Network Pharmacology and Molecular Docking Elucidate the Underlying Pharmacological Mechanisms of the Herb Houttuynia cordata in Treating Pneumonia Caused by SARS-CoV-2

Used in Asian countries, including China, Japan, and Thailand, Houttuynia cordata Thumb (H. cordata; Saururaceae, HC) is a traditional herbal medicine that possesses favorable antiviral properties. As a potent folk therapy used to treat pulmonary infections, further research is required to fully elucidate the mechanisms of its pharmacological activities and explore its therapeutic potential for treating pneumonia caused by SARS-CoV-2. This study explores the pharmacological mechanism of HC on pneumonia using a network pharmacological approach combined with reprocessing expression profiling by high-throughput sequencing to demonstrate the therapeutic mechanisms of HC for treating pneumonia at a systemic level. The integration of these analyses suggested that target factors are involved in four signaling pathways, including PI3K-Akt, Jak-STAT, MAPK, and NF-kB. Molecular docking and molecular dynamics simulation were applied to verify these results, indicating a stable combination between four metabolites (Afzelin, Apigenin, Kaempferol, Quercetin) and six targets (DPP4, ELANE, HSP90AA1, IL6, MAPK1, SERPINE1). These natural metabolites have also been reported to bind with ACE2 and 3CLpro of SARS-CoV-2, respectively. The data suggest that HC exerts collective therapeutic effects against pneumonia caused by SARS-CoV-2 and provides a theoretical basis for further study of the active drug-like ingredients and mechanism of HC in treating pneumonia.     

基于网络药理学及分子对接技术探讨五苓散治疗慢性心力衰竭的作用机制

目的应用网络药理学及分子对接技术探讨五苓散治疗慢性心力衰竭(CHF)的作用机制。方法在中药系统药理学技术平台(TCMSP)检索五苓散主要成分及对应靶点;检索GeneCards、TTD、DrugBank、DisGeNET数据库,筛选CHF相关靶点;取疾病与药物交集靶点,构建韦恩图;应用Cytoscape 3.8.0软件建立五苓散药物-活性成分-靶点网络及药物成分-交集靶点网络,获得关键化合物;应用STRING平台构建交集靶点蛋白-蛋白相互作用(PPI)的网络图,分析网络图得到关键靶点;应用Metascape数据库对交集基因进行基因本体(GO)及京都基因与基因组百科全书(KEGG)通路富集分析。比较关键靶点及KEGG通路富集基因,选取主要靶点蛋白及关键化合物,应用CB-Dock平台进行分子对接验证。结果通过口服生物利用度(OB)及生物活性分子类药性(DL)筛选得到五苓散共有46个活性成分,共涉及63个作用靶点,与CHF重合的靶点有36个,得到谷甾醇、3β-乙酰氧基-白术酮、二氢槲皮素等10个关键化合物,NOS3、CASP3、PTGS2等10个关键靶点。GO分析得到与循环系统、细胞膜成分及蛋白质相关的注释条目。KEGG通路富集通路主要包括AGE-RAGE信号通路、细胞凋亡、白细胞介素-17(IL-17)信号通路、肿瘤坏死因子(TNF)信号通路等。分子对接结果显示,五苓散关键化合物与新型利尿剂托伐普坦,与治疗靶点均具有良好结合活性。结论五苓散包括多个活性成分,作用于多个靶点,通过抑制细胞凋亡、氧化应激、心肌重构、炎症通路等多种机制作用于CHF,体现了中药治疗疾病多成分、多靶点、多途径的特点。     

