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1.
Biochemistry (Mosc) ; 84(11): 1411-1423, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31760927

RESUMO

Ischemic stroke and neonatal hypoxic-ischemic encephalopathy are two of the leading causes of disability in adults and infants. The energy demands of the brain are provided by mitochondrial oxidative phosphorylation. Ischemia/reperfusion (I/R) affects the production of ATP in brain mitochondria, leading to energy failure and death of the affected tissue. Among the enzymes of the mitochondrial respiratory chain, mitochondrial complex I is the most sensitive to I/R; however, the mechanisms of its inhibition are poorly understood. This article reviews some of the existing data on the mitochondria impairment during I/R and proposes two distinct mechanisms of complex I damage emerging from recent studies. One mechanism is a reversible dissociation of natural flavin mononucleotide cofactor from the enzyme I after ischemia. Another mechanism is a modification of critical cysteine residue of complex I involved into the active/deactive conformational transition of the enzyme. I describe potential effects of these two processes in the development of mitochondrial I/R injury and briefly discuss possible neuroprotective strategies to ameliorate I/R brain injury.


Assuntos
Encéfalo/metabolismo , Complexo I de Transporte de Elétrons/metabolismo , Traumatismo por Reperfusão/patologia , Animais , Flavinas/química , Flavinas/metabolismo , Humanos , Mitocôndrias/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Traumatismo por Reperfusão/metabolismo , Compostos de Sulfidrila/química
2.
Life Sci ; 236: 116921, 2019 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-31610196

RESUMO

AIMS: To assess the role of glycogen synthase kinase-3ß (GSK3ß) and ß-catenin in the protection of ischemic injury by dexmedetomidine (Dex). MAIN METHODS: Adult male Sprague-Dawley rats were subjected to (middle cerebral artery occlusion, MCAO) for 2 h followed by reperfusion and Dex was administered 30min before MCAO. The neurological deficit score, cerebral infarct size and neuron survival were evaluated at 24 h after reperfusion. The expression of pAKT, pGSK3ß and ß-catenin in the ischemic penumbra was assayed by Western blot at 2 h after reperfusion. KEY FINDINGS: We found that the Dex-induced increment of neuron survival in the ischemic penumbra was diminished by the PI3K inhibitor LY294002 and the ß-catenin inhibitor XAV939, respectively. The increasing expression of pAKT, pGSK3ß and ß-catenin induced by Dex was markedly inhibited by LY294002. And the increasing expression of ß-catenin in nuclei induced by Dex was markedly inhibited by XAV939. At the same time, the GSK3ß inhibitor SB216763 also caused an increment of neuron survival and an increasing expression of pGSK3ß and ß-catenin in the ischemic penumbra. SIGNIFICANCE: Our data suggested that treatment with Dex reduced cerebral injury in rats exposed to cerebral ischemia-reperfusion (I/R) by the activation of the PI3K/AKT/GSK3ß pathways as well the activation of downstream Wnt/ß-catenin pathway. And the Wnt/ß-catenin pathway may play an important role in the protection against cerebral ischemia/reperfusion injury in rats.


Assuntos
Agonistas de Receptores Adrenérgicos alfa 2/farmacologia , Dexmedetomidina/farmacologia , Infarto da Artéria Cerebral Média/prevenção & controle , Traumatismo por Reperfusão/prevenção & controle , Transdução de Sinais/efeitos dos fármacos , Proteínas Wnt/metabolismo , beta Catenina/metabolismo , Animais , Apoptose , Infarto da Artéria Cerebral Média/metabolismo , Infarto da Artéria Cerebral Média/patologia , Masculino , Fármacos Neuroprotetores/farmacologia , Ratos , Ratos Sprague-Dawley , Traumatismo por Reperfusão/metabolismo , Traumatismo por Reperfusão/patologia , Proteínas Wnt/genética , beta Catenina/genética
3.
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
4.
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
5.
Chem Commun (Camb) ; 55(72): 10740-10743, 2019 Sep 16.
Artigo em Inglês | MEDLINE | ID: mdl-31432813

RESUMO

We constructed a two-photon fluorescence ratio probe (CST) for in situ quantitative real-time detection of mitochondrial O2˙-. Fluorescence imaging showed that O2˙- was over-generated from mitochondria and conveyed to the cytoplasm via voltage-dependent anion channels in hepatic ischemia-reperfusion mice, damaging the important functional protein aconitase in the cytoplasm.


