👤 Abdulrahman Alshehri

This study investigated an intranasal nose-to-brain delivery strategy to repurpose ondansetron (OND) for anxiety management using PLGA nanoparticles co-loaded with superparamagnetic iron oxide nanoparticles (SPIONs) and incorporated into a Carbopol 940 mucoadhesive gel. Nanoparticles were optimized using an I-optimal experimental design evaluating PLGA concentration and surfactant type. The optimized SPION/OND-PLGA nanoparticles showed a small particle size (141.547 ± 1.31 nm), narrow distribution (PDI = 0.235 ± 0.002), relatively high zeta potential (-34.307 ± 0.53 mV), and satisfactory encapsulation efficiency (42.09 ± 1.34%). The developed nanogel exhibited acceptable organoleptic properties, shear-thinning behavior, sustained drug release, and enhanced ex vivo nasal permeability, with OND permeation values of 996.96 ± 6.53 μg, 621.92 ± 7.54 μg, and 317.87 ± 2.88 μg per cm Show less

Neuroinflammation appears in a variety of neurological disorders, including multiple sclerosis (MS), Parkinson's disease (PD), Alzheimer's disease (AD), and amyotrophic lateral sclerosis. The adenosine A₂A receptor (A₂AR), a Gs protein-coupled receptor that affects cAMP signaling and downstream kinases like PKA, CREB, and NF-κB, is one of the primary regulators of this process. Context-dependent effects of A₂AR activation include lowering acute inflammation and promoting neuronal survival when stimulated moderately, but increasing glial activation and cytokine production when overexpressed over an extended period of time. In microglia and astrocytes, A₂AR signaling regulates inflammatory pathways mediated by NF-κB and MAPK, affecting oxidative stress, blood-brain barrier (BBB) stability, and excitotoxicity. Acute or transient (short-term) A₂AR activation, on the other hand, increases the production of anti-inflammatory cytokines like IL-10 and enhances neurotrophic support through BDNF. A₂AR antagonists, including istradefylline and SCH58261, may reduce microglial triggering and have neuroprotective benefits, according to clinical and experimental data. The context-dependent activity of the receptor is shown by the fact that total receptor blockage interferes with adaptive immune control. Therefore, the therapeutic challenge is to carefully modify A₂AR signaling in particular cell populations, specifically targeting astrocytic or microglial receptors while maintaining the peripheral immunoregulatory activities. The dual regulatory role of A₂AR in neuroinflammation is summarized in this review along with its molecular mechanisms, disease-specific actions, and therapeutic significance. Developing next-generation neuroprotective strategies that reduce A₂AR signaling's pro-inflammatory and neurotoxic effects while preserving its beneficial homeostatic effects will require an understanding of the temporal and cell-specific dynamics of this signaling. Show less

Myocardial infarction (MI) is one of the leading causes of mortality in Saudi Arabia, with individuals sharing genetic, lifestyle, and environmental risk factors. The present investigation aimed to review the literature on genetic susceptibility to MI among Saudi individuals, with a specific emphasis on genome-wide association studies (GWAS) for coronary artery disease (CAD) and MI. Studies have revealed the relationship between polymorphisms in genes such as proprotein convertase subtilisin/kexin type 9 (PCSK9), cholesteryl ester transfer protein (CETP), and cyclin-dependent kinase inhibitor 2B antisense RNA 1 (CDKN2B-AS1), which are involved in lipid metabolism, inflammation, and endothelial function. This PROSPERO-registered systematic review and meta-analysis (CRD42024603752) evaluates genetic determinants of myocardial infarction among Saudi adults. Five databases were searched (1989-Oct 2024) according to PRISMA guidelines. Case-control and cohort studies that met the inclusion criteria were analyzed using random-effects models. Findings suggest that several polymorphic genes are highly associated with MI in Saudi citizens. There is strong evidence indicating that PCSK9, CETP, and CDKN2B-AS1 contribute to susceptibility to MI, though the effect of these polymorphic genes varies. The meta-analysis confirmed that MI is a polygenic disease, and genetic predisposition, in combination with individual lifestyle factors, determines disease progression. This study establishes that genetic factors significantly contribute to MI in Saudi Arabia. Integrating genetic screening with traditional cardiovascular risk assessments can enhance early intervention strategies. The findings highlight the need for MI prevention programs tailored to specific genotypes in the Saudi population. Show less

