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Background: Oral aphthosis is one of the major manifestations of Behçet’s disease (BD), a chronic, multisystemic vasculitis. BD etio-pathogenicity related to oral health lack. Objective: This study investigated the possible relationships between poor oral hygiene, oral activity, disease severity and saliva’s Interleukin (IL)-32, IL-6, IL-10 and nitric oxide (NO) levels in Behçet’s patients to determine their role in disease prognosis and their potential therapeutic interest. Method: Fifty-six patients with BD (22 orally active; 34 orally inactive) and 31 healthy subjects have been included in our study. Salivary levels of IL-32, IL-6, and IL-10 were measured using ELISA, while NO levels were assessed by modified Griess’s method. Oral health status and disease severity scores were recorded for each participant. Kruskal-Wallis test and Spearman’s test were performed for statistical analyses. Results: We observed that the tested molecules were increased in BD patients compared to healthy controls (p˂0.05). Moreover, only IL-32 levels were associated with oral activity in patients (p˂0.05). Interestingly, the disease severity score was noted to be correlated positively and significantly with both IL-32 saliva levels (p˂0.01) and plaque index (p˂0.05) in BD patients. Furthermore, IL-32 levels were correlated with plaque index (p˂0.0001). Conclusion: Our results suggest that IL-32, IL- 6, IL-10 and NO were increased in saliva during BD. Our study indicated that IL-32 was associated with the genesis of oral ulcers in response to dental plaque. Ultimately, salivary IL-32 may serve as a prognostic biomarker and a possible therapeutic target for managing Behçet’s disease severity.

Background: Pistacia lentiscus L. (PL) is a flowering plant traditionally used in the treatment of gastrointestinal disorders. The extracts of this plant are endowed with strong pharmacological activities. The aim of our current study was to investigate the anti-inflammatory and potential therapeutic effects of PL leaves aqueous extract (PLAE) against Dextran Sulfate Sodium (DSS)-induced acute colitis. Materials and methods: The therapeutic effect of PLAE was evaluated after orally administration of 3% DSS alone or concomitantly with PLAE (50, 100 or 200 mg/Kg). Mucosal lesions were assessed by macroscopic and histopathological examination. In this context, hemorrhage, diarrhea, weight loss, and disease activity index (DAI) were determined daily throughout the experiment. In the same way, hematoxylin-eosin and Alcian blue staining of colonic mucosal were used to evaluate respectively mucosal damages and mucus production. Furthermore, the levels of nitric oxide (NO), and pro-inflammatory cytokines [tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6)] were measured in plasma, as well as in colonic explants and peritoneal macrophages cultures supernatants.Results: Administration of DSS+PLAE indicated a significant reduction in clinical score of acute colitis DAI compared to DSS alone administration. Interestingly, histological analysis of the mucosa showed that DSS+PLAE-treated groups exhibited almost normal histology evidenced by an intact epithelium structure and less inflammatory cell infiltration in the mucosa. Alcian bleu staining revealed that DSS+PLAE-treated groups displayed almost normal mucus production. Importantly, a significant decrease in pro-inflammatory mediators (NO, IL-6 and TNF-α) levels in dose dependent manner was reported in plasma, and culture supernatants of colonic explants and peritoneal macrophages from DSS+ PLAE-treated mice compared to the DSS group.Conclusion: Our results showed that the systemic and local anti-inflammatory activities of aqueous leaves extract of PL improve the clinical signs of acute colitis. Our data suggest that PLAE has beneficial effects and could constitute a promising approach against acute ulcerative colitis by targeting the deregulated immune response.

