Decoding the anti-cataractogenic mechanism of grapes via a systemic pharmacology approach

Introduction: Our previous study has indicated that grapes may be able to protect against in vivo ultraviolet B (UV-B) radiation-induced cataract. To better understand the mechanism of action of grapes in cataract prevention, this follow-up study was designed to identify the molecular targets of grapes in the lens by using a systemic pharmacology approach. Methods: As recommended by the California Table Grape Commission (CTGC), we selected four compounds including resveratrol, catechin, quercetin, and anthocyanins as the major phytoconstituents of grapes for target prediction. All genes that can be regulated by grapes were obtained from NCBI (www.pubmed.gov) and TCMSP (http://lsp.nwu.edu.cn/tcmsp.php). Genes that are associated with cataracts were collected from GeneCards (www.GeneCards.org). The comparison between grape-related targets and cataract-associated genes was conducted using Cytoscape 3.2.1 with ClueGo plugin. Gene Ontology (GO) enrichment analysis of grape-regulated genes was conducted using Database for Annotation, Visualization, and Integrated Discovery (www.david.ncifcrf.gov). Results: A total of 332 targets that are grape regulated were identified and visualized by protein network. Subsequently, 147 GO functional pathways were clustered, including anti-apoptotic, anti-inflammation, PI3K-Akt signaling, ATP binding, and FOXO pathways. Among these protein targets, X-linked inhibitor of apoptosis (XIAP), heat shock protein (HSP) 90, and prostaglandin-endoperoxide synthase (PTGS) were correlated with all of the active ingredients of grapes. Comparison between grape targets and cataract disease genes showed that thirteen grape targets overlapped with cataract associated genes, including PTGS2, HSP90AA1, HSP90AA2P, mitogen-activated protein kinase 1 (MAPK1), MAPK14, MAPK3, amyloid precursor protein (APP), glycogen synthase kinase 3B (GSK3B), protein kinase α (PRKCA), protein kinase C delta (PRKCD), B-cell lymphoma 2 (BCL2), BCL2L1, and K-ras (KRAS). Conclusions: The anticataractogenesis effects of grapes may involve not only directly scavenging free radicals but also activating the antiapoptotic pathway.