Microglia activation contributed to the development of Parkinson's disease (PD)-associated cognitive impairment and targeting microglia may be a promising strategy for improving the cognitive function in PD. O-GlcNAclytion is a novel protein post-translational modification with cognitive enhancing effects. This study aimed to investigate the effects of Thiamet-G (TMG), an O-GlcNAcase inhibitor that can increase the intracellular O-GlcNAclytion levels, on PD-associated cognitive impairment and the mechanism related to microglia activation. A PD mouse model was established using rotenone (ROT) and the cognitive functions of these mice were investigated by behavioral tests. The anti-inflammatory effects of TMG were tested in the BV2 microglia cells. TMG treatment significantly improved the cognitive function in the ROT-induced PD mouse model as evidenced by the Y-maze test and objective recognition test. Histological studies showed that TMG decreased the reactive microglia via increasing the total protein O-GlcNAclytion levels in the hippocampus of the PD mice. In the in vitro studies, TMG inhibited ROT-induced inflammation via decreasing the pro-inflammatory cytokines such as TNF-α, IL-1β and IL-6 in BV2 microglia cells. Bioinformatic analysis revealed that STING, a core protein in the innate immunity regulation, might be a novel target of O-GlcNAclytion. The immunoprecipitation experiments further confirmed that TMG inhibited STING phosphorylation via increasing O-GlcNAcylation. Taken together, TMG might ameliorate PD-associated cognitive impairment via increasing O-GlcNAcylation of STING in microglia, which provided evidence supporting that inhibiting the inflammatory response of microglia by elevating the O-GlcNAclytion levels might be an effective strategy for improving the cognitive function in PD.

2025-07-01·ACTA PHARMACOLOGICA SINICA

Inhibition of CDC27 O-GlcNAcylation coordinates the antitumor efficacy in multiple myeloma through the autophagy-lysosome pathway

Article

作者: Xiao, Fan ; Zheng, Zi-Han ; Zheng, Jing-Peng ; Meng, Yan-Fang ; Tang, Yuan ; Qin, Ren-Cai ; Liu, Jie-Na ; Li, Wei-Jie ; Ma, Kong-Yang ; Lu, Li-Wei ; Tan, Hong-Mei ; Liu, Yu ; Duan, Fang-Fang ; Wu, Hai-Qi ; Tang, Chun ; Deng, Chong ; Dai, Xiao-Yan

Abstract:

Multiple myeloma (MM) is a prevalent hematologic malignancy characterized by abnormal proliferation of cloned plasma cells. Given the aggressive nature and drug resistance of MM cells, identification of novel genes could provide valuable insights for treatment. In this study we performed machine learning in the RNA microarray data of purified myeloma plasma cell samples from five independent MM cohorts with 957 MM patients, and identified O-GlcNAcylation transferase (OGT) and cell division cycle 27 (CDC27) as the key prognostic genes for MM. We demonstrated a close link between OGT and CDC27 in MM cells by knockdown of OGT with siOGT, pharmacological inhibition of O-GlcNAcylation with OSMI-1 and pharmacological accumulation of O-GlcNAcylation with Thiamet G. Using mass spectrometry and immunoprecipitation, we identified the O-GlcNAcylated CDC27 protein as a key target protein that may be directly downregulated by OSMI-1 in MM.1S cells. We further revealed that O-GlcNAcylation maintained CDC27 protein stability by blocking the autophagy-lysosome pathway (ALP). Moreover, we demonstrated the enhanced antitumor efficacy of combined OSMI-1 and bortezomib (BTZ) treatment in MM cells both in vivo and in vitro. Thus, this study identifies a novel function of O-GlcNAcylation-related ALP in regulating CDC27 protein stability and a potential therapeutic strategy for treating MM.

2025-07-01·BRAIN RESEARCH

Effects of mitochondrial O-GlcNAcylation in pericytes after mechanical injury

Article

作者: Takase, Hajime ; Guo, Shuzhen ; Park, Ji Hyun ; Tanaka, Masayoshi ; Back, Dong Bin ; Lo, Eng H ; Arai, Ken ; Hayakawa, Kazuhide ; Whalen, Michael J

Damage to vascular cells comprise an important part of traumatic brain injury (TBI) but the underlying pathophysiology remains to be fully elucidated. Here, we investigate the loss of O-Linked β-N-acetylglucosamine(O-GlcNAc) modification (O-GlcNAcylation) and mitochondrial disruption in vascular pericytes as a candidate mechanism. In mouse models in vivo, TBI rapidly induces vascular oxidative stress and down-regulates mitochondrial O-GlcNAcylation. In pericytes but not brain endothelial cultures in vitro, mechanical stretch injury down-regulates mitochondrial O-GlcNAcylation. This is accompanied by disruptions in mitochondrial dynamics, comprising a decrease in mitochondrial fusion and an increase in mitochondrial fission proteins. Pharmacologic rescue of endogenous mitochondrial O-GlcNAcylation with an O-GlcNAcase inhibitor Thiamet-G or addition of exogenous O-GlcNAc-enhanced extracellular mitochondria ameliorates the mitochondrial disruption in pericytes damaged by mechanical injury. Finally, in a pericyte-endothelial co-culture model, mechanical injury increased trans-cellular permeability; adding Thiamet-G or O-GlcNAc-enhanced extracellular mitochondria rescued trans-cellular permeability following mechanical injury. These proof-of-concept findings suggest that mitochondrial O-GlcNAcylation in pericytes may represent a novel therapeutic target for ameliorating oxidative stress and vascular damage after mechanical injury following TBI.

100 项与 Thiamet-G 相关的药物交易

登录后查看更多信息