Soyasapogenol-B as a Potential Multitarget Therapeutic Agent for Neurodegenerative Disorders: Molecular Docking and Dynamics Study.

Neurodegenerative disorders involve various pathophysiological pathways, and finding a solution for these issues is still an uphill task for the scientific community. In the present study, a combination of molecular docking and dynamics approaches was applied to target different pathways leading to neurodegenerative disorders such as Alzheimer's disease. Initially, abrineurin natural inducers were screened using physicochemical properties and toxicity assessment. Out of five screened compounds, a pentacyclic triterpenoid, i.e., Soyasapogenol B appeared to be the most promising after molecular docking and simulation analysis. Soyasapogenol B showed low TPSA (60.69), high absorption (82.6%), no Lipinski rule violation, and no toxicity. Docking interaction analysis revealed that Soyasapogenol B bound effectively to all of the targeted proteins (AChE, BuChE MAO-A, MAO-B, GSK3ß, and NMDA), in contrast to other screened abrineurin natural inducers and inhibitors. Importantly, Soyasapogenol B bound to active site residues of the targeted proteins in a similar pattern to the native ligand inhibitor. Further, 100 ns molecular dynamics simulations analysis showed that Soyasapogenol B formed stable complexes against all of the targeted proteins. RMSD analysis showed that the Soyasapogenol B-protein complex exhibited average RMSD values of 1.94 Å, 2.11 Å, 5.07 Å, 2.56 Å, 3.83 Å and 4.07 Å. Furthermore, the RMSF analysis and secondary structure analysis also indicated the stability of the Soyasapogenol B-protein complexes.

PPM1A Methylation Is Associated With Vascular Recurrence in Aspirin-Treated Patients.

BACKGROUND AND PURPOSE: Despite great efforts by pharmacogenetic studies, the causes of aspirin failure to prevent the recurrence of ischemic events remain unclear. Our aim was to study whether epigenetics could be associated with the risk of vascular recurrence in aspirin-treated stroke patients. METHODS: We performed an epigenetic joint analysis study in 327 patients treated with aspirin. In the discovery stage, we performed a nested case-control study in 38 matched ischemic stroke patients in whom 450 000 methylation sites were analyzed. Nineteen patients presented vascular recurrence after stroke, and 19 matched patients did not present vascular recurrence during the first year of follow-up. In a second stage, 289 new patients were analyzed by EpiTYPER. RESULTS: The following 3 differentially methylated candidate CpG sites, were identified in the discovery stage and analyzed in the second stage: cg26039762 (P=9.69×10(-06), RAF1), cg04985020 (P=3.47×10(-03), PPM1A), and cg08419850 (P=3.47×10(-03), KCNQ1). Joint analysis identified an epigenome-wide association for cg04985020 (PPM1A; P=1.78×10(-07)), with vascular recurrence in patients treated with aspirin. CONCLUSIONS: The pattern of differential methylation in PPM1A is associated with vascular recurrence in aspirin-treated stroke patients.

Effect of Date Palm (Phoenix dactylifera) Phytochemicals on Aß1-40 Amyloid Formation: An in-silico Analysis.

