👤 Nesrine S El Sayed

The accumulation of CAG nucleotide duplicates in the huntingtin (HTT) gene triggers a neurological ailment described as Huntington's disease (HD), which is an irreversible, progressive, and inherited condition and affects both motor and cognitive abilities, resulting in a range of symptoms, including irregular gestures (chorea, dyskinesia), psychological disorders, and advanced dementia. Agomelatine is a novel antidepressant and melatonin analog. It exerts a synergistic pharmacological mechanism, combining stimulation of both MT1/MT2 melatonergic receptors with inhibition of 5-HT2C receptors. It was evaluated for its potential neuroprotective impact against HD triggered by 3-nitropropionic acid (3-NP) in rats. Four groups were established using a total of 40 rats: Group I (CTRL), Group II (AGO), Group III (3-NP), and Group IV (AGO + 3-NP). Deficits in motor function provoked by 3-NP were alleviated by agomelatine, as evidenced by increased ambulation and rearing frequencies, alongside a notable decline in immobility time of the open field assessment, elevated final falloff time of the rotarod assessment, and improved grip strength. Agomelatine also improved synaptic plasticity and neuronal survival by optimizing the expression and activity of the BDNF/TrKB/PI3K/AKT pathway and inhibiting apoptosis, microglial, and astrocytic activation. Furthermore, agomelatine administration reduced the expression of ROCK1, suppressing the release of inflammatory responses. Finally, agomelatine possessed neuroprotective activity, as proved by enhancing motor activity and histopathological abnormalities via improving the BDNF/TrKB/PI3K/AKT survival cascade and suppressing the ROCK1 inflammatory pathway. Show less

Hypertrophic cardiomyopathy (HCM) is a prevalent inherited cardiac disorder characterized by left ventricular hypertrophy and contractile dysfunction. Mutations in sarcomeric genes, particularly cardiac myosin-binding protein C (MYBPC3), are a leading cause of HCM. Here, we generated two induced pluripotent stem cell (iPSC) lines from peripheral blood mononuclear cells of patients carrying distinct MYBPC3 mutations (c.2490dupT and c.1800delA). Both lines displayed normal morphology, stable karyotypes, robust expression of pluripotency markers, and trilineage differentiation potential. These patient-specific iPSC lines provide a valuable platform for modeling MYBPC3-associated HCM and enable mechanistic and therapeutic studies of inherited cardiac disease. 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

Hyperlipidemia, a key risk factor for cardiovascular disease, is characterized by elevated low-density lipoprotein cholesterol (LDL-C), triglycerides, and reduced high-density lipoprotein cholesterol (HDL-C). Cholesteryl ester transfer protein (CETP) inhibitors, such as anacetrapib, obicetrapib, evacetrapib, dalcetrapib, and torcetrapib, aim to improve lipid profiles by increasing HDL-C and reducing LDL-C, but their comparative efficacy remains unclear. This systematic review and frequentist network meta-analysis, conducted per PRISMA-NMA guidelines, included 33 randomized controlled trials (RCTs) involving 120,292 adults with hyperlipidemia. We compared CETP inhibitors, alone or with statins, against placebo or other lipid-lowering therapies. Primary outcome was LDL-C reduction; secondary outcomes included HDL-C, triglycerides, and total cholesterol changes. Random-effects models calculated mean differences (MD) with 95% confidence intervals (CI), and P-scores ranked interventions. Atorvastatin + obicetrapib showed the largest reduction in LDL-C levels (MD: -69.00, 95% CI: -95.96 to -42.04, p < 0.0001), followed by rosuvastatin + obicetrapib (MD: -60.70, 95% CI: -99.28 to -22.12, p = 0.0020). Atorvastatin + obicetrapib yielded highly significant increase in HDL-C levels (MD: 149.90, 95% CI: 121.70 to 178.10, p < 0.0001), but rosuvastatin + obicetrapib showed the greatest increase (MD: 158.90, 95% CI: 118.59 to 199.21, p < 0.0001) and obicetrapib monotherapy (MD: 139.00, 95% CI: 129.05 to 148.96, p < 0.0001), while rosuvastatin + evacetrapib led triglyceride reductions (MD: -31.70 mg/dL). Rosuvastatin was most effective for total cholesterol (MD: -31.60 mg/dL). CETP inhibitors, particularly anacetrapib and obicetrapib combined with statins, significantly improve lipid profiles, offering potential therapeutic benefits for hyperlipidemia management and cardiovascular risk reduction. The study was registered with PROSPERO to ensure transparency and adherence to methodological rigor (Registration ID: CRD420250652666). Show less

