👤 Saud O Alshammari

Hyperlipidemia remains a leading modifiable risk factor for cardiovascular morbidity and mortality. Statins are considered the cornerstone of treatment; however, their adverse effects and limited efficacy in certain patient populations necessitate exploration of novel therapeutic avenues. Epiafzelechin (EZN), a flavanol with established antioxidant and anti-inflammatory properties, was investigated for its potential role in lipid metabolism using an integrative approach combining network pharmacology, molecular docking, and in vivo validation. Putative EZN targets were predicted through SuperPred, Way2Drug, and PharmMapper, and intersected with hyperlipidemia-related genes from GeneCards, DisGeNET, and CTD. Overlapping genes were subjected to protein-protein interaction (PPI) mapping, hub gene identification, and pathway enrichment analysis. Molecular docking was conducted to assess the binding affinity of EZN to lipid-regulating proteins. Therapeutic efficacy of EZN was also evaluated in a TWR-1339-induced hyperlipidemic rat model using biochemical assays and real-time PCR for gene expression profiling. A total of 105 genes were identified, involved in lipid transport, inflammatory signaling, and metabolic regulation. Functional enrichment and PPI analysis highlighted HMGCR, PCSK9, PPAR- Show less

Type 2 Diabetes Mellitus (T2DM) is a widespread metabolic disorder that can affect brain health, primarily through the damaging effects of prolonged hyperglycemia. This condition increases oxidative stress (OS), neuroinflammation, and neuroapoptosis, ultimately impairing cognitive function. Acrylamide (ACY), a neurotoxicant formed during high-temperature food processing and present in cigarette smoke, may further aggravate these neurological disturbances. The present experiment examined the exacerbating effects of T2DM and ACY exposure on cognitive function, neurodegeneration, OS, neuroinflammation, and neuroapoptosis in diabetic rats. T2DM was induced via intraperitoneal injections of nicotinamide and streptozotocin, followed by daily oral doses of ACY for a month. Behavioral assessments (EPM, NOR, and Y-maze) evaluated cognitive performance. Brain tissues were analyzed for biochemical markers of neurodegeneration (GSK-3β, AChE, BACE1), OS (MDA, GSH, Catalase), neuroinflammation (NF-κB, TNF-α, PGE2, COX-2), and neuroapoptosis (Bcl-2, Bax, Caspase-3). Immunohistochemistry of Bcl-2, Bcl-6, CD138, and NF assessed structural brain changes. Results indicated that T2DM and ACY exposure significantly increased the incidence of neurological disturbances. Notably, through increased COX-2, PGE2, MDA, Bax, Bcl-6, Caspase-3, and cognitive decline deficits. This study highlights the harmful neurotoxic amplification of T2DM and ACY exposure, emphasizing the importance of public health measures to reduce ACY exposure through dietary and lifestyle changes, particularly among T2DM populations. Further research into neuroprotective strategies and underlying mechanisms is necessary. Show less

Plant-derived compounds have recently gained attention owing to their better safety profile and multi-targeted actions. Charantin, a plant-based natural compound known for its diverse pharmacological properties, was investigated for its anti-hyperlipdemic activity using both in-silico and in-vivo approaches. A detailed network pharmacology analysis was used to predict charantin-related targets, cross-referenced with hyperlipidemia-associated genes from GeneCards, DisGeNET, and CTD. Shared targets were subjected to protein-protein interaction analysis and functional enrichment using STRING, Cytoscape, and ShinyGO. Molecular docking studies assessed charantin's binding interactions with key lipid-regulating proteins (HMGCR, PCSK9, LDLR, PPAR-α, PI3K). In-vivo efficacy of charantin (100 and 200 mg/kg) was evaluated in Sprague-Dawley rats fed with high-lipid diet (HLD) for 12 days. Lipid profiles, liver enzymes and transcript levels of lipid-regulating genes were analyzed. A total of 242 overlapping genes were identified between charantin targets and hyperlipidemia-associated genes, with enrichment analyses highlighting key lipid metabolic and inflammatory pathways. Molecular docking revealed that charantin exhibited stronger binding affinities than simvastatin across multiple targets. In HLD animal model, charantin significantly reduced total cholesterol, triglycerides, LDL, and VLDL, while increasing HDL levels in a dose-dependent manner. Liver function remained preserved, accompanied by downregulation of HMGCR, PCSK9, and APOB, and upregulation of LDLR and PPAR-α at both gene and protein levels. Charantin exerts potent lipid-lowering effects through modulation of multiple pathways, including cholesterol biosynthesis, lipoprotein metabolism, and nuclear receptor activation. Its efficacy and hepatoprotective properties reiterate its potential as a safe, effective alternative or adjunct to conventional therapies for hyperlipidemia. Show less

