Overview of cytokines and nitric oxide involvement in immuno-pathogenesis of inflammatory bowel diseases

Inflammatory bowel diseases(IBDs), including Crohn's disease and ulcerative colitis are complex disorders with undetermined etiology. Several hypotheses suggest that IBDs result from an abnormal immune response against endogenous flora and luminal antigens in genetically susceptible individuals. The dysfunction of the mucosal immune response is implicated in the pathogenesis of IBD. The balance between pro-inflammatory cytokines [tumor necrosis factor(TNF)-α, interleukin(IL)-1b, IL-8, and IL-17A], anti-inflammatory cytokines(IL-4 and IL-13), and immunoregulatory cytokines(IL-10 and transforming growth factors b) is disturbed. Moreover, evidence from animal and clinical studies demonstrate a positive correlation between an increased concentration of nitric oxide(NO) and the severity of the disease. Interestingly, proinflammatory cytokines are involved in the up-regulation of inducible oxide synthase(iN OS) expression in IBD. However, anti-inflammatory and immunoregulatory cytokines are responsible for the negative regulation of iN OS. A positive correlation between NO production and increased pro-inflammatory cytokine levels(TNF-α, IL-6, IL-17, IL-12, and interferon-γ) were reported in patients with IBD. This review focuses on the role of cytokines in intestinal inflammation and their relationship with NO in IBD.

Antihydatic and immunomodulatory effects of Punica granatum peel aqueous extract in a murine model of echinococcosis

Objective:To investigate the effect of pomegranate peel aqueous extract(PGE) on the development of secondary experimental echinococcosis and on the viability of Echinococcux granulosus protoscoleces,and the immunomodulatory properties of PGE.Methods:Swiss mice were inoculated intraperitoneally with viable protoscoleces.Then,PGE was orally administered daily during cystic echinococcosis development.Cyst development and hepatic damage were macroscopically and histologically analyzed.The production of nitric oxide and TNF-α was assessed in plasma and the hepatic expression of iNOS.TNF-α,NF-κB and CD68 was examined.Moreover,protoscoleces were cultured and treated with different concentrations of PGE.Results:It was observed that in vitro treatment of protoscoleces caused a significant decrease in viability in a PGE-dose-dependent manner.In vivo,after treatment of cystic echinococcosis infected mice with PGE,a significant decrease in nitric oxide levels(P<0.000 1)and TNF-α levels(P<0.001) was observed.This decline was strongly related to the inhibition of cyst development(rate of hydatid cyst growth inhibition=63.08%) and a decrease in CD68 expression in both the pericystic layer of hepatic hydatid cysts and liver tissue(P<0.000 1).A significant diminution of iNOS,TNF-α and NF-κB expression was also observed in liver tissue of treated mice(P<0.000 1).Conclusions:Our results indicate an antihydatic scolicidal effect and immunomodulatory properties of PGE,suggesting its potential therapeutic role against Echinococcuss granulosus infection.

NOD2/CARD15 gene mutations in North Algerian patients with inflammatory bowel disease

