Background: Genetic factors are known to contribute to COPD susceptibility and these factors are not fully understood. Conflicting results have been reported for many genetic studies of candidate genes based on their role in the disease. Genome-wide association studies in combination with expression profiling have identified a number of new candidates includingIREB2. A meta-analysis has implicated transforming growth factor beta-1 (TGFbeta1) as a contributor to disease susceptibility.Methods: We have examined previously reported associations in both genes in a collection of 1017 white COPD patients and 912 non-diseased smoking controls. Genotype information was obtained for seven SNPs in theIREB2gene, and for four SNPs in theTGFbeta1gene. Allele and genotype frequencies were compared between COPD cases and controls, and odds ratios were calculated. The analysis was adjusted for age, sex, smoking and centre, including interactions of age, sex and smoking with centre.Results: Our data replicate the association ofIREB2SNPs in association with COPD for SNP rs2568494, rs2656069 and rs12593229 with respective adjusted p-values of 0.0018, 0.0039 and 0.0053. No significant associations were identified forTGFbeta1.Conclusions: These studies have therefore confirmed that theIREB2locus is a contributor to COPD susceptibility and suggests a new pathway in COPD pathogenesis invoking iron homeostasis.

Aims: This study is aimed at evaluating the antidiabetic effects of thymoquinone (TQ) on streptozotocin (STZ)-induced diabetes in rats, and exploring the possible underlying mechanisms. Methods: Diabetes was induced in adult male Wistar rats by intraperitoneal injection of freshly prepared STZ (65 mg/kg). After disease induction, 42 rats were equally assigned to: controls, STZ-diabetic group, and STZ-diabetic group treated with oral TQ (35 mg/kg/day) for 5 weeks. Fasting blood glucose levels were determined weekly, and the animals were euthanized at day 38 post-STZ injection. Blood samples were assessed for glucose-insulin homeostasis parameters (plasma glucose, glycated hemoglobin, serum insulin, homeostatic model assessment of insulin resistance, and insulin sensitivity index) and lipid profile. Resected pancreases were subjected to histological examination and immunohistochemical or enzyme-linked immunosorbent assay assessment to determine the pancreatic expression of insulin sensitizing β-cells, anti-apoptotic protein “survivin,” apoptosis-inducer “caspase-3,” prototypic angiogenic factors (vascular endothelial growth factor [VEGF] and endothelial cluster of differentiation 31 [CD31]), pro- and anti-inflammatory cytokines (interleukin-1beta [IL-1β] and interleukin-10 [IL-10], respectively), thiobarbituric acid reactive substances (TBARS), total glutathione (GSH), and superoxide dismutase (SOD). The hepato-renal statuses were assessed biochemically and histologically. Results: Therapy with TQ markedly improved the integrity of pancreatic islets, glucose-insulin homeostasis-related parameters, lipid profile parameters, and hepato-renal functional and histomorphological statuses that collectively were severely deteriorated in untreated diabetic group. Mechanistically, TQ therapy efficiently increased insulin producing β-cells, upregulated survivin, VEGF, CD31, IL-10, GSH and SOD, and downregulated caspase-3, IL-1β, and TBARSs in the pancreatic tissues of STZ-diabetic rats. Conclusions: These findings prove the anti-diabetic potential of TQ and its efficacy in regenerating pancreatic β-cells and ameliorating pancreatic inflammation and oxidative stress, and highlight its novelty in repressing apoptosis of β-cells and enhancing islet revascularization in STZ-diabetic rats. Further studies are required to support these findings and realize their possible clinical significance.

Current treatments of hepatocellular carcinoma (HCC) are ineffective and unsatisfactory in many aspects. Cancer-targeting gene virotherapy using oncolytic adenoviruses (OAds) armed with anticancer genes has shown efficacy and safety in clinical trials. Nowadays, both inhibitor of growth 4 (ING4), as a multimodal tumor suppressor gene, and tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), as a potent apoptosis-inducing gene, are experiencing a renaissance in cancer gene therapy. Herein we investigated the antitumor activity and safety of mono- and combined therapy with OAds armed with ING4 (Ad-ΔB/ING4) and TRAIL (Ad-ΔB/TRAIL) gene, respectively, on preclinical models of human HCC. OAd-mediated expression of ING4 or TRAIL transgene was confirmed. Ad-ΔB/TRAIL and/or Ad-ΔB/ING4 exhibited potent killing effect on human HCC cells (HuH7 and Hep3B) but not on normal liver cells. Most importantly, systemic therapy with Ad-ΔB/ING4 plus Ad-ΔB/TRAIL elicited more eradicative effect on an orthotopic mouse model of human HCC than their monotherapy, without causing obvious overlapping toxicity. Mechanistically, Ad-ΔB/ING4 and Ad-ΔB/TRAIL were remarkably cooperated to induce antitumor apoptosis and immune response, and to repress tumor angiogenesis. This is the first study showing that concomitant therapy with Ad-ΔB/ING4 and Ad-ΔB/TRAIL may provide a potential strategy for HCC therapy and merits further investigations to realize its possible clinical translation.

