基于分子网络研究四逆散抗抑郁症作用的潜在生物学机制

目的 基于分子网络研究四逆散治疗抑郁症的潜在生物学机制。方法 借助于中药系统药理学数据库和分析平台（TCMSP）数据库筛选四逆散的活性成分,筛选条件为口服利用率、药物相似性和血脑屏障透过率,并挖掘四逆散活性成分靶点和抑郁症的治疗靶点。利用韦恩图找到活性成分靶点和疾病靶点的交集靶点,对应相应成分定义为四逆散抗抑郁的有效成分。利用String在线数据库进行交集靶点蛋白质-蛋白质相互作用网络的预测,并利用DAVID数据库进行交集靶点KEGG信号通路的富集分析。最后使用Cytoscape 3.6软件进行活性成分-靶点网络及有效成分-靶点-信号通路的构建和拓扑分析。结果 筛选出了四逆散107个有效成分和28个重要的抗抑郁症靶点。四逆散抗抑郁症的重要靶点显著富集于神经活性配体-受体相互作用、5-羟色胺能突触、多巴胺能突触、逆行内源性大麻素信号传导、钙信号通路等10个信号通路中。结论 本研究从分子网络的角度初步揭示了四逆散治疗抑郁症的潜在作用机制,其主要的生物学机制可能与以神经活性配体-受体相互作用为中心的信号通路有关。     

基于整合网络药理学和实验验证的人参皂苷Rb1抗代谢相关脂肪性肝病的作用机制探讨

目的 探究人参皂苷Rb₁（ginsenoside Rb₁，Rb₁）治疗大鼠代谢相关脂肪性肝病（MAFLD）的作用靶点及机制。方法 采用网络药理学方法系统地预测Rb₁治疗MAFLD的核心靶点，通过STRING平台和Cytoscape3.9.1软件分别绘制蛋白质相互作用（PPI）网络图谱和“Rb₁-MAFLD靶点”网络模型，利用DAVID数据库对核心靶点进行基因本体（GO）功能富集与京都基因与基因组百科全书（KEGG）通路富集分析。动物体内实验进行验证，高脂饲料诱导建立实验性MAFLD大鼠模型。测定各组大鼠体质量、肝脏系数、肝功能指标[天冬氨酸氨基转移酶（AST）、丙氨酸氨基转移酶（ALT）]及血脂指标[三酰甘油（TG）、总胆固醇（TC）、低密度脂蛋白胆固醇（LDL-C）、高密度脂蛋白胆固醇（HDL-C）]；HE染色观察肝组织病理学变化；酶联免疫吸附（ELISA）和实时荧光定量聚合酶链式反应（qRT-PCR）法分别检测大鼠血清和肝脏中炎症因子[白细胞介素-6（IL-6）、IL-10、肿瘤坏死因子-α（TNF-α）和转化生长因子-β1（TGF-β1）]表达水平以验证网络药理学预测结果；16 S rDNA测序分析评估Rb₁对MAFLD大鼠肠道菌群组成的影响。结果 获得134个Rb₁治疗MAFLD的潜在靶点，富集分析显示Rb₁干预MAFLD的生物学过程与转录调控、细胞增殖、炎症反应等相关，作用的通路主要为癌症、炎症、脂质和动脉粥样硬化、糖尿病等途径。动物实验结果显示，与对照组相比较，MAFLD模型组大鼠肝脏系数、肝功能指标、炎症因子水平显著升高，血脂代谢紊乱，且肠道菌群结构紊乱。Rb₁可改善肝组织中脂肪变性及炎症细胞浸润，显著降低血清中AST、ALT、TC、TG、LDL-C水平，增加HDL-C水平，且有效抑制MAFLD大鼠中炎症因子的过表达；此外，Rb₁改变了MAFLD大鼠的肠道菌群的组成，以拟杆菌门、乳杆菌属、布劳特氏菌属富集和脱硫弧菌减少为特征。结论 Rb₁能通过改善血脂紊乱与肝功能、抑制炎症反应和调节肠道菌群的稳态，最终发挥抗MAFLD的作用。     

