Design and synthesis of new fused carbazole-imidazole derivatives as anti-diabetic agents: In vitro α-glucosidase inhibition,kinetic, and in silico studies

Twenty three fused carbazole–imidazoles 6a–w were designed, synthesized, and screened as new α-glucosidase inhibitors. All the synthesized fused carbazole-imidazoles 6a-w were found to be more active than acarbose (IC₅₀?=?750.0?±?1.5?µM) against yeast α-glucosidase with IC₅₀ values in the range of 74.0?±?0.7–298.3?±?0.9?µM. Kinetic study of the most potent compound 6v demonstrated that this compound is a competitive inhibitor for α-glucosidase (K_i value?=?75?µM). Furthermore, the in silico studies of the most potent compounds 6v and 6o confirmed that these compounds interacted with the key residues in the active site of α-glucosidase.     

Using phylogeographic approaches to analyse the dispersal history,velocity and direction of viral lineages — Application to rabies virus spread in Iran

Recent years have seen the extensive use of phylogeographic approaches to unveil the dispersal history of virus epidemics. Spatially explicit reconstructions of viral spread represent valuable sources of lineage movement data that can be exploited to investigate the impact of underlying environmental layers on the dispersal of pathogens. Here, we performed phylogeographic inference and applied different post hoc approaches to analyse a new and comprehensive data set of viral genomes to elucidate the dispersal history and dynamics of rabies virus (RABV) in Iran, which have remained largely unknown. We first analysed the association between environmental factors and variations in dispersal velocity among lineages. Second, we present, test and apply a new approach to study the link between environmental conditions and the dispersal direction of lineages. The statistical performance (power of detection, false‐positive rate) of this new method was assessed using simulations. We performed phylogeographic analyses of RABV genomes, allowing us to describe the large diversity of RABV in Iran and to confirm the cocirculation of several clades in the country. Overall, we estimate a relatively high lineage dispersal velocity, similar to previous estimates for dog rabies virus spread in northern Africa. Finally, we highlight a tendency for RABV lineages to spread in accessible areas associated with high human population density. Our analytical workflow illustrates how phylogeographic approaches can be used to investigate the impact of environmental factors on several aspects of viral dispersal dynamics.     

Long‐term ethanol consumption promotes changes in β‐defensin isoform gene expression and induces structural changes and oxidative DNA damage to the epididymis of rats

Chronic alcohol ingestion causes sexual dysfunction, impairs sperm motility and fertility, and changes semen quality. Considering the key role of epididymis in sperm development, the aim of the present study was to evaluate the effects of long‐term ethanol consumption on epididymis changes, including alterations in β‐defensin isoform gene expression, oxidative stress, and pathological changes, such as cell proliferation and fibrosis in the epididymis of rats. In this study, male Wistar rats were equally divided into control and ethanol (4.5 g/kg BW) groups. After six weeks of treatment, the results revealed the proliferation of epididymis cells, fibrosis in the epididymis tissue, and a significant rise in the level of 8‐OHdG and nicotinamide adenine dinucleotide phosphate (NADPH) oxidase in the ethanol group, compared with the control group. Moreover, the ethanol group showed an increase in the gene expression of epididymal β‐defensin isoforms 15 and 21 and a reduction in the gene expression of β‐defensin isoforms 27 and 30, compared with the controls. These findings indicate that ethanol‐induced epididymal damage and sperm abnormalities might be partly associated with changes in β‐defensin isoforms and epididymal structure, mediated by the increased activities of 8‐OHdG and NADPH oxidase.     