基于网络药理学和分子对接技术探讨瓜蒌薤白半夏汤治疗冠心病的作用机制

目的基于网络药理学探讨瓜蒌薤白半夏汤治疗冠心病的作用机制。方法检索中药系统药理学技术平台(TCMSP)数据库中各中药化合物,并将化合物的靶蛋白信息导入UniProt网站进行基因名转换。将整合的数据导入Cytoscape 3.5.1软件,构建“中药-化合物-靶点”可视化网络图。登录DisGeNET、GeneCards、DrugBank、OMIM、GAD、TTD数据库对冠心病基因靶点进行检索,并将疾病与药物的交集靶点录入STRING网站构建蛋白-蛋白互作(PPI)网络,对节点信息进行分析与计算后筛选得到核心靶点。将靶点基因导入Metascape网站进行基因本体(GO)功能富集分析和京都基因与基因组百科全书(KEGG)通路富集分析,同时对通路进行预测。运用AutoDock 4.2、PyMOL 2.3.2软件对核心靶点进行分子对接验证。结果共筛选出瓜蒌薤白半夏汤包含的32种化合物,度值较高的是β-谷甾醇、豆甾醇、柚皮素等。通过Cytoscape 3.5.1软件构建的PPI网络包含98个节点、1318条边,核心靶点为前列腺素内过氧化物合酶2(PTGS2)、磷脂酰肌醇3-激酶催化亚基a(PIK3CA)、基质金属蛋白酶2(MMP2)、血管内皮生长因子A(VEGFA)等。通过GO及KEGG富集筛选出与冠心病相关的磷脂酰肌醇3-激酶-蛋白激酶B(PI3K-Akt)等10条核心通路,并采用分子对接方法对结果进行了验证。结论柚皮素、β-谷甾醇、豆甾醇、松柏苷、槲皮素可能是瓜蒌薤白半夏汤治疗冠心病发挥关键作用的化合物,可能通过作用于PTGS2、PIK3CA、MMP2、VEGFA等靶点对肾素-血管紧张素系统(RAS)、RAS相关蛋白-A(Rap1)、血管内皮生长因子(VEGF)等通路进行调控,而PI3K-Akt可能是瓜蒌薤白半夏汤治疗冠心病的核心通路。     

Potential Molecular Mechanisms of Rare Anti-Tumor Immune Response by SARS-CoV-2 in Isolated Cases of Lymphomas

Recently, two cases of complete remission of classical Hodgkin lymphoma (cHL) and follicular lymphoma (FL) after SARS-CoV-2 infection were reported. However, the precise molecular mechanism of this rare event is yet to be understood. Here, we hypothesize a potential anti-tumor immune response of SARS-CoV-2 and based on a computational approach show that: (i) SARS-CoV-2 Spike-RBD may bind to the extracellular domains of CD15, CD27, CD45, and CD152 receptors of cHL or FL and may directly inhibit cell proliferation. (ii) Alternately, upon internalization after binding to these CD molecules, the SARS-CoV-2 membrane (M) protein and ORF3a may bind to gamma-tubulin complex component 3 (GCP3) at its tubulin gamma-1 chain (TUBG1) binding site. (iii) The M protein may also interact with TUBG1, blocking its binding to GCP3. (iv) Both the M and ORF3a proteins may render the GCP2-GCP3 lateral binding where the M protein possibly interacts with GCP2 at its GCP3 binding site and the ORF3a protein to GCP3 at its GCP2 interacting residues. (v) Interactions of the M and ORF3a proteins with these gamma-tubulin ring complex components potentially block the initial process of microtubule nucleation, leading to cell-cycle arrest and apoptosis. (vi) The Spike-RBD may also interact with and block PD-1 signaling similar to pembrolizumab and nivolumab- like monoclonal antibodies and may induce B-cell apoptosis and remission. (vii) Finally, the TRADD interacting “PVQLSY” motif of Epstein-Barr virus LMP-1, that is responsible for NF-kB mediated oncogenesis, potentially interacts with SARS-CoV-2 M^pro, NSP7, NSP10, and spike (S) proteins, and may inhibit the LMP-1 mediated cell proliferation. Taken together, our results suggest a possible therapeutic potential of SARS-CoV-2 in lymphoproliferative disorders.     

