👤 Nabieh Ayoub

The apolipoprotein E (APOE) gene ε4 allele leads to increased Alzheimer disease risk and neuroinflammation and is also believed to play a role in postoperative delirium. However, the safety and feasibility of modulating apoE protein signaling to reduce postoperative neuroinflammation and delirium in older adults are unclear. To assess the safety and feasibility of the apoE mimetic peptide CN-105 for reducing delirium incidence and severity and neuroinflammation after noncardiac or nonintracranial surgery in older adults. This triple-blind, escalating dose, phase 2 randomized clinical trial enrolled patients from April 17, 2019, to December 28, 2022, at a tertiary academic medical center. Included patients were 60 years or older and scheduled for a noncardiac or nonintracranial surgery. Exclusion criteria were incarceration, planned chemotherapy within 6 weeks after surgery, or inability to undergo lumbar punctures. Data analyses were based on a modified intention-to-treat approach and were performed from August 14, 2023, to August 22, 2025. Patients were randomly assigned 3:1 to the CN-105 group or placebo group. The CN-105 group received intravenous CN-105 doses of 0.1, 0.5, or 1 mg/kg starting within 1 hour before surgery and administered every 6 hours afterward until hospital discharge or 13 doses were received. Patients in the placebo group followed the same administration schedule. The primary outcome was safety-the incidence and number of postoperative adverse events (AEs). Secondary outcomes included feasibility (rate of drug doses administered within 90 minutes of schedule), postoperative delirium incidence and severity, and postoperative changes in cerebrospinal fluid (CSF) cytokine levels (interleukin [IL] 6, granulocyte-colony stimulating factor [G-CSF], monocyte chemoattractant protein-1 [MCP-1], and IL-8). Among 203 enrolled patients, 186 (mean [SD] age, 68.7 [5.2] years; 119 males [64.0%]) were randomized (137 to the CN-105 group, 49 to the placebo group) and underwent surgery. The rates of grade 2 or higher AEs among patients in the CN-105 and placebo groups were 76.6% and 87.8% (relative risk [RR], 0.87; 95% CI, 0.76-1.00; P = .10). The CN-105 vs placebo group had fewer grade 2 or higher AEs per patient (median [IQR], 1 [1-3] vs 2 [1-5]; P = .03). The percentage of CN-105 doses administered within the time window was 94.6% (860 of 909; 95% CI, 92.9%-96.0%) in the CN-105 group and 93.8% (346 of 369; 95% CI, 90.8%-96.0%) in the placebo group. Among patients in the CN-105 vs placebo group, the postoperative delirium incidence was 19.3% vs 26.5% (odds ratio [OR], 0.66; 95% CI, 0.31-1.42; P = .29); the median (IQR) postoperative delirium severity scores were 1 (1-2) vs 2 (1-2) (P = .19); and the median difference in preoperative to 24-hour postoperative CSF cytokine-level changes were as follows: -0.39 pg/mL (95% CI, -0.93 to 0.14 pg/mL, P = .12) for IL-6, -0.84 pg/mL (95% CI, -3.06 to 1.40 pg/mL; P = .18) for G-CSF,-23.32 pg/mL (95% CI, -94.36 to 44.93 pg/mL; P = .57) for IL-8, and -2.36 pg/mL (95% CI, -58.57 to 58.62 pg/mL; P = .50) for MCP-1. In this phase 2 randomized clinical trial of older surgical patients, CN-105 (vs placebo) administration was feasible and did not increase AEs. A phase 3 trial is warranted to further evaluate the efficacy of CN-105 for reducing postoperative AEs and to more precisely determine its effects on postoperative delirium incidence and severity. ClinicalTrials.gov Identifier: NCT03802396. Show less

