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The arachidonate 5-lipoxygenase activating protein (ALOX5AP) regulates leukotrienes (LTs) synthesis. LTs are involved in inflammation which is implicated in cardiovascular diseases (CVDs) and stroke. Variations in ALOX5AP gene are associated with CVDs, stroke and others because of their possible effects on ALOX5AP stability and function. In this study we investigated with molecular dynamics (MD) simulation the structural impacts of L12F, A56V, G75R, and G87R variants on ALOX5AP. We employed an array of bioinformatics techniques, including SIFT, PolyPhen-2, PANTHER, SNPs&GO, PhD-SNP, i-Mutant, MuPro, MutPred, ConSurf, and GROMACS. Results showed that the L12F variant increased structural compactness, as indicated by diminished solvent accessibility, a reduced radius of gyration, and a decrease in hydrogen bonding capacity. The A56V variant destabilized the ALOX5AP, demonstrating elevated root mean square deviation (RMSD), augmented solvent-accessible surface area, and diminished ALOX5AP compactness. The G75R and G87R variants exhibited mild effects on ALOX5AP wildtype. However, simulation trajectory snapshots results indicated G75R and G87R variants induce instability leading to structural perturbations of ALOX5AP probably due to the charge of arginine introduced by the G75R and G87R mutation. The G75R and G87R variants potentially influence ALOX5AP dynamics, stability, and function. These results require further verification in future case-control and protein functional studies.

The full-length BRCA1-associated RING domain 1 (BARD1) gene encodes a 777-aa protein. BARD1 displays a dual role in cancer development and progression as it acts as a tumor suppressor and an oncogene. Structurally, BARD1 has homologous domains to BRCA1 that aid their heterodimer interaction to inhibit the progression of different cancers such as breast and ovarian cancers following the BRCA1-dependant pathway. In addition, BARD1 was shown to be involved in other pathways that are involved in tumor suppression (BRCA1-independent pathway) such as the TP53-dependent apoptotic signaling pathway. However, there are abundant BARD1 isoforms exist that are different from the full-length BARD1 due to nonsense and frameshift mutations, or deletions were found to be associated with susceptibility to various cancers including neuroblastoma, lung, breast, and cervical cancers. This article reviews the spectrum of BARD1 full-length genes and its different isoforms and their anticipated associated risk. Additionally, the study also highlights the role of BARD1 as an oncogene in breast cancer patients and its potential uses as a prognostic/diagnostic biomarker and as a therapeutic target for cancer susceptibility testing and treatment.

SF3B1 gene mutations are prevalent in myelodysplastic syndrome (MDS) and define a distinct disease subtype. These mutations are associated with dysregulated genes and pathways, offering potential for novel therapeutic approaches. However, the aberrant mRNA alternative splicing landscape in SF3B1 -deficient MDS cells remains underexplored. In this study, we investigated the influence of SF3B1 gene alterations on the pre-mRNA splicing landscape in MDS cells using transcriptomic data from two independent MDS cohorts. we identified over 5000 significant differential alternative splicing events associated with SF3B1 mutation. This work corroborates previous studies, showing significant enrichment of MYC activity and heme metabolism in SF3B1 mutant cells. A key novel finding of this study is the identification of a gene expression signature driven by SF3B1 mutations, centered on protein post-translational modifications. Notably, we discovered aberrant alternative splicing of the tumor suppressor gene UBA7 , leading to significantly reduced gene expression. This dysregulation implicates UBA7 as a critical player in MDS pathogenesis. Importantly, the clinical relevance of this finding is underscored by the observation that low UBA7 gene expression was associated with poor overall survival in chronic lymphocytic leukemia (CLL), another hematological malignancy with frequent SF3B1 mutations. Furthermore, a similar association between low UBA7 gene expression and poor survival outcomes was observed across multiple tumor types in the TCGA database, highlighting the broader implications of UBA7 dysregulation in cancer biology. These findings provide new insights into the mechanisms by which SF3B1 mutations reshape the pre-mRNA splicing landscape and drive disease pathogenesis in MDS. Furthermore, they underscore the potential of UBA7 as a biomarker to stratify SF3B1-mutant MDS and CLL patients, offering a refined approach for risk assessment and highlighting opportunities for targeted therapeutic interventions.