Assuntos
Fígado/metabolismo , Mitocôndrias/química , Imagem Óptica , Fótons , Traumatismo por Reperfusão/metabolismo , Superóxidos/química , Animais , Ânions/química , Ânions/metabolismo , Transporte Biológico , Corantes Fluorescentes/química , Camundongos , Mitocôndrias/metabolismo , Estrutura Molecular , Superóxidos/metabolismo
6.
DNA Cell Biol ; 38(9): 895-904, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31347925

RESUMO

Ischemia-reperfusion injury is a major reason for acute kidney injury and various kidney diseases. Autophagy plays an important role during renal ischemia-reperfusion injury (RIRI), but it remains controversial whether autophagy contributes to cell survival or ischemia-reperfusion-induced cell death. In the review, we summarized the function of autophagy in the progression of acute ischemic kidney injury, as well as its related molecular mechanisms. While analyzing the opposite roles of autophagy in RIRI, it was concluded that the protective or detrimental function of autophagy was depending on the timing and amount of the activation of cell autophagy. We also summarized the regulatory agents, including active compounds, proteins, or microRNAs (miRNAs), which regulated the cell autophagy during renal acute ischemic kidney injury process. This explained why the opposite conclusion occurred when cell autophagy was studied in the RIRI models from different researchers. Therefore, the article provided a hypothesis to control cell autophagy at the appropriate timing and intensity so as to alleviate renal injury and sustain cell survival of the renal cell.


Assuntos
Autofagia , Rim/irrigação sanguínea , Traumatismo por Reperfusão/metabolismo , Animais , Proteínas Relacionadas à Autofagia/genética , Proteínas Relacionadas à Autofagia/metabolismo , Humanos , Rim/metabolismo
7.
Life Sci ; 232: 116632, 2019 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-31278944

RESUMO

AIMS: The inflammation modulation effects of mesenchymal stromal cell-derived exosomes (MSC-EXO) are well established. We aimed to explore the mechanism behind the inflammatory responses of numerous exosomal cargo molecules that have been neglected in molecular biology research, and to develop an exosomal cargo delivery system that can exert a stronger therapeutic effect on myocardial ischemia-reperfusion (I/R) injury. MAIN METHODS: Computational approaches were used to identify key exosomal miRNAs and their downstream mRNAs that are expressed in the inflammatory response. Direct interactions between miRNA-181a and the c-Fos mRNA complex were confirmed by luciferase reporter assay. MSC-EXO carrying miRNA-181a-overexpressing lentiviruses were intramyocardially injected into a mouse model of myocardial I/R injury. I/R progression was evaluated through echocardiography and immunofluorescence microscopy. KEY FINDINGS: miRNA-181a provided substantial coverage against a host of immune-related genes through the miRNA-mRNA network. miRNA-181a delivery by MSC-EXO combined the immune-suppressing effect of miRNA-181a and the cell targeting capability of MSC-EXO to exert a stronger therapeutic effect on myocardium I/R injury. SIGNIFICANCE: We showed the potential of MSC-EXO as a tool for the specific delivery of small RNAs in vivo. This study shed new light on the potential application of miRNA-181a-overexpressing MSC-EXO as a therapeutic strategy for myocardial I/R injury.


Assuntos
Células-Tronco Mesenquimais/metabolismo , MicroRNAs/sangue , Traumatismo por Reperfusão Miocárdica/metabolismo , Animais , Movimento Celular/fisiologia , Proliferação de Células/fisiologia , Transplante de Células-Tronco de Sangue do Cordão Umbilical/métodos , Exossomos , Humanos , Inflamação/terapia , Masculino , Transplante de Células-Tronco Mesenquimais/métodos , Células-Tronco Mesenquimais/citologia , Camundongos , Camundongos Endogâmicos C57BL , MicroRNAs/genética , MicroRNAs/metabolismo , Traumatismo por Reperfusão Miocárdica/genética , Traumatismo por Reperfusão Miocárdica/patologia , Traumatismo por Reperfusão/genética , Traumatismo por Reperfusão/metabolismo
8.
Chin J Nat Med ; 17(6): 424-434, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31262455

