Molecular mechanisms of Biyu decoction as treatment for psoriasis:A network pharmacology and molecular docking study

BACKGROUND The therapeutic effects of a combination of Chinese medicines called Biyu decoction have been clinically verified,although its molecular targets in psoriasis remain unknown.AIM To explore the molecular mechanisms of Biyu decoction for psoriasis treatment.METHODS In this network pharmacology and molecular docking study,the Traditional Chinese Medicine Systems Pharmacology database was searched for Biyu decoction active ingredients.GeneCards,Online Mendelian Inheritance in Man,PharmGkb,Therapeutic Target Database,and DrugBank databases were searched for psoriasis-related genes.The genes targeted by the decoction’s active ingredient and disease genes were intersected to obtain predictive targets of the drug during psoriasis treatment.Cytoscape 3.8.0 was used to construct a drug component/target disease network.The The functional protein association networks database and Cytoscape were used to construct a protein-protein interaction network and streamline the core network.The Gene Ontology and Kyoto Encyclopedia of Genes and Genomes were used for pathway enrichment analysis.Molecular docking technology was used to verify the drug component/target disease network.RESULTS We screened 117 major active ingredients,including quercetin,kaempferol,naringenin,and acetyl-shikonin,and identified 213 gene targets,such as MAPK3,JUN,FOS,MYC,MAPK8,STAT3,and NFKBIA.Using a molecular docking analysis,the main active ingredients demonstrated good binding to the core targets.The Gene Ontology analysis showed that these ingredients were significantly associated with biological activities,such as transcription factor DNA binding,RNA polymerase II-specific DNA binding of transcription factors,and cytokine receptor binding;responses to lipopolysaccharides,molecules of bacterial origin,and oxidative stress;and were mainly distributed in membrane rafts,microdomains,and regions.The Kyoto Encyclopedia of Genes and Genomes analysis showed that decoction ingredients act on Th17 cell differentiation,tumor necrosis factor and mitogen-activated protein signaling pathways,the interleukin-17 signaling pathway,and the PI3K-Akt signaling pathway.CONCLUSION Biyu decoction may be effective against psoriasis through multi-component,multi-target,and multi-channel synergy.

Rheum palmatum L. and Salvia miltiorrhiza Bge. Alleviates Acute Pancreatitis by Regulating Th17 Cell Differentiation: An Integrated Network Pharmacology Analysis, Molecular Dynamics Simulation and Experimental Validation

Objective: To identify the core targets of Rheum palmatum L. and Salvia miltiorrhiza Bge.,(Dahuang-Danshen, DH-DS) and the mechanism underlying its therapeutic efficacy in acute pancreatitis(AP)using a network pharmacology approach and validate the findings in animal experiments. Methods: Network pharmacology analysis was used to elucidate the mechanisms underlying the therapeutic effects of DH-DS in AP. The reliability of the results was verified by molecular docking simulation and molecular dynamics simulation.Finally, the results of network pharmacology enrichment analysis were verified by immunohistochemistry,Western blot analysis and real-time quantitative PCR, respectively. Results: Sixty-seven common targets of DH-DS in AP were identified and mitogen-activated protein kinase 3(MAPK3), Janus kinase 2(JAK2), signal transducer and activator of transcription 3(STAT3), protein c-Fos(FOS) were identified as core targets in the protein interaction(PPI) network analysis. Gene ontology analysis showed that cellular response to organic substance was the main functions of DH-DS in AP, and Kyoto Encyclopedia of Genes and Genomes analysis showed that the main pathway included Th17 cell differentiation. Molecular docking simulation confirmed that DH-DS binds with strong affinity to MAPK3, STAT3 and FOS. Molecular dynamics simulation revealed that FOS-isotanshinone Ⅱ and STAT3-dan-shexinkum d had good binding capacity. Animal experiments indicated that compared with the AP model group, DH-DS treatment effectively alleviated AP by inhibiting the expression of interleukin-1β, interleukin-6 and tumor necrosis factor-α, and blocking the activation of Th17 cell differentiation(P<0.01). Conclusion: DH-DS could inhibit the expression of inflammatory factors and protect pancreatic tissues,which would be functioned by regulating Th17 cell differentiation-related m RNA and protein expressions.

