Curcumin suppresses gastric NF-��B activation and macromolecular leakage in Helicobacter pylori-infected rats

AIM:To investigate whether curcumin could attenuate nuclear factor(NF)-κB p65 expression and macromolecular leakage in the gastric mucosa of Helicobacter pylori(H.pylori)-infected rats.METHODS:Twenty-five male Sprague-Dawley rats were equally divided into five groups:control rats(Control),control rats supplemented with 600 mg/kg curcumin,H.pylori-infected rats(Hp),H.pylori-infected rats supplemented with 200 mg/kg curcumin(Hp + curIn H.pylori-infected groups,rats were inoculated with H.pylori suspension twi...     

Helicobacter pylori tumor necrosis factor-α inducing protein promotes cytokine expression via nuclear factor-κB

AIM:To study the effects of Helicobacter pylori(H. pylori)tumor necrosis factor-α(TNF)inducing protein (Tip-α)on cytokine expression and its mechanism. METHODS:We cloned Tip-αfrom the H.pylori strain 26695,transformed Escherichia coli with an expression plasmid,and then confirmed the expression product by Western blotting.Using different concentrations of Tip-αthat affected SGC7901 and GES-1 cells at different times,we assessed cytokine levels using enzyme-linked immunosorbent assay.We blocked SGC7901 cells with pyrrolidine dithiocarbamate(PDTC),a specific inhibitor of nuclear factorκB(NF-κB).We then detected interleukin(IL)-1βand TNF-αlevels in SGC7901 cells. RESULTS:Western blot analysis using an anti-Tip-α antibody revealed a 23-kDa protein,which indicated that recombinant Tip-αprotein was recombined successfully.The levels of IL-1β,IL-8 and TNF-αwere sig-nificantly higher following Tip-αinterference,whether GES-1 cells or SGC-7901 cells were used(P<0.05).However,the levels of cytokines(including IL-1β,IL-8 and TNF-α)secreted by SGC-7901 cells were greater than those secreted by GES-1 cells following treatment with Tip-αat the same concentration and for the same duration(P<0.05).After blocking NF-κB with PDTC, the cells(GES-1 cells and SGC-7901 cells)underwent interference with Tip-α.We found that IL-1βand TNF-αlevels were significantly decreased compared to cells that only underwent Tip-αinterference(P<0.05). CONCLUSION:Tip-αplays an important role in cyto-kine expression through NF-κB.     

Medicinal plant activity on Helicobacter pylori related diseases

More than 50%of the world population is infected with Helicobacter pylori(H.pylori).The bacterium highly links to peptic ulcer diseases and duodenal ulcer,which was classified as a groupⅠcarcinogen in 1994 by the WHO.The pathogenesis of H.pylori is contributed by its virulence factors including urease,flagella,vacuolating cytotoxin A(VacA),cytotoxin-associated gene antigen(Cag A),and others.Of those virulence factors,VacA and CagA play the key roles.Infection with H.pylori vacA-positive strains can lead to vacuolation and apoptosis,whereas infection with cagA-positive strains might result in severe gastric inflammation and gastric cancer.Numerous medicinal plants have been reported for their anti-H.pylori activity,and the relevant active compounds including polyphenols,flavonoids,quinones,coumarins,terpenoids,and alkaloids have been studied.The anti-H.pylori action mechanisms,including inhibition of enzymatic(urease,DNA gyrase,dihydrofolate reductase,N-acetyltransferase,and myeloperoxidase)and adhesive activities,high redox potential,and hydrophilic/hydrophobic natures of compounds,have also been discussed in detail.H.pylori-induced gastric inflammation may progress to superficial gastritis,atrophic gastritis,and finally gastric cancer.Many natural products have anti-H.pylori-induced inflammation activity and the relevant mechanisms include suppression of nuclear factor-κB and mitogen-activated protein kinase pathway activation and inhibition of oxidative stress.Anti-H.pylori induced gastric inflammatory effects of plant products,including quercetin,apigenin,carotenoids-rich algae,tea product,garlic extract,apple peel polyphenol,and finger-root extract,have been documented.In conclusion,many medicinal plant products possess anti-H.pylori activity as well as an anti-H.pylori-induced gastric inflammatory effect.Those plant products have showed great potential as pharmaceutical candidates for H.pylori eradication and H.pylori induced related gastric disease prevention.     