Isoxazole 9 (ISX9) is a neurogenesis-promoting small molecule compound that can up-regulate the expression of NeuroD1 and induce differentiation of neuronal, cardiac and islet endocrine progenitors. So far, the molecular mechanisms underlying the action of ISX9 still remain elusive. To identify a novel agonist of the Wnt/β-catenin, a cell-based SuperTOPFlash reporter system was used to screen known-compound libraries. An activation effect of ISX9 on the Wnt/β-catenin pathway was analysed with the SuperTOPFlash or SuperFOPFlash reporter system. Effects of ISX9 on Axin1/LRP6 interaction were examined using a mammalian two-hybrid system, co-immunoprecipitation, microscale thermophoresis, emission spectra and mass spectrometry assays. The expression of Wnt target and stemmness marker genes were evaluated with real-time PCR and immunoblotting. In vivo hair regeneration abilities of ISX9 were analysed by immunohistochemical staining, real-time PCR and immunoblotting in hair regrowth model using C57BL/6J mice. In this study, ISX9 was identified as a novel agonist of the Wnt/β-catenin pathway. ISX9 targeted Axin1 by covalently binding to its N-terminal region and potentiated the LRP6-Axin1 interaction, thereby resulting in the stabilization of β-catenin and up-regulation of Wnt target genes and stemmness marker genes. Moreover, the topical application of ISX9 markedly promoted hair regrowth in C57BL/6J mice and induced hair follicle transition from telogen to anagen via enhancing Wnt/β-catenin pathway. Taken together, our study unravelled that ISX9 could activate Wnt/β-catenin signalling by potentiating the association between LRP6 and Axin1, and may be a promising therapeutic agent for alopecia treatment. Show less

In Alzheimer's disease (AD), the accumulation of amyloid-β plaques, overactivity of MAO-B, and phosphorylated tau protein in the central nervous system result in neuroinflammation and cognitive impairments. Therefore, the multi-targeting of these therapeutic targets has emerged as a promising strategy for the development of AD treatments. The current study reports the isolation and identification of seven amide alkaloids, namely, Show less

Sporadic Alzheimer's disease (SAD) is a slowly progressive neurodegenerative disorder. This study aimed to investigate neuroprotective potential of tadalafil (TAD) and bergapten (BG) in SAD-induced cognitive impairment in mice. SAD was induced by single injection of streptozotocin (STZ; 3 mg/kg, ICV). STZ resulted in AD-like pathologies including Aβ deposition, tau aggregation, impaired insulin and Wnt/β-catenin signaling, as well as autophagic dysfunction and neuroinflammation. Administration of TAD or BG at doses of 20 and 25 mg/kg, respectively, for 21 consecutive days attenuated STZ-induced hippocampal insult, preserved neuronal integrity, and improved cognitive function in the Morris water maze and object recognition tests paralleled by reduction in Aβ expression by 79 and 89% and tau hyperphosphorylation by 60 and 61%, respectively. TAD and BG also enhanced protein expression of pAkt, pGSK-3β, beclin-1 and methylated protein phosphatase 2A (PP2A) and gene expression of cyclin D1, while raised BDNF immunoreactivity. Furthermore, TAD and BG boosted hippocampal levels of cGMP, PKG, Wnt3a, and AMPK and reduced expression of β-catenin and mTOR by 74% and 51%, respectively. TAD and BG also halted neuroinflammation by reducing IL-23 and IL-27 levels, as well as protein expression of NF-κB by 62% & 61%, respectively. In conclusion, this study offers novel insights on the neuroprotective effects of TAD or BG in the management of SAD as evidenced by improved cognitive function and histological architecture. This could be attributed to modulation of the crosstalk among PI3K/Akt/GSK-3β, PP2A, mTOR/autophagy, cGMP/PKG, and Wnt/β-catenin signaling cascades and mitigation of neuroinflammation. Show less

The progression toward low-cost and rapid next-generation sequencing has uncovered a multitude of variants of uncertain significance (VUS) in both patients and asymptomatic "healthy" individuals. A VUS is a rare or novel variant for which disease pathogenicity has not been conclusively demonstrated or excluded, and thus cannot be definitively annotated. VUS, therefore, pose critical clinical interpretation and risk-assessment challenges, and new methods are urgently needed to better characterize their pathogenicity. To address this challenge and showcase the uncertainty surrounding genomic variant interpretation, we recruited a "healthy" asymptomatic individual, lacking cardiac-disease clinical history, carrying a hypertrophic cardiomyopathy (HCM)-associated genetic variant (NM₀₀₀₂₅₈.2:c.170C>A, NP₀₀₀₂₄₉.1:p.Ala57Asp) in the sarcomeric gene MYL3, reported by the ClinVar database to be "likely pathogenic." Human-induced pluripotent stem cells (iPSCs) were derived from the heterozygous VUS MYL3 The heterozygous VUS MYL3 Our study illustrates the ability of clustered regularly interspaced short palindromic repeats/Cas9 genome-editing of carrier-specific iPSCs to elucidate both benign and pathogenic HCM functional phenotypes in a carrier-specific manner in a dish. As such, this platform represents a promising VUS risk-assessment tool that can be used for assessing HCM-associated VUS specifically, and VUS in general, and thus significantly contribute to the arsenal of precision medicine tools available in this emerging field. Show less