S-methyl-L-cysteine Protects against Antimycin A-induced Mitochondrial Dysfunction in Neural Cells via Mimicking Endogenous Methionine-centered Redox Cycle

Mitochondrial superoxide overproduction is believed to be responsible for the neurotoxicity associated with neurodegeneration.Mitochondria-targeted antioxidants,such as MitoQ,have emerged as potentially effective antioxidant therapies.Methionine sulfoxide reductase A(MsrA)is a key mitochondrial-localized endogenous antioxidative enzyme and it can scavenge oxidizing species by catalyzing the methionine(Met)-centered redox cycle(MCRC).In this study,we observed that the natural L-Met acted as a good scavenger for antimycin A-induced mitochondrial superoxide overproduction in PC12 cells.This antioxidation was largely dependent on the Met oxidase activity of MsrA.S-methyl-L-cysteine(SMLC),a natural analogue of Met that is abundantly found in garlic and cabbage,could activate the Met oxidase activity of MsrA to scavenge free radicals.Furthermore,SMLC protected against antimycin A-induced mitochondrial membrane depolarization and alleviated 1-methyl-4-phenylpyridinium(MPP+)-induced neurotoxicity.Thus,our data highlighted the possibility for SMLC supplement in the detoxication of mitochondrial damage by activating the Met oxidase activity of MsrA.

Microglia:A Central Player in Depression

Microglia are the major immune cells in the central nervous system and play a key role in the normal function of the brain.Microglia exhibit functional diversity,and they control the inflammation in central nervous system through releasing inflammatory cytokine,clearing apoptotic cells via phagocytosis,regulating synaptic plasticity and the formation of neural network by synapse pruning.Recent studies have strongly indicated that the microglial dysfunction is associated with a variety of neuropsychiatric diseases such as depression,which have been termed as“microgliopathy”.The emergency of advanced technologies and tools has enabled us to comprehensively understand the role of microglia in physiology and pathology,and growing studies have targetted microglia to explore the treatment of neuropsychiatric diseases.Here,we describe the key progress of microglia research,and review the recent developments in the understanding of the role of microglia in physiology and etiology of depression.

Design,synthesis,and evaluation of PD-L1 degraders to enhance T cell killing activity against melanoma

Inhibitor targeting immune checkpoint is a promising new anticancer therapy.Blocking the interaction between PD-1 and PD-L1 can reverse the immunosuppression state and improve the lethality of immune cells to tumor cells.Here,we report PROTAC-based PD-L1 degraders to enhance T cell killing activity against melanoma.Four series of PD-L1 degraders were designed and synthesized to VHL,CRBN,MDM2 or c IAP E3 ligase system,in which CRBN-ligand-based compound BMS-37-C3 was identified as the most active PROTAC molecule.BMS-37-C3 also significantly enhanced the killing ability of T cells in a co-culture model of A375 and T cells.Furthermore,western blot data and flow cytometry demonstrated that BMS-37-C3 could reduce the protein levels of PD-L1 in dose and time dependent manner,which may provide a new therapeutic method for tumor immunotherapy.