肠道菌群生态对慢性乙型病毒肝炎患者疾病进展影响的研究进展

目的 了解慢性乙型病毒肝炎患者的肠道微生态环境对其原发病的发展进程的影响,为慢乙肝的诊治提供可靠循证依据。方法 通过对国内外近20年来的文献查阅、整理与分析,阐述肠道菌群生态对慢性乙型病毒肝炎患者疾病进展的影响。结果 乙型肝炎患者的肠道菌群结构多样性较正常人明显减少,慢性肝脏疾病也可以加重肠道菌群失调,反之,肠道微生态的紊乱会导致慢乙肝的症状加重或病程延长,两种因素彼此制约,造成不良的因果循环。结论 针对失衡的肠道微生态环境进行研究,通过补充益生菌或移植粪菌改善肠道生态,进而延缓肝病的进展成为新的切入点。     

抗肿瘤药物的耐药性及临床治疗对策

目的 总结抗肿瘤药物产生耐药性的相关机制,探讨临床治疗对策。方法 检索PubMed、Medline、Cochrane图书馆、中国期刊全文数据库（清华同方CJFD）、维普中文科技期刊全文数据库（VIP）、万方数据库发表与抗肿瘤药物的耐药性及临床治疗对策相关的文献,并结合当前抗肿瘤药物使用情况对其进行综述。结果 抗肿瘤药耐药性的产生受多种因素的影响,如药物外排增加使肿瘤细胞中的药物浓度降低、解毒作用加强、DNA修复损伤功能增加、肿瘤细胞通道信号异常、靶点改变等。结论 临床可根据产生耐药性的不同机制予以针对性治疗,中药具有多靶点作用,其逆转耐药优势突出。     

肠道菌群对某些疾病及药物疗效与毒性的影响

经过长期的协同进化,肠道菌群与宿主间形成了密切的共生关系,并对宿主的多种生理功能起着重要作用。在相关疾病的治疗过程中,药物对肠道菌群的影响以及肠道菌群对药物和疾病的影响相互交织,并有可能改变药物在体内的药动学过程及药效。综述药物、肠道菌群以及疾病三者间的相互作用与联系,提出利用药物调节肠道菌群以治疗相关疾病的思路,为现有药物的新药理作用的发现和以肠道菌群为作用靶点的新型药物的研发提供有益信息。     

基于“脑-肠轴”理论及网络药理学的黄连治疗慢性肠炎、失眠、抑郁症异病同治的作用机制探讨

目的 基于“脑-肠轴”理论,通过网络药理学和分子对接法,分析黄连治疗慢性肠炎、失眠、抑郁症异病同治的作用机制。方法 利用中药系统药理学数据库与分析平台（TCMSP）数据库获取黄连的活性成分及相关靶点,检索GeneCards、OMIM、Drugbank数据库预测慢性肠炎、失眠、抑郁症的相关靶点。通过STRING数据库构建交集靶点的蛋白质相互作用（PPI）网络,通过网络拓扑参数预测核心靶点,利用Metascape平台对核心靶点进行基因本体（GO）注释及京都基因与基因组百科全书（KEGG）通路富集分析,最后利用分子对接验证核心成分及核心靶点的结合能力。结果 筛选得到黄连活性化合物9种,主要活性成分包括槲皮素、氢化小檗碱、小檗浸碱、黄藤素、小檗碱;活性成分靶点与慢性肠炎、失眠、抑郁症的交集靶点38个,核心靶点19个,其中IL-6、IL-1β、AKT1、TNF、FOS等靶点度值较高。GO和KEGG分析表明核心靶点主要通过AGE-RAGE、IL-17、TNF等多条信号通路发挥调节作用,核心成分及核心靶点分子对接显示出良好的结合活性。结论 慢性肠炎、失眠、抑郁症3者虽为不同疾病,但通过“脑-肠轴”互为联系。网络药理学分析显示黄连通过多组分、多靶点、多通路的药理作用治疗慢性肠炎、失眠及抑郁症。     

