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1.
Int Immunopharmacol ; 134: 112257, 2024 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-38759366

RESUMO

BACKGROUND: Hypoxic-ischemic encephalopathy (HIE) is a major contributor to neonatal mortality and neurodevelopmental disorders, but currently there is no effective therapy drug for HIE. Mitochondrial dysfunction plays a pivotal role in hypoxic-ischemic brain damage(HIBD). Menaquinone-4 (MK-4), a subtype of vitamin K2 prevalent in the brain, has been shown to enhance mitochondrial function and exhibit protective effects against ischemia-reperfusion injury. However, the impact and underlying molecular mechanism of MK-4 in HIE have not been fully elucidated. METHODS: In this study, we established the neonatal rats HIBD model in vivo and oxygen-glucose deprivation and reperfusion (OGD/R) of primary neurons in vitro to explore the neuroprotective effects of MK-4 on HI damage, and illuminate the potential mechanism. RESULTS: Our findings revealed that MK-4 ameliorated mitochondrial dysfunction, reduced oxidative stress, and prevented HI-induced neuronal apoptosis by activating the Sirt1-PGC-1α-TFAM signaling pathway through Sirt1 mediation. Importantly, these protective effects were partially reversed by EX-527, a Sirt1 inhibitor. CONCLUSION: Our study elucidated the potential therapeutic mechanism of MK-4 in neonatal HIE, suggesting its viability as an agent for enhancing recovery from HI-induced cerebral damage in newborns. Further exploration into MK-4 could lead to novel interventions for HIE therapy.


Assuntos
Animais Recém-Nascidos , Apoptose , Hipóxia-Isquemia Encefálica , Mitocôndrias , Neurônios , Fármacos Neuroprotetores , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo , Ratos Sprague-Dawley , Transdução de Sinais , Sirtuína 1 , Vitamina K 2 , Animais , Sirtuína 1/metabolismo , Hipóxia-Isquemia Encefálica/tratamento farmacológico , Hipóxia-Isquemia Encefálica/metabolismo , Hipóxia-Isquemia Encefálica/patologia , Transdução de Sinais/efeitos dos fármacos , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Vitamina K 2/análogos & derivados , Vitamina K 2/farmacologia , Vitamina K 2/uso terapêutico , Fármacos Neuroprotetores/farmacologia , Fármacos Neuroprotetores/uso terapêutico , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/metabolismo , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/genética , Ratos , Neurônios/efeitos dos fármacos , Neurônios/patologia , Apoptose/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Células Cultivadas , Modelos Animais de Doenças , Fatores de Transcrição/metabolismo , Encéfalo/efeitos dos fármacos , Encéfalo/patologia , Encéfalo/metabolismo
2.
Int Immunopharmacol ; 124(Pt B): 111030, 2023 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-37844463

RESUMO

Hypoxic-ischemic encephalopathy (HIE) is a perinatal brain disease caused by hypoxia in neonates. It is one of the leading causes of neonatal death in the perinatal period, as well as disability beyond the neonatal period. Due to the lack of a unified and comprehensive treatment strategy for HIE, research into its pathogenesis is essential. Diallyl disulfide (DADS) is an allicin extract, with detoxifying, antibacterial, and cardiovascular disease protective effects. This study aimed to determine whether DADS can alleviate HIE induced brain damage in rats and oxygen-glucose deprivation (OGD)-induced pyroptosis in PC12 cells, as well as whether it can inhibit pyroptosis via the NLRP3/Caspase-1/IL-1ß signaling pathway. In vivo, DADS significantly reduced the cerebral infarction volume, alleviated inflammatory reaction, reduced astrocyte activation, promoted tissue structure recovery, improved pyroptosis caused by HIE and improved the prognosis following HI injury. In vitro findings indicated that DADS increased cell activity, decreased LDH activity and reduced the expression of pyroptosis-related proteins, including IL-1ß, IL-18, and certain inflammatory factors in PC12 cells caused by OGD. Mechanistically, DADS inhibited pyroptosis and protected against HIE via the NLRP3/Caspase-1/IL-1ß pathway. The specific inhibitor of caspase-1, VX-765, inhibited caspase-1 activation, and IL-1ß expression was determined. Additionally, the overexpression of NLRP3 reversed the protective effect of allicin against OGD-induced pyroptosis. In conclusion, these findings demonstrated that DADS inhibits the NLRP3/Caspase-1/IL-1ß signaling pathway and decreases HI brain damage.


Assuntos
Hipóxia-Isquemia Encefálica , Piroptose , Gravidez , Feminino , Ratos , Animais , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Animais Recém-Nascidos , Caspase 1/metabolismo , Hipóxia-Isquemia Encefálica/patologia , Oxigênio/farmacologia , Encéfalo/metabolismo , Transdução de Sinais , Inflamassomos/metabolismo
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