PTP1B inhibitory activity and molecular docking analysis of stilbene derivatives from the rhizomes of Rheum undulatum L.

Stilbene derivatives, the principal constituent of Rheum undulatum L., are known to have a wide range of biological activities, such as anti-allergic, anti-diabetic, antioxidant, and anti-inflammatory activities. A phytochemical study on the methanol extract of Korean rhubarb (R. undulatum L.) led to the isolation of nine stilbene derivatives (1-9) and one flavonoid (10). All structures were elucidated based on a comprehensive analysis of spectroscopic data. Compound 1 (5-methoxy-cis-rhapontigenin) was elucidated as a new compound, while compound 2 (5-methoxy-trans-rhapontigenin) was isolated from a natural source for the first time. Among the isolated compounds, stilbene derivatives (7-9) showed a strong inhibitory effect on protein tyrosine phosphatase 1B (PTP1B) with IC50 values ranging from 4.25 to 6.78 µM, which was significantly higher than that of the positive control, ursolic acid (IC50 = 11.34 µM). Furthermore, for the first time, kinetic analysis and molecular docking simulations were performed in order to understand the inhibition type as well as the interaction and binding mode of the active stilbenes (7-9) with PTP1B. Our results showed that the types of PTP1B inhibition were noncompetitive for ɛ-viniferin (8) and mixed for piceatannol (7) and δ-viniferin (9). Docking simulations of these stilbenes demonstrated negative binding energies and close proximity to residues in the binding pocket of PTP1B.

Desoxyrhapontigenin inhibits RANKL­induced osteoclast formation and prevents inflammation­mediated bone loss.

Desoxyrhapontigenin (DRG), a stilbene compound from Rheum undulatum, has been found to exhibit various pharmacological activities, however, its impact on osteoclast formation has not been investigated. The present study investigated the effect of DRG on receptor activator of nuclear factor­κB ligand (RANKL)­induced osteoclast differentiation in mouse bone marrow macrophages (BMMs) and inflammation­induced bone loss in vivo. BMMs or RAW264.7 cells were treated with DRG, followed by an evaluation of cell viability, RANKL­induced osteoclast differentiation, actin­ring formation and resorption pits activity. The effects of DRG on the RANKL­induced phosphorylation of MAPK and the expression of nuclear factor of activated T cells cytoplasmic 1 (NFATc1) and c­Fos were evaluated using western blot analysis once the BMMs were exposed to RANKL and DRG. The expression levels of osteoclast marker genes were also evaluated using western blot analysis and reverse transcription­quantitative polymerase chain reaction A lipopolysaccharide (LPS)­induced murine bone loss model was used to evaluate the protective effect of DRG on inflammation­induced bone­loss. The results demonstrated that DRG suppressed the RANKL­induced differentiation of BMMs into osteoclasts, osteoclast actin­ring formation and bone resorption activity in a dose­dependent manner. Furthermore, DRG significantly inhibited LPS­induced bone loss in a mouse model. At the molecular level, DRG inhibited the RANKL­induced activation of extracellular signal­regulated kinase, the expression of c­Fos, and the induction of NFATc1, a crucial transcription factor for osteoclast formation. DRG decreased the expression levels of osteoclast marker genes, including matrix metalloproteinase­9, tartrate­resistant acid phosphatase and cathepsin K. In conclusion, these findings suggested that DRG inhibited the differentiation of BMMs into mature osteoclasts by suppressing the RANKL­induced activator protein­1 and NFATc1 signaling pathways, and may be a potential candidate for treating and/or preventing osteoclast­associated diseases, including osteoporosis.

Cutaneous Metastatic Undifferentiated Pleomorphic Sarcoma from a Mediastinal Sarcoma.

Undifferentiated pleomorphic sarcoma, known as malignant fibrous histiocytoma, is a malignant neoplasm that arises in both soft tissue and bones. In 2002, the World Health Organization declassified malignant fibrous histocytoma as a formal diagnostic entity and renamed it 'undifferentiated pleomorphic sarcoma not otherwise specified.' It most commonly occurs in the lower extremities and rarely metastasizes cutaneously. We report a case of cutaneous metastatic undifferentiated pleomorphic sarcoma of the buttocks occurring in a 73-year-old man diagnosed with mediastinal sarcoma 4 years previously. He first noticed the mass approximately 2 months previously. Histological findings with immunomarkers led to a final diagnosis of cutaneous metastatic sarcoma from mediastinal undifferentiated pleomorphic sarcoma.

Induction of melanogenesis by rapamycin in human MNT-1 melanoma cells.

BACKGROUND: Melanogenesis is one of the characteristic parameters of differentiation in melanocytes and melanoma cells. Specific inhibitors of phosphatidylinositol 3-kinase (PI3K), such as wortmannin and LY294002, stimulate melanin production in mouse and in human melanoma cells, suggesting that PI3K and mammalian target of rapamycin (mTOR) might be involved in the regulation of melanogenesis. OBJECTIVE: The involvement of the mTOR pathway in regulating melanogenesis was examined using human MNT-1 melanoma cells, and the effects of the potent inhibitor of mTOR, rapamycin, in the presence or absence of α-melanocyte-stimulating hormone (α-MSH) were evaluated. METHODS: In cells treated with rapamycin, cell viability, melanin content, and tyrosinase (TYR) activity were measured and compared with untreated controls. Protein levels of TYR, tyrosinase-related protein (TYRP)-1, TYRP-2, and microphthalmia-associated transcription factor (MITF) were also analyzed by Western blot. RESULTS: In rapamycin-treated cells, the melanin content increased concomitantly with an elevation in TYR activity, which plays a major role in melanogenesis. There was also an up-regulation of TYR, TYRP-1, and MITF proteins. Combined treatment with rapamycin or wortmannin and α-MSH increased melanogenesis more strongly than α-MSH alone. CONCLUSION: Rapamycin-induced melanin formation may be mediated through the up-regulation of TYR protein and activity. Furthermore, rapamycin and wortmannin, inhibitors of mTOR and PI3K, respectively, have co-stimulatory effects with α-MSH in enhancing melanogenesis in melanocyte cells.