Browsing by Author "Maher, Ahmed"

Now showing 1 - 8 of 8

Enhanced alveo pulmonary deposition of nebulized ciclesonide for attenuating airways inflammations: a strategy to overcome metered dose inhaler drawbacks
(Taylor and Francis, 2021-04) El-Laithy, Hanan M; Youssef, Amal; El-Husseney, Shereen S; El Sayed, Nesrine S; Maher, Ahmed
Ciclesonide (CIC), an inhaled corticosteroid for bronchial asthma is currently available as metered dose inhaler (CIC–MDI) which possesses a major challenge in the management of the elderly, critically ill patients and children. In this work, nebulized CIC nano-structure lipid particles (CIC-NLPs) were prepared and evaluated for their deep pulmonary delivery and cytotoxicity to provide additional clinical benefits to patients in controlled manner and lower dose. The bio-efficacy following nebulization in ovalbumin (OVA) induced asthma Balb/c mice compared to commercial (CIC–MDI) was also assessed. The developed NLPs of 222.6 nm successfully entrapped CIC (entrapment efficiency 93.3%) and exhibited favorable aerosolization efficiency (mass median aerodynamic diameter (MMAD) 2.03 μm and fine particle fraction (FPF) of 84.51%) at lower impactor stages indicating deep lung deposition without imparting any cytotoxic effect up to a concentration of 100 μg/ml. The nebulization of 40 µg dose of the developed CIC-NLPs revealed significant therapeutic impact in the mitigation of the allergic airways inflammations when compared to 80 µg dose of the commercial CIC–MDI inhaler (Alvesco®). Superior anti-inflammatory and antioxidative stress effects characterized by significant decrease (p< .0001) in inflammatory cytokines IL-4 and 13, serum IgE levels, malondialdehyde (MDA), nitric oxide (NO), TNF-α, and activated nuclear factor-κB (NF-κB) activity were obvious with concomitant increase in superoxide dismutase (SOD) activity. Histological examination with inhibition of inflammatory cell infiltration in the respiratory tract was correlated well with observed biochemical improvement.
Evaluation of Urinary Human Telomerase Reverse Transcriptase mRNA and Scatter Factor Protein as Urine Markers for Diagnosis of Bladder Cancer
(Clin Lab, 2013) Eissa, Sanaa; Motawi, Tarek; Badr, Soheir; Zaghlool, Ashraf; Maher, Ahmed
Background: Expression of the human telomerase reverse transcriptase (hTERT) gene, which codes for the catalytic subunit of telomerase is considered an important tumor marker used for bladder cancer detection being found in the majority of cancer cells. Scatter Factor (SF) is a secretory protein produced by fibroblasts and smooth muscles and induces scattering of the epithelial cells. The aim of the current study was to evaluate the potential usefulness of hTERT and SF measurement as urinary markers for bladder cancer diagnosis. Methods: Voided urine specimens were collected from patients with histologically confirmed bladder urothelial carcinoma (malignant group: n = 60), urological patients without urothelial carcinoma (benign group: n = 25), and healthy volunteers (control group: n = 20). All cases underwent urine cytology, serological schistosomiasis antibody assay and detection of urinary hTERT mRNA using RT-PCR and SF using ELISA. Results: Positivity rate of hTERT mRNA was markedly higher in malignant versus benign or control cases (86.67%, 8%, and 0%, respectively, p-value < 0.001). Combining hTERT and cytology increased the sensitivity of cytology to 95%. According to a cut-off value of urinary SF (≥ 410 ng/mg protein), 57 (95%) of the patients with bladder carcinoma, 10 (40%) with benign lesions, and non of the control individuals were positive and the difference between the 3 groups was statistically significant (p < 0.001). The sensitivity of cytology was increased to 98.33% when combined with the SF assay. When associating the two urinary markers with different clinicopathological factors of the bladder cancer group, only SF exerted a significantly higher positivity rate at the invasive stage (100%) than the superficial stage (88.46%) as well as in transitional cell carcinoma (100%) than squamous cell carcinoma type (87.5%). Conclusions: hTERT and SF can be considered potential useful markers for detection of bladder cancer.