Streptococcus pneumoniae is a notorious Gram-positive pathogen present asymptomatically in the nasophayrnx of humans. According to the World Health Organization (W.H.O), pneumococcus causes approximately one million deaths yearly. Antibiotic resistance in S. pneumoniae is raising considerable concern around the world. There is an immediate need to address the major issues that have arisen as a result of persistent infections caused by S. pneumoniae. In the present study, subtractive proteomics was used in which the entire proteome of the pathogen consisting of 1947 proteins is effectively decreased to a finite number of possible targets. Various kinds of bioinformatics tools and software were applied for the discovery of novel inhibitors. The CD-HIT analysis revealed 1887 non-redundant sequences from the entire proteome. These non-redundant proteins were submitted to the BLASTp against the human proteome and 1423 proteins were screened as non-homologous. Further, databases of essential genes (DEGG) and J browser identified almost 171 essential proteins. Moreover, non-homologous, essential proteins were subjected in KEGG Pathway Database which shortlisted six unique proteins. In addition, the subcellular localization of these unique proteins was checked and cytoplasmic proteins were chosen for the druggability analysis, which resulted in three proteins, namely DNA binding response regulator (SPD_1085), UDP-N-acetylmuramate—L-alanine Ligase (SPD_1349) and RNA polymerase sigma factor (SPD_0958), which can act as a promising potent drug candidate to limit the toxicity caused by S. pneumoniae. The 3D structures of these proteins were predicted by Swiss Model, utilizing the homology modeling approach. Later, molecular docking by PyRx software 0.8 version was used to screen a library of phytochemicals retrieved from PubChem and ZINC databases and already approved drugs from DrugBank database against novel druggable targets to check their binding affinity with receptor proteins. The top two molecules from each receptor protein were selected based on the binding affinity, RMSD value, and the highest conformation. Finally, the absorption, distribution, metabolism, excretion, and toxicity (ADMET) analyses were carried out by utilizing the SWISS ADME and Protox tools. This research supported the discovery of cost-effective drugs against S. pneumoniae. However, more in vivo/in vitro research should be conducted on these targets to investigate their pharmacological efficacy and their function as efficient inhibitors.

Polyunsaturated fatty acids (PUFAs) constitute a significant lipid class with essential nutritional and health benefits for both animal and human health; however, their effect and interaction with the gut microbiota ecosystem are still unclear. Therefore, the present study aims to investigate the effect of fish oil (FO) on ruminal fermentation and bacterial abundance under high- and low-forage diets. Thirty-six ruminal fluid samples were allocated into two experiments. The first was on high-forage diet and included three groups: the control (basal diet with 70% forage and 30% concentrate), group 2 (basal diet + 5 mL/L FO), and group 3 (basal diet + 10 mL/L). The second experiment was on low-forage diet: the control (basal diet with 30% forage and 70% concentrate), group 2 (basal diet + 5 mL/L FO), and group 3 (basal diet + 10 mL/L). The results showed that although FO supplementation did not affect the pH level among different diets, it significantly decreased methane under a high-forage diet. In addition, regarding the fatty acids profile, FO supplementation in high-forage diet significantly decreased fatty acids in both; however, under a low-forage diet, FO groups showed significantly higher fatty acid content than the control. However, FO supplementation increased the abundance of Anaerovibirio, Selenomonas, pseudobutyrivibrio, and butyrivibrio through a high-forage diet. In contrast, the abundance of Prevotella, Rikenellaceae RC9 gut group, and Saccharofermentans was depressed with FO supplementation. Whereas under low-forage diet, FO supplementation increased Ruminobacter, Anaerovibirio, Megasphaera, Pseudobutyrivibrio, Streptococcus, Butyrivibrio, unclassified_lachnospiraceae; it also decreased Prevotella and Rikenellaceae RC9 abundance similar to the high-forage diet. Based on the KEGG pathway results, FO supplementation significantly downregulated genes mainly related to folding, sorting and degradation, environmental adaptation, cell motility, transcription, membrane transport, and signal transduction. The results revealed that FO has a depressing effect on ruminal fermentation and some bacterial population; however, this negative effect can be minimized in high-concentrate diets.