早期肠道菌群干预对帕金森病患者便秘症状及多巴丝肼疗效的影响

目的 探讨早期肠道菌群干预对帕金森病（PD）患者肠道便秘症状及多巴丝肼疗效的影响,为临床治疗提供参考。方法 纳入2015月1月至2017年10月我院神经内科初次诊断的PD患者114例,随机分为肠道菌群干预组（n=57）与对照组（n=57）,两组均予多巴丝肼片常规初始治疗,干预组在此基础上加用三联活菌制剂调理肠道菌群,采用便秘患者生活质量量表（PAC-QOL）等评估患者便秘症状及满意度,采用统一帕金森病评定量表（UPDRS-Ⅲ）等评估两组患者治疗前后的运动症状及心理状态。结果 1干预组较治疗前及较对照组的PAC-QOL,Bristol粪便性状量表（BSFS）评分改善显著,差异有统计学意义（P<0.05）;2两组患者较治疗前UPDRS-Ⅲ运动评分均有改善,差异有统计学意义（P<0.05）,干预组较对照组4周时UPDRS-Ⅲ评分有下降,差异有统计学意义（P<0.05）;3干预组较对照组治疗后医院焦虑量表（HAD-A）、医院抑郁量表（HAD-D）、匹兹堡睡眠质量指数（PSQI）评分均有下降,差异有统计学意义（P<0.05）。结论 早期肠道菌群干预能有效改善PD患者的便秘症状及焦虑睡眠等心理状态,可能有早期增强多巴丝肼制剂对运动症状的疗效,但远期影响仍有待研究。     

口服难吸收中药重塑肠道微生态干预代谢相关脂肪性肝病的研究进展

代谢相关脂肪性肝病（MAFLD）是多系统代谢紊乱的肝脏疾病,其发病机制的复杂性和治疗目标的多元化导致临床缺乏效果理想的药物。中药对防治肝脏疾病有很好的疗效,口服给药是最普遍的给药方式,药物不仅可以通过肠道与肠道菌群建立联系,而且经肠道细菌作用后可改善吸收差、生物利用度低的问题。然而,肠道微生态紊乱会导致机体免疫功能障碍并促进MAFLD的发生发展。因此,口服难吸收中药对肠道菌群的调节作用可能是治疗MAFLD的潜在靶点。从口服难吸收中药的药理作用、相关代谢、肠道菌群作用等不同角度总结了中药对MAFLD的治疗作用以及肠道菌群与MAFLD的联系,为研究中药、MAFLD和肠道菌群间的关系提供理论依据,为进一步研究中药治疗MAFLD奠定药效物质基础,为从肠道菌群角度研究中药治疗MAFLD的作用机制与靶点奠定基础。     

胆汁酸-肠道菌群轴在2型糖尿病中的作用

目的 分析2型糖尿病(type 2 diabetes mellitus,T2DM)患者和正常人群胆汁酸与肠道菌群差异,探讨胆汁酸-肠道菌群轴在T2DM中的作用。方法 利用代谢组学、16S rRNA测序手段分别对T2DM患者中的血清胆汁酸含量及粪便肠道微生物进行检测及分析,结合斯皮尔曼相关性分析,明确胆汁酸-肠道菌群在T2DM中的代谢对话关系。结果 血清胆汁酸含量和肠道微生物的丰度在T2DM患者与正常人群中存在一定的差异。与正常人群相比,甘氨熊脱氧胆酸、牛磺鹅脱氧胆酸、甘氨鹅脱氧胆酸的含量在T2DM患者中显著降低;T2DM患者中肺炎克雷伯菌属、普拉梭菌属的相对丰度较正常人群明显升高,而狄氏副拟杆菌属、普雷沃菌属、艾克曼菌属、双歧杆菌属的相对丰度明显降低;斯皮尔曼相关性分析表明甘氨熊脱氧胆酸与狄氏副拟杆菌属、艾克曼菌属呈正相关,与克雷伯氏菌属呈负相关。结论 胆汁酸-肠道菌群轴是维持机体稳态的必要因素,在T2DM中发挥重要作用。     

基于网络药理学与分子对接的温胆汤治疗冠心病合并抑郁作用机制探讨

目的 运用网络药理学联合分子对接方法探讨温胆汤治疗冠心病合并抑郁的作用机制。方法 通过TCMSP与TCMIP数据库获取温胆汤的活性成分及其作用靶点,以UniProt数据库将靶点规范化命名。通过GeneCards、Disgenet数据库获取冠心病与抑郁相关疾病靶点并取二者交集,取温胆汤与冠心病合并抑郁的交集靶点并进行基因本体论（GO）功能分析和京都基因和基因组百科全书（KEGG）通路富集分析,利用AutoDock软件将主要的活性成分与核心靶点进行分子对接验证。结果 网络药理学分析显示温胆汤中43个有效成分与49个靶点与冠心病合并抑郁关联密切,与炎症反应、免疫反应、细胞凋亡、胰岛素抵抗、NO的生物合成、平滑肌细胞增殖调控、DNA结合转录因子的调控、细胞外间隙、类固醇结合等生物学过程密切相关,作用涉及HIF-1、肿瘤通路、雌激素信号通路、TNF信号通路、T细胞受体通路等,分子对接结果显示成分与靶点结合较好的是黄芩苷-ALB与黄芩苷-TNF。结论 温胆汤作为一种临床常用方剂可以通过多靶点、多通路、多机制对冠心病合并抑郁进行干预。     

