Network pharmacology-based approach for exploring the biotargets and mechanisms of vitamin A for the treatment of diabetic foot ulcers

Background:In some developing countries,people have little knowledge about the causes of diabetic foot ulcers.Therefore,public health education for patients on these conditions is a prerequisite for effective pharmacological treatment.Diabetic foot ulcers are a complex symptom of diabetes and are hard to cure due to the lack of efficacious medicine and alternative treatment approaches.Vitamin A(VA)is known to have potent biological functions,including skin repair and immunoregulation.However,the potential pharmacological effects and molecular mechanisms of VA on foot ulcers are still to be discovered.Methods:By using bioinformatic/computational analyses,including network pharmacology,gene ontology and the Kyoto Encyclopedia of Genes and Genomes enrichment analysis,we aimed to identify and reveal the pharmacological targets,molecular mechanisms,biological functions,and signaling pathways of VA in the treatment of diabetic foot ulcers.Results:A total of 66 intersection genes were identified as candidate targets of VA,which are related to diabetic foot ulcers.Therein,18 core genes/targets,namely JUN,MAPK1,THRB,MAPK14,MTNR1B,CXCR3,ESR1,AR,HDAC1,IL-10,CNR1,DRD2,EGFR,ADRA2A,CCND1,RXRB,RARA,and RXRA,were further identified.Furthermore,the biological processes,cell components,and molecular functions which may underlie the effects of VA against diabetic foot ulcers were characterized.Conclusion:Based on our findings,we concluded that the pharmacological effects of VA on diabetic foot ulcers primarily involve the promotion of cellular regeneration and proliferation and the inhibition of inflammatory response.The core genes/targets may potentially serve as promising biomarkers for the diagnosis of diabetic foot ulcers.

Vitamin C exerts anti-cadmium induced fracture functions/targets:bioinformatic and biostructural findings

Background:Epidemiological data indicate an association between cadmium exposure and risk of bone fracture;however,clinical treatment of cadmium-induced fracture is limited.Although vitamin C(VC)reportedly reduces cadmium-induced fracture,its pharmacological mechanism remains unexplored.Methods:Thus,we used a network pharmacology approach and molecular docking analysis to identify core targets,functional processes,and biological pathways involved in the anti-fracture action of VC.Results:Bioinformatics identified 17 intersection targets of VC and cadmium-induced fracture,Nine core targets were characterized,including tumor protein p53,epidermal growth factor receptor,proto-oncogene c,mitogen-activated protein kinase-1(MAPK1),MAPK3,signal transducer and activator of transcription-3,MAPK14,prostaglandin-endoperoxide synthase 2,and estrogen receptor alpha.Interestingly,findings of molecular docking analysis indicated that VC exerted effective binding capacity in cadmium-induced fracture.Furthermore,biological processes,cell components,molecular functions,and pharmacological pathways involved in the action of VC against cadmium-induced fracture were identified and visualized.Conclusions:Based on these findings,we conclude that VC exhibits its anti-cadmium-induced fracture effects by promoting osteoblastic regeneration and proliferation,and inhibiting inflammatory stress.The core targets may serve as biomarkers for diagnosing cadmium-induced fractures.

In-silico analysis reveals the core targets and mechanisms of CA028,a new derivative of calycosin,in the treatment of colorectal cancer

Background Colorectal cancer(CRC)is a type of malignant gastroenteric tumors associated with a high mortal-ity rate worldwide.Calycosin,a natural phytoestrogen,possesses potent anti-cancer properties.We structurally modified calycosin to improve its physicochemical properties,and generated a novel small molecule termed CA028.Methods By using network pharmacology,followed by gene ontology and Kyoto Encyclopedia of Genes and Genomes enrichment analysis and molecular docking,we aimed to predict and disclose the biological functions and mechanism of CA028 in the treatment of CRC through bioinformatic analyses.Results By searching the online Swiss Target Prediction and TargetNet databases,we identified 150 genes shared by CA028 and CRC.Using the Search Tool for the Retrieval of Interacting Genes(STRING)database and Cytoscape software,we identified 14 hub-functional genes,namely the FYN proto-oncogene,a Src family tyrosine kinase(F YN),mitogen-activated protein kinase 1(MAPK1),MAPK8,MAPK14,Rac family small GTPase 1(RAC1),epi-dermal growth factor receptor(EGFR),protein tyrosine kinase 2(PTK2),sphingosine-1-phosphate receptor 1(S1PR1),S1PR2,Janus kinase 1(JAK1),JAK2,the RELA proto-oncogene NF-𝜅B subunit(RELA),bradykinin re-ceptor B1(BDKRB1),and BDKRB2.Additionally,biological docking analysis using the Autodock Vina software revealed that FYN and MAPK1 were the main pharmacological proteins of CA028 against CRC.The gene ontol-ogy analysis using R-language packages further revealed the anti-CRC functions of CA028,including biological processes,cell components,and molecular pathways.Conclusion CA028 exhibits effective pharmacological activity against CRC by suppressing the proliferation of CRC cells and improving the tumor microenvironment.Importantly,certain predicted genes(e.g.,FYN and MAPK1)may be the pharmacological targets of CA028 in the treatment of CRC.