Crateva magna (Cm) was utilized as a folkloric medicine against neurological disorders. This study aimed to investigate the phytochemical profile of Cm leaf extract and its endophytic fungus, Nigrospora oryzae (No) extract. Additionally, the neuroprotective potential of their optimized bilosomes (BLs) will be assessed as an approach to Alzheimer's disease (AD) treatment. UPLC-ESI-MS/MS chemical profiling was performed. In vitro anti-Alzheimer activity of Cm and No extracts was evaluated against AChE and BACE1 enzymes. Cm-BLs and No-BLs were prepared using the thin-film hydration technique. In vivo anti-Alzheimer potential was assessed in a streptozotocin (STZ)-induced sporadic AD mouse model. Behavioral assays, neurochemical assays, RT-PCR analysis, histopathological examination, and immunohistochemical analysis were performed. Chemical profiling revealed diverse metabolites from various chemical classes. The major class identified in Cm extract was flavonoids, e.g., kaempferol-O-hexoside, whereas in No extract, it was alkaloids, e.g., phenazine carboxamide. The neuropathological markers (Aβ1-42, IL-6, and p-Tau protein) were reduced by ≈50% and 60% in mice receiving Cm-BLs and No-BLs, respectively, relative to the STZ group. Also, the BLs exhibited the greatest ability to downregulate the expression of p-JNK, p-P38, and p-ERK in the brain. Histopathological examination revealed that No-BLs showed the highest protection for the hippocampus and cerebral cortex regions. Also, it revealed a significantly decreased reaction for NFκB in cerebral cortex neurons. Cm-BLs and No-BLs exhibit considerable potential as novel adjuvant therapies for AD, utilizing natural bioactive compounds to improve the efficiency of targeted drug delivery and enhance therapeutic outcomes. Show less

Alzheimer's disease (AD), one of the most common types of dementia, is an urgent and growing global challenge. AD pathogenesis is associated with increased activity of the acetylcholinesterase enzyme (AChE) and the β-site amyloid precursor protein cleaving enzyme (β-secretase, BACE1). This study aimed to evaluate the AChE and BACE1 inhibitory activities of the n-hexane soluble fraction of Crateva magna leaf extract (CMHF) and its cytotoxic properties against cancer and normal cell lines using MTT assay, also this study aimed to identify the volatile constituents of CMHF by gas chromatography-mass spectrometry (GC-MS) analysis. GC-MS analysis revealed a total of 13 metabolites which represent 92.42% of the detected compounds. Phytol was the major constituent of CMHF, representing 20.52% followed by (Z, Z, Z)-9,12,15-octadecatrienoic acid ethyl ester (19.04%), γ-sitosterol (13.71%), hexadecanoic acid ethyl ester (12.63%) and others. CMHF revealed potent AChE and BACE1 inhibitory activities with IC Show less

Oncogenic alterations in fibroblast growth factor receptor (FGFR)-family proteins occur across cancers, including pediatric gliomas. Our genomic analysis of 11,635 gliomas across ages finds that 5.3% of all gliomas harbor FGFR alterations, with an incidence of almost 9% in pediatric gliomas. Alterations in FGFR proteins are differentially enriched by age, tumor grade, and histology, with FGFR1 alterations associated with glioneuronal histologies. Leveraging isogenic systems, we confirm FGFR1 alterations to induce downstream Mitogen Activated Protein Kinase (MAPK) and mTOR signaling pathways, drive gliomagenesis, activate neuronal transcriptional programs and exhibit sensitivity to MAPK pathway and pan-FGFR inhibitors. Finally, we perform a retrospective analysis of clinical responses in children diagnosed with FGFR-altered gliomas and find that treatment with currently available inhibitors is largely associated with stability of disease. This study provides key insights into the biology of FGFR1-altered gliomas, therapeutic strategies to target them and associated challenges that still need to be overcome. Show less

