scholarly journals Stingray Venom Proteins: Mechanisms of Action Revealed Using a Novel Network Pharmacology Approach

Marine Drugs ◽  
2021 ◽  
Vol 20 (1) ◽  
pp. 27
Author(s):  
Kim N. Kirchhoff ◽  
André Billion ◽  
Christian R. Voolstra ◽  
Stephan Kremb ◽  
Thomas Wilke ◽  
...  
Keyword(s):  
Signaling Pathways ◽  
Functional Data ◽  
Calcium Release ◽  
Mechanisms Of Action ◽  
Network Pharmacology ◽  
Synergistic Activity ◽  
Drug Leads ◽  
Animal Venoms ◽  
Venom Proteins ◽  
Tumor Proteins

Animal venoms offer a valuable source of potent new drug leads, but their mechanisms of action are largely unknown. We therefore developed a novel network pharmacology approach based on multi-omics functional data integration to predict how stingray venom disrupts the physiological systems of target animals. We integrated 10 million transcripts from five stingray venom transcriptomes and 848,640 records from three high-content venom bioactivity datasets into a large functional data network. The network featured 216 signaling pathways, 29 of which were shared and targeted by 70 transcripts and 70 bioactivity hits. The network revealed clusters for single envenomation outcomes, such as pain, cardiotoxicity and hemorrhage. We carried out a detailed analysis of the pain cluster representing a primary envenomation symptom, revealing bibrotoxin and cholecystotoxin-like transcripts encoding pain-inducing candidate proteins in stingray venom. The cluster also suggested that such pain-inducing toxins primarily activate the inositol-3-phosphate receptor cascade, inducing intracellular calcium release. We also found strong evidence for synergistic activity among these candidates, with nerve growth factors cooperating with the most abundant translationally-controlled tumor proteins to activate pain signaling pathways. Our network pharmacology approach, here applied to stingray venom, can be used as a template for drug discovery in neglected venomous species.

scholarly journals Phylogeny-Guided Selection of Priority Groups for Venom Bioprospecting: Harvesting Toxin Sequences in Tarantulas as a Case Study

Toxins ◽  
2019 ◽  
Vol 11 (9) ◽  
pp. 488 ◽  
Author(s):  
Tim Lüddecke ◽  
Andreas Vilcinskas ◽  
Sarah Lemke
Keyword(s):  
Success Rate ◽  
Mechanisms Of Action ◽  
Rational Selection ◽  
Almost All ◽  
Novel Drug ◽  
Drug Leads ◽  
Novel Structures ◽  
Animal Venoms ◽  
Selection Of

Animal venoms are promising sources of novel drug leads, but their translational potential is hampered by the low success rate of earlier biodiscovery programs, in part reflecting the narrow selection of targets for investigation. To increase the number of lead candidates, here we discuss a phylogeny-guided approach for the rational selection of venomous taxa, using tarantulas (family Theraphosidae) as a case study. We found that previous biodiscovery programs have prioritized the three subfamilies Ornithoctoninae, Selenocosmiinae, and Theraphosinae, which provide almost all of the toxin sequences currently available in public databases. The remaining subfamilies are poorly represented, if at all. These overlooked subfamilies include several that form entire clades of the theraphosid life tree, such as the subfamilies Eumenophorinae, Harpactirinae, and Stromatopelminae, indicating that biodiversity space has not been covered effectively for venom biodiscovery in Theraphosidae. Focusing on these underrepresented taxa will increase the likelihood that promising candidates with novel structures and mechanisms of action can be identified in future bioprospecting programs.

scholarly journals Identification of Active Compounds of Mahuang Fuzi Xixin Decoction and Their Mechanisms of Action by LC-MS/MS and Network Pharmacology

2020 ◽  
Vol 2020 ◽  
pp. 1-11
Author(s):  
Xiao Liang ◽  
Chang-Shun Liu ◽  
Ting Xia ◽  
Qing-Fa Tang ◽  
Xiao-Mei Tan
Keyword(s):  
Signaling Pathways ◽  
Bioactive Compounds ◽  
Cell Receptor ◽  
Mechanisms Of Action ◽  
Network Pharmacology ◽  
Therapeutic Effects ◽  
Active Compounds ◽  
Beneficial Effects ◽  
T Cell Receptor Signaling ◽  
Therapeutic Mechanisms

