To explore the material basis and mechanisms of the anti-inflammatory effects of Hibiscus mutabilis L..The active ingredients and potential targets of Hibiscus mutabilis L.were obtained through the literature review a...To explore the material basis and mechanisms of the anti-inflammatory effects of Hibiscus mutabilis L..The active ingredients and potential targets of Hibiscus mutabilis L.were obtained through the literature review and SwissADME platform.Genes related to the inflammation were collected using Genecards and OMIM databases,and the intersection genes were submitted on STRING and DAVID websites.Then,the protein interaction network(PPI),gene ontology(GO)and pathway(KEGG)were analyzed.Cytoscape 3.7.2 software was used to construct the“Hibiscus mutabilis L.-active ingredient-target-inflammation”network diagram,and AutoDockTools-1.5.6 software was used for the molecular docking verification.The antiinflammatory effect of Hibiscus mutabilis L.active ingredient was verified by the RAW264.7 inflammatory cell model.The results showed that 11 active components and 94 potential targets,1029 inflammatory targets and 24 intersection targets were obtained from Hibiscus mutabilis L..The key anti-inflammatory active ingredients of Hibiscus mutabilis L.are quercetin,apigenin and luteolin.Its action pathway is mainly related to NF-κB,cancer pathway and TNF signaling pathway.Cell experiments showed that total flavonoids of Hibiscus mutabilis L.could effectively inhibit the expression of tumor necrosis factor(TNF-α),interleukin 8(IL-8)and epidermal growth factor receptor(EGFR)in LPS-induced RAW 264.7 inflammatory cells.It also downregulates the phosphorylation of human nuclear factor ĸB inhibitory protein α(IĸBα)and NF-κB p65 subunit protein(p65).Overall,the anti-inflammatory effect of Hibiscus mutabilis L.is related to many active components,many signal pathways and targets,which provides a theoretical basis for its further development and application.展开更多
Trifluoromethyl pyridine(TFMP)motif is commonly discovered in structures of active pharmaceuticals.Flonicamid,characterized by the TFMP moiety,is well known as a prodrug in the knockdown of pests.The azobenzene-modifi...Trifluoromethyl pyridine(TFMP)motif is commonly discovered in structures of active pharmaceuticals.Flonicamid,characterized by the TFMP moiety,is well known as a prodrug in the knockdown of pests.The azobenzene-modified TFMP derivatives have been previously reported with excellent insecticidal activities.Herein,twenty-one TFMP derivatives were designed by the introduction of carbonyl-bridged aryl groups and synthesized via a one-step synthesis using Flonicamid as the starting material.The structure-activity relationships of these compounds were well analyzed and discussed.A molecular docking study and calcium ion concentration analysis indicated that compound FC13 could have interacted with the nicotinamidase enzyme,which further influenced the Ca^(2+)influx.展开更多
Objectives:Oxidative stress(OS)plays a pivotal role in chronic and neurodegenerative diseases,which has sparked interest in molecules that modulate redox-regulating enzymes.Melatonin and its metabolites exhibit antiox...Objectives:Oxidative stress(OS)plays a pivotal role in chronic and neurodegenerative diseases,which has sparked interest in molecules that modulate redox-regulating enzymes.Melatonin and its metabolites exhibit antioxidant properties;however,their molecular mechanisms of enzymatic and transcriptional modulation remain unclear.This study aimed to investigate,through an exploratory in silico approach,the interactions of melatonin and related compounds with OS-related enzymes to generate hypotheses about their role in cellular redox control.Methods:A rational selection of antioxidant,pro-oxidant,and transcriptional targets was performed.Ligands were optimized at the DFT level(M05-2X/6-311+G(d,p))and docked to OS related enzymes.Docking results were analyzed using polygenic antioxidant indices(PAOX)and a similarity interaction index(SSI).Molecular dynamics simulations of selected complexes provided additional insight into potential ligand-protein interaction mechanisms.Results:In silico analyses revealed that N1-acetyl-5-methoxykynuramine(AMK),N1-acetyl-N2-formyl-5-methoxykynuramine(AFMK),and 3-hydroxymelatonin(3OH-M)could partially inhibit pro-oxidant enzymes such as neuronal nitric oxide synthase(nNOS),5-lipoxygenase(5-LOX),thioredoxin reductase(TrxR),and nicotinamide adenine dinucleotide phosphate oxidase(NOX5).The N-(2-(2-acetyl-6,7-dihydroxy-1H-indol-3-yl)ethyl)acetamide(IIcD)and N-(2-(6-hydroxy-7-mercapto-5-methoxy-1H-indol)ethyl)acetamide(dM38)derivatives could potentially stabilize superoxide dismutase(SOD1)and catalase(CAT)enzymes,respectively.Finally,AFMK and dM38 showed consistent interactions with transcriptional regulators,particularly peroxisome proliferator-activated receptor alpha(PPARα)and Kelchlike ECH-associated protein 1(KEAP1).Conclusion:These studies about melatonin-related compounds support a multifactorial profile of redox modulation and provide mechanistic hypotheses for future experimental validation.Among these approaches,the interaction-similarity index is introduced as a novel tool to facilitate the identification of promising redox-active candidates.展开更多
Population aging is one of the common challenges in the current world.As people age,the body’s tissues including cells,and molecules inevitably degrade,and their functions gradually decline,causing various age-relate...Population aging is one of the common challenges in the current world.As people age,the body’s tissues including cells,and molecules inevitably degrade,and their functions gradually decline,causing various age-related diseases like Alzheimer’s disease,osteoporosis,low immunity,glucose and lipid metabolism disorders,and cardiovascular diseases.With the continuous increase of the elderly population,the pressure on the medical industry is increasing.To lower the burden on the medical industry and increase the average age of the elderly,it is vital to explore effective anti-aging materials.Ginseng Radix et Rhizoma(Renshen),as a traditional and precious Chinese medicinal herb,is known as the“king of all herbs”.It is famous for its effects of“tonifying Qi,restoring pulse”(helping with the generation of Qi(the fundamental,vital energy that continuously flows within the body)and the circulation of blood)and strengthening the body,nourishing the spleen and lungs,generating fluids and nourishing blood,calming the mind and improving intelligence.Recently,its anti-aging effect has received increasing attention from modern scientific research.This study summarizes the pharmacological effects of the main active ingredients of Renshen(ginsenosides,polysaccharides,etc.)on resisting aging,including preventing neuroaging,suppressing skin aging,mitigating ovarian aging,inhibiting osteoporosis and arthritis,enhancing the immune system of the elderly,protecting the cardiovascular system,resisting aging-induced fatigue and exerting the anti-tumor effects.Through network pharmacology and molecular docking,the anti-aging active ingredients of Renshen were screened,and the key targets and pathways of anti-aging active ingredients in Renshen were determined.Using network pharmacology,totally 106 drug targets and 3,479 disease targets were screened,and 79 common targets between aging and Renshen were identified.Three core targets were identified in the PPI network,including TNF,AKT1,and IL-1β.Molecular docking was used to obtain further verification.This study emphasizes the potential of Renshen as a source of anti-aging activity,which can be developed into a novel drug for the treatment of age-related diseases.展开更多
Background:Bone tumors represent a significant clinical challenge characterized by high morbidity and complex therapeutic requirements.Although Astragali Radix(Huangqi)is recognized for its potential pharmacological b...Background:Bone tumors represent a significant clinical challenge characterized by high morbidity and complex therapeutic requirements.Although Astragali Radix(Huangqi)is recognized for its potential pharmacological benefits in cancer therapy,the specific molecular mechanisms and their influence on vitamin metabolism pathways in bone malignancies are not well defined.Methods:We conducted an integrated analysis of prognostic genes and survival outcomes in osteosarcoma,focusing on the expression of GPC2 and its correlation with tumor progression and patient survival rates.In order to explore the therapeutic relevance of 20 bioactive compounds extracted from Huangqi,molecular docking was performed to quantify their binding free energies to the GPC2 receptor,shedding light on their potential affinity and biological activity.Furthermore,the expression levels of GPC2 in tumor cells compared to normal cells were analyzed using qRT-PCR.Additionally,the effects of GPC2 overexpression and silencing on cellular viability,apoptotic response,and migratory capacity were systematically investigated.Results:In our study,GPC2 emerged as a significant prognostic gene,where high expression levels correlated with reduced overall survival.The molecular interactions between Astragalus components and the GPC2 receptor reveal compounds with strong affinity,suggesting their potential as effective targets.Furthermore,the overexpression of GPC2 enhanced tumor cell viability and migration,while its knockdown resulted in decreased cell viability and expanded apoptosis.Conclusion:This study demonstrates that Huangqi-derived components may exert anticancer effects by regulating the expression of the GPC2 gene within the vitamin metabolism pathway.These findings offer new insights into the therapeutic potential of traditional herbal medicine for improving bone tumor prognosis and provide a scientific foundation for future translational research.展开更多
