Interactions between phenolic constituents of Scutellaria salviifolia and key targets associated with inflammation: network pharmacology, molecular docking analysis and in vitro assays.

Scutellaria salviifolia Benth. (SS), an endemic plant for Turkey, is used for gastric ailments as folk medicine. In this study, we aimed to uncover the underlying molecular mechanisms with the help of network pharmacology and molecular docking analysis in the inflammation processes of gastric ailments. Gene enrichment analysis and target screening were carried out. Experimental validation was performed via cytokines of nitric oxide (NO) and interleukin-6 (IL-6) in LPS stimulated RAW 264.7 cells. Furthermore, antioxidant activity studies were performed by radical scavenging effects on different radicals. A total of 144 targets were listed for the isolated compounds where 26 of them were related to selected inflammation targets. According to the gene enrichment analysis, HIF1 signaling pathway and TNF signaling pathway were found to be involved in inflammation. We also defined AKT1, TNF, EGFR, and COX2 as key targets due to the protein-protein interactions of 26 common targets. The extract inhibited NO and IL-6 production at 100 and 200 µg/mL, while flavonoid-rich fraction possessed significant anti-inflammatory activity at the concentration of 50 and 100 µg/mL via NO and IL-6 production, respectively. It is thought that the anti-inflammatory effects of extracts, fractions and pure compounds were achieved by reducing NO and IL-6 levels via regulating the NF-κB pathway or reducing NO production by suppressing iNOS through the HIF-1 pathway when evaluated together with the results of network analysis and literature. Anti-inflammatory activities of the extract and fractions were promising and comparably with S. baicalensis, commonly used for its anti-inflammatory activity.

Constitution of a comprehensive phytochemical profile and network pharmacology based investigation to decipher molecular mechanisms of Teucrium polium L. in the treatment of type 2 diabetes mellitus.

BACKGROUND: Type 2 diabetes mellitus (T2DM) is a metabolic disease affecting a huge population worldwide. Teucrium polium L. has been used as a folk medicine for the treatment of T2DM in Anatolia, Turkey. The antihyperglycemic effect of the plant was reported previously. However, there was no detailed study on the underlying molecular mechanisms. In this study, we generated a research plan to clarify the active constituents of the extract and uncover the molecular mechanisms using network pharmacology analysis. METHODS: For this purpose, we composed a dataset of 126 compounds for the phytochemical profile of the aerial parts of T. polium. Drug-likeness of the compounds was evaluated, and 52 compounds were selected for further investigation. A total of 252 T2DM related targets hit by selected compounds were subjected to DAVID database. RESULTS: The KEGG pathway analysis showed enrichment for the TNF signaling pathway, insulin resistance, the HIF-1 signaling pathway, apoptosis, the PI3K-AKT signaling pathway, the FOXO signaling pathway, the insulin signaling pathway, and type 2 diabetes mellitus which are related to T2DM . AKT1, IL6, STAT3, TP53, INS, and VEGFA were found to be key targets in protein-protein interaction. Besides these key targets, with this study the role of GSK3ß, GLUT4, and PDX1 were also discussed through literature and considered as important targets in the antidiabetic effect of T. polium. Various compounds of T. polium were shown to interact with the key targets activating PI3K-AKT and insulin signaling pathways. CONCLUSIONS: According to these findings, mainly phenolic compounds were identified as the active components and IRS1/PI3K/AKT signaling and insulin resistance were identified as the main pathways regulated by T. polium. This study reveals the relationship of the compounds in T. polium with the targets of T2DM in human. Our findings suggested the use of T. polium as an effective herbal drug in the treatment of T2DM and provides new insights for further research on the antidiabetic effect of T. polium.

Cytotoxic phenylethanoid glycosides from Digitalis davisiana Heywood: Evaluation of structure activity relationships and chemotaxonomical significance of isolated compounds.

The phytochemical studies on the aerial parts of Digitalis davisiana Heywood led to the isolation of three undescribed phenylethanoid glycosides named as digidavisoside A (5), digidavisoside B (7), and davisoside (8), along with 9 known compounds, ferruginoside B (1), isolugrandoside (2), lugrandoside (3), maxoside (4), 3″″-O-methylmaxoside (6), trans-lamiuside E (9), digiciliside B (10), p-hydroxyacetophenone (11), and chrysoeriol (12). For the first time compound 11 was reported for Digitalis genus. The chemotaxonomical significance of these compounds in Plantaginaceae family was evaluated and 3'-O-glucosyl substituted phenylethanoid glycosides 4-8 and 10 were found to be chemotaxonomically important for the family. Cytotoxic activity of the aqueous fraction of the methanolic extract was also tested against HEp-2 (human larynx epidermoid carcinoma) and HepG2 (human hepatocellular carcinoma) cancer cell lines. The aqueous fraction showed stronger cytotoxicity on HEp-2 cells than on HepG2. Therefore, the cytotoxic activity of 1-4, 6, 7 and 9 were tested against HEp-2 and L929 (mouse fibroblast cell) cell lines. Other isolated compounds could not be tested due to their insufficient amount. The results were evaluated in the point of structure-activity relationships. IC50 values against HEp-2 cells were established in a range of 71.9-220 µM. Maxoside (4), isolugrandoside (2) and lugrandoside (3) showed higher cytotoxicity against HEp-2 cell line than other isolated compounds.

New knowledge about old drugs; a cardenolide type glycoside with cytotoxic effect and unusual secondary metabolites from Digitalis grandiflora Miller.

Phytochemical investigation of the aerial parts of Digitalis grandiflora Miller (Plantaginaceae) led to the isolation of an undescribed cardenolide type glycoside digigrandifloroside (1) along with five known compounds, rengyoside A (2), rengyoside B (3), cleroindicin A (4), salidroside (5), and cornoside (6), from its aqueous fraction of methanolic extract. Structures of the isolated compounds were determined by means of spectroscopic techniques. 1-6 were isolated for the first time from D. grandiflora. 2 and 3 are being reported for the first time from Digitalis genus and Plantaginaceae family with this study. This is the second report for occurrence of 4 from a Digitalis species. Cytotoxic activity of the aqueous fraction was also tested against HEp-2 (Human larynx epidermoid carcinoma) and HepG2 (Human hepatocellular carcinoma) cancer cell lines and L929 (Mouse fibroblast cell) non-cancerous cell line. Aqueous fraction showed stronger cytotoxicity on HEp-2 cells than HepG2. Therefore, the cytotoxic activity of 1, 2, 4, and 6 were tested against HEp-2 and L929 cell lines. 3 and 5 couldn't be tested due to their insufficient amount. 1 showed the highest cytotoxicity against HEp-2 cells with IC50 value 10.1 µM when compared with the positive control, etoposide and 2-6 (IC50 of etoposide; 39.5 µM).