonists in limiting inflammation in a range of preclinical models of inflammation, including colitis, atherosclerosis, multiple sclerosis, and ischemia-reperfusion injury. Recent work in preclinical models of inflammation raises two questions: by what mechanisms do CB2 agonists provide anti-inflammatory effects during acute inflammation and what challenges exist in the translation of CB2 modulating therapeutics into the clinic.


Assuntos
Aterosclerose/genética , Colite/genética , Esclerose Múltipla/genética , Neutrófilos/metabolismo , Receptor CB2 de Canabinoide/genética , Traumatismo por Reperfusão/genética , Animais , Aterosclerose/tratamento farmacológico , Aterosclerose/metabolismo , Aterosclerose/patologia , Agonistas de Receptores de Canabinoides/uso terapêutico , Antagonistas de Receptores de Canabinoides/uso terapêutico , Colite/tratamento farmacológico , Colite/metabolismo , Colite/patologia , Citocinas/metabolismo , Citocinas/farmacologia , Modelos Animais de Doenças , Regulação da Expressão Gênica , Humanos , Inflamação , Ligantes , Camundongos , Camundongos Knockout , Esclerose Múltipla/tratamento farmacológico , Esclerose Múltipla/metabolismo , Esclerose Múltipla/patologia , Infiltração de Neutrófilos , Neutrófilos/efeitos dos fármacos , Neutrófilos/patologia , Receptor CB2 de Canabinoide/agonistas , Receptor CB2 de Canabinoide/antagonistas & inibidores , Receptor CB2 de Canabinoide/deficiência , Traumatismo por Reperfusão/tratamento farmacológico , Traumatismo por Reperfusão/metabolismo , Traumatismo por Reperfusão/patologia
6.
Cell Physiol Biochem ; 53(4): 587-605, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31535830

RESUMO

BACKGROUND/AIMS: To investigate the role of the sympathetic nervous system (SNS) and renin-angiotensin system (RAS) in renal ischemia/reperfusion-induced (I/R) cardiac inflammatoryprofile. METHODS: Left kidney ischemia was induced in male C57BL/6 mice for 60 min, followed by reperfusion for 12 days, and treatment with or without atenolol, losartan, or enalapril. The expression of vimentin in kidney and atrial natriuretic factor (ANF) in the heart has been investigated by RT-PCR. In cardiac tissue, levels of ß1-adrenoreceptors, adenylyl cyclase, cyclic AMP-dependent protein kinase (PKA), noradrenaline, adrenaline (components of SNS), type 1 angiotensin II receptors (AT1R), angiotensinogen/Ang II and renin (components of RAS) have been measured by Western blotting and HPLC analysis. A panel of cytokines - tumour necrosis factor (TNF-α), interleukin IL-6, and interferon gamma (IFN-γ) - was selected as cardiac inflammatory markers. RESULTS: Renal vimentin mRNA levels increased by >10 times in I/R mice, indicative of kidney injury. ANF, a marker of cardiac lesion, increased after renal I/R, the values being restored to the level of Sham group after atenolol or enalapril treatment. The cardiac inflammatory profile was confirmed by the marked increase in the levels of mRNAs of TNF-α, IL-6, and IFN-γ. Atenolol and losartan reversed the upregulation of TNF-α expression, whereas enalapril restored IL-6 levels to Sham levels; both atenolol and enalapril normalized IFN-γ levels. I/R mice showed upregulation of ß1-adrenoreceptors, adenylyl cyclase, PKA and noradrenaline. Renal I/R increased cardiac levels of AT1R, which decreased after losartan or enalapril treatment. Renin expression also increased, with the upregulation returning to Sham levels after treatment with SNS and RAS blockers. Angiotensinogen/Ang II levels in heart were unaffected by renal I/R, but they were significantly decreased after treatment with losartan and enalapril, whereas increase in renin levels decreased. CONCLUSION: Renal I/R-induced cardiac inflammatory events provoked by the simultaneous upregulation of SNS and RAS in the heart, possibly underpin the mechanism involved in the development of cardiorenal syndrome.


