Search Results (126)

Background: Given the limited research on mitochondrial diseases in our area, specifically regarding their genetic variability and diverse clinical manifestations, and considering the significant number of consanguineous marriages in our region, we aimed to investigate the clinical and molecular characteristics of patients with mitochondrial disorders in Saudi Arabia. Methods: This retrospective cross-sectional cohort study involved a chart review of patients diagnosed with mitochondrial disorders at the Ministry of National Guard Health Affairs tertiary health care centers in Saudi Arabia between 2013 and 2022. Results: The study population comprised 116 patients with a mean age of 10 years (±7 SD). Among the study cohort, 34.5% (n = 40) had died. The primary cause of death was cardiopulmonary arrest (55.0%, n = 22). The most prevalent condition was developmental delay (67.9%). Around 56.9% were diagnosed using Whole Exome Sequencing (WES), 10.3% by Whole Genome Sequencing due to negative WES, 23.3% through a single-gene approach, 7.8% were analyzed through a mitochondrial panel, and 1.7% via a gene panel. The distributions of current age and age at diagnosis were significantly different between the nuclear and mitochondrial gene types. Notably, the diagnostic delay time (time taken from symptom onset to genetic diagnosis) averaged 1.5 years for nDNA variants compared to an average of 10 years for mDNA variants. Conclusions: This study shows that gene type affects clinical characteristics, highlighting the importance of genetic studies in disease manifestation. Full article

Diabetes is increasingly recognized as a chronic inflammatory disease marked by systemic metabolic disturbances, with endothelial dysfunction playing a central role in its complications. Hyperglycemia, a hallmark of diabetes, drives endothelial damage by inducing excessive reactive oxygen species (ROS) production, particularly hydrogen peroxide (H₂O₂). This oxidative stress impairs endothelial cells, which are vital for vascular health, leading to severe complications such as diabetic nephropathy, retinopathy, and coronary artery disease—major causes of morbidity and mortality in diabetic patients. Recent studies have highlighted the therapeutic potential of placenta-derived mesenchymal stem cells (pMSCs), in mitigating these complications. pMSCs exhibit anti-inflammatory, antioxidant, and tissue-repair properties, showing promise in reversing endothelial damage in laboratory settings. To explore their efficacy in a more physiologically relevant context, we used a streptozotocin (STZ)-induced diabetic mouse model, which mimics type 1 diabetes by destroying pancreatic beta cells and causing hyperglycemia. pMSCs were administered via intra-peritoneal injections, and their effects on endothelial injury and tissue damage were assessed. Metabolic tests, including glucose tolerance tests (GTTs) and insulin tolerance tests (ITTs) revealed that pMSCs did not restore metabolic homeostasis or improve glucose regulation. However, histopathological kidney, heart, and eye tissue analyses demonstrated significant protective effects. pMSCs preserved glomerular structure in the kidneys, protected cardiac blood vessels, and maintained retinal integrity, suggesting their potential to address diabetes-related tissue injuries. Although these findings underscore the therapeutic potential of pMSCs for diabetic complications, further research is needed to optimize dosing, elucidate molecular mechanisms, and evaluate long-term safety and efficacy. Combining pMSCs with other therapies may enhance their benefits, paving the way for future clinical applications. Full article

Background: Nursing students usually face excessive academic and clinical demands that negatively impact their sleep quality. Physical activity (PA) has been proposed to enhance sleep, yet few investigations have focused on this correlation within the Saudi environment. The purpose of this research was to determine the relationship between PA and sleep quality in Saudi nursing students. Methodology: A cross-sectional study was conducted among a sample of 554 nursing students from different universities in Saudi Arabia. The International Physical Activity Questionnaire–Short Form (IPAQ-SF) and the Pittsburgh Sleep Quality Index (PSQI) were used to collect data. Snowball sampling was used to recruit the participants through social media. Descriptive statistics, Pearson correlation, and inferential tests were employed for the analysis. Results: Most participants were female (85.1%) and aged 18–34 years (95.5%). LPA levels were reported by 59.6% of students, and only 8.2% engaged in VPA. The majority (91%) reported poor sleep duration (<5 h), and 57.4% had poor sleep efficiency. Overall, 86.7% of students experienced poor sleep quality. Gender and GPA were significantly associated with both PA and sleep quality. Female students and those with lower GPAs were more likely to report LPA and poor sleep. Marital status was also associated with higher levels of VPA. No significant associations were found with age, academic year, region, income, or parental education. A statistically significant positive correlation was found between PA and sleep quality (r = 0.192, p < 0.001), suggesting that increased PA is modestly associated with better sleep. Conclusion: The research shows a high rate of poor sleep and low physical activity in nursing students, indicating an alarming health trend. Although PA was linked significantly to better sleep, the modest strength indicates the necessity for multi-component interventions. Structured PA programs and sleep hygiene education should be incorporated into nursing curricula by universities to foster students’ well-being and academic performance. Full article

