KM Convergence Research Division, Korea Institute of Oriental Medicine, Daejeon 34054, South Korea; College of Pharmacy, Natural Products Research Institute, Seoul National University, Seoul 08826, South Korea.
KM Convergence Research Division, Korea Institute of Oriental Medicine, Daejeon 34054, South Korea.
Phytomedicine. 2022 Sep;104:154318. doi: 10.1016/j.phymed.2022.154318. Epub 2022 Jul 4.
Terminalia chebula (TC) is a traditional medicinal plant used for treating various diseases in humans. However, pharmacological mechanisms underlying the effects of TC in atopic treatment remain unelucidated.
HYPOTHESIS/PURPOSE: We investigated the therapeutic effects of TC extract in a mouse model of atopic dermatitis (AD) in vivo and the anti-inflammatory mechanism in vitro.
STUDY DESIGN/METHODS: For the in vivo study, AD was induced by Dermatophagoides farinae extract (Dfe) in NC/Nga mice. After 14 days of oral administration, the effects of TC concentrations of 30, 100, and 300 mg/kg were analyzed by assessing morphological changes visually; measuring serum levels of inflammatory chemokines/cytokines, IgE, histamine, MDC, TARC, RANTES, and TSLP using ELISA kits; and counting infiltrated mast cells. For in vitro analyses, we used IFNγ/TNF-α-stimulated human keratinocyte cell lines to study the mechanism of action. The production of chemokines/cytokines in the IFNγ/TNF-α-stimulated HaCaT cells was measured using ELISA and a bead array kit. The signaling pathways were analyzed by western blotting and the expression of the transcriptional factors using RT-PCR and luciferase assay.
Administration of TC significantly alleviated AD-like symptoms in vivo and decreased the ear thickness, dermatitis score, keratinization, and mast cell infiltration. It also resulted in decreased serum levels of IgE, histamine, and inflammation-related mediators MDC, TARC, RANTES, and TSLP compared with those in the Dfe treatment group. Moreover, TC downregulated the expression of the inflammatory chemokines RANTES and MDC in IFNγ/TNF-α-stimulated HaCaT cells. TC inhibited phosphorylated STAT1/3 and NK-κB subunits and nuclear translocation of NF-κB. It also suppressed the transcription of IFNγ, IL-6, IL-8 and MCP-1 in the IFNγ/TNF-α-stimulated HaCaT cells. TC and its constituents, chebulic acid, gallic acid, corlagin, chebulanin, chbulagic acid, ellagic acid, and chebulinic acid, strongly inhibited the nuclear translocation of NF-κB, STAT1, and STAT3 and decreased the expression of inflammatory cytokines at the mRNA level.
Overall, TC extract alleviated AD-like symptoms by regulating anti-inflammatory factors in vivo and suppressing STAT1/3 and NF-κB signaling in vitro. In addition, our results show the in vivo effect of partial improvements in AD, as well as the in vitro effect on inflammatory factors by the constituents of TC. This finding provides that TC extract and its components could be potential therapeutic drugs for AD.
诃子（TC）是一种传统的药用植物，用于治疗人类的各种疾病。然而，TC 在特应性皮炎治疗中的作用的药理机制仍不清楚。
假说/目的：我们研究了 TC 提取物在特应性皮炎（AD）小鼠模型中的体内治疗作用和体外抗炎机制。
研究设计/方法：在体内研究中，用尘螨提取物（Dfe）诱导 NC/Nga 小鼠 AD。在口服给药 14 天后，通过观察肉眼形态变化、检测血清中炎症趋化因子/细胞因子、IgE、组胺、MDC、TARC、RANTES 和 TSLP 的水平，分析 TC 浓度为 30、100 和 300mg/kg 的效果，采用 ELISA 试剂盒；并计数浸润的肥大细胞。对于体外分析，我们使用 IFNγ/TNF-α 刺激的人角质形成细胞系来研究作用机制。通过 ELISA 和珠子阵列试剂盒测量 IFNγ/TNF-α 刺激的 HaCaT 细胞中趋化因子/细胞因子的产生。通过 Western blot 分析信号通路，并通过 RT-PCR 和荧光素酶测定法分析转录因子的表达。
TC 给药显著缓解了体内 AD 样症状，降低了耳厚度、皮炎评分、角化和肥大细胞浸润。与 Dfe 治疗组相比，血清 IgE、组胺和炎症相关介质 MDC、TARC、RANTES 和 TSLP 水平也降低。此外，TC 下调了 IFNγ/TNF-α 刺激的 HaCaT 细胞中炎症趋化因子 RANTES 和 MDC 的表达。TC 抑制磷酸化 STAT1/3 和 NK-κB 亚基以及 NF-κB 的核易位。它还抑制了 IFNγ/TNF-α 刺激的 HaCaT 细胞中 IFNγ、IL-6、IL-8 和 MCP-1 的转录。TC 及其成分诃子酸、没食子酸、考来维林、诃子宁、诃子酸、鞣花酸和诃子酸，强烈抑制 NF-κB、STAT1 和 STAT3 的核易位，并降低炎症细胞因子的 mRNA 水平表达。
总之，TC 提取物通过调节体内抗炎因子和抑制 STAT1/3 和 NF-κB 信号通路，缓解 AD 样症状。此外，我们的结果表明，TC 的部分改善对 AD 具有体内作用，以及对 TC 成分的炎症因子具有体外作用。这一发现表明 TC 提取物及其成分可能是 AD 的潜在治疗药物。
