Gamal Allam

Immunomodulatory effects of curcumin treatment on murine schistosomiasis mansoni

Curcumin is a polyphenol derived from the dietary spice turmeric. It has been shown to regulate numerous transcription factors, cytokines, adhesion molecules, and enzymes that have been linked to inflammation. In addition to inhibiting the growth of a variety of pathogens, curcumin has been shown to have nematocidal activity. The present study was designed to evaluate the schistosomicidal activity of curcumin in vivo as well as immunomodulation of granulomatous inflammation and liver pathology in acute schistosomiasis mansoni. Mice were infected each with 80 Schistosoma (S.) mansoni cercariae and injected intraperitoneally with curcumin at a total dose of 400mg/kg body weight. Curcumin was effective in reducing worm and tissue-egg burdens, hepatic granuloma volume and liver collagen content by 44.4%, 30.9%, 79%, and 38.6%, respectively. Curcumin treatment restored hepatic enzymes activities to the normal levels and enhanced catalase activity in the liver tissue of infected mice. Moreover, hepato-spleenomegaly and eosinophilia induced by S. mansoni infection were largely improved with curcumin treatment. Infected mice treated with curcumin showed low serum level of both interleukin (IL)-12 and tumor necrosis factor alpha (TNF-alpha), but IL-10 level was not significantly altered. Specific IgG and IgG1 responses against both soluble worm antigen (SWAP) and soluble egg antigen (SEA) were augmented with curcumin treatment, but IgM and IgG2a responses were not significantly changed. In conclusion, curcumin treatment modulates cellular and humoral immune responses of infected mice and lead to a significant reduction of parasite burden and liver pathology in acute murine schistosomiasis mansoni.

Hesperidin Inhibits Inflammatory Response Induced byAeromonas hydrophilaInfection and Alters CD4+/CD8+T Cell Ratio

Background. Aeromonas hydrophila is an opportunistic bacterial pathogen that is associated with a number of human diseases. Hesperidin (HES) has been reported to exert antioxidant and anti-inflammatory activities. Objectives. The aim of this study was to investigate the potential effect of HES treatment on inflammatory response induced by A. hydrophila infection in murine. Methods. A. hydrophila-infected mice were treated with HES at 250 mg/kg b.wt./week for 4 consecutive weeks. Phagocytosis, reactive oxygen species production, CD4+/CD8+ T cell ratio, and CD14 expression on intestinal infiltrating monocytes were evaluated. The expression of E-selectin and intercellular adhesion molecule 1 on stimulated HUVECs and RAW macrophage was evaluated. Results. Percentage of CD4+ T cells in the intestinal tissues of infected treated mice was highly significantly increased; however, phagocytic index, ROS production, CD8+ T cells percentage, and CD14 expression on monocytes were significantly reduced. On the other hand, HES significantly inhibited A-LPS- and A-ECP-induced E-selectin and ICAM-1 expression on HUVECs and ICAM-1 expression on RAW macrophage. Conclusion. Present data indicated that HES has a potential role in the suppression of inflammatory response induced by A. hydrophila toxins through downmodulation of ROS production and CD14 and adhesion molecules expression, as well as increase of CD4+/CD8+ cell ratio.

Antimicrobial and immunomodulating activities of hesperidin and ellagic acid against diarrheic Aeromonas hydrophila in a murine model.

AIMS The present study is designed to evaluate the in vitro and in vivo bactericidal and immunomodulating activities of hesperidin (HES) and ellagic acid (EA) against Aeromonas hydrophila. A hydrophila, an uncommon human pathogen, can cause invasive infections in immunocompromised individuals and common clinical presentations in acute gastrointestinal illness, soft-tissue infections and sepsis. The antimicrobial activities of medicinal plants against A. hydrophila have received only cursory attention. METHODS We examined the minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC) values in vitro. Moreover, the effects of HES and EA against bacterial colonization were studied in vivo. Also, humoral immune response was tested against A. hydrophila-LPS or A. hydrophila-ECP antigen preparations and the intestinal histopathological alterations were studied. RESULTS Data revealed that the treatments with HES and EA each had antimicrobial activities against A. hydrophila. Both HES and EA treatments significantly increased anti-LPS IgM levels and reduced anti-LPS and anti-ECP IgA levels to their normal values in comparison to the infected group, which recorded significantly elevated levels two week post-infection. In conclusion, the present data suggest that HES and EA have antimicrobial and immunomodulating activities against murine A. hydrophila infections. SIGNIFICANT These data warrant clinical studies to delineate HES and EA roles in human infectious diseases.

