Optimized integration of metabolomics and lipidomics reveals brain region-specific changes of oxidative stress and neuroinflammation in type 1 diabetic mice with cognitive decline.

INTRODUCTION: Type 1 diabetes (T1D) causes cognitive decline and has been associated with brain metabolic disorders, but its potential molecular mechanisms remain unclear. OBJECTIVES: The purpose of this study was to explore the molecular mechanisms underlying T1D-induced cognitive impairment using metabolomics and lipidomics. METHODS: We developed an optimized integration approach of metabolomics and lipidomics for brain tissue based on UPLC-Q-TOF-MS and analyzed a comprehensive characterization of metabolite and lipid profiles in the hippocampus and frontal cortex of T1D male mice with cognitive decline (T1DCD) and age-matched control (CONT) mice. RESULTS: The results show that T1DCD mice had brain metabolic disorders in a region-specific manner relative to CONT mice, and the frontal cortex exhibited a higher lipid peroxidation than the hippocampus in T1DCD mice. Based on metabolic changes, we found that microglia was activated under diabetic condition and thereby promoted oxidative stress and neuroinflammation, leading to neuronal injury, and this event was more pronounced in the frontal cortex than the hippocampus. CONCLUSION: Our results suggest that brain region-specific shifts in oxidative stress and neuroinflammation may contribute to diabetic cognitive decline, and the frontal cortex could be the more vulnerable brain region than the hippocampus.

Sex-dependent effects on the gut microbiota and host metabolome in type 1 diabetic mice.

Sexual dimorphism exists in the onset and development of type 1 diabetes (T1D), but its potential pathological mechanism is poorly understood. In the present study, we examined sex-specific changes in the gut microbiome and host metabolome of T1D mice via 16S rRNA gene sequencing and nuclear magnetic resonance (NMR)-based metabolomics approach, and aimed to investigate potential mechanism of the gut microbiota-host metabolic interaction in the sexual dimorphism of T1D. Our results demonstrate that female mice had a greater shift in the gut microbiota than male mice during the development of T1D; however, host metabolome was more susceptible to T1D in male mice. The correlation network analysis indicates that T1D-induced host metabolic changes may be regulated by the gut microbiota in a sex-specific manner, mainly involving short-chain fatty acids (SCFAs) metabolism, energy metabolism, amino acid metabolism, and choline metabolism. Therefore, our study suggests that sex-dependent "gut microbiota-host metabolism axis" may be implicated in the sexual dimorphism of T1D, and the link between microbes and metabolites might contribute to the prevention and treatment of T1D.

ß-carotene provides neuro protection after experimental traumatic brain injury via the Nrf2-ARE pathway.

We investigate whether ß-carotene, a known natural antioxidant, can reduce oxidative stress induced by traumatic brain injury. In addition, we investigated the underlying mechanism of traumatic brain injury focusing on the NF-E2-related factor (Nrf2) pathway. A controlled cortical impact model was used to mimic traumatic brain injury. Using this model, we evaluated brain edema, lesion volume, neurologic deficits, reactive oxygen species, and the expression of Nrf2-related protein markers. The results of our study demonstrated that cognitive performance and neural functions were improved with ß-carotene administration. In addition, ß-carotene reduced brain edema and reactive oxygen species levels after traumatic brain injury. Nrf2 nuclear accumulation was increased and was accompanied by decreased Keap1 expression. The expression of quinone oxidoreductase 1, a target gene of the Nrf2 signaling pathway was increased. However, lesion volume was not significantly reduced after ß-carotene treatment. Taken together, our data demonstrated that ß-carotene administration was neuroprotective and alleviated oxidative stress by modulating the Nrf2/Keap1- mediated antioxidant pathway in the traumatic brain injury model.