Citrulluside H and citrulluside T from young watermelon fruit attenuate ultraviolet B radiation-induced matrix metalloproteinase expression through the scavenging of generated reactive oxygen species in human dermal fibroblasts.

BACKGROUND: Prolonged exposure to UV radiation disrupts the oxidative stress defense systems; in the absence of adequate reactive oxygen species (ROS)-scavenging mechanisms, the ROS produced cause oxidative damage to DNA, proteins, carbohydrates, and lipids. Thus, ROS elimination can protect against photoaging and possibly skin cancer. We recently isolated two novel phenolic glycosides (citrulluside H and citrulluside T) with antioxidative activity from young watermelon (Citrullus lanatus) fruits. In the present study, we evaluated the protective effect of these compounds against UV-B-induced photodamage in normal human dermal fibroblasts (NHDFs). METHODS: NHDFs were exposed to UV-B irradiation at 25 mJ/cm2 . Matrix metalloproteinase (MMP)-1 and MMP-3 mRNA levels were measured by quantitative real-time PCR. MMP protein expression, as well as MAPK and NF-κB signaling, was investigated by Western blot analysis. Activation protein-1 (AP-1) transcriptional activity was determined using a luciferase reporter assay. Intracellular ROS levels were measured using the CellROX™ Deep Red Reagent. RESULTS: Citrulluside H and citrulluside T significantly downregulated the protein and mRNA expression of MMP-1 and MMP-3, which are associated with the onset of skin wrinkle formation. Importantly, inhibition of UV-B-induced MMP expression in NHDFs by citrulluside H and citrulluside T was primarily due to the attenuation of MAPK/AP-1 and NF-κB signaling via scavenging of the generated ROS. CONCLUSION: Our findings delineated both citrulluside H and citrulluside T as potential agents for alleviating UV-induced skin photoaging.

Comparative analysis of stilbene and benzofuran neolignan derivatives as acetylcholinesterase inhibitors with neuroprotective and anti-inflammatory activities.

Stilbenes and benzofuran neolignans are important groups of plant phenolics therefore they play a significant role in plants and human health. The objective of this study was to investigate the structure-activity relationships of naturally occurring stilbene and benzofuran neolignan derivatives as acetylcholinesterase inhibitors. A series of these compounds were prepared and assessed for their inhibition on acetylcholinesterase activity. δ-Viniferin, pterostilbene trans-dehydrodimer, pallidol, grossamide, and boehmenan exerted acetylcholinesterase inhibitory potential. The several oligomeric compounds protected against cell damage resulting from t-BHP exposure and inhibited lipopolysaccharide/interferon-gamma (LPS/IFNγ)-induced NO production in vitro. Our findings highlight the great potential of pterostilbene trans-dehydrodimer, pallidol, and boehmenan as multifunctional nutraceuticals for management of neurodegenerative diseases.

Sentulic acid isolated from Sandoricum koetjape Merr attenuates lipopolysaccharide and interferon gamma co-stimulated nitric oxide production in murine macrophage RAW264 cells.

A seco-triterpenoid, sentulic acid (SA) isolated from Sandoricum koetjape Merr attenuated nitric oxide (NO) production following co-stimulation with lipopolysaccharide (LPS) and interferon-gamma (IFNγ) in RAW264.7 macrophage cells. The mRNA expression levels of proinflammatory cytokines such as tumor necrosis factor-alpha (TNF-α), IFNγ, interleukin (IL)-6, and IL-12 in LPS/IFNγ co-stimulated RAW264.7 cells also decreased upon SA treatment. To determine the molecular mechanisms underlying the inhibitory effect of SA on LPS/IFNγ-induced NO production in RAW264.7 cells, we further analyzed Toll-like receptor (TLR) signaling by western blotting. The expression of TLR4 and IFN signaling molecules in cells treated with SA was significantly suppressed compared to that in cells not treated with SA. Additionally, SA inhibited the binding of LPS to the TLR4 receptor in RAW264.7 cells stimulated with Alexa Fluor 488-conjugated LPS. These results demonstrate that SA attenuates NO production after LPS/IFNγ co-stimulation in RAW264.7 cells by inhibiting the binding of LPS to TLR4. Our findings suggest that SA is beneficial for the treatment of inflammatory diseases.