Helicobacter pylori-induced inflammation and epigenetic changes during gastric carcinogenesis

The sequence of events associated with the development of gastric cancer has been described as “the gastric precancerous cascade”. This cascade is a dynamic process that includes lesions, such as atrophic gastritis, intestinal metaplasia and dysplasia. According to this model, Helicobacter pylori (H. pylori) infection targets the normal gastric mucosa causing non-atrophic gastritis, an initiating lesion that can be cured by clearing H. pylori with antibiotics or that may then linger in the case of chronic infection and progress to atrophic gastritis. The presence of virulence factors in the infecting H. pylori drives the carcinogenesis process. Independent epidemiological and animal studies have confirmed the sequential progression of these precancerous lesions. Particularly long-term follow-up studies estimated a risk of 0.1% for atrophic gastritis/intestinal metaplasia and 6% in case of dysplasia for the long-term development of gastric cancer. With this in mind, a better understanding of the genetic and epigenetic changes associated with progression of the cascade is critical in determining the risk of gastric cancer associated with H. pylori infection. In this review, we will summarize some of the most relevant mechanisms and focus predominantly but not exclusively on the discussion of gene promoter methylation and miRNAs in this context.     

Helicobacter pylori and gastric mucosa-associated lymphoid tissue lymphoma:Recent progress in pathogenesis and management

Recent progress in the research regarding the molecular pathogenesis and management of gastric mucosaassociated lymphoid tissue(MALT)lymphoma is reviewed.In approximately 90%of cases,Helicobacter pylori(H.pylori)infection plays the causative role in the pathogenesis,and H.pylori eradication is nowadays the first-line treatment for this disease,which leads to complete disease remission in 50%-90%of cases.In H.pylori-dependent cases,microbe-generated immune responses,including interaction between B and T cells involving CD40 and CD40L co-stimulatory molecules,are considered to induce the development of MALT lymphoma.In H.pylori-independent cases,activation of the nuclear factor-κB pathway by oncogenic products of specific chromosomal translocations such as t(11;18)/API2-MALT1,or inactivation of tumor necrosis factor alpha-induced protein 3(A20)are considered to contribute to the lymphomagenesis.Recently,a largescale Japanese multicenter study confirmed that the long-term clinical outcome of gastric MALT lymphoma after H.pylori eradication is excellent.Treatment modalities for patients not responding to H.pylori eradication include a"watch and wait"strategy,radiotherapy,chemotherapy,rituximab immunotherapy,and a combination of these.Because of the indolent behavior of MALT lymphoma,second-line treatment should be tailored in consideration of the clinical stage and extent of the disease in each patient.     

Lactobacillus plantarum B7 inhibits Helicobacter pylori growth and attenuates gastric inflammation