In the current study, the hepatoprotective activity of vanillic acid, silymarin, and vanillic acid-loaded silver nanoparticles (AgNPs) against CCl4-induced hepatotoxicity was tested in male rats for four weeks. Thirty male rats were divided into five groups (n = 6). The 1st group was a negative control, the 2nd group was a positive control, the 3rd group was treated with 100 mg/kg b.w. of vanillic acid, the 4th group was treated with 100 mg/kg b.w. of vanillic acid–AgNPs, and the 5th group was treated with 50 mg/kg b.w. of silymarin. The CCl4-induced hepatic toxicity in the 2nd group was revealed by the liver function and all other biochemical tests. Liver enzymes, bilirubin, lipid peroxidation, lactate dehydrogenase, and interleukin-6 were elevated, whereas, total protein, antioxidant enzymes, and irisin were decreased compared to the negative control. The hepatic tissues were also injured as a result of the CCl4-induced hepatotoxicity. Treating the hepatotoxic rats with vanillic acid moderately protected the rats of the 3rd group, whereas treatment with vanillic AgNPs and silymarin in G4 and G5, respectively, greatly protected the rats against the CCl4 hepatotoxicity, approaching the normal biochemical levels and liver tissue appearance. The biochemical tests were confirmed by the histological investigations of liver tissue.

In the original publication [...]

Background: Autosomal dominant polycystic kidney disease (ADPKD) is a condition usually caused by a single gene mutation and manifested by both renal and extrarenal features, eventually leading to end-stage renal disease (ESRD) by the median age of 60 years worldwide. Approximately 89% of ADPKD patients had either PKD1 or PKD2 gene mutations. The majority (85%) of the mutations are in the PKD1 gene, especially in the context of family history. Objectives: This study investigated the genetic basis and the undiscovered genes that are involved in ADPKD development among the Saudi population. Materials and Methods: In this study, 11 patients with chronic kidney disease were enrolled. The diagnosis of ADPKD was based on history and diagnostic images: CT images include enlargement of renal outlines, renal echogenicity, and presence of multiple renal cysts with dilated collecting ducts, loss of corticomedullary differentiation, and changes in GFR and serum creatinine levels. Next-generation whole-exome sequencing was conducted using the Ion Torrent PGM platform. Results: Of the 11 Saudi patients diagnosed with chronic kidney disease (CKD) and ADPKD, the most common heterozygote nonsynonymous variant in the PKD1 gene was exon15: (c.4264G > A). Two missense mutations were identified with a PKD1 (c.1758A > C and c.9774T > G), and one patient had a PKD2 mutation (c.1445T > G). Three detected variants were novel, identified at PKD1 (c.1758A > C), PKD2L2 (c.1364A > T), and TSC2 (deletion of a’a at the 3’UTR, R1680C) genes. Other variants in PKD1L1 (c.3813_381 4delinsTG) and PKD1L2 (c.404C > T) were also detected. The median age of end-stage renal disease for ADPK patients in Saudi Arabia was 30 years. Conclusion: This study reported a common variant in the PKD1 gene in Saudi patients with typical ADPKD. We also reported (to our knowledge) for the first time two novel missense variants in PKD1 and PKD2L2 genes and one indel mutation at the 3’UTR of the TSC2 gene. This study establishes that the reported mutations in the affected genes resulted in ADPKD development in the Saudi population by a median age of 30. Nevertheless, future protein–protein interaction studies to investigate the influence of these mutations on PKD1 and PKD2 functions are required. Furthermore, large-scale population-based studies to verify these findings are recommended.

Colorectal cancer (CRC) remains a leading cause of cancer-related mortality worldwide, underscoring the need for non-invasive biomarkers that can support earlier detection and risk stratification. This exploratory study investigated the combined diagnostic performance of circulating microRNA-155 (miR-155) and vascular endothelial growth factor (VEGF) in CRC, with mechanistic support from molecular docking and integration into an AI-based predictive model. In a case-control design, plasma levels of miR-155 and VEGF were quantified in CRC patients, individuals with benign colorectal conditions, and healthy controls. Diagnostic accuracy was assessed using ROC curve analysis, with comparisons across subgroup analyses (CRC vs benign, CRC vs controls, CRC vs benign + controls). Molecular docking provided comparative predictions of miR-155 interactions with regulatory proteins (IL-13RA1, SOCS1, PTEN, BCL-6, TP53INP1). An AI model (logistic regression with L2 regularization, stratified tenfold cross-validation) integrated biomarkers with clinical factors to evaluate predictive performance. Both miR-155 and VEGF were significantly elevated in CRC patients compared with benign and control groups. Individually, miR-155 achieved an AUC of 0.85 and VEGF an AUC of 0.79; combined analysis improved performance (AUC = 0.93). Subgroup ROC analyses confirmed robust discriminatory power across clinically relevant comparisons. The AI-integrated model achieved the highest accuracy (AUC = 0.96) under cross-validation. Docking suggested preferential interactions of miR-155 with IL-13RA1, SOCS1, and PTEN, supporting their mechanistic involvement. miR-155 and VEGF show promise as synergistic biomarkers for CRC detection, particularly when integrated with clinical risk factors. Molecular docking provides hypothesis-generating mechanistic insights, while AI modeling demonstrates the potential of multi-parametric integration. Given the modest, single-center sample size and lack of external validation, these findings should be considered exploratory. Larger, multi-center validation studies are essential before clinical translation.

