مقالات پذیرفته شده در نهمین کنگره بین المللی زیست پزشکی
Comparative GO Enrichment of Crocin, Picrocrocin, and Kaempferol Targets
Comparative GO Enrichment of Crocin, Picrocrocin, and Kaempferol Targets
Fatemeh Shams,1Elina Khannehzar,2Amirsajad jafari,3,*
1. Student Research Committee, Shiraz University of Medical Sciences, Shiraz, Iran; Medicinal and Natural Products Chemistry Research Center, Shiraz University of Medical Sciences, Shiraz, Iran 3. Department of Basic Sciences, School of Veterinary Medicine, Shiraz University, Shiraz, Iran; Medicinal and Natural Products Chemistry Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
Introduction: Natural products often act via multi-target mechanisms. We compared the functional footprints of three major Crocus sativus bioactives(kaempferol, crocin, and picrocrocin) in breast carcinoma by integrating predicted human protein targets with protein-protein interaction (PPI) networks and Gene Ontology (GO) enrichment. Our goal was to identify convergent cancer-relevant processes and compound-specific distinctions that could guide enrichment strategies and early drug discovery.
Methods: SMILES for each compound were queried against the Similarity Ensemble Approach (SEA) to retrieve hypothetical targets. Targets were curated to human, reviewed gene names in UniProt. Disease relevance and draggability were prioritized by retaining genes listed for breast carcinoma in Pharos with Tclin/Tchem Target Development Levels. We built a STRING v11.5 PPI network (confidence ≥0.4; all evidence) from the union of retained targets and visualized it in Cytoscape; isolated nodes and pseudogenes were removed. Intersection analyses were performed in InteractiVenn. GO Biological Process enrichment was performed using ToppFun with Bonferroni correction (q < 0.01). All numerical summaries below come directly from the provided Cytoscape tables and ToppFun output.
Results: The curated network comprised 86 unique targets, of which 34 are flagged as breast-cancer related in the Cytoscape table. Degree centrality highlighted ESR1 as the top hub (degree = 30), followed by IL2 (17), CYP1A1 (15), AKR1B1 (14), and FGF2 (13). Compound contributions to the network were asymmetric: kaempferol accounted for 54 targets, crocin∩picrocrocin for 15 shared targets (with picrocrocin-only 11 and crocin-only 3), and two targets were common to all three. These patterns support a polypharmacology model in which kaempferol provides breadth, while crocin/picrocrocin reinforce a focused subset (notably including FGF2 and lectin/glycol-related proteins).
GO enrichment showed strong convergence on cancer-relevant processes. The top terms included:
1.Positive regulation of cell migration / motility / locomotion (each with 12 hits; Bonferroni q ≤ 3×10⁻⁶), with contributors such as SELL, SELP, FGF1/2, CYP1B1, ABCC1, NOX4, MYLK, TERT (ToppFun rows 1–3).
2.Angiogenesis / vasculature development (e.g., positive regulation of angiogenesis, 7–8 hits; q ≈ 10⁻⁶–10⁻⁷).
3.Cellular response to xenobiotic stimulus and xenobiotic transport, driven by ABCB1, ABCG2, ABCC1 (Bonferroni-significant).
A notable compound-specific distinction was metabolic emphasis in the kaempferol subset: one-carbon metabolic process (reflecting CA1, CA3, CA4, CA12) was Bonferroni-significant (q ≈ 3×10⁻⁵). This aligns with kaempferol’s targeting of multiple carbonic anhydrases, implicating tumor pH regulation and metabolism. In contrast, the crocin/picrocrocin set enriched migration/angiogenesis terms via FGF2, LGALS3, and oxidative enzymes (e.g., NOX4). Although some apoptosis-related annotations appeared as trends, the most robust signals across compounds centered on motility/invasion, angiogenesis, and xenobiotic/drug transport.
Intersection analysis clarified synergy potential. Crocin and picrocrocin share most of their curated targets (15 shared; minimal crocin-only), indicating mechanistic convergence. Their shared nodes (e.g., FGF2, LGALS3) feed the enriched migration/angiogenesis terms, offering a plausible basis for reported functional synergy. Kaempferol overlaps with the crocin/picrocrocin core on ABC transporters and signaling nodes yet uniquely injects carbonic anhydrases and estrogen-axis targets (ESR1/ESR2), which may broaden anti-tumor coverage toward hormone response and metabolic reprogramming.
Conclusion: Across three saffron bioactives, cell motility/invasion, angiogenesis, and xenobiotic/drug transport emerge as consistently and significantly enriched biological processes, directly aligned with breast-cancer hallmarks. Kaempferol adds a distinctive metabolic/hormonal signature (carbonic anhydrases, ESR1/ESR2), while crocin/picrocrocin reinforce a common axis centered on FGF2, lectins, and oxidative enzymes. Network hubs (ESR1, IL2, CYP1A1, FGF2) highlight tractable intervention points and suggest that combining compounds could produce complementary pathway coverage: anti-migration/anti-angiogenesis (crocin/picrocrocin) plus metabolic and endocrine modulation (kaempferol). These results, grounded in curated SEA→UniProt→Pharos targets, STRING PPI topology, and Bonferroni-corrected GO enrichment, support the rationale for multi-compound enrichment strategies and nominate kaempferol as a lead for further optimization with crocin/picrocrocin as synergistic adjuncts.