The decoction is an important dosage form of traditional Chinese medicine (TCM) administration. The Mahuang Fuzi Xixin decoction (MFXD) is widely used to treat allergic rhinitis (AR) in China. However, its active compounds and therapeutic mechanisms are unclear. The aim of this study was to establish an integrative method to identify the bioactive compounds and reveal the mechanisms of action of MFXD. LC-MS/MS was used to identify the compounds in MFXD, followed by screening for oral bioavailability. TCMSP, BindingDB, STRING, DAVID, and KEGG databases and algorithms were used to gather information. Cytoscape was used to visualize the networks. Twenty-four bioactive compounds were identified, and thirty-seven predicted targets of these compounds were associated with AR. DAVID analysis suggested that these compounds exert their therapeutic effects by modulating the Fc epsilon RI, B-cell receptor, Toll-like receptor, TNF, NF-κB, and T-cell receptor signaling pathways. The PI3K/AKT and cAMP signaling pathways were also implicated. Ten of the identified compounds, quercetin, pseudoephedrine, ephedrine, β-asarone, methylephedrine, α-linolenic acid, cathine, ferulic acid, nardosinone, and higenamine, seemed to account for most of the beneficial effects of MFXD in AR. This study showed that LC-MS/MS followed by network pharmacology analysis is useful to elucidate the complex mechanisms of action of TCM formulas.

scholarly journals Network Pharmacology Analysis of the Therapeutic Mechanisms Underlying Beimu-Gualou Formula Activity against Bronchiectasis with In Silico Molecular Docking Validation

2021 ◽  
Vol 2021 ◽  
pp. 1-17
Author(s):  
Xin Shen ◽  
Hong Li ◽  
Wen-Jun Zou ◽  
Jian-Ming Wu ◽  
Long Wang ◽  
...  
Keyword(s):  
Molecular Docking ◽  
Signaling Pathways ◽  
Cellular Response ◽  
Inflammatory Responses ◽  
Interaction Network ◽  
Mechanisms Of Action ◽  
Network Pharmacology ◽  
Therapeutic Effects ◽  
Target Interaction ◽  
In Silico Molecular Docking

Background. The classical Chinese herbal prescription Beimu-Gualou formula (BMGLF) has been diffusely applied to the treatment of respiratory diseases, including bronchiectasis. Although concerning bronchiectasis the effects and mechanisms of action of the BMGLF constituents have been partially elucidated, it remains to be determined how the formula in its entirety exerts therapeutic effects. Methods. In this study, the multitarget mechanisms of BMGLF against bronchiectasis were predicted with network pharmacology analysis. Using prepared data, a drug-target interaction network was established and subsequently the core therapeutic targets of BMGLF were identified. Furthermore, the biological function and pathway enrichment of potential targets were analyzed to evaluate the therapeutic effects and pivotal signaling pathways of BMGLF. Finally, virtual molecular docking was performed to assess the affinities of compounds for the candidate targets. Results. The therapeutic action of BMGLF against bronchiectasis involves 18 core target proteins, including the aforementioned candidates (i.e., ALB, ICAM1, IL10, and MAPK1), which are assumed to be related to biological processes such as drug response, cellular response to lipopolysaccharide, immune response, and positive regulation of NF-κB activity in bronchiectasis. Among the top 20 signaling pathways identified, mechanisms of action appear to be primarily related to Chagas disease, allograft rejection, hepatitis B, and inflammatory bowel disease. Conclusion. In summary, using a network pharmacology approach, we initially predicted the complex regulatory profile of BMGLF against bronchiectasis in which multilink suppression of immune/inflammatory responses plays an essential role. These results may provide a basis for novel pharmacotherapeutic approaches for bronchiectasis.

scholarly journals Network Pharmacological Analysis and Experimental Validation of the Mechanisms of Action of Si-Ni-San Against Liver Fibrosis

2021 ◽  
Vol 12 ◽  
Author(s):  
Siliang Wang ◽  
Cheng Tang ◽  
Heng Zhao ◽  
Peiliang Shen ◽  
Chao Lin ◽  
...  
Keyword(s):  
Liver Fibrosis ◽  
Hepatic Stellate Cells ◽  
Stellate Cells ◽  
Mechanisms Of Action ◽  
Network Pharmacology ◽  
Related Factor ◽  
Alcoholic Fatty Liver ◽  
Ppar Γ ◽  
Liver Tissues

