Rutin inhibits UVB radiation-induced expression of COX-2 and iNOS in hairless mouse skin: p38 MAP kinase and JNK as potential targets.

Exposure to ultraviolet B (UVB) radiation, a complete environmental carcinogen, induces oxidative and inflammatory skin damage, thereby increasing the risk of skin carcinogenesis. The antioxidant and anti-inflammatory activities of a wide variety of plant polyphenols have been reported. Rutin (3-rhamnosyl-glucosylquercetin), a polyphenol present in many edible plants, possesses diverse pharmacological properties including antioxidant, anti-inflammatory, antimutagenic and anticancer activities. The present study was aimed to investigate the effects of rutin on UVB-induced inflammation in mouse skin in vivo. Topical application of rutin onto the dorsal skin of female HR-1 hairless mice 30 min prior to UVB irradiation diminished epidermal hyperplasia and the levels of proteins modified by 4-hydroxynonenal, which is a biochemical hallmark of lipid peroxidation. Topical application of rutin also significantly inhibited UVB-induced expression of cyclooxygenase-2 (COX-2) and inducible nitric oxide synthase (iNOS), two representative inflammatory enzymes, in hairless mouse skin. Rutin inhibited the DNA binding of activator protein-1 (AP-1) and phosphorylation of signal transducer and activator of transcription-3 (STAT3) in mouse skin exposed to UVB. Moreover, rutin attenuated UVB-induced phosphorylation of p38 mitogen-activated protein (MAP) kinase and c-Jun-N-terminal kinase (JNK). Pharmacological inhibition of p38 MAP kinase and JNK decreased UVB-induced expression of COX-2 in mouse skin. Taken together, these findings suggest that rutin exerts anti-inflammatory effects in UVB-irradiated mouse skin by inhibiting expression of COX-2 and iNOS, which is attributable to its suppression of p38 MAP kinase and JNK signaling responsible for AP-1 activation.

Effect of chemical and structural feature of graphene on surface enhanced Raman scattering.

Graphene nanomaterial has been reported as a chemical mechanism based surface-enhanced Raman scattering (SERS) substrate which has advantages of accuracy in the peak assignment with less peak shift and broader choice in the laser sources. Here we present a systematic study to investigate the effect of graphene oxide (GO), reduced graphene oxide (RGO), two- and three-dimensional (2D and 3D) graphene structure as well as their nanocomposites with gold nanoparticle (Au NP) as a SERS substrate to detect Rhodamine 6G (R6G) molecules. Compared with a glass substrate, the Raman signals were enhanced by 1.6 x 10(2) and 1.0 x 10(2)-fold in the 2D GO and 2D RGO, respectively, while 3D GO structure shows 2.2 x 10(2)-fold increase in the intensity over the glass substrate. These results imply that the GO is a better SERS substrate than the corresponding RGO, and the 3D structure of GO improves the sensitivity more than the 2D GO sheets by 1.4-fold due to the local electromagnetic effect derived from the oxygen-containing functional groups and the 3D morphology of GO. The Au NP composite with the 2D GO and 3D GO shows the increased Raman signal over the 2D GO and 3D GO by 5-fold and 3.8-fold, respectively, suggesting the synergistic effect of the Au NP on the graphene in the SERS measurements. These results imply that the optimization of the structural feature and chemical modification of the graphene is necessary to maximize the capability of graphene as a SERS substrate to detect various chemical and biomoleculs with high sensitivity.

Diallyl trisulfide suppresses dextran sodium sulfate-induced mouse colitis: NF-κB and STAT3 as potential targets.