Gene signatures to therapeutics:Assessing the potential of ivermectin against t(4;14)multiple myeloma

BACKGROUND Multiple myeloma(MM)is a terminal differentiated B-cell tumor disease characterized by clonal proliferation of malignant plasma cells and excessive levels of monoclonal immunoglobulins in the bone marrow.The translocation,(t)(4;14),results in high-risk MM with limited treatment alternatives.Thus,there is an urgent need for identification and validation of potential treatments for this MM subtype.Microarray data and sequencing information from public databases could offer opportunities for the discovery of new diagnostic or therapeutic targets.AIM To elucidate the molecular basis and search for potential effective drugs of t(4;14)MM subtype by employing a comprehensive approach.METHODS The transcriptional signature of t(4;14)MM was sourced from the Gene Expression Omnibus.Two datasets,GSE16558 and GSE116294,which included 17 and 15 t(4;14)MM bone marrow samples,and five and four normal bone marrow samples,respectively.After the differentially expressed genes were identified,the Cytohubba tool was used to screen for hub genes.Then,the hub genes were analyzed using Gene Ontology and Kyoto Encyclopedia of Genes and Genomes analysis.Using the STRING database and Cytoscape,protein–protein interaction networks and core targets were identified.Potential small-molecule drugs were identified and validated using the Connectivity Map database and molecular docking analysis,respectively.RESULTS In this study,a total of 258 differentially expressed genes with enriched functions in cancer pathways,namely cytokine receptor interactions,nuclear factor(NF)-κB signaling pathway,lipid metabolism,atherosclerosis,and Hippo signaling pathway,were identified.Ten hub genes(cd45,vcam1,ccl3,cd56,app,cd48,btk,ccr2,cybb,and cxcl12)were identified.Nine drugs,including ivermectin,deforolimus,and isoliquiritigenin,were predicted by the Connectivity Map database to have potential therapeutic effects on t(4;14)MM.In molecular docking,ivermectin showed strong binding affinity to all 10 identified targets,especially cd45 and cybb.Ivermectin inhibited t(4;14)MM cell growth via the NF-κB pathway and induced MM cell apoptosis in vitro.Furthermore,ivermectin increased reactive oxygen species accumulation and altered the mitochondrial membrane potential in t(4;14)MM cells.CONCLUSION Collectively,the findings offer valuable molecular insights for biomarker validation and potential drug development in t(4;14)MM diagnosis and treatment,with ivermectin emerging as a potential therapeutic alternative.

Discovery of Benzimidazole Derivatives as Novel Aldosterone Synthase Inhibitors:QSAR,Docking Studies,and Molecular Dynamics Simulation

Aldosterone synthase inhibitors can lessen the production of aldosterone in organisms,which effec-tively affecting the treatment of hypertension.A series of computational approaches like QSAR,docking,DFT and molecular dynamics simulation are applied on 40 benzimidazole derivatives of aldosterone synthase(CYP11B2)in-hibitors.Statistical parameters:Q^(2)=0.877,R^(2)=0.983(CoMFA)and Q^(2)=0.848,R^(2)=0.994(CoMSIA)indicate on good predictive power of both models and DFT’s result illustrates the stability of both models.Besides,Y-randomization test is also performed to ensure the robustness of the obtained 3D-QSAR models.Docking studies show inhibitors rely onπ-πinteraction with residues,such as Phe130,Ala313 and Phe481.Molecular dynamics simulation results further confirm that the hydrophobic interaction with proteins enhances the inhibitor’s inhibitory effect.Based on QSAR studies and molecular docking,we designed novel compounds with enhanced activity against aldosterone synthase.Furthermore,the newly designed compounds are analyzed for their ADMET proper-ties and drug likeness and the results show that they all have excellent bioavailability.

