Biology subjects

Magzoub, M.

Publications and source records attributed to Magzoub, M..

6 recordsLinked to original sources

bioRxiv2026

Nuclear βactin dependent chromatin accessibility governs stem cell pluripotency and extracellular matrix gene programs to maintain cellular biomechanics for cell lineage decisions

Pluripotency requires coordinated regulation of chromatin state, transcription and extracellular matrix (ECM) mechanics, but how these layers are integrated remains unclear. Here, using {beta}-actin knockout mouse embryonic stem cells (mESCs) and a nuclear-targeted {beta}-actin rescue, we identify nuclear {beta}-actin as a key regulator linking chromatin accessibility to mechanosensitive control of cell fate. {beta}-actin loss reduced OCT4, SOX2 and NANOG, broadly rewired the transcriptome and proteome and decreased accessibility at pluripotency regulatory regions. Integrated RNA-seq and ATAC-seq revealed coordinated dysregulation of stemness, ECM, mechanotransduction and early-lineage programs. These changes were accompanied by fibronectin and collagen upregulation, altered nuclear morphology, reduced Lamin A/C and mechanosensing proteins, increased nuclear YAP1 and greater ECM stiffness heterogeneity. Functionally, knockout cells displayed biased lineage specification, failed neuronal differentiation, ectopic cardiomyocyte-like differentiation, and markedly reduced teratoma growth with diminished ectodermal representation. Nuclear {beta}-actin re-expression restored many molecular, mechanical and differentiation defects, although chromatin rescue remained incomplete. Together, these findings establish nuclear {beta}-actin as an integrator of chromatin regulation and ECM-dependent mechanotransduction that preserves pluripotency and developmental competence.

cell biology↗

bioRxiv2025

Prion protein-derived cell-penetrating peptide inhibits type II diabetes-associated islet amyloid polypeptide aggregation and cytotoxicity

Islet amyloid polypeptide (IAPP) is a 37-residue peptide hormone co-packaged and co-secreted with insulin by pancreatic {beta}-cells. A pathological hallmark of type II diabetes is the self-assembly of IAPP into {beta}-sheet rich amyloid fibers, which is associated with {beta}-cell impairment. Previously, we showed that a cell-penetrating peptide (CPP) construct, consisting of a hydrophobic signal sequence coupled to a polycationic nuclear localization signal (NLS)-like sequence, exhibited potent anti-prion activity and antagonism of Alzheimers disease-associated amyloid-{beta} (A{beta}) peptide aggregation and neurotoxicity. Here, we have extended this approach towards type II diabetes by assessing the efficacy of the CPP construct, designated as NCAM1-PrP, in inhibiting IAPP oligomerization, fiber formation and associated cytotoxicity. Using complementary in vitro and in silico experiments, we show that NCAM1-PrP effectively modulates IAPPs toxic structures into non-toxic conformations. This study underlines the potential of our designed CPP-based therapeutic approach as a versatile tool in the battle against amyloid-associated pathologies.

biochemistry↗

bioRxiv2025

pH-Responsive Near Infrared Light Triggered Hydroxyapatite Nanoparticles for Targeted Photothermal Cancer Therapy

Photothermal therapy (PTT), which utilizes photothermal agents (PTAs) to induce localized hyperthermia within tumors upon light irradiation, has emerged as a promising cancer treatment strategy. However, low water solubility, poor in vivo circulation stability and a lack of tumor specificity of many common PTAs limit their applicability. To address these issues, we have developed a simple, yet highly potent, tumor-targeted nanotheranostic system that consists of lipid/PEG-coated hydroxyapatite nanoparticles (LHAPNs) encapsulating the near-infrared (NIR) photothermal dye IR106 (LHAPNIRs). The lipid coat serves to retain the encapsulated dye and prevent serum protein adsorption and macrophage recognition, which would otherwise destabilize the nanoparticles and hinder their tumor targeting efficiency. Additionally, the coat is functionalized with the tumor-acidity-triggered rational membrane (ATRAM) peptide for efficient and specific internalization into tumor cells in the mildly acidic microenvironment of tumors. The nanoparticles facilitated real-time fluorescence and thermal imaging of tumors and demonstrated potent NIR-light triggered anticancer activity in vitro and in vivo, without adversely affecting healthy tissue, leading to markedly prolonged survival. Our results demonstrate that the biocompatible and biodegradable ATRAM-functionalized LHAPNIRs (ALHAPNIRs) effectively combine dual-mode diagnostic imaging with targeted cancer PTT.

bioengineering↗

bioRxiv2023

pH-responsive upconversion mesoporous silica nanospheres for combined multimodal diagnostic imaging and targeted photodynamic and photothermal cancer therapy

