Zaafar, D., H. M. A. Khalil, G. E. Elkhouly, A. S. Sedeky, Y. H. Ahmed, M. G. Khalil, and Y. Abo-Zeid, "Preparation and characterization of Sorafenib nano-emulsion: impact on pharmacokinetics and toxicity; an in vitro and in vivo study.", Drug delivery and translational research, 2024. Abstract

Hepatocellular carcinoma (HCC) ranks as the third leading cause of cancer-related deaths worldwide. Current treatment strategies include surgical resection, liver transplantation, liver-directed therapy, and systemic therapy. Sorafenib (Sor) is the first systemic drug authorized by the US Food and Drug Administration (FDA) for HCC treatment. Nevertheless, the conventional oral administration of Sor presents several limitations: poor solubility, low bioavailability, drug resistance development, and off-target tissue accumulation, leading to numerous adverse effects. Nano-emulsion, a nano-delivery system, is a viable carrier for poorly water-soluble drugs. It aims to enhance drug bioavailability, target organ accumulation, and reduce off-target tissue exposure, thus improving therapeutic outcomes while minimizing side effects. This study formulated Sor nano-emulsion (Sor NanoEm) using the homogenization technique. The resultant nano-emulsion was characterized by particle size (121.75 ± 12 nm), polydispersity index (PDI; 0.310), zeta potential (-12.33 ± 1.34 mV), viscosity (34,776 ± 3276 CPs), and pH (4.38 ± 0.3). Transmission Electron Microscopy exhibited spherical nano-droplets with no aggregation signs indicating stability. Furthermore, the encapsulation of Sor within the nano-emulsion sustained its release, potentially reducing the frequency of therapeutic doses. Cytotoxicity assessments on the HepG2 cell line revealed that Sor NanoEm had a significantly (P < 0.05) more potent cytotoxic effect compared to Sor suspension. Subsequent tests highlighted superior pharmacokinetic parameters and reduced dosage requirements of Sor NanoEm in mice. It exhibited an enhanced safety profile, particularly in behavior, brain, and liver, compared to its suspended form. These findings underscore the enhanced pharmacological and toxicological attributes of Sor Nano-emulsion, suggesting its potential utility in HCC treatment.

Hamdan, D. I., N. Tawfeek, R. A. El-Shiekh, H. M. A. Khalil, M. Y. Mahmoud, A. F. Bakr, D. Zaafar, N. Farrag, M. Wink, and A. M. El-Shazly, "Salix subserrata Bark Extract-Loaded Chitosan Nanoparticles Attenuate Neurotoxicity Induced by Sodium Arsenate in Rats in Relation with HPLC-PDA-ESI-MS/MS Profile.", AAPS PharmSciTech, vol. 24, issue 1, pp. 15, 2022. Abstract

Pollution is a worldwide environmental risk. Arsenic (As) is an environmental pollutant with a major health concern due to its toxic effects on multiple body organs, including the brain. Humans are exposed to As through eating contaminated food and water or via skin contact. Salix species (willow) are plants with medicinal efficacy. Salix subserrata Willd bark extract-loaded chitosan nanoparticles (SBE.CNPs) was formulated, characterized, and evaluated against As-induced neurotoxicity. The stem bark was selected for nanoparticle formulation based on HPLC-PDA-ESI-MS/MS profiling and in vitro antioxidant assessment using free radical scavenging activity. SBE.CNPs demonstrated an average un-hydrated diameter of 193.4 ± 24.5 nm and zeta potential of + 39.6 ± 0.4 mV with an encapsulation efficiency of 83.7 ± 4.3%. Compared to As-intoxicated rats, SBE.CNP-treated rats exhibited anxiolytic activity and memory-boosting as evidenced in open field test, light-dark activity box, and Y-maze. Also, it increased the antioxidant biomarkers, including superoxide dismutase and glutathione peroxidase associated with reducing the malondialdehyde levels and apoptotic activity. Besides this, SBE.CNPs maintained the brain architecture and downregulated both nuclear factor-kappa B and heme oxygenase-1 expression. These results suggest that SBE.CNP administration showed promising potent neuroprotective and antioxidative efficiencies against arsenic-induced oxidative threats.