Network pharmacology and molecular docking study on the effect of Kaempferol in treatment of metabolic associated fatty liver disease

OBJECTIVE: To study therapeutic effect of kaempferol on metabolic associated fatty liver disease(MAFLD) by network pharmacology and molecular docking combined with cell experiments. METHODS: First, use the Swiss Target Prediction database to predict the targets of kaempferol, and collect the targets of MAFLD through the Disgenet database and the Gene Cards database. Then, the common target of kaempferol and MAFLD was enriched and analyzed by the Gene Ontology(GO) and Kyoto Encyclopedia of Genes and Genomes, and the protein-protein interaction(PPI) network was constructed through the string database to obtain the key targets, and carry out molecular docking of key targets with kaempferol;In cell experiment, oleic acid induced steatosis in Hep G2 cells, which was intervened by kaempferol, the level of triglyceride(TG) was detected, the lipid deposition was observed by oil red O staining, and the protein expression was detected by Western blot. RESULTS: The results showed that there are 33 common targets for kaempferol and MAFLD. The biological process of GO is related to the regulation of protein kinase B, cell apoptosis, inflammatory factors, lipoxygenase, etc. Its action pathway is related to the phosphatidylinositol-3-kinase and protein kinase B(PI3K-AKT) signaling pathway, hypoxia-inducible factor 1 signaling pathway, forkhead box protein O signaling pathway, AMP-activated protein kinase signaling pathway, tumor necrosis factor signaling pathway, etc., the key targets are protein kinase B(AKT1), prostaglandin G/H synthase 2, matrix metalloproteinase-9, epidermal growth factor receptor, and the molecular docking of kaempferol with the four key targets shows good binding properties. Cell experiments show that kaempferol can reduce cell TG levels, reduce lipid deposition, increase the expression of PI3K, AKT, and beclin-1, and reduce the expression of caspase-3 and nuclear factor-kappa B. Kaempferol can treat MAFLD by regulating the PI3K-AKT signaling pathway to regulate cell autophagy, apoptosis, and inflammation. CONCLUSIONS: This study shows that kaempferol can regulate lipid metabolism, reduce apoptosis, regulate inflammation and autophagy in the fatty liver cell model. It reveals the therapeutic mechanism of kaempferol on MAFLD and provides a natural product candidate for the treatment of MAFLD.

Exploring the mechanism of hirudin in the treatment of diabetic kidney disease using network pharmacology combined with molecular docking verification

OBJECTIVE:To explore the mechanism of hirudin in the treatment of diabetic kidney disease(DKD).METHOD:Cytoscape software was used to analyze the network between hirudin targets and active components in the treatment of DKD.The biological function and mechanism of effective targets of hirudin for DKD treatment were analyzed by the Database for Annotation,Visualization and Integrated Discovery(DAVID)database.Molecular docking technology was used to simulate the docking of key targets,and the DKD rat model was used to verify the first 4 key targets with high"Hydrogen number"among the top 10 targets verified by molecular docking.RESULTS:Total of 12334 DKD targets were screened in Gene Cards,OMIM and other databases,Hirudin and DKD had 247 common target genes,and the protein interaction network got 2115 edges.The DAVID database was used for the Gene Ontology and Kyoto Encyclopedia of Genes and Genomes enrichment analysis,confirming that hirudin in treatment of DKD involves multiple signaling pathways such as the forkhead box O signaling pathway,the phosphatidylinositol 3-kinase-protein kinase B signaling pathway,the vascular endothelial-derived growth factor signaling pathway and other signaling pathways.The top ten key targets of hirudin in treatment of DKD were verified by molecular docking.Animal experiments showed that hirudin could decrease the expression of caspase-3 in renal tissue of DKD rats,and increase the expression of RAC-alpha serine/threonineprotein kinase,Catalase,and Heat shock protein HSP 90-alpha in renal tissue of DKD rats.CONCLUSION:This study preliminarily reveals that hirudin treats DKD through multiple targets and pathways,and molecular docking and animal experiments indicates the feasibility of this study.Hirudin may be directly or indirectly involved in the regulation of cell metabolism,oxidative stress and other mechanisms in the treatment of DKD,which will lay the foundation for future molecular biological experiments of hirudin in the treatment of DKD.