Background: Si-Ni-San (SNS), a commonly used traditional Chinese medicine (TCM) formula, has potency against liver diseases, such as hepatitis and non-alcoholic fatty liver disease (NAFLD). However, the therapeutic efficacy and pharmacological mechanisms of action of SNS against liver fibrosis remain largely unclear.Methods: A carbon tetrachloride (CCl4)-induced liver fibrosis mouse model was adopted for the first time to investigate the beneficial effects of SNS on liver fibrosis. The potential mechanisms of action of SNS were explored using the network pharmacology-based strategy and validated with the aid of diverse assays.Results: SNS treatment reduced collagen and ECM deposition, downregulated fibrosis-related factor (hyaluronic acid and laminin) contents in serum, maintained the morphological structure of liver tissue, and improved liver function in the liver fibrosis model. Based on network pharmacology results, apoptosis, inflammation and angiogenesis, together with the associated pathways (including VEGF, TNF, caspase, PPAR-γ and NF-κB), were identified as the mechanisms underlying the effects of SNS on liver fibrosis. Further in vivo experiments validated the significant mitigatory effects of SNS on inflammatory infiltration and pro-inflammatory cytokine contents (IFNγ, IL-1β and TGF-β1) in liver tissues of mice with liver fibrosis. SNS suppressed pathologic neovascularization as well as levels of VEGFR1, VEGF and VEGFR2 in liver tissues. SNS treatment additionally inhibited hepatic parenchyma cell apoptosis in liver tissues of mice with liver fibrosis and regulated apoptin expression while protecting L02 cells against apoptosis induced by TNF-α and Act D in vitro. Activation of hepatic stellate cells was suppressed and the balance between MMP13 and TIMP1 maintained in vitro by SNS. These activities may be associated with SNS-induced NF-κB suppression and PPAR-γ activation.Conclusion: SNS effectively impedes liver fibrosis progression through alleviating inflammation, ECM accumulation, aberrant angiogenesis and apoptosis of hepatic parenchymal cells along with inhibiting activation of hepatic stellate cells through effects on multiple targets and may thus serve as a novel therapeutic regimen for this condition.

scholarly journals NMPA-approved traditional Chinese medicine-Pingwei Pill: new indication for colistin recovery against MCR-positive bacteria infection

2021 ◽  
Vol 16 (1) ◽  
Author(s):  
Qiushuang Sheng ◽  
Runbao Du ◽  
Cunhui Ma ◽  
Yonglin Zhou ◽  
Xue Shen ◽  
...  
Keyword(s):  
Molecular Docking ◽  
Bacterial Infection ◽  
Molecular Mechanisms ◽  
Topological Analysis ◽  
Network Pharmacology ◽  
Synergistic Activity ◽  
Colistin Resistance ◽  
Western Blot Assay ◽  
Gram Negative

Abstract Background The wide spread of plasmid-mediated colistin resistance by mobile colistin resistance (MCR) in Enterobacteriaceae severely limits the clinical application of colistin as a last-line drug against bacterial infection. The identification of colistin potentiator from natural plants or their compound preparation as antibiotic adjuncts is a new promising strategy to meet this challenge. Methods Herein, the synergistic activity, as well as the potential mechanism, of Pingwei pill plus antibiotics against MCR-positive Gram-negative pathogens was examined using checkerboard assay, time-killing curves, combined disk test, western blot assay, and microscope analysis. Additionally, the Salmonella sp. HYM2 infection models of mouse and chick were employed to examine the in vivo efficacy of Pingwei pill in combination with colistin against bacteria infection. Finally, network pharmacology and molecular docking assay were used to predicate other actions of Pingwei pill for Salmonella infection. Results Our results revealed that Pingwei Pill synergistically potentiated the antibacterial activity of colistin against MCR-1-positive bacteria by accelerating the damage and permeability of the bacterial outer membrane with an FIC (Fractional Inhibitory Concentration) index less than 0.5. The treatment of Pingwei Pill neither inhibited bacterial growth nor affected MCR production. Notably, Pingwei Pill in combination with colistin significantly prolonged the median survival in mouse and chick models of infection using the Salmonella sp. strain HYM2, decreased bacteria burden and organ index of infected animal, alleviated pathological damage of cecum, which suggest that Pingwei Pill recovered the therapeutic performance of colistin for MCR-1- positive Salmonella infection in mice and the naturally infected host chick. Pharmacological network topological analysis, molecular docking, bacterial adhesion, and invasion pathway verification assays were performed to identify the other molecular mechanisms of Pingwei Pill as a colistin potentiator against Gram-negative bacteria infection. Conclusion Taken together, NMPA (National Medical Products Administration)-approved Pingwei Pill is a promising adjuvant with colistin for MCR-positive bacterial infection with a shortened R&D (research and development) cycle and affordable R&D cost and risk.