This study explored the therapeutic targets and molecular mechanisms of Huangqi Guizhi Decoction (HGD) in alleviatingpulmonary embolism (PE) by employing network pharmacology and molecular docking techniques. Firstly,...This study explored the therapeutic targets and molecular mechanisms of Huangqi Guizhi Decoction (HGD) in alleviatingpulmonary embolism (PE) by employing network pharmacology and molecular docking techniques. Firstly, the effective activecomponents of the Chinese herbs in HGD were retrieved from the Traditional Chinese Medicine Systems Pharmacology Database(TCMSP), and their potential therapeutic targets were predicted using the Swiss Target Prediction platform. Subsequently, PErelatedtarget genes were obtained from the Online Mendelian Inheritance in Man (OMIM) database and GeneCards database.Then, the Wei Sheng Xin tool was used to generate a Venn diagram for identifying the common targets between the herb-relatedtargets and PE-related targets. After screening these common targets, a “drug-component-target network” and a protein-proteininteraction (PPI) network were constructed. Furthermore, Gene Ontology (GO) enrichment analysis and Kyoto Encyclopedia ofGenes and Genomes (KEGG) enrichment analysis were conducted on the intersecting targets, and molecular docking verificationwas performed using AutoDockTools and PyMol software. Finally, 20 active components were screened from Astragali Radix, 7from Cinnamomi Ramulus, 13 from Paeoniae Radix Alba, 5 from Zingiberis Rhizoma Recens, and 29 from Jujubae Fructus, witha total of 983 therapeutic targets. Among these targets, 134 were associated with PE, and protein kinase B1 (AKT1), mitogenactivatedprotein kinase 1 (MAPK1), and transformation-related protein 53 (TP53) served as the core targets. The results of GOand KEGG enrichment analyses indicated that the alleviation of PE by HGD is mainly related to pathways including immuneresponse, regulation of gene expression, atherosclerosis, and tumorigenesis. Molecular docking results showed that the keyactive components in HGD could bind to the core targets spontaneously and stably. This study revealed that HGD may alleviatesymptoms in PE patients by regulating signaling pathways, modulating platelet function to exert anticoagulant effects, andregulating the expression of anti-inflammatory genes, which provided a direction for subsequent experimental research.展开更多
Background:Parkinson’s disease(PD)is one of the most common movement disorders worldwide.Ziyin Xifeng Decoction(ZYXFD),a traditional Chinese medicine compound formula,has shown therapeutic efficacy in treating PD,but...Background:Parkinson’s disease(PD)is one of the most common movement disorders worldwide.Ziyin Xifeng Decoction(ZYXFD),a traditional Chinese medicine compound formula,has shown therapeutic efficacy in treating PD,but its specific mechanisms of action have not been fully elucidated.Methods:Firstly,we employed network pharmacology and untargeted metabolomics analysis to identify the core targets,pathways,and key metabolites of ZYXFD in the treatment of PD.Subsequently,we evaluated the protective effects of ZYXFD and further investigated its anti-PD mechanisms by validating the analytical results.Results:Combined analyses of network pharmacology and metabolomics identify the core targets including EGFR,SRC,PTGS2,and CDK2,while the effects of ZYXFD against PD are likely mediated primarily through the PI3K/AKT/mTOR signaling pathway.Pharmacodynamic evaluation demonstrated that a high dose of ZYXFD significantly improved behavioral deficits in chronic PD mice,downregulatedα-synuclein protein expression,and protected dopaminergic neurons.It also regulated the expression of core targets,inhibited the PI3K/AKT/mTOR signaling pathway,promoted autophagy,and reduced apoptosis.In vitro experiments further verified that the therapeutic effect of ZYXFD on PD is dependent on autophagy regulation.Conclusion:The findings demonstrated that ZYXFD alleviates PD by modulating related proteins and metabolites,inhibiting the PI3K/AKT/mTOR signaling pathway,and enhancing autophagy.This provides a theoretical basis for its broader application in PD treatment.展开更多
OBJECTIVE:To investigate the mechanism of action of Qinlian Jiangxia decoction(芩连姜夏汤,QLJXD)in the treatment of type 2 diabetes mellitus(T2DM)complicated by hyperlipidemia using network pharmacology,molecular dock...OBJECTIVE:To investigate the mechanism of action of Qinlian Jiangxia decoction(芩连姜夏汤,QLJXD)in the treatment of type 2 diabetes mellitus(T2DM)complicated by hyperlipidemia using network pharmacology,molecular docking,molecular dynamics simulation and in vivo experiments.METHODS:Drug components,targets and disease targets were identified using databases such as TCM systems pharmacology database and analysis platform and Gene Cards.The intersecting targets were subjected to protein-protein interaction analysis using the search tool for the retrieval of interacting genes/proteins database.Subsequently,Gene Ontology and Kyoto Encyclopedia of Genes and Genomes analysis of the intersecting targets were conducted using the Metascape platform to identify core components and targets.The results were validated using molecular docking,molecular dynamics simulations and in vivo experiments.RESULTS:QLJXD contains 76 active ingredients and 136 disease targets.The core ingredients are quercetin,β-sitosterol,wogonin and baicalein,while the core targets are fatty acid binding protein 4(FABP4)and peroxisome proliferative activated receptor gamma(PPARG).Molecular docking and molecular dynamics simulations revealed that the core ingredients bound well to the core targets.Animal experiments demonstrated that QLJXD effectively inhibited the expression of FABP4 and increased the expression of PPARG,thereby enhancing disorders of glycolipid metabolism.CONCLUSION:The putative therapeutic efficacy of QLJXD in the management of T2DM complicated with hyperlipidemia may be ascribed to the synergistic actions of multiple components,such as quercetin,β-sitosterol,wogonin,and baicalein,which collectively modulate FABP4 and PPARG molecular targets.展开更多
Background:Pistacia chinensis Bunge has been traditionally used to manage various conditions,including asthma,pain,inflammation,hepatoprotection,and diabetes.The study was conducted to investigate the antioxidant and ...Background:Pistacia chinensis Bunge has been traditionally used to manage various conditions,including asthma,pain,inflammation,hepatoprotection,and diabetes.The study was conducted to investigate the antioxidant and anti-lipoxygenase(LOX)properties of the isolated compound 2-(3,4-dihydroxyphenyl)-5,7-dihydroxy-4H-chromen-4-one from Pistacia chinensis.Methods:LOX assay and antioxidant activity using 2,2-diphenyl-1-picrylhydrazyl(DPPH)assay were performed.Molecular docking studies were conducted using a molecular operating environment.Results:The LOX assay revealed significant inhibitory effects at 0.2µM concentration,with an IC50 value of 37.80µM.The antioxidant effect demonstrated dose-dependency across 5 to 100µg/mL concentrations,reaching 93.09%at 100µg/mL,comparable to ascorbic acid’s 95.43%effect.Molecular docking studies highlighted strong interactions with the lipoxygenase enzyme,presenting an excellent docking score of-10.98 kcal/mol.Conclusion:These findings provide valuable insights into Pistacia chinensis’chemical components and biological effects,reinforcing its traditional medicinal applications.展开更多
