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Sevoflurane (Sev) is a commonly used anesthetic in hospitals that can cause neurotoxicity. Postoperative cognitive dysfunction (POCD) is a common clinical problem induced by some anesthetics. However, the exact mechanism of neurotoxicity induced by Sev is unclear. Here we studied a new mechanism of POCD induced by Sev. We treated 15-month-old mice with 2% Sev for 6 hours, and we had found that Sev causes POCD. Using isobaric tags for relative and absolute quantitation (iTRAQ), we found that the transporter and the metabolism of carbohydrates and inorganic ions were involved in the cognitive impairment induced by Sev. Using synchrotron radiation micro-X-ray fluorescence (μ-XRF), we showed that Sev caused the iron overload in the brain of 15-month-old mice. Subsequently, excessive iron led to oxidative stress and impaired mitochondrial function that further led to glucose metabolism disorder and reduced ATP production by regulating the expression of key enzyme genes or proteins including G6Pase, Pck1, and Cs. Meanwhile, Sev also inhibited the oxygen consumption rate and glucose absorption by downregulating the expression of glucose transporter 1 in cerebral vascular endothelial cells. The cross-dysfunction of iron and glucose metabolism caused the apoptosis in the cortex and hippocampus through Bcl2/Bax pathway. In conclusion, the data here showed a new mechanism that Sev caused apoptosis by cross-dysregulation of iron and glucose metabolism and induced energy stress in mice. Maintaining iron and glucose metabolism homeostasis may play an important role in cognitive impairment induced by Sev.

Parkinson’s disease (PD) is a progressive nervous system disorder. Until now, the molecular mechanism of its occurrence is not fully understood. Paraquat (PQ) was identified as a neurotoxicant and is linked to increased PD risk and PD-like neuropathology. Ferroptosis is recognized as a new form of regulated cell death. Here, we revealed a new underlying mechanism by which ferritinophagy-mediated ferroptosis is involved in PD induced by PQ. The effect of PQ on movement injury in mice was investigated by the bar fatigue and pole-climbing test. SH-SY5Y human neuroblastoma cells were used to evaluate the mechanism of ferroptosis. Our results showed that PQ induced movement injury by causing the decrease in tyrosine hydroxylase in mice. In vitro, PQ significantly caused the iron accumulation in cytoplasm and mitochondria through ferritinophagy pathway induced by NCOA4. Iron overload initiated lipid peroxidation through 12Lox, further inducing ferroptosis by producing lipid ROS. PQ downregulated SLC7A11 and GPX4 expression and upregulated Cox2 expression significantly, which were important markers in ferroptosis. Fer-1, an inhibitor of ferroptosis, could significantly ameliorate the ferroptosis induced by PQ. Meanwhile, Bcl2, Bax, and p-38 were involved in apoptosis induced by PQ. In conclusion, ferritinophagy-mediated ferroptosis pathway played an important role in PD occurrence. Bcl2/Bax and P-p38/p38 pathways mediated the cross-talk between ferroptosis and apoptosis induced by PQ. These data further demonstrated the complexity of PD occurrence. The inhibition of the ferroptosis and apoptosis together may be a new strategy for the prevention of neurotoxicity or PD in the future.

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Objectives Essential hypertensive patients with elevated homocysteine in plasma, which is called H-type hypertension, has a high incidence in Chinese population; Though a point mutation in methylenetetrahydrofolate reductase (MTHFR C677T) has been associated with increased plasma homocysteine (Hcy) levels, pathogenetic mechanisms involved are still a matter of debate. Therefore, our study was designed to explore the influence of genetic and lifestyle factors on H-type hypertension risk in the rural area of Anqing, China. Methods We used PCR-restriction fragment length polymorphism (PCR-RFLP) to determine C677T polymorphism in MTHFR gene in hypertension patients. Then based on the three types of MTHFR genotypes (CC, CT&TT), we enrolled 241 cases of hypertension in total and each genotype had nearly equal number patients (n=76, 85&80). Then we examined the plasma Hcy level with HPLC, measured blood pressure with Standard Desktop mercury Sphygmomanometer and calculated the body mass index (BMI). A questionnaire was used to collect the lifestyle information of cigarette and/or alcohol consumption status. Results 1. The average level of plasma Hcy was significantly higher in male than female (12.8±7.2 umol/l vs 9.7±4.7 umol/l, p<0.01); Patients with TT genotype had a significantly higher level of Hcy than those with CC or CT genotypes ( p<0.01). 2. The proportion of H-type hypertension in all the hypertension cases was up to 44.4%. H-type hypertension was much more common in male patients, which was 60.3% compared to 29.6% in female. The risk of H-type hypertension in TT genotype was pronouncedly higher than in CT and CC genotypes (OR 3.2, 95% CI 1.7 to 5.8, p<0.01). 3. Multiple linear/logistic regression analysis with adjustment by multivariate didn't identify marked relevance of Hcy level or H-type hypertension risk with other environmental variables including age, alcohol drinking, cigarette smoking, BMI, and baseline DBP and SBP. Conclusions Our present study suggested that the MTHFR C677T genetic variant may be associated with a high risk of H-type hypertension, but not for drinking, smoking, age, BMI and blood pressure, in rural community of Anqing, China.