Journals
2025 EN
Bayoumi Hatem Hussein · Ibrahim MohamedKamal · Dahab Mohammed A.
+2 more
ABSTRACT New phthalazine‐derived inhibitors for VEGFR‐2 were synthesized for anticancer evaluations. Also, docking studies were performed to explore the suggested binding orientations of the novel derivatives inside the binding site of VEGFR‐2. The achieved biological data were extremely interrelated to that of docking study. In specific, derivative 3f was the greatest effective compound against HepG2 and MCF‐7 cancer cell lines with IC 50 = 0.17 ± 0.01 and 0.08 ± 0.01 µM individually. The six highly active derivatives 3b, 3e, 3f, 3g, 6a, and 6b were estimated for their VEGFR‐2 inhibitory effects. Derivative 3f was the greatest effective compound which inhibited VEGFR‐2 at IC 50 = 0.0557 ± 0.002 µM. The activities of 3f were assessed against MCF‐7 cancer cells for apoptosis induction, cell cycle distribution, and growth inhibition. Compound 3f induced early apoptosis (21.44%) by more than 36 folds over the control (0.59%). The obtained results showed that compound 3f induced necrotic effect (6.03%) by more than threefolds over the control (1.75%). On the other hand, compound 3f improved the level of the pro‐apoptotic protein; Bax by approximately fivefolds. Moreover, compound 3f noticeably decreased the levels of the anti‐apoptotic proteins Bcl‐2 by nearly fourfolds in comparison to the control. In addition, derivative 3f remarkably enhanced the Bax/Bcl2 ratio by nearly 18 folds, as compared to the control. Finally, our derivatives 3f, 3g, and 6b revealed good in silico considered ADMET profile in comparing to sorafenib.
Journals
2025 EN
Shaaban Saad · Alabdali Aya Yaseen Mahmood · Mousa Mai H. A.
+7 more
ABSTRACT Herein, we report the design, synthesis, and characterization of novel organoselenium (OSe) hybrids ( 5 – 19 ) via modifications of the lead, N ‐(4‐selaneylphenyl)‐2‐selaneylacetamide. The OSe‐based thiazol 9 showed the highest growth inhibition % (GI%) of 64.72% relative to the positive reference doxorubicin (DOX), with a GI% of 79.5%. Furthermore, the novel OSe derivatives showed low GI% values compared to the normal cell lines employed, demonstrating their selectivity. The OSe tethered N ‐chloroacetamide 5 and Schiff base 19 showed a cytotoxic effect with an IC 50 of (25.07 and 11.61 µM), respectively, against the A549 tumor cell line and IC 50 of (34.22 and 20.12 µM), respectively, against the HELA cancer cell line. Enzyme‐linked immunosorbent assay to study the JAK1 and the STAT3 inhibitory potentials of OSe compounds 5 and 19 in the A549 cancer cells both showed promising inhibitory activities with IC 50 values of 25.07 and 11.61 µM, respectively. Protein expression analysis on the A549 cancer cell line on OSe compounds 5 and 19 showed upregulation of P53, BAX, and Caspases 3, 6, 8, and 9 as apoptotic proteins. However, both candidates expressed downregulation of the antiapoptotic proteins (BCL2, MMP2, and MMP9). Moreover, OSe compounds 5 and 19 described the downregulation of the examined inflammatory proteins: COX2, IL‐6, and IL‐1β. In addition, OSe compound 19 showed potential cell cycle arrest at the G0, S, and G2‐M layers, with an increase in cellular levels. Finally, molecular docking studies of OSe compound 19 showed the most promising inhibitory potential toward the JAK1 and STAT3 target receptors, with binding scores and interactions exceeding that of the cocrystallized inhibitor of JAK1.
Journals
2025 EN
Khafagy ElSayed · Saqr Ahmed Al · Almutairy Bjad K.
