Aiouea padiformis extract exhibits anti-inflammatory effects by inhibiting the ATPase activity of NLRP3.

Inflammation is implicated as a cause in many diseases. Most of the anti-inflammatory agents in use are synthetic and there is an unmet need for natural substance-derived anti-inflammatory agents with minimal side effects. Aiouea padiformis belongs to the Lauraceae family and is primarily found in tropical regions. While some members of the Aiouea genus are known to possess anti-inflammatory properties, the anti-inflammatory properties of Aiouea padiformis extract (AP) have not been investigated. In this study, we aimed to examine the anti-inflammatory function of AP through the NOD-, LRR- and pyrin domain-containing protein 3 (NLRP3) inflammasome and elucidate the underlying mechanisms. Treatment with AP inhibited the secretion of interleukin-1 beta (IL-1ß) mediated by NLRP3 inflammasome in J774A.1 and THP-1 cells without affecting the viability. In addition, AP treatment did not influence NF-κB signaling, potassium efflux, or intracellular reactive oxygen species (ROS) production-all of which are associated with NLRP3 inflammasome activation. However, intriguingly, AP treatment significantly reduced the ATPase activity of NLRP3, leading to the inhibition of ASC oligomerization and speck formation. Consistent with cellular experiments, the anti-inflammatory property of AP in vivo was also evaluated using an LPS-induced inflammation model in zebrafish, demonstrating that AP hinders NLRP3 inflammasome activation.

Enhanced neuronal activity by suffruticosol A extracted from Paeonia lactiflora via partly BDNF signaling in scopolamine-induced memory-impaired mice.

Neurodegenerative diseases are explained by progressive defects of cognitive function and memory. These defects of cognition and memory dysfunction can be induced by the loss of brain-derived neurotrophic factors (BDNF) signaling. Paeonia lactiflora is a traditionally used medicinal herb in Asian countries and some beneficial effects have been reported, including anti-oxidative, anti-inflammatory, anti-cancer activity, and potential neuroprotective effects recently. In this study, we found that suffruticosol A is a major compound in seeds of Paeonia lactiflora. When treated in a SH-SY5 cell line for measuring cell viability and cell survival, suffruticosol A increased cell viability (at 20 µM) and recovered scopolamine-induced neurodegenerative characteristics in the cells. To further confirm its neural amelioration effects in the animals, suffruticosol A (4 or 15 ng, twice a week) was administered into the third ventricle beside the brain of C57BL/6 mice for one month then the scopolamine was intraperitoneally injected into these mice to induce impairments of cognition and memory before conducting behavioral experiments. Central administration of suffruticosol A into the brain restored the memory and cognition behaviors in mice that received the scopolamine. Consistently, the central treatments of suffruticosol A showed rescued cholinergic deficits and BDNF signaling in the hippocampus of mice. Finally, we measured the long-term potentiation (LTP) in the hippocampal CA3-CA1 synapse to figure out the restoration of the synaptic mechanism of learning and memory. Bath application of suffruticosol A (40 µM) improved LTP impairment induced by scopolamine in hippocampal slices. In conclusion, the central administration of suffruticosol A ameliorated neuronal effects partly through elevated BDNF signaling.

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.

Galla rhois water extract inhibits enzymatic browning in apple juice partly by binding to and inactivating polyphenol oxidase.

Although Galla rhois has been used as a traditional medicine in Asian countries, there was no application of it in anti-browning food additives. Here, we tested whether Galla rhois inhibits apple juice browning. Apple juice browning was blocked at 250-1000 µg/ml of Galla rhois for 16 days but the effect of vitamin C did not last until a day. In vitro assays showed that the antioxidant capacity of Galla rhois was stronger than that of vitamin C. Further analysis by UPLC-MS/MS identified 17 phytochemicals containing gallotannin derivatives. Docking simulation and polyphenol oxidase activity assay indicate that the mechanisms underlying Galla rhois-mediated inhibition of the enzymatic browning include but are not limited to the combined effects of multiple compounds including galloylglucose- and gallate-derivates. Although marketability and long-term toxicity of Galla rhois should be tested, it may be applied as a food additive to elevate food quality.

