Protein C Promotor Haplotypes Associated with Large-Artery Atherosclerosis Stroke in Iranian Population.

Ischemic stroke (IS) is a complex disease regarding its risk factors; among those factors, genetics has an important role. Protein C (PC) is an important antithrombotic enzyme which its genetic variations disrupt the normal cascade of blood coagulation, resulting in thrombosis and increases the chance of stroke. Therefore, we aimed to investigate three single-nucleotide polymorphisms (SNPs) located in the core promoter of PC in order to find their role in this condition in the Iranian population. Blood samples from IS patients (n = 249) and healthy volunteers (n = 203) were collected. Biochemical analysis was performed. Genotyping was conducted on the extracted DNA from blood samples via the HRM technique. Bioinformatic investigations were used to assess how these SNPs may be involved in the IS. Smoking, hypertension, low-density lipoprotein cholesterol, and fasting blood glucose were significantly different between healthy and IS groups. rs1799809 and rs1799810 SNPs were significantly more frequent among IS patients. Also, among four identified haplotypes, CGT was found associated with IS (p = 0.001). It was also found that these SNPs may interfere with the binding of transcription factors to alter the expression of PC. Our data predict that SNPs at the core promoter of PC can affect the binding affinity of transcription factors which in turn reduces the expression of PC and increases the risk of IS.

Interferon-inducer antivirals: Potential candidates to combat COVID-19.

Coronavirus disease 2019 (COVID-19) is an infective disease generated by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Given the pandemic urgency and lack of an effective cure for this disease, drug repurposing could open the way for finding a solution. Lots of investigations are ongoing to test the compounds already identified as antivirals. On the other hand, induction of type I interferons are found to play an important role in the generation of immune responses against SARS-CoV-2. Therefore, it was opined that the antivirals capable of triggering the interferons and their signaling pathway, could rationally be beneficial for treating COVID-19. On this basis, using a database of antivirals, called drugvirus, some antiviral agents were derived, followed by searches on their relevance to interferon induction. The examined list included drugs from different categories such as antibiotics, immunosuppressants, anti-cancers, non-steroidal anti-inflammatory drugs (NSAID), calcium channel blocker compounds, and some others. The results as briefed here, could help in finding potential drug candidates for COVID-19 treatment. However, their advantages and risks should be taken into account through precise studies, considering a systemic approach. Even though the adverse effects of some of these drugs may overweight their benefits, considering their mechanisms and structures may give a clue for designing novel drugs in the future. Furthermore, the antiviral effect and IFN-modifying mechanisms possessed by some of these drugs might lead to a synergistic effect against SARS-CoV-2, which deserve to be evaluated in further investigations.

Anti-Toxoplasma gondii activity of 5-oxo-hexahydroquinoline derivatives: synthesis, in vitro and in vivo evaluations, and molecular docking analysis.

BACKGROUND AND PURPOSE: The aim of this study was to evaluate the in vitro and in vivo anti-Toxoplasma gondii (T. gondii) effect of 5-oxo-hexahydroquinoline compounds. Moreover, molecular docking study of the compounds into the active site of enoyl-acyl carrier protein reductase (ENR) as a necessary enzyme for the vitality of apicoplast was carried out. EXPERIMENTAL APPROACH: A number of 5-oxo-hexahydoquinoline derivatives (Z1-Z4) were synthesized. The T. gondii tachyzoites of RH strain were treated by different concentrations (1-64 µg/mL) of the compounds. The viability of the encountered parasites with compounds was assessed using flow cytometry and propidium iodide (PI) staining. Due to the high mortality effect of Z3 and Z4 in vitro, their chemotherapy effect was assessed by inoculation of tachyzoites to four BALB/c mice groups (n = 5), followed by the gavage of various concentrations of the compounds to the mice. Molecular docking was done to study the binding affinity of the synthesized 5-oxo-hexahydroquinolines into ENR enzyme active site byusing AutoDock Vina® software. Docking was performed by a Lamarckian Genetic Algorithm with 100 runs. FINDINGS / RESULTS: Flow cytometry assay results indicated compounds Z3 and Z4 had relevant mortality effect on parasite tachyzoites. Besides, in vivo experiments were also performed and a partial increase of mice longevity between control and experiment groups was recorded. Molecular docking of Z3 and Z4 in the binding site of ENR enzyme indicated that the compounds were well accommodated within the binding site. Therefore, it could be suggested that these compounds may exert their anti-T. gondii activity through the inhibition of the ENR enzyme. CONCLUSION AND IMPLICATIONS: Compounds Z3 and Z4 are good leads in order to develop better anti-T. gondii agents as they demonstrated both in vitro and in vivo inhibitory effects on tachyzoites viability and infection. Further studies on altering the route of administration along with additional pharmacokinetics evaluations are needed to improve the anti-T. gondii impacts of 5-oxo-hexahydroquinoline compounds.