The Laminated layer of Echinococcus granulosus (LL) is the outer layer of the hydatic cyst. It plays a pivotal role in protecting the metacestode from host immunity. In our current study, we investigated the immunomodulatory effect of the LL on mouse spleen cells in presence of Lipopolysaccharide (LPS). Mouse spleen cells were cultured with or without LL in presence of LPS. After 24 h, the nitrites level representative of Nitric oxide (NO) production was measured in the culture supernatant by Griess-modified method. In addition, the mRNA expression levels of cytokines (IFN-γ, IL-1β, TGF-β, IL-10), Foxp3, and CTLA-4 were measured by quantitative Real-Time Polymerase chain reaction (qRT-PCR). Interestingly, our results showed a significant decrease (p< 0.01) in NO production and IFN-γ mRNA level (p< 0.001) from LPS- induced spleen cells in response to LL after 24h of culture. Moreover, LPS induced high level of IL-1β that was significantly (p

Cystic echinococcosis, an endemic zoonosis in Algeria, is caused by the development of the helminth Echinococcus granulosus. Surgery remains the main treatment despite inducing relapse and several adverse reactions. In this context, natural scolicidal agents seem to be promising tools to overcome these reactions. In our study, we evaluated the phytochemical contents, antioxidant activity and scolicidal effect of Atriplex halimus. In this context, the aqueous extract from AH leaves (AHE) was subjected to preliminary phytochemical screening by HPLC. The in vitro antioxidant activity was determined by DPPH test. The cytotoxicity of AHE was evaluated in murine peritoneal macrophages and cell viability was examined by MTT assay. Moreover, different concentrations of AHE (20, 40, 50, 60 and 100 mg/ml) were tested on E. granulosus protoscoleces (PSC) cultures, during different times of incubation (15, 30, 60, 90, 120 and 180 min). The viability was evaluated by eosin exclusion test. The morphological and ultrastructural damages were evaluated by SEM. Our results indicate that total phenolic and flavonoids contents were 37.93 μg of Gallic acid equivalent per mg of extract (GAE/mg E) and 18.86 μg of Quercetin equivalent per mg (QE/mg E) respectively. Furthermore, AHE has an antioxidant activity with an IC50 of 0.95 mg/ml. Interestingly, the extracts did not exhibit any cytotoxic effect against murine peritoneal macrophages. Moreover, our study indicated a significant scolicidal activity time- and dose-dependent. At 60 and 100 mg/ml; and after 120 min of incubation; the mortality rate was 99.36 and 100%, respectively. The parasite's tegument is one of the plant's targets as demonstrated by SEM. Our findings show the benefits of Atriplex halimus extract as a new promising scolicidal tool in hydatid cyst treatment.

Ethnopharmacological relevance Pistacia lentiscus L. (Anacardiaceae) (PL) is a flowering plant that grows in the Mediterranean area. It is traditionally used in the treatment of various skin, respiratory and gastrointestinal disorders Aim of the study In the present study, we investigated the anti-ulcerogenic activity of Pistacia lentiscus fatty oil (PLFO) on ethanol-induced gastric ulcers in Wistar rats Material and methods PLFO was orally administered to two experimental groups of rats before or after ethanol induction of gastric ulcer. The lesions of the gastric mucosa were evaluated by macroscopic and histopathological examination. In addition, the amount of nitric oxide (NO) and pro-inflammatory cytokines [tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6)] in the supernatant from cultures of gastric mucosa explants were assessed. Finally, the mucus production and iNOS (inducible NO synthase) expression were determined by histochemical and immunohistochemical analysis, respectively Result Our results indicated that the PLFO pretreatment or PLFO treatment significantly reduced ulcerated and hemorrhagic areas. Additionally, pretreatment or treatment with PLFO after ethanol-induced ulceration significantly reduced the plasma concentration of NO. Furthermore, a significant decrease of NO, IL-6 and TNF-α levels was observed in explant culture supernatants. iNOS expression was also reduced in the gastric mucosa. In contrast, mucus production by goblet cells was enhanced. Interestingly, histological analysis of the gastric mucosa has indicated that PLFO- pretreated and treated groups displayed normal histology Conclusion Our results demonstrate that PLFO display significant prophylactic and therapeutic effects against gastric ulcers. Importantly, the mechanism underlying PLFO activities might implicate inhibition of inflammatory responses during gastric ulcer.

