Structural characterization of Russula griseocarnosa polysaccharide and its improvement on hematopoietic function.

The hematopoietic function of a polysaccharide derived from Russula griseocarnosa was demonstrated in K562 cells, and subsequently purified through chromatography to obtain RGP1. RGP1 is a galactan composed of 1,6-α-D-Galp as the main chain, with partial substitutions. A -CH3 substitution was detected at O-3 of 1,6-α-D-Galp. The possible branches at O-2 of 1,6-α-D-Galp was α-L-Fucp. In mice with cyclophosphamide (CTX)-induced hematopoietic dysfunction, RGP1 alleviated bone marrow damage and multinucleated giant cell infiltration of the spleen, increased the number of long-term hematopoietic stem cells, and regulated the levels of myeloid cells in the peripheral blood. Furthermore, RGP1 promoted the differentiation of activated T cells and CD4+ T cells without affecting natural killer cells and B cells. Proteomic analysis, detection of cytokines, and western blotting revealed that RGP1 could alleviate hematopoietic dysfunction by promoting the activation of CD4+ T cells and the Janus kinase/ signal transducer and activator of transcription 3 pathway. The present study provides experimental evidence to support the application of RGP1 in CTX-induced hematopoietic dysfunction.

Macrophage NFATc3 prevents foam cell formation and atherosclerosis: evidence and mechanisms.

AIMS: Our previous study demonstrated that Ca2+ influx through the Orai1 store-operated Ca2+ channel in macrophages contributes to foam cell formation and atherosclerosis via the calcineurin-ASK1 pathway, not the classical calcineurin-nuclear factor of activated T-cell (NFAT) pathway. Moreover, up-regulation of NFATc3 in macrophages inhibits foam cell formation, suggesting that macrophage NFATc3 is a negative regulator of atherogenesis. Hence, this study investigated the precise role of macrophage NFATc3 in atherogenesis. METHODS AND RESULTS: Macrophage-specific NFATc3 knockout mice were generated to determine the effect of NFATc3 on atherosclerosis in a mouse model of adeno-associated virus-mutant PCSK9-induced atherosclerosis. NFATc3 expression was decreased in macrophages within human and mouse atherosclerotic lesions. Moreover, NFATc3 levels in peripheral blood mononuclear cells from atherosclerotic patients were negatively associated with plaque instability. Furthermore, macrophage-specific ablation of NFATc3 in mice led to the atherosclerotic plaque formation, whereas macrophage-specific NFATc3 transgenic mice exhibited the opposite phenotype. NFATc3 deficiency in macrophages promoted foam cell formation by potentiating SR-A- and CD36-meditated lipid uptake. NFATc3 directly targeted and transcriptionally up-regulated miR-204 levels. Mature miR-204-5p suppressed SR-A expression via canonical regulation. Unexpectedly, miR-204-3p localized in the nucleus and inhibited CD36 transcription. Restoration of miR-204 abolished the proatherogenic phenotype observed in the macrophage-specific NFATc3 knockout mice, and blockade of miR-204 function reversed the beneficial effects of NFATc3 in macrophages. CONCLUSION: Macrophage NFATc3 up-regulates miR-204 to reduce SR-A and CD36 levels, thereby preventing foam cell formation and atherosclerosis, indicating that the NFATc3/miR-204 axis may be a potential therapeutic target against atherosclerosis.

Design, synthesis and biological evaluation of novel indolin-2-ones as potent anticancer compounds.

The indolin-2-one core is a privileged structure for antitumor agents, especially kinase inhibitors. Twenty-three novel indolin-2-ones were designed by molecular dissection of the anticancer drug indirubin. Seventeen of them exhibited significant inhibition against the tested cell lines, and two of them (1c and 1h) showed IC50 values at the submicromolar level against HCT-116 cells. Compounds 1c and 2c were also potent inhibitors of the triple-negative breast cancer (TNBC) cell line MDA-MB-231. Flow cytometry was utilized to explore the antitumor mechanism of 1c and 2c with MDA-MB-231 cells, and distinct effects were observed on 2c. Furthermore, immunocytochemical examination of 1c suggested a destabilization of microtubules, which was significantly different from the effect of IM, an indirubin derivative.