BACKGROUND Colorectal cancer(CRC)is the third most common cancer globally,causing over 900000 deaths annually.Risk factors include aging,diet,obesity,sedentary lifestyle,tobacco use,genetic predisposition,and inflamma...BACKGROUND Colorectal cancer(CRC)is the third most common cancer globally,causing over 900000 deaths annually.Risk factors include aging,diet,obesity,sedentary lifestyle,tobacco use,genetic predisposition,and inflammatory bowel disease.Despite current treatments,survival rates for advanced CRC remain low,highlighting the need for better therapeutic strategies.AIM To evaluate both the clinical significance and the pathological implications of the Kinesin family member 14(KIF14)expression within CRC specimens.Additionally,this study aims to investigate the interaction between nitidine chloride(NC)and KIF14,considering their potential as therapeutic targets.METHODS The expression of the KIF14 protein in CRC was analyzed using immunohistochemical staining.The integration of multicenter high-throughput data facilitated the calculation of the standardized mean difference(SMD)for KIF14 mRNA levels.The assessment of clinical and pathological impact was enhanced by analyzing combined receiver operating characteristic curves,along with measures of sensitivity,specificity,and likelihood ratios.Additionally,clustered regularly interspaced short palindromic repeats knockout screening for cell growth and single-cell sequencing were employed to validate the significance of KIF14 expression in CRC.Survival analysis established the prognostic value of KIF14 in CRC.The molecular mechanism of NC against CRC was elucidated through whole-genome sequencing and enrichment analysis,and molecular docking was utilized to explore the targeting affinity between NC and KIF14.RESULTS KIF14 was highly expressed in 208 CRC patients.Data from 17 platforms involving 2436 CRC samples and 1320 noncancerous colorectal tissue controls indicated that KIF14 expression was significantly higher in CRC samples,with an SMD of 1.92(95%CI:1.49-2.35).The area under the curve was 0.94(95%CI:0.92-0.96),with a sensitivity of 0.85(95%CI:0.78-0.90)and a specificity of 0.90(95%CI:0.85-0.93).The positive and negative likelihood ratios were 8.38(95%CI:5.39-13.02)and 0.17(95%CI:0.11-0.26),respectively.At the single-cell level,significant overexpression of KIF14 was observed in CRC cells(P<0.001),with 35 CRC cell lines dependent on KIF14 for growth.The K-M plots demonstrated that KIF14 possesses prognostic value in CRC patients within the GSE71187 and GSE103679 datasets(P<0.05).Binding energy calculations indicated that KIF14 is a potential target for NC(binding energy:10.3 kcal/mol).CONCLUSION KIF14 promotes the growth of CRC cells and acts as an oncogenic factor,potentially serving as a therapeutic target for NC in the treatment of CRC.展开更多
Ethiprole is widely used as a second-generation phenyl pyrazole insecticide.Previous studies indicated that ethiprole exhibited thyroid toxicity while two main metabolites(ethiprole sulfone(M1)and ethiprole sulfide(M2...Ethiprole is widely used as a second-generation phenyl pyrazole insecticide.Previous studies indicated that ethiprole exhibited thyroid toxicity while two main metabolites(ethiprole sulfone(M1)and ethiprole sulfide(M2))of ethiprole showed higher acute toxicity than ethiprole.Therefore,assessing the thyroid toxicity of its metabolites is crucial for safety assessment.In this study,the thyroid toxicity and underlying mechanisms of ethiprole and its metabolites were explored using in silico,in vitro,and in vivo assays,with the aim of conducting a comparative study on thyroid toxicity.Molecular docking analysis showed that ethiprole,M1 and M2 could bind with thyroid receptor isoforms and exhibited higher binding affinity compared to 3,3,5-triiodothyronine(T3).GH3 cell proliferation assays revealed that ethiprole,M1 and M2 all served as thyroid hormone antagonists to hinder the T3-induced cell proliferation.Using the zebrafish model,we further investigated that exposure to ethiprole,M1,and M2 disrupted thyroid hormone levels and the transcriptional expressions of hypothalamus-pituitary-thyroid(HPT)axis-related genes.Ethiprole induced thyroid disrupting effects by binding with the thyroid receptor beta,M1 mainly through binding with the corticotropin releasing factor receptor-1,and M2 exposure firstly inhibited the thyroid peroxidase enzyme activity.M2 showed the highest developmental toxicity and thyroid disrupting effects,which significantly reducing hatching rates,increasing deformity rates,exhibiting the lowest lethal concentration 50 value and showing the most serious transcription inhibitory effects on the HPT axis.This study suggested the risk assessment of metabolites should be considered in assessing potential environmental risk of ethiprole.展开更多
Objective To evaluate the antibacterial potential of bioactive compounds from Persicaria hydropiper(L.)(P.hydropiper)against bacterial virulence proteins through molecular docking(MD)and experimental validation.Method...Objective To evaluate the antibacterial potential of bioactive compounds from Persicaria hydropiper(L.)(P.hydropiper)against bacterial virulence proteins through molecular docking(MD)and experimental validation.Methods Six bioactive compounds from P.hydropiper were investigated:catechin(CAT1),hyperin(HYP1),ombuin(OMB1),pinosylvin(PSV1),quercetin 3-sulfate(QSF1),and scutellarein(SCR1).Their binding affinities and potential binding pockets were assessed through MD against four bacterial target proteins with Protein Data Bank identifiers(PDB IDs):topoisomerase IV from Escherichia coli(E.coli)(PDB ID:3FV5),Staphylococcus aureus(S.aureus)gyrase ATPase binding domain(PDB ID:3U2K),CviR from Chromobacterium violaceum(C.violaceum)(PDB ID:3QP1),and glycosyl hydrolase from Pseudomonas aeruginosa(P.aeruginosa)(PDB ID:5BX9).Molecular dynamics simulations(MDS)were performed on the most promising compound-protein complexes for 50 nanoseconds(ns).Drug-likeness was evaluated using Lipinski's Rule of Five(RO5),followed by absorption,distribution,metabolism,excretion,and toxicity(ADMET)analysis using SwissADME and pkCSM web servers.Antibacterial activity was evaluated through disc diffusion assays,testing both individual compounds and combinations with conventional antibiotics[cefotaxime(CTX1,30μg/disc),ceftazidime(CAZ1,30μg/disc),and piperacillin(PIP1,100μg/disc)].Results MD revealed strong binding affinity(ranging from-9.3 to-5.9 kcal/mol)for all compounds,with CAT1 showing exceptional binding to 3QP1(-9.3 kcal/mol)and 5BX9(-8.4 kcal/mol).MDS confirmed the stability of CAT1-protein complexes with binding free energies of-84.71 kJ/mol(5BX9-CAT1)and-95.59 kJ/mol(3QP1-CAT1).Five compounds(CAT1,SCR1,PSV1,OMB1,and QSF1)complied with Lipinski's RO5 and showed favorable ADMET profiles.All compounds were non-carcinogenic,with CAT1 classified in the lowest toxicity class(VI).In antibacterial assays,CAT1 demonstrated significant activity against both gram-positive bacteria[Streptococcus pneumoniae(S.pneumoniae),S.aureus,and Bacillus cereus(B.cereus)][zone diameter of inhibition(ZDI):10-22 mm]and gram-negative bacteria[Acinetobacter baumannii(A.baumannii),E.coli,and P.aeruginosa](ZDI:14-27 mm).Synergistic effects were observed when CAT1 was combined with antibiotics and the growth inhibitory indices(GII)was 0.69-1.00.Conclusion P.hydropiper bioactive compounds,particularly CAT1,show promising antibacterial potential through multiple mechanisms,including direct inhibition of bacterial virulence proteins and synergistic activity with conventional antibiotics.The favorable pharmacological properties and low toxicity profiles support their potential development as therapeutic agents against bacterial infections.展开更多
OBJECTIVE:To explore the mechanism of Danggui Buxue decoction(当归补血汤,DBD)for the treatment of gastric ulcer(GU),based on network pharmacology and in vivo experiments.METHODS:A network pharmacology strategy was use...OBJECTIVE:To explore the mechanism of Danggui Buxue decoction(当归补血汤,DBD)for the treatment of gastric ulcer(GU),based on network pharmacology and in vivo experiments.METHODS:A network pharmacology strategy was used to predict the main components,candidate targets,and potential signaling pathways.Then,molecular docking was performed to further investigate the interactions and binding affinities between the main components and primary targets.Finally,a mouse model of ethanolinduced gastric ulcers was established to confirm the efficacy and potential therapeutic benefits of DBD,and candidate targets were finally identified.RESULTS:A total of 22 active components and 220 target genes were found to be associated with DBD.In addition,343 GU-related target genes and 57 target genes specific to DBD treatment of GU were identified.The Gene Ontology functional enrichment analysis revealed 510 entries for biological processes,36 entries for cell composition,and 69 entries for molecular functions.In the pathway enrichment analysis,143 signaling pathways were identified.Additionally,the molecular docking results revealed that the main active components of DBD exhibited a strong binding capacity with key proteins,including tumor necrosis factor,AKT serine/threonine kinase 1,interleukin-6,vascular endothelial growth factor,and interleukin-1 Beta.Among these,quercetin,kaempferol,formononetin,isorhamnetin,and beta-sitosterol displayed the strongest binding affinities for these key proteins.in vivo experiments showed that DBD pretreatment effectively protected gastric mucosa,and the benefits might be attributed to the downregulation of above key proteins.CONCLUSIONS:Based on network pharmacology analysis and in vivo experiments,we conclude that DBD leads to the protection and healing of the gastric mucosa by targeting genes and pathways,thus effectively countering the development and progression of GU.展开更多