Assuntos
Rim/metabolismo , Miocárdio/metabolismo , Sistema Renina-Angiotensina , Sistema Nervoso Simpático/metabolismo , Animais , Atenolol/farmacologia , Atenolol/uso terapêutico , Fator Natriurético Atrial/genética , Fator Natriurético Atrial/metabolismo , Catecolaminas/metabolismo , Enalapril/farmacologia , Enalapril/uso terapêutico , Interleucina-6/metabolismo , Losartan/farmacologia , Losartan/uso terapêutico , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Receptor Tipo 1 de Angiotensina/genética , Receptor Tipo 1 de Angiotensina/metabolismo , Receptores Adrenérgicos beta 1/genética , Receptores Adrenérgicos beta 1/metabolismo , Sistema Renina-Angiotensina/efeitos dos fármacos , Traumatismo por Reperfusão/tratamento farmacológico , Traumatismo por Reperfusão/metabolismo , Traumatismo por Reperfusão/patologia , Sistema Nervoso Simpático/efeitos dos fármacos , Fator de Necrose Tumoral alfa/metabolismo , Regulação para Cima/efeitos dos fármacos , Vimentina/genética , Vimentina/metabolismo
7.
Bratisl Lek Listy ; 120(8): 558-562, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31379176

RESUMO

Genistein is a natural compound from the class of isoflavonoids found in high concentrations in legumes and soybeans. In this experimental study; we suggest that genistein might cause favorable outcomes in the hepatic surgery because of its protective effects on hepatic ischemia‒reperfusion injury (Tab. 2, Fig. 6, Ref. 28). Keywords: genistein, isoflavonoids,legumes, soybeans, hepatic surgery, ischemia‒reperfusion injury.


Assuntos
Genisteína/farmacologia , Hepatopatias/tratamento farmacológico , Fígado/cirurgia , Traumatismo por Reperfusão/tratamento farmacológico , Animais , Fígado/fisiopatologia , Ratos , Soja/química
8.
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
9.
Life Sci ; 231: 116569, 2019 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-31202841

RESUMO

AIM: The IRE1 signaling pathway is implicated in I/R injury. However, little is known about the involvement of this pathway in low-dose LPS treatment of myocardial I/R injury. Thus, an attempt was made to determine the relationship between the IRE1 pathway and I/R injury using rats or in vitro H9C2 cell myocardial I/R injury models. MAIN METHODS: Sprague-Dawley rats and cultured H9C2 cells were pretreated with low-dose LPS and subjected to myocardial I/R injury models. KEY FINDINGS: Low-dose LPS did not affect normal rat or cellular function. Compared with the I/R group, treatment with LPS attenuated myocardial apoptosis, decreased plasma LDH and CK-MB activities, reduced myocardium infarct size, and downregulated caspase-3 expression. Moreover, the protein or mRNA expression levels of the IRE1 signaling pathway-related proteins Grp78, IRE1, p-ASK1, ASK1, p-JNK, and JNK were notably increased during I/R injury but significantly decreased by low-dose LPS treatment both in rats and in H9C2 cells. SIGNIFICANCE: Low-dose LPS exhibited therapeutic effects in myocardial I/R injury. Most importantly, the cardioprotective mechanism of low-dose LPS may be associated with the IRE1 signaling pathway.


Assuntos
Proteínas de Membrana/metabolismo , Isquemia Miocárdica/tratamento farmacológico , Proteínas Serina-Treonina Quinases/metabolismo , Traumatismo por Reperfusão/tratamento farmacológico , Animais , Apoptose/efeitos dos fármacos , Modelos Animais de Doenças , Proteínas de Choque Térmico/metabolismo , Lipopolissacarídeos/farmacologia , MAP Quinase Quinase Quinase 5/metabolismo , Sistema de Sinalização das MAP Quinases/fisiologia , Masculino , Infarto do Miocárdio/metabolismo , Isquemia Miocárdica/metabolismo , Isquemia Miocárdica/fisiopatologia , Traumatismo por Reperfusão Miocárdica/metabolismo , Miocárdio/metabolismo , Miócitos Cardíacos/metabolismo , Substâncias Protetoras/farmacologia , Ratos , Ratos Sprague-Dawley , Traumatismo por Reperfusão/metabolismo , Traumatismo por Reperfusão/fisiopatologia , Transdução de Sinais/efeitos dos fármacos
10.
Life Sci ; 232: 116599, 2019 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-31247210