+5 more
ABSTRACT The global antibiotic resistance crisis demands innovative strategies targeting bacterial virulence rather than survival. Quorum sensing (QS), a key regulator of virulence and biofilm formation, offers a promising avenue to mitigate resistance by disarming pathogens without bactericidal pressure. This study investigates the repurposing of nitroimidazoles as anti‐QS and anti‐virulence agents at subminimum inhibitory concentrations (sub‐MICs). In Silico analyses, including molecular docking and molecular dynamics (MD) simulations, were performed to investigate ligand‐receptor interactions with structurally distinct Lux‐type QS receptors and assess binding stability and conformational dynamics over time. In Vitro assays evaluated the effects of representative nitroimidazoles, metronidazole (MET) and secnidazole (SEC), on QS‐controlled phenotypes, including violacein production in Chromobacterium violaceum and biofilm formation and protease activity in Pseudomonas aeruginosa , Acinetobacter baumannii , Salmonella enterica , and Proteus mirabilis . In Vivo efficacy was assessed using a murine infection model and HeLa cell invasion assays. Molecular docking revealed high‐affinity binding to QS receptors, corroborating their mechanistic interference. Sub‐MIC MET/SEC significantly suppressed violacein synthesis, biofilm biomass, and protease secretion in Gram‐negative pathogens. Both compounds reduced bacterial invasiveness in HeLa cells and In Vivo protected mice from lethal P. aeruginosa infections. Crucially, nitroimidazoles attenuated virulence without affecting bacterial viability, preserving microbial ecology. These findings position nitroimidazoles as dual‐function agents; antimicrobial at bactericidal doses and anti‐virulence at sub‐MICs. Their validated efficacy across In Silico, In Vitro, and In Vivo models underscores their potential as adjunctive therapies, bridging the gap between drug repurposing and next‐generation anti‐infective development.
Journals
2025 EN
Anwar Mostafa Abd ElMohsen · Mohammed Eman R. · El Moghazy Samir M.
+6 more
ABSTRACT A novel series of 1,1‐disubstituted cyclohexane 7a‐e , 8a‐e , and 9a‐e were designed, synthesized, and evaluated for their anticonvulsant activities. Compounds 7c , 8c , 8d , and 9a displayed significant anticonvulsant activity in both maximum electroshock seizure (MES) and pentylenetetrazol (PTZ) induced seizure during the preliminary screening with no neurotoxicity. The phase II quantitative anticonvulsant activity revealed that compound 8c demonstrated the most potent activity as compared to the conventional drugs phenobarbital. The expression of nuclear factor erythroid 2‐related factor‐ antioxidant response element (Nrf2‐ARE) signaling pathways, oxidative stress parameters were also observed. Additionally, histopathological examination of brain of animals treated with compounds 7c , 8c , 8d , and 9a was performed and the results were corroborated the neuroprotective properties. Further neurochemical investigation was performed to unravel the effect of the most active compounds, compounds 7c , 8c , 8d , and 9a demonstrated significant protection by ameliorating GABA levels, which were initially reduced to 61% by PTZ administration, suggesting enhanced GABAergic neurotransmission. Computational parameters including docking analysis on GABAA exhibiting good binding on the active site, Moreover, In silico prediction was carried out indicating that most of compounds have favorable oral bioavailability and BBB permeability they might be viewed as helpful models for future research and derivatization.
Journals
2025 EN
Mohammed Esraa Z. · ElDydamony Nehad M. · Mehany Ahmed B. M.
+3 more
ABSTRACT In the current study, new pyrazolo [1,5‐a]pyrimidine‐3‐carbonitriles were synthesized and evaluated for their inhibitory activity against Pim‐1 kinase. The most potent inhibitors were 4d , 5d, and 9a with IC 50 values (0.61, 0.54 and 0.68 μM) compared to quercetin (IC 50 = 0.91 μM), with some selectivity towards Pim‐1 and Pim‐3 over Pim‐2. Compound 4d exhibited a 1.5‐fold increased cytotoxic activity compared to doxorubicin against the MCF‐7 cell line, whereas compound 9a showed an analogous activity to doxorubicin. Furthermore, compounds 4d , 5d, and 9a arrested the cell cycle at G2‐M phase with a decrease in the G1‐phase population. Compounds 4d , 5d, and 9a induced apoptosis in MCF‐7 cells by a 94‐, 64‐, and 78‐fold increase in the entire apoptotic and necrotic cells compared to the untreated control cells and increased the levels of wild p53 in MCF‐7 cells by 6.5, 6, and 5.7‐fold indicating that these compounds may induce apoptosis via increasing the expression level of p53. Moreover, a promising safety profile was shown for compound 4d on MCF‐10A normal breast cells. Besides, docking of the desired compounds into Pim‐1 ATP binding site showed a noteworthy binding mode for the enzyme inhibition. Additionally, a 2D QSAR identified the potential structural features controlling the Pim‐1 inhibitory activity attained via the targeted pyrazolo[1,5‐a]pyrimidines.