Background: Accurate assessment of drug cytotoxicity in vitro is essential for preclinical evaluation of anticancer agents. Methodological parameters such as cell density and solvent concentrations can significantly influence the reproducibility and reliability of cell-based assay results. Objective: This study aims to optimize cell seeding density and evaluate the cytotoxic effects of common solvents (DMSO and ethanol) on different cancer cell lines, complemented by in silico analysis to elucidate underlying mechanisms. Materials and Methods: Six cancer cell lines (HepG2, Huh7, HT29, SW480, MCF-7, and MDA-MB-231) were seeded at different densities to determine the optimal cell seeding number ideal for cell viability assay at 24, 48, and 72 h. The cytotoxicity of DMSO and ethanol was assessed in these cell lines using an MTT assay at multiple time points. In silico docking studies were conducted to investigate the interactions between solvents and key proteins involved in apoptosis, membrane function, and metabolism. Results: A cell density of 2000 cells per well yielded consistent linear viability across cell lines and time points. DMSO at 0.3125% showed minimal cytotoxicity across all cell lines (except MCF-7) and time points; the cytotoxic effect at higher concentrations is variable depending on cell type and exposure duration. Ethanol exhibited rapid and concentration-dependent cytotoxicity, reducing viability by more than 30% at as low as 0.3125% concentration after 24 h. Docking analyses revealed that DMSO binds specifically to apoptotic and membrane proteins, suggesting a role in inducing apoptosis. In contrast, ethanol primarily interacts with metabolic proteins, consistent with its effect on membrane disruption and rapid cell death. Conclusion: DMSO at 0.3125% is a good choice as a solvent since it has low toxicity in most tested cell lines; however, the safe concentration limit is dependent on cell type and exposure duration. Ethanol exhibited higher cytotoxicity, necessitating careful concentration management. The in silico analysis supports these findings, indicating that DMSO interacts with apoptosis-related proteins, whereas ethanol primarily affects metabolic processes. These results highlight the importance of precise cell density optimization and solvents for reliable cytotoxicity assessment in cell-based assays. Full article

Marine algae offer environmentally friendly platforms for green nanoparticle synthesis. This study reports the biosynthesis of silver nanoparticles using polysaccharides isolated from the brown alga Chnoospora minima (PAgNPs) and evaluates their therapeutic potential. Fourier Transform Infrared Spectroscopy (FTIR) confirmed algal polysaccharide functional groups. Dynamic Light Scattering (DLS), Scanning Electron Microscopy (SEM), and Energy Dispersive X-ray (EDX) analysis characterized the nanoparticles as spherical (~84 nm average size), stable (zeta potential −18.5 mV), and containing elemental silver without nitrogen. The PAgNPs exhibited potent antioxidant activity (~100% DPPH scavenging) and significant antimicrobial efficacy, particularly against Staphylococcus aureus and Candida species. Crucially, PAgNPs displayed potent antiproliferative activity against human lung cancer cells (A549, IC₅₀: 13.59 µg/mL). In contrast, toxicity to normal Vero cells was significantly lower (IC₅₀: 300.2 µg/mL), demonstrating notable cancer cell selectivity (SI 22.1). Moderate activity was observed against MCF-7 breast cancer cells (IC₅₀: 100.7 µg/mL). These results demonstrate that C. minima polysaccharide facilitates the synthesis of biocompatible AgNPs with promising antimicrobial and selective anticancer capabilities, highlighting their potential for further development as nanotherapeutics. Full article