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.

The prevalence of vascular dementia is increasing at an alarming rate. The Confirmation of the clinical diagnosis of vascular dementia depends on post-mortem examination of the brain. In our study, we investigated the vascular disease and neuroinflammation during vascular dementia. Our results showed a β-amyloid deposits, neovascularization, neuronal hypertrophy and neuroinflammation in the hippocampus tissue. Interestingly, the neuroinflammation was characterized by a higher expression of TNF-α, IL-1β, TGF-β and iNOS which are TLR4/RelA pathway dependent. Finally, the finding of necroptosis by impaired blood supply and inflammation state suggests that the cognitive impairment was caused by vascular disease and neuroinflammation.

The role of nitric oxide (NO) in host defense against Echinococcus granulosus larvae was previously reported. However, NO production by NOS2 (inducible NO synthase) is counteracted by the expression of Arginase. In the present study, our aim is to evaluate the involvement of the laminated layer (external layer of parasitic cyst) in Arginase induction and the protoscoleces (living and infective part of the cyst) survival. Our in vitro results indicate that this cystic compound increases the Arginase activity in macrophages. Moreover, C-type lectin receptors (CLRs) with specificity for mannan and the TGF-β are implicated in this effect as shown after adding Mannan and Anti-TGFβ. Interestingly, the laminated layer increases protoscoleces survival in macrophages-parasite co-cultures. Our results indicate that the laminated layer protects E. granulosus against the NOS2 protective response through Arginase pathway, a hallmark of M2 macrophages.

Background Several studies highlight the implication of nitric oxide (NO) in the airways inflammation during asthma. Moreover, asthma is thought to be associated with a systemic inflammation. However, little is known about the systemic production of NO in asmathic patients. In this sense, our aim was to evaluate the in vivo and ex vivo production of NO in Algerian patients with severe asthma. Moreover, the effect of helminthes infection on asthma is still inconclusive. In this sense, the second part of this study aims to investigate the effect of the helminth Echinococcus granulosus on this production. This parasite causes cyst formation particularly in lungs and liver.

Background Inflammatory bowel disease is an immunologically mediated disease. Notably, it is less common in countries where there is a greater risk of exposure to helminths. In our study, we examined the modulatory effect of the laminated layer extracted from the cyst wall of a helminth parasite, Echinococcus granulosus, on dextran sulfate sodium (DSS)-induced colitis in mice. Methods An acute colitis was induced in BALB/c mice using 2.5% w/v DSS in drinking water. The crude extract of E. granulosus laminated layer was injected intraperitoneally daily, starting 3 days before colitis induction. The Disease Activity Index was monitored daily, colon length and weight were measured and histological scores were evaluated. Nitric oxide (NO) and cytokine levels (interferon γ (IFN-γ), tumor necrosis factor α (TNF-α) and interleukin 10 (IL-10)) were assessed by enzyme-linked immunosorbent assay. In addition, the colonic expression of inducible nitric oxide synthase (iNOS) and nuclear factor-κB (NF-κB) was examined. Statistical analyses were performed by one-way analysis of variance and the survival rate was analyzed by the long rank test. Results Hydatid laminated layer pretreatment significantly improved the clinical symptoms and histological scores (*** p

