评估LM49片在中国健康受试者中单次和多次口服给药后的安全性和耐受性；次要目的：评估LM49片在中国健康受试者中单次和多次口服给药后的药代动力学（PK）特征；评估LM49片在中国健康受试者中单次和多次口服给药后的药效动力学（PD）特征；评估食物对LM49片在中国健康受试者中PK的影响；血浆和尿液中代谢物鉴定及相对定量；探索性目的：初步评价LM49片在中国健康受试者单次和多次口服给药后的血药浓度与QTc间期的关系

开始日期-

申办/合作机构

山西医科大学

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100 项与 LM49 相关的临床结果

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100 项与 LM49 相关的转化医学

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100 项与 LM49 相关的专利（医药）

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项与 LM49 相关的文献（医药）

2022-11-01·Toxicology and Applied Pharmacology

Improving endothelial cell junction integrity by diphenylmethanone derivatives at oxidative stress: A dual-action directly targeting caveolar caveolin-1

Article

作者: Feng, Xiu-E ; Ren, Jin-Hong ; Yuan, Hong-Xia ; Qiao, Yuan-Biao ; Sun, Jian ; Li, Qing-Shan ; Zhang, Yuan-Lin

Directly targeting caveolar caveolin-1 is a potential mechanism to regulate endothelial permeability, especially during oxidative stress, but little evidence on the topic limits therapeutics discoveries. In this study, we investigated the pharmacological effect of an antioxidant LM49 (5,2'-dibromo-2,4',5'-trihydroxydiphenylmethanoe) and its five diphenylmethanone derivatives on endothelial permeability and establish two distinct mechanisms of action. Multiplex molecular assays with theoretical modeling indicate that diphenylmethanone molecules, including LM49, directly bind the caveolin-1 steric pocket of ASN53/ARG54, ILE49/ASP50, ILE18, LEU59, ASN60, GLU48 and ARG19 residues. They also indicated dynamic binding-affinity for diphenylmethanone derivatives. First, this molecular interaction at caveolin-1 pocket inhibits its phosphorylation at TYR14 residue in H₂O₂-injured endothelial cell. A positive correlation was established between diphenylmethanone derivative binding-affinity and caveolin-1 phosphorylation inhibition. Inhibition of caveolin-1 phosphorylation, however, was independent of the LM49-mediated variation of protein tyrosine kinase activity, suggesting a direct blockage of adenosine triphosphate substrate diffusion into cavelion-1 structure. Second, LM49 increases the expression of cellular adhesive and tight junction proteins, VE-cadherin and occludin, in H₂O₂-injured cell, in a dose dependent manner. A leakage assay of fluorescein isothiocyanate-labeled dextran 40 across cell monolayer suggested improvement in endothelial barrier integrity with diphenylmethanone treatments. Our results demonstrate a direct targeting effect of caveolin-1 on endothelial permeability, and should guide the diphenylmethanone therapy against oxidative stress-induced junction dysfunction, especially at caveolar membrane invagination.

2021-07-01·International Immunopharmacology2区 · 医学

An active marine halophenol derivative attenuates lipopolysaccharide-induced acute liver injury in mice by improving M2 macrophage-mediated therapy

2区 · 医学

Article

作者: Yang, Fan ; Feng, XiuE ; Xiao, BaoGuo ; Zhang, XiaoYan ; Sun, Jian ; Zhang, Xuan ; Li, QingShan ; Cai, HongHong ; Yuan, HongXia

2,4',5'-Trihydroxyl-5,2'-dibromo diphenylmethanone (LM49), an active halophenol derivative synthesized by our group, which exhibits a broad spectrum of therapeutic properties, such as antioxidant and anti-inflammatory activities. In this study, we found LM49 could obviously attenuate acute liver injury induced by lipopolysaccharide (LPS) in mice by polarizing macrophages. The protective effect was described by reducing the hepatic inflammation and improving hepatic function using aspartate transaminase (AST) and alanine transaminase (ALT) assay. Further study revealed that LM49 pretreatment induced the Kupffer cells (KCs) to M2 polarization and decreased the production of inflammatory cytokines. The action mechanism in RAW 264.7 macrophages showed that LM49 could induce the activation of JAK1/STAT6 signaling pathway and the inhibition of TLR-4/NF-kB axis. Morever, LM49 also upregulated the expression of SOCS1 and FLK-4, which can promote M2 polarization by cooperating with STAT6 and inhibit M1 formation by reducing JAK1/STAT1. Our results suggested that LM49 could protect against LPS-induced acute liver injury in mice via anti-inflammatory signaling pathways and subsequent induction of M2 Kupffer cells. The results provided the first experimental evidence of active halophenols for the anti-inflammatory therapy by targeting M2 macrophages.

2020-08-01·Pharmacological Reports4区 · 医学

A novel marine halophenol derivative attenuates lipopolysaccharide-induced inflammation in RAW264.7 cells via activating phosphoinositide 3-kinase/Akt pathway

4区 · 医学

Article

作者: Yang, Fan ; Li, Qing-Shan ; Feng, Xiu-E ; Cai, Hong-Hong

BACKGROUND2,4',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.METHODSRAW264.7 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.RESULTSOur 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.CONCLUSIONThese 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.

100 项与 LM49 相关的药物交易

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