Diallyl trisulfide (DATS), one of the volatile constituents of garlic oil, has been reported to possess antioxidant, anti-inflammatory, and anti-carcinogenic properties. In this study, DATS (10µmol) given orally for 7days before and for another 7days after starting administration of 2.5% dextran sulfate sodium (DSS) in drinking water protected against colitis induced by DSS in male ICR mice. DATS significantly inhibited the DSS-induced DNA binding of NF-κB, phosphorylation of IκBα and the expression of pro-inflammatory proteins, such as cyclooxygenase-2 and inducible nitric oxide synthase, which are major target proteins of NF-κB. The DSS-induced DNA binding and phosphorylation at the Tyr 705 residue of signal transducer and activator of transcription 3 (STAT3), and expression of its major target protein cyclin D1 in mouse colonic mucosa were also attenuated by DATS administration. Likewise, DSS-induced phosphorylation of extracellular signal-regulated kinase 1/2 was suppressed by DATS treatment. In conclusion, DATS ameliorates the DSS-induced mouse colitis presumably by blocking inflammatory signaling mediated by NF-κB and STAT3.

Attenuation of cysteamine-induced duodenal ulcer with Cochinchina momordica seed extract through inhibiting cytoplasmic phospholipase A2/5-lipoxygenase and activating γ-glutamylcysteine synthetase.

BACKGROUND AND AIM: Cysteamine is a reducing aminothiol used for inducing duodenal ulcer through mechanisms of oxidative stress related to thiol-derived H(2)O(2) reaction. Cochinchina momordica saponins have been suggested to be protective against various gastric diseases based on their cytoprotective and anti-inflammatory mechanisms. This study was aimed to document the preventive effects of Cochinchina momordica seed extract against cysteamine-induced duodenal ulcer as well as the elucidation of its pharmacological mechanisms. METHODS: Cochinchina momordica seed extract (50, 100, 200 mg/kg) was administrated intragastrically before cysteamine administration, after which the incidence of the duodenal ulcer, ulcer size, serum gastrin level, and the ratio of reduced glutathione (GSH)/oxidized glutathione disulfide (GSSG) as well as biochemical and molecular measurements of cytoplasmic phospholipase A(2) (cPLA(2)), cyclooxygenase-2 (COX-2), 5-lipoxygenase and the expression of proinflammatory genes including IL-1ß, IL-6, COX-2 were measured in rat model. Additional experiments of electron spin resonance measurement and the changes of glutathione were performed. RESULTS: Cochinchina momordica seed extract effectively prevented cysteamine-induced duodenal ulcer in a dose-dependent manner as reflected with significant decreases in either duodenal ulcerogenesis or perforation accompanied with significantly decreased in serum gastrin in addition to inflammatory mediators including cPLA(2), COX-2, and 5-lipoxygenase. Cochinchina momordica seed extract induced the expression of γ-glutamylcysteine synthetase (γ-GCS)-related glutathione synthesis as well as significantly reduced the expression of cPLA(2). Cochinchina momordica seed extract preserved reduced glutathione through increased expressions of γ-GCS. CONCLUSION: Cochinchina momordica seed extracts exerted significantly protective effect against cysteamine-induced duodenal ulcer by either cPLA2 inhibition or glutathione preservation.

Inhibition of Hydrogen Sulfide-induced Angiogenesis and Inflammation in Vascular Endothelial Cells: Potential Mechanisms of Gastric Cancer Prevention by Korean Red Ginseng.