Elevated lipoprotein(a) [Lp(a)] and low high-density lipoprotein-cholesterol (HDL-C) are established cardiovascular (CV) risk factors, but their combined impact on mortality and sex differences remains unclear. This retrospective study analyzed 97 396 patients with measured Lp(a) and HDL-C. Groups were stratified by Lp(a) (≥50 vs. <50 mg/dl) and HDL-C [low (<40), optimal (40-60), high (>60 mg/dl)]. Mortality was assessed using the Kaplan-Meier curve and Cox models. Over a median of 5.9 years, 7794 deaths occurred. Compared to optimal HDL-C/low Lp(a) (reference), high HDL-C/low Lp(a) had the lowest mortality [adjusted hazard ratio (aHR): 0.85; 95% confidence interval (CI): 0.80-0.91], while low HDL-C/high Lp(a) had the highest risk (aHR: 1.55; 1.41-1.71). High HDL-C protective effect was insignificant with elevated Lp(a) (aHR: 0.98; 0.89-1.08). Sex-stratified analyses revealed divergent effects: women with high HDL-C/high Lp(a) retained the HDL-C protective effect (aHR: 0.82; 0.72-0.93), whereas men faced increased risk (aHR: 1.22; 1.05-1.42). Elevated Lp(a) enhances mortality risk despite elevated HDL-C levels, with sex-specific differences: women retain mortality benefits from high HDL-C despite elevated Lp(a), whereas men with concurrent elevations in HDL-C and Lp(a) experienced mortality risks comparable to those with low HDL-C. Findings underscore sex-specific CV risk stratification incorporating HDL-C and Lp(a), challenging the HDL-C universal protective role. Show less

Hypertrophic cardiomyopathy (HCM) is the most common inherited cardiomyopathy. It follows an autosomal dominant inheritance pattern in most cases, with incomplete penetrance and heterogeneity. It is familial in 60% of cases and most of these are caused by pathogenic variants in the core sarcomeric genes ( Show less

DNA double-strand breaks (DSBs) are highly toxic lesions that threaten genome integrity and cell survival. To avoid harmful repercussions of DSBs, a wide variety of DNA repair factors are recruited to execute DSB repair. Previously, we demonstrated that RBM6 splicing factor facilitates homologous recombination (HR) of DSB by regulating alternative splicing-coupled nonstop-decay of the HR protein APBB1/Fe65. Here, we describe a splicing-independent function of RBM6 in promoting HR repair of DSBs. We show that RBM6 is recruited to DSB sites and PARP1 activity indirectly regulates RBM6 recruitment to DNA breakage sites. Deletion mapping analysis revealed a region containing five glycine residues within the G-patch domain that regulates RBM6 accumulation at DNA damage sites. We further ascertain that RBM6 interacts with Rad51, and this interaction is attenuated in RBM6 mutant lacking the G-patch domain (RBM6 Show less

RNA-binding proteins regulate mRNA processing and translation and are often aberrantly expressed in cancer. The RNA-binding motif protein 6, RBM6, is a known alternative splicing factor that harbors tumor suppressor activity and is frequently mutated in human cancer. Here, we identify RBM6 as a novel regulator of homologous recombination (HR) repair of DNA double-strand breaks (DSBs). Mechanistically, we show that RBM6 regulates alternative splicing-coupled nonstop-decay of a positive HR regulator, Fe65/APBB1. RBM6 knockdown leads to a severe reduction in Fe65 protein levels and consequently impairs HR of DSBs. Accordingly, RBM6-deficient cancer cells are vulnerable to ATM and PARP inhibition and show remarkable sensitivity to cisplatin. Concordantly, cisplatin administration inhibits the growth of breast tumor devoid of RBM6 in mouse xenograft model. Furthermore, we observe that RBM6 protein is significantly lost in metastatic breast tumors compared with primary tumors, thus suggesting RBM6 as a potential therapeutic target of advanced breast cancer. Collectively, our results elucidate the link between the multifaceted roles of RBM6 in regulating alternative splicing and HR of DSBs that may contribute to tumorigenesis, and pave the way for new avenues of therapy for RBM6-deficient tumors. Show less

KDM4D is a lysine demethylase that removes tri- and di- methylated residues from H3K9 and is involved in transcriptional regulation and carcinogenesis. We recently showed that KDM4D is recruited to DNA damage sites in a PARP1-dependent manner and facilitates double-strand break repair in human cells. Moreover, we demonstrated that KDM4D is an RNA binding protein and mapped its RNA-binding motifs. Interestingly, KDM4D-RNA interaction is essential for its localization on chromatin and subsequently for efficient demethylation of its histone substrate H3K9me3. Here, we provide new data that shed mechanistic insights into KDM4D accumulation at DNA damage sites. We show for the first time that KDM4D binds poly(ADP-ribose) (PAR) in vitro via its C-terminal region. In addition, we demonstrate that KDM4D-RNA interaction is required for KDM4D accumulation at DNA breakage sites. Finally, we discuss the recruitment mode and the biological functions of additional lysine demethylases including KDM4B, KDM5B, JMJD1C, and LSD1 in DNA damage response. Show less