The development of orally bioavailable non-peptidomimetic glucagon-like peptide-1 receptor agonists (GLP-1RAs) offers a promising therapeutic avenue for the treatment of type 2 diabetes mellitus (T2DM) and obesity. An extensive in silico approach combining structure-based drug design and ligand-based strategies together with pharmacokinetic properties and drug-likeness predictions is implemented to identify novel non-peptidic GLP-1RAs from the COCONUT and Marine Natural Products (CMNPD) libraries. More than 700,000 compounds were screened by shape-based similarity filtering in combination with precision docking against the orthosteric site of the GLP-1 receptor (PDB ID: 6X1A). The docked candidates were further assessed with the molecular mechanics MM-GBSA tool to check the binding affinities; the final list of candidates was validated by running a 500 ns long MD simulation. Twenty final hits were identified, ten from each database. The hits contained compounds with reported antidiabetic effects but with no evidence of GLP-1 agonist activity, including hits 1, 6, 7, and 10. These findings proposed a novel mechanism for these hits through GLP-1 activity and positioned the other hits as potential promising scaffolds. Among the studied compounds—especially hits 1, 5, and 9—possessed strong and stable interactions with critical amino acid residues such as TRP-203, PHE-381, and GLN-221 at the active site of the 6X1A-substrate along with favorable pharmacokinetic profiles. Moreover, the RMSF and RMSD plots further suggested the possibility of stable interactions. Specifically, hit 9 possessed the best docking score with a ΔG_bind value of −102.78 kcal/mol, surpassing even the control compound in binding affinity. The ADMET profiling also showed desirable drug-likeness and pharmacokinetic characteristics for hit 9. The pipeline of computational integration underscores the potential of non-peptidic alternatives in natural product libraries to pursue GLP-1-mediated metabolic therapy into advanced preclinical validation. Full article

Background/Objectives: Melanoma remains a difficult malignancy to treat because it employs tolerance mechanisms like negative immune checkpoint (IC) molecules to avoid antitumor immune responses. Thus, immune checkpoint inhibitors (ICIs) are increasingly used to treat melanoma. However, many patients do not respond, indicating resistance mechanisms like intrinsic tumor characteristics and an immunosuppressive tumor microenvironment (TME). An inflamed TME was associated with improved ICI efficacy by upregulating the T-cell inflamed TME gene signatures, an array of genes associated with dendritic cells (DCs) and cytotoxic CD8⁺ T-cell-mediated anti-tumor responses. As histone deacetylases (HDACs) have been shown to play crucial roles in regulating gene expression and aberrant HDAC expression has been reported in melanoma and also implicated in the regulation of IC, programmed cell death protein 1 (PD-1), and its ligand (PD-L1) and various immune evasion genes, we investigated the relationship between T-cell inflamed TME gene signatures and the HDAC family, particularly HDAC4. Methods: We used the skin cutaneous melanoma (SKCM) database, ICI-pretreated melanoma dataset, and other platforms including cBioPortal, TIMER 2.0, TISIDB, and UALCAN for the analysis. Results: We identified that high HDAC4 expression negatively modulated the TME by decreasing the abundance of DCs and cytotoxic CD8⁺ T-cells. The group of melanoma patients with elevated HDAC4 expression exhibited not only poor prognosis but also diminished transcription of T-cell inflamed TME gene signatures and increased DNA methylation of T-cell inflamed TME gene signatures. Importantly, elevated HDAC4 expression was associated with decreased CD8⁺ T-cells and a decreased ESTIMATE immune score in ICI-pretreated melanoma patients. Conclusions: Our findings suggest that HDAC4 may transform the TME into a non-inflamed phenotype, thereby reducing ICI efficacy in melanoma. Overall, this research shows that a combination of HDAC4 inhibitors and ICIs could result in better melanoma prognosis. Full article

