Search

Background: 2,4',5'-Trihydroxyl-5,2'-dibromo diphenylmethanone (LM49), a novel active halophenol derivative synthesized by our group from marine plants, exhibits strong anti-inflammatory activities. However, molecular machineries involved in its effect have not been fully identified. The study was aimed to investigate the anti-inflammatory effect of LM49 on lipopolysaccharide (LPS)-stimulated RAW264.7 cells and its underlying mechanism., Methods: RAW264.7 cells were treated with LPS (10 μg/mL) and then exposed to different concentrations of LM49 (i.e., 5, 10, and 15 μM) for 24 h. Cytokine release in culture medium of RAW264.7 cells was measured by enzyme-linked immunosorbent assay (ELISA). Phagocytic capacity (FITC-dextran uptake) was determined by flow cytometry. The protein level of phosphoinositide 3-kinase (PI3K), AKT and p-AKT was measured by western blot analysis., Results: Our findings revealed that LM49 reduced the production and mRNA levels of cytokines related to inflammation such as interleukin (IL)-6, IL-1β, and tumor necrosis factor-α (TNF-α), and increased the level of IL-10, an anti-inflammatory cytokine. In addition, LM49 decreased the production of nitric oxide and reactive oxygen species. Moreover, flow cytometry showed that LM49 significantly enhanced the phagocytic capacity (FITC-dextran uptake) of macrophages. The effects of LM49 were significantly inhibited by the phosphoinositide 3-kinase (PI3K) inhibitor, LY294002. In particular, LY294002 attenuated the phagocytic capacity of RAW264.7 cells induced by LM49 and prevented the effects on cytokines., Conclusion: These findings suggest that LM49 possesses anti-inflammatory activity on LPS-stimulated RAW264.7 cells, in which the PI3K/Akt pathway plays an essential role. LM49 may have clinical utility as an anti-inflammatory agent. In this study, we demonstrated that a halophenol derivative (LM49) could possess anti-inflammatory activity on LPS-stimulated RAW264.7 cells by reducing pro-inflammatory cytokines and enhancing the phagocytic capacity, in which the PI3K/Akt pathway plays an essential role. LM49 may have clinical utility as an anti-inflammatory agent.

Inflammation and reactive oxygen species (ROS) are important factors in the pathogenesis of atherosclerosis (AS). 5,2'-dibromo-2,4',5'-trihydroxydiphenylmethanone (TDD), possess anti-atherogenic properties; however, its underlying mechanism of action remains unclear. Therefore, we sought to understand the therapeutic molecular mechanism of TDD in inflammatory response and oxidative stress in EA.hy926 cells. Microarray analysis revealed that the expression of homeobox containing 1 (HMBOX1) was dramatically upregulated in TDD-treated EA.hy926 cells. According to the gene ontology (GO) analysis of microarray data, TDD significantly influenced the response to lipopolysaccharide (LPS); it suppressed the LPS-induced adhesion of monocytes to EA.hy926 cells. Simultaneously, TDD dose-dependently inhibited the production or expression of IL-6, IL-1β, MCP-1, TNF-α, VCAM-1, ICAM-1 and E-selectin as well as ROS in LPS-stimulated EA.hy926 cells. HMBOX1 knockdown using RNA interference attenuated the anti-inflammatory and anti-oxidative effects of TDD. Furthermore, TDD inhibited LPS-induced NF-κB and MAPK activation in EA.hy926 cells, but this effect was abolished by HMBOX1 knockdown. Overall, these results demonstrate that TDD activates HMBOX1, which is an inducible protective mechanism that inhibits LPS-induced inflammation and ROS production in EA.hy926 cells by the subsequent inhibition of redox-sensitive NF-κB and MAPK activation. Our study suggested that TDD may be a potential novel agent for treating endothelial cells dysfunction in AS., (© 2018 The Authors. Journal of Cellular and Molecular Medicine published by John Wiley & Sons Ltd and Foundation for Cellular and Molecular Medicine.)

Antibiotics are still the primary therapy for acute pyelonephritis (APN); rarely, natural polyphenols are also used. LM49 is a novel marine bromophenol derivative displaying strong anti-inflammatory effects. We investigated the therapeutic efficacy of LM49 in an experimental rat model of APN. The model was established by injecting 0.5 mL Escherichia coli (ATCC 25922, 10 8  CFU/mL) into the urinary bladders of Sprague Dawley rats. This model showed increased kidney viscera indices and renal bacterial growth scores, as well as pathological changes in kidneys. We also performed a broth microdilution antimicrobial susceptibility test of the E. coli strain. Both norfloxacin and LM49 treatment reduced kidney viscera indices and decreased microbial counts in urine cultures and kidney homogenates in APN rats. However, in vitro experiments showed that LM49 did not directly inhibit bacteria. Rather, LM49 treatment inhibited inflammatory cell infiltration or abscess and improved tissue lesions in the renal medullary junction, renal pelvis, and calyx, and high-dose LM49 treatment inhibited the production of inflammatory interleukin-1β (IL-1β) and interleukin-6 (IL-6) in serum. CD4 + T cells were higher in the LM49 groups treated with high, medium, and low doses than in the model group, whereas only high-dose LM49 treatment increased the number of CD8 + T cells, as compared with that in the model group. However, LM49 treatment did not influence hematological parameters. Our results show that LM49 therapeutic effects in an APN animal model may be achieved by regulating immune responses and inhibiting inflammatory mediators, suggesting it as a candidate APN treatment., (Copyright © 2018 Elsevier B.V. All rights reserved.)

A series of novel 4-substituted benzoxazolone derivatives was synthesized, characterized and evaluated as human soluble epoxide hydrolase (sEH) inhibitors and anti-inflammatory agents. Some compounds showed moderate sEH inhibitory activities in vitro, and two novel compounds, 3g and 4j, exhibited the highest activities with IC50 values of 1.72 and 1.07 μM, respectively. Structure-activity relationships (SARs) revealed that introduction of a lipophilic amino acid resulted in an obvious increase in the sEH inhibitory activity, especially for derivatives containing a phenyl (3d, IC(50) = 2.67 μM), pyrrolidine (3g, IC(50) = 1.72 μM), or sulfhydryl group (3e, IC(50)=3.02 μM). Several compounds (3a-3g) were tested in vivo using a xylene-induced ear edema mouse model. Three compounds (3d, 3f, and 3g) showed strong anti-inflammatory activities in vivo which were higher than that of Chlorzoxazone, a reference drug widely used in the clinic. Our investigation provided a novel type of sEH inhibitor and anti-inflammatory agent that may lead to the discovery of a potential candidate for clinical use., (Copyright © 2013 Elsevier Ltd. All rights reserved.)