Network pharmacology-based elucidation of bioactive compounds in propolis and putative underlying mechanisms against type-2 diabetes mellitus

• Published in: Pharmacological research. Modern Chinese medicine 2022-12, Vol.5, p.100183, Article 100183
• Main Authors: Ugwor, Emmanuel I., James, Adewale S., Amuzat, Adekunle I., Ezenandu, Emmanuel O., Ugbaja, Victory C., Ugbaja, Regina N.
• Format: Article
• Language: English
• Subjects: Bioactive compounds; Network pharmacology; Nigerian propolis; Type-2 diabetes
• ISSN: 2667-1425; 2667-1425
• DOI: 10.1016/j.prmcm.2022.100183

•We used network analyses to unravel the anti-T2DM property of Nigeria propolis (NP).•Network analyses revealed 167 putative anti-T2DM targets of NP compounds.•44 compounds in NP interacted with T2DM-associated targets.•2-ethyl-1,4-dimethoxybenzene was the most active component in nP.•NP ethanol extract showed appreciable inhibitory effects against T2DM targets. Propolis is a common remedy in Chinese medicine. We have previously demonstrated the anti-diabetic potentials of Nigerian propolis. However, the underlying mechanisms against type-2 diabetes mellitus (T2DM) remain unclear. This study used network pharmacology-based analysis to unravel the possible mechanisms of NP's anti-T2DM activity. Previously identified compounds in NP were retrieved from literature, screened for drug-likeness, and used to retrieve targets associated with T2DM, from which compound-target, protein-protein interaction, and target-pathways networks were constructed. Network pharmacology-based and enrichment analyses were conducted on the networks. Further, NP's inhibitory activity against targets identified in network analyses was assessed in-vitro. Library search revealed 202 previously reported compounds in NP; 96 were retained after screening for drug-likeness. However, only 44 NP compounds interacted with T2DM-associated targets, with 2-ethyl-1,4-dimethoxybenzene as the most active component. Network analyses revealed 167 putative targets, with HSP90AA1, JUN, ESR1, STAT3, CYP3A4, PTGS2, RELA, VEGFA, CYP2C9, and PPARG as the core anti-T2DM targets of NP compounds. Gene ontology analyses indicated that these targets were predominantly localised in the plasma membrane and cytoplasm and primarily involved in regulatory, signal transduction and cellular response processes. KEGG pathway enrichment implicated metabolic pathways (involving lipids), AGE-RAGE, and calcium/cAMP, among others, in the anti-T2DM effects of the compounds. Furthermore, in vitro pharmacological assessment demonstrated appreciable inhibitory effects of 2-ethyl-1,4-dimethoxybenzene against α-amylase, α-glucosidase, and HMG-CoA reductase. This study provides holistic mechanistic insights into the anti-T2DM activities of the constituents of Nigerian propolis. [Display omitted]