AIM:To determine the anti-Helicobacter property of Lactobacillus plantarum B7(L.plantarum)B7 supernatants in vitro and the protective effects of L.plantarum B7 on serum tumor necrosis factor-alpha(TNF-?),gastric malondialdehyde(MDA)level,apoptosis,and histopathology in Helicobacter pylori(H.pylori)-induced gastric inflammation in rats. METHODS:In vitro,the inhibition of H.pylori growth was examined using L.plantarum B7 supernatants at pH 4 and pH 7 and at the concentration of 1×,5×and 10×on plates inoculated with H.pylori.The inhibitory effect of H.pylori was interpreted by the size of the inhibition zone.In vitro,male Sprague-Dawley rats were randomly divided into four groups including group 1(control group),group 2(H.pylori infected group), group 3(H.pylori infected with L.plantarum B7 106 CFUs/mL treated group)and group 4(H.pylori infected with L.plantarum B7 1010 CFUs/mL treated group).One week after H.pylori inoculation,L.plantarum B7 106 CFUs/mL or 10 10 CFUs/mL were fed once daily to group 3 and group 4,respectively,for one week.Blood and gastric samples were collected at the end of the study. RESULTS:In vitro,at intact pH 4,mean inhibitory zone diameters of 8.5 mm and 13 mm were noted at concentrations of 5×and 10×of L.plantarum B7 supernatant disks,respectively.At adjusted pH 7, L.plantarum B7 supernatants at concentrations of 5 ×and 10×yielded mean inhibitory zone diameters of 6.5 mm and 11 mm,respectively.In the in vitro study, in group 2,stomach histopathology revealed mild to moderate H.pylori colonization and inflammation.The level of gastric MDA and epithelial cell apoptosis were significantly increased compared with group 1.The serum TNF-??level was significant decreased in group 3 compared with group 2(P0.05).In addition,L.plantarum B7 treatments resulted in a significant improvement in stomach pathology,and decreased gastric MDA level and apoptotic epithelial cells. CONCLUSION:L.plantarum B7 supernatant inhibits H.pylori growth.This inhibition was dose-dependent and greater at pH 4.Moreover,L.plantarum B7 attenuated H.pylori-induced gastric inflammation.     

Curcumin as a potential therapeutic candidate for Helicobacter pylori associated diseases

Curcumin, a yellow pigment and principal polyphenolic Curcuminoid obtained from the turmeric rhizome Curcuma longa, is commonly used as a food-coloring agent. Studies suggest that curcumin has a wide range of beneficial properties e.g., anti-inflammatory, anti-oxidant, anti-cancer, anti-proliferative, anti-fungal and anti-microbial. These pleiotropic activities prompted several research groups to elucidate the role of curcumin in Helicobacter pylori (H. pylori) infection. This is the first review with this heading where we discussed regarding the role of curcumin as an anti-H. pylori agent along with its potential in other gastrointestinal diseases. Based on several in vitro, early cell culture, animal research and few pre-clinical trials, curcumin projected as a potential therapeutic candidate against H. pylori mediated gastric pathogenesis. This review sheds light on the anti-H. pylori effects of curcumin in different models with meticulous emphasis on its anti-oxidant, anti-inflammatory and anti-carcinogenic effects as well as some critical signaling and effecter molecules. Remarkably, non-toxic molecule curcumin fulfills the characteristics for an ideal chemopreventive agent against H. pylori mediated gastric carcinogenesis but the foremost challenge is to obtain the optimum therapeutic levels of curcumin, due to its low solubility and poor bioavailability. Further, we have discussed about the possibilities for improving its efficacy and bioavailability. Lastly, we concluded with the anticipation that in near future curcumin may be used to develop a therapeutic drug against H. pylori mediated gastric ailments through improved formulation or delivery systems, facilitating its enhanced absorption and cellular uptake.     

Treatment for Eradication of Helicobacter pylori Infection among Chronic Hepatitis C Patients

Background/Aims

Helicobacter pylori infection causes gastritis, peptic ulcers and gastric malignancies, and its eradication has been advocated by many groups. We determined the H. pylori carrier status and eradication rates of patients with chronic hepatitis C virus (HCV) infection.

Methods

In total, 76 chronically HCV-infected patients were enrolled for comparison with 228 HCV-noninfected, age- and sex-matched controls. H. pylori infection was confirmed by H. pylori antibody and urea breath testing.

Results

The H. pylori infection rate was significantly higher for HCV-infected patients (67 of 76, 88.2%) than for HCV-noninfected controls (158 of 228, 69.3%). Endoscopic findings showed that the rates of gastric ulcers and gastritis were significantly higher for the 67 HCV-infected patients with H. pylori infection (34.3% and 77.6%) than for the 158 HCV-noninfected controls with H. pylori infection (15.2% and 57.6%). Treatment to eradicate H. pylori had a significantly higher success rate for HCV-infected patients (61 of 67, 91.0%) than for HCV-noninfected controls (115 of 158, 72.8%).