Behavioral Effects of Ethanol in Cerebellum Are Age Dependent: Potential System and Molecular Mechanisms

Background: Adolescent rats are less sensitive to the motor‐impairing effects of ethanol than adults. However, the cellular and molecular mechanisms underlying this age‐dependent effect of ethanol have yet to be fully elucidated. Method: Male rats of various ages were used to investigate ethanol‐induced ataxia and its underlying cellular correlates. In addition, Purkinje neurons from adolescent and adult rats were recorded both in vivo and in vitro. Finally, protein kinase C (PKCγ) expression was determined in 3 brain regions in both adolescent and adult rats. Results: The present multi‐methodological investigation confirms that adolescents are less sensitive to the motor‐impairing effects of ethanol, and this differential effect is not because of differential blood ethanol levels. In addition, we identify a particular cellular correlate that may underlie the reduced motor impairment. Specifically, the in vivo firing rate of cerebellar Purkinje neurons recorded from adolescent rats was insensitive to an acute ethanol challenge, while the firing rate of adult cerebellar Purkinje neurons was significantly depressed. Finally, it is demonstrated that PKCγ expression in the cortex and cerebellum mirrors the age‐dependent effect of ethanol: adolescents have significantly less PKCγ expression compared to adults. Conclusions: Adolescents are less sensitive than adults to the motor‐impairing effects of ethanol, and a similar effect is seen with in vivo electrophysiological recordings of cerebellar Purkinje neurons. While still under investigation, PKCγ expression mirrors the age effect of ethanol and may contribute to the age‐dependent differences in the ataxic effects of ethanol.     

基于网络药理学的血必清注射液治疗新型冠状病毒感染合并心肌炎的作用机制研究

目的 基于网络药理学探索血必清注射液作用于新型冠状病毒感染合并心肌炎的主要活性成分及作用机制.方法 利用TCMSP数据库对血必清注射液的主要活性成分及其靶点筛选,再运用GeneCards数据库和OMIM数据库筛选新型冠状病毒感染合并心肌炎的相关靶点,最后对药物靶点和疾病靶点进行Venn分析,得到血必清注射液作用于新型冠...     

A Bioinformatics Investigation into the Pharmacological Mechanisms of Sodium-Glucose Co-transporter 2 Inhibitors in Diabetes Mellitus and Heart Failure Based on Network Pharmacology

Cardiovascular Drugs and Therapy - Diabetes mellitus (DM) is a major risk factor for the development of heart failure (HF). Sodium-glucose co-transporter 2 (SGLT2) inhibitors have demonstrated...     

人巨细胞病毒损伤血管的分子机制

较多体外实验及临床研究结果均提示人巨细胞病毒感染与血管损伤相关,本综述将对其可能的分子机制进行初步阐述,主要包括氧化应激、信号转导及免疫炎症反应。病毒与宿主通过上述机制相互作用,多种因子及细胞参与其中,影响血管内皮细胞及平滑肌细胞的存活、增生及凋亡,导致血管结构及功能发生病理性改变,进而引发或加重多种心血管疾病。     

Tissue Renin-Angiotensin Systems Aspects of Molecular Biology and Pharmacology

Advances in molecular biology over the last few years have made it possible to extend studies concerned with the role of renin in blood pressure regulation and fluid balance to the genetic level. Epidemiological data from cross-sectional population studies as well as experimental findings in spontanously hypertensive rats suggest a greater disposition towards hypertension in males than in females. Testosterone (T) is known to raise blood pressure in female and castrated male SH-rats, while concomitantly increasing tissue renin activities. The availability of recombinant DNA technology and of a ³²P labeled mouse submandibular gland renin cRNA as a hybridization probe enabled us to quantitatively assess whether this increase is paralled by enhanced renin gene expression.