Human hydatidosis is characterized by a prolonged coexistence of Echinococcus granulosus and its host without effective rejection of the parasite. This parasitic infection constitutes a major health problem in Algeria. In this study, we investigated in vivo production of nitrite (NO2 − + NO3 −) in sera of Algerian patients carrying different cyst locations. Nitrite (NO2 − + NO3 −) levels were evaluated by the Griess method. Our results indicated that the levels of nitrite were significantly higher in the sera of hydatic patients than those of healthy controls supporting the involvement of nitric oxide (NO) in antihydatic action. The levels of nitrite in sera of the patients with hepatic hydatidosis were significantly higher than those with pulmonary infection. The lower serum (NO2 − + NO3 −) levels were observed in the relapsing cases. In addition, (NO2 − + NO3 −) levels of fertile hydatic fluids were significantly higher compared to infertile fluids. Our results suggest that the presence of NO products in hydatic fluids seems to be related to the location and the fertility of hydatic cysts. The assessment of protein concentration in hydatic fluids showed that the concentration of proteins was not exclusively dependent on the fertility but on the cyst locations. The assessment of (NO2 − + NO3 −) production in hydatic patients may be a useful tool to evaluate effector mechanisms of NO and clinical manifestations.

The pathogenesis of inflammatory bowel disease (IBD) is complex, involving a wide range of molecules including cytokines. Abnormalities in the expression of immunoregulatory cytokines such as interferon-γ (IFN-γ) and interleukin-12 (IL-12) may indicate a dysregulation of intestinal immunity probably associated with pathogenic events. The aim of this work was to study the implication of IFN-γ and nitric oxide (NO) in bowel disease pathogenesis. In this study, we investigated the circulating IFN-γ and IL-12 production in 2 groups of Algerian patients with IBD (Crohn's disease and ulcerative colitis). Moreover, systemic NO concentrations and NO generation by colonic mucosa were determined in these patients. Finally, we examined the effect of IFN-γ on NO production by peripheral blood mononuclear cells (PBMCs) of these patients. Our results indicate that IFN-γ/IL-12 production in IBD patients was increased in comparison to healthy donors. This strong production correlates with high levels of NO in sera and colonic mucosa culture. Interestingly, NO production was related to the clinical stage of IBD patients (inactive or active stage). The relationship between IFN-γ and NO production in IBD patients were confirmed by in vitro experiments and the role of IFN-γ in NO synthase induction in patients' PBMC culture was suggested. Collectively, our results show that IFN-γ plays a pivotal role in IBD pathogenesis through NO pathway.

Hydatidosis is characterized by the long-term coexistence of larvaEchinococcus granulosusand its host without effective rejection. Previous studies demonstrated nitric oxide (NO) production (in vivo and in vitro) during hydatidosis. In this study, we investigated the direct in vitro effects of NO species: nitrite (NO2−), nitrate (NO3−) and peroxynitrite (ONOO−) on protoscolices (PSCs) viability and hydatid cyst layers integrity for 24 hours and 48 hours. Our results showed protoscolicidal activity ofNO2−andONOO−24 hours and 3 hours after treatment with 320 μM and 80 μM respectively. Degenerative effects were observed on germinal and laminated layers. The comparison of the in vitro effects of NO species on the PSCs viability indicated thatONOO−is more cytotoxic thanNO2−. In contrast,NO3−has no effect. These results suggest possible involvement ofNO2−andONOO−in antihydatic action and point the efficacy of these metabolites as scolicidal agents.

Human echinococcosis is one of the world's major zoonotic infections. In this study, our aim is to clarify one of the strategies used by the parasite for evasion and prolonged infestation in the host. We wished to provide further immunological evidence for the involvement of IL-10/IL-4 in these mechanisms. In this regard, we investigated the effects of IL-4 and IL-10 on protoscoleces (PSC: the larval form of the parasite), co-cultured with patient PBMC. Furthermore, we used IL-4 and IL-10 antibodies to confirm this effect. Our results showed that IL-4 and IL-10 reduced PSC killing. This reduction correlates with an decrease in NO production by PBMC. In conclusion, the results reported here suggest that IL-4/IL-10 impairs the Th1 protective response and allows the parasite to survive in hydatid patients.