Alzheimer's disease (AD) is a neurodegenerative disease and the most prevalent form of dementia. The generation of oxygen free radicals and oxidative damage is believed to be involved in the pathogenesis of AD. It has been suggested that date palm, a plant rich in phenolic compounds and flavonoids, can provide an alternative treatment to fight memory loss and cognitive dysfunction due to its potent antioxidant activity. Thus, we studied the effect of flavonoids present in date palm on Aß1-40 amyloid formation using molecular docking and molecular dynamics simulation. AutoDock. Myricetin was used as a positive control drug. The flavonoids Diosmetin, Luteolin, and Rutin were found to be potent inhibitors of aggregation (docking energies ≤ -8.05 kcal mol-1) targeting Aß1-40 fibrils (both 2LMO and 6TI5), simultaneously. Further screening by physicochemical properties and drug-likeness analysis suggested that all flavonoids except Rutin followed Lipinski's rule of five. Rutin was, thus, taken as a negative control (due to its violation of Lipinski's rule) to compare its dynamics with Diosmetin. Diosmetin exhibited the highest positive scores for drug likeness. Since Luteolin exhibited moderate drug-likeness and better absorption properties, it was also included in molecular dynamics simulation. Molecular dynamics of shortlisted compounds (Rutin, Diosmetin, and Luteolin) were performed for 200 ns, and the results were analyzed by monitoring root mean square deviations (RMSD), root mean square fluctuation (RMSF) analysis, the radius of gyration (Rg), and solvent accessible surface area (SASA). The results proved the formation of a stable protein-compound complex. Based on binding energies and non-bonded interactions, Rutin and Luteolin emerged as better lead molecules than Diosmetin. However, high MW (610.5), lowest absorption rate (16.04%), and more than one violation of Lipinski's rule make Rutin a less likely candidate as an anti-amyloidogenic agent. Moreover, among non-violators of Lipinski's rule, Diosmetin exhibited a greater absorption rate than Luteolin as well as the highest positive scores for drug-likeness. Thus, we can conclude that Diosmetin and Luteolin may serve as a scaffold for the design of better inhibitors with higher affinities toward the target proteins. However, these results warrant in-vitro and in-vivo validation before practical use.

High-Throughput Screening and Molecular Dynamics Simulation of Natural Product-like Compounds against Alzheimer's Disease through Multitarget Approach.

Alzheimer's disease (AD) is a progressive neurological disorder that affects 50 million people. Despite this, only two classes of medication have been approved by the FDA. Therefore, we have planned to develop therapeutics by multitarget approach. We have explored the library of 2029 natural product-like compounds for their multi-targeting potential against AD by inhibiting AChE, BChE (cholinergic pathway) MAO-A, and MOA-B (oxidative stress pathway) through in silico high-throughput screening and molecular dynamics simulation. Based on the binding energy of these target enzymes, approximately 189 compounds exhibited a score of less than -10 kcal/mol against all targets. However, none of the control inhibitors exhibited a binding affinity of less than -10 kcal/mol. Among these, the top 10 hits of compounds against all four targets were selected for ADME-T analysis. As a result, only F0850-4777 exhibited an acceptable range of physicochemical properties, drug-likeness, pharmacokinetics, and suitability for BBB permeation with high GI-A and non-toxic effects. The molecular dynamics study confirmed that F0850-4777 remained inside the binding cavity of targets in a stable conformation throughout the simulation and Prime-MM/GBSA study revealed that van der Waals' energy (ΔGvdW) and non-polar solvation or lipophilic energy (ΔGSol_Lipo) contribute favorably towards the formation of a stable protein-ligand complex. Thus, F0850-4777 could be a potential candidate against multiple targets of two pathophysiological pathways of AD and opens the doors for further confirmation through in vitro and in vivo systems.

Seroprevalence of Viral Hepatitis B and C among Blood Donors in the Northern Region of Riyadh Province, Saudi Arabia.