The continuous discovery of novel effective antibacterial agents using nano-based materials is of high significance. In this study, we utilized Polymerylated divalent-metal-doped ferrite nanoparticles (PMFe₂O₄ NPs) and studied their antibacterial inhibition effects. Different panels of PVP- and PEG-coated metal-doped MFe₂O₄ (M ≅ Co, Ni, and Zn) were prepared via the Ko-precipitation Hydrolytic Basic (KHB) methodology and thoroughly analyzed using TEM, XRD, FTIR, and VSM. The as-synthesized doped ferrites displayed stable quasi-spherical particles (7–15 nm in size), well-ordered crystalline cubic spinel phases, and high-saturation magnetizations reaching up to 68 emu/g. The antibacterial efficacy of the doped ferrites was then assessed against a Gram-negative E. coli bacterial strain. The results demonstrated that both metal doping and polymer functionalization influence the antimicrobial efficacies and performance of the ferrite NPs. The presence of the PVP polymer along with the divalent metal ions, particularly Co and Ni, resulted in the highest antibacterial inhibition and effective inactivation of the bacterial cells. The antibacterial performance was as follows: PVP-CoFe₂O₄ > PVP-NiFe₂O₄ > PVP-ZnFe₂O₄. Lastly, cell viability assays conducted on human breast fibroblast (HBF) cells confirmed the good safety profiles of the doped ferrites. These interesting results demonstrate the distinctive inhibitory features of the biocompatible metal-doped ferrites in enhancing bacterial killing and highlights their promising potential as effective antimicrobial agents, with possible applications in areas such as water disinfection, biomedical devices, and antimicrobial coatings. Full article

Background/Objectives: Bladder cancer, the most common and heterogeneous malignancy of the urinary tract, presents with diverse types and treatment options, making comprehensive patient education essential. As large language models (LLMs) emerge as a promising resource for disseminating medical information, their accuracy and validity compared to traditional methods remain under-explored. This study aims to evaluate the effectiveness of LLMs in educating the public about bladder cancer. Methods: Frequently asked questions regarding bladder cancer were sourced from reputable educational materials and assessed for accuracy, comprehensiveness, readability, and consistency by two independent board-certified urologists, with a third resolving any discrepancies. The study utilized a 3-point Likert scale for accuracy, a 5-point Likert scale for comprehensiveness, and the Flesch–Kincaid (FK) Grade Level and Flesch Reading Ease (FRE) scores to gauge readability. Results: ChatGPT-3.5, ChatGPT-4, and Gemini were evaluated on 12 general questions, 6 questions related to diagnosis, 28 concerning treatment, and 7 focused on prevention. Across all categories, the correct response rate was notably high, with ChatGPT-3.5 and ChatGPT-4 achieving 92.5%, compared to 86.3% for Gemini, with no significant difference in accuracy. However, there was a significant difference in comprehensiveness (p = 0.011) across the models. Overall, a significant difference in performance was observed among the LLMs (p < 0.001), with ChatGPT-4 providing the most college-level responses, though these were the most challenging to read. Conclusions: In conclusion, our study adds value to the applications of Artificial Intelligence (AI) in bladder cancer education, with notable insights into the accuracy, comprehensiveness, and stability of the three LLMs. Full article

In individuals with type 2 diabetes mellitus (T2DM), elevated levels of both plasma and urinary cystatin C (Cys-C) contribute to increased oxidation, which in turn accelerates the oxidation of low-density lipoprotein (LDL). This process may worsen the development of atherosclerosis and cardiovascular disease by promoting endothelial dysfunction and inflammation. Despite its potential significance, the relationship between Cys-C and oxidized LDL (ox-LDL) in T2DM remains poorly understood. This study investigated the relationship between plasma and urinary Cys-C and ox-LDL levels in T2DM patients. The cohort included 57 patients with T2DM (mean age 61.14 ± 9.99 years; HbA1c 8.66 ± 1.60% and BMI 35.15 ± 6.65 kg/m²). Notably, 95% of the patients had hypertension, 82% had dyslipidemia, 59% had an estimated glomerular filtration rate (eGFR) < 60 mL/min/1.73 m², 14% had coronary artery disease (CAD), and 5% had a history of stroke. Plasma and urinary Cys-C and ox-LDL levels were measured using ELISA. Adipokine and cytokine levels were measured using the multiplex^® MAP Human Adipokine Magnetic Bead Panels. Spearman’s correlation analysis revealed a significant positive correlation of plasma and urinary Cys-C with ox-LDL (r = 0.569, p = 0.0001 and r = 0.485, p = 0.0001, respectively). Multivariable regression analysis indicated that both plasma and urinary Cys-C were independently associated with ox-LDL, after adjusting for confounding factors (β = 0.057, p = 0.0001 and β = 0.486, p = 0.003, respectively). Stepwise linear regression identified TNFα and adiponectin as the strongest predictors of the relationship between urinary Cys-C and ox-LDL (β = 0.382, p = 0.0001; r² = 0.64), while adiponectin alone was the best predictor of the plasma Cys-C and ox-LDL association (β = 0.051, p = 0.005; r² = 0.46). Furthermore, adiponectin partly mediated the relationship between plasma Cys-C and ox-LDL, explaining 18% of the variance in this association. In contrast, TNFα partly mediated the relationship between urinary Cys-C and ox-LDL, accounting for 28% of the variance. This study emphasizes the complex interaction between Cys-C and ox-LDL in T2DM. It highlights the need for additional research involving larger patient cohorts to improve our understanding of the therapeutic potential of plasma and urinary Cys-C in conjunction with ox-LDL for managing complications associated with T2DM. Full article

