Neuroinflammation is closely associated with the pathophysiology of neurodegenerative diseases including Parkinson's disease (PD). Recent evidence indicates that astrocytes also play pro-inflammatory roles in the central nervous system (CNS) by activation with toll-like receptor (TLR) ligands. Therefore, targeting anti-inflammation may provide a promising therapeutic strategy for PD. Curcumin, a polyphenolic compound isolated from Curcuma longa root, has been commonly used for the treatment of neurodegenerative diseases. However, the details of how curcumin exerts neuroprotection remain uncertain. Here, we investigated the protective effect of curcumin on 1-methyl-4-phenylpyridinium ion-(MPP(+)-) stimulated primary astrocytes. Our results showed that MPP(+) stimulation resulted in significant production of tumor necrosis factor (TNF)-α, interleukin (IL-6), and reactive oxygen species (ROS) in primary mesencephalic astrocytes. Curcumin pretreatment decreased the levels of these pro-inflammatory cytokines while increased IL-10 expression in MPP(+)-stimulated astrocytes. In addition, curcumin increased the levels of antioxidant glutathione (GSH) and reduced ROS production. Our results further showed that curcumin decreased the levels of TLR4 and its downstream effectors including NF-κB, IRF3, MyD88, and TIRF that are induced by MPP(+) as well as inhibited the immunoreactivity of TLR4 and morphological activation in MPP(+)-stimulated astrocytes. Together, data suggest that curcumin might exert a beneficial effect on neuroinflammation in the pathophysiology of PD.

MicroRNAs (miRNAs) are short non-coding RNAs that regulate gene expression through the endogenous RNA interference machinery. Treatments with combination of chemotherapy with surgery are essential for advanced-stage colorectal cancer. However, the development of chemoresistance is a major obstacle for clinical application of anticancer drugs. In this study, we report a miR-203-SIK2 axis that involves in the regulation of Taxol sensitivity in colon cancer cells. MiR-203 is downregulated in human colon tumor specimens and cell lines compared with their normal counterparts. We report miR-203 is correlated with Taxol sensitivity: overexpression of miR-203 sensitizes colon cancer cells and the Taxol-resistant cells display downregulated miR-203 compared with Taxol-sensitive cells. We identify SIK2 as a direct target of miR-203 in colorectal cancer cells. Overexpression of miR-203 complementary pairs to the 3' untranslated region (UTR) of SIK2, leading to the sensitization of Taxol resistant cells. In addition, miR-203 and the salt-inducible kinase 2 (SIK2) are reverse expressed in human colorectal tumors. Finally, we demonstrate recovery of SIK2 by overexpression of SIK2-desensitized Taxol-resistant cells, supporting the miR-203-mediated sensitization to Taxol, is through the inhibition of SIK2. In general, our study will provide mechanisms of the microRNA-based anti-tumor therapy to develop anti-chemoresistance drugs.

Abstract. Radiotherapy (RT) is commonly used to treat multi-tumors to attenuate the risk of recurrence. Despite impressive initial clinical responses, a large proportion of patients experience resistance to RT. Therefore, identification of functionally relevant biomarkers would be beneficial for radioresistant patients. Adenosine monophosphate-activated kinase (AMPK) is recognized as a mediator of tumor suppressor gene function. In the present study, radio-sensitive and -resistant colon cancer patient samples were compared and the AMPK pathway was observed to be highly activated in radioresistant patients. In addition, the protein and mRNA levels of AMPK were upregulated in radioresistant colon cancer cells in comparison to radiosensitive colon cancer cells. The present study provides evidence that activation of AMPK by metformin contributes to radioresistance. Inhibition of AMPK by either small interfering RNA or Compound C, which is a specific inhibitor of AMPK, re-sensitized radiation resistant cells. The data presented indicates a synergistic effect on radiation resistant cancer cells by the combination of Compound C and radiation. In summary, the present study proposes that inhibition of the AMPK pathway is a potential strategy for reversing radiation resistance and may contribute to the development of therapeutic anticancer drugs.