RESUMEN
OBJECTIVE: To investigate the cerebroprotective effects of leptin in vitro and in vivo via the Janus kinase-2 (JAK2)/transcription factor signal transducer and activators of transcription-3 (STAT3) pathway and leptin receptors (LEPR). METHODS: The study used the cellular oxygen-glucose deprivation (OGD) model in PC12 cells and the middle cerebral artery occlusion (MCAO) rat model of cerebral ischaemia-reperfusion injury (CIRI) to assess changes in gene expression and protein levels following leptin pretreatment. The methylated DNA immunoprecipitation (MeDIP) assay measured DNA methylation levels. RESULTS: The optimal leptin concentration for exerting neuroprotective effects against ischaemia-reperfusion injury in PC12 cells was 200 ng/ml in vitro, but excessive leptin diminished this effect. Leptin pretreatment in the MCAO rat model demonstrated a similar effect to previously reported leptin administration post-CIRI. In addition to regulating the expression of inflammation-related cytokines, Western blot analysis showed that leptin pretreatment upregulated BCL-2 and downregulated caspase 3 levels. The MeDIP analysis demonstrated that DNA methylation regulated LEPR gene expression in the MCAO rat model when leptin pretreatment was used. CONCLUSION: Exogenous leptin might bind to extra-activated LEPR by reducing the methylation level of the LEPR gene promoter region, which leads to an increase in phosphorylated JAK2/STAT3 and apoptotic signalling pathways.
Asunto(s)
Metilación de ADN , Janus Quinasa 2 , Leptina , Ratas Sprague-Dawley , Receptores de Leptina , Daño por Reperfusión , Factor de Transcripción STAT3 , Transducción de Señal , Animales , Daño por Reperfusión/metabolismo , Daño por Reperfusión/patología , Janus Quinasa 2/metabolismo , Ratas , Factor de Transcripción STAT3/metabolismo , Transducción de Señal/efectos de los fármacos , Receptores de Leptina/metabolismo , Receptores de Leptina/genética , Masculino , Leptina/metabolismo , Células PC12 , Infarto de la Arteria Cerebral Media/metabolismo , Infarto de la Arteria Cerebral Media/patología , Modelos Animales de Enfermedad , Fármacos Neuroprotectores/farmacología , Apoptosis/efectos de los fármacos , Isquemia Encefálica/metabolismo , Isquemia Encefálica/patología , Caspasa 3/metabolismoRESUMEN
Recent studies have demonstrated that hyperglycemia may result in a poor prognosis following aneurysmal subarachnoid hemorrhage (aSAH). However, the association between hyperglycemia and the clinical outcome of aSAH has not been clearly established thus far. Therefore, we performed a systematic review and meta-analysis to investigate the association between hyperglycemia and the development of aSAH. We completed a literature search in four databases (PubMed, EMBASE, Cochrane Library, and Web of Science) up to November 1, 2021, including all eligible studies investigating the prognostic value of hyperglycemia in patients with aSAH. We performed a quality assessment of included studies using the Newcastle-Ottawa Quality Assessment Scale. The pooled odds ratios (ORs) with corresponding 95% confidence intervals (CIs) were calculated to assess the association of hyperglycemia in aneurysmal subarachnoid hemorrhage. A total of 35 studies with 11,519 patients were finally included in the meta-analysis. Nineteen studies reported the association between hyperglycemia and poor outcome, 12 studies reported the association between hyperglycemia and all-cause mortality, 7 studies reported the association between hyperglycemia and cerebral vasospasm, and 9 studies reported the association between hyperglycemia and cerebral infarction. The pooled data of these studies suggested that hyperglycemia was significantly associated with poor functional outcomes (odds ratio [OR], 1.29; 95% confidence interval [CI], 1.17-1.42; P < 0.00001; I2 = 83%), all-cause mortality (OR, 1.02; 95% CI, 1.01-1.04; P = 0.0006; I2 = 89%), cerebral vasospasm (OR, 1.02; 95% CI, 1.01-1.02; P = 0.0002; I2 = 35%), and cerebral infarction (OR, 1.16; 95% CI, 1.09-1.23; P < 0.00001; I2 = 10%) in aSAH patients. These findings suggested that assessing for hyperglycemia at admission may help clinicians to identify critically ill patients and complete patient stratification early, which may achieve better management and improve the prognosis of patients with aSAH.