RESUMO

AIM: Ischemia/reperfusion (I/R) injury is the major cause of neurological deficit following stroke. Our previous study showed neuroprotective effects of hispidulin against cerebral ischemia reperfusion injury (IRI). In this study, we further examined the involvement of pyroptosis in this neuroprotective function. MATERIALS AND METHODS: IRI was simulated in a rat model by middle cerebral artery occlusion (MCAO) surgery, and the animals were treated with different doses of hispidulin. The neurological function of the rats was evaluated by the neural function defect score (NFDS), balance beam test and limb placement test. The infarct volume and brain water content were measured 72 h following IRI. Neuronal cell survival and pyroptosis in the ischemic cortex were respectively detected by Nissl staining and TUNEL assay. The relative expression of pyroptosis markers was determined by qRT-PCR, Western blotting and ELISA as appropriate. IRI was simulated in vitro in primary cerebral astrocytes using the OGD/R procedure. AMPKα was blocked genetically or pharmacologically using siRNA and compound C respectively. CCK-8 and LDH release assays were performed using suitable kits. RESULTS: Hispidulin improved the neurological symptoms of the rats after IRI, in addition to decreasing the infarct size and brain edema. Mechanistically, hispidulin exerted its neuroprotective effects in vivo and in vitro by suppressing NLRP3-mediated pyroptosis by modulating the AMPK/GSK3ß signaling pathway. CONCLUSION: Hispidulin is a neuroprotective agent with clinical potential against IR-induced neurological injury.


Assuntos
Isquemia Encefálica/tratamento farmacológico , Flavonas/farmacologia , Traumatismo por Reperfusão/tratamento farmacológico , Proteínas Quinases Ativadas por AMP/metabolismo , Animais , Apoptose/efeitos dos fármacos , Encéfalo/irrigação sanguínea , Encéfalo/metabolismo , Isquemia Encefálica/metabolismo , Isquemia Encefálica/patologia , Sobrevivência Celular/efeitos dos fármacos , Glicogênio Sintase Quinase 3 beta/metabolismo , Infarto da Artéria Cerebral Média/tratamento farmacológico , Masculino , Proteína 3 que Contém Domínio de Pirina da Família NLR/efeitos dos fármacos , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Fármacos Neuroprotetores/farmacologia , Piroptose/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley , Traumatismo por Reperfusão/metabolismo , Traumatismo por Reperfusão/patologia , Transdução de Sinais/efeitos dos fármacos , Acidente Vascular Cerebral/tratamento farmacológico
11.
Sheng Li Xue Bao ; 71(3): 424-430, 2019 Jun 25.
Artigo em Chinês | MEDLINE | ID: mdl-31218333

RESUMO

The present study was aimed to investigate the protective effect and anti-inflammation mechanism of astragaloside IV (AST-IV) on cerebral ischemia and reperfusion injury. Following the establishment of cerebral ischemia and reperfusion model in rats by modified suture method, neurological deficit scores and cerebral infarct volume were used to evaluate the pharmacological effect of AST-IV against cerebral ischemia-reperfusion injury. Western blot was used to detect the expression levels of NLRP3, pro-Caspase-1, Caspase-1, pro-IL-1ß, IL-1ß, pro-IL-18, IL-18, phosphorylated and total nuclear factor kappa B (NF-κB)/p65 protein in the brain tissue. The results showed that compared with model group, the intervention of AST-IV decreased the neurological deficit scores, reduced the cerebral infarct volume, decreased the levels of NLRP3, Caspase-1, pro-IL-1ß, IL-1ß, pro-IL-18 and IL-18, and inhibited the expression of phosphorylated NF-κB in brain tissue. The results suggest that AST-IV has a protective effect against cerebral ischemia and reperfusion injury, and its mechanism is related to inhibiting the phosphorylation of NF-κB and NLRP3 inflammasome activation.


