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.

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.