Previously, we reported that Helicobacter pylori-associated gastritis and gastric cancer are closely associated with increased levels of hydrogen sulfide (H2S) and that Korean red ginseng significantly reduced the severity of H. pylori-associated gastric diseases by attenuating H2S generation. Because the incubation of endothelial cells with H2S has been known to enhance their angiogenic activities, we hypothesized that the amelioration of H2S-induced gastric inflammation or angiogenesis in human umbilical vascular endothelial cells (HUVECs) might explain the preventive effect of Korean red ginseng on H. pylori-associated carcinogenesis. The expression of inflammatory mediators, angiogenic growth factors, and angiogenic activities in the absence or presence of Korean red ginseng extracts (KRGE) were evaluated in HUVECs stimulated with the H2S generator sodium hydrogen sulfide (NaHS). KRGE efficiently decreased the expression of cystathionine ß-synthase and cystathionine γ-lyase, enzymes that are essential for H2S synthesis. Concomitantly, a significant decrease in the expression of inflammatory mediators, including cyclooxygenase-2 and inducible nitric oxide synthase, and several angiogenic factors, including interleukin (IL)-8, hypoxia inducible factor-1a, vascular endothelial growth factor, IL-6, and matrix metalloproteinases, was observed; all of these factors are normally induced after NaHS. An in vitro angiogenesis assay demonstrated that NaHS significantly increased tube formation in endothelial cells, whereas KRGE pretreatment significantly attenuated tube formation. NaHS activated p38 and Akt, increasing the expression of angiogenic factors and the proliferation of HUVECs, whereas KRGE effectively abrogated this H2S-activated angiogenesis and the increase in inflammatory mediators in vascular endothelial cells. In conclusion, KRGE was able to mitigate H2S-induced angiogenesis, implying that antagonistic action against H2S-induced angiogenesis may be the mechanism underlying the gastric cancer preventive effects of KRGE in H. pylori infection.

Prevention of colitis-associated colorectal cancer with 8-hydroxydeoxyguanosine.

Colitis-associated cancer (CAC) is one of clear examples of inflammation-carcinogenesis sequence, by which the strict control of colitis with potent anti-inflammatory or antioxidative agent offers the chance of cancer prevention. Supported with the facts that Rac1 binds and activates STAT3, which are significantly upregulated in inflammatory bowel disease (IBD) as well as CAC, but 8-hydroxydeoxyguanosine (8-oxo-7,8-dihydrodeoxyguanosine or 8-OHdG) paradoxically can block Rac1 activation and subsequent NADPH oxidase (NOX) inactivation in various inflammation models, we hypothesized that attenuated Rac1-STAT3 and COX-NF-κB pathway by exogenous 8-OHdG administration may ameliorate inflammatory signaling in dextran sodium sulfate (DSS)-induced colitis and can prevent CAC. Before commencing carcinogenesis model, we checked whether exogenous 8-OHdG can alleviate IBD, for which interleukin (IL)-10 knockout mice were designed to ingest 5% DSS for 1 week, and 8-OHdG is given through intraperitoneal route daily. 8-OHdG treatment groups significantly reduced pathologic grade of DSS-induced colitis as well as various inflammatory mediators such as TNF-α, IL-6, COX-2, and iNOS in a dose-dependent manner. To document the cancer prevention effects of 8-OHdG, mice were injected azoxymethane followed by drinking 2.5% DSS for 1 week, after which 8-OHdG-containing diets were given for 20 weeks. As results, mice that consumed 8-OHdG-containing diet significantly reduced both tumor incidence and multiplicity. Rac1 activity and phosphorylated STAT3 level were significantly attenuated in the 8-OHdG-treated group. Significantly decreased levels of malondialdehyde, monocyte chemotactic protein-1, matrix metalloproteinasess, COX-2, NOX4, and ß-catenin nuclear accumulation were responsible for cancer prevention effects of exogenous 8-OHdG. In conclusion, we clearly showed cancer-preventive effect of exogenous 8-OHdG against CAC.

A novel approach for stress-induced gastritis based on paradoxical anti-oxidative and anti-inflammatory action of exogenous 8-hydroxydeoxyguanosine.