The multi-functional roles of forkhead box protein O in skin aging and diseases.

Forkhead box, class O (FoxO) family members are multifunctional transcription factors that are involved in several metabolic processes, including energy metabolism, apoptosis, DNA repair, and oxidative stress. However, their roles in skin health have not been well-documented. Recent studies have indicated that FoxOs are important factors to control skin homeostasis and health. The activation or deactivation of some FoxO family members is closely related to melanogenesis, wound healing, acne, and melanoma. In this review, we have discussed the recent findings that demonstrate the relationship between FoxOs and skin health as well as the underlying mechanisms associated with their functions.

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.

Anti-Osteoporotic Effects of Kukoamine B Isolated from Lycii Radicis Cortex Extract on Osteoblast and Osteoclast Cells and Ovariectomized Osteoporosis Model Mice.

Osteoporosis is an abnormal bone remodeling condition characterized by decreased bone density, which leads to high risks of fracture. Previous study has demonstrated that Lycii Radicis Cortex (LRC) extract inhibits bone loss in ovariectomized (OVX) mice by enhancing osteoblast differentiation. A bioactive compound, kukoamine B (KB), was identified from fractionation of an LRC extract as a candidate component responsible for an anti-osteoporotic effect. This study investigated the anti-osteoporotic effects of KB using in vitro and in vivo osteoporosis models. KB treatment significantly increased the osteoblastic differentiation and mineralized nodule formation of osteoblastic MC3T3-E1 cells, while it significantly decreased the osteoclast differentiation of primary-cultured monocytes derived from mouse bone marrow. The effects of KB on osteoblastic and osteoclastic differentiations under more physiological conditions were also examined. In the co-culture of MC3T3-E1 cells and monocytes, KB promoted osteoblast differentiation but did not affect osteoclast differentiation. In vivo experiments revealed that KB significantly inhibited OVX-induced bone mineral density loss and restored the impaired bone structural properties in osteoporosis model mice. These results suggest that KB may be a potential therapeutic candidate for the treatment of osteoporosis.

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.

Antiadipogenic Effects of Loganic Acid in 3T3-L1 Preadipocytes and Ovariectomized Mice.

Obesity is caused by an excess storage of body fat, resulting from a chronic imbalance between energy intake and expenditure. Gentiana lutea L. (GL) root has been reported to reduce lipid accumulation in the aortic wall of diabetic rats. Here, we performed fractionation and isolation of the bioactive constituent(s) that may be responsible for the antiadipogenic effects of the GL root extract. A single compound, loganic acid, was identified as a candidate component in the 30% ethanol extract of GL. Loganic acid treatment significantly decreased the adipocyte differentiation of 3T3-L1 preadipocytes in a dose-dependent manner. The expression of key adipogenesis-related genes such as adiponectin (Adipoq), peroxisome proliferator-activated receptor gamma (Pparg), lipoprotein lipase (Lpl), perilipin1 (Plin1), fatty acid binding protein 4 (Fabp4), glucose transporter type 4 (Slc2a4), CCAAT/enhancer-binding protein alpha (Cebpa), and tumor necrosis factor-alpha (Tnf) were significantly reduced following treatment with loganic acid. In vivo experiments in an ovariectomy-induced obesity mouse model showed that loganic acid (oral administration with 10 and 50 mg/kg/day) significantly inhibited body weight gain, total fat increase, fatty hepatocyte deposition in the liver, and adipocyte enlargement in the abdominal visceral fat tissues. These results suggest that loganic acid in the GL root extract has antiadipogenic effects in vitro and in vivo. Loganic acid may be beneficial for the prevention and treatment of obesity, particularly in menopausal obese women.

Hochu-ekki-to Treatment Improves Reproductive and Immune Modulation in the Stress-Induced Rat Model of Polycystic Ovarian Syndrome.