Photodynamic therapy (PDT) and photothermal therapy (PTT) have garnered considerable interest as non-invasive cancer treatment modalities. However, these approaches remain limited by low solubility, poor stability and inefficient targeting of many common photosensitizers (PSs) and photothermal agents (PTAs). To overcome these limitations, we have designed biocompatible and biodegradable tumor-targeted upconversion nanospheres with imaging capabilities. The multifunctional nanospheres consist of a sodium yttrium fluoride core doped with lanthanides (ytterbium, erbium and gadolinium) and bismuth selenide (NaYF4:Yb/Er/Gd,Bi2Se3) within a mesoporous silica shell that encapsulates a PS, Chlorin e6 (Ce6), in its pores. NaYF4:Yb/Er converts deeply penetrating near-infrared (NIR) light to visible light, which excites the Ce6 to generate cytotoxic reactive oxygen species (ROS), while the PTA Bi2Se3 efficiently converts absorbed NIR light to heat. Additionally, Gd enables magnetic resonance imaging (MRI) of the nanospheres. The mesoporous silica shell is coated with lipid/polyethylene glycol (DPPC/cholesterol/DSPE-PEG) to ensure retention of the encapsulated Ce6 and minimize interactions with serum proteins and macrophages that impede tumor targeting. Finally, the coat is functionalized with the acidity-triggered rational membrane (ATRAM) peptide, which promotes specific and efficient internalization into cancer cells within the mildly acidic tumor microenvironment. Following uptake by cancer cells in vitro, NIR laser irradiation of the nanospheres caused substantial cytotoxicity due to ROS production and hyperthermia. The nanospheres facilitated tumor MRI and thermal imaging, and exhibited potent NIR laser light-induced antitumor effects in vivo via combined PDT and PTT, with no observable toxicity to healthy tissue, thereby substantially prolonging survival. Our results demonstrate that the ATRAM-functionalized, lipid/PEG-coated upconversion mesoporous silica nanospheres (ALUMSNs) offer multimodal diagnostic imaging and targeted combinatorial cancer therapy.

bioengineering↗

bioRxiv2022

Regulation of oxidative phosphorylation by Nuclear myosin 1 protects cells from metabolic reprogramming and tumorigenesis in mice

Metabolic reprogramming is one of the hallmarks of tumorigenesis. Using a combination of multi-omics, here we show that nuclear myosin 1 (NM1) serves as a key regulator of cellular metabolism. As part of the nutrient-sensing PI3K/Akt/mTOR pathway, NM1 forms a positive feedback loop with mTOR and directly affects mitochondrial oxidative phosphorylation (OXPHOS) via transcriptional regulation of mitochondrial transcription factors TFAM and PGC1. NM1 depletion leads to suppression of PI3K/Akt/mTOR pathway, underdevelopment of mitochondria inner cristae, and redistribution of mitochondria within the cell, which is associated with reduced expression of OXPHOS genes, decreased mitochondrial DNA copy number and deregulated mitochondrial dynamics. This leads to metabolic reprogramming of NM1 KO cells from OXPHOS to aerobic glycolysis and with a metabolomic profile typical for cancer cells, namely, increased amino acid-, fatty acid-, and sugar metabolism, and increased glucose uptake, lactate production, and intracellular acidity. We show that NM1 KO cells form solid tumors in a nude mouse model even though they have suppressed the PI3K/Akt/mTOR signaling pathway suggesting that the metabolic switch towards aerobic glycolysis provides a sufficient signal for carcinogenesis. We suggest that NM1 plays a key role as a tumor suppressor and that NM1 depletion may contribute to the Warburg effect at the early onset of tumorigenesis.

cell biology↗

bioRxiv2020

Protein mimetic amyloid inhibitor potently abrogates cancer-associated mutant p53 aggregation and restores tumor suppressor function

Missense mutations in p53 are severely deleterious and occur in over 50% of all human cancers. The vast majority of these mutations are located in the inherently unstable DNA-binding domain (DBD), many of which destabilize the domain further and expose its aggregation-prone hydrophobic core, prompting self-assembly of mutant p53 into inactive cytosolic amyloid-like aggregates. Screening an oligopyridylamide library, previously shown to inhibit amyloid formation associated with Alzheimers disease and type II diabetes, identified a tripyridylamide, ADH-6, that potently abrogates self-assembly of the aggregation-nucleating subdomain of mutant p53 DBD. Moreover, ADH-6 effectively targets and dissociates mutant p53 aggregates in human cancer cells, which restores p53s transcriptional activity, leading to cell cycle arrest and apoptosis. Notably, ADH-6 treatment substantially shrinks xenografts harboring mutant p53 and prolongs survival, while exhibiting no toxicity to healthy tissue. This study demonstrates the first successful application of a bona fide small-molecule amyloid inhibitor as an anticancer agent.

cancer biology↗