Conclusions

The markedly high H. pylori eradication rate observed in this study shows that eradication of H. pylori holds promise for the improvement of the long-term health condition of patients with chronic HCV infection.     

Propofol induces apoptosis and increases gemcitabine sensitivity in pancreatic cancer cells in vitro by inhibition of nuclear factor-κ B activity

AIM:To investigate the effect of propofol on human pancreatic cells and the molecular mechanism of propofol action.METHODS:We used the human pancreatic cancer cell line MIAPaCa-2 for in vitro studies measuring growth inhibition and degree of apoptotic cell death induced by propofol alone,gemcitabine alone,or propofol followed by gemcitabine.All experiments were conducted in triplicate and carried out on three or more separate occasions.Data were means of the three or more independent experiments±SE.Statistically significant differences were determined by two-tailed unpaired Student’s t test and defined as P<0.05.RESULTS:Pretreatment of cells with propofol for 24 h followed by gemcitabine resulted in 24%-75% growth inhibition compared with 6%-18%when gemcitabine was used alone.Overall growth inhibition was directly correlated with apoptotic cell death.We also showed that propofol potentiated gemcitabine-induced killing by downregulation of nuclear factor-κB(NF-κB).In contrast,NF-κB was upregulated when pancreatic cancer cells were exposed to gemcitabine alone,suggesting a potential mechanism of acquired chemoresistance.CONCLUSION:Inactivation of the NF-κB signaling pathway by propofol might abrogate gemcitabineinduced activation of NF-κB,resulting in chemosensitization of pancreatic tumors to gemcitabine.     

Epigenetic regulation of DNA repair machinery in Helicobacter pylori-induced gastric carcinogenesis

Although thousands of DNA damaging events occur in each cell every day, efficient DNA repair pathways have evolved to counteract them. The DNA repair machinery plays a key role in maintaining genomic stability by avoiding the maintenance of mutations. The DNA repair enzymes continuously monitor the chromosomes to correct any damage that is caused by exogenous and endogenous mutagens. If DNA damage in proliferating cells is not repaired because of an inadequate expression of DNA repair genes, it might increase the risk of cancer. In addition to mutations, which can be either inherited or somatically acquired, epigenetic silencing of DNA repair genes has been associated with carcinogenesis. Gastric cancer represents the second highest cause of cancer mortality worldwide. The disease develops from the accumulation of several genetic and epigenetic changes during the lifetime. Among the risk factors, Helicobacter pylori (H. pylori) infection is considered the main driving factor to gastric cancer development. Thus, in this review, we summarize the current knowledge of the role of H. pylori infection on the epigenetic regulation of DNA repair machinery in gastric carcinogenesis.     

Helicobacter pylori in Thai patients with cholangiocarcinoma and its association with biliary inflammation and proliferation

Objectives

To investigate whether Helicobacter spp. infection and the cagA of H. pylori are associated with hepatobiliary pathology, specifically biliary inflammation, cell proliferation and cholangiocarcinoma (CCA).

Methods

Helicobacter species including H. pylori, H. bilis and H. hepaticus were detected in the specimens using the polymerase chain reaction (PCR). Biliary inflammation of the liver and gallbladders was semi-quantitatively graded on hematoxylin and eosin (H&E)-stained slides. Biliary proliferation was evaluated by immunohistochemistry using the Ki-67-labelling index.

Results

Helicobacter pylori was found in 66.7%, 41.5% and 25.0% of the patients in the CCA, cholelithiasis and control groups (P < 0.05), respectively. By comparison, H. bilis was found in 14.9% and 9.4% of the patients with CCA and cholelithiasis, respectively (P > 0.05), and was absent in the control group. The cagA gene of H. pylori was detected in 36.2% and 9.1% of the patients with CCA and cholelithiasis, respectively (P < 0.05). Among patients with CCA, cell inflammation and proliferation in the liver and gallbladder were significantly higher among those DNA H. pylori positive than negative.

