The aim of the present study was to examine the antioxidative activity of (+)-lariciresinol (LRSL), an optically active lignan isolated from Rubia philippinensis in several in vitro assays. LRSL was also subjected to evaluate its inhibitory effect against the generation of reactive oxygen species (ROS) in murine macrophage (RAW 264.7) cells. The results showed that LRSL possessed very strong radical scavenging activity and reducing power, as well as inhibited ROS generation in a dose-dependent manner without showing any cytotoxicity. The transcriptional and translational levels of superoxide dismutase (SOD), glutathione peroxidase (GPx) and catalase (CAT) were markedly higher in the sample treated group. LRSL treatment also increased the transcriptional and translational activities of NF-E2-related factor-2 (Nrf-2) with a corresponding increase in the transcriptional and translational activities of the heme oxygenase-1 (HO-1). LRSL activated p38 and treatments with SB239063 (a p38 inhibitor) suppressed the LRSL-induced activation of Nrf2, resulting in a decrease in HO-1 expression. Collectively, the data demonstrated that LRSL has potent antioxidative activity, decreasing ROS generation in RAW 264.7 cells and increasing the transcriptional and translational levels of antioxidant enzymes by activating Nrf2-mediated HO-1 induction via p38 signaling.

We examined the anti-inflammatory effects of (+)-syringaresinol (SGRS), a lignan isolated from Rubia philippinensis, in lipopolysaccharide (LPS)-stimulated RAW 264.7 cells using enzyme-based immuno assay, Western blotting, and RT-PCR analyses. Additionally, in vivo effects of SGRS in the acute inflammatory state were examined by using the carrageenan-induced hind paw edema assay in experimental mice. As a result, treatment with SGRS (25, 50, and 100 μM) inhibited protein expression of lipopolysaccharide-stimulated inducible nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2), and nuclear factor kappa B (NF-κB) as well as production of nitric oxide (NO), prostaglandin E2 (PGE2), tumor necrosis factor-alpha (TNF-α), interleukin-1beta (IL-1β), and interleukin-6 (IL-6) induced by LPS. Moreover, SGRS also reduced LPS-induced mRNA expression levels of iNOS and COX-2, including NO, PGE2, TNF-α, IL-1β, and IL-6 cytokines in a dose-dependent fashion. Furthermore, carrageenan-induced paw edema assay validated the in vivo anti-edema effect of SGRS. Interestingly, SGRS (30 mg/kg) suppressed carrageenan-induced elevation of iNOS, COX-2, TNF-α, IL-1β, and IL-6 mRNA levels as well as COX-2 and NF-κB protein levels, suggesting SGRS may possess anti-inflammatory activities.

*These two authors contributed equally to this work. BACKGROUND AND PURPOSEThe proliferation and migration of vascular smooth muscle cells (VSMCs) induced by platelet-derived growth factor (PDGF) are important steps in cardiovascular diseases, including neointimal lesion formation, myocardial infarction and atherosclerosis. Here, we evaluated the rubiarbonone C-mediated signalling pathways that regulate PDGF-induced VSMC proliferation and migration. EXPERIMENTAL APPROACHCell proliferation and migration were measured in cells treated with rubiarbonone C followed by PDGF BB using the MTT assay, [ 3 H]-thymidine incorporation, flow cytometry and wound-healing migration assay, MMP gelatin zymography, a fluorescence assay for F-actin. Western blotting of molecules including MAPK, focal adhesion kinase (FAK) and STAT3 and an immunofluorescence assay using anti-PCNA and -STAT3 antibodies were performed to evaluate rubiarbonone C signalling pathway(s). The medial thickness of the carotid artery was evaluated using a mouse carotid ligation model. KEY RESULTSRubiarbonone C inhibited PDGF-induced VSMC proliferation and migration and diminished the ligation-induced increase in medial thickness of the carotid artery. In PDGF-stimulated VSMCs rubiarbonone C decreased the following: (i) levels of cyclindependent kinases, cyclins, PCNA and hyperphosphorylated retinoblastoma protein; (ii) levels and activity of MMP2 and MMP9; (iii) activation of MAPK; (iv) F-actin reorganization, by reducing FAK activation; (v) activation of STAT3. CONCLUSIONS AND IMPLICATIONSThese findings suggest that rubiarbonone C inhibits the proliferation and migration of VSMCs by inhibiting the FAK, MAPK and STAT3 signalling pathways. Therefore, rubiarbonone C could be a good candidate for the treatment of cardiovascular disease. AbbreviationsCDK, cyclin-dependent kinases; FAK, focal adhesion kinase; LCA, left carotid artery; PDGF, platelet-derived growth factor; pRb, retinoblastoma protein; STAT3, signal transducer and activator of transcription 3; VSMC, vascular smooth muscle cell

Our findings demonstrate that the new cucurbitane-type triterpenoids have potential for prevention and management of diabetes by improving insulin sensitivity and glucose homeostasis.