AIM: To analyse allelic frequency of NOD2 gene variantsand to assess their correlation with inflammatory bowel disease(IBD) in Algeria.METHODS: We studied 132 unrelated patients diagnosed with IBD, 86 with Crohn's disease(CD) and 46 with ulcerative colitis(UC). Data was prospectively collected between January 2011 and December 2013. The demographic and clinical characteristics were recorded for all the patients. A group of 114 healthy unrelated individuals were selected as controls. All groups studied originated from different regions of North Algeria and confirmed the Algerian origin of their parents and grandparents. Informed and written consent was obtained from each of the participants. All individuals were genotyped for the three CDassociated NOD2 variants(p.Arg702 Trp, p.Gly908 Arg and p.Leu1007 fsins C mutations) using the polymerase chain reaction-restriction fragment length polymorphism method. Allele and genotype frequencies in patients and control subjects were compared by χ2 test and Fisher's exact test where appropriate. Odds ratios(OR) and 95% confidence intervals(95%CI) were also estimated. Association analyses were performed to study the influence of these variants on IBD and on clinical phenotypes.RESULTS: The p.Arg702 Trp mutation showed the highest frequency in CD patients(8%) compared to UC patients(2%)(P = 0.09, OR = 3.67, 95%CI: 0.48-4.87) and controls(5%)(P = 0.4, OR = 1.47, 95%CI: 0.65-3.31). In CD patients allelic frequencies of p.Gly908 Arg and p.Leu1007 fsins C variants compared to HC were 3% vs 2%(P = 0.5, OR = 1.67, 95%CI: 0.44-6.34); 2% vs 1%(P = 0.4 OR = 2.69 95%CI: 0.48-14.87 respectively). In UC patients, allelic frequencies of p.Gly908 Arg and p.Leu1007 fsins C variants compared to HC were 1% vs 2%(P = 1, OR = 1.62, 95%CI: 0.17-4.74) and 2% vs 1%(P = 0.32, OR = 0.39, 95%CI: 0.05-2.87). The total frequency of the mutated NOD2 chromosomes was higher in CD(13%), than in HC(8%) and UC(5%). In addition, NOD2 variants were linked to a particular clinical sub-phenotype in CD in this Algerian cohort. As expected, the three NOD2 variants showed a significant association with CD but did not reach statistical significance, despite the fact that the allele frequency of NOD2 variants was in the range found in most of the European populations. This might be due to the non-exposure of the NOD2 carriers to environmental factors, required for the expression of the disease.CONCLUSION: Further analyses are necessary to study genetic and environmental factors in IBD in the Algerian population, using larger patient groups.

Antihydatic and immunomodulatory effects of Algerian propolis ethanolic extract:In vitro and in vivo study

Objective: To evaluate the in vitro and in vivo effect of the Algerian propolis ethanolic extract(EEP) against Echinococcus granulosus(E. granulosus) infection. Methods: In vitro scolicidal activity of EEP was investigated on the protoscolices of hydatid cyst. This in vitro study was conducted by using an in vivo assay. BALB/c mice were inoculated with E. granulosus and treated with propolis for three months. Hydatid cysts development was assessed. Nitric oxide(NO), tumor necrosis factor alpha(TNF-α) production and inducible NO synthase, NF-κB, and TNF-α spleen expression were estimated by Griess method and immunofluorescence respectively.Results: Our study revealed that EEP has a high scolicidal activity against E. granulosus. Oral administration of EEP decreased TNF-α, NF-κB and inducible NO synthase expression in the spleen tissues in the CE+EEP group, in comparison with the CE group. Concomitantly, EEP treatment caused an important systemic decrease in NO and TNF-α levels. These findings are associated with the reduction of CE development. Conclusions: This is the first report demonstrating with interest the antihydatic and immunomodulatory effects of the Algerian EEP, suggesting its therapeutic potential for the hydatid disease treatment.

In vitro anti-hydatic and immunomodulatory effects of ginger and [6]-gingerol

Objective: To study in vitro anti-hydatic and immunomodulatory effects of ginger and [6]-gingerol as an alternative therapy for Cystic echinococcosis. Methods: Effect of a commonly used herbal product and ginger(Zingiber officinale) towards protoscoleces(PSC) and cyst wall in vitro was studied. The effect of [6]-gingerol, and the pungent constituent of ginger, was also evaluated on PSC culture. Furthermore, the activity of both extracts in association with interferon-gamma(IFN-γ) on PSC co-cultured with mononuclear cells of hydatic patients was evaluated. The nitric oxide(NO) production was measured in each co-culture. Results: Ginger exhibited a concentration- and time-dependent cytotoxic effect against PSC and cyst wall. Interestingly, ginger was more effective than the [6]-gingerol. Moreover, additional parasitic effect between extracts and IFN-γ are also observed in co-cultures. Furthermore, both extracts attenuated the NO production elicited by this infection or by the IFN-γ. Conclusions: Ginger has an important anti-hydatic effect in vitro. This effect is amplified in the presence of IFN-γ. Moreover, this herbal product may protect against host's cell death by reducing the high levels of NO. Ginger may act, at least, through the [6]-gingerol. All our data suggest the promising use of ginger in the treatment of Echinococcus granulosus infection.