BACKGROUND Xuanshen decoction(XSD)is a traditional Chinese medicine formulation that is often applied in treating slow transit constipation(STC).However,its specific therapeutic mechanism remains to be characterized.A...BACKGROUND Xuanshen decoction(XSD)is a traditional Chinese medicine formulation that is often applied in treating slow transit constipation(STC).However,its specific therapeutic mechanism remains to be characterized.AIM To investigate the mechanism of XSD for STC,we combined network pharmacology prediction,molecular docking analysis,and in vivo studies.METHODS The therapeutic effects of XSD on loperamide-induced STC in rats were assessed through 24-hour fecal number,fecal moisture content,and intestinal propelling rate.Hematoxylin–eosin and Alcian blue/periodic acid-Schiff staining were applied to analyze colonic mucosa for histopathological presentation and mucin production.Next,the mechanism of action of XSD for STC was elucidated through network pharmacology and molecular docking analyses,and the findings were validated by the animal experiments.RESULTS XSD significantly alleviated the symptoms of STC in rats.Relative to the STC rats,in the medium-dose XSD and high-dose XSD rats,stem cell factor,C-kit,phosphophosphoinositide 3-kinase/phosphoinositide 3-kinase,phospho-protein kinase B/protein kinase B,catalase,and superoxide dismutase were substantially upregulated(P<0.01);nuclear factor erythroid 2-related factor 2(nuclear/cytoplasmic)and B-cell lymphoma 2(Bcl-2)were increased(P<0.05),while cleaved caspase-3,Bcl-2-associated X protein(Bax)/Bcl-2,and malondialdehyde were significantly reduced(P<0.01).Heme oxygenase-1 and glutathione peroxidase in the high-dose XSD group were significantly increased(P<0.01),and Bax was statistically lowered(P<0.01);glutathione peroxidase in the medium-dose XSD group was increased(P<0.05),while Bax was reduced(P<0.05).CONCLUSION XSD may inhibit oxidative-stress-induced apoptosis in interstitial cells of Cajal by stimulating the phosphoinositide 3-kinase/protein kinase B/nuclear factor erythroid 2-related factor 2 pathway,thereby effectively treating STC.展开更多
BACKGROUND The stearoyl-coenzyme A desaturase(SCD)gene influences colorectal cancer(CRC)pathogenesis,with its expression linked to tumor cell survival and resistance,necessitating further investigation into its role i...BACKGROUND The stearoyl-coenzyme A desaturase(SCD)gene influences colorectal cancer(CRC)pathogenesis,with its expression linked to tumor cell survival and resistance,necessitating further investigation into its role in CRC.AIM To explore the clinical and pathological significance of SCD expression in CRC tissues and to evaluate the affinity between nitidine chloride(NC)and SCD as a target.METHODS Multi-center high-throughput data related to CRC were integrated to calculate the standardized mean difference of SCD mRNA expression levels.Immunohistochemical staining results,Clustered Regularly Interspaced Short Palindromic Repeats knockout screening results of cell growth,and single-cell sequencing were employed to verify the significance of SCD expression in CRC.The clinical and pathological significance of SCD was assessed using pooled receiver operating characteristic curves,sensitivity,specificity,and likelihood ratios.The molecular mechanism of NC against CRC was clarified using the SwissTarget Prediction and functional enrichment,and molecular docking techniques were utilized to explore the targeting affinity between NC and SCD.RESULTS Data from 18 platforms,including 2482 CRC samples and 1334 non-cancerous colorectal tissue controls.SCD expression was significantly upregulated in CRC,with a standardized mean difference of 2.05[95%confidence interval(CI):1.69-2.41].The area under the pooled receiver operating characteristic curve was 0.95(95%CI:0.92-0.96),with a sensitivity of 0.86(95%CI:0.81-0.90)and a specificity of 0.90(95%CI:0.87-0.93).Positive and negative likelihood ratios were 9.02(95%CI:6.49-12.51)and 0.15(95%CI:0.10-0.22),respectively.High SCD protein expression was noted in 208 CRC patients,significantly associated with vascular invasion(P<0.001).At the singlecell level,SCD was significantly overexpressed in CRC cells(P<0.001).A total of 33 CRC cell lines depended on SCD for growth.The potential mechanism of NC against CRC might involve modulation of the cell cycle,positioning SCD as a potential target for NC.CONCLUSION SCD promotes CRC cell growth and thus acts as an oncogenic factor,making it a potential therapeutic target for NC in CRC treatment.展开更多
BACKGROUND Hepatocellular carcinoma(HCC)is at the forefront of the global spectrum of cancer incidence and mortality,with conventional therapies like tyrosine kinase inhibitors limited by resistance.Recent studies hav...BACKGROUND Hepatocellular carcinoma(HCC)is at the forefront of the global spectrum of cancer incidence and mortality,with conventional therapies like tyrosine kinase inhibitors limited by resistance.Recent studies have highlighted the promising anticancer effects of nitidine chloride(NC)against HCC.SAC3 domain containing 1(SAC3D1)is critical for centrosome replication and spindle formation.However,research on SAC3D1 in HCC and NC remains limited.AIM To investigate the mechanisms underlying SAC3D1’s role in HCC progression and evaluated its potential as a therapeutic target of NC.METHODS RNA sequencing(RNA-seq)identified SAC3D1 expression changes in HCC cells after NC treatment.Molecular docking was further employed to validate the direct binding between NC and SAC3D1.Additionally,HCC multicenter data(The Cancer Genome Atlas_GTEx,ArrayExpress),pathway analysis,Pearson correlation analysis and SAC3D1 in vitro knockdown experiments were integrated to explore the molecular mechanisms underlying SAC3D1's involvement in HCC progression.RESULTS RNA-seq showed that NC treatment significantly downregulated SAC3D1 expression[log2(fold change)=-0.95,P<0.05],with molecular docking revealing that NC directly bound to SAC3D1 proteins(binding energy:-9.7 kcal/mol).Enrichment analysis showed that most pathways were closely related to the cell cycle.Pearson correlation analysis indicated that SAC3D1 and cell cycle genes were significantly positively correlated(correlation coefficient≥0.3,P<0.05).SAC3D1 knockdown inhibited HCC cell invasion,migration,and proliferation by arresting cells in the S and G2/M phases.Flow cytometry confirmed that after SAC3D1 knockdown,the early and total apoptosis percentage of HCC cells decreased,while the late apoptosis percentage increased.CONCLUSION As a potential target of NC,SAC3D1 may inhibit HCC progression through cell cycle regulation following its downregulation by NC.展开更多
文摘To explore the material basis and mechanisms of the anti-inflammatory effects of Hibiscus mutabilis L..The active ingredients and potential targets of Hibiscus mutabilis L.were obtained through the literature review and SwissADME platform.Genes related to the inflammation were collected using Genecards and OMIM databases,and the intersection genes were submitted on STRING and DAVID websites.Then,the protein interaction network(PPI),gene ontology(GO)and pathway(KEGG)were analyzed.Cytoscape 3.7.2 software was used to construct the“Hibiscus mutabilis L.-active ingredient-target-inflammation”network diagram,and AutoDockTools-1.5.6 software was used for the molecular docking verification.The antiinflammatory effect of Hibiscus mutabilis L.active ingredient was verified by the RAW264.7 inflammatory cell model.The results showed that 11 active components and 94 potential targets,1029 inflammatory targets and 24 intersection targets were obtained from Hibiscus mutabilis L..The key anti-inflammatory active ingredients of Hibiscus mutabilis L.are quercetin,apigenin and luteolin.Its action pathway is mainly related to NF-κB,cancer pathway and TNF signaling pathway.Cell experiments showed that total flavonoids of Hibiscus mutabilis L.could effectively inhibit the expression of tumor necrosis factor(TNF-α),interleukin 8(IL-8)and epidermal growth factor receptor(EGFR)in LPS-induced RAW 264.7 inflammatory cells.It also downregulates the phosphorylation of human nuclear factor ĸB inhibitory protein α(IĸBα)and NF-κB p65 subunit protein(p65).Overall,the anti-inflammatory effect of Hibiscus mutabilis L.is related to many active components,many signal pathways and targets,which provides a theoretical basis for its further development and application.