RESUMO

To examine the effects of Populus tomentiglandulosa (PT) extract on the expressions of antioxidant enzymes and neurotrophic factors in the cornu ammonis 1 (CA1) region of the hippocampus at 5 min after inducing transient global cerebral ischemia (TGCI) in gerbils, TGCI was induced by occlusion of common carotid arteries for 5 min. Before ischemic surgery, 200 mg·kg-1 PT extract was orally administrated once daily for 7 d. We performed neuronal nuclear antigen immunohistochemistry and Fluoro-Jade B staining. Furthermore, we determined in situ production of superoxide anion radical, expression levels of SOD1 and SOD2 as antioxidant enzymes and brain-derived neurotrophic factor (BDNF) and insulin-like growth factor I (IGF-I) as neurotrophic factors. Pretreatment with 200 mg·kg-1 PT extract prevented neuronal death (loss). Furthermore, pretreatment with 200 mg·kg-1 PT extract significantly inhibited the production of superoxide anion radical, increased expressions of SODs and maintained expressions of BDNF and IGF-I. Such increased expressions of SODs were maintained in the neurons after IRI. In summary, pretreated PT extract can significantly increase levels of SODs and protect the neurons against TGCI, suggesting that PT can be a useful natural agent to protect against TGCI.


Assuntos
Fator Neurotrófico Derivado do Encéfalo/metabolismo , Região CA1 Hipocampal/efeitos dos fármacos , Fator de Crescimento Insulin-Like I/metabolismo , Extratos Vegetais/administração & dosagem , Populus/química , Células Piramidais/efeitos dos fármacos , Traumatismo por Reperfusão/tratamento farmacológico , Superóxido Dismutase/metabolismo , Animais , Fator Neurotrófico Derivado do Encéfalo/genética , Região CA1 Hipocampal/metabolismo , Gerbillinae , Humanos , Fator de Crescimento Insulin-Like I/genética , Masculino , Fármacos Neuroprotetores/administração & dosagem , Células Piramidais/metabolismo , Traumatismo por Reperfusão/genética , Traumatismo por Reperfusão/metabolismo , Superóxido Dismutase/genética , Regulação para Cima/efeitos dos fármacos
9.
Life Sci ; 232: 116619, 2019 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-31265855

RESUMO

AIMS: Clinical treatment strategies for patients with myocardial ischemia typically include coronary artery recanalization to restore myocardial blood supply. However, myocardial reperfusion insult often induces oxidative stress and inflammation, which further leads to apoptosis and necrosis of myocardial cells. Increasing evidence suggests that microRNAs (miRNAs) participate in the pathological and physiological processes associated with myocardial ischemia reperfusion. MAIN METHODS: In this study, we established a myocardial H/R H9C2 cell model and a mouse I/R model to detect molecules implicated in myocardial I/R regulation and to determine the underlying signal transduction pathways. KEY FINDINGS: Herein, we showed that the expression of miR-374a-5p decreased in a myocardial cell model (H9C2 cells) of hypoxia/reoxygenation (H/R) and mouse model of ischemia/reperfusion (I/R). Alternatively, overexpression of miR-374a-5p was found to ameliorate myocardial cell damage within both in vivo and in vitro models of ischemia. Further, mitogen-activated protein kinase 6 (MAPK6) was identified as a direct target of miR-374a-5p. Thus, by targeting MAPK6, miR-374a-5p was found to negatively regulate MAPK6 expression. However, up-regulation of MAPK6 functioned to inhibit the previously observed protective effect of miR-374a-5p in the H9C2 H/R model. SIGNIFICANCE: Taken together, our study suggests that miR-374a-5p may have protective effects against cardiac I/R injury in vivo, and H/R injury in vitro, thereby providing novel insights into the molecular mechanisms associated with ischemia/reperfusion injury and a potential novel therapeutic target.


