作者: Zhong, Huayu ; Dai, Shijie ; Hao, Han ; Yu, Xialin ; Zhao, Weixin ; Hao, Shikang ; Tian, Ziyu ; Liu, Haiyan ; Chen, Mengyu ; Dong, Lilong ; Liu, Shuangyu

BACKGROUND:

Discovering lead compounds with anti-inflammatory and analgesic activities from natural products with minimal toxic side effects has been a long-term goal for researchers. 4-Methylesculetin (4-ME), a natural coumarin derivative, has been reported to have anti-inflammatory and antioxidant properties, but its analgesic effect has not yet been studied. This research investigates the analgesic effect and underlying mechanism of 4-ME in peripheral inflammatory pain.

METHODS:

Acute or chronic inflammatory pain model was established by injecting formalin or Complete Freund's Adjuvant (CFA) into the right hindpaw of rat, respectively. The mechanical and thermal thresholds were detected by using Von Frey and thermal radiation instrument. Patch-clamp recording was performed to study the electrophysiological properties of ion channel. RT-qPCR, western blot, and immunofluorescence were used to analyze mRNA and protein expressions of relevant signaling pathway molecules.

RESULTS:

Intraperitoneal injection of 4-ME could significantly alleviate mechanical and thermal hyperalgesia induced by CFA injection, as well as spontaneous pain induced by formalin injection. In the CFA-induced chronic pain model, 4-ME reduced the levels of IL-6, TNF-α, IL-1β, and inhibited ERK, NF-κB, NLRP3 pathways in dorsal root ganglia (DRG). It downregulated abnormally high expression of TRPV1 caused by CFA injection in DRG, without altering the electrophysiological properties of TRPV1 channel. Further mechanistic studies demonstrated that 4-ME regulated the expression of TRPV1 by inhibiting the transcription factor Sp1. Compared to other coumarin derivatives, 4-ME exhibited a better analgesic effect at low dosage.

CONCLUSION:

Our study reveals for the first time that 4-ME could alleviate peripheral inflammatory pain by inhibiting Sp1-TRPV1 pathway, suggests 4-ME as a potential analgesic, and provides a theoretical basis for 4-ME translation into clinical application.

2018-01-01·Chemico-biological interactions

4-methylesculetin, a coumarin derivative, ameliorates dextran sulfate sodium-induced intestinal inflammation

Article

作者: Di Stasi, Luiz Claudio ; Sartori, Alexandrina ; de Oliveira, Ellen Cristina Souza ; Zorzella-Pezavento, Sofia Fernanda Gonçalves ; Tanimoto, Alexandre ; de Oliveira, Silvio Luis ; Witaicenis, Aline

4-methylesculetin is one of the coumarin derivatives with great anti-oxidant and anti-inflammatory activities. Recent studies have shown that 4-methylesculetin has a promising potentiality to treat inflammatory diseases, especially those related to reactive oxygen species, as inflammatory bowel disease. Based on this, the present study aims to investigate the intestinal anti-inflammatory activity of 4-methylesculetin in dextran sulfate sodium (DSS) model. For this purpose, mice received DSS 5% for 5 days followed by 2 days of filtered tap water. Treated groups received orally 5 or 25 mg/kg of 4-methylesculetin daily since the first day. Macroscopic, microscopic and biochemical parameters were evaluated. 4-methylesculetin (25 mg/kg) improved microscopic parameters, decreased MPO activity, reduced the colonic levels of IL-6 and counteracted GSH depletion when compared with DSS-control group. Our results show the intestinal anti-inflammatory activity of 4-methylesculetin in DSS model, which is related to its antioxidant and anti-inflammatory properties. This way, 4-methylesculetin, is a new potential compound for treatment of both types of IBD.

2015-07-01·Drug metabolism and disposition: the biological fate of chemicals2区 · 医学

UDP-Glucuronosyltransferases 1A6 and 1A9 are the Major Isozymes Responsible for the 7-O-Glucuronidation of Esculetin and 4-Methylesculetin in Human Liver Microsomes

2区 · 医学

Article

作者: Lu, Linlin ; Dai, Peimin ; Luo, Feifei ; Wang, Ying ; Hu, Ming ; Wu, Peng ; Zeng, Shan ; Liu, Zhongqiu ; Liu, Liang ; Zhu, Lijun

Esculetin (6,7-dihydroxycoumarin, ET) and 4-methylesculetin (6,7-dihydroxy-4-methylcoumarin, 4-ME) are typical coumarin derivatives that are attracting considerable attention because of their wide spectrum of biologic activities, but their metabolism remains unknown. This study aimed to elucidate the in vitro UDP-glucuronosyltransferase (UGT) metabolism characteristics of ET and 4-ME. 7-O-monoglucuronide esculetin (ET-G) and 7-O-monoglucuronide 4-methylesculetin (4-ME-G) were identified by liquid chromatography-mass spectrometry (LC-MS) and (1)H-nuclear magnetic resonance ((1)HNMR) when ET or 4-ME was incubated with human liver (HLM) in the presence of UDP-glucuronic acid. Screening assays with 12 human expressed UGTs demonstrated that the formations of ET-G and 4-ME-G were almost exclusively catalyzed by UGT1A6 and UGT1A9. Phenylbutazone and carvacrol (UGT1A6 and UGT1A9 chemical inhibitors, respectively) at different concentrations (50, 100, and 200 μM) significantly inhibited the formation of glucuronidates of ET and 4-ME in HLM, UGT1A6, and UGT1A9 when the concentrations of ET and 4-ME ranged from 10 to 300 μM (P < 0.05). Clearance rates of ET in HLM, HIM, UGT1A6, and UGT1A9 were 0.54, 0.16, 0.69, and 0.14 ml/min/mg, respectively. Corresponding clearance rates values of 4-ME were 0.59, 0.03, 0.14, and 0.04 ml/min/mg, respectively. In conclusion, 7-O-monoglucuronidation by UGT1A6 and UGT1A9 was the predominant UGT metabolic pathway for both ET and 4-ME in vitro. The liver is probably the major contributor to the glucuronidation metabolism of ET and 4-ME. ET showed more rapid metabolism than 4-ME in glucuronidation.

100 项与 4-Methylesculetin 相关的药物交易

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