Flexible n-type thermoelectric materials by organic intercalation of layered transition metal dichalcogenide TiS2.

Organic semiconductors are attracting increasing interest as flexible thermoelectric materials owing to material abundance, easy processing and low thermal conductivity. Although progress in p-type polymers and composites has been reported, their n-type counterpart has fallen behind owing to difficulties in n-type doping of organic semiconductors. Here, we present an approach to synthesize n-type flexible thermoelectric materials through a facile electrochemical intercalation method, fabricating a hybrid superlattice of alternating inorganic TiS2 monolayers and organic cations. Electrons were externally injected into the inorganic layers and then stabilized by organic cations, providing n-type carriers for current and energy transport. An electrical conductivity of 790 S cm(-1) and a power factor of 0.45 mW m(-1) K(-2) were obtained for a hybrid superlattice of TiS2/[(hexylammonium)x(H2O)y(DMSO)z], with an in-plane lattice thermal conductivity of 0.12 ± 0.03 W m(-1) K(-1), which is two orders of magnitude smaller than the thermal conductivities of the single-layer and bulk TiS2. High power factor and low thermal conductivity contributed to a thermoelectric figure of merit, ZT, of 0.28 at 373 K, which might find application in wearable electronics.

A synthesized nostocionone derivative potentiates programmed cell death in human T-cell leukemia Jurkat cells through mitochondria via the release of endonuclease G.

Nostocionone (Nost), a compound isolated from Nostoc commune, and its synthesized derivatives (NostDs) were evaluated for in vitro cytotoxicity against human T-cell leukemia Jurkat cells. NostD3 [(1E,4E)-1-(3,4-dihydroxyphenyl)-5-(2,6,6-trimethylcyclohex-1-enyl)penta-1,4-dien-3-one] inhibited cell growth more potently than Nost. To elucidate the mechanisms of NostD3-induced cell death, we examined changes in cell morphology, the loss of mitochondrial membrane potential (MMT), and DNA fragmentation. From these results, the cytotoxic effects of NostD3 were found to be mainly due to Type I programmed cell death (PCDI; i.e., apoptosis). Using caspase inhibitors, we further found that NostD-3-induced PCDI occurred through a caspase-independent pathway. Moreover, NostD3 decreased MMT and modulated multiple signaling molecules (MAPKs, Akt, Bcl-2, Bax, and c-Myc) in Jurkat cells, thereby inducing the release of endonuclease G (Endo-G) from mitochondria. The level of intracellular reactive oxygen species (ROS) in cells treated with NostD3 was elevated up to 1 h after the treatment. However, suppression of ROS by N-acetyl-l-cysteine restored Jurkat cell growth. Taken together, our data suggested that ROS production acted as a trigger in NostD3-induced PCDI in Jurkat cells through release of Endo-G from the mitochondria.

Regulation of the differentiation of osteoblasts and osteoclasts by a hot-water extract of adzuki beans (Vigna angularis).

Osteoporosis is a global public health problem thought to be caused by an imbalance in bone metabolism. We examined in this study the 40% ethanol fraction of HP-20 resin in combination with a hot-water adzuki extract (EtEx.40) for its effect on osteoblast and osteoclast differentiation. EtEx.40-treated murine preosteoblast MC3T3-E1 cells exhibited significantly elevated alkaline phosphatase activity and mineralization. EtEx.40 facilitated osteoblast differentiation by up-regulating such osteoblast differentiation-related molecules as runt-related transcription factor 2, distal-less homeobox 5, and osterix via p38 mitogen-activated protein kinase. EtEx.40 also suppressed the formation of large tartrate-resistant acid phosphatase-positive multinucleated cells in RAW264.7 cells that had been stimulated with the receptor activator of the nuclear factor κB ligand/macrophage colony-stimulating factor. EtEx.40 significantly inhibited NF-κB activation, thus reducing the expression of such downstream molecules as c-Fos and NFATc1. Our findings suggest that EtEx.40 could be used to maintain bone mass.

