👤 Fai I M Alsharif

Obesity and diabetes are escalating worldwide health concerns, prompting the use of non-caloric sweeteners such as aspartame and stevia as substitutes for sucrose; however, their long-term physiological and behavioral consequences remain incompletely understood. This work presents a comparative experimental study examining the long-term effects of sucrose, aspartame, and stevia intake on liver, heart, and brain functions in rats, while exploring the capacity of astaxanthin (ASTX) to attenuate the resulting tissue impairments. Seven rat groups-including control, sucrose, aspartame, stevia, and each sweetener combined with ASTX-were treated for 8 weeks to compare the organ-specific toxicity of the sweeteners and assess the protective effects of ASTX. Comprehensive evaluations of liver, heart, and brain were conducted using biochemical, behavioral, and histopathological analyses. All three sweeteners induced hyperglycemia, disrupted lipid metabolism (triglycerides, LDL, HDL), and increased oxidative stress (MDA), suppressing Nrf2/HO-1 antioxidant pathway and activating TLR4/NF-κB-mediated inflammation, leading to apoptosis. Biomarkers revealed liver dysfunction (ALT, AST, ALP), cardiac injury (troponin I, CK-MB, MEF2), and cognitive impairment (amyloid-beta, tau, BDNF), alongside altered monoamine neurotransmitters and Wnt3a/GSK-3β/β-catenin dysregulation. Bax/Bcl-2 ratio indicated enhanced apoptosis, with aspartame exerting the highest toxicity and stevia the least. While ASTX effectively alleviated these biochemical, histological, and functional changes. These findings suggest that aspartame has the strongest negative impact on liver, heart, and brain health, while stevia has the least, and that ASTX may serve as a potential protective agent against these harmful impacts. Show less

Alzheimer's disease is a neurodegenerative disorder that causes significant cognitive impairment and memory loss. It is the leading cause of dementia on a global scale and is distinguished by the pathological build-up of amyloid-beta peptides and tau protein. This study presents the development of E-pharmacophore modeling, which utilizes reported co-crystal structure involving beta-site amyloid precursor protein cleaving enzyme 1 (BACE1) to screen the eMolecules database. The present study comprehensively dealt with the virtual screening and structure-based prediction of thiazole compounds against BACE1 protein. To investigate the binding mode of virtual-screened hits (VS-hits), top 100 VS-hits were docked into BACE1 followed by in silico ADMET prediction. Top two VS-hits (CP1 and CP2) with highest docking scores along with co-crystalized ligand (CPZ) were further subjected to MESP, HOMO, LUMO, MD simulation, and MMGBSA analysis to inspect the dynamic stability of inhibitor-BACE1 complexes and the key molecular interaction responsible for their improved binding affinity toward BACE1. This research identified CP1 and CP2 as top two potential novel BACE1 inhibitors from the library of natural products, whose Glide docking scores range from -8.87 to -7.89 kcal/mol-1. Interestingly, both ligands were able to establish interactions with a set of conserved residues F108, I110, I118, L30, Q12, G13, G11, A335, S229, D228, G230, D32, G34, S35, and Y71. ADMET assessment of the selected compounds was also noted to be within acceptable ranges. The preliminary in-silico ADMET evaluation revealed encouraging results for all the modeled and in-house library compounds. The RMSD and RMSF analysis revealed that both ligands remained stable and maintained their interaction throughout the simulation time (100 nanoseconds). The MM/GBSA (ranging from -36.734 to -27.431 kcal/mol) predicted binding affinities are in strong correlation with that of the docking score, which not only supports the docking results but also suggests that CP1 exhibits superior binding affinity towards BACE1. Keeping in view these findings, CP1 might be a promising candidate for drug discovery against BACE1 inhibitors. The findings of this research have the potential to offer valuable recommendations for the advancement of novel, potent, and efficacious BACE1 inhibitors. Show less

Diabetes is a chronic disease resulting from insufficient insulin secretion or impaired insulin function. Diabetic nephropathy (DN) is one of the most common complications of diabetes and a leading cause of end-stage renal disease. Early diagnosis of DN is crucial for timely intervention and effective disease management. Gene expression profiles GSE142025 and GSE220226 were retrieved from the GEO database and combined into a metadata cohort, while GSE189007 was obtained as an independent validation dataset. Differentially expressed genes (DEGs) were identified in 46 glomerular samples from DN patients and 31 control samples. Gene Ontology (GO) and Disease Ontology (DO) enrichment analyses, gene set enrichment analysis (GSEA), least absolute shrinkage and selection operator (LASSO) regression, support vector machine-recursive feature elimination (SVM-RFE) analysis, and area under the curve (AUC) calculations were performed. A total of 109 DEGs were identified. Among them, DUSP1, EGR1, FPR1, G6PC, GDF15, LOX, LPL, PRKAR2B, PTGDS, and TPPP3 were selected as potential diagnostic biomarkers for DN. These biomarkers exhibited a positive correlation with immune cell infiltration. Experimental validation identified LOX as the most promising novel diagnostic biomarker for DN. This study provides new insights into the early diagnosis, pathogenesis, and molecular mechanisms of DN. Show less

Polyubiquitination by E2 and E3 enzymes is a predominant mechanism regulating protein function. Some RING E3s, including anaphase-promoting complex/cyclosome (APC), catalyze polyubiquitination by sequential reactions with two different E2s. An initiating E2 ligates ubiquitin to an E3-bound substrate. Another E2 grows a polyubiquitin chain on the ubiquitin-primed substrate through poorly defined mechanisms. Here we show that human APC's RING domain is repurposed for dual functions in polyubiquitination. The canonical RING surface activates an initiating E2-ubiquitin intermediate for substrate modification. However, APC engages and activates its specialized ubiquitin chain-elongating E2 UBE2S in ways that differ from current paradigms. During chain assembly, a distinct APC11 RING surface helps deliver a substrate-linked ubiquitin to accept another ubiquitin from UBE2S. Our data define mechanisms of APC/UBE2S-mediated polyubiquitination, reveal diverse functions of RING E3s and E2s, and provide a framework for understanding distinctive RING E3 features specifying ubiquitin chain elongation. Show less