基于网络药理学和分子对接技术探究槐花散治疗溃疡性结肠炎的作用机制＊

目的 该研究采用网络药理学和分子对接的研究方法结合体内实验探讨槐花散治疗溃疡性结肠炎（ulcerative colitis， UC）的主要化合物和靶点，并分析其作用机制。方法 利用多个数据库筛选药物活性成分、药物靶点和UC疾病基因，并进行拓扑分析，构建“化合物-药物靶点-疾病基因”关系网络。利用DAVID在线分析工具对候选靶点进行基因本体（Gene ontology， GO）功能和生物通路（KEGG）富集分析。通过SYBYL X2.0软件进行分子对接，获取总评分、共识评分和结合位点。利用硫酸葡聚糖钠盐（dextran sodium sulfate，DSS）建立UC小鼠模型，槐花散干预后，评估疾病活动指数和结肠病理，RT-qPCR检测白介素6（IL-6）、白介素17（IL-17）mRNA表达水平，Western Blot检测IL-6、IL-17蛋白表达水平。结果 槐花散中有20个化合物对应375个靶点对121个UC疾病基因产生影响。对72个关键靶点作GO功能分析筛选得303个GO条目，其中生物过程相关的条目223条，细胞组成相关的条目25条，分子功能相关的条目55条。KEGG富集分析筛选得到88条通路。分子对接结果显示关键靶点与对应的化合物有较好的结合活性。体内实验显示，槐花散可以改善UC小鼠DAI评分，下调IL-6、IL-17的表达，减轻结肠组织病理损伤。结论 槐花散治疗UC具有多成分、多靶点、多通路的特点，为槐花散治疗UC的进一步研究提供了理论依据。     

WHO药品预认证微生物实验室质量管理的要求与思考

目的:介绍世界卫生组织(WHO)对药品微生物检测实验室的预认证要求,推动我国药品检测质量管理体系的完善和发展。方法:从预认证实验室应遵循的质量管理原则出发,对照我国实验室ISO/IEC 17025体系要求,分析药品微生物检测实验室在质量管理中的不足。结果:预认证实验室更多地采纳了《药品生产质量管理规范》(GMP)的质量管理理念,而我国药品微生物检测实验室在记录与数据可靠性、基于风险的变更控制和偏差调查等方面的应用与实施还存在较大差距。结论:我国药品微生物检测实验室应学习和借鉴国内外GMP的质量管理经验,不断更新理念,改进质量管理体系,更多地以风险评估方式保障检测数据的可靠性。     

Pharmacokinetics of oral and intravenous cannabidiol and its antidepressant-like effects in chronic mild stress mouse model

Cannabidiol (CBD) exhibits significant efficacy in mental and inflammatory diseases. Several studies have recently reported on the rapid antidepressant-like effects of CBD, suggesting that CBD is a potential anti-depressant or anti-stress drug. However, CBD is mainly administered orally or by inhalation with poor bioavailability, resulting in high costs. We aim to explore the efficacy of long-term periodic administration of CBD in chronic mild stress (CMS) via two routes and its pharmacokinetics. We treated ICR mice with CBD administered orally and intravenously and then determined the kinetic constants. A single bolus intravenous injection of CBD resulted in a half-life of 3.9 h, mean residence time of 3.3 h, and oral bioavailability of about 8.6%. The antidepressant-like effects of periodically administered CBD on the chronic mild stress mouse model are evaluated. Results demonstrated that such treatment at a high dose of 100 mg/kg CBD (p.o.) or a low dose of 10 mg/kg CBD (i.v.), elicited significant antidepressant-like behavioral effects in forced swim test, following increased mRNA expression of brain-derived neurotrophic factor (BDNF) and synaptophysin in the prefrontal cortex and the hippocampus. Our findings are expected to provide a reference for the development of intravenous antidepressant formulations of CBD.     

乳癖病证源流考略

对乳癖的病名源流进行初步考证,并梳理了古代医籍中关于乳癖病因病机及证治的论述。乳癖的病名提出约在宋代以前,至明代后期该病名方与妇人乳房肿块建立起确切的联系,清代医家逐步丰富了乳癖的理法方药。     

雷藤舒对TNF-α诱导的人类风湿关节炎滑膜成纤维细胞促凋亡、抗炎及对Ras-MAPKs信号通路的调节作用

目的:观察雷藤舒(LLDT-8)对肿瘤坏死因子-α(TNF-α)诱导的人类风湿关节炎滑膜成纤维细胞(RA-HFLS)的促凋亡、抗炎作用,以及可能的作用机制。方法:在体外培养的RA-HFLS体系中,实验组加入终浓度为50 nmol/L的LLDT-8与终浓度为20 ng/ml TNF-α共孵育,同时设置细胞空白对照组和TNF-α刺激组。采用TUNEL法检测RA-HFLS细胞的凋亡;RT-PCR检测Bcl-2 mRNA表达水平;ELISA和RTPCR分别检测IL-6、MMP-3的表达;Western-blot检测Ras-MAPKs信号通路的磷酸化水平和蛋白表达。结果:与空白对照组比较,LLDT-8组细胞凋亡率明显增加(P0.01)。LLDT-8能显著抑制TNF-α诱导的RA-HFLS分泌IL-6、MMP-3的表达(P0.01);能明显抑制Ras蛋白和p-P38磷酸化水平,而各组之间pERK、p-JNK、c-Fos、c-Jun和c-Myc的磷酸化水平和蛋白表达差异无统计学意义。结论:LLDT-8能够抑制Ras-p38 MAPK信号转导通路的异常活化,从而抑制RA滑膜的增殖,减轻滑膜细胞的炎症。     

Methods for development of a core outcome set for clinical trials integrating traditional Chinese medicine and Western medicine