Antimicrobial and anti-inflammatory properties of nostocionone isolated from Nostoc commune Vauch and its derivatives against Propionibacterium acnes.

Propionibacterium acnes is the primary pathogenic agent responsible for acne vulgaris on the skin and hair follicles. Overgrowth of this bacterium inhibits growth and promotes follicular inflammation, with an associated increase in pro-inflammatory cytokine production. P. acnes has therefore been considered the main target for the prevention and medical treatment of acne vulgaris. The aim of this study was to evaluate the in vitro anti-P. acnes and anti-inflammatory properties of 6 compounds isolated from Nostoc commune. One of these compounds, nostocionone (Nost), and one of its derivatives, NostD3 [(1E,4E)-1-(3,4-dihydroxyphenyl)-5-(2,6,6-trimethylcyclohex-1-enyl)penta-1,4-dien-3-one], significantly inhibited P. acnes growth. Furthermore, we investigated the effects of Nost and NostD3 on heat-killed (hk) P. acnes-induced inflammation in macrophages. Both Nost and NostD3 suppressed hk P. acnes-induced nitric oxide (NO) production through the suppression of inducible NO synthase expression, following inactivation of nuclear factor kappa B. Taken together, our findings suggested that both Nost and NostD3 were promising agents for the treatment of acne vulgaris, and that NostD3 showed higher efficacy than Nost.

A kavalactone derivative inhibits lipopolysaccharide-stimulated iNOS induction and NO production through activation of Nrf2 signaling in BV2 microglial cells.

Neuroinflammation and oxidative stress are involved in the pathogenesis of neurodegenerative diseases such as Alzheimer's diseases and Parkinson's disease. Naturally derived kavalactones isolated from Piper methysticum (Piperaceae) have been shown to exhibit neuroprotective effects. We have previously reported that a chemically synthesized kavalactone derivative, 2',6'-dichloro-5-methoxymethyl-5,6-dehydrokawain (compound 1) protects against oxidative stress-induced neuronal cell death through activation of Nrf2 signaling. In the present study, we examined the effect of compound 1 on neuroinflammation. In BV2 microglial cells, compound 1 strongly inhibited LPS-stimulated iNOS induction and NO production, but did not affect LPS-stimulated induction of COX2. At 6h after LPS challenge, when iNOS induction was not clearly seen, treatment with LPS or compound 1 alone increased expression of heme oxygenase 1 (HO-1) whose transcription is regulated by Nrf2. When treated with both, compound 1 enhanced LPS-stimulated HO-1 induction, which was more evident at 24h after LPS treatment. Furthermore, LPS-stimulated activation of Nrf2 signaling and nuclear translocation of Nrf2 were potentiated by compound 1. The mechanism by which compound 1 activated Nrf2 signaling was supposed to be a covalent modification of the sulfhydryl groups of Keap1 by an α,ß-unsaturated carbonyl group present in the compound 1. Treatment with hemin, a HO-1 inducer, and with [Ru(CO)3Cl2]2, a CO donor, decreased LPS-stimulated iNOS induction and NO production. In contrast, siRNA-mediated knockdown of HO-1 expression reduced the inhibitory effect of compound 1 on LPS-stimulated iNOS induction and NO production. The compound 1 inhibited LPS-stimulated ERK phosphorylation after LPS treatment. Finally, compound 1 suppressed LPS/IFN-γ-stimulated NO production in primary microglial cells. These results suggest that compound 1 is capable of inhibiting LPS-stimulated iNOS induction and NO production via activation of Nrf2 signaling and HO-1 induction in microglial cells. Taken together, compound 1 has a potential to reduce neuroinflammation as well as oxidative stress in neurodegenerative diseases through activation of Nrf2 signaling.

Microvesicle-mediated RNA molecule delivery system using monocytes/macrophages.