Cystic echinococcosis (CE) is caused by infection with the larval stage of the cestode Echinococcus granulosus. It is one of the world's major zoonotic infections. Variability and severity of clinical expression of this parasitosis are associated with duration and intensity of infection. They are also related to the variety of human immunological responses to the hydatic antigens. The aim of this work is to study the inflammatory response associated with human hydatidosis by evaluating the possible roles of the proinflammatory cytokines in hydatic patients. We investigated the patterns of IL-12 and IL-8 in serum from Algerian hydatic patients. Serum IL-12 and IL-8 levels are significantly higher in patients with hydatidosis than in control subjects. Furthermore, cytokines secretion correlates with disease statues (cystic localizations and clinical stage). These data indicate that infection with E. granulosus is associated with high levels of circulating IL-12 and IL-8. Moreover, our data, to our knowledge, constitute the first report of IL-12 and IL-8 diffusion into the hydatid cyst. Our results underline the permeability of the cyst wall to the soluble immune system of the host. The relationship between cyst fertility and cytokine infiltration indicates a strong host-parasite interaction. All these findings have important implications for the diagnosis of hydatidosis in humans.

Hydatidosis is a widely endemic helminthic disease vectored in human by the larval stage of the metacestode Echinococcus granulosus. It is characterized by the long-term coexistence of chronic infection with detectable humoral and cellular responses against the macroparasite. Previous studies demonstrated interferon-gamma (IFN-gamma) and nitric oxide (NO) production (in vivo and in vitro) during hydatidosis. In this study, we tested the hypothesis that NO production after IFN-gamma induction may constitute a host defense against E. granulosus. We also investigated the IFN-gamma effect on protoscolices (larval form of the parasite) viability in coculture with hydatid patients' peripheral blood mononuclear cells (PBMC). PBMCs from hydatic patients incubated with IFN-gamma (100 U/mL) alone are effective in the killing of protoscolices. This scolicidal activity is concomitant with elevation of nitrite levels. NO release and cytotoxic activity are inhibited by N-monomethyl-L-arginine (L-NMMA), a specific inhibitor of the NO pathway and increased by L-arginine, an NO precursor, and tetrahydrobiopterin (BH4), a nitric oxide synthase (NOS) cofactor. Our results indicate that IFN-gamma mediated iNOS induction as one of host defense mechanism against human E. granulosus infection.

Inflammatory bowel disease is less common in countries where there is a greater risk of exposure to helminths. In our study, we examined the modulatory effect of the laminated layer extracted from the cyst wall of a helminth parasite, Echinococcus granulosus, on dextran sulfate sodium (DSS)-induced colitis in mice. Crude extract of E. granulosus laminated layer was injected intra-peritoneally daily, starting 3 days before colitis induction. The Disease Activity Index was monitored daily and histological scores were evaluated. Nitric oxide (NO) and cytokine levels (interferon γ (IFN- γ ) , tumor necrosis factor α (TNF- α ) and interleukin 10 (IL-10)) were assessed. In addition, the colonic expression of inducible nitric oxide synthase (iNOS) and nuclear factor- κ B (NF- κ B) was examined. Importantly, our results indicate that hydatid laminated layer pretreatment significantly improved the clinical symptoms and histological scores observed during DSS-induced colitis. Furthermore, treatment with hydatid laminated layer caused a significant decrease in NO (∗∗p α production (∗p κ B expression. Our results demonstrate the potent protective effect of hydatid laminated layer in DSS induced colitis through downregulation of IFN- γ and TNF- α and up regulation IL-10 production. Furthermore, hydatid laminated layer played a beneficial role in maintaining the integrity of the intestinal mucosal barrier against DSS-induced injury suggesting the crucial role of helminth in immuno-protection against IBD.