Taohong Siwu decoction(桃红四物汤)ameliorates atherosclerosis in rats possibly through toll-like receptor 4/myeloid differentiation primary response protein 88/nuclear factor-κB signal pathway

OBJECTIVE:To investigate the effect of Taohong Siwu decoction(桃红四物汤,TSD)on atherosclerosis in rats as well as investigate the underlying mechanism based on molecular docking.METHODS:Sixty healthy male Sprague-Dawley rats were randomly divided into 6 groups with 10 rats in each group:control group,model group,atorvastatin group(AT,2.0 mg/kg),and TSD groups(20,10,5 g/kg)after 7 d of acclimation.The model of atherosclerosis was successfully established except the control group by high fat diet(HFD)and vitamin D2.Biochemical analyzers were used to detect the levels of triglyceride(TG),total cholestero(TC),low density lipoprotein-cholesterol(LDLC)and high density lipid-cholesterol(HDL-C)in blood lipid.The levels of tumor necrosis factor-α(TNF-α),interleukin-6(IL-6)and interleukin-1β(IL-1β)were determined by enzyme-linked immunosorbent assay.Sudan IV staining and Hematoxylin and eosin staining(HE staining)were performed to observe the pathological changes in aortic tissue.Molecular docking technology was used to predict the best matching between the main components of TSD and the target proteins.The expression of target proteins was further detected by quantitative real time polymerase chain reaction(q RTPCR)and Western blot analysis.RESULTS:The results showed that TSD restricted atherosclerosis development and decreased the inflammatory cytokines in plasma.Molecular docking results predicted that the main components of TSD showed a strong binding ability with toll-like receptor(TLR4),myeloid differentiation primary response protein 88(My D88),and nuclear factor kappa-B(NF-κB).The results of q RT-PCR and Western blot analysis showed that the m RNA and protein expressions of TLR4,My D88 and NF-κB p65 in the aorta were reduced in atorvastatin group and TSD group.CONCLUSIONS:TSD can ameliorate atherosclerosis in rats,and the underlying mechanism is supposed be related to the suppression of inflammatory response by regulating TLR4/My D88/NF-κB signal pathway.

Investigation of the active ingredients and mechanism of Shuangling extract in dextran sulfate sodium salt induced ulcerative colitis mice based on network pharmacology and experimental verification

OBJECTIVE: To explore the pharmacodynamic effects and potential mechanisms of Shuangling extract against ulcerative colitis(UC). METHODS: The bioinformatics method was used to predict the active ingredients and action targets of Shuangling extract against UC in mice. And the biological experiments such as serum biochemical indexes and histopathological staining were used to verify the pharmacological effect and mechanism of Shuangling extract against UC in mice. RESULTS: The Shuangling extract reduced the levels of seruminterleukin-1β(IL-1β), tumor necrosis factor-α(TNF-N), interleukin-6(IL-6) and other inflammatory factors in UC mice and inhibited the inflammatory response. AKT Serine/threonine Kinase 1 and IL-6 may be the main targets of the anti-UC action of Shuangling extract, and the TNF signaling pathway, Forkhead box O signaling pathway and T-cell receptor signaling pathway may be the main signaling pathways. CONCLUSION: The Shuangling extract could inhibit the inflammatory response induced by UC and regulate intestinal immune function through multiple targets and multiple channels, which provided a new option and theoretical basis for anti-UC.

Efficacy of Danlou tablet(丹蒌片)on myocardial ischemia/reperfusion injury assessed by network pharmacology and experimental verification

