Design, synthesis, in vitro and in vivo biological evaluation of pterostilbene derivatives for anti-inflammation therapy.

Pterostilbene (PST) is a naturally derived stilbene compound in grapes, blueberries, and other fruits. It is also a natural dietary compound with a wide range of biological activities such as antioxidant, anti-inflammatory, antitumor, and so on. Structural modifications based on the chemical scaffold of the pterostilbene skeleton are of great importance for drug discovery. In this study, pterostilbene skeletons were used to design novel anti-inflammatory compounds with high activity and low toxicity. A total of 30 new were found and synthesised, and their anti-inflammatory activity and safety were screened. Among them, compound E2 was the most active (against NO: IC50 = 0.7 µM) than celecoxib. Further studies showed that compound E2 exerted anti-inflammatory activity by blocking LPS-induced NF-κB/MAPK signalling pathway activation. In vivo experiments revealed that compound E2 had a good alleviating effect on acute colitis in mice. In conclusion, compound E2 may be a promising anti-inflammatory lead compound.

Discovery of pterostilbene analogs as novel NLRP3 inflammasome inhibitors for potential treatment of DSS-induced colitis in mice.

The pterostilbene skeleton is a promising chemical scaffold that exerts anti-inflammatory, anti-depressant, and anti-tumor effects. In this study, we aim to reduce in vivo and in vitro toxicity of compound 32 (preliminary work) and maintain its biological activity. A series of novel pterostilbene derivatives (D1-D43) were designed and synthesized, and their anti-inflammatory activities were screened. All compounds were screened to evaluate their inhibitory effect on LPS/Nigericin-induced IL-1ß production and pyroptosis. The structure-activity relationships was deduced, and finally 1-((E)-4-(2-ethoxyethoxy)styryl)-3,5-dimethoxy-2-((E)-2-nitrovinyl)benzene (D22) was found to be a low-toxic compound with most potent inhibitory efficacy (against IL-1ß: IC50 = 2.41 µM). Preliminary mechanism studies showed that compound D22 may affect the assembly of NLRP3 inflammasome by targeting NLRP3 protein, thereby inhibiting the activation of NLRP3 inflammasome. The in vivo anti-inflammatory activity indicated that compound D22 had significant therapeutic effects on DSS-induced mouse acute colitis models.

Microcystin-LR-induced nuclear translocation of cGAS promotes mutagenesis in human hepatocytes by impeding homologous recombination repair.

Microcystin-LR (MC-LR) has been recognized as a typical hepatotoxic cyclic peptides produced by cyanobacteria. Nowadays, due to the frequent occurrence of cyanobacterial blooms, the underlying hepatotoxic mechanism of MC-LR has become the focus of attention. In our present work, the mutagenic effect of MC-LR on human normal hepatic (HL-7702) cells regulated by cGAS was mainly studied. Here, we showed that exposure to MC-LR for 1-4 days could activate the cGAS-STING signaling pathway and then trigger immune response in HL-7702 cells. Notably, relative to the treatment with 1 µM MC-LR for 1-3 days, it was observed that when HL-7702 cells were exposed to 1 µM MC-LR for 4 days, the mutation frequency at the Hprt locus was remarkably increased. In addition, cGAS in HL-7702 cells was also found to complete the nuclear translocation after 4-day exposure. Moreover, co-immunoprecipitation and homologous recombination (HR)-directed DSB repair assay were applied to show that homologous recombination repair was inhibited after 4-day exposure. However, the intervention of the nuclear translocation of cGAS by transfecting BLK overexpression plasmid restored homologous recombination repair and reduced the mutation frequency at the Hprt locus in HL-7702 cells exposed to MC-LR. Our study unveiled the distinct roles of cGAS in the cytoplasm and nucleus of human hepatocytes as well as potential mutagenic mechanism under the early and late stage of exposure to MC-LR, and provided a novel insight into the prevention and control measures about the hazards of cGAS-targeted MC-LR.

Synthesis and in vitro and in vivo anti-inflammatory activity of novel 4-ferrocenylchroman-2-one derivatives.

A series of novel 4-ferrocenylchroman-2-one derivatives were designed and synthesised to discover potent anti-inflammatory agents for treatment of arthritis. All the target compounds had been screened for their anti-inflammatory activity by evaluating the inhibition effect of LPS-induced NO production in RAW 264.7 macrophages. Among them, 4-ferrocenyl-3,4-dihydro-2H-benzo[g]chromen-2-one (3h) was found to be the most potent compound in inhibiting the productions of NO with low toxicity. This compound also exhibited significant inhibition of the productions of IL-6 and TNF-α in RAW 264.7 macrophages. Preliminary mechanism studies indicated that compound 3h could inhibit the activation of LPS-induced NF-κB and MAPKs signalling pathways. The in vivo anti-inflammatory effect of this compound was determined in the rat adjuvant-induced arthritis model.