Background Helminth parasites are highly antigenic and some types favour the generation or exacerbation of allergic responses by inducing strong Th2-type responses (with the production of cytokines, particularly IL-4). Moreover, recent data suggest that Arginase is involved in the pathogenesis of multiple aspects of allergic disease. In the present work, our aim is to study whether the parasite Echinococcus granulosus induces Th2-type response and whether this is beneficial for the host or not. Echinococcus g. infection, which induces hydatidosis, remains a serious parasitic disease in Algeria. In human, the larval form develops into large cysts especially in the liver and lungs. Methods We have investigated the effect of laminated-layer (accelullar layer of hydatic cyst) extract (LLs) on IL-4, and IFN-γ production and Arginase activity in culture performed with mononuclear cells (PBMC). These cells are prepared from peripheral blood of hydatic patients (before and after surgery) and healthy donors. Of note, IFN-γ (Th1 cytokine) downregulates Th2-derived cytokines (like IL-4) which are the best inducer of Arginase pathway. Finally, we have investigated the effects of LLs and IL-4 on protoscoleces (larval form of parasite) viability in PBMC-protoscoleces coculture. Results We have found that LLs enhanced IL-4 production and Arginase activity and reduced IFN-γ production by PBMC. Furthermore, LLs and IL-4 also enhanced parasite survival in PBMC-Parasite cocultures. Moreover, we have purified by chromatography one of the major antigenic protein in LLs: the fraction 4 (F4, 12kDa). This fraction has the same effect as LLs on Th1/Th2 balance. Interestingly, similar findings are observed in cultures and cocultures performed with PBMC of presurgical and postsurgical patient and healthy donors. Conclusions Taken together, our results suggest that the laminated layer of Echinococcus g. may promote allergic response in humans directly by inducting the Th2 pathway. Moreover, this response allows the parasite survival.

Introduction Human hydatidosis is caused by the larval stage of the metacestode Echinococcus granulosus (E.g.). It is one of the world’s major zoonotic infections. It usually manifests as unilocular cyst(s) mainly located in the liver. The prolonged coexistence of the parasite and its host involve the laminated layer (LL). This acellular layer represents an important barrier against immunological and physiological reactions of the host.We have previously highlighted an evident role of IFNγ in parasite killing by NOS2 (Nitric oxide Synthase2) pathway 1 . Moreover, IL-10/Arginase pathways seem to be implicated in parasite escape to host defense 2 . Moreover, LL impairs Th1/Th17 protective responses and allows the parasite to survive. This role may be mediated by Treg up-regulation by LL. Methods In the present work, we aim to identify the early effect of LL in parasite establishment. In this sense, the effect of LL on macrophages phenotype and expression of some M1/M2 markers was investigated. NOS2 and Arginase activities were evaluated in cultures performed with PBMC of hydatid patients and healthy donors. Moreover, implication of mannose receptor (MR) and TGFβ on Arginase activity was evaluated using mannose (MR antagonist) and Anti-TGFβ. Activity of NADPH oxydase (ROS production) was also evaluated by chemiluminescence in cultures performed with human monocytes primed with NADPH oxydase agonists (like opsonized zymosan). Finally, TLR2, TLR4, CD14 and CD23 expression by the same cells was evaluated by flow cytometric immunoassay. Results We have found that NOS2 and NADPH activities are inhibited by LL. This effect is associated with Arginase activity stimulation. Interestingly, MR and TGFβ seem to be implicated in the Arginase induction by LL. Moreover, LL increases TLR2 and CD14 expression and decreases TLR4 and CD23 expression by monocytes. Conclusion Collectively, ours finding suggest that e.g. laminated layer induced M2 phenotype. These macrophages induce Treg cells and impair M1/Th1/Th17 protective responses allowing parasite survival. Inhibition of these mechanisms seems to be important issue to address during the design of anti-hydatic treatment.

Background The effect of helminth infections on allergic diseases is still inconclusive. Several studies show that Treg cell induced by parasites down regulate the host Th2-mediated allergic response. However, some studies highlight the importance of alternative activated macrophages (AAM) in the pathogenesis of allergic diseases. This phenotype is also implicated in helminth survival. Our aim is to study the immunomodulatory effect of laminated layer (LL, accelullar layer of hydatic cyst) of the helminth Echinococcus granulosus. This infection remains a serious parasitic disease in Algeria.