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Diabetes mellitus is characterized by chronic hyperglycemia and its diverse complications. Hyperglycemia is associated with inflammatory responses in different organs and diabetic patients have a higher risk of developing neurodegenerative disorders. Methylglyoxal is a reactive advanced glycation end product precursor that accumulates in diabetic patients. It induces various stress responses in the central nervous system and causes neuronal dysfunction. Astrocytes are actively involved in maintaining neuronal homeostasis and possibly play a role in protecting the brain against neurodegeneration. However it is not clear whether methylglyoxal exerts any adverse effects towards these astrocytes. In the present study we investigated the effects of methylglyoxal in astrocytic cultures and hippocampi of experimental animals. The cells from the astrocytic line DITNC1 were treated with methylglyoxal for 1 to 24 h. For the in vivo model, 3 months old C57BL/6 mice were treated with methylglyoxal solution for 6 weeks by intraperitoneal injection. Following the treatment, both astrocytes and hippocampi were harvested for MTT assay, Western blot and real time PCR analyses. We found that methylglyoxal induced astrogliosis in DITNC1 astrocytic cultures and C57BL/6 mice. Further, activation of the pro-inflammatory JNK signaling pathway and its downstream effectors c-Jun were observed. Furthermore, increased gene expression of pro-inflammatory cytokines and astrocytic markers were observed from real time PCR analyses. In addition, inhibition of JNK activities resulted in down-regulation of TNF-α gene expression in methylglyoxal treated astrocytes. Our results suggest that methylglyoxal may contribute to the progression of diabetes related neurodegeneration through JNK pathway activation in astrocytes and the subsequent neuroinflammatory responses in the central nervous system.

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Our earliest phytochemical separation of Miliusa sinensis aided us in the isolation of a class of unique miliusanes, which were demonstrated as anticancer lead molecules. In the present study, we isolated 19 miliusanes (1–19), including 11 novel ones (5 and 10–19) from another Miliusa plant (M. balansae), and synthesized additional derivatives to elucidate the structure–activity relationship of miliusanes. When extrapolated to various carcinoma xenograft mouse models, miliusol (1) and its derivatives 20, 26, and 27 (7.5–40 mg/kg) were demonstrated with tumor inhibitory efficacy comparable or even superior to the mainstay chemotherapeutics paclitaxel or fluorouracil. To gain a molecular insight into their anticancer mechanism, 1–3 (GI50 0.03–4.79) were administered to a wide spectrum of human cancer cell lines, including those with specific drug resistance. We further revealed that the antiproliferative properties of miliusanes in carcinoma cells were highly associated with the p21-dependent induction of cellular senescence.

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