OBJECTIVE:To investigate the potential pharmacological mechanism of Danlou tablet(丹蒌片,DLT)with a long-term clinical application in the treatment of myocardial ischemia/reperfusion(I/R)injury through network pharmacology,molecular docking and experimental verification.METHODS:The main chemical ingredients in DLT were retrieved from the Traditional Chinese Medicine(TCM)System Pharmacology Database,the TCM information database,the bioinformatics analysis tool for molecular mechanism of TCM,and HERB database.Disease targets of I/R were accessed from the databases of Online Mendelian Inheritance in Man,Gene Cards,Therapeutic Target Database,and Dis Ge NET database.The overlaying genes of DLT and I/R were obtained from the Venny online platform.The core targets and proteinprotein interaction network were constructed and analyzed via the Search Tool for the Retrieval of Interacting Genes Proteins database and Cytoscape software.Furthermore,Gene Ontology(GO)analysis and Kyoto Encyclopedia of Genes and Genomes(KEGG)pathway enrichment analysis were performed by the Metascape platform.Based on the results,the component-target-pathway network was constructed and drafted via the Cytoscape software and the platform of Bioinformatics.Furthermore,we performed molecular docking to predict the binding information between chemical molecules and target proteins.Finally,oxygenglucose deprivation/recovery(OGD/R)-induced H9c2 cardiomyocytes were used to validate the results of network pharmacology in vitro.RESULTS:A total of 189 active chemical components in DLT and 849 correlative targets of I/R were screened.Of note,133 overlaying genes found from the Venny online platform were concentrated into 28 core genes.Furthermore,the GO and KEGG pathway enrichment analysis presented that DLT might participate in 42 types of GO molecular functions,747 types of GO biological processes,19 types of GO cellular components,and 140 kinds of pathways to treat I/R.In the component-targetpathway network,the indirect relationship between herbs and their possible effective pathways was clarified.Based on the molecular docking,we speculated that Baicalein-prostaglandin G/H synthase 2(PTGS2)with-3.24 kcal/mol,Luteolin-heat shock protein 90 alpha family class A member 1(HSP90AA1)with-3.22 kcal/mol,Baicalein-HSP90AA1 with-3.13 kcal/mol,and QuercetinHSP90AA1 with-3.05 kcal/mol possessed the strongest binding force of less than-3 kcal/mol,sequentially.Experimental verification showed that Quercetin,Luteolin,and Baicalein could increase the relative cell viability of OGD/R-stimulated cardiomyocytes,probably by suppressing PTGS2,and activating HSP90AA1 and estrogen receptor 1 expression.CONCLUSIONS:We predicted the potential active compounds as the material basis of DLT that may provide a new approach to elucidate the novel pharmacological mechanism underlying the treatment of cardiac I/R damage.

Discovering peptides and computational investigations of a multiepitope vaccine target Mycobacterium tuberculosis

Mycobacterium tuberculosis(MTB)is the causative agent of tuberculosis(TB),a prevalent airborne infectious disease.Despite the availability of the Bacille Calmette-Guerin vaccine,its global efficacy remains modest,and tuberculosis persists as a significant global public health threat.Addressing this challenge and advancing towards the End MTB Strategy,we developed a multiepitope vaccine(MEV)based on immunoinformatics and compu-tational approaches.Immunoinformatics screening of MBT protein identified immune-dominant epitopes based on Major Histocompatibility Complex(MHC)allele binding,immunogenicity,antigenicity,allergenicity,toxicity,and cytokine inducibility.Selected epitopes were integrated into an MEV construct with adjuvant and linkers,forming a fully immunogenic vaccine candidate.Comprehensive analyses encompassed the evaluation of immunological and physicochemical properties,determination of tertiary structure,molecular docking with Toll-Like Receptors(TLR),molecular dynamics(MD)simulations for all atoms,and immune simulations.Our MEV comprises 534 amino acids,featuring 6 cytotoxic T lymphocyte,8 helper T lymphocyte,and 7 linear B lymphocyte epitopes,demonstrating high antigenicity and stability.Notably,molecular docking studies and triplicate MD simulations revealed enhanced interactions and stability of MEV with the TLR4 complex compared to TLR2.In addition,the immune simulation indicated the capacity to effectively induce elevated levels of an-tibodies and cytokines,emphasizing the vaccine’s robust immunogenic response.This study presents a promising MEV against TB,exhibiting favorable immunological and physicochemical attributes.The findings provide theoretical support for TB vaccine development.Our study aligns with the global initiative of the End MTB Strategy,emphasizing its potential impact on addressing persistent challenges in TB control.