The pathways that signal double-strand DNA breaks (DSBs) in mammalian cells are central to the maintenance of genome integrity. We have reported (Ayoub et al., Nature 2008; 453: 682-6) that the rapid mobilization of the heterochromatin protein, HP1beta, within seconds from DSB sites promotes chromatin changes like H2AX phosphorylation that trigger this response. Notably, this paper and a subsequent report (Ayoub et al., Cell Cycle 2009; 8: 1494-500), demonstrate that transient HP1beta mobilization is followed by its accumulation over time at DSB sites. Indeed, two recent papers (Luijsterburg et al., J Cell Biol 2009; 185:577-86 and Zarebski et al., Cytometry A May 2009) suggest that HP1 recruitment to damage sites, rather than its rapid mobilization, is the predominant behaviour exhibited by this protein. Here, we present new experimental analyses which corroborate that fluorophore-tagged HP1beta exhibits two distinct behaviours at DSB sites in living cells - rapid, transient mobilization, most evident in heterochromatic regions, followed by slower recruitment. Experimental methods allowing visualization of these behaviours are described. Interestingly, chemical inhibition of the DNA-damage responsive enzyme, casein kinase 2 (CK2), suppresses HP1beta mobilization while permitting recruitment. Our findings reconcile recent findings in a new model, wherein rapid HP1beta mobilization from DSBs mediated by its phosphorylation on Thr51 by CK2, is followed by, and may overlap with, its accumulation at these sites via the chromoshadow domain, independent of Thr51. Our analyses provide fresh insight into the earliest events that trigger the DNA damage response in mammalian cells. Show less

The dynamics of chromatin-associated proteins control the accessibility of DNA to essential biological transactions like transcription, replication, recombination and repair. Here, we briefly outline what is known about the chromatin changes that occur during the cellular response to DNA breakage, focusing on our recent findings revealing that the chromatin factor HP1beta is mobilized within seconds after DNA damage by an unrecognized signaling cascade mediated by casein kinase 2 (CK2) phosphorylation, paving the way for histone H2AX phosphorylation. We also show here that HP1beta mobilization is neither associated with histone H3 modification on Ser10, an alteration proposed to assist in HP1 ejection from chromatin, nor with evidence of a physical interaction between HP1beta and the CK2 regulatory subunit. Interestingly, following its rapid mobilization, we find that HP1beta gradually re-accumulates on damaged chromatin over a longer time period, suggesting that temporal changes in HP1beta dynamics and interaction with chromatin may assist in different stages of the cellular response to DNA breakage. Show less

Minutes after DNA damage, the variant histone H2AX is phosphorylated by protein kinases of the phosphoinositide kinase family, including ATM, ATR or DNA-PK. Phosphorylated (gamma)-H2AX-which recruits molecules that sense or signal the presence of DNA breaks, activating the response that leads to repair-is the earliest known marker of chromosomal DNA breakage. Here we identify a dynamic change in chromatin that promotes H2AX phosphorylation in mammalian cells. DNA breaks swiftly mobilize heterochromatin protein 1 (HP1)-beta (also called CBX1), a chromatin factor bound to histone H3 methylated on lysine 9 (H3K9me). Local changes in histone-tail modifications are not apparent. Instead, phosphorylation of HP1-beta on amino acid Thr 51 accompanies mobilization, releasing HP1-beta from chromatin by disrupting hydrogen bonds that fold its chromodomain around H3K9me. Inhibition of casein kinase 2 (CK2), an enzyme implicated in DNA damage sensing and repair, suppresses Thr 51 phosphorylation and HP1-beta mobilization in living cells. CK2 inhibition, or a constitutively chromatin-bound HP1-beta mutant, diminishes H2AX phosphorylation. Our findings reveal an unrecognized signalling cascade that helps to initiate the DNA damage response, altering chromatin by modifying a histone-code mediator protein, HP1, but not the code itself. Show less