Anti-Adipogenic Activity of Secondary Metabolites Isolated from Smilax sieboldii Miq. on 3T3-L1 Adipocytes.

Smilax sieboldii, a climbing tree belonging to Smilacaceae, has been used in traditional oriental medicine for treating arthritis, tumors, leprosy, psoriasis, and lumbago. To evaluate the anti-obesity effects of S. sieboldii (Smilacaceae), we screened methylene chloride (CH2Cl2), ethyl acetate (EtOAc), aqueous-saturated n-butanol, and ethanol (EtOH) extracts of the whole plant at various concentrations to inhibit adipogenesis in adipocytes. The 3T3-L1 cell line with Oil red O staining with the help of fluorometry was used as an indicator of anti-obesity activity. Bioactivity-guided fractionation of the EtOH extract and subsequent phytochemical investigation of the active CH2Cl2- and EtOAc-soluble fractions resulted in the isolation of 19 secondary metabolites (1-19), including a new α-hydroxy acid derivative (16) and two new lanostane-type triterpenoids (17 and 18). The structures of these compounds were characterized using various spectroscopic methods. All the isolated compounds were screened for adipogenesis inhibition at a concentration of 100 µM. Of these, compounds 1, 2, 4-9, 15, and 19 significantly reduced fat accumulation in 3T3-L1 adipocytes, especially compounds 4, 7, 9, and 19, showing 37.05 ± 0.95, 8.60 ± 0.41 15.82 ± 1.23, and 17.73 ± 1.28% lipid content, respectively, at a concentration of 100 µM. These findings provide experimental evidence that isolates from S. sieboldii extracts exert beneficial effects regarding the regulation of adipocyte differentiation.

pH-sensitive gallol-rich chitosan hydrogel beads for on-off controlled drug delivery.

Malignant tumors have emerged as a serious health issue, and the interest in developing pH-sensitive polymers for site-specific drug delivery has increased. The physical and/or chemical properties of pH-sensitive polymers depend on the pH, and thus, drugs can be released by cleaving dynamic covalent and/or noncovalent bonds. In this study, gallic acid (GA) was conjugated to chitosan (CS) to prepare self-crosslinked hydrogel beads containing Schiff base (imine bond) crosslinks. The CS-GA hydrogel beads were formed by the dropwise addition of the CS-GA conjugate solution into a Tris-HCl buffer solution (TBS, pH 8.5). The pH-sensitivity of pristine CS was significantly enhanced following the introduction of GA moiety, and as a result, the CS-GA hydrogel beads swelled more than approximately 5000 % at pH 4.0, indicating an excellent swelling/deswelling ability of the beads at different pH (pH 4.0 and 8.5). The reversible breakage/recovery of the imine crosslinks in the CS-GA hydrogel beads was confirmed through X-ray photoelectron spectroscopic and rheological studies. Finally, Rhodamine B was loaded onto the hydrogel beads as a model drug to investigate the pH-sensitive drug release behavior. At pH 4, the drug was released up to approximately 83 % within 12 h. The findings indicate that the CS-GA hydrogel beads have great potential as a drug delivery system that is sensitive to acidic tumor sites in the body.

Benzylideneacetone Derivatives Inhibit Osteoclastogenesis and Activate Osteoblastogenesis Independently Based on Specific Structure-Activity Relationship.

(E)-3,4-Dihydroxybenzylideneacetone (compound 1) inhibited receptor activator of NF-κB ligand-induced osteoclastogenesis of C57BL/6 bone marrow monocyte/macrophages with IC50 of 7.8 µM (IC50 of alendronate, 3.7 µM) while stimulating the differentiation of MC3T3-E1 osteoblastic cells, accompanied by the induction of Runt-related transcription factor 2, alkaline phosphatase, and osteocalcin. (E)-4-(3-Hydroxy-4-methoxyphenyl)-3-buten-2-one (compound 2c) showed a dramatically increased osteoclast-inhibitory potency with IC50 of 0.11 µM while sustaining osteoblast-stimulatory activity. (E)-4-(4-Hydroxy-3-methoxyphenyl)-3-buten-2-one (compound 2g) stimulated alkaline phosphatase production 2-fold at 50 µM without changing osteoclast-inhibitory activity, compared with compound 1. Oral administration of compounds 1, 2c, and 2g prevented ovariectomy-induced osteoporosis in ddY mice to a degree proportional to their osteoclastogenesis-inhibitory potencies. The administration of 1 (mg/kg)/d compound 2c ameliorated histomorphometry of osteoporotic bone to a degree comparable with 10 (mg/kg)/d alendronate. Conclusively, the in vitro capacity of a few benzylideneacetone derivatives to inhibit osteoclastogenesis supported by independent osteoblastogenesis activation was convincingly reflected in in vivo management of osteoporosis, suggesting a potential novel therapeutics for osteopenic diseases.