Journals
2025 EN
Olowu Babatunde Ibrahim · Zakariya Maryam Ebunoluwa · Abdulkareem Abdulmuheez Abiola
+3 more
ABSTRACT Intracellular bacteria exploit host cell niches, such as lysosomes, phagosomes, cytosol, entire cells, and even erythrocytes, to evade immune clearance and escape conventional antibiotics. These environments pose numerous therapeutic challenges, including crossing host cell membranes, navigating endosomal trafficking, tolerating acidic and redox conditions, bypassing efflux mechanisms, and countering phenotypic tolerance. Although recent advancements in nanotechnology—such as carriers, prodrugs, and host‐directed therapies—offer promising solutions, current strategies remain narrowly focused on “getting the drug inside the cell”, leaving therapeutic agents vulnerable to off‐site targeting, degradation, and functional failure. This review introduces a next‐generation approach for intracellular antibacterial therapy, incorporating subcellular targeting, dual‐function delivery systems, innovative biomimetic carriers, precise intracellular pharmacokinetics/pharmacodynamics (PK/PD) assessment, and artificial intelligence‐assisted drug design. Highlighting frameworks for multimodal regimens targeting intracellular bacteria, we advocate a transition from solely facilitating cellular entry to achieving precise spatiotemporal regulation of drug activity within infected host cells. This paradigm informs the development of therapeutics designed to persist within the intracellular bacterial niche, minimizing relapse and reducing the emergence of antimicrobial resistance.
Journals
2025 EN
Mohammed Ghada Farouk · AlDhubaibi Mohammed Saleh · Bahaj Saleh Salem
+3 more
ABSTRACT Introduction Hair removal is a fundamental aspect of daily life, with various hair removal methods evolving throughout hair removal history to meet cultural, aesthetic, and spiritual needs. Traditional hair removal practices have long sought effective hair removal products that not only remove hair but also promote skin health. Cyperus rotundus L. ( C r L.), known as nut grass or purple nut sedge, has long been used in traditional medicinal systems like Ayurveda and Traditional Chinese Medicine (TCM) for treating various ailments, including skin conditions and depilation. Aim To understand the role of C r L. in decreasing hair growth. Results C r L. contains essential oils (EOs) and phytochemicals such as flavonoids, alkaloids, and saponins, which contribute to its hair‐removal properties. These compounds target hair follicles, dissolve keratin, and inhibit hair regrowth by modulating biological pathways. γ‐curcumene, a key component, has been shown to suppress hair growth. Recent clinical trials have demonstrated the efficacy of Cyperus rotundus EO (CREO) in reducing hair growth, with minimal side effects. CREO has been found as effective as Alexandrite laser treatments in some cases, particularly in reducing white hair. This positions C r L. as a promising natural alternative to chemical depilatories, which often cause skin irritation. Conclusion C r L. shows significant potential as a natural hair removal agent. With its strong safety profile and growing consumer demand for natural, sustainable beauty products, C r L. could serve as a viable alternative to synthetic depilatories, pending further clinical validation.
Journals
2025 EN
AlDhubaibi Mohammed Saleh · Mohammed Ghada Farouk · Bahaj Saleh Salem
+3 more
ABSTRACT Aim This study aims to provide a comprehensive analysis of keratinocytes, the predominant cell type in the epidermis, by examining their structural, functional, and regulatory roles in skin biology. The study explores the intricate processes of keratinocyte differentiation, proliferation, and immune interactions, emphasizing their essential contributions to skin homeostasis, wound healing, and barrier integrity. Additionally, it investigates the involvement of keratinocytes in dermatological disorders such as psoriasis, atopic dermatitis, and skin cancer, highlighting their pathological alterations and molecular mechanisms. Methods This review covers a broad range of studies, including in vitro and in vivo research on keratinocyte biology, their interactions with growth factors, and their contributions to inflammatory responses in the skin. It also discusses therapeutic advancements such as biologics and gene therapy that focus on restoring keratinocyte function in skin diseases. Results The review highlights that keratinocytes play a pivotal role in skin inflammation and the regulation of growth factors that promote wound healing and skin regeneration. Dysregulation of keratinocyte function is linked to several skin diseases, emphasizing the need for targeted therapeutic approaches. Recent advancements in treatments, such as gene therapy and biologics, offer promising outcomes for managing conditions driven by keratinocyte dysfunction. Conclusion The primary aim of this review is to provide an in‐depth overview of the functions of keratinocytes, particularly their roles in skin health, inflammation, and disease development. The review also aims to highlight the latest therapeutic strategies targeting keratinocytes for the treatment of skin diseases.
