RESUMEN
Neonatal hypoxic-ischemic encephalopathy (HIE) is a critical condition characterized by significant brain damage due to insufficient blood flow and oxygen delivery at birth, leading to high rates of neonatal mortality and long-term neurological deficits worldwide. 2,3-Diphosphoglyceric acid (2,3-DPG), a small molecule metabolite prevalent in erythrocytes, plays an important role in regulating oxygen delivery, but its potential neuroprotective role in hypoxic-ischemic brain damage (HIBD) has yet to be fully elucidated. Our research reveals that the administration of 2,3-DPG effectively reduces neuron damage caused by hypoxia-ischemia (HI) both in vitro and in vivo. We observed a notable decrease in HI-induced neuronal cell apoptosis, attributed to the downregulation of Bax and cleaved-caspase 3, alongside an upregulation of Bcl-2 expression. Furthermore, 2,3-DPG significantly alleviates oxidative stress and mitochondrial damage induced by oxygen-glucose deprivation/reperfusion (OGD/R). The administration of 2,3-DPG in rats subjected to HIBD resulted in a marked reduction in brain edema and infarct volume, achieved through the suppression of neuronal apoptosis and neuroinflammation. Using RNA-seq analysis, we validated that 2,3-DPG offers protection against neuronal apoptosis under HI conditions by modulating the p38 MAPK pathway. These insights indicated that 2,3-DPG might act as a promising novel therapeutic candidate for HIE.
Asunto(s)
Apoptosis , Hipoxia-Isquemia Encefálica , Proteínas Quinasas p38 Activadas por Mitógenos , Animales , Hipoxia-Isquemia Encefálica/metabolismo , Hipoxia-Isquemia Encefálica/tratamiento farmacológico , Hipoxia-Isquemia Encefálica/patología , Proteínas Quinasas p38 Activadas por Mitógenos/metabolismo , Ratas , Apoptosis/efectos de los fármacos , Estrés Oxidativo/efectos de los fármacos , Fármacos Neuroprotectores/farmacología , Fármacos Neuroprotectores/uso terapéutico , Neuronas/metabolismo , Neuronas/efectos de los fármacos , Neuronas/patología , Ratas Sprague-Dawley , Masculino , Mitocondrias/metabolismo , Mitocondrias/efectos de los fármacosRESUMEN
Hypoxic-ischemic brain damage (HIBD) is a cerebral injury resulting from the combination of ischemia and hypoxia in neonatal brain tissue. Presently, there exists no efficacious remedy for HIBD. A mounting body of evidence indicates that dynamic metabolites formed during metabolic procedures assume a vital role in neuronal maturation and recuperation. However, it remains unclear whether any endogenous metabolites are involved in the pathogenesis of HIBD. Here, an untargeted metabolomics analysis was conducted by gas chromatography-mass spectrometry and liquid chromatography-mass spectrometry (GC/LC-MS) in OGD/R (oxygen-glucose deprivation/reoxygenation)-induced HT-22 cells. We observed that ferroptosis signaling plays an essential role in HI-induced neuronal injury. Interestingly, we also found that the differentially expressed metabolite, 2-phosphoglyceric acid, significantly improved the neuronal cell survival of OGD/R HT-22 cells by inhibiting ferroptosis. Moreover, 2-phosphoglyceric acid effectively rescued the cell activity of HT-22 cells treated with the ferroptosis inducer RSL-3. Furthermore, 2-phosphoglyceric acid alleviated cerebral infarction and reduced HIBD-induced neuronal cell loss of the central nervous system in neonatal rats by regulating GPX4 expression. Taken together, we found that 2-phosphoglyceric acid, which was downregulated in HT-22 cells induced by OGD/R, exerted neuronal protective effects on OGD/R-treated HT-22 cells and HIBD-induced neonatal rats by inhibiting hypoxic-ischemic-induced ferroptosis through the regulation of the GPX4/ACSL4 axis.