scholarly journals Study on the Mechanism of Lianpu Drink for the Treatment of Chronic Gastritis Based on Network Pharmacology

2021 ◽  
Vol 2021 ◽  
pp. 1-13
Author(s):  
Shuhan Zhou ◽  
Yanjun Duan ◽  
Yu Deng ◽  
Miao Wang ◽  
Chaoqun Huang ◽  
...  
Keyword(s):  
Chinese Medicine ◽  
Traditional Chinese Medicine ◽  
Signaling Pathway ◽  
Chronic Gastritis ◽  
Mechanisms Of Action ◽  
Network Pharmacology ◽  
Biological Pathway ◽  
Disease Network ◽  
Target Disease ◽  
Compound Target

Chronic gastritis (CG) places a considerable burden on the healthcare system worldwide. Traditional Chinese Medicine (TCM) formulas characterized by multicompounds and multitargets have been acknowledged with striking effects in the treatment of CG in China’s history. Nevertheless, their accurate mechanisms of action are still ambiguous. In this study, we analyzed the effective compounds, potential targets, and related biological pathway of Lianpu Drink (LPD), a TCM formula which has been reported to have a therapeutic effect on CG, by contrasting a “compound-target-disease” network. According to the results, 92 compounds and 5762 putative targets of LPD were screened; among them, 8 compounds derived from different herbs in LPD and 30 common targets related to LPD and CG were selected as candidate compounds and precision targets, respectively. Meanwhile, the predicted common targets were verified by Kyoto Encyclopedia of Genes and Genomes (KEGG) signaling pathway analysis and pharmacological experiments. The results demonstrated that quercetin, ephedrine, trigonelline, crocetin, and β-sitosterol were major effective compounds of LPD responsible for the CG treatment by inhibiting the activation of the JAK 2-STAT 3 signaling pathway to reduce the expressions of cyclin D1 and Bcl-2 proteins. The study provides evidence for the mechanism of understanding of LPD for the treatment of CG.

Polyphenols: Novel Signaling Pathways

2018 ◽  
Vol 24 (2) ◽  
pp. 158-170 ◽  
Author(s):  
Marie-Louise Ricketts ◽  
Bradley S. Ferguson
Keyword(s):  
Risk Factors ◽  
Signaling Pathways ◽  
Molecular Mechanisms ◽  
Density Lipoprotein ◽  
Mechanisms Of Action ◽  
Metabolic Effects ◽  
Special Focus ◽  
In Vivo Models ◽  
Alcoholic Fatty Liver ◽  
The Metabolic Syndrome

Background: Cardiovascular disease (CVD) is currently the leading cause of death globally. The metabolic syndrome (MetS), a clustering of risk factors including hypertension, hyperglycemia, elevated low-density lipoprotein (LDL) cholesterol, reduced high-density lipoprotein (HDL) cholesterol and increased visceral adiposity, is a significant risk factor for the development of CVD. Non-alcoholic fatty liver disease (NAFLD), often referred to as the hepatic manifestation of MetS, is a constellation of progressive liver disorders closely linked to obesity, diabetes, and insulin resistance. NAFLD initially presents as relatively benign, non-progressive hepatic steatosis, but it may, in certain individuals, progress to nonalcoholic steatohepatitis, fibrosis, cirrhosis, or hepatocellular carcinoma. Currently, there are no validated treatments for NAFLD. Polyphenols are important bioactive dietary compounds and may represent a natural complementary and integrative therapy for the treatment of CVDassociated risk factors, including elevated serum cholesterol and triglyceride levels, as well as NAFLD. Understanding their molecular mechanisms of action is important in the design of future human intervention studies. Methods: Several studies utilizing in vitro and in vivo models have helped to identify underlying molecular mechanisms of action of polyphenols. Results: This review will highlight recent advances regarding the molecular actions of dietary procyanidins, with a special focus on those originating from procyanidin-rich grape seed extracts, with a focus on the signaling pathways utilized to exert beneficial metabolic effects. Conclusion: Modulation of nuclear receptor activity and histone deacetylase inhibition has been identified as underlying mechanisms contributing to procyanidin-mediated amelioration of dyslipidemia and steatosis.

scholarly journals Analysis of the Molecular Mechanisms of the Effects of Prunella vulgaris against Subacute Thyroiditis Based on Network Pharmacology