Clinical trial outcome reporting differs between studies integrating traditional Chinese medicine (TCM) and Western medicine, so that some clinical trials are not eligible for inclusion in a systematic review. The excluded studies are therefore less widely disseminated, and even valid studies are less likely to yield impact. This problem may be addressed by developing core outcome sets (COSs) for integrative medicine in specific healthcare areas. The first stage of development is to define the scope of the COS for integrative medicine, the second stage is to establish the need for such a COS, and the third stage is to develop a protocol and register the COS. The final stage involves three steps: (i) development of a comprehensive list of outcomes (including efficacy outcomes and safety outcomes and TCM syndromes) using systematic review, qualitative or cross-sectional research, and reviews of package inserts and medical records; (ii) merging and grouping of outcomes within domains; (iii) conducting two rounds of Delphi survey and consensus meetings with a range of stakeholders. The final COS will include a general COS and core TCM syndrome- set. Development of COSs for clinical trials of integrative medicine may help to standardize outcome reporting and reduce publication bias in the future.     

DW14006 as a direct AMPKα1 activator improves pathology of AD model mice by regulating microglial phagocytosis and neuroinflammation

Alzheimer’s disease (AD) is a progressively neurodegenerative disease with typical hallmarks of amyloid β (Aβ) plaque accumulation, neurofibrillary tangle (NFT) formation and neuronal death extension. In AD brain, activated microglia phagocytose Aβ and neuronal debris, but also aggravate inflammation stress by releasing inflammatory factors and cytotoxins. Improving microglia on Aβ catabolism and neuroinflammatory intervention is thus believed to be a promising therapeutic strategy for AD. AMP-activated protein kinase (AMPK) is highly expressed in microglia with AMPKα1 being tightly implicated in neuroinflammatory events. Since indirect AMPKα1 activators may cause side effects with undesired intracellular AMP/ATP ratio, we focused on direct AMPKα1 activator study by exploring its potential function in ameliorating AD-like pathology of AD model mice. Here, we reported that direct AMPKα1 activator DW14006 (2-(3-(7-chloro-6-(2′-hydroxy-[1,1′-biphenyl]-4-yl)-2-oxo-1,2-dihydroquinolin-3-yl)phenyl)acetic acid) effectively improved learning and memory impairments of APP/PS1 mice, and the underlying mechanisms have been intensively investigated. DW14006 reduced amyloid plaque deposition by promoting microglial o-Aβ₄₂ phagocytosis and ameliorated innate immune response by polarizing microglia to an anti-inflammatory phenotype. It selectively enhanced microglial phagocytosis of o-Aβ₄₂ by upgrading scavenger receptor CD36 through AMPKα1/PPARγ/CD36 signaling and suppressed inflammation by AMPKα1/IκB/NFκB signaling. Together, our work has detailed the crosstalk between AMPKα1 and microglia in AD model mice, and highlighted the potential of DW14006 in the treatment of AD.     

从调节免疫力谈中医药防治新型冠状病毒肺炎

从中医扶正祛邪、调和阴阳的防治大法,审证求因、辨证论治的指导原则,以及未病先防、既病防变的"治未病"核心内涵3个方面阐释中医药通过调节人体免疫力来防治新型冠状病毒肺炎的作用及意义。认为中医药可有效防治该疫病归因于其独具特色的"正气"理论,这一学术思想与现代免疫学的内涵有异曲同工之处。     

Quantitative Estimation of Plasma Free Drug Fraction in Patients With Varying Degrees of Hepatic Impairment: A Methodological Evaluation

Quantitative prediction of unbound drug fraction (f_u) is essential for scaling pharmacokinetics through physiologically based approaches. However, few attempts have been made to evaluate the projection of f_u values under pathological conditions. The primary objective of this study was to predict f_u values (n = 105) of 56 compounds with or without the information of predominant binding protein in patients with varying degrees of hepatic insufficiency by accounting for quantitative changes in molar concentrations of either the major binding protein or albumin plus alpha 1-acid glycoprotein associated with differing levels of hepatic dysfunction. For the purpose of scaling, data pertaining to albumin and α1-acid glycoprotein levels in response to differing degrees of hepatic impairment were systematically collected from 919 adult donors. The results of the present study demonstrate for the first time the feasibility of physiologically based scaling f_u in hepatic dysfunction after verifying with experimentally measured data of a wide variety of compounds from individuals with varying degrees of hepatic insufficiency. Furthermore, the high level of predictive accuracy indicates that the inter-relation between the severity of hepatic impairment and these plasma protein levels are physiologically accurate. The present study enhances the confidence in predicting f_u in hepatic insufficiency, particularly for albumin-bound drugs.     

In vitro and in vivo correlation for lipid-based formulations: Current status and future perspectives

Lipid-based formulations (LBFs) have demonstrated a great potential in enhancing the oral absorption of poorly water-soluble drugs. However, construction of in vitro and in vivo correlations (IVIVCs) for LBFs is quite challenging, owing to a complex in vivo processing of these formulations. In this paper, we start with a brief introduction on the gastrointestinal digestion of lipid/LBFs and its relation to enhanced oral drug absorption; based on the concept of IVIVCs, the current status of in vitro models to establish IVIVCs for LBFs is reviewed, while future perspectives in this field are discussed. In vitro tests, which facilitate the understanding and prediction of the in vivo performance of solid dosage forms, frequently fail to mimic the in vivo processing of LBFs, leading to inconsistent results. In vitro digestion models, which more closely simulate gastrointestinal physiology, are a more promising option. Despite some successes in IVIVC modeling, the accuracy and consistency of these models are yet to be validated, particularly for human data. A reliable IVIVC model can not only reduce the risk, time, and cost of formulation development but can also contribute to the formulation design and optimization, thus promoting the clinical translation of LBFs.