Meta-Analysis of miRNAs and Their Involvement as Biomarkers in Oral Cancers

Oral Squamous Cell Carcinoma (OSCC) is one of the most common cancers worldwide. Recent studies have highlighted the role of miRNA in disease pathology, indicating its potential use as an early diagnostic marker. Dysregulated expression of miRNAs is known to affect cell growth, and these may function as tumor suppressors or oncogenes in various cancers. The main objective of this study was to characterize the extracellular miRNAs involved in oral cancer (OC) that can potentially be used as biomarkers of OC. A total of 318 miRNAs involved in oral carcinoma were shortlisted. Differentially expressed genes (DEGs) of oral carcinoma from reported experiments were identified. Common genes between lists of DEGs of OC of each miRNA were identified. These common genes are the targets of specific miRNA, which may be used as biomarkers of OC. A list of significant biomarkers for cancer was generated like CDH2 and CDK7, and functional enrichment analysis identified the role of miRNAs in major pathways like cell adhesion molecules pathway affected by cancer. We observed that at least 25 genes like ABCF3, ALDH2, CD163L1, and so forth are regulated by a maximum number of miRNAs; thereby, they can be used as biomarkers of OC

Structure-Based Virtual Screening of Tumor Necrosis Factor-α Inhibitors by Cheminformatics Approaches and Bio-Molecular Simulation

Tumor necrosis factor-α (TNF-α) is a drug target in rheumatoid arthritis and several other auto-immune disorders. TNF-α binds with TNF receptors (TNFR), located on the surface of several immunological cells to exert its effect. Hence, the use of inhibitors that can hinder the complex formation of TNF-α/TNFR can be of medicinal significance. In this study, multiple chem-informatics approaches, including descriptor-based screening, 2D-similarity searching, and pharmacophore modelling were applied to screen new TNF-α inhibitors. Subsequently, multiple-docking protocols were used, and four-fold post-docking results were analyzed by consensus approach. After structure-based virtual screening, seventeen compounds were mutually ranked in top-ranked position by all the docking programs. Those identified hits target TNF-α dimer and effectively block TNF-α/TNFR interface. The predicted pharmacokinetics and physiological properties of the selected hits revealed that, out of seventeen, seven compounds (4, 5, 10, 11, 13–15) possessed excellent ADMET profile. These seven compounds plus three more molecules (7, 8 and 9) were chosen for molecular dynamics simulation studies to probe into ligand-induced structural and dynamic behavior of TNF-α, followed by ligand-TNF-α binding free energy calculation using MM-PBSA. The MM-PBSA calculations revealed that compounds 4, 5, 7 and 9 possess highest affinity for TNF-α; 8, 11, 13–15 exhibited moderate affinities, while compound 10 showed weaker binding affinity with TNF-α. This study provides valuable insights to design more potent and selective inhibitors of TNF-α, that will help to treat inflammatory disorders

High prevalence of G3 rotavirus in hospitalized children in Rawalpindi, Pakistan during 2014.

Rotavirus A species (RVA) is the leading cause of severe diarrhea among children in both developed and developing countries. Among different RVA G types, humans are most commonly infected with G1, G2, G3, G4 and G9. During 2003-2004, G3 rotavirus termed as "new variant G3" emerged in Japan that later disseminated to multiple countries across the world. Although G3 rotaviruses are now commonly detected globally, they have been rarely reported from Pakistan. We investigated the genetic diversity of G3 strains responsible RVA gastroenteritis in children hospitalized in Rawalpindi, Pakistan during 2014. G3P[8] (18.3%; n = 24) was detected as the most common genotype causing majority of infections in children less than 06 months. Phylogenetic analysis of Pakistani G3 strains showed high amino acid similarity to "new variant G3" and G3 strains reported from China, Russia, USA, Japan, Belgium and Hungary during 2007-2012. Pakistani G3 strains belonged to lineage 3 within sub-lineage 3d, containing an extra N-linked glycosylation site compared to the G3 strain of RotaTeqTM. To our knowledge, this is the first report on the molecular epidemiology of G3 rotavirus strains from Pakistan and calls for immediate response measures to introduce RV vaccine in the routine immunization program of the country on priority

In Vitro and In Silico Approaches for the Evaluation of Antimicrobial Activity, Time-Kill Kinetics, and Anti-Biofilm Potential of Thymoquinone (2-Methyl-5-propan-2-ylcyclohexa-2,5-diene-1,4-dione) against Selected Human Pathogens