基金supported by National Natural Science Foundation of China(32472610,32402439,32072441)National Key Research and Development Program of China(2018YFD0200100)+3 种基金Innovation Program of Shanghai Municipal Education Commission(2017-01-07-00-02-E00037)Tobacco and Health funding program(2022539200340111)Shanghai Frontiers Science Center of Optogenetic Techniques for Cell Metabolism(Shanghai Municipal Education Commission)the project of National Key Laboratory of Green Pesticide/Key Laboratory of Green Pesticide and Agricultural Bioengineering,Ministry of Education,Guizhou University(SKL-GPL-KF202405).
文摘Trifluoromethyl pyridine(TFMP)motif is commonly discovered in structures of active pharmaceuticals.Flonicamid,characterized by the TFMP moiety,is well known as a prodrug in the knockdown of pests.The azobenzene-modified TFMP derivatives have been previously reported with excellent insecticidal activities.Herein,twenty-one TFMP derivatives were designed by the introduction of carbonyl-bridged aryl groups and synthesized via a one-step synthesis using Flonicamid as the starting material.The structure-activity relationships of these compounds were well analyzed and discussed.A molecular docking study and calcium ion concentration analysis indicated that compound FC13 could have interacted with the nicotinamidase enzyme,which further influenced the Ca^(2+)influx.
基金supported by the SECIHTI project Ciencia Basica y de Frontera(No.CBF2023-2024-1141)https://secihti.mx/(accessed on 01 August 2025).
文摘Objectives:Oxidative stress(OS)plays a pivotal role in chronic and neurodegenerative diseases,which has sparked interest in molecules that modulate redox-regulating enzymes.Melatonin and its metabolites exhibit antioxidant properties;however,their molecular mechanisms of enzymatic and transcriptional modulation remain unclear.This study aimed to investigate,through an exploratory in silico approach,the interactions of melatonin and related compounds with OS-related enzymes to generate hypotheses about their role in cellular redox control.Methods:A rational selection of antioxidant,pro-oxidant,and transcriptional targets was performed.Ligands were optimized at the DFT level(M05-2X/6-311+G(d,p))and docked to OS related enzymes.Docking results were analyzed using polygenic antioxidant indices(PAOX)and a similarity interaction index(SSI).Molecular dynamics simulations of selected complexes provided additional insight into potential ligand-protein interaction mechanisms.Results:In silico analyses revealed that N1-acetyl-5-methoxykynuramine(AMK),N1-acetyl-N2-formyl-5-methoxykynuramine(AFMK),and 3-hydroxymelatonin(3OH-M)could partially inhibit pro-oxidant enzymes such as neuronal nitric oxide synthase(nNOS),5-lipoxygenase(5-LOX),thioredoxin reductase(TrxR),and nicotinamide adenine dinucleotide phosphate oxidase(NOX5).The N-(2-(2-acetyl-6,7-dihydroxy-1H-indol-3-yl)ethyl)acetamide(IIcD)and N-(2-(6-hydroxy-7-mercapto-5-methoxy-1H-indol)ethyl)acetamide(dM38)derivatives could potentially stabilize superoxide dismutase(SOD1)and catalase(CAT)enzymes,respectively.Finally,AFMK and dM38 showed consistent interactions with transcriptional regulators,particularly peroxisome proliferator-activated receptor alpha(PPARα)and Kelchlike ECH-associated protein 1(KEAP1).Conclusion:These studies about melatonin-related compounds support a multifactorial profile of redox modulation and provide mechanistic hypotheses for future experimental validation.Among these approaches,the interaction-similarity index is introduced as a novel tool to facilitate the identification of promising redox-active candidates.
基金supported by the Jilin Science and Technology Development Talent Special Project,Nos.20240601086RC,23JQ08(all to ZH)YDZJ202502CXJD077+1 种基金JLARS-2025-0802-09YDZJ202501ZYTS706.
文摘Population aging is one of the common challenges in the current world.As people age,the body’s tissues including cells,and molecules inevitably degrade,and their functions gradually decline,causing various age-related diseases like Alzheimer’s disease,osteoporosis,low immunity,glucose and lipid metabolism disorders,and cardiovascular diseases.With the continuous increase of the elderly population,the pressure on the medical industry is increasing.To lower the burden on the medical industry and increase the average age of the elderly,it is vital to explore effective anti-aging materials.Ginseng Radix et Rhizoma(Renshen),as a traditional and precious Chinese medicinal herb,is known as the“king of all herbs”.It is famous for its effects of“tonifying Qi,restoring pulse”(helping with the generation of Qi(the fundamental,vital energy that continuously flows within the body)and the circulation of blood)and strengthening the body,nourishing the spleen and lungs,generating fluids and nourishing blood,calming the mind and improving intelligence.Recently,its anti-aging effect has received increasing attention from modern scientific research.This study summarizes the pharmacological effects of the main active ingredients of Renshen(ginsenosides,polysaccharides,etc.)on resisting aging,including preventing neuroaging,suppressing skin aging,mitigating ovarian aging,inhibiting osteoporosis and arthritis,enhancing the immune system of the elderly,protecting the cardiovascular system,resisting aging-induced fatigue and exerting the anti-tumor effects.Through network pharmacology and molecular docking,the anti-aging active ingredients of Renshen were screened,and the key targets and pathways of anti-aging active ingredients in Renshen were determined.Using network pharmacology,totally 106 drug targets and 3,479 disease targets were screened,and 79 common targets between aging and Renshen were identified.Three core targets were identified in the PPI network,including TNF,AKT1,and IL-1β.Molecular docking was used to obtain further verification.This study emphasizes the potential of Renshen as a source of anti-aging activity,which can be developed into a novel drug for the treatment of age-related diseases.
文摘Background:Bone tumors represent a significant clinical challenge characterized by high morbidity and complex therapeutic requirements.Although Astragali Radix(Huangqi)is recognized for its potential pharmacological benefits in cancer therapy,the specific molecular mechanisms and their influence on vitamin metabolism pathways in bone malignancies are not well defined.Methods:We conducted an integrated analysis of prognostic genes and survival outcomes in osteosarcoma,focusing on the expression of GPC2 and its correlation with tumor progression and patient survival rates.In order to explore the therapeutic relevance of 20 bioactive compounds extracted from Huangqi,molecular docking was performed to quantify their binding free energies to the GPC2 receptor,shedding light on their potential affinity and biological activity.Furthermore,the expression levels of GPC2 in tumor cells compared to normal cells were analyzed using qRT-PCR.Additionally,the effects of GPC2 overexpression and silencing on cellular viability,apoptotic response,and migratory capacity were systematically investigated.Results:In our study,GPC2 emerged as a significant prognostic gene,where high expression levels correlated with reduced overall survival.The molecular interactions between Astragalus components and the GPC2 receptor reveal compounds with strong affinity,suggesting their potential as effective targets.Furthermore,the overexpression of GPC2 enhanced tumor cell viability and migration,while its knockdown resulted in decreased cell viability and expanded apoptosis.Conclusion:This study demonstrates that Huangqi-derived components may exert anticancer effects by regulating the expression of the GPC2 gene within the vitamin metabolism pathway.These findings offer new insights into the therapeutic potential of traditional herbal medicine for improving bone tumor prognosis and provide a scientific foundation for future translational research.