Golgi_traff is a Pfam clan containing two members, Dymeclin (DYM) and HID1 domain-containing protein (HID). Interrogation of over 900 eukaryotic genomes with sequence models showed that both are ancient eukaryotic genes, which have exhibited different paths of gene loss, including from major taxonomic groups. For example, the Metazoa have both genes, whereas the Viridiplantae and Dikarya have lost HID and DYM, respectively. A unique replication event occurred within the genus Schizosaccharomyces in that all sequenced species possess three HID-encoding paralogs, whereas its nearest fungal relatives and other eukaryotes are almost exclusively monogenic. A phylogenetic analysis of yeasts revealed that the Golgi-resident paralog Human ortholog 3 (SPAC17A5.16) is more similar to the HID of other yeasts than to its paralogs. Transmission electron microscopy revealed that the SPAC17A5.16 mutant lacks a stacked Golgi apparatus (GA) form, suggesting a role in maintaining GA structure. Altered proliferation of the SPAC17A5.16 mutant in response to GA disrupting chemical agents indicated a perturbation of GA-related functions. Structural models suggest SPAC17A5.16 has a long, disordered N-terminal region that may facilitate anchoring to GA membranes. A modification to Schizosaccharomyces HID nomenclature is proposed to reflect their evolutionary and functional characteristics. The potential of the Golgi_traff clan to serve as a model for the diversification of protein function according to the concepts of sub/neofunctionalization is discussed. Show less

The incidence and mortality of endometrial cancer (EC) have increased in recent years. There is mounting evidence that diabetes may play a role in the greater incidence of EC. The molecular mechanisms of the interaction between type 2 diabetes and EC are not yet clearly understood yet. The present study was undertaken to investigate the plasma proteomics of EC patients with diabetes in comparison to those of EC patients without diabetes. Plasma samples were obtained from age-matched patients (EC diabetic and EC nondiabetic). Untargeted proteomic analysis was carried out using a two-dimensional differential gel electrophoresis coupled with matrix-assisted laser desorption/ionization time-of-flight mass spectrometry. Of the 33 proteins identified, which significantly differed in the plasma abundance between groups, 17 were upregulated and 16 were downregulated. The majority of the altered proteins are involved in the acute phase reaction, cholesterol metabolism, scavenging of heme from plasma, and plasma lipoprotein assembly and mobilization. α-2-macroglobulin, Ras association domain-containing protein 3, apolipoprotein A-I, α-1B-glycoprotein, and zinc-α-2-glycoprotein were significantly upregulated. The significantly downregulated proteins included haptoglobin, apolipoprotein A-IV, hemopexin, and α-1-antichymotrypsin. The differential expression of proteins found in patients who had EC and diabetes indicated severe disease and a poor prognosis. The protein interaction analysis showed dysregulation of cholesterol metabolism and heme scavenging pathways in these patients. Show less

This work describes the design and synthesis of new hybrids of thienopyrimidine and sulfonamides. The binding affinity of the prepared compounds to FGFR-1 enzyme and caspase-3 was investigated via molecular docking. The cytotoxic effect was estimated for the synthesized compounds against human breast cancer cell lines (MCF-7 and MDA-MB231) using Doxorubicin as a reference. All the tested compounds exhibited moderate to excellent anticancer efficacy against both tested cell lines, among which Show less

Familial hypercholesterolemia (FH) is an autosomal dominant inherited genetic disorder and results in the development of coronary artery disease (CAD). Clinical diagnosis of homozygous HH patients is usually straightforward because persistent hypercholesterolemia can produce xanthoma and corneal arcus. However, xanthoma may also be misdiagnosed as skin lesions and could therefore be mistreated. The aim of this case study report is to highlight the plight of patients with FH as means of raising awareness of the condition among dermatologists and health care practitioners, also to determine the genotype-phenotype correlation in severely affected homozygous FH proband patients. Genetic screening of FH associated genes was performed by Ion Torrent next-generation sequencing and cascade screening by capillary sequencing. We present two clinical cases with prominent skin lesions seen in a dermatology clinic that were referred to plastic surgery for excision. Genetic testing was performed later, and confirmed common single nucleotide deletion variant (c.2027delG) in the The present report indicates the need for increased awareness of FH, among the public and healthcare practitioners and supports the need for diagnostic screening and cascade genetic testing of this high-risk condition, which could ultimately lead to better prevention of CHD in this lethal condition. Show less