Assuntos
MicroRNAs/biossíntese , Traumatismo por Reperfusão/metabolismo , Animais , Apoptose/efeitos dos fármacos , Hipóxia Celular/fisiologia , Hipóxia/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , MicroRNAs/genética , Proteína Quinase 6 Ativada por Mitógeno/genética , Proteína Quinase 6 Ativada por Mitógeno/metabolismo , Isquemia Miocárdica/genética , Isquemia Miocárdica/metabolismo , Traumatismo por Reperfusão Miocárdica/genética , Traumatismo por Reperfusão Miocárdica/metabolismo , Miocárdio/metabolismo , Miócitos Cardíacos/metabolismo , Estresse Oxidativo/fisiologia , Ratos , Traumatismo por Reperfusão/genética , Transdução de Sinais
10.
Life Sci ; 232: 116611, 2019 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-31260683

RESUMO

PURPOSE: To observe the effect of dexmedetomidine (DEX) on mitochondrial apoptosis of hippocampal neurons in hypoxia/reoxygenation (H/R) brain injury in developing rats, and to investigate its regulatory mechanism on HIF-1α/p53 signaling pathway. METHODS: Hypoxia/reoxygenation model was used in this study. TUNEL assay was performed to detect cell apoptosis. Immunohistochemical analysis and Western-blotting analysis were conducted to detect Cytochrome-C (Cyt-c), APAF-1, Caspase-3, Neuroglobin (Ngb), HIF-1α and p53 expression. After 28 days, Morris water maze (MWM) was performed. RESULTS: 50 µg/kg DEX improved H/R-induced brain injury and inhibited mitochondrial apoptosis in rats. Western-blotting and Immunohistochemical results demonstrated that DEX could up-regulate Ngb through α2 receptor to inhibit H/R-induced mitochondrial apoptosis. In addition, by adding inhibitors yohimbine and 2-methoxyestradiol (2ME2), we found that DEX could activate HIF-1α/p53 signaling pathway. MWM test showed that DEX could enhance long-term learning and memory of H/R brain injury rats. CONCLUSION: DEX alleviates H/R-induced brain injury and mitochondrial apoptosis in developing rats through α2 receptor, which may be related to activation of HIF-1α/p53 signaling pathway to up-regulate the expression of Ngb.


Assuntos
Hipóxia Celular/efeitos dos fármacos , Dexmedetomidina/farmacologia , Hipocampo/efeitos dos fármacos , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Neurônios/efeitos dos fármacos , Proteína Supressora de Tumor p53/metabolismo , Animais , Apoptose/efeitos dos fármacos , Apoptose/fisiologia , Hipocampo/metabolismo , Hipocampo/patologia , Subunidade alfa do Fator 1 Induzível por Hipóxia/genética , Masculino , Mitocôndrias/metabolismo , Neurônios/metabolismo , Neurônios/patologia , Substâncias Protetoras/farmacologia , Ratos , Ratos Sprague-Dawley , Traumatismo por Reperfusão/metabolismo , Transdução de Sinais/efeitos dos fármacos , Proteína Supressora de Tumor p53/efeitos dos fármacos
11.
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
12.
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
13.
Int J Mol Sci ; 20(11)2019 Jun 03.
Artigo em Inglês | MEDLINE | ID: mdl-31163581

RESUMO

(1) Background: Heme oxygenase-1 (HO-1) degrades heme and generates carbon monoxide (CO), producing various anti-inflammatory, anti-oxidative, and anti-apoptotic effects. This study aimed to confirm the effects of CO on the ischemia-reperfusion injury (IRI) of donor lungs using a high-pressure gas (HPG) preservation method. (2) Methods: Donor rat and canine lungs were preserved in a chamber filled with CO (1.5 atm) and oxygen (O2; 2 atm) and were ventilated with either CO and O2 mixture (CO/O2 group) or air (air group) immediately before storage. Rat lungs were subjected to heterotopic cervical transplantation and evaluated after reperfusion, whereas canine lungs were subjected to allogeneic transplantation and evaluated. (3) Results: Alveolar hemorrhage in the CO/O2 group was significantly milder than that in the air group. mRNA expression levels of HO-1 remained unchanged in both the groups; however, inflammatory mediator levels were significantly lower in the CO/O2 group than in the air group. The oxygenation of graft lungs was comparable between the two groups, but lactic acid level tended to be higher in the air group. (4) Conclusions: The HO-1/CO system in the HPG preservation method is effective in suppressing IRI and preserving donor lungs.