基金supported by Research Project on Traditional Chinese Medicine in Heilongjiang Province in 2025(Research on the pharmacological substance basis of Huangqi Guizhi decoction in improving acute pulmonary embolism and lung injury based on the theory of“Diaphoresis and expanding meridian”No.ZHY2025-043).
文摘This study explored the therapeutic targets and molecular mechanisms of Huangqi Guizhi Decoction (HGD) in alleviatingpulmonary embolism (PE) by employing network pharmacology and molecular docking techniques. Firstly, the effective activecomponents of the Chinese herbs in HGD were retrieved from the Traditional Chinese Medicine Systems Pharmacology Database(TCMSP), and their potential therapeutic targets were predicted using the Swiss Target Prediction platform. Subsequently, PErelatedtarget genes were obtained from the Online Mendelian Inheritance in Man (OMIM) database and GeneCards database.Then, the Wei Sheng Xin tool was used to generate a Venn diagram for identifying the common targets between the herb-relatedtargets and PE-related targets. After screening these common targets, a “drug-component-target network” and a protein-proteininteraction (PPI) network were constructed. Furthermore, Gene Ontology (GO) enrichment analysis and Kyoto Encyclopedia ofGenes and Genomes (KEGG) enrichment analysis were conducted on the intersecting targets, and molecular docking verificationwas performed using AutoDockTools and PyMol software. Finally, 20 active components were screened from Astragali Radix, 7from Cinnamomi Ramulus, 13 from Paeoniae Radix Alba, 5 from Zingiberis Rhizoma Recens, and 29 from Jujubae Fructus, witha total of 983 therapeutic targets. Among these targets, 134 were associated with PE, and protein kinase B1 (AKT1), mitogenactivatedprotein kinase 1 (MAPK1), and transformation-related protein 53 (TP53) served as the core targets. The results of GOand KEGG enrichment analyses indicated that the alleviation of PE by HGD is mainly related to pathways including immuneresponse, regulation of gene expression, atherosclerosis, and tumorigenesis. Molecular docking results showed that the keyactive components in HGD could bind to the core targets spontaneously and stably. This study revealed that HGD may alleviatesymptoms in PE patients by regulating signaling pathways, modulating platelet function to exert anticoagulant effects, andregulating the expression of anti-inflammatory genes, which provided a direction for subsequent experimental research.
基金funded by Zhejiang Province Traditional Chinese Medicine Science and Technology Program(No.2021ZZ012)The Changlin Qiu National Distinguished Senior Traditional Chinese Medicine Expert Heritage Workshop Project(No.GZS2021007).
文摘Background:Parkinson’s disease(PD)is one of the most common movement disorders worldwide.Ziyin Xifeng Decoction(ZYXFD),a traditional Chinese medicine compound formula,has shown therapeutic efficacy in treating PD,but its specific mechanisms of action have not been fully elucidated.Methods:Firstly,we employed network pharmacology and untargeted metabolomics analysis to identify the core targets,pathways,and key metabolites of ZYXFD in the treatment of PD.Subsequently,we evaluated the protective effects of ZYXFD and further investigated its anti-PD mechanisms by validating the analytical results.Results:Combined analyses of network pharmacology and metabolomics identify the core targets including EGFR,SRC,PTGS2,and CDK2,while the effects of ZYXFD against PD are likely mediated primarily through the PI3K/AKT/mTOR signaling pathway.Pharmacodynamic evaluation demonstrated that a high dose of ZYXFD significantly improved behavioral deficits in chronic PD mice,downregulatedα-synuclein protein expression,and protected dopaminergic neurons.It also regulated the expression of core targets,inhibited the PI3K/AKT/mTOR signaling pathway,promoted autophagy,and reduced apoptosis.In vitro experiments further verified that the therapeutic effect of ZYXFD on PD is dependent on autophagy regulation.Conclusion:The findings demonstrated that ZYXFD alleviates PD by modulating related proteins and metabolites,inhibiting the PI3K/AKT/mTOR signaling pathway,and enhancing autophagy.This provides a theoretical basis for its broader application in PD treatment.
文摘OBJECTIVE:To investigate the mechanism of action of Qinlian Jiangxia decoction(芩连姜夏汤,QLJXD)in the treatment of type 2 diabetes mellitus(T2DM)complicated by hyperlipidemia using network pharmacology,molecular docking,molecular dynamics simulation and in vivo experiments.METHODS:Drug components,targets and disease targets were identified using databases such as TCM systems pharmacology database and analysis platform and Gene Cards.The intersecting targets were subjected to protein-protein interaction analysis using the search tool for the retrieval of interacting genes/proteins database.Subsequently,Gene Ontology and Kyoto Encyclopedia of Genes and Genomes analysis of the intersecting targets were conducted using the Metascape platform to identify core components and targets.The results were validated using molecular docking,molecular dynamics simulations and in vivo experiments.RESULTS:QLJXD contains 76 active ingredients and 136 disease targets.The core ingredients are quercetin,β-sitosterol,wogonin and baicalein,while the core targets are fatty acid binding protein 4(FABP4)and peroxisome proliferative activated receptor gamma(PPARG).Molecular docking and molecular dynamics simulations revealed that the core ingredients bound well to the core targets.Animal experiments demonstrated that QLJXD effectively inhibited the expression of FABP4 and increased the expression of PPARG,thereby enhancing disorders of glycolipid metabolism.CONCLUSION:The putative therapeutic efficacy of QLJXD in the management of T2DM complicated with hyperlipidemia may be ascribed to the synergistic actions of multiple components,such as quercetin,β-sitosterol,wogonin,and baicalein,which collectively modulate FABP4 and PPARG molecular targets.
文摘Background:Pistacia chinensis Bunge has been traditionally used to manage various conditions,including asthma,pain,inflammation,hepatoprotection,and diabetes.The study was conducted to investigate the antioxidant and anti-lipoxygenase(LOX)properties of the isolated compound 2-(3,4-dihydroxyphenyl)-5,7-dihydroxy-4H-chromen-4-one from Pistacia chinensis.Methods:LOX assay and antioxidant activity using 2,2-diphenyl-1-picrylhydrazyl(DPPH)assay were performed.Molecular docking studies were conducted using a molecular operating environment.Results:The LOX assay revealed significant inhibitory effects at 0.2µM concentration,with an IC50 value of 37.80µM.The antioxidant effect demonstrated dose-dependency across 5 to 100µg/mL concentrations,reaching 93.09%at 100µg/mL,comparable to ascorbic acid’s 95.43%effect.Molecular docking studies highlighted strong interactions with the lipoxygenase enzyme,presenting an excellent docking score of-10.98 kcal/mol.Conclusion:These findings provide valuable insights into Pistacia chinensis’chemical components and biological effects,reinforcing its traditional medicinal applications.
基金Natural Science Foundation of Shandong Province,No.ZR2020QH185Scientific Research Nurturing Fund of The First Affiliated Hospital of Shandong First Medical University&Shandong Provincial Qianfoshan Hospital,No.QYPY2020NSFC0803+2 种基金Guangxi Zhuang Autonomous Region Health Commission Scientific Research Project,No.Z-A20220415Guangxi Medical University Teacher Teaching Ability Development Project,No.2022JFA02Guangxi Medical University Undergraduate Education and Teaching Reform Project,No.2023Y05.