Globally, iron-deficiency anemia (IDA) remains a major health obstacle. This health condition has been identified in 47% of pre-school students (aged 0 to 5 years), 42% of pregnant females, and 30% of non-pregnant females (aged 15 to 50 years) worldwide according to the WHO. Environmental and genetic factors play a crucial role in the development of IDA; genetic testing has revealed the association of a number of polymorphisms with iron status and serum ferritin. The current study aims to reveal the association of TMPRSS6 rs141312 and BMP2 rs235756 with the iron status of females in Saudi Arabia. A cohort of 108 female university students aged 18-25 years was randomly selected to participate: 50 healthy and 58 classified as iron deficient. A 3-5 mL sample of blood was collected from each one and analyzed based on hematological and biochemical iron status followed by genotyping by PCR. The genotype distribution of TMPRSS6 rs141312 was 8% (TT), 88% (TC) and 4% (CC) in the healthy group compared with 3.45% (TT), 89.66% (TC) and 6.89% (CC) in the iron-deficient group (P = 0.492), an insignificant difference in the allelic distribution. The genotype distribution of BMP2 rs235756 was 8% (TT), 90% (TC) and 2% (CC) in the healthy group compared with 3.45% (TT), 82.76% (TC) and 13.79% (CC) in iron-deficient group (P = 0.050) and was significantly associated with decreased ferritin status (P = 0.050). In addition, TMPRSS6 rs141312 is significantly (P<0.001) associated with dominant genotypes (TC+CC) and increased risk of IDA while BMP2 rs235756 is significantly (P<0.026) associated with recessive homozygote CC genotypes and increased risk of IDA. Our finding potentially helps in the early prediction of iron deficiency in females through the genetic testing.

Natural copolymer (e.g., chitosan-loaded) and synthetic (e.g., silver nitrate-loaded) nanopolymers have many medical applications in drug delivery research for enhancing the effectuality of traditional medicine. This study aimed to investigate the potential protective activity of vanillic acid, silver nanoparticles (AgNPs) of vanillic acid, and silymarin against carbon tetrachloride (CCl4)-induced nephrotoxicity in male rats. Rats were divided into five groups; the first group (G1) was a negative control, and the other rats were treated intraperitoneally with CCl4 to induce kidney toxicity twice weekly, and then divided into four groups, G2 was a positive control and left without treatment, the third group was treated with vanillic acid, the fourth (G4) was treated with vanillic acid-AgNPs, and the fifth (G5) was treated with silymarin. In G2, renal function indices (urea, creatinine, and uric acid) showed elevated levels indicating renal toxicity. Na, K, and Ca ions were decreased, whereas Cl− was increased. Antioxidants (glutathione S-transferase, glutathione reduced, total antioxidant capacity, superoxide dismutase, and catalase) were decreased, whereas lipid peroxidation was increased in the kidney tissue homogenate. IL1 was increased, whereas CYP-450 was decreased. In the treated group, all biochemical and renal tissue texture were alleviated as a result of treatment with vanillic acid in G3, vanillic acid AgNPs in G4, and silymarin in G5. Vanillic acid AgNPs and silymarin treatment in G4 and G5, respectively, were more efficient than vanillic acid in G5 in protecting the kidneys against CCl4-induced nephrotoxicity.

The main protease (Mpro) is a potential druggable target in SARS-CoV-2 replication. Herein, an in silico study was conducted to mine for Mpro inhibitors from toxin sources. A toxin and toxin-target database (T3DB) was virtually screened for inhibitor activity towards the Mpro enzyme utilizing molecular docking calculations. Promising toxins were subsequently characterized using a combination of molecular dynamics (MD) simulations and molecular mechanics-generalized Born surface area (MM-GBSA) binding energy estimations. According to the MM-GBSA binding energies over 200 ns MD simulations, three toxins—namely philanthotoxin (T3D2489), azaspiracid (T3D2672), and taziprinone (T3D2378)—demonstrated higher binding affinities against SARS-CoV-2 Mpro than the co-crystalized inhibitor XF7 with MM-GBSA binding energies of −58.9, −55.9, −50.1, and −43.7 kcal/mol, respectively. The molecular network analyses showed that philanthotoxin provides a ligand lead using the STRING database, which includes the biochemical top 20 signaling genes CTSB, CTSL, and CTSK. Ultimately, pathway enrichment analysis (PEA) and Reactome mining results revealed that philanthotoxin could prevent severe lung injury in COVID-19 patients through the remodeling of interleukins (IL-4 and IL-13) and the matrix metalloproteinases (MMPs). These findings have identified that philanthotoxin—a venom of the Egyptian solitary wasp—holds promise as a potential Mpro inhibitor and warrants further in vitro/in vivo validation.