Hypoxia-triggered O-GlcNAcylation in the brain drives the glutamate-glutamine cycle and reduces sensitivity to sevoflurane in mice.

BACKGROUND: Hypersensitivity to general anaesthetics predicts adverse postoperative outcomes in patients. Hypoxia exerts extensive pathophysiological effects on the brain; however, whether hypoxia influences sevoflurane sensitivity and its underlying mechanisms remain poorly understood. METHODS: Mice were acclimated to hypoxia (oxygen 10% for 8 h day-1) for 28 days and anaesthetised with sevoflurane; the effective concentrations for 50% of the animals (EC50) showing loss of righting reflex (LORR) and loss of tail-pinch withdrawal response (LTWR) were determined. Positron emission tomography-computed tomography, O-glycoproteomics, seahorse analysis, carbon-13 tracing, site-specific mutagenesis, and electrophysiological techniques were performed to explore the underlying mechanisms. RESULTS: Compared with the control group, the hypoxia-acclimated mice required higher concentrations of sevoflurane to present LORR and LTWR (EC50LORR: 1.61 [0.03]% vs 1.46 [0.04]%, P<0.01; EC50LTWR: 2.46 [0.14]% vs 2.22 [0.06]%, P<0.01). Hypoxia-induced reduction in sevoflurane sensitivity was correlated with elevation of protein O-linked N-acetylglucosamine (O-GlcNAc) modification in brain, especially in the thalamus, and could be abolished by 6-diazo-5-oxo-l-norleucine, a glutamine fructose-6-phosphate amidotransferase inhibitor, and mimicked by thiamet-G, a selective O-GlcNAcase inhibitor. Mechanistically, O-GlcNAcylation drives de novo synthesis of glutamine from glucose in astrocytes and promotes the glutamate-glutamine cycle, partially via glycolytic flux and activation of glutamine synthetase. CONCLUSIONS: Intermittent hypoxia exposure decreased mouse sensitivity to sevoflurane anaesthesia through enhanced O-GlcNAc-dependent modulation of the glutamate-glutamine cycle in the brain.

Transplantation of bone marrow-derived mesenchymal stem cells (BMSCs) improves brain ischemia-induced pulmonary injury in rats associated to TNF-α expression.

BACKGROUND: Bone marrow mesenchymal stem cell (BMSCs)-based therapy seems to be a promising treatment for acute lung injury, but the therapeutic effects of BMSCs transplantation on acute lung injury induced by brain ischemia and the mechanisms have not been totally elucidated. This study explores the effects of transplantation of BMSCs on acute lung injury induced by focal cerebral ischemia and investigates the underlying mechanism. METHODS: Acute lung injury model was induced by middle cerebral artery occlusion (MCAO). BMSCs (with concentration of 1 × 10(6)/ml) were transplanted into host through tail vein 1 day after MCAO. Then, the survival, proliferation and migration of BMSCs in lung were observed at 4 days after transplantation, and histology observation and lung function were assessed for 7 days. Meanwhile, in situ hybridization (ISH), qRT-PCR and western blotting were employed to detect the expression of TNF-α in lung. RESULTS: Neurobehavioral deficits and acute lung injury could be seen in brain ischemia rats. Implanted BMSCs could survive in the lung, and relieve pulmonary edema, improve lung function, as well as down regulate TNF-α expression. CONCLUSIONS: The grafted BMSCs can survive and migrate widespread in lung and ameliorate lung injury induced by focal cerebral ischemia in the MCAO rat models. The underlying molecular mechanism, at least partially, is related to the suppression of TNF-α.

Stratified analysis of the association between anti-obesity medications and digestive adverse events: a real-world study based on the FDA adverse event reporting system database.

