Meta-analysis of the Selected Genetic Variants in Immune-Related Genes and Multiple Sclerosis Risk.

Previous studies have suggested that certain variants in immune-related genes may participate in the pathogenesis of multiple sclerosis (MS), including rs17824933 in the CD6 gene, rs1883832 in the CD40 gene, rs2300747 in the CD58 gene, rs763361 in the CD226 gene, rs16944 in the IL-1ß gene, rs2243250 in the IL-4 gene, and rs12722489 and rs2104286 in the IL-2Rα gene. However, the results remained inconclusive and conflicting. In view of this, a comprehensive meta-analysis including all eligible studies was conducted to investigate the association between these 8 selected genetic variants and MS risk. Up to June 2023, 64 related studies were finally included in this meta-analysis. The odds ratios (ORs) and corresponding 95% confidence intervals (CIs) calculated by the random-effects model were used to evaluate the strength of association. Publication bias test, sensitivity analyses, and trial sequential analysis (TSA) were conducted to examine the reliability of statistical results. Our results indicated that rs17824933 in the CD6 gene, rs1883832 in the CD40 gene, rs2300747 in the CD58 gene, rs763361 in the CD226 gene, and rs12722489 and rs2104286 in the IL-2Rα gene may serve as the susceptible factors for MS pathogenesis, while rs16944 in the IL-1ß gene and rs2243250 in the IL-4 gene may not be associated with MS risk. However, the present findings need to be confirmed and reinforced in future studies.

Active components from Lagotis brachystachya maintain uric acid homeostasis by inhibiting renal TLR4-NLRP3 signaling in hyperuricemic mice.

Lagotis brachystachya Maxim is a herb widely used in traditional Tibetan medicine. Our previous study indicated that total extracts from Lagotis brachystachya could lower uric acid levels. This study aimed to further elucidate the active components (luteolin, luteoloside and apigenin) isolated from Lagotis brachystachya and the underlying mechanism in vitro and in vivo. The results showed that treatment with luteolin and luteoloside reversed the reduction of organic anion transporter 1 (OAT1) levels, while apigenin attenuated the elevation of urate transporter 1 (URAT1) and glucose transporter 9 (GLUT9) levels in uric acid-treated HK-2 cells, which was consistent with the finding in the kidneys of potassium oxonate (PO)-induced mice. On the other hand, hepatic xanthine oxidase activity was inhibited by the components. In addition, all of these active components improved the morphology of the kidney in hyperuricemic mice. Moreover, molecular docking showed that luteolin, luteoloside and apigenin could bind Toll-like receptor 4 (TLR4) and NLR family pyrin domain containing 3 (NLRP3). Congruently, western blot analysis showed that the components inhibited TLR4/myeloid differentiation primary response 88 (MyD88)/NLRP3 signaling. In conclusion, these results indicated that luteolin, luteoloside and apigenin could attenuate hyperuricemia by decreasing the production and increasing the excretion of uric acid, which were mediated by inhibiting inflammatory signaling pathways.

Hippocampal BDNF signaling is required for the antidepressant effects of perillaldehyde.

BACKGROUND: Perillaldehyde is one of the main components in perilla. Previous studies have shown that perillaldehyde exerted an antidepressant effect in mice, some of which is mediated through regulation of the anti-inflammatory system and the monoamine system. The primary objective of this study was to investigate the possible effects of perillaldehyde on the neurotrophic system and to elucidate whether its antidepressant effect requires brain-derived neurotrophic factor (BDNF) signaling. METHODS: Mice were exposed to chronic unpredictable mild stress (CUMS) and orally administrated with perillaldehyde for 4 weeks for behavioral testing. RESULTS: Perillaldehyde not only reversed the decrease in sucrose preference but also attenuated the increase in feeding latency. In addition, perillaldehyde can attenuate the reduction of CUMS-induced hippocampal BDNF levels. Our further study found that the BDNF receptor tropomyosin receptor kinase B (TrkB) antagonist K252a completely blocked the antidepressant effect of perillaldehyde in mice. Biochemical analysis showed that K252a pretreatment completely prevented the improvement of BDNF, extracellular signal-regulated kinase (ERK) phosphorylation and synaptic protein. CONCLUSIONS: These results indicated that activation of BDNF-ERK signaling in the hippocampus was required, at least in part for the antidepressant effects of perillaldehyde.

Gallic acid activates hippocampal BDNF-Akt-mTOR signaling in chronic mild stress.

Gallic acid (3,4,5-trihydroxybenzoic acid) is a naturally occurring polyphenolic compound. Previous study has shown that gallic acid possessed significant antidepressant-like activity in mice, which was partly mediated by increasing serotonin and catecholamine levels. The main aim of the present study is to investigate the possible effects of gallic acid on brain-derived neurotrophic factor (BDNF) signaling activation. Mice were exposed to chronic mild stress (CMS) and orally administrated with gallic acid for four weeks. The behavioral results showed that gallic acid not only reversed the decreased sucrose preference, but also attenuated the increased immobility time. In addition, gallic acid promoted both the BDNF and p-TrkB levels in the hippocampus induced by CMS. Moreover, the results also demonstrated that the inactivated Akt-mTOR signaling pathway, as well as its downstream effectors induced by CMS was activated again by gallic acid. Last, immunofluorescence detection indicated that gallic acid reversed the newborn neurons inhibition in the dentate gyrus by CMS. In conclusion, these results show that the activation of the hippocampal BDNF-Akt-mTOR signaling is involved in the antidepressant-like effects of gallic acid.