Transgenerational bone toxicity in F3 medaka (Oryzias latipes) induced by ancestral benzo[a]pyrene exposure: Cellular and transcriptomic insights

Benzo[a]pyrene(BaP),a ubiquitous pollutant,raises environmental health concerns due to induction of bone toxicity in the unexposed offspring.Exposure of F0 ancestor medaka(Oryzias latipes)to 1μg/L BaP for 21 days causes reduced vertebral bone thickness in the unexposed F3 male offspring.To reveal the inherited modifications,osteoblast(OB)abundance and molecular signaling pathways of transgenerational BaP-induced bone thinning were assessed.Histomorphometric analysis showed a reduction in OB abundance.Analyses of the miRNA and mRNA transcriptomes revealed the dysregulation of Wnt signaling(frzb/ola-miR-1–3p,sfrp5/ola-miR-96–5p/miR-455–5p)and bone morphogenetic protein(Bmp)signaling(bmp3/ola-miR-96–5p/miR-181b-5p/miR-199a-5p/miR-205–5p/miR-455–5p).Both pathways are major indicators of impaired bone formation,while the altered Rank signaling in osteoclasts(c-fos/miR-205–5p)suggests a potentially augmented bone resorption.Interestingly,a typical BaP-responsive pathway,the Nrf2-mediated oxidative stress response(gst/ola-miR-181b-5p/miR-199a-5p/miR-205),was also affected.Moreover,mRNA levels of epigenetic modification enzymes(e.g.,hdac6,hdac7,kdm5b)were found dysregulated.The findings indicated that epigenetic factors(e.g.,miRNAs,histone modifications)may directly regulate the expression of genes associated with transgenerational BaP bone toxicity and warrants further studies.The identified candidate genes and miRNAs may serve as potential biomarkers for BaP-induced bone disease and as indicators of historic exposures in wild fish for conservation purposes.

Anti-hepatic carcinoma mechanisms of calycosin through targeting ferroptosis

Background Ferroptosis,a pathologic state induced by lipid-driven oxidative stress,is associated with the development of human cancers.Calycosin,a natural compound with antioxidant and anti-inflammatory activities,has promising antitumor effects.However,the ferroptosis-related mechanism of calycosin in the treatment of hepatic carcinoma has not been reported.Methods This study applied network pharmacology and bioinformatic approaches(including Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathway enrichment analysis)to investigate the pharmacologic targets and mechanism of action of calycosin in the treatment of hepatic carcinoma through targeting ferroptosis.By searching online databases including The Cancer Genome Atlas,FerrDb,GeneCards,SwissTargetPrediction,SuperPred,BindingDB,TargetNet,BATMAN-TCM,and Drugbank,we identified 13 ferroptosis-related putative target genes of calycosin against hepatic carcinoma including IL-6,PTGS2,SRC,HRAS,NQO1,NOX4,PGK1,G6PD,GPI,MIF,NOS2,ALDOA,and SQSTM1.Results Molecular docking analysis revealed that calycosin potentially binded directly with the target proteins IL-6,PTGS2,and SRC.Functional enrichment analysis of these proteins indicated that they were involved in gluconeogenesis and apoptosis through regulation of ERK1,ERK2,and MAPK activities(P<0.05).Conclusion Calycosin exerts antitumor effects in hepatic carcinoma by targeting ferroptosis through regulation of IL-6,PTGS2,and SRC.