The pterostilbene-dihydropyrazole derivative Ptd-1 ameliorates vascular calcification by regulating inflammation.

Vascular calcification is an independent risk factor for cardiovascular disease. However, there is still a lack of adequate treatment. This study aimed to examine the potential of (E)-1-(5-(2-(4-fluorobenzyloxy)Styryl)-4,6-dimethoxyphenyl)-3-methyl-4,5-dihydro-1H-pyrazole-1-yl) ethyl ketone (Ptd-1) to alleviate vascular calcification. ApoE-deficient mice were fed a high-fat diet for 12/16 weeks to induce intimal calcification, and wild-type mice were induced with a combination of nicotine and vitamin D3 to induce medial calcification. Human aortic smooth muscle cells (HASMCs) and aortic osteogenic differentiation were induced in vitro with phosphate. In the mouse model of atherosclerosis, Ptd-1 significantly ameliorated the progression of atherosclerosis and intimal calcification, and there were significant reductions in lipid deposition and calcium salt deposition in the aorta and aortic root. In addition, Ptd-1 significantly improved medial calcification in vivo and osteogenic differentiation in vitro. Mechanistically, Ptd-1 reduced the levels of the inflammatory factors IL-1ß, TNFα and IL-6 in vivo and in vitro. Furthermore, we demonstrated that Ptd-1 could attenuate the expression of p-ERK1/2 and ß-catenin, and that the levels of inflammatory factors were elevated in the presence of ERK1/2 and ß-catenin agonists. Interestingly, we determined that activation of the ERK1/2 pathway promoted ß-catenin expression, which further regulated the IL-6/STAT3 signaling pathway. Ptd-1 blocked ERK1/2 signaling, leading to decreased expression of inflammatory factors, which in turn improved vascular calcification. Taken together, our study reveals that Ptd-1 ameliorates vascular calcification by regulating the production of inflammatory factors, providing new ideas for the treatment of vascular calcification.

Design, synthesis, and SAR study of novel flavone 1,2,4-oxadiazole derivatives with anti-inflammatory activities for the treatment of Parkinson's disease.

Inflammation is one of a major feature of Parkinson's disease (PD) which poses a threat to people's health in the world. It has been reported that antioxidation and anti-inflammation have significant effects on the treatment of PD. 1,2,4-oxadiazole and flavone derivatives have remarkable antioxidant and anti-inflammatory activities. In order to find highly effective drugs for PD treatment, based on the remarkable anti-inflammatory and antioxidant activities of the 1,2,4-oxadiazole pharmacophore and the flavonoid pharmacophore, we designed and synthesized a novel series of 3-methyl-8-(3-methyl-1,2,4-oxadiazol-5-yl)-2-phenyl-4H-chromen-4-one derivatives by pharmacophore combination, and evaluated their anti-inflammatory and antioxidation activities for PD treatment. Preliminary structure-activity relationship (SAR) analysis was conducted by their inhibitory activities against reactive oxygen species (ROS) and NO release in LPS-induced BV2 Microglia cells, and the optimal compound Flo8 exhibited the most potent anti-inflammatory and antioxidant activities. Both in vivo and in vitro results showed that Flo8 inhibited neuronal apoptosis by inhibiting inflammatory and apoptotic signaling pathways. In vivo studies also showed that the compound Flo8 ameliorated motor and behavioral deficits and increased serum dopamine levels in MPTP-induced PD model mice. Taken together, this study demonstrated the compound Flo8 could be a promising agent for the treatment of PD.