Conclusions

The present findings suggest that H. pylori, especially the cagA-positive strains, may be involved in the pathogenesis of hepatobiliary diseases, especially CCA through enhanced biliary cell inflammation and proliferation.     

Novel role of toll-like receptors in Helicobacter pylori-induced gastric malignancy

Helicobacter pylori(H.pylori)infects the human stomach during infancy and develops into chronic activeinflammation.The majority of H.pylori tend to colonize within the mucous gel layer of the stomach.Thestomach lacks its own immune function,thus innateimmunity as the first line of defense is vital for specificimmunity against H.pylori.We review recent discoveries in the pathophysiologic roles of toll-like receptors(TLRs),mainly TLR2 and TLR4,in H.pylori-induced inflammation.In addition,the TLR pathways activated byH.pylori-induced inflammation have been shown to beclosely associated not only with gastric carcinogenesis,but also with formation of the tumor microenvironmentthrough the production of pro-inflammatory cytokines,chemokines,and reactive oxygen species.Althoughthe correlation between single nucleotide polymorphisms of TLRs and gastric cancer risk remains unclear,a recent study demonstrated that STAT3-driven upregulation of TLR2 might promote gastric tumorigenesis independent of inflammation.Further research onthe regulation of TLRs in H.pylori-associated gastriccarcinogenesis will uncover diagnostic/predictive biomarkers and therapeutic targets for gastric cancer.     

Helicobacter pylori eradication in gastric diffuse large B cell lymphoma

Diffuse large B cell lymphoma(DLBCL) of the stomach is a heterogenous disease. There are tumors without histological evidence of mucosa-associated lymphoid tissue(MALT) lymphoma, which are classified as pure or de novo DLBCL and those with evidence of MALT, which are classified as DLBCL(MALT). The association between Helicobacter pylori(H. pylori) and gastric MALT lymphoma and remission with H. pylori eradication was shown in the 1990 s. In recent years, scientists from Taiwan and others have shown that high-grade gastric lymphomas may be dependent on H. pylori and eradication of this microorganism is effective in these cases. This entity is biologically distinct from H. pylori(-) cases and has a better clinical outcome. There are sufficient data about the complete remission in some of these cases with brief treatment with antibiotics. With this strategy, it is possible to save some of these cases from the harmful effects of standard chemotherapy. It is time to treat these cases with H. pylori eradication. However, strict histopathological follow-up is crucial and histopathological response must be evaluated according to the scoring system proposed by Groupe d’Etude des Lymphomes de l’Adulte. If there is no sufficient response, chemotherapy must be given immediately. These results suggest that H. pylori dependency and high-grade transformation in gastric MALT lymphomas are distinct events.     

First-line eradication for Helicobacter pylori-positive gastritis by esomeprazole-based triple therapy is influenced by CYP2C19 genotype

AIM: To evaluate the effect of first line esomeprazole (EPZ)-based triple therapy on Helicobacter pylori (H. pylori) eradication.METHODS: A total of 80 Japanese patients with gastritis who were diagnosed as positive for H. pylori infection by endoscopic biopsy-based or ¹³C-urea breath tests were included in this study. The average age of the patients was 57.2 years (male/female, 42/38). These patients were treated by first-line eradication therapy with EPZ 40 mg/d, amoxicillin 1500 mg/d, and clarithromycin 400 mg/d for 7 d. All drugs were given twice per day. Correlations between H. pylori eradication, CYP2C19 genotype, and serum pepsinogen (PG) level were analyzed. This study was registered with the UMIN Clinical Trials Registry (UMIN000009642).RESULTS: The H. pylori eradication rates by EPZ-based triple therapy evaluated by intention-to-treat and per protocol were 67.5% and 68.4%, respectively, which were similar to triple therapies with other first-generation proton pump inhibitors (PPIs). The eradication rates in three different CYP2C19 genotypes, described as extensive metabolizer (EM), intermediate metabolizer, and poor metabolizer, were 52.2%, 72.1%, and 84.6%, respectively. The H. pylori eradication rate was significantly lower in EM than non-EM (P < 0.05). The serum PG I level and PG I/II ratio were significantly increased after eradication of H. pylori (P < 0.01), suggesting that gastric atrophy was improved by H. pylori eradication. Thus, first-line eradication by EPZ-based triple therapy for patients with H. pylori-positive gastritis was influenced by CYP2C19 genotype, and the eradication rate was on the same level with other first-generation PPIs in the Japanese population.CONCLUSION: The results from this study suggest that there is no advantage to EPZ-based triple therapy on H. pylori eradication compared to other first-generation PPIs.     