Glycopentanolones A-D, four new geranylated quinolone alkaloids from Glycosmis pentaphylla.

The ethanolic extract obtained from the stems of Glycosmis pentaphylla was found to suppress antigen-mediated degranulation of rat basophilic leukemia (RBL-2H3) cells. Four new geranylated 2-quinolone alkaloids, named glycopentanolones A-D (1-4), and 12 known metabolites (5-16) were isolated from the ethanolic extract from the stems of G. pentaphylla using bioassay-guided fractionation. Their structures were elucidated by a combination of 1D and 2D NMR, and HRESI-MS. The inhibitory effects of the isolated constituents on ß-hexosaminidase release from RBL-2H3 cells were examined, and compounds 1, 5, 8 and 11 exhibited potent inhibitory activity with IC50 values between 0.05 and 4.28 µM.

Inhibition of ß-site amyloid precursor protein cleaving enzyme 1 and cholinesterases by pterosins via a specific structure-activity relationship with a strong BBB permeability.

We extracted 15 pterosin derivatives from Pteridium aquilinum that inhibited ß-site amyloid precursor protein cleaving enzyme 1 (BACE1) and cholinesterases involved in the pathogenesis of Alzheimer's disease (AD). (2R)-Pterosin B inhibited BACE1, acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) with an IC50 of 29.6, 16.2 and 48.1 µM, respectively. The Ki values and binding energies (kcal/mol) between pterosins and BACE1, AChE, and BChE corresponded to the respective IC50 values. (2R)-Pterosin B was a noncompetitive inhibitor against human BACE1 and BChE as well as a mixed-type inhibitor against AChE, binding to the active sites of the corresponding enzymes. Molecular docking simulation of mixed-type and noncompetitive inhibitors for BACE1, AChE, and BChE indicated novel binding site-directed inhibition of the enzymes by pterosins and the structure-activity relationship. (2R)-Pterosin B exhibited a strong BBB permeability with an effective permeability (Pe) of 60.3×10-6 cm/s on PAMPA-BBB. (2R)-Pterosin B and (2R,3 R)-pteroside C significantly decreased the secretion of Aß peptides from neuroblastoma cells that overexpressed human ß-amyloid precursor protein at 500 µM. Conclusively, our study suggested that several pterosins are potential scaffolds for multitarget-directed ligands (MTDLs) for AD therapeutics.

Metaplastic Meningioma Overspreading the Cerebral Convexity.

Meningioma is relatively common, benign, and extra-axial tumor accounting for about 20% of primary brain and spinal cord tumors. The World Health Organization (WHO) classified these tumors into Grade I (benign), Grade II (atypical), and Grade III (anaplastic) meningioma. Grade I meningioma which is slowly growing tumor and have some rare subtypes. Among them, metaplastic subtype is defined as a tumor containing focal or widespread mesenchymal components including osseous, cartilaginous, lipomatous, myxoid or xanthomatous tissue, singly or in combinations. We report a rare metaplastic meningioma overspreading nearly whole cerebral convexity from main extra-axial tumor bulk in the parietal lobe.

Anti-melanogenic effects of resveratryl triglycolate, a novel hybrid compound derived by esterification of resveratrol with glycolic acid.

Resveratrol is known to inhibit cellular melanin synthesis by multiple mechanisms. Glycolic acid (GA) is used in skin care products for its excellent skin penetration. The purpose of this study was to examine the anti-melanogenic effects of resveratryl triglycolate (RTG), a novel hybrid compound of resveratrol and GA, in comparison with resveratrol, GA, resveratryl triacetate (RTA) and arbutin. Resveratrol, RTG, and RTA inhibited the catalytic activity human tyrosinase (TYR) more potently than arbutin or GA did. Their cytotoxic and anti-melanogenic effects were examined using murine melanoma B16/F10 cells and human epidermal melanocytes (HEMs). The cytotoxicity of RTG was similar to that of resveratrol and RTA. RTG at 3-10 µM decreased melanin levels and cellular TYR activities in α-melanocyte-stimulating hormone-stimulated B16/F10 cells, and L-tyrosine-stimulated HEMs. RTG also suppressed mRNA and protein expression of TYR, tyrosinase-related protein 1, L-3,4-dihydroxyphenylalanine chrome tautomerase, and microphthalmia-associated transcription factor (MITF) in HEMs stimulated with L-tyrosine. This study suggests that, like resveratrol and RTA, RTG can attenuate cellular melanin synthesis effectively through the suppression of MITF-dependent expression of melanogenic enzymes and the inhibition of catalytic activity of TYR enzyme. RTG therefore has potential for use as a cosmeceutical ingredient for skin whitening.

