Systems biology approach to identify biomarkers and therapeutic targets for colorectal cancer.

Background: Colorectal cancer (CRC), is the third most prevalent cancer across the globe, and is often detected at advanced stage. Late diagnosis of CRC, leave the chemotherapy and radiotherapy as the main options for the possible treatment of the disease which are associated with severe side effects. In the present study, we seek to explore CRC gene expression data using a systems biology framework to identify potential biomarkers and therapeutic targets for earlier diagnosis and treatment of the disease. Methods: The expression data was retrieved from the gene expression omnibus (GEO). Differential gene expression analysis was conducted using R/Bioconductor package. The PPI network was reconstructed by the STRING. Cystoscope and Gephi software packages were used for visualization and centrality analysis of the PPI network. Clustering analysis of the PPI network was carried out using k-mean algorithm. Gene-set enrichment based on Gene Ontology (GO) and KEGG pathway databases was carried out to identify the biological functions and pathways associated with gene groups. Prognostic value of the selected identified hub genes was examined by survival analysis, using GEPIA. Results: A total of 848 differentially expressed genes were identified. Centrality analysis of the PPI network resulted in identification of 99 hubs genes. Clustering analysis dissected the PPI network into seven interactive modules. While several DEGs and the central genes in each module have already reported to contribute to CRC progression, survival analysis confirmed high expression of central genes, CCNA2, CD44, and ACAN contribute to poor prognosis of CRC patients. In addition, high expression of TUBA8, AMPD3, TRPC1, ARHGAP6, JPH3, DYRK1A and ACTA1 was found to associate with decreased survival rate. Conclusion: Our results identified several genes with high centrality in PPI network that contribute to progression of CRC. The fact that several of the identified genes have already been reported to be relevant to diagnosis and treatment of CRC, other highlighted genes with limited literature information may hold potential to be explored in the context of CRC biomarker and drug target discovery.

A systems pharmacology approach to identify the autophagy-inducing effects of Traditional Persian medicinal plants.

Aging is correlated with several complex diseases, including type 2 diabetes, neurodegeneration diseases, and cancer. Identifying the nature of this correlation and treatment of age-related diseases has been a major subject of both modern and traditional medicine. Traditional Persian Medicine (TPM) embodies many prescriptions for the treatment of ARDs. Given that autophagy plays a critical role in antiaging processes, the present study aimed to examine whether the documented effect of plants used in TPM might be relevant to the induction of autophagy? To this end, the TPM-based medicinal herbs used in the treatment of the ARDs were identified from modern and traditional references. The known phytochemicals of these plants were then examined against literature for evidence of having autophagy inducing effects. As a result, several plants were identified to have multiple active ingredients, which indeed regulate the autophagy or its upstream pathways. In addition, gene set enrichment analysis of the identified targets confirmed the collective contribution of the identified targets in autophagy regulating processes. Also, the protein-protein interaction (PPI) network of the targets was reconstructed. Network centrality analysis of the PPI network identified mTOR as the key network hub. Given the well-documented role of mTOR in inhibiting autophagy, our results hence support the hypothesis that the antiaging mechanism of TPM-based medicines might involve autophagy induction. Chemoinformatics study of the phytochemicals using docking and molecular dynamics simulation identified, among other compounds, the cyclo-trijuglone of Juglans regia L. as a potential ATP-competitive inhibitor of mTOR. Our results hence, provide a basis for the study of TPM-based prescriptions using modern tools in the quest for developing synergistic therapies for ARDs.

Expression and purification of truncated recombinant B8/1 protein of Echinococcus granulosus for diagnosis of hydatid infection in human.

Hydatidosis is one of the most important diseases common between animals and human beings. Caused by Echinococcus granulosus tapeworm, the disease has a global epidemic. The serological diagnostic tests that are now utilized to confirm the imaging approaches have some drawbacks such as low sensitivity and cross-reaction with the serum of the patients infected with other parasites. The application of recombinant and synthetic antigens has proven improvement in the functionality of serological diagnostic tests. The purpose of this study was to demonstrate the expression and purification of truncated recombinant B8/1 (trB8/1) antigen and its application in ELISA for diagnosis of hydatid infection in human. The tEgB8/1 was colonized in the expression vector pET28b (+) and expressed in different strains of E. coli. This protein was purified by Ni2+-NTA chromatography. The antigenicity of the protein was evaluated by Western blotting and ELISA. In the test, 50 positive serum samples from hydatid infected patients, 50 samples from healthy people, and 30 serum samples from patients with other parasitic diseases were used to determine the sensitivity and the specificity of this antigen. The measured sensitivity and specificity of this antigen were identified to be 75.75% and 96.38% respectively. The P value of <0.0001 by using ROC curve, confirmed that this antigen is able to differentiate between healthy and hydatid-infected individuals. Considering the excellent specificity of this antigen and in order to enhance the sensitivity, it is recommended to use a combination of this antigen with other antigens (e.g., EgB8/2-8/5).