Tobacco consumption, a leading cause of over 8 million deaths annually, exposes individuals to acrylamide (ACY), a neurotoxin in cigarette smoke that disrupts neurotransmitter function and induces oxidative stress, contributing to neurodegeneration. This study evaluated neuroprotective potential of montelukast (MTLU), a leukotriene receptor antagonist with anti-inflammatory and antioxidant properties, against ACY-induced neurotoxicity. Cognitive performance was assessed using elevated plus maze, novel object recognition, and Y-maze tests over 14 days. Biomarkers associated with neurodegeneration (BACE1, GSK-3β, AChE), neuroinflammation (COX-2, PGE2, TNF-α, NF-κB), oxidative stress (GSH, MDA, CAT), and apoptosis (Bcl-2, Caspase-3, Bax) were analyzed. Histopathological analyses of brain tissues were conducted to examine structural damage, and computational studies provided additional support for selected in vivo findings. MTLU significantly ameliorated ACY-induced cognitive deficits and reduced levels of GSK-3β, AChE, COX-2, PGE2, TNF-α, NF-κB, MDA, Bax, and Caspase-3 while enhancing antioxidant defenses (GSH) and upregulating Bcl-2. Histopathological analysis confirmed reduced structural brain damage, and molecular docking indicated strong binding potential for MTLU with AChE, COX-2, GSK-3β, BACE-1, and Caspase-3. While these findings suggest a protective role for MTLU in mitigating ACY-induced cognitive impairments, oxidative stress, neuroinflammation, and apoptosis, further research is needed to confirm its therapeutic potential and clinical relevance. Show less

Dysmorphology syndromes are among the most common referrals to clinical genetics specialists. Inability to match the dysmorphology pattern to a known syndrome can pose a major diagnostic challenge. With an aim to accelerate the establishment of new syndromes and their genetic etiology, we describe our experience with multiplex consanguineous families that appeared to represent novel autosomal recessive dysmorphology syndromes at the time of evaluation. Combined autozygome/exome analysis of multiplex consanguineous families with apparently novel dysmorphology syndromes. Consistent with the apparent novelty of the phenotypes, our analysis revealed a strong candidate variant in genes that were novel at the time of the analysis in the majority of cases, and 10 of these genes are published here for the first time as novel candidates (CDK9, NEK9, ZNF668, TTC28, MBL2, CADPS, CACNA1H, HYAL2, CTU2, and C3ORF17). A significant minority of the phenotypes (6/31, 19%), however, were caused by genes known to cause Mendelian phenotypes, thus expanding the phenotypic spectrum of the diseases linked to these genes. The conspicuous inheritance pattern and the highly specific phenotypes appear to have contributed to the high yield (90%) of plausible molecular diagnoses in our study cohort. Reporting detailed clinical and genomic analysis of a large series of apparently novel dysmorphology syndromes will likely lead to a trend to accelerate the establishment of novel syndromes and their underlying genes through open exchange of data for the benefit of patients, their families, health-care providers, and the research community.Genet Med 18 7, 686-695. Show less

Dyggve--Melchior--Clausen syndrome (DMC) is a chondrodysplasia that bears significant phenotypic resemblance to mucopolysaccharidosis type IV (Morquio disease). Autosomal recessive mutations in DYM are known to cause this disease through its role in Golgi organisation and intracellular traffic, but genetic heterogeneity is suspected. A family with DMC and normal intellectual development underwent clinical evaluation followed by autozygosity mapping and exome sequencing. Immunoblot and immunofluorescence analyses were performed to characterise the effect of the mutation. This multiplex consanguineous family links to a novel locus on 4q31.1. Exome sequencing revealed a missense mutation in RAB33B, which encodes a Rab protein with an established role in retrograde Golgi traffic. The mutation qualitatively replaces the invariant lysine residue in the guanine nucleotide-binding domain of this small GTPase protein and leads to marked protein deficiency, making it the likely causative mutation of DMC in this family. This study identifies a new DMC gene and highlights the role of intracellular traffic in the pathogenesis of this disease. Show less