Assuntos
Isquemia Encefálica/tratamento farmacológico , Infarto da Artéria Cerebral Média/tratamento farmacológico , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Traumatismo por Reperfusão/tratamento farmacológico , Saponinas/farmacologia , Triterpenos/farmacologia , Animais , Inflamassomos/metabolismo , NF-kappa B/metabolismo , Fosforilação , Ratos , Ratos Sprague-Dawley
12.
Int. j. morphol ; 37(2): 428-437, June 2019. tab, graf
Artigo em Inglês | LILACS | ID: biblio-1002239

RESUMO

Oxidative stress and inflammation are the key players in the development of motor dysfunction post-spinal cord ischemic reperfusion injury (SC-IRI). This study investigated the protective effect of concomitant pre-administration of melatonin and alpha-tocopherol on the early complications (after 48 hours) of spinal cord IRI injury in rats. Melatonin or α-tocopherol were preadministered either individually or in combination for 2 weeks, then rats were exposed SC-IRI. Neurological examinations of the hind limbs and various biochemical markers of oxidative stress and inflammation in the SC tissue were assessed. Solely pre-administration of either melanin or α-tocopherol significantly but partially improved motor and sensory function of the hind limbs mediated by partial decreases in SC levels of MDA, AOPP and PGE2 levels and activities of SOD, partial significant decreases in plasma levels of total nitrate/nitrite and significant increases in AC activity of GSH-Px. However, combination therapy of both drugs resulted in the maximum improvements in all neurological assessments tested and biochemical endpoints. In conclusion, by their synergistic antioxidant and antiinflammatory actions, the combination therapy of melatonin and α-tocopherol alleviates SC-IRI induced paraplegia.


El estrés oxidativo y la inflamación son claves en el desarrollo de la disfunción motora posterior a lesión isquémica de la médula espinal (SC-IRI). Este estudio investigó acerca del efecto protector de la administración previa concomitante de la melatonina y alfa-tocoferol en las complicaciones tempranas (después de 48 horas) de la lesión de IRI de la médula espinal en ratas. La melatonina o el α-tocoferol se administraron individualmente o en combinación durante 2 semanas, luego las ratas fueron expuestas a SC-IRI. Se evaluaron los exámenes neurológicos de las miembros pélvicos y diversos marcadores bioquímicos de estrés oxidativo e inflamación en el tejido subcutáneo. Solo la administración previa de melatonina o α-tocoferol mejoró parcial y significativamente la función motora y sensorial de los miembros pélvicos mediadas por disminuciones parciales en los niveles de SC de los niveles de MDA, AOPP y PGE2 y las actividades de la SOD, disminuciones significativas parciales en los niveles plasmáticos del total nitrato / nitrito y aumentos significativos en la actividad de AC de GSH-Px. Sin embargo, se observaron los mejores resultados durante la combinación de ambos fármacos en todas las evaluaciones neurológicas y en los puntos finales bioquímicos. En conclusión, debido a sus acciones antioxidantes y antiinflamatorias sinérgicas, la terapia de melatonina y α-tocoferol alivia la paraplejía inducida por SC-IRI.


Assuntos
Animais , Ratos , Traumatismo por Reperfusão/tratamento farmacológico , Isquemia do Cordão Espinal/tratamento farmacológico , Melatonina/administração & dosagem , Antioxidantes/administração & dosagem , Paraplegia , Medula Espinal/efeitos dos fármacos , Medula Espinal/patologia , Dinoprostona/sangue , Ratos Sprague-Dawley , Estresse Oxidativo/efeitos dos fármacos , Tocoferóis/farmacologia , Melatonina/farmacologia , Nitritos/sangue , Antioxidantes/farmacologia
13.
Drug Des Devel Ther ; 13: 1135-1144, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31040648

