Objectives: Endothelial-to-mesenchymal transition (EndoMT) is a significant biological phenomenon wherein endothelial cells undergo a loss of their endothelial traits and progressively acquire mesenchymal characteristics. Consequently, this transformation leads to both a compromised ability to maintain lumen permeability and alterations in vascular structure, which hampers the preservation of blood-brain barrier integrity. This study aimed to investigate inflammation-induced EndoMT and its etiology, with the goal of impeding the infiltration of peripheral inflammation into the central nervous system. Materials and Methods: Lipolysaccharide (LPS) was administered intraperitoneally to mice several times to establish a chronic inflammatory model. A cellular inflammatory model was established by LPS in human brain microvascular endothelial cells (HBMECs). The mRNA expressions of inflammatory cytokines interleukin-1β (IL-1β) and IL-6 were detected by real-time polymerase chain reaction (PCR). Immunofluorescence staining of platelet endothelial cell adhesion molecule-1 (CD31) and alpha smooth muscle actin (α-SMA) was conducted to assess the level of EndoMT. The expression levels of Occludin, zona occludens protein 1 (ZO-1), Sestrin2, microtubule-associated protein1 light chain 3 (LC3) and inducible nitric oxide synthase (iNOS) were detected by western blotting. Results: LPS treatment induced the downregulation of ZO-1 and Occludin, which was accompanied by the elevated expressions of iNOS, α-SMA, Sestrin2 and LC3-II in the mouse cortex and HBMECs. Mechanistically, the knockdown of Sestrin2 in HBMECs exacerbated the EndoMT induced by LPS treatment, while the overexpression of Sestrin2 inhibited this process. Moreover, the induction of autophagy by rapamycin rescued the EndoMT induced by Sestrin2 knockdown. Conclusion: This study revealed that Sestrin2 inhibited endothelial inflammation and EndoMT via enhanced autophagy, which may provide a potential drug target for cerebrovascular inflammatory injury.

Objective: Energy homeostasis is modulated by the hypothalamic is essential for obesity progression, however, the gene expression profiling remains to be fully understood.Methods: GEO datasets were downloaded from the GEO website and analyzed by the R packages to obtain the DEGs. And, the WGCNA analysis and PPI networks of co-expressed DEGs were designed using STRING to get key genes. In addition, the single-cell sequencing datasets and GTEx database were utilized to receive the neuron-stress genes from the key genes. Further, high-fat diet (HFD)-induced hypothalamic tissue of mice was used as an animal model to validate the mRNA up-regulation of neuron-stress genes. In addition, the Bmi1 gene was identified as a hub gene through the LASSO model and nomogram analysis. Western blot confirmed the high expression of Bmi1 in hypothalamic tissue of HFD mice and PA-stimulated microglia. Immunofluorescence staining showed that HFD induced the activation of microglia and the expression of Bmi1 in hypothalamic tissue.Results: We found that six genes (Sacm1l, Junb, Bmi1, Erbb4, Dkc1, and Suv39h1) are neuron stress-related genes and increased in the HFD-induced mice obesity model, Bmi1gene was identified as a key genes that can reflect the pathophysiology of obesity.Conclusions: Our research depicted a comprehensive activation map of cell abnormality in the obese hypothalamus and Bim1 may be a diagnostic marker in the clinic, which provides a new perspective and basis for investigating the pathogenesis of obesity.

Objective Energy homeostasis is modulated by the hypothalamic is essential for obesity progression; however, the gene expression profiling remains to be fully understood. Methods GEO datasets were downloaded from the GEO website and analysed by the R packages to obtain the DEGs. And, the WGCNA analysis and PPI networks of co-expressed DEGs were designed using STRING to get key genes. In addition, the single-cell sequencing datasets and GTEx database were utilized to receive the neuron-stress genes from the key genes. Further, HFD-induced hypothalamic tissue of mice was used as an animal model to validate the mRNA up-regulation of neuron-stress genes. Finally, the Bmi1 gene was identified as a hub gene through the LASSO model and nomogram analysis. Results It found that six genes (Sacm1l, Junb, Bmi1, Erbb4, Dkc1, and Suv39h1) are neuron stress-related genes and increased in the HFD-induced mice obesity model. Finally, Bmi1gene was identified as hub genes that can reflect the pathophysiology of obesity. Conclusions Our research depicted a comprehensive activation map of cell abnormality in the obese hypothalamus and Bim1 may be a diagnostic marker in the clinic, which provides a new perspective and basis for investigating the pathogenesis of obesity.

Increased glucagon levels are now recognized as a pathophysiological adaptation to counteract overnutrition in type 2 diabetes (T2D). This study aimed to elucidate the role of glucagon in peripheral nerve function in patients with T2D with different body mass indices (BMIs). We consecutively enrolled 174 individuals with T2D and obesity (T2D/OB, BMI ≥ 28 kg/m2), and 480 individuals with T2D and nonobesity (T2D/non-OB, BMI < 28 kg/m2), all of whom underwent oral glucose tolerance tests to determine the area under the curve for glucagon (AUCgla). Electromyography was utilized to assess overall composite Z-scores for latency, amplitude, and nerve conduction velocity (NCV) across all peripheral nerves, specifically examining the median, ulnar, common peroneal, posterior tibial, superficial peroneal, and sural nerves. In the T2D/OB group, the AUCgla exhibited a significant correlation with the latency, amplitude and NCV of each peripheral nerve, as well as with the overall composite Z-scores for latency (r = –0.283, p < 0.001), amplitude (r = 0.295, p < 0.001), and NCV (r = 0.362, p < 0.001). In contrast, the T2D/non-OB group did not exhibit obvious correlations between the AUCgla and the overall composite Z-scores for latency (r = –0.088, p = 0.056), amplitude (r = 0.054, p = 0.251), and NCV (r = 0.116, p = 0.012). Furthermore, multivariate linear regression analyses indicated that elevated AUCgla was independently associated with a lower overall composite Z-score for latency (β = –0.304, t = –3.391, p = 0.001), as well as higher overall composite Z-scores for amplitude (β = 0.256, t = 2.630, p = 0.010) and NCV (β = 0.286, t = 3.503, p = 0.001), after adjusting for other clinical covariates within the T2D/OB group. Increased glucagon levels may be a potential protective factor against peripheral nerve compromise in patients with T2D and obesity.