The traditional herbal medicine, Hochu-ekki-to, has been shown to have preventive effects on viral infection and stress. This study aimed to evaluate the clinical effects of Hochu-ekki-to on two stress-related rat models of polycystic ovarian syndrome. Female Sprague-Dawley rats were divided into control and treatment groups, the latter of which were subjected to stress induced by exposure to adrenocorticotropic hormone (ACTH) or cold temperatures. After these stress inductions, rats were orally treated with dissolved Hochu-ekki-to once per day for 7 days. Rats subjected to the two different stressors exhibited upregulation of steroid hormone receptors (in ovaries) and reproductive hormones (in blood), and consequent stimulation of abnormal follicle development accompanied by elevation of Hsp 90 expression (in ovaries). Treatment with Hochu-ekki-to for 7 days after stress induction increased immune functions, reduced the stress-induced activation of Hsp 90, and normalized the levels of the tested steroid hormone receptors and reproductive hormones. Our findings suggest that stress stimulations may promote the activation of Hsp 90 via the dysregulation of steroid hormone receptors and reproductive hormones, but that post-stress treatment with Hochu-ekki-to improves reproductive and immune functions in the ovaries of stressed rats.

A New Neolignan from Coix lachryma-jobi var. mayuen.

A new neolignan, named coixide A (1), along with fifteen known compounds, (7R,8S)-3'-demethyl-dehydrodiconiferyl alcohol-3'-O-ß-glucopyranoside (2), (7R,8)-3'-demethyl-9'-butoxy-dehydrodiconiferyl-3'-O-ß-glucopyranoside (3),adenosine (4), 2-O-caffeoyl isocitricacid (5), pseudolaroside A (6), 2-hydroxy-7-methoxy-(2H)-1,4-benzoxazin-3(4H)-one (7), 2-O-ß-glucopyranosyl-7-methoxy-2H-1,4-benzoxazin-3(4H)-one (8), 2-O-ß-glucopyranosyl-4-hydroxy-7- methoxy-2H-1,4-benzoxazin-3(4H)-one (9), 2-O-ß-D-glucopyranosyl-7-hydroxy-2H-1,4-benzoxazin-3(4H)-one (10), p-coumaric acid ethyl ester (11), caffeic acid ethyl ester (12), p-coumaric acid (13), cis-N-p-coumaroyltyramine (14) trans-N-p-coumaroyltyramine (15), and coixol (16) have been isolated from Coix lachryma-jobi var. mayuen. Their chemical structures were elucidated by chemical evidence on the basis of spectroscopic and MS data, and as well as by comparison with those reported.

Oleanane-type triterpenoid saponins from the roots of Pulsatilla koreana and their apoptosis-inducing effects on HL-60 human promyelocytic leukemia cells.

Twenty-four oleanane-type triterpenoid saponins were isolated from a methanol extract of the Pulsatilla koreana roots. Their structures were elucidated by comparing spectroscopic data to published values. Among them, compounds 8-12 and 20-24 significantly diminished the proliferation of HL-60 human promyelocytic leukemia cells with IC50 values from 0.3 to 4.2 µM, whereas compounds 7 and 19 showed moderate cytotoxic activity. Furthermore, apoptotic characteristics such as chromatin condensation and increase in the population of sub-G1 hypodiploid cells were observed after the HL-60 cells were treated with these compounds.

Triterpenoid saponins of Pulsatilla koreana root have inhibition effects of tumor necrosis factor-α secretion in lipopolysaccharide-induced RAW264.7 cells.

In the present study, a new oleanane-type triterpenoid saponin, pulsatilloside F (1), along with 21 known compounds (2-22), were isolated from the root of Pulsatilla koreana. Their chemical structures were elucidated by mass, (1)H-, (13)C-NMR, correlation spectroscopy (COSY), heteronuclear multiple quantum coherence (HMQC) and heteronuclear multiple bond connectivity (HMBC) spectroscopy. Anti-inflammatory effects of the compounds were evaluated in terms of inhibitory of tumor necrosis factor α (TNF-α) secretion in the lipopolysaccharide (LPS)-stimulated murine RAW264.7 macrophage cell line. Compounds 19 and 20 exhibited particularly inhibitory effects with respective IC50 values of 0.32 and 0.65 µm. Compounds 1-4, 7 and 10-13 exhibited inhibitory effects with inhibition rates up to 41.55-73.76% at a concentration of 5 µm, respectively.

Diarylheptanoid glycosides from Tacca plantaginea and their effects on NF-κB activation and PPAR transcriptional activity.

