Identification and evaluation of novel drug targets against the human fungal pathogen Aspergillus fumigatus with elaboration on the possible role of RNA-binding protein

Bakground: Aspergillus fumigatus is an airborne opportunistic fungal pathogen that can cause fatal infections in immunocompromised patients. Although the current anti-fungal therapies are relatively efficient, some issues such as drug toxicity, drug interactions, and the emergence of drug-resistant fungi have promoted the intense research toward finding the novel drug targets

Methods: In search of new antifungal drug targets, we have used a bioinformatics approach to identify novel drug targets. We compared the whole proteome of this organism with yeast Saccharomyces cerevisiae to come up with 153 specific proteins. Further screening of these proteins revealed 50 potential molecular targets in A. fumigatus. Amongst them, RNA-binding protein [RBP] was selected for further examination. The aspergillus fumigatus RBP [AfuRBP], as a peptidylprolyl isomerase, was evaluated by homology modeling and bioinformatics tools. RBP-deficient mutant strains of A. fumigatus were generated and characterized. Furthermore, the susceptibility of these strains to known peptidylprolyl isomerase inhibitors was assessed

Results: AfuRBP-deficient mutants demonstrated a normal growth phenotype. MIC assay results using inhibitors of peptidylprolyl isomerase confirmed a higher sensitivity of these mutants compared to the wild type

Conclusion: Our bioinformatics approach revealed a number of fungal-specific proteins that may be considered as new targets for drug discovery purposes. Peptidylprolyl isomerase, as a possible drug target, was evaluated against two potential inhibitors and the promising results were investigated mechanistically. Future studies would confirm the impact of such target on the antifungal discovery investigations

Serum Antibodies against Helicobacter pylori Neutrophil Activating Protein in Carriers of IL-4 C-590T Genetic Polymorphism Amplify the Risk of Gastritis and Gastric Cancer

Background: Gastric cancer arises, mainly, on an inflammatory background. Helicobocter pylori neutrophil activating [HP-NAP] protein functions as a potent pro-inflammatory mediator. Similarly, IL-4 plays a critical role in the inflammation pathway, the levels of which are altered by C to T transition at position -590 in its promoter region. Here, we have aimed to assess the risk of gastritis and gastric cancer in the co-presence of these two inflammation modulating mediators

Methods: Gastritis [n=58] and gastric cancer [n=31] patients were evaluated and compared with H. py/or/-positive asymptomatic controls [n=46], for serum antibodies against recombinant HP-NAP and IL-4 C-590T single nucleotide polymorphism using immunoblotting and PCR-RFLP, respectively. Multivariable logistic regression, adjusting for age, gender and ethnicity, was used for data analysis

Results: In terms of susceptibility to gastritis, seropositivity to HP-NAP projected a risk impact of 4.62 fold [OR=4.62, 95% Cl=l.50-14.22], which when present in IL-4 -590 T carriers augmented the risk up to 9.7 fold [OR=9.70, 95% CI=2.06-45.69]

A similar pattern, but of a stronger magnitude, occurred for the risk of gastric cancer, which was estimated at 9.07 fold [OR=9.07, 95% Cl=1.99-42.0] for HP-NAP-seropositive subjects and was drastically amplified [OR=33.64, 95% 0=2.06-548.68], when double-positive [HP-NAP seropositive/IL-4 -590 T carrier] subjects were examined against double negatives [HP-NAP seronegative/IL-4 -590 CC]

Conclusion: Our preliminary data indicate that serum antibodies against HP-NAP represent a state of risk, which is further exacerbated in IL-4 -590 T carriers. These biomarkers, if validated in larger prospective studies, can be used to screen for gastric cancer susceptibility

Impact of methylenetetrahydrofolate reductase C677T polymorphism on the risk of gastric cancer and its interaction with helicobacter pylori infection

Attempts for early detection of gastric cancer have recently focused on host's genetic susceptibility factors and gene-environment interactions. We have, herein, studied the association of MTHFR C677T single nucleotide polymorphism [SNP] and its interaction with Helicobacter pylori infection, smoking, age and gender on the risk of gastric cancer among an Iranian population. Gastric cancer patients [n = 450] and cancer-free controls [n = 780] were studied for serum H. pylori-specific IgG antibodies by ELISA and MTHFR C677T polymorphism [SNP] by PCR-RFLP. Demographic and life style data were collected through patient interviews. Unconditional logistic regression model estimated odds ratio [OR] and the corresponding 95% confidence intervals [CI]. The interactions of MTHFR genotype with H. pylori infection [P = 0.03], age [P = 0.049] and gender [P = 0.007] were statistically significant. Accordingly, MTHFR C677T carriers who were also positive for H. pylori infection exhibited 80% [OR = 1.8, 95% CI = 1.0-2.9] significant excess risk of non-cardia gastric cancer. Furthermore, subjects over the age of 50 or female subjects carrying MTHFR C677T SNP showed 40 [OR = 1.4, 95% CI = 1.0-2.0] and 100 [OR = 2.0, 95% CI = 1.2-3.2] percent increased risk of gastric cancer, respectively. MTHFR C677T SNP seems to increase the risk of gastric cancer and the effect is significantly inflated by interactions with H. pylori infection, age and gender