Journals
2025 EN
Ibrahim Mahmoud · BaEssa Ebtesam M. · Ahmed Asma
+15 more
ABSTRACT Ramadan fasting is a sacred ritual observed by approximately 1.8 billion Muslims each year, most of whom adhere to fasting due to its significance as a core pillar of Islam. Able‐bodied Muslims who are capable of fasting are religiously required to do so. Ramadan is profoundly spiritual and of great importance in the Muslim community that occurs for roughly 30 days, in alignment with the lunar calendar. During Ramadan, Muslims abstain from food and drink for 11–16 h a day on average; however, this could be significantly shorter or longer depending on the season and the geographic location, ultimately breaking their fast during the sunset meal ‘Iftaar’. Before the great strides were taken in the management of diabetes, these patients were initially considered not able to observe this holy month, creating significant frustration and disconnect with their families and loved ones. As patient outcomes improved through the emergence of better pharmacotherapy and increasing use of technology, these restrictions have been reconsidered. This prompted us to create the 2005 first global statement regarding best practices in the management of diabetes during Ramadan as an official American Diabetes Association (ADA) report. Since then, we have received numerous requests and comments asking for updated versions that include the latest data, medications, and technology. We decided to issue an update every 5 years, including 2010, 2015 and 2020. Our updated recommendations collate some of the more directly implicative findings on patient care for Ramadan fasting and align closely with the ADA's consensus for diabetes management. We recommend the prioritisation of pharmacologic therapies with a low risk profile for hypoglycaemia. Technological advancements, including integrated pump‐sensor systems, hybrid closed‐loop systems, and artificial intelligence (AI)‐equipped continuous glucose monitoring (CGM) devices, show great promise in the monitoring of blood glucose levels and can provide tangible reductions in hypoglycaemia episodes, suggesting possible utility in the facilitation of fasting in patients with type 1 diabetes mellitus (T1D). Our recommendations align with the ADA consensus for the use of CGM devices, in concordance with appropriate time in range (TIR) targets to reduce hypoglycaemia and glycaemic variability. The implications of Ramadan fasting on atherosclerotic cardiovascular disease (ASCVD) risk remain uncertain due to the sparsity of evidence, but the literature suggests an increased risk. Until more conclusive evidence is reported, we advise patients with a high ASCVD risk to avoid Ramadan fasting. We emphasise the pivotal role primary care providers (PCPs) have in counselling, managing, and following patients who intend to fast and advise counselling to begin ideally 6–8 weeks prior to Ramadan start, with particular recommendations to be given to patients post‐bariatric surgery.
Journals
2025 EN
AlBusaidi Ibrahim S. · Seelig Amber D. · Boyko Edward J.
ABSTRACT Aims Although etiologic factors for diabetes‐related lower‐extremity amputation (LEA) have been extensively examined, the role of incident diabetic foot ulcer (DFU) has not been prospectively evaluated. We investigated the independent effect of incident DFU, among other limb‐ and person‐level factors, on LEA risk in a cohort of veterans with diabetes at one Department of Veterans Affairs general internal medicine clinic. Methods We prospectively followed 1458 male U.S. veterans with 2893 lower limbs without DFU between 1990 and 2002 (mean follow‐up = 4.9 years). Potential risk factors were evaluated in proportional hazards and flexible parametric survival models and collected through interviews (demographic, lifestyle, and diabetes characteristics), physical examination (blood pressure, weight, Charcot deformity, visual acuity), and blood (albumin, HbA 1c , and eGFR [estimated Glomerular filtration rate]) and neurovascular (10‐g monofilament, TcPO 2 , and ankle‐brachial index [ABI]) testing. Results During follow‐up, 227 (7.8%) DFUs occurred and 72 (2.5%) LEAs. Significant predictors ( p < 0.05) of LEA in the final model adjusted for time‐updated measurements (hazard ratio, 95% CI) included age ≥ 70 years (0.29, 0.08–0.97), prior amputation (2.31, 1.13–4.74), lower eGFR (1.16, 1.02–1.32), higher systolic blood pressure (1.40, 1.11–1.78), ABI ≤ 0.5 (3.94, 2.03–7.62), and incident DFU (10.44, 6.01–18.15). Conclusions In this 12‐year prospective study, incident DFU emerged as having a substantial independent power in predicting LEA among other person‐ and limb‐specific risk factors. Preventing DFU occurrence is critical for reducing the burden of LEA.