Asunto(s)
Hipoxia-Isquemia Encefálica , Ratas , Animales , Animales Recién Nacidos , Ratas Sprague-Dawley , Hipoxia-Isquemia Encefálica/metabolismo , Hipoxia/metabolismo , Encéfalo/metabolismoRESUMEN
BACKGROUND: Patient-focused evaluation of postoperative recover has been recognized as one of the most important concerns in postoperative medicine. Previous studies have shown that the Quality of Recovery-40 (QoR-40) Questionnaire can be used to accurately assess the quality of recovery from surgery. During thyroid surgery using intraoperative neuromonitoring (IONM) technology, the strategy of low dose of muscle relaxant, intubation of different endotracheal tubes and electrical stimulation on vocal cord are applied. Its still unknown if these performances would affect patients' postoperative recovery in thyroid surgery patients. METHODS: 82 patients were randomly assigned to the neuromonitoring group (NEURO Group) and the control group (CON Group). In the CON Group, rocuronium (0.6 mg / kg) was given for intubation and additional dose was injected if needed, while in the NEURO Group, only rocuronium (0.3 mg / kg) was given when induction. The primary outcome is the QoR-40 scores on postoperative day 1 (POD1) and postoperative day 3 (POD3). Other parameters, such as postoperative nausea or vomiting (PONV) and medical cost were also recorded. RESULTS: One subject in each group was excluded, leaving 80 for analysis. In the NEURO Group, the global QoR-40 score, emotional state, physical comfort, physical independence and pain were significantly lower both on POD1 and POD3 (P<0.05). Patients in the NEURO Group had a higher incidence of PONV (P<0.05) and medical expense (P<0.05). CONCLUSIONS: After thyroidectomy, the patients using IONM suffer worse quality of recovery, more risk of PONV and increased medical expense.
Asunto(s)
Náusea y Vómito Posoperatorios , Glándula Tiroides , Humanos , Rocuronio , Tiroidectomía/efectos adversos , TecnologíaRESUMEN
Hypoxic-ischemic encephalopathy (HIE) is an important factor leading to permanent damage of central nervous system (CNS) and even neonatal death. Long non-coding RNAs (lncRNAs) has been shown to get involved in the pathogenesis of nervous system diseases. LINC00938 is an intergenic lncRNA which is reported to be involved in neurodegenerative disease. However, the potential role of LINC00938 in nerve injury of neonatal HIE is undetermined. Here, we found that the expression of LINC00938 in the whole blood of neonates with HIE was downregulated compared with the non-HIE group. Functional study revealed that the expression of LINC00938 was significantly decreased in oxygen-glucose deprivation (OGD)-induced SH-SY5Y. Knockdown of LINC00938 induced the neural cell apoptosis by increased the protein level of Bax, Cleaved-Caspase3 and decreased the expression of Bcl-2. In addition, overexpression of LINC00938 prevented the apoptosis of SH-SY5Y from OGD injury. RNA-seq analysis showed that MAPK signaling was involved in the anti-apoptosis function of LINC00938. LINC00938 knockdown induced the activation of c-Jun-N-terminal kinase (JNK), p38 mitogen-activated protein kinase, and inhibited the activation of ERK signaling. However, LINC00938 play neuroprotective role in OGD-induced SH-SY5Y by suppression the phosphorylation of JNK and p38 MAPK rather than regulation of ERK signaling pathway. Further analyses illustrated that the cell apoptosis of neuronal cell was dependent on the elevation of reactive oxygen species (ROS) and result in mitochondria dysfunction in LINC00938 knockdown SH-SY5Y. Pretreated with ROS inhibitor N-acetylcysteine amide (NACA) dramatically suppressed LINC00938 knockdown induced oxidative stress and mitochondria dysfunction which induced cell apoptosis. In addition, NACA treatment significantly reduced the expression of p-JNK and p-p38 in OGD-induced SH-SY5Y. Furthermore, overexpression of LINC00938 displayed a notably neuroprotective effect by suppress central nervous system cell apoptosis via alleviating oxidative stress in CoCl2-induced hypoxic HIE model of zebrafish. Taken together, these results suggested that LINC00938 can act as a neuroprotective factor to inhibit oxidative stress and apoptosis of CNS under HIE conditions.