👤 Mostafa Salama

Brain aging is a multifactorial process associated with oxidative stress, chronic neuroinflammation, and synaptic dysfunction, ultimately leading to cognitive decline and increased susceptibility to neurodegenerative disorders. Epigallocatechin gallate (EGCG) is a potent antioxidant and anti-inflammatory agent, but its therapeutic potential is limited by poor stability and bioavailability. In this study, a dual nano delivery system was developed by loading chitosan-EGCG nanoparticles into mesenchymal stem cell-derived exosomes (Ex-Chit-EGCG NPs) and evaluated for neuroprotective efficacy in a D-galactose-induced brain aging model. Intranasal administration of Ex-Chit-EGCG NPs significantly improved cognitive and locomotor performance compared with exosomes alone, as evidenced by enhanced outcomes in Y-maze and open field tests. Biochemical analyses revealed that Ex-Chit-EGCG NPs effectively reduced lipid peroxidation, restored glutathione levels, and reactivated the LKB1/AMPK/SIRT1 signaling pathway. Molecular investigations demonstrated upregulation of Nrf2, BDNF, and SIRT1 together with suppression of NF-κB and Iba-1 expression, indicating attenuation of oxidative and inflammatory responses. Histopathological and immunohistochemical evaluations confirmed these findings, showing preservation of cortical and brain stem architecture with marked reductions in neuronal necrosis, gliosis, BAX, GFAP, and NLRP3 expression. Collectively, the results demonstrate that Ex-Chit-EGCG NPs exert superior neuroprotective effects compared with exosomes alone, highlighting the therapeutic advantage of combining EGCG with chitosan nanocarriers and exosomal delivery. This dual nanotherapeutic strategy offers a promising and non-invasive approach for mitigating brain aging and holds potential for translation into therapies targeting age-related neurodegenerative disorders. Show less

Melanocortin-4 receptor (MC4R) deficiency is the most common cause of monogenic obesity; yet treatment options for children with MC4R mutations are limited. We describe significant improvement in weight in three patients with pathogenic or likely pathogenic MC4R mutations; two adolescents treated with semaglutide, and a younger child treated with metformin and topiramate. These findings indicate GLP-1 receptor agonists, topiramate and metformin can be helpful in managing obesity associated with MC4R deficiency. Show less

Colorectal cancer (CRC) remains a leading cause of cancer-related mortality worldwide, with tumor progression often driven by dysregulated oncogenic pathways. USP6NL, a known regulator of endocytic trafficking, has recently been implicated in tumorigenesis. However, its precise role in CRC remains unclear, and more studies are still needed to deepen our understanding of underlying mechanisms implicated in its oncogenic role. Therefore, silencing USP6NL could provide a novel therapeutic strategy by concurrently disrupting several oncogenic mechanisms, creating a new avenue for CRC management, particularly in patients who develop resistance against conventional therapies. This study investigates the impact of USP6NL knockdown on CRC cell morphology, proliferation, apoptosis, migration, angiogenesis, and metabolic adaptation, providing mechanistic insights into its oncogenic functions. HCT116 colorectal cancer cells were transfected with USP6NL-specific siRNA. Immunocytochemistry was used to confirm successful silencing, functional assays were performed to assess changes in cell morphology using phase-contrast and scanning electron microscopy, and colony formation and wound healing assays were performed to assess cell clonogenic capacity and migration, respectively, in addition to apoptosis assay via flow cytometry, and RT²-Profiler PCR array to measure variation in gene expression of 84 cancer-related genes. Statistical analyses were performed to evaluate significant differences between control and USP6NL-silenced groups. USP6NL depletion led to profound morphological changes, including membrane blebbing, cell shrinkage, and loss of adhesion, reflecting late apoptotic features of cells. These findings were further supported by flow cytometry, which confirmed increased apoptosis, with a higher proportion of late apoptotic cells (20.99% in USP6NL knockdown vs. 2.69% in control, p = 0.042). Colony formation assays revealed a significant reduction in the clonogenic potential, suggesting a critical role of USP6NL in promoting CRC cell proliferation (p ≤ 0.05). The wound healing assay demonstrated impaired migration in USP6NL-silenced cells, with a marked delay in wound closure (p = 0.0201 at 48 h). Gene expression analysis revealed a significant downregulation of VEGFC (-8.62-fold) and ANGPT2 (-4.03-fold), impairing angiogenesis and suppressing FOXC2, SNAI1, and SNAI2, indicating EMT inhibition. Additionally, CASP9, APAF1, and BCL2L11 were upregulated, confirming the activation of intrinsic apoptosis, while metabolic regulators HIF1A and LDHA were downregulated, suggesting impaired tumor hypoxic adaptation. This study establishes USP6NL as a key modulator of CRC progression, regulating proliferation, apoptosis, migration, angiogenesis, and metabolic pathways. The loss of USP6NL leads to EMT suppression, apoptosis induction, and reduced tumor cell viability, positioning it as a potential therapeutic target in colorectal cancer. Further investigations are warranted to explore USP6NL's interactions in oncogenic signaling networks and its feasibility as a target for CRC therapy. It could serve as a promising therapeutic target in colorectal cancer, potentially enhancing tumor cell death and limiting metastasis. Targeting USP6NL could also provide a novel approach in combination with existing therapies, improving treatment efficacy and reducing side effects. Show less

Variants in melanocortin 4 receptor ( We compared the severity of obesity and cardiometabolic risk markers in children with A retrospective chart review was performed in children with obesity who underwent multigene panel testing for monogenic obesity. Data on a total of 104 children were examined, with 93 (89%) identified as White. Thirty-nine (37.5%) patients had clinically reported variants in the Variants in the Show less

various extracts of Moringa oleifera Lam. leaves, were reported to possess antiobesity effect in experimental animals models, yet its active doses and mechanism of action are still unclear. The metabolic profiling of 70% ethanol extract of M. oleifera (MO) leaves was performed using HPLC-MS/MS analysis. The antiobesity activity of MO was tested in high fat diet induced obesity in rats at 200 and 400 mg/kg body weight orally for 1 month. Total cholesterol (TC), high density lipoproteins (HDL-C), low density lipoprotein-cholesterol (LDL-C), triglycerides (TGs), insulin resistance, insulin sensitivity, and adipose tissue index were monitored. In addition, fatty acid synthase (FAS) and HMG-CoA reductase mRNA from liver tissue, Peroxisome Proliferator-Activated Receptor alpha (PPARα) and Melanocortin-4 receptor (MC4R) RNA from adipose tissue were quantified using qRT-PCR. MO hard gelatin capsules (400 mg/capsule) were formulated and standardized using HPLC-RP analysis and tested on fifteen female participants, aged 45-55 with a BMI of 29-34 kg/m Thirteen metabolites were tentatively identified using HPLC-MS/MS analysis including flavonols, flavones and a phenolic acid. MO 400 showed a prominent effect on reducing the rats' final weights, % weight increase and adiposity index (P < 0.05). Glucose, insulin and HOMA-IR were significantly reduced and R-QUICKI was significantly increased by MO 400 (P < 0.001). Mean tissue level of leptin and vaspin were significantly reduced, adiponectin, omentin and GLUT-4 expression were increased significantly by MO 400 (P < 0.01). MO 400 significantly suppressed FAS and HMG-CoA reductase and increased mRNA expression of MC4R and PPAR-α (P < 0.01). Eight weeks administration of MO hard gelatin capsules to obese patients showed significant reduction of the average BMI, TC and LDL compared to the baseline values (p < 0.05). Our results presented a scientific evidence for the traditional use of M. oleifera leaves as antiobesity herbal medicine. Show less