RESUMO

Purpose: The beneficial, neuroprotective effects of curcumin against ischemia-reperfusion injury have been demonstrated. In the present study, whether curcumin exerts neuroprotective effects associated with the inhibition of autophagy and hypoxia inducible factor-1α (HIF-1α) was investigated. Materials and methods: PC12 cellular model of oxygen glucose deprivation/reperfusion (OGD/R) has been developed to mimic cerebral ischemia-reperfusion injury. Cell viability was evaluated using the CellTiter 96® AQueous One Solution Cell Proliferation Assay. Apoptosis was assessed using flow cytometry. The expression levels of HIF-1α and autophagy-associated proteins, LC3 and P62, were examined using Western blot. The autophagy flux was quantitatively estimated based on the number of autophagic compartments using fluorescence microscopy. In addition, 3-methyladenine (3-MA) was administered to PC12 cells to investigate how autophagy affects HIF-1α. Moreover, the inhibitory effects of HIF-1α on autophagy activation level were examined. Results: In this study, curcumin decreased the death and apoptosis of cells, and inhibited autophagy and HIF-1α under OGD/R conditions, consistent with 3-MA treatment or HIF-1α downregulation. Moreover, inhibition of autophagy caused a decrease in HIF-1α, and the attenuation of HIF-1α induced autophagy suppression under OGD/R conditions. Conclusion: The results of this study showed that curcumin exerts neuroprotective effects against ischemia-reperfusion, which is associated with the regulation of the reciprocal function between autophagy and HIF-1α.


Assuntos
Autofagia/efeitos dos fármacos , Curcumina/farmacologia , Subunidade alfa do Fator 1 Induzível por Hipóxia/antagonistas & inibidores , Fármacos Neuroprotetores/farmacologia , Traumatismo por Reperfusão/tratamento farmacológico , Animais , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , Curcumina/química , Relação Dose-Resposta a Droga , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Fármacos Neuroprotetores/química , Imagem Óptica , Células PC12 , Ratos , Traumatismo por Reperfusão/metabolismo , Relação Estrutura-Atividade
14.
Mar Drugs ; 17(5)2019 May 05.
Artigo em Inglês | MEDLINE | ID: mdl-31060323

RESUMO

High intraocular pressure (IOP)-induced retinal ischemia leads to acute glaucoma, which is one of the leading causes of irreversible visual-field loss, characterized by loss of retinal ganglion cells (RGCs) and axonal injury in optic nerves (ONs). Oxidative stress and the inflammatory response play an important role in the ischemic injury of retinal and optic nerves. We focus on 5α-androst-3ß, 5α, 6ß-triol (TRIOL), a synthetic neuroactive derivative of natural marine steroids 24-methylene-cholest-3ß, 5α, 6ß, 19-tetrol and cholestane-3ß, 5α, 6ß-triol, which are two neuroactive polyhydroxysterols isolated from the soft coral Nephthea brassica and the gorgonian Menella kanisa, respectively. We previously demonstrated that TRIOL was a neuroprotective steroid with anti-inflammatory and antioxidative activities. However, the potential role of TRIOL on acute glaucoma and its underlying mechanisms remains unclear. Here, we report TRIOL as a promising neuroprotectant that can protect RGCs and their axons/dendrites from ischemic-reperfusion (I/R) injury in an acute intraocular hypertension (AIH) model. Intravitreal injection of TRIOL significantly alleviated the loss of RGCs and the damage of axons and dendrites in rats and mice with acute glaucoma. As NF-E2-related factor 2 (Nrf2) is one of the most critical regulators in oxidative and inflammatory injury, we further evaluated the effect of TRIOL on Nrf2 knockout mice, and the neuroprotective role of TRIOL on retinal ischemia was not observed in Nrf2 knockout mice, indicating that activation of Nrf2 is responsible for the neuroprotection of TRIOL. Further experiments demonstrated that TRIOL can activate and upregulate Nrf2, along with its downstream hemeoxygenase-1 (HO-1), by negative regulation of Kelch-like ECH (Enoyl-CoA Hydratase) associated Protein-1 (Keap1). In conclusion, our study shed new light on the neuroprotective therapy of retinal ischemia and proposed a promising marine drug candidate, TRIOL, for the therapeutics of acute glaucoma.


