stilbenes and Helicobacter-Infections

Helicobacter pylori (H. pylori) infection causes peptic ulcer disease, mucosa-associated lymphoid tissue (MALT) lymphomas and gastric adenocarcinomas, for which the pathogenesis of chronic gastric inflammation prevails and provides the pathogenic basis. Since the role of H. pylori infection is promoting carcinogenesis rather than acting as a direct carcinogen, as several publications show, eradication alone cannot be the right answer for preventing H. pylori-associated gastric cancer. Therefore, a non-antimicrobial approach has been suggested to attain microbe-associated cancer prevention through controlling H. pylori-related chronic inflammatory processes and mediators responsible for carcinogenesis. Phytoceutical is a term for plant products that are active on biological systems. Phytoceuticals such as Korean red ginseng, green tea, red wine, flavonoids, broccoli sprouts, garlic, probiotics and flavonoids are known to inhibit H. pylori colonization, decrease gastric inflammation by inhibiting cytokine and chemokine release, and repress precancerous changes by inhibiting nuclear factor-kappa B DNA binding, inducing profuse levels of apoptosis and inhibiting mutagenesis. Even though further unsolved issues are awaited before phytoceuticals are accepted as a standard treatment for H. pylori infection, phytoceuticals can be a mighty weapon for either suppressing or modulating the disease-associated footprints of H. pylori infection.

Topics: Flavonoids; Garlic; Gastric Mucosa; Helicobacter Infections; Helicobacter pylori; Humans; Panax; Phytotherapy; Plant Preparations; Resveratrol; Stilbenes; Tea

Naturally derived compounds represent a potential source of pharmacologically active drugs able to contrast different diseases, including gastric cancer, a multifactorial disease, in which the important role played by H. pylori infection has been demonstrated. Carexanes, stilbene derivatives, isolated from plants of the Carex distachya Desf., are unusual secondary metabolites with a tetracyclic skeleton arising from a cyclization of prenylstilbenoid precursors. In this study we firstly showed the ability of three purified carexanes CxB, CxG, and CxI to enhance the antioxidant response of AGS cells and to contrast the effect of the H. pylori's protein HspB. Among them CxI was the molecule that best modified the expression of genes involved in the antioxidant response. In particular, CxI was able to reduce Keap-1 gene expression and induce NQO1 gene expression, both at 4 and 24 h in AGS cells, as showed by real time PCR. Nrf2 induction was evident only at 24 h. Interestingly, the effect of CxI was stronger in HspB-transfected AGS cells, where Keap-1 gene expression was nearly abrogated. Finally, we demonstrated that CxI was able to reduce also COX-2 gene expression in HspB-transfected AGS cells, compared with untreated HspB-transfected cells, both at 4 and 24 h. This study first report that carexanes might represent candidate molecules able to contrast the deleterious effect of HspB protein but also to reduce the inflammatory process induced by H. pylori infection.

Topics: Antioxidants; Bacterial Proteins; Carex Plant; Cell Culture Techniques; Cell Line; Cell Proliferation; Cyclooxygenase 2; Epithelial Cells; Gastric Mucosa; Gene Expression; Heat-Shock Proteins; Helicobacter Infections; Helicobacter pylori; Humans; Kelch-Like ECH-Associated Protein 1; NF-E2-Related Factor 2; Plant Extracts; Stilbenes; Stomach Neoplasms; Transfection

Helicobacter pylori (H. pylori)-induced oxidative stress has been shown to play a very important role in the inflammation of the gastric mucosa and increases the risk of developing gastric cancer. Resveratrol has many biological functions and activities, including antioxidant and anti-inflammatory effect. The purpose of this study was to probe whether resveratrol inhibits H. pylori-induced gastric inflammation and to elucidate the underlying mechanisms of any effect in mice. A mouse model of H. pylori infection was established via oral inoculation with H. pylori. After one week, mice were administered resveratrol (100 mg/kg body weight/day) orally for six weeks. The mRNA and protein levels of iNOS and IL-8 were assessed using RT-PCR, Western blot and ELISA. The expression levels of IκBα and phosphorylated IκBα (which embodies the level and activation of NF-κB), Heme Oxygenase-1 (HO-1; a potent antioxidant enzyme) and nuclear factor-erythroid 2 related factor 2 (Nrf2) were determined using Western blot, and lipid peroxide (LPO) level and myeloperoxidase (MPO) activity were examined using an MPO colorimetric activity assay, thiobarbituric acid reaction, and histological-grade using HE staining of the gastric mucosa. The results showed that resveratrol improved the histological infiltration score and decreased LPO level and MPO activity in the gastric mucosa. Resveratrol down-regulated the H. pylori-induced mRNA transcription and protein expression levels of IL-8 and iNOS, suppressed H. pylori-induced phosphorylation of IκBα, and increased the levels of HO-1 and Nrf2. In conclusion, resveratrol treatment exerted significant effects against oxidative stress and inflammation in H. pylori-infected mucosa through the suppression of IL-8, iNOS, and NF-κB, and moreover through the activation of the Nrf2/HO-1 pathway.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Antioxidants; Disease Models, Animal; Gastric Mucosa; Gastritis; Helicobacter Infections; Helicobacter pylori; Heme Oxygenase-1; Interleukin-8; Lipid Peroxides; Male; Mice; NF-kappa B; Nitric Oxide Synthase Type II; Oxidative Stress; Peroxidase; Phosphorylation; Resveratrol; Stilbenes

