RESUMO
Microsporum gypseum is a keratinophilic fungi grouped under dermatophytes infecting skin, hair and nail portions in human and animals causing tinea corporis, tinea facei and tinea capitis. As both human and fungi are eukaryotes, the available drugs for treating dermatophytes produce some side effects due to drug interaction with human also. Apart from this, the gut microbiota has a very big role in the health of human which should not be affected by the drugs. Hence this study focused on finding a target which is unique and essential to M. gypseum and non-homologous to human and gut microbiota, non-homologous to human domain architecture, highly interacting with other proteins, sub-cellular localization of proteins and non-druggability analysis of the targets using subtractive proteomics approach which resulted with 3 novel drug targets from M. gypseum which were modeled using I-TASSER, refined by ModRefiner and validated by PROCHECK. Further these targets were docked with compounds identified through LC-MS of fractioned methanol extract of B. aegyptiaca fruit pulp using Glide module and the stability of the docked complex was analyzed by molecular dynamics simulation using Desmond module of Schrodinger. Cyanidin-3-O-rhamnoside had better interaction with all the targets and Taurocholic acid had better result with ECCP which suggests the multi-targeting potency of these two compounds against M. gypseum which has to be confirmed by in vitro and in vivo studies.
Assuntos
Arthrodermataceae/efeitos dos fármacos , Balanites/química , Dermatomicoses/tratamento farmacológico , Proteínas Fúngicas/análise , Simulação de Acoplamento Molecular , Proteômica , Humanos , ProteomaRESUMO
Reserpine is a natural indole alkaloid isolated from Rauwolfia serpentina and has potent antioxidant, antimicrobial, and anti-mutagenic properties. Accordingly, this study aimed to investigate the effect of reserpine on DNA repair, cell proliferation, invasion and apoptosis in 7,12-dimethylbenz[a]anthracene(DMBA)-induced hamster buccal pouch (HBP) carcinogenesis. Transforming growth factor-ß (TGF-ß) was found to induce Smad2, 3 and 4 phosphorylation triggering Smad3/Snail mediated DNA repair proteins and Smad2/4 nuclear translocation. In contrast, reserpine inhibits TGF-ß dependent Smad2/3/4 phosphorylation, thereby blockage Smad3/Snail activation and Smad2/4 nuclear translocation. Interruption of these oncogenic signaling pathways leads to downregulating ERCC1, XPF, Ku70, DNA-PKcs, PCNA, cyclin D1, HIF-1α, IL-6, Mcl-1 and stimulates Bax, cytochrome C, Apaf-1, caspase-9, caspase-3 and PARP protein expressions. This study provides therapeutic potential of reserpine in inhibiting DNA repair, cell proliferation, and invasion while simultaneously inducing apoptosis via modulation TGF-ß signals.