From Celecoxib to a Novel Class of Phosphodiesterase 5 Inhibitors: Trisubstituted Pyrazolines as Novel Phosphodiesterase 5 Inhibitors with Extremely High Potency and Phosphodiesterase Isozyme Selectivity
(ACS Publications, 04/03/2021) Abdel-Halim, Mohammad; Sigler, Sara; Racheed, Nora A. S; Hefnawy, Amr; Fathalla, Reem K; Hammam, Mennatallah A; Maher, Ahmed; Maxuitenko, Yulia; Keeton, Adam B; Hartmann, Rolf W; Engel, Matthias; Piazza, Gary A; Abadi, Ashraf H
A ligand-based approach involving systematic modifications of a trisubstituted pyrazoline scaffold derived from the COX2 inhibitor, celecoxib, was used to develop novel PDE5 inhibitors. Novel pyrazolines were identified with potent PDE5 inhibitory activity lacking COX2 inhibitory activity. Compound d12 was the most potent with an IC50 of 1 nM, which was three times more potent than sildenafil and more selective with a selectivity index of >10,000-fold against all other PDE isozymes. Sildenafil inhibited the full-length and catalytic fragment of PDE5, while compound d12 only inhibited the full-length enzyme, suggesting a mechanism of enzyme inhibition distinct from sildenafil. The PDE5 inhibitory activity of compound d12 was confirmed in cells using a cGMP biosensor assay. Oral administration of compound d12 achieved plasma levels >1000-fold higher than IC50 values and showed no discernable toxicity after repeated dosing. These results reveal a novel strategy to inhibit PDE5 with unprecedented potency and isozyme selectivity.
In vivo protection against strychnine toxicity in mice by the glycine receptor agonist ivermectin
(Hindawi, 2014) Maher, Ahmed; Radwan, Rasha; Breitinger, Hans-Georg
The inhibitory glycine receptor, a ligand-gated ion channel that mediates fast synaptic inhibition in mammalian spinal cord and brainstem, is potently and selectively inhibited by the alkaloid strychnine. The anthelminthic and anticonvulsant ivermectin is a strychnine-independent agonist of spinal glycine receptors. Here we show that ivermectin is an effective antidote of strychnine toxicity in vivo and determine time course and extent of ivermectin protection. Mice received doses of 1 mg/kg and 5 mg/kg ivermectin orally or intraperitoneally, followed by an intraperitoneal strychnine challenge (2 mg/kg). Ivermectin, through both routes of application, protected mice against strychnine toxicity. Maximum protection was observed 14 hours after ivermectin administration. Combining intraperitoneal and oral dosage of ivermectin further improved protection, resulting in survival rates of up to 80% of animals and a significant delay of strychnine effects in up to 100% of tested animals. Strychnine action developed within minutes, much faster than ivermectin, which acted on a time scale of hours. The data agree with a two-compartment distribution of ivermectin, with fat deposits acting as storage compartment. The data demonstrate that toxic effects of strychnine in mice can be prevented if a basal level of glycinergic signalling is maintained through receptor activation by ivermectin.
Novel 2,4-disubstituted quinazoline analogs as antibacterial agents with improved cytotoxicity profile: Optimization of the 2,4-substituents
(Elsevier, 10/12/2021) Aboushady, Dina; Rasheed, Sari S; Herrmann, Jennifer; Maher, Ahmed; El-Hossary, Ebaa M; Ibrahim, Eslam S; Abadi, Ashraf H; Engel, Matthias; Müller, Rolf; Abdel-Halim, Mohammad; Hamed, Mostafa M
The emergence of bacterial resistance has triggered a multitude of efforts to develop new antibacterial agents. There are many compounds in literature that were reported as potent antibacterial agents, however, they lacked the required safety to mammalian cells or no clear picture about their toxicity profile was presented. Inspired by discovered hit from our in-house library and by previously reported 2,4-diaminosubstituted quinazolines, we describe the design and synthesis of novel 2,4-disubstituted-thioquinazolines (3–13 and 36), 2-thio-4-amino substituted quinazolines (14–33) and 6-substituted 2,4-diamonsubstituted quinazolines (37–39). The synthe- sized compounds showed potent antibacterial activity against a panel of Gram-positive, efflux deficient E.coli and Mycobacterium smegmatis. The panel also involved resistant strains including methicillin-resistant Staphylococcus aureus, penicillin-resistant Streptococcus pneumoniae, vancomycin-resistant Enterococcus faecalis and vancomycin- resistant Enterococcus faecium, in addition to Mycobacterium smegmatis. The newly synthesized compounds revealed MIC values against the tested strains ranging from 1 to 64 µg/mL with a good safety profile. Most of the 2-thio-4-amino substituted-quinazolines showed significant antimycobacterial activity with the variations at position 2 and 4 offering additional antibacterial activity against the different strains. Compared to previously reported 2,4-diaminosubstituted quinazolines, the bioisosteric replacement of the 2-amino with sulfur offered a successful approach to keep the high antibacterial potency while substantially improving safety profile as indicated by the reduced activity on different cell lines and a lack of hemolytic activity.