Assuntos
Pressão do Ar , Monóxido de Carbono , Pulmão , Preservação de Órgãos , Oxigênio , Animais , Biomarcadores , Gasometria , Modelos Animais de Doenças , Pulmão/metabolismo , Masculino , Preservação de Órgãos/métodos , Ratos , Reperfusão , Traumatismo por Reperfusão/metabolismo , Traumatismo por Reperfusão/terapia
14.
Life Sci ; 231: 116544, 2019 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-31181229

RESUMO

AIMS: To investigate the effect of long-term N-acetyl-l-cysteine (NAC) treatment in Wistar rats subjected to renal ischemia and reperfusion (IR) and a chronic high­sodium diet (HSD). MAIN METHODS: Adult male Wistar rats received an HSD (8.0% NaCl) or a normal­sodium diet (NSD; 1.3% NaCl) and NAC (600 mg/L) or normal drinking water starting at 8 weeks of age. At 11 weeks of age, the rats from both diet and NAC or water treatment groups underwent renal IR or Sham surgery and were followed for 10 weeks. The study consisted of six animal groups: NSD + Sham + water; NSD + IR + water; NSD + IR + NAC; HSD + Sham + water; HSD + IR + water; and HSD + IR + NAC. KEY FINDINGS: Tail blood pressure (tBP) increased with IR and NAC treatment in the NSD group but not in the HSD group. The serum creatinine level was higher after NAC treatment in both diet groups, and creatinine clearance was decreased in only the HSD + IR + NAC group. Albuminuria increased in the HSD + IR + water group and decreased in the HSD + IR + NAC group. Kidney mass was increased in the HSD + IR group and decreased with NAC treatment. Renal fibrosis was prevented with NAC treatment and cardiac fibrosis was decreased with NAC treatment in the HSD + IR group. SIGNIFICANCE: NAC treatment promoted structural improvements, such as decreased albuminuria and fibrosis, in the kidney and heart. However, NAC could not recover kidney function or blood pressure from the effects of IR associated with an HSD. Therefore, in general, long-term NAC treatment is not effective and is deleterious to recovery of function after kidney injury.


Assuntos
Acetilcisteína/farmacologia , Isquemia Encefálica/fisiopatologia , Rim/irrigação sanguínea , Traumatismo por Reperfusão/fisiopatologia , Cloreto de Sódio na Dieta/efeitos adversos , Lesão Renal Aguda/prevenção & controle , Animais , Pressão Sanguínea/efeitos dos fármacos , Isquemia Encefálica/metabolismo , Depuradores de Radicais Livres/farmacologia , Isquemia/etiologia , Isquemia/metabolismo , Isquemia/patologia , Isquemia/fisiopatologia , Rim/efeitos dos fármacos , Rim/metabolismo , Masculino , Ratos , Ratos Wistar , Reperfusão/métodos , Traumatismo por Reperfusão/metabolismo , Cloreto de Sódio na Dieta/administração & dosagem
15.
Biol Res ; 52(1): 32, 2019 Jun 13.
Artigo em Inglês | MEDLINE | ID: mdl-31196153

RESUMO

BACKGROUND: Long non-coding RNA H19 (H19) plays an important role by regulating protein expression in different tissues and organs of the body. However, whether H19 induces hypoxia/reoxygenation (h/R) injury via increase of autophagy in the hepatoma carcinoma cells is unknown. RESULTS: H19 was expressed in the hepatoma carcinoma cells (Hep G2 and HCCLM3 cells) and its expression was most in 8 h/24R. The knockdown of H19 and 3-MA (an autophagy inhibitor) protected against h/R-induced apoptosis, cell damage, the expression of cleaved caspase-3 and cleaved caspase-9, the release of cytochrome c (Cyt c). The knockdown of H19 and 3-MA also decreased the autophagic vesicles (AVs) and the expression of Beclin-1 and the ration of LC3-II/LC3-I, and increased cell viability, the expression of Bcl-2 and P62 and the phosphorylation of PI3K, Akt and mTOR. In addition, chloroquine (CQ, an inhibitor of autophagy flux) markedly decreased formation of autophagy flux (the ration of LC3-II/LC3-I). The results of the knockdown of H19 group were similar to those of the 3-MA (or CQ) group. Rapamycin (a mTOR inhibitor, an autophagy activator) further down-regulated h/R-induced decrease of the phosphorylated PI3K, Akt and mTOR. The knockdown of H19 cancelled the effect of rapamycin. The overexpression of H19 further expanded h/R-induced increase of the ration of LC3-II/LC3-I and decrease of the phosphorylated PI3K, Akt and mTOR. CONCLUSIONS: Our results suggest that the long non-coding RNA H19 induces h/R injury by up-regulation of autophagy via activation of PI3K-Akt-mTOR pathway in the hepatoma carcinoma cells.