睡眠剥夺与肠道菌群紊乱的关系及改善睡眠药物研发的探讨

肠道菌群作为人体内一个复杂的微生态系统,在维持宿主生理功能上起非常重要的作用,也与许多代谢性疾病、免疫性疾病有着密切的关系。分析睡眠剥夺与肠道菌群紊乱相关性研究的提出和再提出,综合分析肠道菌群紊乱与睡眠障碍的关系,为以肠道菌群为靶点的改善睡眠药物开发及防治方法与思路提供参考。     

The influence of gut microbiota on drug metabolism and toxicity

Introduction: Gut microbiota plays critical roles in drug metabolism. The variation of gut microbiota contributes to the interindividual differences toward drug therapy including drug-induced toxicity and efficacy. Accordingly, the investigation and elucidation of gut microbial impacts on drug metabolism and toxicity will not only facilitate the way of personalized medicine, but also improve rational drug design.

Areas covered: This review provides an overview of the microbiota–host co-metabolism on drug metabolism and summarizes 30 clinical drugs that are co-metabolized by host and gut microbiota. Moreover, this review is specifically focused on elucidating the gut microbial modulation of some clinical drugs, in which the gut microbial influences on drug metabolism, drug-induced toxicity and efficacy are discussed.

Expert opinion: The gut microbial contribution to drug metabolism and toxicity is increasingly recognized, but remains largely unexplored due to the extremely complex relationship between gut microbiota and host. The mechanistic elucidation of gut microbiota in drug metabolism is critical before any practical progress in drug design or personalized medicine could be made by modulating human gut microbiota. Analytical technique innovation is urgently required to strengthen our capability in recognizing microbial functions, including metagenomics, metabolomics and the integration of multidisciplinary knowledge.     

Animal inflammation-based models of depression and their application to drug discovery

Introduction: Depression, anxiety and other affective disorders are globally widespread and severely debilitating human brain diseases. Despite their high prevalence and mental health impact, affective pathogenesis is poorly understood, and often remains recurrent and resistant to treatment. The lack of efficient antidepressants and presently limited conceptual innovation necessitate novel approaches and new drug targets in the field of antidepressant therapy.

Areas covered: Herein, the authors discuss the emerging role of neuro-immune interactions in affective pathogenesis, which can become useful targets for CNS drug discovery, including modulating neuroinflammatory pathways to alleviate affective pathogenesis.

Expert opinion: Mounting evidence implicates microglia, polyunsaturated fatty acids (PUFAs), glucocorticoids and gut microbiota in both inflammation and depression. It is suggested that novel antidepressants can be developed based on targeting microglia-, PUFAs-, glucocorticoid- and gut microbiota-mediated cellular pathways. In addition, the authors call for a wider application of novel model organisms, such as zebrafish, in studying shared, evolutionarily conserved (and therefore, core) neuro-immune mechanisms of depression.     

Gut microbiota modulates drug pharmacokinetics

Abstract

Gut microbiota, one of the determinants of pharmacokinetics, has long been underestimated. It is now generally accepted that the gut microbiota plays an important role in drug metabolism during enterohepatic circulation either before drug absorption or through various microbial enzymatic reactions in the gut. In addition, some drugs are metabolized by the intestinal microbiota to specific metabolites that cannot be formed in the liver. More importantly, metabolizing drugs through the gut microbiota prior to absorption can alter the systemic bioavailability of certain drugs. Therefore, understanding intestinal flora-mediated drug metabolism is critical to interpreting changes in drug pharmacokinetics. Here, we summarize the effects of gut microbiota on drug pharmacokinetics, and propose that the influence of intestinal flora on pharmacokinetics should be organically related to the therapeutic effects and side effects of drugs. More importantly, we could rationally perform the strategy of intestinal microflora-mediated metabolism to design drugs.     