Overexpression of NMDAR2B in an inflammatory model of Alzheimer's disease: modulation by NOS inhibitors
(Elsevier, 2014) Maher, Ahmed; Salah-Eldine El-Sayed, Nesrine; Breitinger, Hans-Georg; Zakaria Gad, Mohamed
Background:Alzheimer’sdisease (AD)is a commonformof age-relateddementia, characterizedbydeposition of amyloid A plaques, neuroinflammation and neurodegeneration. N-methyl-d-aspartate receptors (NMDAR) are postsynaptic glutamate receptors that play a role in memory formation and are targets for memantadine, an anti-AD drug. Nitric oxide (NO) signaling has been involved in both memory development through neuronal NO synthase (nNOS), and neuroinflammation through inducible NO synthase (iNOS) which mediates CNS inflammatory processes. Aim: To study the expression of the NMDAR2B subunit in an inflammatory model of AD before and after treatment with NO modulators. Materials and methods: AD was induced in mice by a single dose of lipopolysaccharide (LPS). Behavioral tests for spatial and non-spatial memories and locomotor activity were performed to assess disease severity and progression. The effects of l-NAME (general NOS inhibitor), 1400W (iNOS inhibitor), diflunisal (systemic anti-inflammatory drug that does not cross the blood brain barrier), and l-arginine, the substrate for NOS was determined. Immunohistochemistry was done to confirm AD and brain lysates were tested for A formation, levels of NMDAR2B subunits, and brain NO levels. Results: Systemic LPS induced AD, as shown by cognitive impairment; increased levels of A and concomitant increase in the brain NO concentrations. This was associated with overexpression of NMDAR2B. All tested drugs improved behavioral dysfunction, prevented A formation and NMDAR overexpression, and lead to decrease in NO concentration in the brain. l-Arginine alone, however, did not produce similar improvements. Conclusion: NMDAR2B subunits are overexpressed in an inflammatory model of AD and NO inhibitors ameliorate this expression.
Rolipram rescues memory consolidation deficits caused by sleep deprivation: Implication of the cAMP/PKA and cAMP/Epac pathways
(Bentham Science Publisher, 8/15/2021) Maher, Ahmed; El Sayed, Nesrine; Nafea, Heba; Gad, Mohamed
Background: Over the last few years, the number of people suffering from sleeping disorders has increased significantly despite negative effects on cognition and an association with brain inflammation. Objectives: We assessed memory deficits caused by sleep deprivation (SD) to determine the therapeutic effect of phosphodiesterase 4 (PDE4) inhibitors on SD-induced memory deficits and to investigate whether the modulation of memory deficits by PDE4 inhibitors is mediated by a protein kinase A (PKA)-independent pathway in conjunction with a PKA-dependent pathway. Methods: Adult male mice were divided into four groups. Three SD groups were deprived of Rapid eye movement (REM) sleep for 12 h a day for six consecutive days. They were tested daily in the Morris water maze to evaluate learning and memory. One of the SD groups was injected with a PDE4 inhibitor, rolipram (1 mg/kg ip), whereas another had rolipram co-administered with chlorogenic acid (CHA, 20 mg/kg ip), an inhibitor of PKA. After 6 days, the mice were sacrificed, and the hippocampi were evaluated for cyclic AMP (cAMP) and nuclear factor Nrf-2 levels. The hippocampal expression of PKA, phosphorylated cAMP response element-binding protein (CREB), and phosphorylated glycogen synthase 3β (Ser389) were also evaluated. Results: SD caused a significant decrease in cAMP levels in the brain and had a detrimental effect on learning and memory. The administration of rolipram or rolipram+CHA resulted in an improvement in cognitive function. Conclusion: The present study provides evidence that restoration of memory with PDE4 inhibitors occurs through a dual mechanism involving the PKA and Epac pathways.