Assuntos
Androstanóis/farmacologia , Fator 2 Relacionado a NF-E2/deficiência , Fármacos Neuroprotetores/farmacologia , Traumatismo por Reperfusão/tratamento farmacológico , Células Ganglionares da Retina/efeitos dos fármacos , Esteroides/farmacologia , Animais , Técnicas de Cultura de Células , Hipóxia Celular/efeitos dos fármacos , Modelos Animais de Doenças , Glaucoma , Heme Oxigenase-1/metabolismo , Inflamação/tratamento farmacológico , Proteína 1 Associada a ECH Semelhante a Kelch/metabolismo , Masculino , Proteínas de Membrana/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Microglia/efeitos dos fármacos , Microglia/metabolismo , Fator 2 Relacionado a NF-E2/metabolismo , Hipertensão Ocular/tratamento farmacológico , Estresse Oxidativo/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley
15.
Molecules ; 24(9)2019 May 13.
Artigo em Inglês | MEDLINE | ID: mdl-31086091

RESUMO

Background: Ischemia/reperfusion (I/R) caused by ischemic stroke treatments leads to brain injury, and autophagy plays a role in the pathology. Astragaloside IV is a potential neuroprotectant, but its underlying mechanism on cerebral I/R injury needs to be explored. The objective of this study is to investigate the neuroprotective mechanism of Astragaloside IV against cerebral I/R injury. Methods: Middle cerebral artery occlusion method (MCAO) and oxygen and glucose deprivation/reoxygenation (OGD/R) method were used to simulate cerebral I/R injury in Sprague-Dawley (SD) rats and HT22 cells, respectively. The neurological score, 2,3,5-Triphe-nyltetrazolium chloride (TTC) staining, and transmission electron microscope were used to detect cerebral damage in SD rats. Cell viability and cytotoxicity assay were tested in vitro. Fluorescent staining and flow cytometry were applied to detect the level of apoptosis. Western blotting was conducted to examine the expression of proteins associated with autophagy. Results: This study found that Astragaloside IV could decrease the neurological score, reduce the infarct volume in the brain, and alleviate cerebral I/R injury in MCAO rats. Astragaloside IV promoted cell viability and balanced Bcl-2 and Bax expression in vitro, reduced the rate of apoptosis, decreased the expression of P62, and increased the expression of LC3II/LC3I in HT22 cells after OGD/R. Conclusions: These data suggested that Astragaloside IV plays a neuroprotective role by down-regulating apoptosis by promoting the degree of autophagy.


Assuntos
Apoptose/efeitos dos fármacos , Autofagia/efeitos dos fármacos , Isquemia Encefálica/tratamento farmacológico , Isquemia Encefálica/metabolismo , Traumatismo por Reperfusão/tratamento farmacológico , Traumatismo por Reperfusão/metabolismo , Saponinas/uso terapêutico , Triterpenos/uso terapêutico , Animais , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Masculino , Camundongos , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Ratos , Ratos Sprague-Dawley , Proteína X Associada a bcl-2/metabolismo
16.
Int J Mol Sci ; 20(9)2019 May 08.
Artigo em Inglês | MEDLINE | ID: mdl-31071925

RESUMO

Current organ shortages have led centers to extend the acceptance criteria for organs, increasing the risk for adverse outcomes. Current preservation protocols have not been adapted so as to efficiently protect these organs. Herein, we target oxidative stress, the key mechanism of ischemia reperfusion injury. Vectisol® is a novel antioxidant strategy based on the encapsulation of resveratrol into a cyclodextrin, increasing its bioavailability. We tested this compound as an additive to the most popular static preservation solutions and machine perfusion (LifePort) in a preclinical pig model of kidney autotransplantation. In regard to static preservation, supplementation improved glomerular filtration and proximal tubular function early recovery. Extended follow-up confirmed the higher level of protection, slowing chronic loss of function (creatininemia and proteinuria) and the onset of histological lesions. Regarding machine perfusion, the use of Vectisol® decreased oxidative stress and apoptosis at the onset of reperfusion (30 min post declamping). Improved quality was confirmed with decreased early levels of circulating SOD (Superoxide Dismutase) and ASAT (asparagine amino transferase). Supplementation slowed the onset of chronic loss of function, as well as interstitial fibrosis and tubular atrophy. The simple addition of Vectisol® to the preservation solution significantly improved the performance of organ preservation, with long-term effects on the outcome. This strategy is thus a key player for future multi-drug therapy aimed at ischemia reperfusion in transplantation.


