Novel thiazolidinedione analogues as 15-hydroxyprostaglandin dehydrogenase (15-PGDH) inhibitors were synthesized. Compounds 2, 3, and 4 exhibited IC(50) of 25, 8, and 19 nM, respectively. They also significantly increased levels of PGE(2) in A549 cells. To assess the influence of 15-PGDH inhibitor on cochlear blood flow (CBF), 2 was applied intravenously to guinea pigs. It increased their CBFs. Scratch wounds were also analyzed in confluent monolayers of HaCaT cells. Cells exposed to 4 showed significantly improved wound healing with respect to a control.
High-mobility group box 1 (HMGB1) enhances inflammatory reactions by potentiating the activity of pro-inflammatory mediators and suppressing the phagocytosis of apoptotic neutrophils. However, the effects of HMGB1 on phagocytosis induced by pro-resolving mediators, such as resolvins, have not been studied up until this point. In this study, we investigated the effects and underlying mechanism of HMGB1 on resolvin D1-induced phagocytosis of MDA-MB-231 cells, which were selected as a model system based on their phagocytic capability and ease of transfecting them with a plasmid or siRNA in several cancer cell lines. Then we confirmed effects of HMGB1 in THP-1 cells. Resolvin D1 (RvD1) enhanced phagocytosis in MDA-MB-231 and THP-1 cells. HMGB1 suppressed RvD1-induced phagocytosis in MDA-MB.231 and THP-1 cells. HMGB1 dose-dependently induced the expression of 15-hydroxyprostaglandin dehydrogenase (15-PGDH), the inactivating enzyme in pro-resolving lipid mediators such as RvE1 and RvD1. Involvement of 15-PGDH in-HMGB-1-induced suppression of phagocytosis was examined using siRNA of 15-PGDH or 15-PGDH inhibitor, TD23. Surprisingly, the silencing of 15-PGDH increased phagocytotic activity of MDA-MB-231 cells. TD23 also enhanced phagocytosis of MDA-MB-231 and THP-1 cells. In conclusion, the release of HMGB1 during the inflammatory phase induces 15-PGDH expression, which suppresses the phagocytotic activity of macrophages. These processes might be involved in the mechanism that blocks the resolution of inflammation, thereby allowing acute inflammation to progress to chronic inflammation.
6-(1-azidoalkyl)-DMNQ derivatives compared to 2-(1-azidoalkyl)-DMNQ isomers, exhibited higher cytotoxic activity against L1210 mouse leukemia cells and stronger inhibition of DNA topoisomerase-I (TOPO-I), suggesting involvement of steric hindrance. However, similar antitumor activity against mice bearing S-180 cell was shown by 2- and 6-(1-azidoalkyl)-DMNQ derivatives.
The aim of this work was to evaluate the synthesis and structure-activity relationship of 4-((2,4-dioxothiazolidin-5-ylidene)methyl)phenyl 2-phenylacetate derivatives as potential wound-healing agents. The IC values of the lead compounds ranged from 0.01 to 0.05 µM. These compounds also increased the levels of extracellular prostaglandin E (PGE) in A549 cells. Among the synthesized compounds, compounds 66, 67, 69, and 86 increased PGE levels 3- to 4-fold of those achieved with the negative control. Introduction of a halogen at the intermediate phenyl ring, compounds 66, 67, 69, and 86 resulted in higher IC values, which indicated lower cytotoxicity than that observed upon the introduction of other substituents at the same position. In particular, cells exposed to compound 69 showed significantly improved wound healing, and the wound closure rate achieved was approximately 3.2-fold higher than that of the control. Therefore, compound 69 can be used for tissue regeneration and treatment of diverse diseases caused by PGE deficiency. Overall, our findings suggested that compound 69 might be a novel candidate for skin wound therapy.
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