Assuntos
Carcinoma Hepatocelular/metabolismo , Hipóxia/metabolismo , Neoplasias Hepáticas/metabolismo , RNA Longo não Codificante/metabolismo , Traumatismo por Reperfusão/metabolismo , Apoptose/fisiologia , Autofagia/efeitos dos fármacos , Isquemia Encefálica/metabolismo , Carcinoma Hepatocelular/patologia , Humanos , Neoplasias Hepáticas/patologia , Oxigênio/metabolismo , Regulação para Cima/fisiologia
16.
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
17.
Med Sci Monit ; 25: 4723-4733, 2019 Jun 25.
Artigo em Inglês | MEDLINE | ID: mdl-31237865

RESUMO

BACKGROUND Electroacupuncture (EA) has been commonly used to treat stroke in China. However, the underlying mechanism remains largely unknown. The present study investigated the neuroprotective effects of EA in middle cerebral artery occlusion (MCAO) rats and elucidated the possible anti-inflammatory mechanisms. MATERIAL AND METHODS In this study, modified neurological severity scoring (mNSS) was used to assess neurological deficits, and TTC staining and brain water content were measured to evaluate the degree of brain damage. HE staining, Nissl staining, and TUNEL staining were employed to evaluate apoptotic neuronal death. Molecular biological methods were used to measure the levels of miR-233, NLRP3, caspase-1, IL-1ß, and IL-18 in the peri-infarct cortex. RESULTS Our results showed that EA treatment significantly decreased the neurological deficit score and infarct volume of MCAO rats. The level of miR-223 was increased, while the levels of NLRP3, caspase-1, IL-1ß, and IL-18 were decreased in the peri-infarct cortex of EA-treated MCAO rats. However, the neuroprotective effect of EA was partially blocked by antagomir-223. CONCLUSIONS These data suggest that EA treatment can alleviate neuroinflammation by inhibiting the miR-223/NLRP3 pathway, thus playing a neuroprotective role in MCAO in rats.


Assuntos
Isquemia Encefálica/terapia , Eletroacupuntura/métodos , Infarto da Artéria Cerebral Média/terapia , MicroRNAs/antagonistas & inibidores , Proteína 3 que Contém Domínio de Pirina da Família NLR/antagonistas & inibidores , Pontos de Acupuntura , Animais , Encéfalo/metabolismo , Lesões Encefálicas/metabolismo , Isquemia Encefálica/metabolismo , Córtex Cerebral/metabolismo , Infarto da Artéria Cerebral Média/metabolismo , Masculino , MicroRNAs/genética , MicroRNAs/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/genética , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Neuroproteção/efeitos dos fármacos , Fármacos Neuroprotetores/farmacologia , Ratos , Ratos Sprague-Dawley , Traumatismo por Reperfusão/metabolismo , Transdução de Sinais , Acidente Vascular Cerebral/metabolismo , Acidente Vascular Cerebral/terapia
18.
Life Sci ; 231: 116533, 2019 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-31173783

RESUMO

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


Assuntos
Hipóxia/patologia , Músculo Esquelético/irrigação sanguínea , Traumatismo por Reperfusão/prevenção & controle , Animais , Apoptose/efeitos dos fármacos , Hipóxia/metabolismo , Inflamação/metabolismo , Inflamação/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Músculo Esquelético/metabolismo , Músculo Esquelético/patologia , Traumatismo por Reperfusão/metabolismo , Traumatismo por Reperfusão/patologia , Fator de Necrose Tumoral alfa/metabolismo
19.
Life Sci ; 228: 295-304, 2019 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-31075232

