Intermittent fasting can benefit breast cancer patients undergoing chemotherapy or immunotherapy. However, it is still uncertain how to select immunotherapy drugs to combine with intermittent fasting. Herein we observed that two cycles of fasting treatment significantly inhibited breast tumor growth and lung tissue metastasis, as well as prolonged overall survival in mice bearing 4T1 and 4T07 breast cancer. During this process, both the immunosuppressive monocytic- (M-) and granulocytic- (G-) myeloid-derived suppressor cell (MDSC) decreased, accompanied by an increase in interleukin (IL) 7R+ and granzyme B+ T cells in the tumor microenvironment. Interestingly, we observed that Ly6Glow G-MDSC sharply decreased after fasting treatment, and the cell surface markers and protein mass spectrometry data showed potential therapeutic targets. Mechanistic investigation revealed that glucose metabolism restriction suppressed the splenic granulocyte-monocyte progenitor and the generation of colony-stimulating factors and IL-6, which both contributed to the accumulation of G-MDSC. On the other hand, glucose metabolism restriction can directly induce the apoptosis of Ly6Glow G-MDSC, but not Ly6Ghigh subsets. In summary, these results suggest that glucose metabolism restriction induced by fasting treatment attenuates the immune-suppressive milieu and enhances the activation of CD3+ T cells, providing potential solutions for enhancing immune-based cancer interventions.
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Benzo[a]pyrene (B[a]P) is a food contaminant toxic for cardiovascular diseases. The nuclear translocation of Arylhydrocarbon receptor (AhR) plays an important role in B[a]P-induced oxidative stress and vascular diseases. We confirmed that B[a]P promoted ROS production in vascular smooth muscle cells (VSMCs) in vitro and in vivo, associated with the nuclear translocation of AhR. It is known that phosphorylation inhibits while dephosphorylation of AhR promotes nuclear translocation of AhR. However, from the posttranslational modification level, the mechanism by which B[a]P activates and regulates the nuclear translocation of AhR is unclear. Co-immunoprecipitation results showed that cytoplasmic AhR was phosphorylated before B[a]P stimulation, and switched to O-GlcNAcylation upon B[a]P 1-h stimulation in VSMCs, suggesting there may be a competitively inhibitory relationship between O-GlcNAcylation and phosphorylation of AhR. Next, siRNAs of O-linked N-acetylglucosamine transferase (OGT), O-GlcNAcase (OGA) and OGA inhibitor PUGNAc were used. SiOGT blocks but siOGA and PUGNAc promote B[a]P -dependent AhR nuclear translocation and oxidative stress. Ser11 may be the competitive binding site for phosphorylation and O-GlcNAcylation of AhR. Phosphorylation-mimic variant inhibits but O-GlcNAcylation of AhR promotes AhR nuclear translocation and oxidative stress. Our findings highlight a new perspective for AhR nuclear translocation regulated by the competitive modification between phosphorylation and O-GlcNAcylation.
The increased vascular inflammation is a key event in the development of atherosclerotic lesions. Antrodia cinnamomea has been shown to promote anticancerogenic activity through decreasing inflammation. However, the potential role of A. cinnamomea in cardiovascular diseases remains unexplored. Herein, using carotid arterial ligation models, we found that ethanol extract from A. cinnamomea (EEAC) significantly inhibited neointimal hyperplasia in a dose-dependent manner, accompanied with the reduced expression of activated p65 and inflammatory cytokines. We also show that EEAC ameliorated TNF-α-induced phosphorylation of p65 and pro-inflammatory cytokine expression in both vascular smooth muscle cells (VSMCs) and macrophages in vitro. Mechanistically, EEAC suppressed expression levels of intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule (VCAM-1) in VSMCs, which attenuates the ability of monocytes/macrophages adhesion to VSMCs. Furthermore, the expression level of these adhesion molecules and infiltration of monocytes/macrophages were also decreased in neointimal VSMCs of arteries pretreated with EEAC. Altogether, our results reveal a novel function of A. cinnamomea in suppressing vascular inflammation upon ligation injury during neointimal formation, likely through inhibition of inflammatory cell infiltration via downregulating the adhesion molecules in VSMCs. Thus, A. cinnamomea may offer a pharmacological therapy to slow down disease progression in patients with vascular injury.