Khalil, H. M. A., H. M. A. El Henafy, I. A. Khalil, A. F. Bakr, M. I. Fahmy, N. S. Younis, and R. A. El-Shiekh, "L. Nanoemulsion Mitigates Cisplatin-Induced Chemobrain via Reducing Neurobehavioral Alterations, Oxidative Stress, Neuroinflammation, and Apoptosis in Adult Rats.", Toxics, vol. 11, issue 2, 2023. Abstract

Cisplatin (Cis) is a potent chemotherapeutic agent; however, it is linked with oxidative stress, inflammation, and apoptosis, which may harmfully affect the brain. L. (HP L.) is a strong medicinal plant, but its hydrophobic polyphenolic compounds limit its activity. Therefore, our study aimed to investigate the neuroprotective action of HP L. and its nanoemulsion (NE) against Cis-induced neurotoxicity. The prepared HP.NE was subjected to characterization. The droplet size distribution, surface charge, and morphology were evaluated. In addition, an in vitro dissolution study was conducted. Compared to Cis-intoxicated rats, HP L. and HP.NE-treated rats displayed improved motor activity and spatial working memory. They also showed an increase in their antioxidant defense system and a reduction in the levels of pro-inflammatory cytokines in the brain. Moreover, they showed an increase in the expression levels of the PON-3 and GPX genes, which are associated with a reduction in the brain levels of COX-2 and TP-53. These findings were confirmed by reducing the immunohistochemical expression of nuclear factor kappa (NF-ƘB) and enhanced Ki-67 levels. In conclusion, HP L. is a promising herb and could be used as an adjuvant candidate to ameliorate chemotherapeutic-induced neurotoxicity. Moreover, HP.NE has superior activity in lessening Cis-induced oxidative stress, inflammation, and apoptosis in brain tissue.

Shalaby, O. E., Y. H. Ahmed, A. M. Mekkawy, M. Y. Mahmoud, H. M. A. Khalil, and G. A. Elbargeesy, "Assessment of the neuroprotective effect of selenium-loaded chitosan nanoparticles against silver nanoparticles-induced toxicity in rats.", Neurotoxicology, vol. 95, pp. 232-243, 2023. Abstract

BACKGROUND: With the recent growth in the applications of silver nanoparticles (Ag-NPs), worries about their harmful effects are increasing. Selenium plays a vital role in the antioxidant defense system as well as free radical scavenging activity.

OBJECTIVES: This study aims to inspect the neuroprotective effect of selenium-loaded chitosan nanoparticles (CS-SeNPs) against the adverse impact of Ag-NPs on brain tissue in adult rats.

DESIGN: Rats were divided into four groups: group I (control) was administered distilled water (0.5 mL/kg), group II was administered Ag-NPs (100 mg/kg), group III was administered Ag-NPs (100 mg/kg) and CS- SeNPs (0.5 mg/kg) and group IV received only CS- SeNPs (0.5 mg/kg) daily by oral gavage. After 60 days, rats were subjected to behavioral assessment and then euthanized. Brain tissues were obtained for estimation of total antioxidant capacity (TAC), malondialdehyde (MDA), 8-hydroxy-2-deoxy Guanosine (8-OHdG), and Nuclear Factor Erythroid 2 Like Protein 2 (Nrf2). Also, histological examination of the brain and immunohistochemical detection of glial fibrillary acidic protein (GFAP) were investigated RESULTS: exposure to Ag-NPs induced marked neurotoxicity in the brain tissue of rats that was manifested by decreased levels of TAC and Nrf2 with increased levels of MDA and 8-OHdG. Also, various pathological lesions with an increase in the number of GFAP immunoreactive cells were detected. While brain tissue of rats received Ag-NPs plus CS-SeNPs group (III) revealed significantly fewer pathological changes.

CONCLUSION: Co-administration of CS-SeNPs significantly ameliorates most of the Ag-NPs-induced brain damage.

Khalifa, M., R. H. Fayed, A. A. Sedik, and H. M. A. Khalil, "Dose-dependent toxic effects of di-(2-ethylhexyl) phthalate in male rats: Focus on behavioral alterations and inducing TLR4/NF-κB signaling pathway.", Toxicology and applied pharmacology, vol. 468, pp. 116515, 2023. Abstract

Di -(2-ethylhexyl) phthalate (DEHP) is a widely used phthalate that possesses a public health concern. Different concentrations of DEHP, including 50, 300, and 750 mg/kg were administrated orally for 28 days in male rats. Body weight and vital organs weight were measured as well as anxiety-like behavior, short and long-term memory were investigated. Brain inflammatory cytokines, including IL-1β, TLR4, NF-κB, TNF-α, and IL1-6 were assessed. Brain caspase-3, neuropeptide-Y (NPY), and brain histopathology were also evaluated. DEHP triggers the release of pro-inflammatory cytokines via inducing the nuclear translocation of the signaling pathway; TLR 4/ NF-κB leads to cognitive impairment and neurodegeneration, which is confirmed by the impaired brain architecture. Also, DEHP upgrades the expression levels of brain caspase-3 and NPY. In conclusion, exposure to high doses of DEHP persuades great toxicity visualized by behavioral, biochemical, and histological impairments when compared to the low doses.

