Silibinin suppresses TGFß2-induced lens epithelial cell migration and epithelial-mesenchymal transition.

Growth factor-induced migration of lens epithelial cell (LEC) toward the posterior of lens capsule bag and their epithelial-mesenchymal transition (EMT) is the key process involved in the pathogenesis of posterior capsular opacification (PCO). Silibinin, a natural flavonolignan, confers therapeutic effects to different cells by regulation of signalling pathways; however, its role in the prevention of migration and EMT of LECs is yet to be analysed. In this study, the inhibitory capabilities of silibinin on migration and EMT were analysed in response to TGFß2 stimulation in HLE B-3 cells. The anti-migratory effect of silibinin was analysed using wound healing assay. Transcriptional and translational expression of genes related to LEC migration, EMT, and transcription factors related to EMT were studied by quantitative real-time PCR and Western blotting. Immunofluorescence analysis was utilized to study the localization of fibronectin. Silibinin reduced the viability of LECs in a concentration-dependent manner and inhibited the wound healing capacity of LECs induced by TGFß2. Silibinin also suppressed alteration in the EMT-related markers such as cytoskeletal proteins, cell adhesion markers, extracellular matrix molecules, and transcription factors. Analysis of downstream signalling revealed that treatment with silibinin decreased phosphorylated Akt (Ser473, Thr308), PDK1 (Ser241), PTEN (Ser380), c-Raf (Ser259), and GSK3ß (Ser9) in TGFß-stimulated cells. The effect of silibinin treatment on phosphorylated Akt resembled that of the PI3K inhibitor LY294002. Our results suggest that silibinin can suppress LEC migration and EMT, which involves the inactivation of the PI3K-Akt signalling pathway. Silibinin might be a good candidate for PCO prevention; however, functional evaluation of silibinin using in vivo models is a pre-requisite.

Sexual Dimorphism in Drug Metabolism and Pharmacokinetics.

BACKGROUND: Sex and gender-based differences are observed well beyond the sex organs and affect several physiological and biochemical processes involved in the metabolism of drug molecules. It is essential to understand not only the sex and gender-based differences in the metabolism of the drug but also the molecular mechanisms involved in the regulation of drug metabolism for avoiding sex-related adverse effects of drugs in the human. METHODS: The articles on the sex and gender-based differences in the metabolism of drug molecules were retrieved from the Pub Med database. The articles were classified into the metabolism of the drug molecule, gene expression regulation of drug-metabolizing enzymes, the effect of sex hormones on the metabolism of drug, expression of drugmetabolizing enzymes, etc. Results: Several drug molecules are known, which are metabolized differently in males and females. These differences in metabolism may be due to the genomic and non-genomic action of sex hormones. Several other drug molecules still require further evaluation at the molecular level regarding the sex and gender-based differences in their metabolism. Attention is also required at the effect of signaling cascades associated with the metabolism of drug molecules. CONCLUSION: Sex and gender-based differences in the metabolism of drugs exist at various levels and it may be due to the genomic and non-genomic action of sex hormones. Detailed understanding of the effect of sex and related condition on the metabolism of drug molecules will help clinicians to determine the effective therapeutic doses of drugs dependingon the condition of patient and disease.