RESUMO

AIMS: To investigate the protective effects of downregulating ETaR expression on renal ischemia reperfusion injury (IRI). MAIN METHODS: The renal IRI model was generated by clamping the left renal artery for 60 min followed by nephrectomy of the right kidney. ETaR siRNA were perfused through the renal artery during ischemia. HE staining was performed to assess histological injury. PCR was performed to determine the expression of NF-κb, TNF-α, IFN-γ, IL-6 and TGF-ß. ELISA was used to determine the levels of ET-1, TGF-ß and eNOS. The level of nitric oxide (NO) was tested by the NO detection kit. The expression of PI3K, Akt, sGC and PKG were evaluated by western blot. KEY FINDINGS: ETaR siRNA treatment reduced the levels of serum creatinine and urea nitrogen, decreased the number of apoptotic cells, and ameliorated histological damage after IRI. PCR results demonstrated that IRI increased mRNA levels of inflammatory factors, which were inhibited by ETaR siRNA treatment. ELISA result showed that ETaR siRNA decreased the levels of ET-1, TGF-ß and eNOS in the renal tissues after IRI. Western blot results demonstrated that ETaR siRNA activated the PI3K/Akt and sGC/PKG signaling pathway. Conversely, the NOS inhibitor, L-NAME, reversed the effects of ETaR siRNA treatment. SIGNIFICANCE: ETaR siRNA treatment inhibited inflammatory response and improved renal function after renal IRI. The underlying mechanisms of ETaR siRNA treatment may be through increasing eNOS activity through PI3K/Akt signaling, which subsequently increased NO production. The increased NO reduces the expression of ET-1 by inhibiting transcription of ET-1-associated genes via the sGC/PKG signaling pathway.


Assuntos
Rim/patologia , Óxido Nítrico/metabolismo , RNA Interferente Pequeno/uso terapêutico , Terapêutica com RNAi , Receptor de Endotelina A/genética , Traumatismo por Reperfusão/genética , Traumatismo por Reperfusão/terapia , Animais , Apoptose , Rim/metabolismo , Masculino , Óxido Nítrico Sintase Tipo III/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , RNA Interferente Pequeno/genética , Terapêutica com RNAi/métodos , Ratos Sprague-Dawley , Receptor de Endotelina A/metabolismo , Traumatismo por Reperfusão/metabolismo , Traumatismo por Reperfusão/patologia , Transdução de Sinais
20.
Mol Immunol ; 112: 22-29, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31075559

RESUMO

Hepatic ischemia-reperfusion (I/R) injury frequently occurs after liver transplantation, stroke, and trauma, resulting in organ dysfunction and failure. Hepatocyte apoptosis and inflammation are identified as the hallmarks of liver I/R injury. Long non-coding RNA (lncRNA) metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) is induced following hypoxia or ischemic stimulation, and exerts the contradictory roles in various injury progression. However, its role and mechanism lying beneath hepatic I/R remains ill defined. In this study, elevation of MALAT1 expression was corroborated in human hepatocytes under hypoxia/reoxygenation (H/R)H/R condition. Of interest, depression of MALAT1 blunted H/R-inhibited cell viability, and counteracted lactate dehydrogenase (LDH) and malondialdehyde release. Additionally, MALAT1 cessation antagonized H/R-evoked cell apoptosis and caspase-3 activity. Simultaneously, the increased inflammatory reaction triggered by H/R stimulation was also abrogated following MALAT1 suppression by reducing pro-inflammatory cytokine transcripts and productions including IL-1ß and TNF-α. Mechanistically, H/R exposure activated the pathway of high-mobility group box1 (HMGB1)-TLR4, which was muted after MALAT1 inhibition. More importantly, elevation of HMGB1 reversed MALAT1 down-regulation-mediated inhibition in cell injury and inflammation. Moreover, blocking the TLR4 signaling also ameliorated H/R-evoked hepatocyte apoptosis and inflammatory response. Consequently, these data suggest that MALAT1 may aggravate hepatic I/R injury by regulating the HMGB1-TLR4-triggered cell apoptosis and inflammation, implying a promising therapeutic strategy to fight liver I/R injury.


Assuntos
Proteína HMGB1/metabolismo , Hepatócitos/metabolismo , Hipóxia/metabolismo , Inflamação/metabolismo , RNA Longo não Codificante/metabolismo , Receptor 4 Toll-Like/metabolismo , Apoptose/fisiologia , Proteínas Reguladoras de Apoptose/metabolismo , Linhagem Celular , Citocinas/metabolismo , Regulação para Baixo/fisiologia , Humanos , Interleucina-1beta/metabolismo , Fígado/metabolismo , NF-kappa B/metabolismo , Traumatismo por Reperfusão/metabolismo , Transdução de Sinais/fisiologia , Fator de Necrose Tumoral alfa/metabolismo
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