Reactive oxygen species (ROS) attack guanine bases in DNA and form 8-hydroxydeoxyguanosine (8-OHdG), which has been regarded simply as an oxidative mutagenic by-product. On the other hand, our previous report showed paradoxically ROS attenuating action of generated 8-OHdG. In the current study, both in vitro and in vivo experiments were executed in order to document anti-oxidative and anti-inflammatory actions of 8-OHdG in cell model and to elucidate the therapeutic efficacy against water immersion restraint stress (WIRS)-induced gastritis animal model. Electron spin resonance measurements showed that 8-OHdG at >5µg/ml completely scavenged OH(-) radicals, which was further confirmed by checking 2'-7'-dichlorodihydrofluorescein diacetate (DCFDA) spectroscopy. On molecular assay, 8-OHdG antagonized the action of GTP on Rac, a small GTP binding protein, without affecting Rac-guanosine exchange factor (GEF) or phosphoinositide 3-kinases (PI3K) activity. In Raw264.7 cells, 8-OHdG was found to be associated with marked attenuations of NOX1, NOXO1, and NOXA1 accompanied with the decreased expressions of LPS-induced inflammatory mediators including COX-2, iNOS, IL-1ß, and IL-6. Similarly, 8-OHdG attenuated hypoxia-induced angiogenesis and platelet endothelial cell adhesion molecule-1 (PECAM-1), COX-2, iNOS, IL-8, and VEGF expressions in HUVEC cells. At transcriptional level, 8-OHdG inhibited the nuclear translocation of NF-κB, inhibitory κB kinase (IKK) ß kinase activation, and decreased phospho-IκBα levels. 8-OHdG efficiently ameliorated WIRS-induced gastric mucosal injury as evidenced with improvement of gross lesion index and attenuation of engaging mediators. Taken together, exogenous 8-OHdG can be a functional molecule regulating oxidative stress-induced gastritis through either antagonizing Rac-GTP binding or blocking the signals responsible for gastric inflammatory cascade.

Fabrication of free-standing multilayered graphene and poly(3,4-ethylenedioxythiophene) composite films with enhanced conductive and mechanical properties.

Poly(3,4-ethylenedioxythiophene) (PEDOT)-based film has relatively high conductivity, flexibility, and transmittance. However, the improvement for mechanical strength and conductivity is still required to be adopted for commercial applications. Graphene, a one atom thick planar sheet of sp(2)-bonded carbon atoms, is considered as an ideal nanocomposite material for these purposes. In this study, we have developed PEDOT and graphene composite films, two-layered graphene/PEDOT and three-layered graphene/PEDOT/graphene, by using a spin-coating method. The conductivity of a 32 nm thick PEDOT film was improved more than twice by graphene deposition, while the high transmittance of the composite film was maintained over 90%. The mechanical strength of the PEDOT and graphene composite film shows 6-fold enhancement over the pristine PEDOT film. Because of the contribution of graphene layer for enhancing the mechanical strength, a 44 nm thick graphene/PEDOT/graphene could be obtained as a free-standing film by delaminating the graphene layer from the glass substrate under a weak base solution. These results imply that the graphene not only improves the conductivity and mechanical strength of PEDOT but also enables to produce a free-standing film which could find a variety of applications in the fields of organic electronic, sensors, and optoelectronics.

Progression from chronic atrophic gastritis to gastric cancer; tangle, toggle, tackle with Korea red ginseng.

Key molecular players that link inflammation to carcinogenesis are prostaglandins, cytokines, nuclear factor-kappaB (NF-kappaB), chemokines, angiogenic growth factors, and free radicals, all of which lead to increased mutations and altered functions of important enzymes and proteins, for example, activation of oncogenic products and/or inhibition of tumor suppressor proteins, in inflamed tissues, thus contributing to multi-stage carcinogenesis process. Interpreted reversely, the identification of the molecular mechanisms by which chronic inflammation increases cancer risk or optimal intervention of targeted drugs or agents during the inflammation-associated carcinogenic process could be a necessary basis for developing new strategy of cancer prevention at many sites. In this review, we discuss the possibilities for cancer prevention by controlling inflammation process in Helicobacter pylori (H. pylori)-associated inflamed stomach with Korea red ginseng. Korea red ginseng is a good example of a natural herb that has ubiquitous properties that are conductive to stop inflammatory carcinogenesis that is un wanted outcome of H. pylori infection, rendering rejuvenation of chronic atrophic gastritis.