Toll-like receptor-9(TLR9) can recognize the foreign unmethylated CpG DNA, and thus intrigue a strong Th1 response which plays a crucial role in the innate and adaptive immune responses. To date, C...

Multiple sclerosis (MS) is an autoimmune inflammatory disease. Inflammatory infiltrates and demyelination of the CNS are the major characteristics of MS and its related animal model-experimental autoimmune encephalomyelitis (EAE). Immoderate autoimmune responses of Th17 cells and dysfunction of Treg cells critically contribute to the pathogenesis of MS and EAE. Our previous study showed that Ginsenoside Rd effectively ameliorated the clinical severity in EAE mice, but the mechanism remains unclear. In this study, we investigated the therapeutic effect of Ginsenoside Rd on EAE in vivo and in vitro and also explored the potential mechanisms for alleviating the injury of EAE. The results indicated that Ginsenoside Rd was effective for the treatment of EAE in mice and splenocytes. Ginsenoside Rd treatment on EAE mice ameliorated the severity of EAE and attenuated the characteristic signs of disease. Ginsenoside Rd displayed the therapeutic function to EAE by modulating inflammation and autoimmunity, via the downregulation of related proinflammatory cytokines IL-6 and IL-17, upregulation of inhibitory cytokines TGF-β and IL-10, and modulation of Treg/Th17 imbalance. And the Foxp3/RORγt/JAK2/STAT3 signaling was found to be associated with this protective function. In addition, analysis of gut microbiota showed that Ginsenoside Rd also had modulation potential on gut microbiota in EAE mice. Based on this study, we hypothesize that Ginsenoside Rd could be a potential and promising agent for the treatment of MS.

Immune checkpoint inhibitors targeting the PD-1/PD-L1 pathway have become a "game-changer" in the cancer treatment. However, none of the small molecular inhibitors has been approved yet. To explore the advantages and disadvantages of various scaffolds, different biological evaluations were performed on the three selected small inhibitors, namely Incyte-001, Incyte-011, and BMS-1001. In the HTRF assay, BMS-1001 showed the best binding activity for PD-L1 (IC₅₀ = 0.9 nM) while Incyte-011 (IC₅₀ = 5.293 nM) was twice more potent than the Incyte-001 (IC₅₀ = 11 nM). Also, only Incyte-011 increased the IFN-γ production. Notably, the Incyte-001 exhibited the high-est cytotoxicity (EC₅₀ = 1.635 μM). Interestingly, Incyte-001 (injected intravenously 2mg/kg) also displayed good blood-brain barrier permeability and reached a high concentration in the brain tissue. Finally, molecular docking and modeling studies suggested that the compounds bind in a pocket at the interface of two PD-L1 monomers. Overall, our work shows that PD-1/PD-L1 small molecular inhibitors have different biological characteristics depending on their unique skeletons, which can be further improved to better their clinical application.