基于药效/成分指数（ECI）构建中药品质区划评价模型-以秦艽抗类风湿关节炎（RA）为例

The core of traditional Chinese medicine quality lies in its efficacy. At present, the evaluation standard of quality of traditional Chinese medicine (ingredient) which is based on "chemical quality control" is separated from the active ingredients of blood and can not achieve the purpose of quality control. The quality-efficacy-generation relationship model can reflect more accurately traditional Chinese medicine effect substances, building the effects of the composition index (ECI) can be linked to the active ingredients and efficacy based on quality-efficacy-generation relationship model, it can truly reflect the quality of traditional Chinese medicine. This research group has established the relationship between the chemical composition and ecological factor of Gentiana macrophylla Pall and the ecological suitability, and confirmed its antagonistic effect on the rheumatoid arthritis (RA) rats. In view of this, this study first analyzed its blood components by the UHPLC-QTOF/MS, Peakview and MetabolitePilot based on the anti-RA component group and tumor necrosis factor-α (TNF-α) and other pharmacodynamic indicators, the study also combined with " removal and supplement of ingredients "strategy to clarify the active ingredients and then get the ECI based on the active ingredient effect value. The core of geoherbalism of Chinese traditional medicine lies in the efficacy. Then, MaxEnt and ArcGIS are used to analyze contribution of the different zoning ecological factors (climate, light, soil and water, etc.) for the active components of the blood of Gentiana macrophylla Pall, and established the pharmacodynamic-quality regionalization model to provide new ideas for research of geoherbalism of traditional Chinese medicine.

中药品质的核心在于药效，而目前以“化学质控”为主的中药质量（成分）评价标准脱离入血活性成分，无法准确达到质控目的；质-效-代关系模型可较准确反映中药效应物质，在此基础上构建的效应成分指数（ECI）可将活性成分与药效联系起来，其可真实反映中药品质。本课题组先后建立了秦艽化学成分和生态因子关系及生态适宜性区划，同时证实其对类风湿关节炎（RA）大鼠具有拮抗作用。鉴于此，本研究基于秦艽抗RA成分群和肿瘤坏死因子-α（TNF-α）等药效指标，首先采用UHPLC-QTOF/MS、Peakview和MetabolitePilot分析入血成分，再结合“成分敲除敲入” 策略明确活性成分，然后根据活性成分效应值得到ECI。中药道地性核心在于药效，接着应用MaxEnt和ArcGIS分析不同区划生态因子（气候、光照、土壤和水分等）对秦艽入血活性成分的贡献率，建立药效-品质区划空间模型，为中药道地性研究提供新思路。

中药品质的核心在于药效，而目前以“化学质控”为主的中药质量（成分）评价标准脱离入血活性成分，无法准确达到质控目的；构建的效应成分可将活性成分与药效联系起来，其可真实反映中药品质。. 课题组首先建立了秦艽化学成分（龙胆苦苷、马钱苷酸、獐牙菜苦苷、6'-O-β-D-葡萄糖基龙胆苦苷、獐牙菜苷、异荭草苷和异牡荆苷）和MaxEnt分析秦艽药材综合品质估算的秦艽化学成分区划图。接着继续构建了秦艽在我国的生态适宜性区划，依次分析了秦艽、麻花艽、小秦艽和粗茎秦艽在我国的生态适宜性区划。采用叶绿体基因(cpDNA) 序列和ISSＲ分子标记技术对甘肃祁连山地区麻花秦艽进行序列变异和遗传分化分析，甘肃祁连山地区麻花秦艽在物种水平上遗传多样性较高，具有丰富的单倍型类型，居群的遗传变异主要来自于遗传漂变。我们通过建立胶原诱导型关节炎( CIA)大鼠RA模型，证实秦艽具有显著的抗RA作用，显著降低RA大鼠血清中TNF-α、IL-1β、IL-6、iNOS 及 NO含量，并抑制足跖软组织中NF-κB、TLR2及TLR4蛋白表达，显示其机制主要与抗炎有关。接着我们对RA大鼠入血成分进行检测分析，可检测到龙胆苦苷、马钱苷酸和獐牙菜苦苷等3种原型成分。. 此外，秦艽醇提物（GEE）基于肝脏代谢组学分析和转录组学分析揭示GEE的保肝作用，并从体外细胞实验阐明GEE通过AMPK通路（转录组学筛选的关键信号通路）调控脂质代谢的机制，GEE缓解ALD在代谢物水平上具有多靶点、多途径的特点，主要涉及二肽、嘌呤和嘧啶代谢以及糖脂代谢等。通过RNA对肝组织的测序结果发现，GEE对脂质代谢相关信号通路的影响较为明显，主要包括脂肪酸合成与降解通路、胆固醇合成与降解通路AMPK通路密切相关。我们尚研究了秦艽活性成分龙胆苦苷( GPS) 对非酒精性脂肪肝( NAFLD) 大鼠的保护作用，结果表明，GPS可降低NAFLD大鼠血清中ALT、AST、MDA、TC、TG、LDL-C、FBG和FIN）的活性或含量，增强血清中SOD、GSH-Px活性和HDL-C含量改善胰岛素抵抗情况，降低肝脏中IL-1β、IL-6、TNF-α、NF-κB、p-p65和TLR-4的表达水平，提高p-AMPK与Nrf2蛋白表达水平，GPS改善NAFLD的机制可能与抑制氧化应激、炎症反应和调控TLR-4/NF-κB有关。