A Unique Acylated Flavonol Glycoside from Prunus persica (L.) var. Florida Prince: A New Solid Lipid Nanoparticle Cosmeceutical Formulation for Skincare
(MDPI, 03/12/2021) Mostafa, Eman S; Maher, Ahmed; Mostafa, Dalia A; Gad, Sameh S; Nawwar, Mahmoud A.M; Swilam, Noha
MDPI Open Access Journals zoom_out_map search menu Journals Antioxidants Volume 10 Issue 3 10.3390/antiox10030436 antioxidants-logo Submit to this Journal Review for this Journal Edit a Special Issue ► Article Menu Open AccessArticle A Unique Acylated Flavonol Glycoside from Prunus persica (L.) var. Florida Prince: A New Solid Lipid Nanoparticle Cosmeceutical Formulation for Skincare by Eman S. Mostafa 1,*,Ahmed Maher 2,*OrcID,Dalia A. Mostafa 3OrcID,Sameh S. Gad 4OrcID,Mahmoud A.M. Nawwar 5 andNoha Swilam 6OrcID 1 Department of Pharmacognosy, Faculty of Pharmacy, October University of Modern Sciences and Arts (MSA), Giza 12451, Egypt 2 Department of Biochemistry, Faculty of Pharmacy, October University for Modern Sciences and Arts (MSA), Giza 12451, Egypt 3 Department of Pharmaceutics, Faculty of Pharmacy, October University of Modern Sciences and Arts (MSA), Giza 12451, Egypt 4 Department of Pharmacology, Faculty of Pharmacy, October University for Modern Sciences and Arts (MSA), Giza 12451, Egypt 5 National Research Centre, Department of Phytochemistry, Dokki, Cairo 12622, Egypt 6 Department of Pharmacognosy, Faculty of Pharmacy, The British University in Egypt (BUE), Cairo 11837, Egypt * Authors to whom correspondence should be addressed. Academic Editors: Alfredo Aires and Yong Chool Boo Antioxidants 2021, 10(3), 436; https://doi.org/10.3390/antiox10030436 Received: 24 February 2021 / Revised: 6 March 2021 / Accepted: 8 March 2021 / Published: 12 March 2021 (This article belongs to the Special Issue Phenolics as Antioxidant Agents) View Full-Text Download PDF Browse Figures Citation Export Abstract Polyphenols are known dietary antioxidants. They have recently attracted considerable interest in uses to prevent skin aging and hyperpigmentation resulting from solar UV-irradiation. Prunus persica (L.) leaves are considered by-products and were reported to have a remarkable antioxidant activity due to their high content of polyphenols. This study aimed at the development of a cosmeceutical anti-aging and skin whitening cream preparation using ethanol leaves extract of Prunus persica (L.) (PPEE) loaded in solid lipid nanoparticles (SLNs) to enhance the skin delivery. Chemical investigation of PPEE showed significantly high total phenolic and flavonoids content with notable antioxidant activities (DPPH, ABTS, and β-carotene assays). A unique acylated kaempferol glycoside with a rare structure, kaempferol 3-O-β-4C1-(6″-O-3,4-dihydroxyphenylacetyl glucopyranoside) (KDPAG) was isolated for the first time and its structure fully elucidated. It represents the first example of acylation with 3,4-dihydroxyphenyl acetic acid in flavonoid chemistry. The in-vitro cytotoxicity studies against a human keratinocytes cell line revealed the non-toxicity of PPEE and PPEE-SLNs. Moreover, PPEE, PPEE-SLNs, and KDPAG showed good anti-elastase activity, comparable to that of N-(Methoxysuccinyl)-Ala-Ala-Pro-Val-chloromethyl ketone. Besides, PPEE-SLNs and KDPAG showed significantly (p < 0.001) higher anti-collagenase and anti-tyrosinase activities in comparison to EDTA and kojic acid, respectively. Different PPEE-SLNs cream formulae (2% and 5%) were evaluated for possible anti-wrinkle activity against UV-induced photoaging in a mouse model using a wrinkle scoring method and were shown to offer a highly significant protective effect against UV, as evidenced by tissue biomarkers (SOD) and histopathological studies. Thus, the current study demonstrates that Prunus persica leaf by-products provide an interesting, valuable resource for natural cosmetic ingredients. This provides related data for further studying the potential safe use of PPEE-SLNs in topical anti-aging cosmetic formulations with enhanced skin permeation properties