BACKGROUND: Hepatitis B and C viral infections, which are the most common cause of liver infection worldwide, are major health issues around the globe. People with chronic hepatitis infections remain at risk of liver cirrhosis and hepatic carcinoma, while also being a risk to other diseases. These infections are highly contagious in nature, and the prevention of hepatitis B and C transmission during blood transfusion is a major challenge for healthcare workers. Although epidemiological characteristics of hepatitis B and C infections in blood donors in Saudi Arabia have been previously investigated in multiple studies, due to targeted cohorts and the vast geographical distribution of Saudi Arabia, there are a lot of missing data points, which necessitates further investigations. AIM OF THE STUDY: This study aimed to determine the prevalence of hepatitis B and hepatitis C viral infections among blood donors in the northern region of Riyadh, Saudi Arabia. METHODS: To determine the given objectives, a retrospective study was performed which included data gathered from serological as well as nucleic acid test (NAT) screening of blood donors. Clinical data of 3733 blood donors were collected for a period of 2 years (from January 2019 to December 2020) at the blood bank of King Khalid General Hospital and the associated blood banks and donation camps in the region. Statistical analysis of the clinical data was performed using SPSS. RESULTS: The blood samples of 3733 donors were analyzed to determine the seroprevalence of hepatitis B and C among the blood donors in the northern region of Riyadh, Saudi Arabia. Among the total of 3733 blood donors, 3645 (97.65%) were men and 88 (2.36%) were women. Most of the donors were younger than 27 years of age (n = 1494). The most frequent blood group in our study was O-positive (n = 1534), and the least frequent was AB-negative (n = 29). After statistically analyzing the clinical data, we observed that 7 (0.19%), 203 (5.44%) and 260 (6.96%) donor blood samples were positive for the HBV serological markers HBsAgs, HBsAbs and HBcAbs, respectively, and 12 (0.32%) blood samples reacted positively to anti-HCV antibodies. Moreover, 10 (0.27%) and 1 (0.027%) samples were NAT-HBV positive and NAT-HCV positive, respectively. CONCLUSION: In the current study, low prevalence rates of HBV and HCV were observed in the blood donors. Statistical correlations indicated that both serological tests and NATs are highly effective in screening potential blood donors for HBV and HCV, which, in turn, prevents potential transfusion-transmitted hepatitis.

The prevalence of transfusion-transmitted infections and nucleic acid testing among blood donors in Majmaah, Saudi Arabia.

BACKGROUND: Few studies discussed the prevalence of TTIs in Saudi donor blood samples. Thus, this study investigated the prevalence of hepatitis B virus (HBV), hepatitis C virus (HCV), human immunodeficiency virus (HIV), human T-lymphotropic virus (HTLV), syphilis and malaria in such samples to determine the efficacy of conducting serological and NATs on blood donors at King Khalid General Hospital in Majmaah, Saudi Arabia. METHODS: A total of 3028 donated blood units were collected from August 2015 to March 2017. Serum samples were screened for hepatitis B surface antigens (HBsAgs), HBsAbs, total anti-core antibodies (HBcAbs), HCV antigens and HIV Ab/Ag combinations. Additionally, plasma was screened for syphilis (TPHA) and HTLV. Samples were also tested for malaria with rapid malaria antigen tests. Finally, NATs were performed for the simultaneous direct detection of HBV, HCV and HIV in each sample. RESULTS: Out of the 3028 blood samples, 10 (0.33%) reacted to HBsAgs; 12 (0.40%) reacted to HCV antigens; 4 (0.13%) reacted to HIV Ab/Ag combinations; 6 (0.20%) reacted to HTLV antibodies; 297 (9.81%) reacted to HBcAbs and 236 (7.80%) reacted to HBsAbs. Additionally, NATs showed that 14 (0.46%) reacted to NAT-HBV; 20 (0.66%) samples were reacted to NAT-HCV and 2 (0.07%) samples reacted to NAT-HIV. Finally, 16 (0.53%) were positive for syphilis. No samples were positive for malaria. CONCLUSIONS: The results indicated that NATs are more effective than serology tests for detecting TTIs. Moreover, correlations between standard serology tests and NATs indicated that using NATs could improve test sensitivities and decrease residual risks of TTIs and ensure safe blood transfusions.

Novel presenilin 1 mutation associated with early-onset Alzheimer`s disease in a Saudi patient.

We report a 60-year-old Saudi patient with the clinical diagnosis of Alzheimer`s disease (AD) and a novel mutation in the presenilin gene. We investigated mutations in the presenilin-1 gene in Saudi patients with AD using polymerase chain reaction and direct DNA sequencing methods. We extracted genomic DNA from the whole blood of both patients and normal control individuals. We sequenced and compared amplicons with the sequences of the respective exons of normal individuals as well as data available in GenBank. We detected a homozygous mutation (g-c) in exon 12, resulting in the missense mutation (Arg377Thr), in the DNA of a 60-year-old patient. We located this mutation in the cytoplasmic loop near the transmembrane domain 7.