Apple polyphenols attenuate the binding ability of angiotensin converting enzyme 2 to viral proteins: Computer simulation and in vitro experiments

To investigate the effects of apple polyphenols on ACE2 and its antibody binding, computer simulation and experiments in vitro were conducted. The results of molecular docking and molecular dynamics showed that apple polyphenols had a good binding effect on RBD and RBD-ACE2 complex. Fluorescence analysis exhibited that the three main apple polyphenols had a fluorescence quenching effect on the ACE2 antibodies, and the quenching mechanism was static. The results of the circular dichroism experiment suggested that apple polyphenols could change the secondary structure of the ACE2 antibodies. Western blot results displayed that apple polyphenols inhibited the binding of ACE2 and its antibodies. This study confirmed that apple polyphenols could bind ACE2 antibodies in vitro. Therefore, it is speculated that apple polyphenols have similar effects on a class of proteins with similar ACE2 recognition sites, which may potentially inhibit viral protein and ACE2 recognition, thus preventing viruses from entering host cells.

Organophosphate esters cause thyroid dysfunction via multiple signaling pathways in zebrafish brain

Organophosphate esters(OPEs)are widespread in various environmental media,and can disrupt thyroid endocrine signaling pathways.Mechanisms by which OPEs disrupt thyroid hormone(TH)signal transduction are not fully understood.Here,we present in vivo-in vitro-in silico evidence establishing OPEs as environmental THs competitively entering the brain to inhibit growth of zebrafish via multiple signaling pathways.OPEs can bind to transthyretin(TTR)and thyroxine-binding globulin,thereby affecting the transport of TH in the blood,and to the brain by TTR through the blood-brain barrier.When GH3 cells were exposed to OPEs,cell proliferation was significantly inhibited given that OPEs are competitive inhibitors of TH.Cresyl diphenyl phosphate was shown to be an effective antagonist of TH.Chronic exposure to OPEs significantly inhibited the growth of zebrafish by interfering with thyroperoxidase and thyroglobulin to inhibit TH synthesis.Based on comparisons of modulations of gene expression with the Gene Ontology and Kyoto Encyclopedia of Genes and Genomes databases,signaling pathways related to thyroid endocrine functions,such as receptor-ligand binding and regulation of hormone levels,were identified as being affected by exposure to OPEs.Effects were also associated with the biosynthesis and metabolism of lipids,and neuroactive ligand-receptor interactions.These findings provide a comprehensive understanding of the mechanisms by which OPEs disrupt thyroid pathways in zebrafish.

Farnesoid X receptor regulators from natural products and their biological function

Metabolic syndrome(Met S)has been a growing public health concern worldwide without specific medicine.Through summarizing the chemical structure type and effect mechanisms of natural products targeted on farnesoid X receptor(FXR),to provide the research basis for exploring the treatment of Met S.The following databases were searched for natural products which targeting FXR:Pub Med,Embase,the Cochrane Library,Web of Science,China National Knowledge Infrastructure Database,Wanfang Database,China Science and Technology Journal Database,and Chinese Biomedical Literature Database.Totally 120 natural products were summarized,including terpenoids(51 compounds),steroidal saponins(27 compounds),phenylpropanolds(19 compounds),flavonoids(13 compounds),alkaloids(3 compounds)and others(7 compounds),most researches focus on terpenoids and part of synthetic FXR regulators were based on the structure of terpenoids.FXR regulators could improve cholestasis and liver injury,hyperlipidemia,diabetes and atherosclerosis.FXR is a potential target of treating Met S.Natural products are characteristics with unique novel structures and special biological activity,and they are important sources of bioactive precursor compounds and drug discovery.Exploring the effects and mechanism of natural products and its derivative on Met S by targeting FXR may be a new way to develop the new drugs of treating Met S.

