Suppression of excessive microglial overactivation can prevent the progression of multiple sclerosis (MS). Histone deacetylases 3 inhibitor (HDAC3i) has been demonstrated to exert anti-inflammatory effects by suppressing microglia (M1-liked) activation. Here, we demonstrate that the RGFP966 (a selective inhibitor of HDAC3) protects white matter after cuprizone-induced demyelination, as shown by reductions in neurological behavioral deficits and increases in myelin basic protein. Moreover, in this study, we found that RGFP966 caused a significant reduction in the levels of inflammatory cytokines, including IL-1β, TNF-α, as well as iNOS, and inhibited microglial (M1-liked) activation in the experimental cuprizone model and LPS-stimulated BV2 cells. Meanwhile, RGFP966 alleviated apoptosis of LPS-induced BV2 cells in vitro. Furthermore, RGFP966 suppressed the expression of P2X7R, NLRP3, ASC, IL-18, IL-1β, and caspase-1, inhibited the ratio of phosphorylated-STAT3/STAT3 and phosphorylated NF-κB p65/NF-κB p65, as well as increased acetylated NF-κB p65 in vitro and in vivo. Furthermore, we confirmed that brilliant blue G (antagonists of P2X7R) suppressed the expression of microglial NLRP3, IL-18, IL-1β, caspase-1, NF-κB p65 (including phosphorylated NF-κB p65), and STAT3 (including phosphorylated STAT3) in vitro. These findings demonstrated that RFFP966 alleviated the inflammatory response and exerted a neuroprotective effect possibly by modulating P2X7R/STAT3/NF-κB65/NLRP3 signaling pathways. Thus, HDAD3 might be considered a promising intervention target for neurodegenerative diseases, such as MS.

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Phosphatidylserine (PS) improves learning and memory capacity. In this study, PS formulation was optimized by a response surface methodology. Moreover, we found that PS not only functions as a biologically active component in food preparations but also improves the emulsion’s physical stability. Our results showed that the PS emulsions are characterized by a smaller particle size, higher ζ-potential (negative), higher viscosity, and lower surface tension and centrifugal stability constants than the emulsion without PS. Furthermore, we explored the neuroprotective effects of PS emulsion and its underlying mechanisms. Treatment with 2% (w/w) PS emulsion for three months enhanced spatial learning and memory in 5- and 12-week old mice in the Morris water maze test. Western-blotting analysis displayed that the 2% (w/w) PS emulsion treated group upregulated BDNF, TrkB, PSD95, mTOR, MBP, and ErbB4 expression in the hippocampus of 5- and 12-week old mice. Reverse transcription polymerase chain reaction (RT-PCR) analysis revealed elevated Nrg-1 and ErbB4 mRNA expression in the 2% (w/w) PS emulsion treated groups, and high Nrg-1 and ErbB4 expression levels were associated with better myelination. In conclusion, we reported PS emulsions with high stability and high bioavailability. Meanwhile, 2% (w/w) PS emulsion enhances learning, memory, and myelination in mice by activating the BDNF/TrkB and Nrg-1/ErbB4 signaling.

Comparative analysis of divergence in serum chemical derivatives among yaks living in ecological habitats at different altitudes was performed to determine the physiological adaptation basis in blood metabolites of yaks at extreme high altitudes due to long-term natural selection of plateau ecological environment. Twenty serum samples from yaks were collected, including 10 from those living on the Qinghai-Tibet Plateau at altitudes above 5000 m for a long time and 10 from those living in ecological regions at altitudes of ~4000m. Results revealed 592 metabolites in all samples, of which the highest proportion was attributed to amino acids and their metabolites (18.58%), followed by organic acids and their derivatives (16.20%). Meanwhile, 89 significantly different metabolites (SDMs) were identified between groups, of which 55 were significantly upregulated (e.g., 3-methylcrotonyl glycine, 2-hydroxy-3, and 5-dinitrobenzoic acid, etc.) in the yaks living at extremely high altitude. In addition, 28 metabolites (fumaric acid, serotonin, glycochenodeoxycholic acid, and all trans-retinal) were enriched in 55 KEGG signaling pathways and mainly attributed to organismal systems and metabolism. This work further clarified that long-term natural selection at extremely high altitude prompts animals to have visible physiological adaptations in serum. In addition, the serum of yak living at high altitudes is rich in a series of metabolites (e.g., lysophosphatidylethanolamine, γ-linolenic acid, and 12-hydrox) that are helpful for the treatment of cerebrovascular diseases and respiratory diseases and could contribute to the drug development of anti-plateau in the future.