2020 ◽  
Vol 2020 ◽  
pp. 1-13
Author(s):  
Xin Shen ◽  
Rui Yang ◽  
Jianpeng An ◽  
Xia Zhong
Keyword(s):  
Signaling Pathways ◽  
Molecular Mechanisms ◽  
Kegg Pathway ◽  
Enrichment Analysis ◽  
Subacute Thyroiditis ◽  
Network Pharmacology ◽  
Pharmacokinetic Parameters ◽  
Pathway Enrichment Analysis ◽  
Prunella Vulgaris ◽  
Protein Protein Interaction

Prunella vulgaris (PV) has a long history of application in traditional Chinese and Western medicine as a remedy for the treatment of subacute thyroiditis (SAT). This study applied network pharmacology to elucidate the mechanism of the effects of PV against SAT. Components of the potential therapeutic targets of PV and SAT-related targets were retrieved from databases. To construct a protein-protein interaction (PPI) network, the intersection of SAT-related targets and PV-related targets was input into the STRING platform. Gene ontology (GO) analysis and KEGG pathway enrichment analysis were carried out using the DAVID database. Networks were constructed by Cytoscape for visualization. The results showed that a total of 11 compounds were identified according to the pharmacokinetic parameters of ADME. A total of 126 PV-related targets and 2207 SAT-related targets were collected, and 83 overlapping targets were subsequently obtained. The results of the KEGG pathway and compound-target-pathway (C-T-P) network analysis suggested that the anti-SAT effect of PV mainly occurs through quercetin, luteolin, kaempferol, and beta-sitosterol and is most closely associated with their regulation of inflammation and apoptosis by targeting the PIK3CG, MAPK1, MAPK14, TNF, and PTGS2 proteins and the PI3K-Akt and TNF signaling pathways. The study demonstrated that quercetin, luteolin, kaempferol, and beta-sitosterol in PV may play a major role in the treatment of SAT, which was associated with the regulation of inflammation and apoptosis, by targeting the PI3K-Akt and TNF signaling pathways.

scholarly journals Potential Molecular Target Prediction and Docking Verification of Hua-Feng-Dan in Stroke Based on Network Pharmacology

2020 ◽  
Vol 2020 ◽  
pp. 1-12
Author(s):  
Ping Yang ◽  
Haifeng He ◽  
Shangfu Xu ◽  
Ping Liu ◽  
Xinyu Bai
Keyword(s):  
Molecular Docking ◽  
Signaling Pathways ◽  
Target Genes ◽  
Target Prediction ◽  
Interaction Network ◽  
Network Pharmacology ◽  
Core Network ◽  
Active Ingredients ◽  
Protein Protein Interaction ◽  
Highly Correlated

Objective. Hua-Feng-Dan (HFD) is a Chinese medicine for stroke. This study is to predict and verify potential molecular targets and pathways of HFD against stroke using network pharmacology. Methods. The TCMSP database and TCMID were used to search for the active ingredients of HFD, and GeneCards and DrugBank databases were used to search for stroke-related target genes to construct the “component-target-disease” by Cytoscape 3.7.1, which was further filtered by MCODE to build a core network. The STRING database was used to obtain interrelationships by topology and to construct a protein-protein interaction network. GO and KEGG were carried out through DAVID Bioinformatics. Autodock 4.2 was used for molecular docking. BaseSpace was used to correlate target genes with the GEO database. Results. Based on OB ≥ 30% and DL ≥ 0.18, 42 active ingredients were extracted from HFD, and 107 associated targets were obtained. PPI network and Cytoscape analysis identified 22 key targets. GO analysis suggested 51 cellular biological processes, and KEGG suggested that 60 pathways were related to the antistroke mechanism of HFD, with p53, PI3K-Akt, and apoptosis signaling pathways being most important for HFD effects. Molecular docking verified interactions between the core target (CASP8, CASP9, MDM2, CYCS, RELA, and CCND1) and the active ingredients (beta-sitosterol, luteolin, baicalein, and wogonin). The identified gene targets were highly correlated with the GEO biosets, and the stroke-protection effects of Xuesaitong in the database were verified by identified targets. Conclusion. HFD could regulate the symptoms of stroke through signaling pathways with core targets. This work provided a bioinformatic method to clarify the antistroke mechanism of HFD, and the identified core targets could be valuable to evaluate the antistroke effects of traditional Chinese medicines.

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