Effcacy-oriented compatibility for Tianma(Rhizoma Gastrodiae),Yanlingcao(Trillium tschonoskii Maxim) and Bingpian(Borneolum Syntheticum) on improving cerebral ischemia stroke by network pharmacology and serum pharmacological methods

OBJECTIVE:To evaluate the compatibility of Tianma(Rhizoma Gastrodiae,TM),Yanlingcao(Trillium tschonoskii Maxim,YLC)and Bingpian(Borneolum Syntheticum,BP),and their efficacy in the treatment of cerebral ischemic stroke.METHODS:Network pharmacology was used to determine the compatibility of TM,YLC,and BP,and their potential mechanism.The middle cerebral artery occlusion(MCAO)rat model was used to evaluate the curative effect of the six combinations of TM,YLC,and BP(TZB1-TZB6)on cerebral ischemia,by using the weight matching method to form.The potential component changes of TM and YLC in the blood and brains of rats were analyzed using ultra performance liquid chromatography-mass spectrometry.Finally,molecular docking linked the results of animal experiments and network pharmacology,determining the potential component contributors of TM and YLC to treating ischemic stroke.RESULTS:TZB reduced the cerebral infarct volume and protected the nerve cells in MCAO rats.The components of TM and YLC were also identified in the blood and brain homogenate,and BP can facilitate the entry of the components of TM and YLC into the blood and brain.Diosgenin,pennogenin,and gastrodin induced effective binding activities with adenosine receptor a1.CONCLUSION:We investigate an approach that improves the means of folk prescription combined with multi technology that maybe promote the transformation of Chinese medicinal prescription into component-based Chinese medicine.

Design, synthesis and MAO inhibitory activity of 2-(arylmethylidene)-2,3-dihydro-1-benzofuran-3-one derivatives

A series of 2-（arylmethylidene）-2,3-dihydro-1-benzofuran-3-one derivatives（aurones, 1–20） were synthesized and screened for their inhibitory activity against h MAO. Seventeen compounds（1–5, 7–17,19） were found to be selective towards h MAO-B, while two were non-selective（6 and 20） and one（18）selective towards h MAO-A. Compound 17（Ki = 0.10 0.01 mmol/L） was found to be equally potent and selective towards h MAO-B, when compared with the standard drug Selegiline（Ki = 0.12 0.01 mmol/L）.Nature and position of substitution in aryl ring at 2nd position of benzofuranone influences h MAO-B inhibitory potency, while their structural bulkiness influences selectivity between h MAO-A and h MAO-B.Molecular docking simulation was also carried out to understand the interaction of inhibitor with the enzyme at molecular level, and we found the docking results were in good agreement with the experimental values. Comparison of the activity profile of the aurones with their corresponding flavones reported earlier by our group revealed that there exists no difference in potency as well as selectivity.

Mechanism underlying Fanmugua(Fructus Caricae)leaf multicomponent synergistic therapy for anemia:data mining based on hematopoietic network

OBJECTIVE:To investigate the underlying mechanism of Fanmugua(Fructus Caricae) Leaf(CPL) multicomponent synergistic therapy for anemia.METHODS:The components were identified in the literature.Six databases were searched for targets of CPL.Enrichment analysis was used to determine the targets associated with anemia and in bone marrow.Based on the Kyoto Encyclopedia of Genes and Genomes database,pathways and targets related to hematopoiesis were obtained.The key targets were obtained by protein-protein interaction analysis.Molecular docking was used to analyze the binding ability of key targets and active components.Bone marrow cells were used as an experimental model to verify the drug efficacy.RESULTS:A total of 139 components and 1868 targets of CPL were retrieved from the literature.By disease enrichment analysis,543 targets for hemorrhagic anemia,223 targets for aplastic anemia,and 126 targets for sickle cell anemia were obtained.Target organ enrichment yielded 27,29,and 20 targets of bone marrow.Based on KEGG pathway enrichment,a total of 47 shared hematopoietic pathways and 42 related targets were found.The key targets were vascular endothelial growth factor A(VEGFA),interleukin 10(IL-10),plateletendothelial cell adhesion molecule-1(PECAM1),C-C motif chemokine 2(CCL2),and vascular cell adhesion molecule 1(VCAM1).The CPL active components included ursolic acid,quercetin,and hesperidin.The expression of VEGFA was significantly increased after CPL treatment.Quercetin and ursolic acid acted on VEGFA.Quercetin and Hesperidin acted on VCAM1.Quercetin acted on IL-10,CCL2,VCAM1,and VEGFA.Cell experiments revealed that CPL could promote the proliferation and migration of bone marrow cells.CONCLUSIONS:CPL has the synergistic efficacy of treating anemia through multiple components,targets,and pathways.