Design, synthesis, anti-schistosomal activity and molecular docking of novel 8-hydroxyquinoline-5-sufonyl 1,4-diazepine derivatives.

Schistosomiasis remains one of the most prevalent parasitic infections and has significant public health consequences. Praziquantel (PZQ) is the only drug currently administrated to treat this disease. However, praziquantel-resistant parasites have been identified in endemic areas and can be generated in the laboratory. Therefore, it is essential to find new therapeutics. Herein we report a series of novel 8-hydroxyquinoline-5-sufonyl 1,4-diazepine derivatives, which were synthesized, characterized and tested as anti-schistosomal agents in vitro. Among all tested compounds, compounds 4a, 5b, and 7b at different tested concentrations (50, 100, and 200 μg/mL) showed the highest schistosomicidal activity. Among those 3 compounds, compound 7b was the most potent anti-schistosomal one. Moreover, all tested compound, at 50 μg/mL concentration, significantly reduced oviposition of adult worms in vitro. Furthermore, both compound 4a and 7b, as well as compound 6a, completely diminished egg deposition. To clarify the possible mechanism by which novel 8-hydroxyquinoline-5-sufonyl 1,4-diazepine derivatives act as anti-schistosomal agents, molecular docking of all new compounds was carried out using Molsoft ICM pro 3.5-0a to investigate the binding affinity and binding mode to thioredoxin glutathione reductase enzyme (TGR), a potential drug target for anti-schistosomal agents. The docking results revealed moderate to high affinity of the new compounds towards TGR. Compound 7b scored the highest binding energy (-101.13 kcal/mol) against TGR crystal structure forming eight hydrogen bonds with the amino acid residues at the binding site of the receptor. This result indicates that compound 7b could exert its effect through inhibition of TGR, which is a vital enzyme for schistosome survival.

Association between type 1, type 2 cytokines, diabetic autoantibodies and 25-hydroxyvitamin D in children with type 1 diabetes

AbstractPurpose Vitamin D may play a role in the pathogenesis of type 1 diabetes (T1D). The aim of the current study was to determine the possible association between 25-hydroxyvitamin D [25(OH)D] levels and circulating levels of type 1 and type 2 cytokines, as well as the pathophysiology of T1D in children.MethodsA total of 250 T1D patients and 250 sex- and age-matched T1D-free controls were screened for 25(OH)D, hemoglobin A1c (HbA1c), type 1 and type 2 cytokines, C-reactive protein (CRP) and bone mineral metabolism, as well as antibodies against insulin, glutamic acid decarboxylase (anti-GAD 65) and islet cells.ResultsOur data showed that the plasma level of 25(OH)D was significantly lower in T1D patients and that there was a significant negative correlation between 25(OH)D levels and HbA1c values. There was a significant association between deficient levels of 25(OH)D and higher levels of cytokines (IFN-γ, TNF-α, IL-6, IL-1β, IL-4 and IL-10) and CRP. Total blood hemoglobin, the hematocrit percentage, body mass index SDS values, phosphate and magnesium levels were significantly lower in T1D patients than in T1D-free subjects. The levels of parathyroid hormone and alkaline phosphatase were significantly higher in T1D patients. Higher levels of cytokines were significantly associated with deficient levels of 25(OH)D. Moreover, in T1D patients, higher levels of islet antibodies, anti-GAD antibodies and anti-insulin antibodies were significantly associated with deficient levels of 25(OH)D.ConclusionsIn type 1 diabetic children, deficient levels of 25(OH)D are associated with high levels of HbA1c, circulatory cytokines and antibody markers.

