👤 Anas Shamsi

Alzheimer's disease (AD) is an advancing neurodegenerative disorder distinguished by the formation of amyloid plaques and neurofibrillary tangles in the human brain. Nevertheless, the lack of peripheral biomarkers that can detect the development of AD remains a significant limitation. The main aim of this work was to discover the molecular markers associated with AD. We conducted a comprehensive microarray analysis of gene expression data from hippocampus tissue in AD patients and control samples using three microarray datasets (GSE1297, GSE28146, and GSE29378) collected from Gene Expression Omnibus (GEO). The datasets were pre-processed and normalized, revealing 346 significant genes, 103 of which were upregulated and 243 downregulated. The PPI network of significant genes was constructed to detect the top 50 hub genes, which were then further analyzed using Gene Ontology (GO) terms, Kyoto Encyclopedia of Genes and Genomes pathway (KEGG), and GSEA, revealing 47 key genes involved in AD-related pathways. These key genes were then subjected to feed forward loop (FFL) motif analysis for the prediction of transcriptional factors (TFs) and microRNAs (miRNAs) mediated gene regulatory networks. The interaction of AD-associated TFs HNF4A, SPI1, EGR1, STAT3, and MYC and miRNAs hsa-miR-155-5p and hsa-miR-16-5p in the transcriptional and post-transcriptional events of 3 upregulated and 10 downregulated genes: H2AFZ, MCM3, MYO1C, AXIN1, CCND1, ETS2, MYH9, RELA, RHEB, SOCS3, TBL1X, TBP, TXNIP, and YWHAZ, respectively, has been identified. The miRNA/TF-mediated three types of the FFL motifs, i.e., miRNA-FFL, TF-FFL, and composite-FFL, were constructed, and seven common genes among these FFL were identified: CCND1, MYH9, SOCS3, RHEB, MYO1C, TXNIP, AXIN1, and TXNIP. These findings may provide insights into the development of potential molecular markers for therapeutic management of AD. Show less

β-secretase 1 (BACE1) is an enzyme that is involved in generating beta-amyloid peptides and is believed to have a significant role in the development of Alzheimer's disease (AD). Therefore, BACE1 has gained attention as a potential therapeutic target for treating AD. Modern drug discovery studies are being conducted to identify potential inhibitors of BACE1, with the goal of reducing the production of beta-amyloid peptides and, thus, slowing the progression of AD. Here, we used a multistep virtual screening methodology to identify phytoconstituents from the IMPPAT library that could inhibit the activity of BACE1. Molecular docking was employed to select initial hits based on their binding affinity toward BACE1. Screening for PAINS patterns, ADMET and PASS properties, was then used to identify potential molecules for BACE1 inhibition. In the end, we discovered two natural compounds, Peiminine and 27-Deoxywithaferin A, which demonstrated a strong affinity, effectiveness, and specific interactions for the BACE1-active site. The elucidated molecules also displayed drug likeliness. A 200 ns molecular dynamics (MD) simulation was conducted to investigate the interaction mechanism, complex stability, and conformational dynamics of BACE1 with Peiminine and 27-Deoxywithaferin A. The MD simulations demonstrated that BACE1 was stable during the simulation with Peiminine and 27-Deoxywithaferin A. Overall, the results suggested that Peiminine and 27-Deoxywithaferin A hold significant potential as scaffolds in drug development efforts targeting BACE1 for the purpose of treating AD. Show less

Protein metabolism and urea production maintain protein and amino acid homeostasis in normal status. Ammonia results from amino acid turnover and is produced by intestinal urease-positive bacteria. Ammonia must be detoxified, and the urea cycle converts ammonia into urea. CPS1 is an enzyme in the urea cycle that catalyzes ammonia and bicarbonate condensation. CPS1 deficiency presents in the neonatal period with hyperammonemia, resulting in death or neurological sequelae if patients survive. To share the experience of patients with CPS1 deficiency from Tawam Hospital and to shed light on the spectrum of variants found in those patients. A retrospective chart review was done. All patients with CPS1 deficiency admitted to Tawam Hospital from 2010 to 2023 were included. Collected data included age and ammonia level at presentation, the time needed to drop ammonia level below 100 μmol/L, acute management modality provided, long-term neurological sequelae, sequence variants, severity, and duration of hyperammonemia encephalopathy, age at last follow-up, and, if applicable, survival for at least six months. Only five patients with CPS1 deficiency over 13 years were found; two males and three females. Three patients are doing relatively well at 18 months, 7, and 9 years of age. The presented age was in the neonatal period except in one patient. One patient was found to have frameshift, resulting in a premature stop codon in the Although the presentation was different in severity, three patients are doing relatively well and approaching their developmental milestones. Thus, early recognition, prompt actions to drop high ammonia level, and good follow-up plans are emphasized. Further studies are needed to correlate the genotype-phenotype of reported variants here, which can help predict the severity of CPS1 deficiency. Show less