Modulating Gut Microbiota: An Emerging Approach in the Prevention and Treatment of Multiple Sclerosis

Multiple sclerosis (MS) is a progressive neuromuscular disorder characterized by demyelination of neurons of the central nervous system (CNS). The pathogenesis of the disorder is described as an autoimmune attack targeting the myelin sheath of nerve cell axons in the CNS. Available treatments only reduce the risk of relapse, prolonging the remissions of neurological symptoms and halt the progression of the disorder. Among the new ways of targeting neurological disorders, including MS, there is modulation of gut microbiota since the link between gut microbiota has been rethought within the term gut-brain axis. Gut microbiota is known to help the body with essential functions such as vitamin production and positive regulation of immune, inflammatory, and metabolic pathways. High consumption of saturated fatty acids, gluten, salt, alcohol, artificial sweeteners, or antibiotics is the responsible factor for causing gut dysbiosis. The latter can lead to dysregulation of immune and inflammatory pathways, which eventually results in leaky gut syndrome, systemic inflammation, autoimmune reactions, and increased susceptibility to infections. In modern medicine, scientists have mostly focused on the modulation of gut microbiota in the development of novel and effective therapeutic strategies for numerous disorders, with probiotics and prebiotics being the most widely studied in this regard. Several pieces of evidence from preclinical and clinical studies have supported the positive impact of probiotic and/or prebiotic intake on gut microbiota and MS. This review aims to link gut dysbiosis with the development/progression of MS, and the potential of modulation of gut microbiota in the therapeutics of the disease.     

中医药调节肠道菌群防治冠心病的研究概述

冠状动脉粥样硬化性心脏病(CHD)病程较长,发病机制是多种因素相互作用引发,肠道菌群(GM)的结构紊乱及功能障碍与CHD的进展密切相关。此外,GM的代谢物也可影响CHD的发展和预后。现基于中医学基础理论,探讨GM及代谢物质与CHD之间的关系,进一步论述中医药防治CHD的现代研究进展。     

Pathobiological targets of depression

Introduction: Depression is one of the most prevalent and life-threatening forms of mental illness associated with significant disability and mortality. About 21% of the world's population is affected by depression.

Areas covered: The various pathological factors involved in depression are: monoamine hypothesis, neurotransmitter receptor hypothesis, neurotrophic factor hypothesis, hypothalamic–pituitary–adrenal (HPA) dysregulation, oxidative stress, cytokine hypothesis and NO pathway. Recent drug therapies used to treat depression include: selective serotonin re-uptake inhibitors, norepinephrine and dopamine re-uptake inhibitors and several herbal drugs. The present review focuses on recently unraveled pathogenetic hypotheses and therapeutics of mental depression. Moreover, various evaluation models for antidepressants are discussed.

Expert opinion: Stress can be considered as a major contributor to the development of depressive disorder due to the dysregulation of HPA axis. Cytokine effects on behavior are believed to be related in part to their effects on neurotransmitter and neuropeptide function, synaptic plasticity and neuroendocrine function. Although there are multiple pathways that are involved in the pathogenesis of depression, the current antidepressants mainly target monoaminergic pathway. However, the therapeutic potential of other pathways is still under investigation. Drugs targeting NO, cytokines and the kynurenine acid pathway might be the drugs of choice in near future.     

The role of probiotics on each component of the metabolic syndrome and other cardiovascular risks

Introduction: Probiotics are defined as live microorganisms that when administered in adequate amounts confer health benefits to the host. The consumption of probiotics has gained increasing recognition from the scientific community due to the promising effects on metabolic health through gut microbiota modulation.

Areas covered: This article presents a review of scientific studies investigating probiotic species and their effects on different risk factors of the metabolic syndrome (MetS). This article also presents a summary of the major mechanisms involved with gut microbiota and the components of the MetS and raises the key issues to be considered by scientists in search of probiotics species for treatment of patients suffering from this metabolic disorder.

Expert opinion: Probiotics may confer numerous health benefits to the host through positive gut microbiota modulation. The strain selection is the most important factor for determining health effects. Further studies may consider gut microbiota as a novel target for prevention and management of MetS components and other cardiovascular risks.