In groups of female NMRI mice injected with DHT, we were able to show, that cardiac renin activity was significantly increased after 2 hours (1.6 fold) and 21 days (1.9 fold) of dihydrotestosterone (DHT) treatment compared to controls. DHT had no effect on renin mRNA concentration in the uterus, whereas in the ovary it resulted in a 50% decrease. We conclude that enhanced renin-activity and mRNA levels in peripheral organs and in the central nervous system are due to direct or indirect effects (cis, transacting) of T on renin gene expression. Thus, T may participate in the development of hypertension by stimulating the activity of tissue renin-angiotensin systems.     

Prevention of Ammonia and Glutamate Neurotoxicity by Carnitine: Molecular Mechanisms

Carnitine has beneficial effects in different pathologies and prevents acute ammonia toxicity (ammonia-induced death of animals). Acute ammonia toxicity is mediated by excessive activation of the NMDA-type of glutamate receptors, which mediates glutamate neurotoxicity. We showed that carnitine prevents glutamate neurotoxicity in primary cultures of cerebellar neurons. This supports the idea that the protective effect of carnitine against ammonia toxicity is due to the protective effect against glutamate neurotoxicity. We are studying the mechanism by which carnitine protects against glutamate neurotoxicity. Carnitine increases the binding affinity of glutamate for metabotropic glutamate receptors. The protective effect of carnitine is lost if metabotropic glutamate receptors are blocked with specific antagonists. Moreover, activation of metabotropic glutamate receptors by specific agonists also prevents glutamate neurotoxicity. This indicates that the protective effect of carnitine against glutamate neurotoxicity is mediated by activation of metabotropic glutamate receptors. The molecule of carnitine has a trimethylamine group. Different compounds containing a trimethylamine group (carbachol, betaine, etc.) also prevent ammonia-induced animal death and glutamate-induced neuronal death. Moreover, metabotropic glutamate receptor antagonists also prevent the protective effect of most of these compounds. We summarize here some studies aimed to identify the mechanism and the molecular target that are responsible for the protective effect of carnitine against ammonia and glutamate neurotoxicity. Finally it is also shown that carnitine inhibits the hydrolysis of inositol phospholipids induced by activation of different types of metabotropic receptors, but this effect seems not responsible for its protective effects.     

Mechanisms and Potential Applications of Intestinal Electrical Stimulation

Purpose  

Electrical stimulation of the gut has recently been under intensive investigation and various studies have revealed therapeutic potentials of gastrointestinal electrical stimulation for gastrointestinal motility disorders and obesity. While there have been a number of reviews on gastric electrical stimulation, there is a lack of systematic reviews on intestinal electrical stimulation. The aim of this review is to provide an overview on the effects, mechanisms, and applications of intestinal electrical stimulation.     

Molecular and Biological Mechanisms of Bone Metastasis

Metastatic disease is the cause of death in the majority of cancer patients. Bone marrow is a preferential site of metastasis in breast and prostate cancer, responsible for the majority of skeletal metastases. Micrometastases are often present in the bone marrow of cancer patients and may progress to overt metastases. The survival of these cells and the development of bone metastases depend on the growth support provided by the bone microenvironment and the ability of cancer cells to adapt to this environment, often mimicking the behaviour and gene expression of cells of the bone and bone marrow environment. Experimental evidence suggests that the growth support provided by the bone microenvironment is active during bone resorption. Increased bone turnover as it occurs with hormonal deprivation, therefore, might be a risk factor for developing bone metastases. Interference with bone turnover, however, offers a novel target for preventive and adjuvant therapies. In this review possible mechanisms and factors involved in the development and progression of bone metastases, as well as the molecular, biological and physiological processes of metastases, especially to the bone, are discussed. Furthermore the role of bisphosphonates in the prevention and treatment of bone metastases is reviewed.     