BACKGROUND: Numerous digestive system adverse events (dsAEs) have been observed during the use of anti-obesity medications (AOMs), leading to concerns about the safety of these medications. However, most current studies are limited to the association of one class of drugs with specific digestive disorders, and there is no cascading analysis of AOMs in the digestive system. This study aims to use data from the United States Food and Drug Administration Adverse Event Reporting System (FAERS) for a stratified analysis of the reported associations between AOMs and dsAEs. METHODS: We analyzed adverse event reports submitted to FAERS between January 2015 and December 2023 related to obesity treatment. It is important to note that FAERS data cannot establish causality or incidence rates. Pharmacovigilance (PV) signals were detected by disproportionate analyses through proportionate reporting ratio (PRR), reporting odds ratios (ROR), and information components (IC) to detect dsAEs associated with AOMs. Reporting rates, severity, and response outcomes of digestive adverse events were compared across AOMs by multivariate logistic regression analysis. RESULTS: Among 34,396 adverse events (AEs) related to obesity treatment, 8844 dsAEs were analyzed. Comparing with semaglutide and liraglutide, tirzepatide exhibited fewer reported dsAEs while semaglutide and liraglutide showed a high correlation with non-lethal pancreatitis reports. Bupropion-naltrexone (31.65%) reported the highest number of dsAEs, and a PV signal was detected in mouth and lips AEs (ROR = 2.97, 95% CI: 2.42-3.6). Orlistat (ROR = 3.30, 95% CI: 3.08-3.55) exhibited the highest association with gastrointestinal AEs compared to other AOMs. PV signal for hepatobiliary AEs (ROR = 6.13, 95% CI: 3.45-10.88) with phentermine-topiramate still needs further clarification. CONCLUSIONS: Tirzepatide may be considered for patients with a history of digestive system disease or an elevated risk of pancreatitis based on the pattern of reported dsAEs. Caution is needed for the orofacial AEs when using bupropion-naltrexone. Orlistat has a higher reporting rate of gastrointestinal AEs, but these events are typically less severe. Phentermine-topiramate's association with liver impairment requires further clinical investigation. This article provides insights into the reported associations between AOMs and dsAEs, which may aid clinicians in making more informed decisions about individualizing medication and managing potential adverse events.

MicroRNA-127 targeting of mitoNEET inhibits neurite outgrowth, induces cell apoptosis and contributes to physiological dysfunction after spinal cord transection.

Neuroregeneration and apoptosis are two important pathophysiologic changes after spinal cord injury (SCI), but their underlying mechanisms remain unclear. MicroRNAs (miRNAs) play a crucial role in the regulation of neuroregeneration and neuronal apoptosis, research areas that have been greatly expanded in recent years. Here, using miRNA arrays to profile miRNA transcriptomes, we demonstrated that miR-127-3p was significantly down-regulated after spinal cord transection (SCT). Then, bioinformatics analyses and experimental detection showed that miR-127-3p exhibited specific effects on the regulation of neurite outgrowth and the induction of neuronal apoptosis by regulating the expression of the mitochondrial membrane protein mitoNEET. Moreover, knockdown of MitoNEET leaded to neuronal loss and apoptosis in primary cultured spinal neurons. This study therefore revealed that miR-127-3p, which targets mitoNEET, plays a vital role in regulating neurite outgrowth and neuronal apoptosis after SCT. Thus, modificatioin of the mitoNEET expression, such as mitoNEET activition may provide a new strategy for the treatment of SCI in preclinical trials.

Role of endogenous PDGF-BB in cultured cardiomyocytes exposed to hypoxia.

Platelet-derived growth factor-BB (PDGF-BB) plays a critical role in cell proliferation, angiogenesis and fibrosis. However, its exact role in cardiomyocytes exposed to hypoxia is not well known. This study was therefore designed to detect whether PDGF-BB expression was changed in a hypoxic condition, then the possible role of endogenous PDGF-BB in cardiomyocytes was explored, with interference RNA in a lentiviral vector ex vivo. The results showed that cultured cardiomyocytes exhibited an optimal proliferation from 3 to 10 days. However, LDH level was significantly increased but the heart rhythm was not altered in cardiomyocytes exposed to hypoxia for 24 hours. PDGF-BB expression was substantially upregulated in hypoxic cardiomyocytes. In order to know the role of PDGF-BB, we performed PDGF-BB knockdown in cultured cardiomyocytes. The number of apoptotic cells and the level of LDH were significantly increased but the beat rhythm was reduced in cardiomyocytes with PDGF-BB knockdown. These findings suggest that endogenous PDGF-BB exerts a crucial protective effect to cultured cardiomyocytes exposed to hypoxia.