Lonicerin targets EZH2 to alleviate ulcerative colitis by autophagy-mediated NLRP3 inflammasome inactivation

Aberrant activation of NLRP3 inflammasome in colonic macrophages strongly associates with the occurrence and progression of ulcerative colitis. Although targeting NLRP3 inflammasome has been considered to be a potential therapy, the underlying mechanism through which pathway the intestinal inflammation is modulated remains controversial. By focusing on the flavonoid lonicerin, one of the most abundant constituents existed in a long historical anti-inflammatory and anti-infectious herb Lonicera japonica Thunb., here we report its therapeutic effect on intestinal inflammation by binding directly to enhancer of zeste homolog 2 (EZH2) histone methyltransferase. EZH2-mediated modification of H3K27me3 promotes the expression of autophagy-related protein 5, which in turn leads to enhanced autophagy and accelerates autolysosome-mediated NLRP3 degradation. Mutations of EZH2 residues (His129 and Arg685) indicated by the dynamic simulation study have found to greatly diminish the protective effect of lonicerin. More importantly, in vivo studies verify that lonicerin dose-dependently disrupts the NLRP3–ASC–pro-caspase-1 complex assembly and alleviates colitis, which is compromised by administration of EZH2 overexpression plasmid. Thus, these findings together put forth the stage for further considering lonicerin as an anti-inflammatory epigenetic agent and suggesting EZH2/ATG5/NLRP3 axis may serve as a novel strategy to prevent ulcerative colitis as well as other inflammatory diseases.     

不同透皮促进剂对马钱子碱体外透皮吸收的影响

目的考察不同透皮促进剂对马钱子碱体外透皮吸收的影响。方法采用改良Franz扩散池,选用离体猪耳朵皮为屏障,考察不同类型的透皮促进剂对马钱子碱体外透皮吸收速率、增渗倍数等参数的影响。结果除吐温-80外,各透皮促进剂均能提高马钱子碱的透皮速率,促透能力由弱至强依次为桉叶素<油酸<氮酮<肉豆蔻酸异丙酯<柠檬烯。结论本研究可为马钱子碱外用剂型的选择与优化提供指导。     

Novel chemical permeation enhancers for transdermal drug delivery

Transdermal drug delivery has been accepted as a potential non-invasive route of drug administration, with advantages of prolonged therapeutic action, decreased side effect, easy use and better patient compliance. However, development of transdermal products is primarily hindered by the low permeability of the skin. To overcome this barrier effect, numerous new chemicals have been synthesized as potential permeation enhancers for transdermal drug delivery. In this review, we presented an overview of the investigations in this field, and further implications on selection or design of suitable permeation enhancers for transdermal drug delivery were also discussed.     

依诺沙星角膜透过性的研究

目的:研究依诺沙星(ENX)的角膜透过性,为其处方设计提供理论基础.方法:采用体外扩散实验考察在多种渗透促进剂条件下ENX的离体兔眼角膜透过性.结果:1%的泊洛沙姆F68和2%羟丙基-β-环糊精(HP-β-CD)分别使ENX的表观渗透系数增加1.65和2.05倍,与对照组呈现显著性差异(P<0.01),而0.5%乙二胺四乙酸二钠(EDTA)与0.05%月桂氮(艹卓)酮(Azone)未能显著增大ENX的表观渗透系数(P>0.05);所有渗透促进剂均未显著改变ENX透过角膜的滞后时间;0.05% Azone和1% F68对眼组织具有刺激性.结论:2% HP-β-CD能够显著增加ENX的表观渗透系数,且对角膜无明显刺激性.     

中药透皮吸收促进剂的研究与发展

中药以其自身独特的优势倍受药学界的关注，中药透皮吸收促进剂已成为经皮给药研究的热点之一。研究较多的中药透皮吸收促进剂有薄荷醇、冰片、精油类等多种中药提取物，应用中可单独作用，也可与化学透皮吸收促进剂联合使用。对中药促透机制的研究也是当前药学界的热点之一。在概述这些研究成果的基础上，就中药透皮吸收促进剂的开发提出一些思路。     

小茴香对5—氟脲嘧啶的促渗作用研究

目的：研究小茴香提取物及主要成分茴香醛、茴香脑等对5－氯脲嘧啶（5－Fu）的促渗作用。方法：采用体外透皮实验方法,用Valia-Chien水平扩散池为实验装置,测定模型药物5－氟脲嘧啶的累积渗透量及渗透系数、增渗倍数,确定其促渗效果的强弱。结果：完全了小茴香所含成分小茴香油、茴香脑、茴香醛等对5－氟脲嘧啶的促渗实验,上述药物对5－氟脲嘧啶均有一定的促渗作用,增渗倍数分别为7．14、4．17、9．54。结论：小茴香油、茴香脑、茴香醛等对5－氟脲嘧啶具有一定的促渗作用。     

现代中药凝胶剂的发展概况

中药凝胶剂是近年来兴起的一种药物新剂型,本文就中药凝胶剂的基质与制备工艺,渗透促进剂的应用,释放行为研究和质量控制做一概述,并对中药凝胶剂的前景进行展望。     

壳聚糖对甲硝唑凝胶体外促透作用研究

目的 考察壳聚糖(CS)对甲硝唑凝胶体外透皮速率的影响。方法 将1.0% CS作为吸收促进剂用于甲硝唑凝胶中,以泊洛沙姆p407为凝胶基质,以含2%氮酮的甲硝唑凝胶作为阳性对照,不含任何促渗剂的甲硝唑凝胶作为阴性对照,采用改良Franz扩散池进行大鼠体外皮肤渗透实验,反相高效液相色谱法（RP HPLC）法测定接受液中甲硝唑含量,计算累积透过量Q,得出Q t回归方程及稳态渗透速率J。结果 1.0%CS组和氮酮组J分别为2.841, 2.874 μg&#8226;（cm2） 1&#8226;h 1,两者差异无显著性(P＞0.05),而与阴性组相比均差异有显著性(均P＜0.05),其透皮吸收行为符合一级方程。结论 CS对甲硝唑凝胶的体外透皮吸收有较好的促进作用,值得进一步研究。     

The polycomb group protein enhancer of zeste 2 is a novel therapeutic target for cervical cancer

Enhancer of zeste 2 (EZH2), a polycomb histone methyltransferase, is overexpressed in various cancers, including cervical cancer. Gene expression analysis revealed that increased expression of EZH2 is associated with cervical cancer progression, particularly the progression to invasive squamous cell carcinoma. Enhancer of zeste 2 is known to trimethylate lysine 27 on histone H3, leading to gene silencing that contributes to the progression of tumours into a more aggressive form of cancer. However, the specific molecular mechanisms by which EZH2 contributes to the development of cervical cancer remain largely unknown. Recently, an EZH2 inhibitor was reported to selectively inhibit trimethylated lysine 27 on histone H3 and to reactivate silenced genes in cancer cells. In this study, we found that GSK343 (a specific inhibitor of EZH2 methyltransferase) induces phenotypic reprogramming of cancer cells from mesenchymal to epithelial cells, reducing proliferation and cell motility and blocking the invasion of cervical cancer cell lines both in vitro and in vivo. Treatment with the EZH2 inhibitor led to increased levels of the epithelial marker E‐cadherin and decreased levels of mesenchymal markers such as N‐cadherin and vimentin. The observed reprogramming is associated with restrained cervical cancer progression and provides direct evidence in support of EZH2 as a therapeutic target.