主动脉夹层分子机制的研究进展

主动脉夹层是致死性很高的大血管疾病,其典型的组织学特征是主动脉中层退行性变。由于对主动脉壁退行性变的分子机制尚未阐明,目前尚缺乏有效预防主动脉夹层形成、进展和破裂的措施。近年来由于分子生物学和基因敲除动物的广泛应用,使主动脉夹层的分子机制取得较大进展。本文就近年来主动脉夹层分子机制的进展作简要综述。     

Cellular and Molecular Mechanisms of the Epithelial Repair in IBD

Inflammatory bowel diseases such as ulcerative colitis or Crohn's disease frequently cause epithelial damage in the intestine. In general, the intestinal epithelium is able to rapidly repair itself by the restitution, proliferation, and differentiation of epithelial cells when such tissue damage occurs. However, severe and continuous inflammation could disturb the intrinsic repair system, resulting in refractory ulcers in the intestine. In this review, we will describe the recent findings of the cellular and molecular mechanisms regulating the regeneration process of the intestinal epithelium. Furthermore, we will propose bone marrow cells as a novel source of cells to regenerate the damaged intestinal epithelium. Bone marrow cells are the only cells of extra-gastrointestinal origin that are shown to contribute to the regeneration of the intestinal epithelium. Further studies of these cells and molecules may lead to a novel therapy for the repair of damaged intestinal epithelium.     

Numerically Exploring the Potential of Abating the Energy Flow Peaks through Tough,Single Network Hydrogel Vibration Isolators with Chemical and Physical Cross-Links

Traditional vibration isolation systems, using natural rubber vibration isolators, display large peaks for the energy flow from the machine source and into the receiving foundation, at the unavoidable rigid body resonance frequencies. However, tough, doubly cross-linked, single polymer network hydrogels, with both chemical and physical cross-links, show a high loss factor over a specific frequency range, due to the intensive adhesion–deadhesion activities of the physical cross-links. In this study, vibration isolators, made of this tough hydrogel, are theoretically applied in a realistic vibration isolation system, displaying several rigid body resonances and various energy flow transmission paths. A simulation model is developed, that includes a suitable stress–strain model, and shows a significant reduction of the energy flow peaks. In particular, the reduction is more than 30 times, as compared to the corresponding results using the natural rubber. Finally, it is shown that a significant reduction is possible, also without any optimization of the frequency for the maximum physical loss modulus. This is a clear advantage for polyvinyl alcohol hydrogels, that are somewhat missing the possibility to alter the frequency for the maximum physical loss, due to the physical cross-link system involved—namely, that of the borate esterification.     

缺氧—复氧诱导ECV304细胞与中性粒细胞粘附的分子机制

为探讨缺氧-复氧诱导人脐静脉内皮细胞ECV304与中性粒细胞粘附的信号转导机制，以缺氧-复氧诱导粘附为模型，采用比色法检测粘附率，流式细胞术检测ECV304细胞表面粘附分子E选择素、细胞问粘附分子1的表达，Western blot法检测ECV304细胞亲环素A、磷酸化细胞外信号调节激酶、总细胞外信号调节激酶、磷酸化D70核糖体S6激酶、总p70核糖体S6激酶蛋白的表达。结果发现，经缺氧-复氧处理后，ECV304细胞E选择素、细胞间粘附分子1的表达上调，其表面中性粒细胞粘附增加。总细胞外信号调节激酶、总p70核糖体S6激酶蛋白表达无明显改变，亲环素A蛋白表达明显上调，细胞外信号调节激酶和p70核糖体S6激酶显著活化。亲环素A抑制剂环孢霉素A以及亲环素A反义寡核苷酸均明显减轻缺氧-复氧诱导的细胞外信号调节激酶和p70核糖体S6激酶激活，显著减少ECV304细胞与中性粒细胞粘附。p70核糖体S6激酶阻断剂雷帕霉素显著抑制p70核糖体S6激酶的激活，中性粒细胞与ECV304细胞的粘附亦明显减少。细胞外信号调节激酶信号通路特异性阻断剂PD98059亦显著抑制ECV304细胞与中性粒细胞粘附。结果提示，亲环素A-细胞外信号调节激酶-p70核糖体S6激酶信号通路介导缺氧-复氧诱导的ECV304细胞与中性粒细胞粘附。