Hamdan, D. I., N. Tawfeek, R. A. El-Shiekh, H. M. A. Khalil, M. Y. Mahmoud, A. F. Bakr, D. Zaafar, N. Farrag, M. Wink, and A. M. El-Shazly, "Correction to: Salix subserrata Bark Extract-Loaded Chitosan Nanoparticles Attenuate Neurotoxicity Induced by Sodium Arsenate in Rats in Relation with HPLC-PDA-ESI-MS/MS Profle.", AAPS PharmSciTech, vol. 24, issue 6, pp. 148, 2023.
Khalifa, M., R. H. Fayed, Y. H. Ahmed, A. A. Sedik, N. M. El-Dydamony, and H. M. A. Khalil, "Mitigating effect of ferulic acid on di-(2-ethylhexyl) phthalate-induced neurocognitive dysfunction in male rats with a comprehensive in silico survey.", Naunyn-Schmiedeberg's archives of pharmacology, vol. 397, issue 5, pp. 3493-3512, 2024. Abstract

Di-(2-ethylhexyl) phthalate (DEHP) is the most abundant phthalate threatening public health-induced neurotoxicity. This neurotoxicity is associated with behavioral and biochemical deficits in male rats. Our study investigated the neuroprotective effect of ferulic acid (FA) on male rats exposed to DEHP. Thirty-two male Wistar rats were assigned to four groups. Group I control rats received corn oil, group II intoxicated rats received 300 mg/kg of DEHP, group III received 300 mg/kg of DEHP + 50 mg/kg of FA, and group IV received 50 mg/kg of FA, all agents administrated daily per os for 30 days. Anxiety-like behavior, spatial working memory, and recognition memory were assessed. Also, brain oxidative stress biomarkers, including brain malondialdehyde (MDA), reduced glutathione (GSH), nitric oxide (NO), superoxide dismutase (SOD), brain-derived neurotrophic factor (BDNF) as well as heme oxygenase-1 (HO-1) were measured. Moreover, brain histopathology examinations associated with immunohistochemistry determination of brain caspase-3 were also evaluated. Furthermore, docking simulation was adapted to understand the inhibitory role of FA on caspase-3 and NO synthase. Compared to DEHP-intoxicated rats, FA-treated rats displayed improved cognitive memory associated with a reduced anxious state. Also, the redox state was maintained with increased BNDF levels. These changes were confirmed by restoring the normal architecture of brain tissue and a decrement in the immunohistochemistry caspase-3. In conclusion, FA has potent antioxidant and antiapoptotic properties that confirm the neuroprotective activity of FA, with a possible prospect for its therapeutic capabilities and nutritional supplement value.

Zaafar, D., H. M. A. Khalil, R. Elnaggar, D. Z. Saad, and R. A. Rasheed, "Protective role of hesperetin in sorafenib-induced hepato- and neurotoxicity in mice via modulating apoptotic pathways and mitochondrial reprogramming.", Life sciences, vol. 336, pp. 122295, 2024. Abstract

INTRODUCTION: Sorafenib, an FDA-approved standard chemotherapy for advanced hepatocellular carcinoma, is associated with numerous adverse effects that significantly impact patients' physiological well-being. Consequently, identifying agents that mitigate these side effects while enhancing efficacy is crucial. Hesperetin, a flavone present in fruits and vegetables, possesses antioxidant, anti-inflammatory, and anti-cancer properties. This study aimed to investigate the hepatotoxic and neurotoxic effects of sorafenib and the potential protective role of hesperetin.

MATERIALS AND METHODS: Swiss albino mice were orally administered sorafenib (100 mg/kg) alone or in combination with hesperetin (50 mg/kg) over 21 days. Behavioral assessments for anxiety and depressive-like behaviors were conducted. Additionally, evaluations encompassed apoptotic activity, mitochondrial integrity, liver enzyme levels, proliferation rates, and histopathological changes.

RESULTS: Combining hesperetin with sorafenib showed improvements in behavioral alterations, liver damage, brain mitochondrial dysfunction, and liver apoptosis compared to the sorafenib-only group in mice.

CONCLUSION: Hesperetin exhibits potential as an adjunct to sorafenib, mitigating its side effects by attenuating its toxicity, enhancing efficacy, and potentially reducing the occurrence of sorafenib-induced resistance through the downregulation of hepatocyte growth factor levels.