文摘BACKGROUND Colorectal cancer(CRC)is the third most common cancer globally,causing over 900000 deaths annually.Risk factors include aging,diet,obesity,sedentary lifestyle,tobacco use,genetic predisposition,and inflammatory bowel disease.Despite current treatments,survival rates for advanced CRC remain low,highlighting the need for better therapeutic strategies.AIM To evaluate both the clinical significance and the pathological implications of the Kinesin family member 14(KIF14)expression within CRC specimens.Additionally,this study aims to investigate the interaction between nitidine chloride(NC)and KIF14,considering their potential as therapeutic targets.METHODS The expression of the KIF14 protein in CRC was analyzed using immunohistochemical staining.The integration of multicenter high-throughput data facilitated the calculation of the standardized mean difference(SMD)for KIF14 mRNA levels.The assessment of clinical and pathological impact was enhanced by analyzing combined receiver operating characteristic curves,along with measures of sensitivity,specificity,and likelihood ratios.Additionally,clustered regularly interspaced short palindromic repeats knockout screening for cell growth and single-cell sequencing were employed to validate the significance of KIF14 expression in CRC.Survival analysis established the prognostic value of KIF14 in CRC.The molecular mechanism of NC against CRC was elucidated through whole-genome sequencing and enrichment analysis,and molecular docking was utilized to explore the targeting affinity between NC and KIF14.RESULTS KIF14 was highly expressed in 208 CRC patients.Data from 17 platforms involving 2436 CRC samples and 1320 noncancerous colorectal tissue controls indicated that KIF14 expression was significantly higher in CRC samples,with an SMD of 1.92(95%CI:1.49-2.35).The area under the curve was 0.94(95%CI:0.92-0.96),with a sensitivity of 0.85(95%CI:0.78-0.90)and a specificity of 0.90(95%CI:0.85-0.93).The positive and negative likelihood ratios were 8.38(95%CI:5.39-13.02)and 0.17(95%CI:0.11-0.26),respectively.At the single-cell level,significant overexpression of KIF14 was observed in CRC cells(P<0.001),with 35 CRC cell lines dependent on KIF14 for growth.The K-M plots demonstrated that KIF14 possesses prognostic value in CRC patients within the GSE71187 and GSE103679 datasets(P<0.05).Binding energy calculations indicated that KIF14 is a potential target for NC(binding energy:10.3 kcal/mol).CONCLUSION KIF14 promotes the growth of CRC cells and acts as an oncogenic factor,potentially serving as a therapeutic target for NC in the treatment of CRC.
基金supported by the National Natural Science Foundation of China(Nos.42207320 and 22076214).
文摘Ethiprole is widely used as a second-generation phenyl pyrazole insecticide.Previous studies indicated that ethiprole exhibited thyroid toxicity while two main metabolites(ethiprole sulfone(M1)and ethiprole sulfide(M2))of ethiprole showed higher acute toxicity than ethiprole.Therefore,assessing the thyroid toxicity of its metabolites is crucial for safety assessment.In this study,the thyroid toxicity and underlying mechanisms of ethiprole and its metabolites were explored using in silico,in vitro,and in vivo assays,with the aim of conducting a comparative study on thyroid toxicity.Molecular docking analysis showed that ethiprole,M1 and M2 could bind with thyroid receptor isoforms and exhibited higher binding affinity compared to 3,3,5-triiodothyronine(T3).GH3 cell proliferation assays revealed that ethiprole,M1 and M2 all served as thyroid hormone antagonists to hinder the T3-induced cell proliferation.Using the zebrafish model,we further investigated that exposure to ethiprole,M1,and M2 disrupted thyroid hormone levels and the transcriptional expressions of hypothalamus-pituitary-thyroid(HPT)axis-related genes.Ethiprole induced thyroid disrupting effects by binding with the thyroid receptor beta,M1 mainly through binding with the corticotropin releasing factor receptor-1,and M2 exposure firstly inhibited the thyroid peroxidase enzyme activity.M2 showed the highest developmental toxicity and thyroid disrupting effects,which significantly reducing hatching rates,increasing deformity rates,exhibiting the lowest lethal concentration 50 value and showing the most serious transcription inhibitory effects on the HPT axis.This study suggested the risk assessment of metabolites should be considered in assessing potential environmental risk of ethiprole.
基金Research Grants of Senior Research Fellowship in favor of first author(Gloak Majumdar)from Council of Scientific and Industrial Research(CSIR,New Delhi,Government of India)(CSIR-SRF)with Award No.09/1151/(0008)2020-EMR-I.
文摘Objective To evaluate the antibacterial potential of bioactive compounds from Persicaria hydropiper(L.)(P.hydropiper)against bacterial virulence proteins through molecular docking(MD)and experimental validation.Methods Six bioactive compounds from P.hydropiper were investigated:catechin(CAT1),hyperin(HYP1),ombuin(OMB1),pinosylvin(PSV1),quercetin 3-sulfate(QSF1),and scutellarein(SCR1).Their binding affinities and potential binding pockets were assessed through MD against four bacterial target proteins with Protein Data Bank identifiers(PDB IDs):topoisomerase IV from Escherichia coli(E.coli)(PDB ID:3FV5),Staphylococcus aureus(S.aureus)gyrase ATPase binding domain(PDB ID:3U2K),CviR from Chromobacterium violaceum(C.violaceum)(PDB ID:3QP1),and glycosyl hydrolase from Pseudomonas aeruginosa(P.aeruginosa)(PDB ID:5BX9).Molecular dynamics simulations(MDS)were performed on the most promising compound-protein complexes for 50 nanoseconds(ns).Drug-likeness was evaluated using Lipinski's Rule of Five(RO5),followed by absorption,distribution,metabolism,excretion,and toxicity(ADMET)analysis using SwissADME and pkCSM web servers.Antibacterial activity was evaluated through disc diffusion assays,testing both individual compounds and combinations with conventional antibiotics[cefotaxime(CTX1,30μg/disc),ceftazidime(CAZ1,30μg/disc),and piperacillin(PIP1,100μg/disc)].Results MD revealed strong binding affinity(ranging from-9.3 to-5.9 kcal/mol)for all compounds,with CAT1 showing exceptional binding to 3QP1(-9.3 kcal/mol)and 5BX9(-8.4 kcal/mol).MDS confirmed the stability of CAT1-protein complexes with binding free energies of-84.71 kJ/mol(5BX9-CAT1)and-95.59 kJ/mol(3QP1-CAT1).Five compounds(CAT1,SCR1,PSV1,OMB1,and QSF1)complied with Lipinski's RO5 and showed favorable ADMET profiles.All compounds were non-carcinogenic,with CAT1 classified in the lowest toxicity class(VI).In antibacterial assays,CAT1 demonstrated significant activity against both gram-positive bacteria[Streptococcus pneumoniae(S.pneumoniae),S.aureus,and Bacillus cereus(B.cereus)][zone diameter of inhibition(ZDI):10-22 mm]and gram-negative bacteria[Acinetobacter baumannii(A.baumannii),E.coli,and P.aeruginosa](ZDI:14-27 mm).Synergistic effects were observed when CAT1 was combined with antibiotics and the growth inhibitory indices(GII)was 0.69-1.00.Conclusion P.hydropiper bioactive compounds,particularly CAT1,show promising antibacterial potential through multiple mechanisms,including direct inhibition of bacterial virulence proteins and synergistic activity with conventional antibiotics.The favorable pharmacological properties and low toxicity profiles support their potential development as therapeutic agents against bacterial infections.
