SMEK1 ablation promotes glucose uptake and improves obesity-related metabolic dysfunction via AMPK signaling pathway.

Obesity has become a major risk of global public health. SMEK1 is also known as a regulatory subunit of protein phosphatase 4 (PP4). Both PP4 and SMEK1 have been clarified in many metabolic functions, including the regulation of hepatic gluconeogenesis and glucose transporter gene expression in yeast. Whether SMEK1 participates in obesity and the broader metabolic role in mammals is unknown. Thus, we investigated the function of SMEK1 in white adipose tissue and glucose uptake. GWAS/GEPIA/GEO database was used to analyze the correlation between SMEK1 and metabolic phenotypes/lipid metabolism-related genes/obesity. Smek1 KO mice were generated to identify the role of SMEK1 in obesity and glucose homeostasis. Cell culture and differentiation of stromal-vascular fractions (SVFs) and 3T3-L1 were used to determine the mechanism. 2-NBDG was used to measure the glucose uptake. Compound C was used to confirm the role of AMPK. We elucidated that SMEK1 was correlated with obesity and adipogenesis. Smek1 deletion enhanced adipogenesis in both SVFs and 3T3-L1. Smek1 KO protected mice from obesity and had protective effects on metabolic disorders, including insulin resistance and inflammation. Smek1 KO mice had lower levels of fasting serum glucose. We found that SMEK1 ablation promoted glucose uptake by increasing p-AMPKα(T172) and the transcription of Glut4 when the effect on AMPK-regulated glucose uptake was due to the PP4 catalytic subunits (PPP4C). Our findings reveal a novel role of SMEK1 in obesity and glucose homeostasis, providing a potential new therapeutic target for obesity and metabolic dysfunction.NEW & NOTEWORTHY Our study clarified the relationship between SMEK1 and obesity for the first time and validated the conclusion in multiple ways by combining available data from public databases, human samples, and animal models. In addition, we clarified the role of SMEK1 in glucose uptake, providing an in-depth interpretation for the study of its function in glucose metabolism.

Diagnostic signatures and immune cell infiltration characteristics in anti-GABABR encephalitis.

PURPOSE: Anti-gamma-aminobutyric acid B receptor (GABABR) encephalitis is an uncommon form of autoimmune encephalitis associated with a poor prognosis and a high fatality rate. We aim to find diagnostic markers for anti- GABABR encephalitis as well as the effects of immune cell infiltration on this pathology. METHODS: For quantitative proteomic analysis, isobaric tags for relative and absolute quantitation were used in conjunction with LC-MS/MS analysis. To conduct functional correlation analyses, differentially expressed proteins (DEPs) were identified. Following that, we used bioinformatics analysis to screen for and determine the diagnostic signatures of anti- GABABR encephalitis. ROC curves were used to evaluate the diagnostic values. To assess the inflammatory status of anti- GABABR encephalitis, we used cell-type identification by estimating relative subsets of the RNA transcript (CIBERSORT) and explored the link between diagnostic markers and infiltrating immune cells. RESULTS: Overall, 108 robust DEPs (47 upregulated and 61 downregulated) were identified, of which 11 were immune related. The most impressively enriched pathways were complemented and coagulation cascades, actin cytoskeleton regulation, and cholesterol metabolism; GSEA revealed that the enriched pathways were considerably differentially connected to immune modulation. Eleven immune-related DEPs were chosen for further investigation. We developed a novel diagnostic model based on CSF1R and AZGP1 serum levels using ROC analysis (area under the ROC curve = 1). M1 macrophages and activated natural killer cells are likely to play a role in course of anti- GABABR encephalitis. CONCLUSION: We identified CSF1R and AZGP1 are possible anti-GABABR encephalitis diagnostic indicators, and immune cell infiltration may have a significant impact on the development and occurrence of anti- GABABR encephalitis.

Cytokines/chemokines and soluble immune checkpoint molecules in anti-GABAB receptor encephalitis.

BACKGROUND: Anti-gamma-aminobutyric-acid B receptor (anti-GABABR) encephalitis is a rare form of autoimmune limbic encephalitis (ALE) that is closely associated with tumor comorbidity. The purpose of this study is to identify the expressive pattern of cytokines/ chemokines and soluble immune checkpoint molecules (sICMs) in anti-GABABR encephalitis in order to evaluate the clinical condition and provide new treatment options. METHODS: A total of 40 cytokines/chemokines and 10 sICMs in the serum of 10 patients with anti-GABABR encephalitis and eight controls were measured. The differentially expressed cytokines/chemokines and sICMs were selected to explore the correlations with disease prognosis, CSF routine and antibody titers. RESULTS: Eight cytokines/chemokines were found to be more abundant in patients than in healthy donors (HDs), while 14 were found to be less abundant in patients. In terms of sICMs, patients' serum contained higher level of soluble ICOS and ICOSL but lower level of soluble CD86. Unfavorable prognosis was associated with high serum level of PDGFB, IL-17A, and soluble ICOSL but not with low levels of IL-4. Increased levels of IL-17A, CCL15, and soluble ICOS were found frequently in the patients with CSF-exclusive OCBs, while soluble ICOSL and CCL24 expression was lower in these patients. High levels of IL-1 F2 and TCA-3 were correlated with the presence of tumors in patients. CONCLUSION: The majority of patients with anti- GABABR encephalitis had an unfavorable prognosis in one year of follow-up. Serum PDGFB, IL-17A, IL-4 and soluble ICOSL level were associated with the poor clinical outcomes in one-year follow up.

Effect of dexmedetomidine combined with etomidate on IL-17A and S-100ß expression levels in rats with postoperative cognitive dysfunction.

The present study aimed to explore the effects of dexmedetomidine combined with etomidate on the expression levels of interleukin (IL)-17A and S-100ß in rats with postoperative cognitive dysfunction (POCD). A total of 50 SD rats were randomly allocated into the control group, model group, etomidate group (Eto group), dexmedetomidine group (Dex group) and dexmedetomidine combined with etomidate group (Dex-Eto group). Inhalation anesthesia was used in all five groups. Apart from the control group, partial lobectomy was performed to construct a rat model of cognitive dysfunction. The rats of the model group received no intravenous anesthesia, except general anesthesia with intubation. Morris water maze test was performed before injection (T0), at the 1st day (T1), the 3rd day (T2) and the 5th day (T3) after operation to assess the memory ability of the rats. At the end of T3, the expression levels of IL-17A, S-100ß, TNF-α, IL-6 and IL-1ß in serum were detected by ELISA and the expression of NF-κB p65 by western blot analysis. Compared with the control group, the model group showed an increased escape latency and swimming distance, decreased number of times of crossing the platform and target quadrant residence time, and increased expression levels of IL-17A, S-100ß, TNF-α, IL-6, IL-1ß and NF-κB p65. Compared with the model group, the escape latency and swimming distance in the Dex, Eto and Dex-Eto groups were reduced, whereas the number of times of crossing the platform and the target quadrant residence time were increased. In addition, the expression levels of IL-17A, S-100ß, TNF-α, IL-6, IL-1ß and NF-κB p65 were decreased in the Dex, Eto and Dex-Eto groups, compared with the model group. Among the Dex, Eto and Dex-Eto groups, the escape latency and swimming distance in the Dex-Eto group were the shortest, the number of times of crossing the platform and the target quadrant residence time were the highest, and IL-17A, S-100ß, TNF-α, IL-6, IL-1ß and NF-κB p65 expression levels were the lowest. In conclusion, dexmedetomidine combined with etomidate can effectively improve POCD.