Microvesicles (MVs) and exosomes, which are shed from cells as a cell-to-cell communication tool, are possible vehicles for navigating RNA molecules to body tissues. It is considered that intravenous injection of such MVs or exosomes from patients would not cause severe not-self and toxic reactions. Previously, we found that macrophages take up liposome-entrapped RNA molecules, some of which remain undegraded in the cells. Here, we demonstrate that transfected RNA molecules in human monocytic leukemia THP-1 cells were shed from THP-1 macrophages as contents in MVs during incubation in serum-free medium, which shedding was shown by biochemical analyses such as quantitative reverse transcription (qRT)-PCR, expression of TSG101 (a membrane-associated exosomal protein), and immunoelectron microscopic study. More chemically modified RNA molecules (miR-143BPs) entrapped by MVs (MV-miR-143BPs) were secreted from THP-1 macrophages after miR-143BP transfection compared with the amount after transfection with nonmodified miR-143 transfection. Furthermore, we show that the THP-1 macrophages, which were transfected with the miR-143BP ex vivo, secreted MV-miR-143BPs in xenografted nude mice after intravenous injection, because miR-143 levels were significantly increased in the serum, tumor, and kidney of the host animals. These data suggest that some of the transfected miR-143BPs were secreted from THP-1 macrophages as MV-RNAs both in vitro and in vivo.

Inhibitory effects of 6-alkoxycoumarin and 7-alkoxycoumarin derivatives on lipopolysaccharide/interferon γ-stimulated nitric oxide production in RAW264 cells.

Coumarin and its derivatives are well known for their anti-inflammatory and anti-oxidative effects. In this study, we synthesized 32 coumarin derivatives from commercially available 6-hydroxycoumarin (6HC) and 7-hydroxycoumarin (7HC) and examined their effects on lipopolysaccharide/interferon γ (LPS/IFNγ)-stimulated nitric oxide (NO) production in murine macrophage RAW264 cells. Among these derivatives, 6HC-8 (6-(3-phenylpropoxy)coumarin), 6HC-14 (6-(2-octynyloxy)coumarin), 7HC-14 (7-(2-octynyloxy)coumarin), and 7HC-16 (7-(3,5-dimethoxybenzyloxy)coumarin) markedly suppressed NO production at low concentration (25 µM). These synthesized coumarin derivatives also markedly inhibited inducible NO synthase (iNOS) protein and mRNA expression, as assessed by western blotting and quantitative real time-polymerase chain reaction (RT-PCR).

Hot water extract of adzuki (Vigna angularis) suppresses antigen-stimulated degranulation in rat basophilic leukemia RBL-2H3 cells and passive cutaneous anaphylaxis reaction in mice.

The hot water extract of adzuki (HWEA), which is produced as a byproduct in the adzuki bean boiling process, has anti-tumor, antioxidative, and anti-diabetic activities. In this study, we fractionated HWEA to 4 fractions using stepwise gradient column chromatography with water and ethanol, and demonstrated the effects of each fraction on antigen (Ag)-stimulated degranulation in rat basophilic leukemia RBL-2H3 cells. The 40% ethanol eluate extract (EtEx.40) showed the strongest inhibition level of these fractions. To reveal the inhibitory mechanisms underlying degranulation by EtEx.40, we investigated intracellular reactive oxygen species (ROS) production, intracellular free Ca²âº concentration ([Ca²âº]i), and early intracellular signaling pathways. Treatment with EtEx.40 markedly inactivated Lyn following Ag stimulation, resulting in the suppressions of intracellular elevation of [Ca²âº]i and production of ROS. To identify the active compound in EtEx.40, we isolated 7 flavonoids from EtEx.40 and calculated their inhibition levels on Ag-stimulated degranulation. These flavonoids inhibited degranulation by about 25-60%. We further examined the in vivo effects of HWEA or EtEx.40 using a passive cutaneous anaphylaxis (PCA) reaction. Both extracts strongly suppressed the PCA reaction. These findings suggest that HWEA and/or EtEx.40 are beneficial for alleviating type I allergic symptoms.

Structural and ultrastructural changes of full-cycle cultured Pacific bluefin tuna (Thunnus orientalis) muscle slices during chilled storage.