Al Awadh, A. A., H. Sakagami, S. Amano, A. M. Sayed, M. E. Abouelela, A. H. Alhasaniah, N. Aldabaan, M. S. Refaey, R. A. Abdelhamid, H. M. A. Khalil, et al., "cytotoxicity of (L.) roots and fruits on oral squamous cell carcinoma cell lines: a study supported by flow cytometry, spectral, and computational investigations.", Frontiers in pharmacology, vol. 15, pp. 1325272, 2024. Abstract

Oral cancer is a severe health problem that accounts for an alarmingly high number of fatalities worldwide. (L.) Dunal has been extensively studied against various tumor cell lines from different body organs, rarely from the oral cavity. We thus investigated the cytotoxicity of fruits (W-F) and roots (W-R) hydromethanolic extracts and their chromatographic fractions against oral squamous cell carcinoma (OSCC) cell lines [Ca9-22 (derived from gingiva), HSC-2, HSC-3, and HSC-4 (derived from tongue)] and three normal oral mesenchymal cells [human gingival fibroblast (HGF), human periodontal ligament fibroblast (HPLF), and human pulp cells (HPC)] in comparison to standard drugs. The root polar ethyl acetate (W-R EtOAc) and butanol (W-R BuOH) fractions exhibited the strongest cytotoxicity against the Ca9-22 cell line (CC = 51.8 and 40.1 μg/mL, respectively), which is relatively the same effect as 5-FU at CC = 69.4 μM and melphalan at CC = 36.3 μM on the same cancer cell line. Flow cytometric analysis revealed changes in morphology as well as in the cell cycle profile of the W-R EtOAc and W-R BuOH-treated oral cancer Ca9-22 cells compared to the untreated control. The W-R EtOAc (125 μg/mL) exerted morphological changes and induced subG accumulation, suggesting apoptotic cell death. A UHPLC MS/MS analysis of the extract enabled the identification of 26 compounds, mainly alkaloids, withanolides, withanosides, and flavonoids. Pharmacophore-based inverse virtual screening proposed that BRD3 and CDK2 are the cancer-relevant targets for the annotated withanolides D () and O (), and the flavonoid kaempferol (). Molecular modeling studies highlighted the BRD3 and CDK2 as the most probable oncogenic targets of anticancer activity of these molecules. These findings highlight 's potential as an affordable source of therapeutic agents for a range of oral malignancies.

Alyami, M. H., D. I. Hamdan, H. M. A. Khalil, M. A. A. Orabi, N. M. Aborehab, N. Osama, M. M. Abdelhafez, A. M. Al-mahallawi, and H. S. Alyami, "Preparation and in vivo evaluation of nano sized cubosomal dispersion loaded with Ruta graveolens extracts as a novel approach to reduce asthma-mediated lung inflammation.", Saudi pharmaceutical journal : SPJ : the official publication of the Saudi Pharmaceutical Society, vol. 32, issue 3, pp. 101968, 2024. Abstract

Asthma is a chronic disease affecting people of all ages. Asthma medications are associated with adverse effects restricting their long-term usage, demanding newer alternative therapies. This study aimed to investigate the anti-asthmatic properties of extract and its prepared nano-cubosomal dispersion (Ruta-ND). Firstly, the methanolic extract exhibited higher anti-inflammatory activity on Lipopolysaccharide (LPS)-activated BEAS-2B cells. To ensure best bioavailability and hence best cellular uptake, extract was loaded in nano-cubosomal dispersion (ND). Then, the anti-asthmatic effects of extract and ND were simultaneously evaluated in rats' model with ovalbumin-induced allergic asthma. extract and Ruta-ND subsided asthma score and improved lung function by restoring FEV1/FVC ratio to the expected values in control rats. Also, it showed strong antioxidant and anti-inflammatory activities manifested by lowering levels of malondialdehyde (MDA), IL-4, IL-7, TGF-β, and Ig-E, and increasing levels of superoxide dismutase (SOD) and INF-γ in bronchoalveolar lavage fluid. Our research findings also indicate autophagy induction and apoptosis inhibition by extract and Ruta-ND. Finally, the HPLC MS/MS phytochemical profiling of extract evident production of various alkaloids, flavonoids, coumarins, and other phenolics with reported pharmacological properties corresponding to/emphasize our study findings. In conclusion, exhibited promise in managing Ova-induced allergic asthma and could be developed as an alternative anti-allergic asthma drug.

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