Anti-malarial IgG subclasses pattern and FcγRIIa (CD32) polymorphism among pregnancy-associated malaria in semi-immune Saudi women

BackgroundPregnant women remain are at an increased risk of malaria with primigravidae being at the highest risk. Genetic polymorphism of the Fc receptor IIa for immunologlobulin (Ig) G (FcγRIIa) determines IgG subclass binding. Protection against pregnancy-associated malaria (PAM) is associated with the production of IgG specific for apical membrane antigen-1 (AMA-1). The present study was undertaken to examine the relationship between specific IgG/IgG subclasses and malaria infection. The second aim of the study is to examine the association between FcγRIIa R/H131 polymorphism in correlation with specific anti-malarial IgG antibodies of AMA-1 distribution and asymptomatic malaria infection among Saudi women living in the southern part of Saudi Arabia.MethodsOne hundred and twenty pregnant women living in an area of meso-endemic Plasmodium falciparum malaria infection were consecutively enrolled onto the study. These pregnant women were asymptomatic and attending routine antenatal clinics. The levels of plasma antibodies (IgG and subclasses AMA-1) were measured using indirect enzyme-linked immunosorbent assays (ELISA). Genotyping of FcγRIIa-R/H131 dimorphism was performed using gene-specific polymerase chain reaction (PCR) amplification with allele-specific restriction enzyme digestion (Bst U1) of the PCR product.ResultsA total of sixty-two (52%) pregnant women was diagnosed with asymptomatic malarial infection (ASM) compared with 58 (48%) malaria free controls (MFC). In the ASM group, there were high levels of anti-malarial IgG1 and IgG3, when compared to MFC (P value <0.001, respectively). The FcγRIIa-R/R131 genotype and R131 were found to be statistically significantly more prevalent in the ASM group when compared to the MFC group [55% for ASM versus 12% for MFC, odds ratio (OR) 5.62, 95% confidence interval (CI)= (2.03- 15.58), P value= 0.001]. However, the H/H131 genotype showed statistically significant association with MFC [14% for ASM versus 50% for MFC, OR(0.36), 95% CI= (0.14- 0.95), P value= 0.03].ConclusionsThe study revealed that the ASM patients had higher anti-malarial IgG and IgG subclasses antibody levels when compared to the MFC. The FcγRIIa-R/R131 genotype and R131 allele were found to be statistically prevalent in the ASM when compared to the MFC group. The individuals carrying H/H131 were consistently associated with higher levels of anti-malarial IgG subclasses.

Hesperidin Inhibits Inflammatory Response Induced by Aeromonas hydrophila Infection and Alters CD4+/CD8+ T Cell Ratio

Background. Aeromonas hydrophila is an opportunistic bacterial pathogen that is associated with a number of human diseases. Hesperidin (HES) has been reported to exert antioxidant and anti-inflammatory activities. Objectives. The aim of this study was to investigate the potential effect of HES treatment on inflammatory response induced by A. hydrophila infection in murine. Methods. A. hydrophila-infected mice were treated with HES at 250 mg/kg b.wt./week for 4 consecutive weeks. Phagocytosis, reactive oxygen species production, CD4+/CD8+ T cell ratio, and CD14 expression on intestinal infiltrating monocytes were evaluated. The expression of E-selectin and intercellular adhesion molecule 1 on stimulated HUVECs and RAW macrophage was evaluated. Results. Percentage of CD4+ T cells in the intestinal tissues of infected treated mice was highly significantly increased; however, phagocytic index, ROS production, CD8+ T cells percentage, and CD14 expression on monocytes were significantly reduced. On the other hand, HES significantly inhibited A-LPS- and A-ECP-induced E-selectin and ICAM-1 expression on HUVECs and ICAM-1 expression on RAW macrophage. Conclusion. Present data indicated that HES has a potential role in the suppression of inflammatory response induced by A. hydrophila toxins through downmodulation of ROS production and CD14 and adhesion molecules expression, as well as increase of CD4+/CD8+ cell ratio.