BACKGROUND: This study examined the structural and ultrastructural changes of dorsal and ventral muscle tissues of full-cycle cultured Pacific bluefin tuna (PBT), Thunnus orientalis Temminck & Schlegel 1844, cut into slices simulating sashimi and placed in chilled storage for varying periods. Structural and ultrastructural changes were determined in order to understand the physical texture by breaking strength measurement. RESULTS: Progressive deterioration of myofibril structure was observed during chilled storage (4 °C) of PBT muscle slices over 5 days post mortem. Muscle degradation included detachment between myofibres, detachment of the plasmalemma, disruption of mitochondria, loss of Z-line density and alignment, cementation of myofibrils, loss of the hexagonal arrangement of thick versus thin myofilaments and migration of subsarcolemmal nuclei to intermyofibrillar spaces. CONCLUSION: Loss of myofibre-myofibre adhesion, detachment of the plasmalemma and disruption of other components did not lower the breaking strength of PBT muscle. This provides evidence that the muscle breaking strength of PBT is not only associated with the detachment of myofibres or detachment of the plasmalemma. Other factors that produce cement-like substances, such as cementation of the myofibrillar components and degradation of the sarcoplasmic reticulum, may also increase breaking strength.

MicroRNA-208 modulates BMP-2-stimulated mouse preosteoblast differentiation by directly targeting V-ets erythroblastosis virus E26 oncogene homolog 1.

MicroRNAs (miRs) represent a class of endogenous approximately 18-25 nucleotide RNAs that regulate gene expression through translational repression by binding to a target mRNA. These miRs regulate several biological functions, such as cell growth, cell differentiation, carcinogenesis, and so on. In a previous report, we have indicated that miR-141 and -200a act as preosteoblast differentiation modulators. In the present study, using microRNA array and in silico analyses, we found that miR-208 is closely involved in preosteoblast differentiation by partially regulating the expression of Ets1 (V-ets erythroblastosis virus E26 oncogene homolog 1), which transactivates osteopontin, runt-related transcription factor 2, parathyroid hormone-related protein, and type I procollagen. Furthermore, the enforced expression of mature miR-208 in murine preosteoblast in MC3T3-E1 cells or primary osteoblast cells remarkably attenuated BMP-2-induced preosteoblast differentiation. In addition, we determined that Ets1 is a target gene of miR-208 by using a sensor luciferase reporter assay. Taken together, these results suggest that the down-regulation of miR-208 in BMP-2-stimulated osteoblast differentiation is an important part of the regulatory machinery involved in early osteogenesis.

Molecular hydrogen inhibits lipopolysaccharide/interferon γ-induced nitric oxide production through modulation of signal transduction in macrophages.

Molecular hydrogen has been reported to be effective for a variety of disorders and its effects have been ascribed to the reduction of oxidative stress. However, we have recently demonstrated that hydrogen inhibits type I allergy through modulating intracellular signal transduction. In the present study, we examined the hydrogen effects on lipopolysaccharide/interferon γ LPS/IFNγ-induced nitric oxide (NO) production in murine macrophage RAW264 cells. Treatment with hydrogen reduced LPS/IFNγ-induced NO release, which was associated with a diminished induction of inducible isoform of nitric oxide synthase (iNOS). Hydrogen treatment inhibited LPS/IFNγ-induced phosphorylation of apoptosis signal-regulating kinase 1 (ASK1) and its downstream signaling molecules, p38 MAP kinase and JNK, as well as IκBα, but did not affect activation of NADPH oxidase and production of reactive oxygen species (ROS). As ROS is an upstream activator of ASK1, inhibition of ASK1 by hydrogen without suppressing ROS implies that a potential target molecule of hydrogen should be located at the receptor or immediately downstream of it. These results suggested a role for molecular hydrogen as a signal modulator. Finally, oral intake of hydrogen-rich water alleviated anti-type II collagen antibody-induced arthritis in mice, a model for human rheumatoid arthritis. Taken together, our studies indicate that hydrogen inhibits LPS/IFNγ-induced NO production through modulation of signal transduction in macrophages and ameliorates inflammatory arthritis in mice, providing the molecular basis for hydrogen effects on inflammation and a functional interaction between two gaseous signaling molecules, NO and molecular hydrogen.

Involvement of heme oxygenase-1 induction via Nrf2/ARE activation in protection against H2O2-induced PC12 cell death by a metabolite of sesamin contained in sesame seeds.