Thymoquinone (2-methyl-5-propan-2-ylcyclohexa-2,5-diene-1,4-dione; TQ), a principal bioactive phytoconstituent of Nigella sativa essential oil, has been reported to have high antimicrobial potential. Thus, the current study evaluated TQ’s antimicrobial potential against a range of selected human pathogens using in vitro assays, including time-kill kinetics and anti-biofilm activity. In silico molecular docking of TQ against several antimicrobial target proteins and a detailed intermolecular interaction analysis was performed, including binding energies and docking feasibility. Of the tested bacteria and fungi, S. epidermidis ATCC 12228 and Candida albicans ATCC 10231 were the most susceptible to TQ, with 50.3 ± 0.3 mm and 21.1 ± 0.1 mm zones of inhibition, respectively. Minimum inhibitory concentration (MIC) values of TQ are in the range of 12.5–50 µg/mL, while minimum biocidal concentration (MBC) values are in the range of 25–100 µg/mL against the tested organisms. Time-kill kinetics of TQ revealed that the killing time for the tested bacteria is in the range of 1–6 h with the MBC of TQ. Anti-biofilm activity results demonstrate that the minimum biofilm inhibitory concentration (MBIC) values of TQ are in the range of 25–50 µg/mL, while the minimum biofilm eradication concentration (MBEC) values are in the range of 25–100 µg/mL, for the tested bacteria. In silico molecular docking studies revealed four preferred antibacterial and antifungal target proteins for TQ: D-alanyl-D-alanine synthetase (Ddl) from Thermus thermophilus, transcriptional regulator qacR from Staphylococcus aureus, N-myristoyltransferase from Candida albicans, and NADPH-dependent D-xylose reductase from Candida tenuis. In contrast, the nitroreductase family protein from Bacillus cereus and spore coat polysaccharide biosynthesis protein from Bacillus subtilis and UDP-N-acetylglucosamine pyrophosphorylase from Aspergillus fumigatus are the least preferred antibacterial and antifungal target proteins for TQ, respectively. Molecular dynamics (MD) simulations revealed that TQ could bind to all four target proteins, with Ddl and NADPH-dependent D-xylose reductase being the most efficient. Our findings corroborate TQ’s high antimicrobial potential, suggesting it may be a promising drug candidate for multi-drug resistant (MDR) pathogens, notably Gram-positive bacteria and Candida albicans.</i

Computational Docking Study of p7 Ion Channel from HCV Genotype 3 and Genotype 4 and Its Interaction with Natural Compounds

<div><p>Background</p><p>The current standard care therapy for hepatitis C virus (HCV) infection consists of two regimes, namely interferon-based and interferon-free treatments. The treatment through the combination of ribavirin and pegylated interferon is expensive, only mildly effective, and is associated with severe side effects. In 2011, two direct-acting antiviral (DAA) drugs, boceprevir and telaprevir, were licensed that have shown enhanced sustained virologic response (SVR) in phase III clinical trial, however, these interferon-free treatments are more sensitive to HCV genotype 1 infection. The variable nature of HCV, and the limited number of inhibitors developed thus aim in expanding the repertoire of available drug targets, resulting in targeting the virus assembly therapeutically.</p><p>Aim</p><p>We conducted this study to predict the 3D structure of the p7 protein from the HCV genotypes 3 and 4. Approximately 63 amino acid residues encoded in HCV render this channel sensitive to inhibitors, making p7 a promising target for novel therapies. HCV p7 protein forms a small membrane known as viroporin, and is essential for effective self-assembly of large channels that conduct cation assembly and discharge infectious virion particles.</p><p>Method</p><p>In this study, we screened drugs and flavonoids known to disrupt translation and production of HCV proteins, targeted against the active site of p7 residues of HCV genotype 3 (GT3) (isolatek3a) and HCV genotype 4a (GT4) (isolateED43). Furthermore, we conducted a quantitative structure–activity relationship and docking interaction study.</p><p>Results</p><p>The drug NB-DNJ formed the highest number of hydrogen bond interactions with both modeled p7 proteins with high interaction energy, followed by BIT225. A flavonoid screen demonstrated that Epigallocatechin gallate (EGCG), nobiletin, and quercetin, have more binding modes in GT3 than in GT4. Thus, the predicted p7 protein molecule of HCV from GT3 and GT4 provides a general avenue to target structure-based antiviral compounds.</p><p>Conclusions</p><p>We hypothesize that the inhibitors of viral p7 identified in this screen may be a new class of potent agents, but further confirmation <i>in vitro</i> and <i>in vivo</i> is essential. This structure-guided drug design for both GT3 and GT4 can lead to the identification of drug-like natural compounds, confirming p7 as a new target in the rapidly increasing era of HCV.</p></div

Alignment of antigenic residues in VP4 between the strains contained in Rotarix^TM and RotaTeq^TM and Pakistani P[8] and P[4].

<p><b>(A)</b> Antigenic residues are divided in three antigenic epitopes in VP8* (8–1, 8–2, 8–3 and 8–4). Amino acids in green are different from both Rotarix^TM and G3 strain of RotaTeq^TM. <b>(B)</b> Surface representation of the VP8* core (PDB 1KQR). Antigenic epitopes are colored red 8–1, orange 8–2, green 8–3 and blue 8–4. Surface exposed residues that differ between Pakistani G3P[8] and vaccine Rotarix^TM and RotaTeq^TM are shown in cyan.</p

Comparison of VP7 antigenic epitope sites between Pakistani G3 strains and rotavirus vaccine Rotarix^TM and RotaTeq^TM.

<p><b>(A)</b> Antigenic residues are divided into three antigenic epitopes 7-1a, 7-1b and 7–2. Amino acid highlighted in green are those that differ from G3 strain of RotaTeq^TM while those in gray are different from Rotarix^TM. <b>(B)</b> Surface representation of VP7 trimer (PDB 3FMG). Antigenic epitopes are colored in red 7-1a, purple 7-1b and green 7–2. Surface exposed residues that differ between Pakistani G3 and vaccine strains of Rotarix^TM and RotaTeq^TM are shown in cyan.</p