Assuntos
Antioxidantes/administração & dosagem , Transplante de Rim/efeitos adversos , Rim/fisiopatologia , Resveratrol/química , Transplante Autólogo , Animais , Antioxidantes/química , Ciclodextrinas/administração & dosagem , Ciclodextrinas/química , Modelos Animais de Doenças , Composição de Medicamentos , Humanos , Rim/efeitos dos fármacos , Preservação de Órgãos/métodos , Estresse Oxidativo/efeitos dos fármacos , Traumatismo por Reperfusão/tratamento farmacológico , Traumatismo por Reperfusão/fisiopatologia , Resveratrol/administração & dosagem , Solubilidade , Suínos
17.
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
18.
Neurochem Res ; 44(7): 1549-1566, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31093902

RESUMO

This study aimed to investigate the potential effects of gold nanoparticles (Au-NPs) on rat cortical neurons exposed to oxygen-glucose deprivation/reperfusion (OGD/R) and to elucidate the corresponding mechanisms. Primary rat cortical neurons were exposed to OGD/R, which is commonly used in vitro to mimic ischemic injury, and then treated with 5- or 20-nm Au-NPs. We then evaluated cell viability, apoptosis, oxidative stress, and mitochondrial respiration in these neurons. We found that 20-nm Au-NPs increased cell viability, alleviated neuronal apoptosis and oxidative stress, and improved mitochondrial respiration after OGD/R injury, while opposite effects were observed for 5-nm Au-NPs. In terms of the underlying mechanisms, we found that Au-NPs could regulate Akt signaling. Taken together, these results show that 20-nm Au-NPs can protect primary cortical neurons against OGD/R injury, possibly by decreasing apoptosis and oxidative stress, while activating Akt signaling and mitochondrial pathways. Our results suggest that Au-NPs may be potential therapeutic agents for ischemic stroke.


Assuntos
Glucose/metabolismo , Ouro/uso terapêutico , Nanopartículas Metálicas/uso terapêutico , Fármacos Neuroprotetores/uso terapêutico , Oxigênio/metabolismo , Traumatismo por Reperfusão/tratamento farmacológico , Animais , Antioxidantes/efeitos adversos , Antioxidantes/química , Antioxidantes/uso terapêutico , Apoptose/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , Córtex Cerebral/efeitos dos fármacos , Glicogênio Sintase Quinase 3 beta/metabolismo , Ouro/efeitos adversos , Ouro/química , Inflamação/tratamento farmacológico , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Nanopartículas Metálicas/efeitos adversos , Nanopartículas Metálicas/química , Mitocôndrias/efeitos dos fármacos , Neurônios/citologia , Neurônios/efeitos dos fármacos , Fármacos Neuroprotetores/efeitos adversos , Fármacos Neuroprotetores/química , Estresse Oxidativo/efeitos dos fármacos , Tamanho da Partícula , Proteínas Proto-Oncogênicas c-akt/metabolismo , Ratos Sprague-Dawley , Transdução de Sinais/efeitos dos fármacos
19.
Mol Med Rep ; 20(1): 719-727, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31115556