The abnormal proliferation and migration of vascular smooth muscle cells (VSMCs) are associated with cardiovascular diseases and related complications. Such deleterious proliferation and migration events are triggered by cytokines and growth factors, and among them, platelet-derived growth factor (PDGF) is recognized as the most potent inducer. Despite the genus Rubia being researched to identify valuable commercial and medicinal virtues, Rubia philippinensis has rarely been investigated. Nine arborinane-type triterpenoids (1-9) were identified from this underutilized plant species. In particular, 4 was identified as the first arborinane derivative carrying a ketocarbonyl motif at C-19. The presence of the cyclopentanone moiety and the associated configurational assignment were determined by utilizing NOE and coupling constant analysis. These compounds were assessed for their inhibitory potential on PDGF-induced proliferation and the migration of VSMCs. Treatment with 5 μM compound 5 (62.6 ± 10.7%) and compound 9 (41.1 ± 4.7%) impeded PDGF-stimulated proliferation without exerting cytotoxicity. Compound 7 exhibited antimigration activity in a dose-dependent manner (38.5 ± 3.0% at 10 μM, 57.6 ± 3.2% at 30 μM). These results suggest that the arborinane-type triterpenoids may be a pertinent starting point for the development of cardiovascular drugs capable of preventing the intimal accumulation of VSMCs.

BackgroundCancer is one of the most frequently occurring diseases and is the second leading cause of death worldwide. In this study, anthraquinone derivatives (Compounds 1–5) were evaluated for their anti-cancer potential against various skin and breast cancer cell lines to assess whether these anthraquinone derivatives may serve as a lead for the augmentation of anti-cancer drug.MethodsAnthraquinone derivatives, 2-methyl-1,3,6-trihydroxy-9,10-anthraquinone-3-O-(6′-O-acetyl)-α-rhamnosyl(1 → 2)-β-glucoside (Comp 1), 2-methyl-1,3,6-trihydroxy-9,10-anthraquinone (Comp 2), and alizarin (Comp 3) were isolated from the dichloromethane fraction of the roots of Rubia philippinensis., whereas ethyl acetate fraction yielded xanthopurpurin (Comp 4) and lucidin-ω-methyl ether (Comp 5). Structures of all the isolated compounds were determined by spectral data analysis. All isolated compounds (Comp 1–5) were assessed for cytotoxicity by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay against four different cancer cell lines, i.e. human melanoma (SK-MEL-5), murine melanoma (B16F10), and human breast adenocarcinoma (MCF7 and MDA-MB-231).ResultsSignificant activity of the compounds 4 and 5 was observed against the breast cancer cell line MDA-MB-231 with IC50 values of 14.65 ± 1.45 and 13.03 ± 0.33 μM, respectively. Encouragingly, IC50 values of 67.89 ± 1.02 and 79.01 ± 0.03 μM against normal kidney epithelial cells (MDCK) were also obtained for compounds 4 and 5, respectively, which indicated very low toxicity and favorable selectivity indices for compounds 4 and 5 in the range of 1.85 to 3.95 and 2.11 to 6.06 against skin cancer cell lines (SK-MEL-5, and B16F10), and breast cancer cell lines (MCF7 and MDA-MB-231), respectively.ConclusionOur results suggested that the compounds 4 (xanthopurpurin) and 5 (lucidin-ω-methyl ether) showed high selective toxicity towards breast cancer cells at lower concentrations without showing toxicity towards normal cells, thus could be of potential as new lead molecules in cancer treatment.Electronic supplementary materialThe online version of this article (10.1186/s12906-018-2253-2) contains supplementary material, which is available to authorized users.

Hydrogen bonding is a vital feature of a large ensemble of chemical structures. Soluble epoxide hydrolase (sEH) has been targeted for development of the treatment for inflammation-associated diseases. Compounds 1 and 2 were purified from Rubia philippinensis, and their structures were established via physical data analysis. Compound 1 possesses intramolecular hydrogen bonding, sufficiently robust to transfer heteronuclear magnetization via a nonbonded interaction. The bonding strength was assessed using the 1 H NMR chemical shift temperature coefficients (−1.8 ppb/K), and the heteronuclear coupling constants were measured. The stereochemical details were investigated using interproton distance analysis and ECD. Purified compounds displayed moderate sEH-inhibitory activity.

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