Neonatal infections in Saudi Arabia: Association with cytokine gene polymorphisms

In recent years, many studies have reported potential associations between cytokine gene polymorphisms and the development, course, and outcome of sepsis, often with apparently conflicting results. The objective of this study was to investigate single nucleotide polymorphism (SNP) in the interleukin (IL)-1β –31 T/C, IL-6 –174 G/C, tumor necrosis factor α (TNF-α) –308 G/A, and interferon γ (IFN-γ) +874 A/T genes for their possible association with susceptibility to early onset sepsis (EOS) in Saudi newborn infants. A total of 205 newborn infants aged 1-2 days were consecutively enrolled onto the study having met the inclusion criteria (as per the research protocol). DNA was extracted from filter papers using the Chelex-100 method. The cytokines SNP were genotyping using Taqman 5’ nuclease allelic discrimination. For cytokine measurements we used the commercially available Enzyme-Linked Immunosorbent Assay (ELISA) kit. Our results show that the circulating IL-1β, IL-6, TNF-α, and IFN-γ were significantly (p < 0.001) elevated in EOS patients compared to suspected and sepsis-free control groups; and IL-1β –31C, IL-6 –174G, TNF-α –308G, and IFN-γ +874A alleles were associated with EOS in Saudi infants. In conclusion, analysis of cytokines concentrations and SNP for the four tested genes can be used as a predictor of sepsis outcome in newborns.

The potential pathogenic role of IL-17/Th17 cells in both type 1 and type 2 diabetes mellitus

Diabetes mellitus (DM) is a serious medical problem affecting millions of peoples worldwide, and has a great socio-economic impacts. Cytokines possess a pivotal role in modulation of immune reactions and disease pathogenesis. T-helper type 17 (Th17) cells, an important proinflammatory CD4+ T cell subset secreting interleukin 17 (IL-17), has been embroiled in development of DM. There are recent evidences supporting a definitive role of Th17 cells in the etiology of type 1 diabetes (T1D). In addition, IL-17 has been shown to play a crucial role in inflammation, insulin resistance, and type 2 diabetes (T2D). Recently, small molecules which have been specified to block Th17 cells differentiation are considered as potential therapeutics for the disease. Anti-IL-17 neutralizing antibodies and/or antibodies targeting Th17 cells have been investigated to protect individuals at risk from disease development. In this review we aimed to shed light on the potential role of IL-17 and Th17 cells in both T1D and T2D pathogenesis and future therapeutic strategies.

Ellagic acid alleviates adjuvant induced arthritis by modulation of pro- and anti-inflammatory cytokines

Rheumatoid arthritis (RA) is a chronic inflammatory disease of unknown aetiology, but it is now clear that pro-inflammatory cytokines play a central role in its pathogenesis. Ellagic acid (EA) has a variety of biological activities including anti-oxidant, anti-inflammatory, and anti-cancer properties. The aim of the present study was to evaluate the potential effect of ellagic acid on the prevention and/or treatment of adjuvant induced arthritis (AIA) model in mice. Ellagic acid treatment was started one week before AIA induction and continued for three weeks after induction of AIA. Ellagic acid treatment significantly (p < 0.01) inhibited foot paw oedematous swelling and attenuated AIA-associated pathology. Ellagic acid significantly (p < 0.01) reduced serum levels of pro-inflammatory cytokines: interleukin 1β (IL-1β), tumor necrosis factor α (TNF-α), and interleukin 17 (IL-17). However, serum levels of IL-10 and interferon γ (IFN-γ) significantly increased (p < 0.01 and p < 0.05, respectively), while serum level of transforming growth factor β (TGF-β) did not significantly alter with EA treatment. In conclusion, these results suggest that EA attenuated AIA-associated pathology in the mouse model by downregulation of pro-inflammatory cytokines and upregulation of anti-inflammatory cytokines.