Biology subjects

Abdalla, N.

Publications and source records attributed to Abdalla, N..

4 recordsLinked to original sources

bioRxiv2026

Stage-Specific Regulation of DNA Damage Repair by the Circadian Regulator, CRY1, in Prostate Cancer

Circadian dysregulation is increasingly linked to prostate cancer (PCa) progression, yet its role in directing DNA damage response (DDR) pathway selection remains poorly understood. Here, we identify circadian cryptochrome 1 (CRY1), a core circadian regulator, as a stage-specific determinant of DDR dependencies. Integrated transcriptomic and CRISPR-based analyses reveal that CRY1 promotes non-homologous end joining (NHEJ) and base excision repair (BER)-associated programs in hormone-sensitive disease (HTS), while driving a switch toward homologous recombination (HR) dependency in castration-resistant prostate cancer (CRPC). Mechanistically, CRY1 couples proliferative signaling to genome maintenance, enabling tumor cells to tolerate genotoxic stress and sustain progression. Notably, loss of CRY1 exposes distinct, context-dependent DDR vulnerabilities, revealing repair plasticity as a targetable actionable feature of disease evolution. These findings position CRY1 as a central regulator of DDR rewiring and support CRY1-directed combination strategies with DDR inhibitors as a rationale to delay or prevent progression to advanced, treatment-resistant PCa.

cancer biology↗

bioRxiv2025

Allopurinol improves cardiovascular phenotypes of a mouse model for Williams-Beuren syndrome reducing redox stress

Cardiovascular disease represents the primary cause of morbidity in Williams-Beuren syndrome (WBS), a neurodevelopmental disorder resulting from a hemizygous deletion of 26-28 genes on chromosome 7q11.23. The clinical phenotype includes systemic hypertension, cardiac dysfunction, and progressive vascular remodelling, features that are further exacerbated by increased oxidative stress. Given the early onset and progression of these cardiovascular manifestations, patients often require long-term pharmacological management from childhood. This raises important concerns about cumulative drug toxicity, dosing strategies, and the long-term safety of therapeutic interventions in pediatric populations. Using the Complete deletion (CD) mouse model of WBS, this study aims to evaluate whether pediatric-equivalent doses of Allopurinol (ALO) (20mg/kg/day equivalent to 1,66mg/kg/day in humans) a highly specific xanthine oxidoreductase (XOR) inhibitor, and Losartan (LOS) (12,5 mg/kg/day equivalent to 1 mg/kg/day in humans) an angiotensin II type1 receptor antagonist, will exert beneficial effects on the cardiovascular phenotype of CD mice. To enable comparative analysis, the pharmacological effects of ALO and LOS were evaluated against both untreated CD mice and wild-type (WT) controls. In CD mice, both treatments significantly reduced systemic blood pressure; however, their effects on cardiac outcomes were different. While treatment with ALO improved cardiac pathology, treatment with LOS did not. ALO likely acts by reducing XOR protein levels, reactive oxygen species (ROS) production and NRLP3 activation. These findings support a therapeutic model in which minimal doses of ALO offers broader cardiovascular protection in WBS.

genetics↗

bioRxiv2023

Dysfunctional Mitochondria in Cardiac Fibers of a Williams-Beuren Syndrome Mouse Model

Williams-Beuren Syndrome (WBS) is a rare neurodevelopmental disorder that, together with a rather characteristic neurocognitive profile, presents a strong cardiovascular phenotype. The cardiovascular features of WBS are mainly related to a gene dosage effect due to hemizygosity of the elastin (ELN) gene; however, the phenotypic variability between WBS patients indicates the presence of important modulators of the clinical impact of elastin deficiency. Recently, two genes within the WBS region have been linked to mitochondrial dysfunction. Numerous cardiovascular diseases are related to mitochondrial dysfunction; therefore, it could be a modulator of the phenotype present in WBS. Here, we analyze mitochondrial function and dynamics in cardiac tissue from a WBS complete deletion (CD) model. Our research reveals that cardiac fiber mitochondria from CD animals have altered mitochondrial dynamics, accompanied by respiratory chain dysfunction with decreased ATP production, reproducing alterations observed in fibroblasts from WBS patients. Our results highlight two major factors; on the one hand, that mitochondrial dysfunction is probably a relevant mechanism underlying several risk factors associated with WBS disease; on the other, the CD murine model mimics the mitochondrial phenotype of WBS and could be a great model for carrying out preclinical tests on drugs targeting the mitochondria.

molecular biology↗

bioRxiv2022

Curcumin combined with verapamil improve cardiovascular phenotype of a Williams-Beuren Syndrome mice model reducing oxidative stress

Williams-Beuren syndrome (WBS) is a rare neurodevelopmental disorder with hallmarks in the cardiovascular manifestations and no well-defined therapeutic strategies. We investigated the progression of cardiovascular phenotype present in CD (complete deletion) mice, a murine model of WBS, after chronic treatment with curcumin and verapamil, both compounds with positive effects on related pathologies. Treatment was administered orally dissolved in drinking water. After measuring "in vivo" systolic blood pressure, aortic and left ventricular myocardium were histological and molecular analysed to determine the effects of treatment and its underlying mechanism in CD mice. We observed upregulated xanthine oxidoreductase (XOR) expression in both aortic and left ventricular myocardium of CD mice. This overexpression is concomitant with increased levels of nitrated proteins as example of byproduct-mediated oxidative stress damage, indicating of XOR-generated oxidative stress impact on the pathophysiology of cardiovascular manifestations in WBS, and suggesting that the inhibition of XOR and/or oxidative stress damage could help to ameliorate the severe cardiovascular injuries presented in WBS.

genetics↗