Inhibitory effect of a Chinese quince seed peptide on protein glycation:A mechanism study

Non-enzymatic glycation can cause the formation and accumulation of advanced glycation end products(AGEs),and it poses great threats to human health.It is urgent to search for safe and efficient inhibitors to prevent reducing sugar induced protein glycation.In this study,we inves-tigated the anti-glycation activity and mechanism of an identified peptide,Asparagine-Tyrosine-Arginine-Arginine-Glutamic acid(NYRRE)from Chinese quince seed protein hydrolysate,by mul-tispectroscopy,confocal imaging,and computational molecular simulation.Firstly,it was found that NYRRE could scavenge hydroxyl radicals and chelate Fe 2+.Besides,the NYRRE was effective in every stage of fructose induced bovine serum albumin(BSA)glycation.The NYRRE could re-duce the formation of fructosamine,carbonyl compounds,glycoxidation products and𝛽-amyloid structure.Meanwhile,NYRRE could protect thiol groups and stabilize the spatial conformation of BSA.The NYRRE presented strong inhibition in fluorescent AGEs,and 68.19%of total AGEs formation was prevented with NYRRE at 15 mmol/L.The results of molecular simulation indi-cated that NYRRE could insert into the hydrophobic pocket of BSA and interact with hot spots,including arginine and lysine residues.The mechanism of NYRRE inhibiting protein glycation could be due to its antioxidant activity,BSA structure stabilizing ability,and specific bond with glycation sites of BSA.These results provided a valuable reference for developing NYRRE as an efficient antiglycation agent in preventing glycation-mediated diseases.

Deciphering the chemical profile and pharmacological mechanism of Jinlingzi powder(金铃子散)against bile reflux gastritis using ultra-high performance liquid chromatography coupled with Q exactive focus mass spectrometry,network pharmacology,and molecular docking

OBJECTIVE:To elucidate the chemical profile and the pharmacological mechanism by which Jinlingzi powder(金铃子散,JLZP)treats bile reflux gastritis(BRG).METHODS:A BRG model was established in rats by oral administration of the model solution.JLZP was orally administered for 35 d.Residual gastric rate and tumor necrosis factor(TNF)-α,interleukin(IL)-6,and gastrin levels in the serum were measured,and stomach tissues were collected for histopathological analysis.We used ultra-high performance liquid chromatography coupled with Q Exactive Focus mass spectrometry to identify the chemical ingredients in JLZP.Then,protein-protein interaction and herb-compound-target networks were constructed to screen potential bioactive compounds and targets.Kyoto Encyclopedia of Genes and Genomes pathway analysis was then performed to elucidate the pathway involved in the JLZP-mediated treatment of BRG.After constructing the core compound-target-pathway interaction network,molecular docking was performed to study the binding free energy of core bioactive compounds and two candidate targets[RAC-alpha serine/threonine-protein kinase(AKT1)and phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha isoform(PIK3CA)].RESULTS:JLZP extracts significantly promoted gastric emptying,regulating the release of cytokines(TNF-αand IL-6)and improving gastrin secretion and mucosal repair.Fifty-six compounds were tentatively characterized in JLZP.Moreover,the network pharmacology and molecular docking results showed that alkaloids and flavonoids might be the bioactive compounds in JLZP that treat BRG.JLZP might improve mucosal repair during BRG progression by modulating the phosphatidylinositol-4,5-bisphosphate 3-kinase-protein kinase B,hypoxia inducible factor-1,mitogen-activated protein kinase,forkhead box O,TNF,and IL-17 signaling pathways.CONCLUSIONS:We elucidated the chemical constituents and the pharmacological mechanism of JLZP in treating BRG and provided a basis for clinical application.