Induction of phase II antioxidant enzymes by activation of Nrf2/ARE (antioxidant response element) signaling has been considered as a promising strategy to combat with oxidative stress-related diseases. In the present study, we tested for potential effects of sesamin, a major lignan contained in sesame seeds, its stereoisomer episesamin, and their metabolites on Nrf2/ARE activation in rat pheochromocytoma PC12 cells. Luciferase reporter assays showed that primary metabolites of sesamin and episesamin, SC-1 and EC-1 were the most potent ARE activators among all tested compounds. SC-1 {(1R,2S,5R,6S)-6-(3,4-dihydroxyphenyl)-2-(3,4-methylenedioxyphenyl)-3,7-dioxabicyclo-[3,3,0]octane} enhanced nuclear translocation of Nrf2 and up-regulated expression of phase II antioxidant enzymes including heme oxygenase-1 (HO-1). Treatment with SC-1 resulted in increased phosphorylation of p38 MAP kinase and transient increase in intracellular ROS levels. N-acetylcysteine (NAC) treatment abolished p38 phosphorylation as well as HO-1 induction caused by SC-1, indicating that ROS are upstream signals of p38 in Nrf2/ARE activation by SC-1. Furthermore, preconditioning with SC-1 attenuated H(2)O(2)-induced cell death in a dose-dependent manner. Finally, treatment with a HO-1 inhibitor, Zn-protoporphyrin (ZnPP), and overexpression of a dominant-negative mutant of Nrf2 diminished SC-1-mediated neuroprotection. Our results demonstrate that SC-1 is capable of protecting against oxidative stress-induced neuronal cell death in part through induction of HO-1 via Nrf2/ARE activation, suggesting its potential to reduce oxidative stress and ameliorate oxidative stress-related neurodegenerative diseases.

[5-FU/l-LV therapy is useful for hemodialysis patients with advanced gastric cancer].

A 71-year-old man receiving maintenance dialysis because of diabetic nephropathy presented with hematemesis at another hospital in January 2008. A gastrointestinal endoscopy demonstrated a II a-like lesion in the angle of the stomach, and he was admitted to our hospital. A diagnosis of gastric adenocarcinoma (cT2N2M0, Stage IIIA) was made. An operation could not be performed because of the high risk, so combination chemotherapy with 5-FU and l-LV was initiated. After 3 courses of treatment, the size of the primary tumor was markedly reduced. After 6 courses, the primary lesion had changed to a scar, and an endoscopic biopsy revealed no cancer cells. His performance status did not deteriorate, and no serious adverse events occurred during the course of treatment. Chemotherapy was continued because the overall response was SD. 5-FU/l-LV therapy should be considered as a safe and useful treatment for a hemodialysis patient with advanced gastric cancer.

Chalcone glycosides isolated from aerial parts of Brassica rapa L. 'hidabeni' suppress antigen-stimulated degranulation in rat basophilic leukemia RBL-2H3 cells.

We isolated three chalcone glycosides along with other glycoside constituents from the aerial parts of Brassica rapa L. 'hidabeni' and examined the effects of these compounds on the antigen-stimulated degranulation in rat basophilic leukemia RBL-2H3 cells. Treatments with both 4'-O-ß-D-glucopyranosyl-4-hydroxy-3'-methoxychalcone (C1) and 4'-O-ß-D-glucopyranosyl-3',4-dimethoxychalcone (C2) markedly inhibited antigen (Ag)-stimulated degranulation. To gain further insight into the inhibitory mechanisms by C1 and C2, we examined early intracellular signaling events, Ca(2+) mobilization and intracellular reactive oxygen species (ROS) production. Both C1 and C2 did not affect early intracellular signaling events but exhibited the suppression of intracellular ROS production through NADPH oxidase (NOX) inactivation. From these results, we proposed that the inhibitory effects of C1 and C2 on Ag-stimulated degranulation were mainly due to suppression of intracellular Ca(2+) elevation by suppression of intracellular ROS production through NOX inactivation. Our findings suggest that C1 and C2 would be beneficial to alleviate symptoms of type I allergy.

A novel kavalactone derivative protects against H2O2-induced PC12 cell death via Nrf2/ARE activation.