基金Supported by the National Natural Science Foundation of China:Mechanism of Danggui Buxue Decoction in Promoting Liver Regulation by Modulating Kupffer Cell Glycolysis-Mediated Histone Lactylation in Hepatocytes(No.82474299)XingLin Scholars Program of Chengdu University of Traditional Chinese Medicine:Study on the Role and Mechanism of Electrospun Astragalus Polysaccharide and Angelica Polysaccharide in Promoting Liver Regeneration(No.YYZX2020036)。
文摘OBJECTIVE:To explore the mechanism of Danggui Buxue decoction(当归补血汤,DBD)for the treatment of gastric ulcer(GU),based on network pharmacology and in vivo experiments.METHODS:A network pharmacology strategy was used to predict the main components,candidate targets,and potential signaling pathways.Then,molecular docking was performed to further investigate the interactions and binding affinities between the main components and primary targets.Finally,a mouse model of ethanolinduced gastric ulcers was established to confirm the efficacy and potential therapeutic benefits of DBD,and candidate targets were finally identified.RESULTS:A total of 22 active components and 220 target genes were found to be associated with DBD.In addition,343 GU-related target genes and 57 target genes specific to DBD treatment of GU were identified.The Gene Ontology functional enrichment analysis revealed 510 entries for biological processes,36 entries for cell composition,and 69 entries for molecular functions.In the pathway enrichment analysis,143 signaling pathways were identified.Additionally,the molecular docking results revealed that the main active components of DBD exhibited a strong binding capacity with key proteins,including tumor necrosis factor,AKT serine/threonine kinase 1,interleukin-6,vascular endothelial growth factor,and interleukin-1 Beta.Among these,quercetin,kaempferol,formononetin,isorhamnetin,and beta-sitosterol displayed the strongest binding affinities for these key proteins.in vivo experiments showed that DBD pretreatment effectively protected gastric mucosa,and the benefits might be attributed to the downregulation of above key proteins.CONCLUSIONS:Based on network pharmacology analysis and in vivo experiments,we conclude that DBD leads to the protection and healing of the gastric mucosa by targeting genes and pathways,thus effectively countering the development and progression of GU.
基金Supported by the 2024 Hospital Innovation Talent Cultivation Fund Project,No.2024YGKT12.
文摘BACKGROUND Xuanshen decoction(XSD)is a traditional Chinese medicine formulation that is often applied in treating slow transit constipation(STC).However,its specific therapeutic mechanism remains to be characterized.AIM To investigate the mechanism of XSD for STC,we combined network pharmacology prediction,molecular docking analysis,and in vivo studies.METHODS The therapeutic effects of XSD on loperamide-induced STC in rats were assessed through 24-hour fecal number,fecal moisture content,and intestinal propelling rate.Hematoxylin–eosin and Alcian blue/periodic acid-Schiff staining were applied to analyze colonic mucosa for histopathological presentation and mucin production.Next,the mechanism of action of XSD for STC was elucidated through network pharmacology and molecular docking analyses,and the findings were validated by the animal experiments.RESULTS XSD significantly alleviated the symptoms of STC in rats.Relative to the STC rats,in the medium-dose XSD and high-dose XSD rats,stem cell factor,C-kit,phosphophosphoinositide 3-kinase/phosphoinositide 3-kinase,phospho-protein kinase B/protein kinase B,catalase,and superoxide dismutase were substantially upregulated(P<0.01);nuclear factor erythroid 2-related factor 2(nuclear/cytoplasmic)and B-cell lymphoma 2(Bcl-2)were increased(P<0.05),while cleaved caspase-3,Bcl-2-associated X protein(Bax)/Bcl-2,and malondialdehyde were significantly reduced(P<0.01).Heme oxygenase-1 and glutathione peroxidase in the high-dose XSD group were significantly increased(P<0.01),and Bax was statistically lowered(P<0.01);glutathione peroxidase in the medium-dose XSD group was increased(P<0.05),while Bax was reduced(P<0.05).CONCLUSION XSD may inhibit oxidative-stress-induced apoptosis in interstitial cells of Cajal by stimulating the phosphoinositide 3-kinase/protein kinase B/nuclear factor erythroid 2-related factor 2 pathway,thereby effectively treating STC.
基金Supported by Natural Science Foundation of Shandong Province,No.ZR2020QH185Scientific Research Nurturing Fund of the First Affiliated Hospital of Shandong First Medical University&Shandong Provincial Qianfoshan Hospital,No.QYPY2020NSFC0803Guangxi Zhuang Autonomous Region Health Commission Scientific Research Project,No.Z20210442.
文摘BACKGROUND The stearoyl-coenzyme A desaturase(SCD)gene influences colorectal cancer(CRC)pathogenesis,with its expression linked to tumor cell survival and resistance,necessitating further investigation into its role in CRC.AIM To explore the clinical and pathological significance of SCD expression in CRC tissues and to evaluate the affinity between nitidine chloride(NC)and SCD as a target.METHODS Multi-center high-throughput data related to CRC were integrated to calculate the standardized mean difference of SCD mRNA expression levels.Immunohistochemical staining results,Clustered Regularly Interspaced Short Palindromic Repeats knockout screening results of cell growth,and single-cell sequencing were employed to verify the significance of SCD expression in CRC.The clinical and pathological significance of SCD was assessed using pooled receiver operating characteristic curves,sensitivity,specificity,and likelihood ratios.The molecular mechanism of NC against CRC was clarified using the SwissTarget Prediction and functional enrichment,and molecular docking techniques were utilized to explore the targeting affinity between NC and SCD.RESULTS Data from 18 platforms,including 2482 CRC samples and 1334 non-cancerous colorectal tissue controls.SCD expression was significantly upregulated in CRC,with a standardized mean difference of 2.05[95%confidence interval(CI):1.69-2.41].The area under the pooled receiver operating characteristic curve was 0.95(95%CI:0.92-0.96),with a sensitivity of 0.86(95%CI:0.81-0.90)and a specificity of 0.90(95%CI:0.87-0.93).Positive and negative likelihood ratios were 9.02(95%CI:6.49-12.51)and 0.15(95%CI:0.10-0.22),respectively.High SCD protein expression was noted in 208 CRC patients,significantly associated with vascular invasion(P<0.001).At the singlecell level,SCD was significantly overexpressed in CRC cells(P<0.001).A total of 33 CRC cell lines depended on SCD for growth.The potential mechanism of NC against CRC might involve modulation of the cell cycle,positioning SCD as a potential target for NC.CONCLUSION SCD promotes CRC cell growth and thus acts as an oncogenic factor,making it a potential therapeutic target for NC in CRC treatment.
基金Supported by National Natural Science Foundation of China,No.82160762 and No.82460783Guangxi Medical University“Four New”Project,No.SX202403+2 种基金Innovation Project of Guangxi Graduate Education,No.JGY2023068Guangxi Higher Education Undergraduate Teaching Reform Project,No.2022JGA146China Undergraduate Innovation and Entrepreneurship Training Program,No.202310598045.
文摘BACKGROUND Hepatocellular carcinoma(HCC)is at the forefront of the global spectrum of cancer incidence and mortality,with conventional therapies like tyrosine kinase inhibitors limited by resistance.Recent studies have highlighted the promising anticancer effects of nitidine chloride(NC)against HCC.SAC3 domain containing 1(SAC3D1)is critical for centrosome replication and spindle formation.However,research on SAC3D1 in HCC and NC remains limited.AIM To investigate the mechanisms underlying SAC3D1’s role in HCC progression and evaluated its potential as a therapeutic target of NC.METHODS RNA sequencing(RNA-seq)identified SAC3D1 expression changes in HCC cells after NC treatment.Molecular docking was further employed to validate the direct binding between NC and SAC3D1.Additionally,HCC multicenter data(The Cancer Genome Atlas_GTEx,ArrayExpress),pathway analysis,Pearson correlation analysis and SAC3D1 in vitro knockdown experiments were integrated to explore the molecular mechanisms underlying SAC3D1's involvement in HCC progression.RESULTS RNA-seq showed that NC treatment significantly downregulated SAC3D1 expression[log2(fold change)=-0.95,P<0.05],with molecular docking revealing that NC directly bound to SAC3D1 proteins(binding energy:-9.7 kcal/mol).Enrichment analysis showed that most pathways were closely related to the cell cycle.Pearson correlation analysis indicated that SAC3D1 and cell cycle genes were significantly positively correlated(correlation coefficient≥0.3,P<0.05).SAC3D1 knockdown inhibited HCC cell invasion,migration,and proliferation by arresting cells in the S and G2/M phases.Flow cytometry confirmed that after SAC3D1 knockdown,the early and total apoptosis percentage of HCC cells decreased,while the late apoptosis percentage increased.CONCLUSION As a potential target of NC,SAC3D1 may inhibit HCC progression through cell cycle regulation following its downregulation by NC.