Sickle cell disease (SCD) is a severe inherited blood disorder characterized by abnormal hemoglobin (HbS) that leads to varying degrees of severity, including chronic hemolysis, episodic vaso-occlusion, and damage to multiple organs, causing significant morbidity and mortality. While SCD is a monogenic disease, its complications are influenced by polygenic factors. SCD prevalence is notably high in regions including the Middle East, with Saudi Arabia reporting significant cases, particularly in the Eastern Province. Most genetic factors associated with SCD outcomes have been identified in populations predominantly from Africa or of African ancestry. This study aims to identify genetic variants that characterize Saudi SCD patients with the potential to influence disease outcomes in this population. A multicenter case-control genome-wide association study (GWAS) was conducted involving 350 adult Saudi SCD patients and 202 healthy controls. Participants were genotyped using the Affymetrix Axiom array, covering 683,030 markers. Rigorous quality control measures were applied to ensure data integrity. Fisher’s exact was used to identify genetic variants with a significant difference in allele frequency (p < 5 × 10⁻⁸). Functional annotations and regulatory functions of variants were determined using the Ensembl Variant Effect Predictor (VEP) and RegulomeDB databases. The GWAS identified numerous significant genetic variants characterizing SCD cases in the Saudi population. These variants, distributed across multiple chromosomes, were found in genes with known functional consequences. A substantial proportion of the markers were detected in the olfactory receptor cluster, TRIM family, and HBB locus genes. Many of the identified genes were reported in previous studies showing significant associations with various SCD outcomes, including hemoglobin regulation, inflammation, immune response, and vascular function. The findings highlight the genetic complexity underlying SCD and its clinical manifestations. The identified variants suggest potential molecular biomarkers and therapeutic targets, enhancing our understanding of the molecular basis of SCD in the Saudi population. This is the first genetic analysis characterizing SCD patients compared to healthy individuals, uncovering genetic markers that could serve as diagnostic biomarkers and therapeutic targets. Given the known molecular mechanisms of the detected genetic loci, these provide a foundation for precision medicine in SCD management, highlighting the need for further studies to validate these results and explore their clinical implications. Full article

Background and objectives: Type 2 diabetes mellitus (T2DM) affects brain white matter microstructure. While diffusion tensor imaging (DTI) has been used to study white matter abnormalities in T2DM, it lacks specificity for complex white matter tracts. Neurite orientation dispersion and density imaging (NODDI) offers a more specific approach to characterising white matter microstructures. This study aims to explore white matter alterations in T2DM using both DTI and NODDI and assess their association with disease duration and glycaemic control, as indicated by HbA1c levels. Methods and Materials: We analysed white matter microstructure in 48 tracts using data from the UK Biobank, involving 1023 T2DM participants (39% women, mean age 66) and 30,744 non-T2DM controls (53% women, mean age 64). Participants underwent 3.0T multiparametric brain imaging, including T1-weighted and diffusion imaging for DTI and NODDI. We performed region-of-interest analyses on fractional anisotropy (FA), mean diffusivity (MD), axial diffusivity (AD), radial diffusivity (RD), orientation dispersion index (ODI), intracellular volume fraction (ICVF), and isotropic water fraction (IsoVF) to assess white matter abnormalities. Results: We observed reduced FA and ICVF, and increased MD, AD, RD, ODI, and IsoVF in T2DM participants compared to controls (p < 0.05). These changes were associated with longer disease duration and higher HbA1c levels (0 < r ≤ 0.2, p < 0.05). NODDI identified microstructural changes in white matter that were proxies for reduced neurite density and disrupted fibre orientation, correlating with disease progression and poor glucose control. In conclusion, NODDI contributed to DTI in capturing white matter differences in participants with type 2 diabetes, suggesting the feasibility of NODDI in detecting white matter alterations in type 2 diabetes. Type 2 diabetes can cause white matter microstructural abnormalities that have associations with glucose control. Conclusions: The NODDI diffusion model allows the characterisation of white matter neuroaxonal pathology in type 2 diabetes, giving biophysical information for understanding the impact of type 2 diabetes on brain microstructure. Future research should focus on the longitudinal tracking of these microstructural changes to better understand their potential as early biomarkers for cognitive decline in T2DM. Full article