Comparison of expression optimization of new derivative of staphylokinase (SAK-2RGD-TTI) with the rSAK

Staphylokinase (SAK) is a promising thrombolytic agent for the treatment of patients suffering from blood-clotting disorders. To increase the potency of SAK and to minimize vessel reocclusion, a new construct bearing SAK motif fused to tsetse thrombin inhibitor (TTI) via a 20-amino acid linker with 2 RGD (2 × arginine-glycine-aspartic acid inhibiting platelet aggregation via attachment to integrin receptors of platelet) was codon optimized and expressed comparatively in Pichia pastoris GS115 as a Mut⁺ strain and KM71H as a Mut^s strain. Fusion protein was optimized in terms of best expression condition and fibrinolytic activity and compared with the rSAK. Expression level of the designed construct reached up to 175 mg/L of the culture medium after 72-hr stimulation with 2.5% methanol and remained steady for 3–4 days. The highest expression was obtained at the range of 2–3% methanol. The SAK-2RGD-TT (relative activity >82%) was more active at 25–37 °C than rSAK (relative activity of 93%). Further, it showed relative activity >80% at pH ranges of 7–9. Western blot analysis showed two bands of nearly 27 and 24 kDa at ratio of 5 to 3, respectively. The specific fibrinolytic activity of the SAK-2RGD-TTI was measured as 8,269 U/mg, and 19,616 U/mg for the nonpurified and purified proteins, respectively. Deglycosylation by using tunicamycin in culture medium resulted in higher fibrinolytic activity of SAK-2RGD-TTI (2.2 fold). Consequently, compared to the rSAK, at the same equimolar proportion, addition of RGD and TTI fragments could increase fibrinolytic activity. Also, P. pastoris can be considered as an efficient host for overexpression of the soluble SAK-2RGD-TTI with high activity without requiring a complicated purification procedure.     

Modulation of Apoptosis and Oxidative Stress with Nesfatin-1 in Doxorubicin Induced Cardiotoxicity in Male Rat

International Journal of Peptide Research and Therapeutics - Fibroblast growth factor 21 (FGF21) is a metabolic regulator with a wide range of biological functions. Although previous studies have...     

CTNNBIP1 downregulation is associated with tumor grade and viral infections in gastric adenocarcinoma

Gastric cancer is a life-threatening disease; resulting from interaction among genetic, epigenetic, and environmental factors. Aberrant dysregulation and methylation changes in Wnt/β-catenin signaling downstream elements are a prevalent phenomenon encountered in gastric tumorigenesis. Also, viral infections play a role in gastric cancer development. CTNNBIP1 (β-catenin interacting protein 1) gene is an antagonist of Wnt signaling which binds to the β-catenin molecules. The CTNNBIP1 function as tumor suppressor gene or oncogene in different types of cancer is controversial. Moreover, its function and regulatory mechanisms in gastric cancer progression is unknown. In the present study, we examined CTNNBIP1 gene expression, the methylation status of the regulatory region of the gene, and their association with Epstein–Barr virus (EBV), and cytomegalovirus (CMV) and Helicobacter pylori infections in human gastric adenocarcinoma tissues in comparison with their adjacent nontumoral tissues. Our data revealed a significant downregulation of CTNNBIP1 in gastric tumors. Female patients showed lower level of CTNNBIP1 than males (p < 0.05). Also, decreased expression of CTNNBIP1 was markedly associated with well-differentiated tumor grades (p < 0.05). No methylation change was observed between tumoral and nontumoral tissues. Additionally, CTNNBIP1 down regulation was significantly associated with CMV infection (p < 0.05). In the absence of EBV infection, lower expression of CTNNBIP1 was observed. There was no association between H. pylori infection and CTNNBIP1 expression. Our findings revealed the tumor suppressor role for CTNNBIP1 in gastric adenocarcinoma. Interestingly, EBV and CMV infections modulate CTNNBIP1 expression.     

Wnt lipidation: Roles in trafficking,modulation, and function

The Wnt signaling pathway consists of various downstream target proteins that have substantial roles in mammalian cell proliferation, differentiation, and development. Its aberrant activity can lead to uncontrolled proliferation and tumorigenesis. The posttranslational connection of fatty acyl chains to Wnt proteins provides the unique capacity for regulation of Wnt activity. In spite of the past belief that Wnt molecules are subject to dual acylation, it has been shown that these proteins have only one acylation site and undergo monounsaturated fatty acylation. The Wnt monounsaturated fatty acyl chain is more than just a hydrophobic coating and appears to be critical for Wnt signaling, transport, and receptor activation. Here, we provide an overview of recent findings in Wnt monounsaturated fatty acylation and the mechanism by which this lipid moiety regulates Wnt activity from the site of production to its receptor interactions.