The increasing therapeutic failures against Helicobacter pylori infection has determined the need to develop new drugs. The susceptibility to resveratrol (1) of twenty-six H. pylori strains representing nine CagA+ strains from patients with gastric carcinoma and eight CagA- and nine CagA+ strains from patients with chronic gastritis only was evaluated. Compound 1 was dissolved in DMSO and double diluted in Brucella broth with 10% BFS; ca. 10(6) organisms were added to each dilution. After incubation, subcultures were performed using Columbia-blood agar plates. The lowest concentration in broth at which all the organisms were killed was considered the minimum bactericidal concentration (MBC). Tests were performed in triplicate. The mean MBC of 1 for CagA positive GC strains was significantly lower than those for both CagA positive and CagA negative CG strains. An F1 ATPase of H. pylori showed a significant linear homology with a human ATPase considered a possible target of 1. It was hypothesized that strains infecting patients with gastric carcinoma have a reduced expression of F-type ATPases, which normally protect the bacteria from low pH levels by maintaining a proton gradient across membranes. Such behavior can be considered as an adaptive response to decreased gastric acidity. Since the targets of resveratrol (1) are also the bacterial ATPases, their putative reduced expression could increase the susceptibility to this compound, so that it saturates its targets more quickly and efficiently.

Topics: Adult; Anti-Bacterial Agents; Antigens, Bacterial; Bacterial Proteins; Female; Helicobacter Infections; Helicobacter pylori; Humans; Proton-Translocating ATPases; Resveratrol; Stilbenes; Stomach Neoplasms

Increasing resistance to currently used antimicrobials has resulted in the evaluation of other agents that have antimicrobial activity against Helicobacter pylori. H. pylori American Type Culture Collection (ATCC) strain 49503 (a toxin-producing strain known to be associated with gastric cancer) was grown, a cell suspension prepared in 2 mL PBS and diluted 10-fold. One hundred microL of this cell suspension was added to vitamin C 0.5%, vitamin E 0.5%, garcinol 100 microg/mL, Protykin (containing 50% trans-resveratrol) 100 microg/mL and garcinol + Protykin 100 microg/mL in Lennox broth, and incubated for 16 h under microaerophilic conditions. Three replicates of 10 microL from each 10(-7) dilution tube were plated, colonies were counted after 16 h, and growth of H. pylori was confirmed by the CLO test. These colony counts were compared to control cultures without the addition of any antioxidants. The experiments were then repeated with the addition of 15 microg/mL of clarithromycin to experimental and control samples. Enhanced killing of H. pylori by 37.6% was noted when vitamin C was added, which increased to 66% when clarithromycin was added, compared to controls (p < 0.05). With garcinol and Protykin alone there was 91.4 and 87% killing of H. pylori, respectively, while a combination of garcinol + Protykin resulted in 90.8% killing compared to controls (p < 0.05). When clarithromycin was added, there was 76.3% increased killing with garcinol alone, 55.3% with Protykin alone, and 73.7% with garcinol + Protykin compared to controls (containing clarithromycin) (p < 0.05). Vitamin E had no effect on H. pylori growth compared to controls. We conclude from this study that some antioxidants such as vitamin C, garcinol and Protykin, but not vitamin E, may have potential as antimicrobial agents against H. pylori.

Topics: Anti-Bacterial Agents; Anti-Infective Agents; Antioxidants; Ascorbic Acid; Clarithromycin; Helicobacter Infections; Helicobacter pylori; Microbial Sensitivity Tests; Stilbenes; Time Factors; Urease; Vitamin E