Polyhydroxylated macrolides from Seimatosporium discosioides and their effects on the activation of peroxisome proliferator-activated receptor gamma.

Two new polyhydroxylated macrolides, seimatopolides A (1) and B (2), were isolated from an EtOAc extract of Seimatosporium discosioides culture medium. The structures of the new compounds were established on the basis of spectroscopic analysis, including 1D and 2D NMR, and their absolute configurations were determined using the modified Mosher's method. Seimatopolides A (1) and B (2) activated peroxisome proliferator-activated receptor (PPAR)-γ with EC(50) values of 1.15 and 11.05 µM, respectively. The expression of PPAR-γ target genes in HepG2 hepatocytes was significantly altered; in particular, expression of the gluconeogenic genes glucose-6-phosphatase (G6Pase) and phosphoenolpyruvate carboxykinase (PEPCK) was reduced upon stimulation with 1, supporting the proposal that compound 1 is both a PPAR-γ agonist and a possible therapeutic candidate for treatment of diabetes.

Anti-inflammatory effects of ß-sitosterol-ß-D-glucoside from Trachelospermum jasminoides (Apocynaceae) in lipopolysaccharide-stimulated RAW 264.7 murine macrophages.

Trachelospermum jasminoides (Apocynaceae) has pharmacological effects that include anti-inflammatory, anti-bacterial and anti-viral activities, which have been observed from various studies. Of these pharmacological effects, the anti-inflammatory capacity of compounds from T. jasminoides is not yet known exactly. In this study, we investigated the compound that can be used for the suppression of lipopolysacchaide (LPS) stimulated inflammatory responses in macrophages among the five isolated compounds. ß-sitosterol-ß-D-glucoside (1) was found to reduce nitric oxide (NO) production from LPS-induced RAW 264.7 cells the most. In addition, compound 1 strongly inhibited the interleukin 6 (IL-6) activities of stimulated macrophages. Treatment of RAW 264.7 cells with compound 1 reduced secretion of inflammatory elements including tumour necrosis factor - alpha (TNF-α) and interleukin 1 beta (IL-1ß). Thus, compound 1 may be a useful candidate for the development of new drugs to treat endotoxemia and inflammation accompanied by the overproduction of NO.

Phenolic compounds from Pueraria lobata protect PC12 cells against Aß-induced toxicity.

Bioassay-guided fractionation of the EtOAc-soluble extract of Pueraria lobata based on the inhibition of Aß-induced toxicity in PC12 cells resulted in the isolation of four known active compounds, genistein (8), biochanin A (9), sissotrin (10), and puerol B (11). Of these, genistein (8) and biochanin A (9) exhibited potent neuroprotective effects with ED(50) values of 33.7 and 27.8 µM, respectively. In addition, a new coumestan, 2-(α,α-dimethylallyl)coumestrol (1) was isolated and characterized, but proved to be inactive, as were additional seven known compounds. The structure of new compound 1 was determined using spectroscopic techniques.

Neuroprotective effects of constituents of Eragrostis ferruginea against Aß-induced toxicity in PC12 cells.

A new flavonoid, 7-demethylageconyflavone A (1), and five known compounds, tricin (2), ageconyflavone A (3), corylin (4), nectandrin B (5), and 4-ketopinoresinol (6) were isolated from the aerial parts of Eragrostis ferruginea. Their structures were determined using spectroscopic techniques, including 1D- and 2D-NMR. All compounds were tested for the neuroprotective effects against amyloid beta peptide (Abeta) using PC12 cells, a major cause of the pathology of Alzheimer's disease. Tricin (2) was found to have a neuroprotective effect with an ED(50) value of 20.3 microM against Abeta-induced toxicity in PC12 cells. Ageconyflavone A (3), nectandrin B (5) and 4-ketopinoresinol (6) demonstrated moderate neuroprotective effects with ED(50) values of 58.7, 44.1, and 54.8 microM, respectively.