OBJECTIVES: To investigate the therapeutic mechanism of 2,6-dimethoxy-1,4-benzoquinone (DMQ) for alleviating dextran sulfate sodium (DSS)-induced ulcerative colitis (UC) in mice. METHODS: Eighteen male C57BL/6J mice were equally randomized into control group, DSS group and DMQ treatment group. In DSS and DMQ groups, the mice were treated with DSS in drinking water to induce UC, and received intraperitoneal injections of sterile PBS or DMQ (20 mg/kg) during modeling. The changes in body weight, disease activity index (DAI), colon length, spleen weight, and colon histological scores of the mice were examined, and the percentages of Th17 and IFN-γ⁺ CD8⁺ T cells in the mesenteric lymph nodes and spleen were analyzed using flow cytometry. The expressions of tight junction proteins (Occludin and ZO-1), proteins associated with inflammasome activation (caspase-1 and p20), IL-1β and TNF-α in the colon tissues were detected using Western blotting or ELISA. In the cell experiment, mouse bone marrow-derived macrophages (BMDMs) primed with lipopolysaccharide (LPS) were treated with DMQ, followed by stmulation with nigericin to activate the classical NLRP3 inflammasome pathway. In cultured human peripheral blood mononuclear cells (PBMCs) treated with either LPS alone or LPS plus nigericin, the effects of DMQ on inflammasome activation, pyroptosis, and cytokine release were evaluated via Western blotting, ELISA, and flow cytometry. RESULTS: In DSS-treated mice, DMQ treatment significantly alleviated DSS-induced body weight loss, colon shortening, spleen enlargement, and colon inflammation. The DMQ-treated mice showed significantly reduced percentages of Th17 cells and IFN-γ⁺ CD8⁺ T cells in the mesenteric lymph nodes and spleen, with increased occludin and ZO-1 expressions and decreased caspase-1 expression in the colon tissue. DMQ obviously inhibited classical NLRP3 inflammasome activation in mouse BMDMs and both the classical and alternative pathways of NLRP3 activation in human PBMCs, causing also suppression of caspase-1-dependent pyroptosis. CONCLUSIONS DMQ ameliorates DSS-induced UC in mice by inhibiting NLRP3 inflammasome activation.
Animals ; NLR Family, Pyrin Domain-Containing 3 Protein/metabolism* ; Mice, Inbred C57BL ; Colitis, Ulcerative/metabolism* ; Dextran Sulfate/adverse effects* ; Male ; Inflammasomes/metabolism* ; Mice ; Benzoquinones/therapeutic use* ; Th17 Cells ; Caspase 1/metabolism*

Apoptosis ; drug effects ; Benzoquinones ; pharmacology ; Carcinoma, Non-Small-Cell Lung ; drug therapy ; metabolism ; pathology ; Drug Resistance, Neoplasm ; HSP90 Heat-Shock Proteins ; antagonists & inhibitors ; Humans ; Lactams, Macrocyclic ; pharmacology ; Lung Neoplasms ; drug therapy ; metabolism ; pathology ; Mutation ; Oncogene Proteins, Fusion ; antagonists & inhibitors ; genetics ; metabolism ; Protein Kinase Inhibitors ; therapeutic use ; Pyrazoles ; therapeutic use ; Pyridines ; therapeutic use ; Triazoles ; pharmacology

Heat shock protein 90 is a new target of antitumor drug, the inhibitor of Hsp90 fight against tumor by destroy and degrade the structure of protein. In recent years, looking for Hsp90 inhibitor is not only via structure modifying of natural products, but also via high throughput screening and computer aided drug design to find and synthesize new kinds of Hsp90 inhibitor. Anyway, Hsp90 inhibitor has considered as an important biology target and to pay more and more attention. This review describes recent developments of small molecule Hsp90 inhibitors.
Adenine ; analogs & derivatives ; chemistry ; pharmacology ; Animals ; Anisoles ; chemistry ; pharmacology ; Antineoplastic Agents ; chemistry ; pharmacology ; therapeutic use ; Benzoquinones ; chemistry ; therapeutic use ; Catechin ; analogs & derivatives ; chemistry ; pharmacology ; Cell Line, Tumor ; Crystallization ; HSP90 Heat-Shock Proteins ; antagonists & inhibitors ; chemistry ; Heterocyclic Compounds, 2-Ring ; chemistry ; pharmacology ; Humans ; Lactams, Macrocyclic ; chemistry ; therapeutic use ; Macrolides ; chemistry ; pharmacology ; Molecular Structure ; Neoplasms ; drug therapy ; pathology ; Pyrazoles ; chemistry ; pharmacology ; Structure-Activity Relationship

AIMTo search for novel antiasthmatic agents.

METHODSCoupling seratrodast (SD), an antiasthmatic drug, with several different types of NO donors including oxatriazoles, N-hydroxyguanidines and furoxans; evaluating the antiasthmatic effects of coupled compounds by determining their inhibitory activity of guinea pig asthma induced by acetylcholine and histamine; and assessing NO releasing ability.

RESULTSNine novel target compounds (I1-9) were synthesized, and their structures were established by IR, NMR, MS and elemental analysis. Preliminary pharmacological test showed that most of the compounds showed high antiasthmatic activities (the latent period of induced asthma was prolonged from 10 s (SD) to 26-62 s), among which 3 compounds (I4, I6, I7) were more potent than SD (P < 0.05, P < 0.01) and released more NO than others. The maximum concentrations (Cmax) of NO-release in vitro were 0.1878, 0.1393 and 0.2473 mg x L(-1), respectively.

CONCLUSIONNO donating-SD derivatives are worthy to be futher investigated.

Acetylcholine ; Animals ; Anti-Asthmatic Agents ; chemical synthesis ; pharmacology ; therapeutic use ; Asthma ; chemically induced ; prevention & control ; Benzoquinones ; chemical synthesis ; pharmacology ; therapeutic use ; Guanidines ; chemistry ; pharmacology ; Guinea Pigs ; Heptanoic Acids ; chemical synthesis ; pharmacology ; therapeutic use ; Histamine ; Nitric Oxide ; metabolism ; Nitric Oxide Donors ; chemistry ; pharmacology ; Oxadiazoles ; chemistry ; pharmacology ; Structure-Activity Relationship