Oxidative stress is involved in the pathogenesis of neurodegenerative disorders such as Parkinson's and Alzheimer's diseases. Natural kavalactones isolated from Piper methysticum (Piperaceae) are capable of activating the Nrf2/ARE (antioxidant response element) pathway and thus enhancing the expression of phase II antioxidant enzymes such as heme oxygenase-1 (HO-1). In an attempt to identify kavalactone derivatives that are more potent in Nrf2/ARE activation than natural compounds, we synthesized a series of chemically-modified kavalactones and studied their effects on the ARE enhancer activity in rat pheochromocytoma PC12 cells. Among 81 compounds tested, a kavalactone derivative, 2',6'-dichloro-5-methoxymethyl-5,6-dehydrokawain [(E)-6-(2',6'-dichlorostyryl)-4-methoxy-5-(methoxymethyl)-2H-pyran-2-one] (1), exhibited the strongest ARE enhancer activity. The ARE activation and HO-1 protein induction by the compound 1 were higher than those by natural kavalactones. The compound did not affect cell viability and induced expression of various phase II enzymes. Nuclear translocation of Nrf2 after treatment with 1 was preceded by phosphorylation of ERK1/2 and p38. The compound transiently increased intracellular ROS levels. Finally, pretreatment with the compound ameliorated H(2)O(2)-induced cell death, which was associated with increased expression of HO-1. These results suggest that the compound 1 protects against oxidative stress-induced neuronal cell death via a preconditioning effect on the Nrf2/ARE activation.

Phenolic constituents isolated from Fragaria ananassa Duch. inhibit antigen-stimulated degranulation through direct inhibition of spleen tyrosine kinase activation.

We isolated eight phenolic constituents from Fragaria ananassa Duch. (strawberry) and determined their structures using 1D, 2D-NMR. Among the isolated compounds, linocinnamarin (LN), 1-O-trans-cinnamoyl-beta-d-glucopyranose (CG), and cinnamic acid (CA) exhibited antigen (Ag)-stimulated degranulation in rat basophilic leukemia RBL-2H3 cells. In order to reveal the underlying mechanisms, we examined the effects of LN and CA on cellular responses induced by antigen stimulation. Treatment with both LN and CA markedly inhibited antigen-stimulated elevation of intracellular free Ca(2+) concentration and reactive oxygen species (ROS). Both LN and CA suppressed Ag-stimulated spleen tyrosine kinase (Syk) activation. These results indicate that inhibition of antigen-stimulated degranulation by LN and CA is mainly due to inactivation of Syk/phospholipase Cgamma (PLCgamma) pathways. Our findings suggest that LN and CA isolated from F. ananassa Duch. (strawberry) could be beneficial agents for alleviating symptoms of type I allergy.

Identification of organoselenium compounds that possess chemopreventive properties in human prostate cancer LNCaP cells.

The process of cancer development consists of three sequential stages termed initiation, promotion, and progression. Oxidative stress damages DNA and introduces mutations into oncogenes or tumor suppressor genes, thus contributing to cancer development. Cancer chemoprevention is defined to prevent or delay the development of cancer by the use of natural or synthetic substances. In the present study, we synthesized a series of organoselenium compounds and evaluated their possible chemopreventive properties in human prostate cancer LNCaP cells. Among 42 organoselenium compounds tested, two compounds, 3-selena-1-dethiacephem 13 and 3-selena-1-dethiacephem 14 strongly activated the Nrf2/ARE (antioxidant response element) signaling and thus markedly increased expression of heme oxygenase-1 (HO-1), a phase II antioxidant enzyme. Translocation of Nrf2 to the nucleus preceded HO-1 protein induction by two compounds. The intracellular ROS level was strongly reduced immediately after treatment with these compounds, showing that they are potent antioxidants. Finally, both compounds inhibited cell growth via cell cycle arrest. Our findings suggest that compounds 13 and 14 could not only attenuate oxidative stress through Nrf2/ARE activation and direct ROS scavenging but also inhibit cell growth. Thus, these compounds possess the potential as pharmacological agents for chemoprevention of human prostate cancer.