In the screening search for NF-κB inhibitory and PPAR transactivational agents from medicinal plants, a methanol extract of the whole plant of Tacca plantaginea and its aqueous fraction showed the significant activities. Bioassay-guided fractionation combined with repeated chromatographic separation of the aqueous fraction of the methanol extract of T. plantaginea resulted in the isolation of two new diarylheptanoid glycosides, plantagineosides A (1) and B (2), an unusual new cyclic diarylheptanoid glycoside, plantagineoside C (3), and three known compounds (4-6). Their structures were determined by extensive spectroscopic and chemical methods. Compounds 3-6 significantly inhibited TNFα-induced NF-κB transcriptional activity in HepG2 cells in a dose-dependent manner, with IC(50) values ranging from 0.9 to 9.4 µM. Compounds 1-6 significantly activated the transcriptional activity of PPARs in a dose-dependent manner, with EC(50) values ranging from 0.30 to 10.4 µM. In addition, the transactivational effects of compounds 1-6 were evaluated on three individual PPAR subtypes, including PPARα, γ, and ß(δ). Compounds 1-6 significantly enhanced the transcriptional activity of PPARß(δ), with EC(50) values in a range of 11.0-30.1 µM. These data provide the rationale for using T. plantaginea and its components for the prevention and treatment of inflammatory and metabolic diseases.

New guaiane sesquiterpene lactones from Ixeris dentata.

Three new guaiane-type sesquiterpene lactones (1-3), together with nine related sesquiterpenes (4-12), were isolated from the whole extract of Ixeris dentata (Asteraceae). The chemical structures of isolates 1-12 were established by spectroscopic analyses as 3 ß,8 ß-dihydroxy-guaia-10(14)-en-1 α,4 α,5 α,6 ß,7 α,11 ßH-12,6 α-olide (1), ixerin N 6'- O-acetate (2), ixerisoside A 6'- O-acetate (3), ixerin N ( 4), ixerisoside A (5), ixerin M (6), tectroside (7), 8-epidesacylcynaropicrin glucoside (8), 8-epiisolipidiol (9), 11 ßH-11,13-dihydrointegrifolin (10) 8 ß-hydroxy-4 ß,15-dihydrozaluzanin C (11), and integrifolin (12). Compounds 1-12 were evaluated for their inhibitory effect on the proliferation of the cultured human tumor cell lines MES-SA, MES-SA/DX5, HCT-15, and HCT15/CL02 in vitro.

Galbanic acid, a cytotoxic sesquiterpene from the gum resin of Ferula asafoetida, blocks protein farnesyltransferase.

Farnesylation of the activated RAS oncogene product by protein farnesyltransferase (FTase) is a critical step for its oncogenic function. Bioassay-guided purification of Ferula asafoetida (Umbelliferae) extract led to the isolation of the coumarin-derived sesquiterpene galbanic acid (1) as an active principal for FTase inhibitory activity, together with the four structurally related sesquiterpenes karatavicinol (2), umbelliprenin (3), farnesiferol B (4), and farnesiferol C (5). The 50 % inhibitory concentration (IC (50)) of 1 against FTase in an enzyme-based assay was calculated as 2.5 µM. Compound 1 also demonstrated potent inhibition of the proliferation of oncogenic RAS-transformed NIH3T3/Hras-F in a dose-dependent manner. The IC (50) value of 1 on the proliferation of oncogenic RAS-transformed NIH3T3/Hras-F cells was calculated as 16.2 µM, whereas its IC (50) value on control vector-transfected normal RAS-containing NIH3T3/ZIPneo cells was 58.5 µM.

Antiproliferative effects of saponins from the roots of Platycodon grandiflorum on cultured human tumor cells.

Three new triterpenoid saponins, platyconic acid B lactone (1), deapio-platyconic acid B lactone (2), and deapio-platycodin D(2) (3), together with 17 known triterpenoid saponins, were isolated from a root extract of Platycodon grandiflorum. The structures of 1-3 were determined on the basis of spectroscopic data interpretation and chemical transformation. Saponins with a platycodigenin or polygalacic acid unit as a sapogenin demonstrated significant inhibitory effects on the proliferation of a small panel of cultured human tumor cells.