Background: There is an urgent need to identify new biomarkers for early diagnosis and development of therapeutic strategies for diabetes mellitus (DM) patients who have invasive breast cancer (BC). We previously reported the increased activated form of 70 kDa ribosomal protein S6 kinase 1 (phospho-p70S6K1) in a triple-negative BC (TNBC) cell line MDA-MB-231 exposed to glycated albumin (GA) and in invasive ductal carcinoma tissues from T2DM patients, compared to untreated cells and their non-diabetic counterparts, respectively. Objective: We aimed to explore the function of p70S6K1 in GA-promoted TNBC progression. Methods: By employing small interference (si)RNA technology or blocking its kinase activity using its specific pharmacological inhibitor, we monitored cell invasion using Transwell^® inserts and the expression levels of activated signaling proteins and cancer-related proteins using Western blot. Results: In silico analysis revealed that high mRNA levels of p70S6K1 were associated with an unfavorable prognosis and progression to advanced stages of TNBC in DM patients. The downregulation/blockade of p70S6K1 inhibited GA-promoted MDA-MB-231 cell invasion and the phosphorylation of protein S6 and ERK1/2, the p70S6K1 downstream effector, and the key oncogenic signaling protein, respectively. The suppression of the expression of GA-upregulated cancer proteins, including enolase-2, capping protein CapG, galectin-3, and cathepsin D, was observed after p70S6K1 downregulation/blockade. Further in silico validation analyses revealed increased gene expression of galectin-3 in DM TNBC patients, resulting in poor overall survival and disease-free survival. Conclusions: Targeting p70S6K1 may present a valuable therapeutic strategy, while galectin-3 could serve as a potential prognostic biomarker for invasive BC progression in DM patients. Full article

Atrial natriuretic peptide (ANP) and oxidized low-density lipoprotein (ox-LDL) play essential roles in the development and progression of vascular complications associated with type 2 diabetes mellitus (T2DM), and both are independently linked to cardiovascular diseases (CVD). However, the relationship between ANP and ox-LDL in patients with T2DM remains unclear as previous studies have primarily focused on circulating levels in various diseases. This study investigated the relationship between ANP and ox-LDL levels in obese individuals with T2DM. The cohort included 57 patients with T2DM (mean age 61.14 ± 9.99 years; HbA1c 8.66 ± 1.60%; BMI 35.15 ± 6.65 kg/m²). Notably, 95% of the patients had hypertension, 82% had dyslipidemia, 59% had an estimated glomerular filtration rate (eGFR) < 60 mL/min/1.73 m², 14% had coronary artery disease (CAD), and 5% had a history of stroke. Plasma concentrations of ANP and ox-LDL were measured using ELISA. Adipokines and cytokines levels were measured using the multiplex^® MAP Human Adipokine Magnetic Beads Spearman’s correlation analysis which revealed a negative correlation between ANP and ox-LDL (r = −0.446, p = 0.001) as well as with the ox-LDL/apoB ratio (r = −0.423, p = 0.001) and ox-LDL/LDLc ratio (r = −0.307, p = 0.038). Multivariable regression analysis indicated that ANP was independently associated with ox-LDL (β = −115.736, p = 0.005). Stepwise linear regression further identified TNFα, leptin, and adiponectin as the strongest predictors influencing the relationship between ANP and ox-LDL levels (β = −64.664, p = 0.0311, and r² = 0.546 for the model). However, these factors did not significantly mediate this association. This study emphasizes the need for further exploration of the complex interaction between ANP and ox-LDL in larger patient populations. This could provide valuable insights into potential therapeutic approaches for managing vascular complications in obese individuals with T2DM. Full article