Inhibitory effects of emodin,baicalin, schizandrin and berberine on hef A gene: Treatment of Helicobacter pylori-induced multidrug resistance

AIM: To investigate the inhibitory effects of emodin, baicalin, etc. on the hefA gene of multidrug resistance(MDR) in Helicobacter pylori(H. pylori).METHODS: The double dilution method was used to screen MDR H. pylori strains and determine the minimum inhibitory concentrations(MICs) of emodin, baicalin, schizandrin, berberine, clarithromycin, metronidazole, tetracycline, amoxicillin and levofloxacin against H. pylori strains. After the screened MDR stains were treated with emodin, baicalin, schizandrin or berberine at a 1/2 MIC concentration for 48 h, changes in MICs of amoxicillin, tetracycline, levofloxacin, metronidazole and clarithromycin were determined.MDR strains with reduced MICs of amoxicillin were selected to detect the hefA mR NA expression by realtime quantitative PCR.RESULTS: A total of four MDR H. pylori strains were screened. Treatment with emodin, baicalin, schizandrin and berberine significantly decreased the MICs of amoxicillin and tetracycline against some strains, decreased by 1 to 2 times, but did not significantly change the MICs of clarithromycin, levofloxacin, and metronidazole against MDR strains. In the majority of strains with reduced MICs of amoxicillin, hef A m RNA expression was decreased; one-way ANOVA(SPSS 12.0) used for comparative analysis, P < 0.05.CONCLUSION: Emodin, baicalin, schizandrin and berberine significantly decreased the MICs of amoxicillin and tetracycline against some H. pylori strains, possibly by mechanisms associated with decreasing hefA mR NA expression.     

High Frequency of Inherited Variants in the <Emphasis Type="Italic">MEFV</Emphasis> Gene in Acute Lymphocytic Leukemia

In the present study, we aimed to determine the frequency of inherited variants in the MEFV (Mediterranean FeVer), the gene responsible for familial Mediterranean fever (FMF), gene in patients with acute lymphocytic leukemia (ALL). The eight MEFV gene variants (M694I, M694V, M680I (G/C-A), V726A, R761H, E148Q and P369S) were detected in 36 patients with ALL and 65 healthy controls; none had own and/or family history compatible with FMF. We identified 11 heterozygous inherited variants in the MEFV gene in both ALL patients and controls. The mean overall frequency of inherited variants in the MEFV gene rate was higher in ALL patients than healthy controls (P = 0.040). It is interesting to note that M680I/0 is predominant variant in patients with ALL. In addition, E148Q variant frequency was also significantly higher in the patient group than the controls (P = 0.012). In conclusion, overall frequency of inherited variants in the MEFV gene was found to be higher in patients with ALL. Based on the present data, it is difficult to reach a definitive conclusion regarding the possibility that inherited variants in the MEFV gene could represent a causative role in ALL. However, the data of our study may provide some new insights in understanding of individual genetic differences in susceptibility to these neoplasms. Further investigations are needed to determine the actual role of inherited variants in the MEFV gene in pathogenesis of ALL.