Systems Biology Approach to Bioremediation of Nitroaromatics: Constraint-Based Analysis of 2,4,6-Trinitrotoluene Biotransformation by Escherichia coli.

Microbial remediation of nitroaromatic compounds (NACs) is a promising environmentally friendly and cost-effective approach to the removal of these life-threating agents. Escherichia coli (E. coli) has shown remarkable capability for the biotransformation of 2,4,6-trinitro-toluene (TNT). Efforts to develop E. coli as an efficient TNT degrading biocatalyst will benefit from holistic flux-level description of interactions between multiple TNT transforming pathways operating in the strain. To gain such an insight, we extended the genome-scale constraint-based model of E. coli to account for a curated version of major TNT transformation pathways known or evidently hypothesized to be active in E. coli in present of TNT. Using constraint-based analysis (CBA) methods, we then performed several series of in silico experiments to elucidate the contribution of these pathways individually or in combination to the E. coli TNT transformation capacity. Results of our analyses were validated by replicating several experimentally observed TNT degradation phenotypes in E. coli cultures. We further used the extended model to explore the influence of process parameters, including aeration regime, TNT concentration, cell density, and carbon source on TNT degradation efficiency. We also conducted an in silico metabolic engineering study to design a series of E. coli mutants capable of degrading TNT at higher yield compared with the wild-type strain. Our study, therefore, extends the application of CBA to bioremediation of nitroaromatics and demonstrates the usefulness of this approach to inform bioremediation research.

Solubilization Behavior of Polyene Antibiotics in Nanomicellar System: Insights from Molecular Dynamics Simulation of the Amphotericin B and Nystatin Interactions with Polysorbate 80.

Amphotericin B (AmB) and Nystatin (Nys) are the drugs of choice for treatment of systemic and superficial mycotic infections, respectively, with their full clinical potential unrealized due to the lack of high therapeutic index formulations for their solubilized delivery. In the present study, using a coarse-grained (CG) molecular dynamics (MD) simulation approach, we investigated the interaction of AmB and Nys with Polysorbate 80 (P80) to gain insight into the behavior of these polyene antibiotics (PAs) in nanomicellar solution and derive potential implications for their formulation development. While the encapsulation process was predominantly governed by hydrophobic forces, the dynamics, hydration, localization, orientation, and solvation of PAs in the micelle were largely controlled by hydrophilic interactions. Simulation results rationalized the experimentally observed capability of P80 in solubilizing PAs by indicating (i) the dominant kinetics of drugs encapsulation over self-association; (ii) significantly lower hydration of the drugs at encapsulated state compared with aggregated state; (iii) monomeric solubilization of the drugs; (iv) contribution of drug-micelle interactions to the solubilization; (v) suppressed diffusivity of the encapsulated drugs; (vi) high loading capacity of the micelle; and (vii) the structural robustness of the micelle against drug loading. Supported from the experimental data, our simulations determined the preferred location of PAs to be the core-shell interface at the relatively shallow depth of 75% of micelle radius. Deeper penetration of PAs was impeded by the synergistic effects of (i) limited diffusion of water; and (ii) perpendicular orientation of these drug molecules with respect to the micelle radius. PAs were solvated almost exclusively in the aqueous poly-oxyethylene (POE) medium due to the distance-related lack of interaction with the core, explaining the documented insensitivity of Nys solubilization to drug-core compatibility in detergent micelles. Based on the obtained results, the dearth of water at interior sites of micelle and the large lateral occupation space of PAs lead to shallow insertion, broad radial distribution, and lack of core interactions of the amphiphilic drugs. Hence, controlled promotion of micelle permeability and optimization of chain crowding in palisade layer may help to achieve more efficient solubilization of the PAs.

Frequency of human enterovirus 71 in children under 8 years old with aseptic menengitis in Tehran.

BACKGROUND: Human enterovirus 71 (HEV71) was isolated for the first time from an infant with encephalitis in California in 1969 and then spread through the world. It has emerged as a major cause of a vast variety of diseases such as epidemics of hand, foot and mouth disease (HFMD), aseptic meningitis (AM), acute flaccid paralysis, and encephalitis. The aim of this study was to determine the prevalence of enterovirus 71 in children < 8 years old who were hospitalized due to primary diagnosis of AM in Tehran. METHODS: One hundred cerebrospinal fluid samples (CSF) were collected by physicians from children with a diagnosis of AM and transported on ice to the Pasteur Institute of Iran for further processing. Viral RNA was extracted and EV71 infection was detected by RT-PCR method using the specific primers. RESULTS: EV71 infection was detected in 14 patients (14%). Eight (57.14%) patients were younger than 2 years old, 11 (78.57%) were male and 3 (21.43%) were female. The seasonal peaks of EV71 were observed during autumn and winter with 6 (42.86%) and 5 (35.71%) cases, respectively. CONCLUSIONS: EV71 should be considered as a causative agent of AM in Iran with the epidemiological pattern similar to that of other enteroviruses as males are more susceptible to be affected by these viruses. Further studies on this virus are needed to improve our knowledge about them in our country.