RESUMO

Puerarin, a major bioactive constituent of the Radix puerariae, can ameliorate myocardial ischemia/reperfusion (I/R) injury. Emerging evidence supports that microRNA (miR)­21 functions as a protective factor against I/R and/or hypoxia­reperfusion (H/R)­induced myocardial injury. However, the role of miR­21 in the cardioprotective effect of puerarin remains unclear. Therefore, the purpose of the present study was to demonstrate the involvement of miR­21 in the cardioprotective mechanisms of puerarin using a cell model of I/R injury, generated by culturing rat H9c2 cardiomyocytes under H/R conditions. The results demonstrated that pre­treatment with puerarin significantly increased cell viability, decreased lactate dehydrogenase activity and upregulated miR­21 expression in H/R­treated H9c2 cells. Transfection of an miR­21 inhibitor led to an increase in H/R­induced cytotoxicity and reversed the protective effects of puerarin. Additionally, miR­21 inhibition attenuated the puerarin­induced decrease in the rate of apoptosis, caspase­3 activity and the expression of apoptosis regulator Bax, and increased apoptosis regulator Bcl­2 expression, under H/R conditions. Furthermore, puerarin mitigated H/R­induced oxidative stress as evidenced by the decrease in endogenous reactive oxygen species production, malondialdehyde content and NADPH oxidase 2 expression, and enhanced the antioxidative defense system as illustrated by the increase in superoxide dismutase activity, catalase and glutathione peroxidase levels. These effects were all eliminated by miR­21 inhibitor transfection. Furthermore, the miR­21 inhibitor exacerbated the H/R­induced oxidative stress and attenuated the antioxidative defense system in H/R­treated H9c2 cells. Taken together, the results suggested that miR­21 mediated the cardioprotective effects of puerarin against myocardial H/R injury by inhibiting apoptosis and oxidative stress.


Assuntos
Isoflavonas/farmacologia , MicroRNAs/genética , Estresse Oxidativo/efeitos dos fármacos , Traumatismo por Reperfusão/tratamento farmacológico , Animais , Antioxidantes/farmacologia , Apoptose/efeitos dos fármacos , Apoptose/genética , Cardiotônicos/farmacologia , Sobrevivência Celular/efeitos dos fármacos , Modelos Animais de Doenças , Humanos , Masculino , Miócitos Cardíacos/efeitos dos fármacos , Estresse Oxidativo/genética , Ratos , Espécies Reativas de Oxigênio/metabolismo , Traumatismo por Reperfusão/genética , Traumatismo por Reperfusão/patologia
20.
Life Sci ; 226: 202-209, 2019 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-30991061

RESUMO

INTRODUCTION: Ischemic stroke is one of the leading causes of death worldwide, and extensive efforts have focused on the neuroprotective strategies to minimize complications due to ischemia. This study aimed to examine neuroprotective potential of chrysin, as a natural potent antioxidative and anti-inflammatory agent in an animal model of bilateral common carotid artery occlusion and reperfusion (BCCAO/R). METHODS: Adult male Wistar rats (250-300 g) were randomly divided into 6 groups and submitted to either sham surgery or BCCAO/R after pretreatment with chrysin (10, 30 and 100 mg/kg, once daily, for 21 consecutive days) or saline containing %5 DMSO. To make the animal model of BCCAO/R, bilateral common carotid arteries were occluded for 20 min, followed by reperfusion. Subsequently, spatial cognitive performance was evaluated in a Morris water maze (MWM), hippocampal long-term potentiation (LTP) was recorded from hippocampal dentate gyrus region, after then the hippocampal tissue content of IL-1ß and TNF-α were assayed using ELISA kits. RESULTS: The results showed that pretreatment with chrysin significantly prevented BCCAO/R-induced cognitive and hippocampal LTP impairments (p < 0.001). Additionally, BCCAO/R- induced elevation in hippocampal content of IL-1ß and TNF-α significantly (p < 0.01, p < 0.01 respectively) while pre-treatment with chrysin restored them (p < 0.01). CONCLUSION: Our data confirm that chrysin could prevent brain inflammation and thereby prevents cognitive and LTP impairments due to cerebral ischemia. So it could be a promising neuroprotective agent against cerebrovascular insufficiency states.


Assuntos
Disfunção Cognitiva/prevenção & controle , Flavonoides/farmacologia , Traumatismo por Reperfusão/tratamento farmacológico , Animais , Antioxidantes , Isquemia Encefálica/complicações , Artérias Carótidas , Artéria Carótida Primitiva , Cognição/efeitos dos fármacos , Cognição/fisiologia , Modelos Animais de Doenças , Encefalite/tratamento farmacológico , Encefalite/prevenção & controle , Flavonoides/uso terapêutico , Hipocampo/efeitos dos fármacos , Inflamação , Potenciação de Longa Duração/efeitos dos fármacos , Potenciação de Longa Duração/fisiologia , Masculino , Fármacos Neuroprotetores , Estresse Oxidativo , Ratos , Ratos Wistar
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