Abdulrahman M. Saleh

The increase in global life expectancy has resulted in a significant rise in the occurrence of Alzheimer's disease (AD), making it a critical public health burden. Therefore, there is an urgent need to create effective methods to prevent or slow down the progression of the disease. In this regard, fifteen previously reported hybrid molecules ( 7a–c , 10a–j , and 13a,b ), combining 4‐hydroxycoumarin and pyrazolyl indolin‐2‐one structures, were resynthesized and tested for their antioxidant and anti‐Alzheimer properties. Several of these compounds showed moderate to strong biological activity. Among these, compound 7a demonstrated excellent antioxidant capacity (TAC = 80.65 mg gallic acid/g; IRP = 68.90 µg/mL) and impressive free radical scavenging abilities (DPPH = 5.33 µg/mL; ABTS = 4.59 µg/mL; NO = 6.76 µg/mL), comparable to the standard antioxidant ascorbic acid. Additionally, compound 7a demonstrated the robust inhibition of acetylcholinesterase (AChE) with an IC ₅₀ of 6.89 µg/mL, as well as potent inhibition of butyrylcholinesterase (BChE) (IC ₅₀ = 5.93 µg/mL). Molecular docking analyses of compound 7a revealed favorable binding interactions and stable conformations within the enzyme's active site, supporting its strong inhibitory effect. Overall, these findings indicate that this group of hybrid molecules offers a promising framework for developing new cholinesterase‐targeting treatments for AD.

Klebsiella oxytoca is an emerging opportunistic pathogen capable of causing bovine mastitis and neonatal colonization. This study provides a comprehensive molecular and phenotypic characterization of K. oxytoca across dairy supply nodes and pediatric host matrices while evaluating a probiotic-based bio-intervention strategy. K. oxytoca was isolated from 27.9% (39/140) of examined samples across dairy supply nodes and infant stool in Egypt, with equal peak prevalence in clinical mastitic milk (40.0%, 8/20) and infant fecal specimens (40.0%, 8/20). High rates of multidrug resistance (MDR; 66.7%, 26/39) were observed, with all isolates (100%) confirmed as extended-spectrum β-lactamase (ESBL) producers. Colistin (CT) and azithromycin resistance reached 46.2% (18/39) overall, peaking in commercial milk (69.2% for CT). Molecular screening revealed high frequencies of the mobile colistin resistance gene mcr-1 (41.0%, 16/39) and the ESBL determinant blaCTX-M (66.7%, 26/39), alongside fimbrial adhesion (mrkA, 76.9%) and iron acquisition (kfuBC, 82.1%) loci. All isolates (100%) exhibited strong biofilm-forming capacity (mean OD₅₇₀ = 0.63 ± 0.016), while toxin-antitoxin (TA) modules (symE, ccdB, relE) correlated positively with MDR profiles (p = 0.024). Bacterial virulence gene burden showed strong statistical associations with host tissue damage and inflammatory markers, including elevated milk lactate dehydrogenase (LDH; r = 0.918), haptoglobin (r = 0.954), and neonatal fecal calprotectin (FC; 83.34 ± 21.13 μg/g vs. 22.4 ± 2.0 μg/g in controls, p = 0.02). Crucially, milk-based cell-free metabolic supernatant (CFS) from Lactobacillus acidophilus demonstrated superior antagonistic activity compared to broth-based CFS (inhibition zones up to 40 mm vs. 12 mm against CT-resistant isolates). In silico molecular docking predicted strong binding affinities of putative L. acidophilus bioactive peptides (Acidocin 8912 score: −108.07 kcal/mol; Acidocin B score: 80.63 kcal/mol) to K. oxytoca outer membrane porin CymA and transport targets. These findings highlight the co-occurrence of resilient K. oxytoca lineages across food and pediatric matrices and demonstrate the therapeutic potential of probiotic-derived CFS as a non-antibiotic control strategy within a One Health framework.

The current study devised and synthesized a novel class of pyrazole derivatives based on indole as possible inhibitors of cyclin‐dependent kinase‐2 (CDK‐2). ¹ H NMR, ¹³ C NMR, NOESY, HMQC, and elemental analysis were used to confirm the structural integrity of the synthesized compounds. Promising CDK‐2 inhibitory activity was observed in biological assays, and numerous compounds exhibited sub‐micromolar IC ₅₀ values. Compound 5 d outperformed the reference inhibitor Roscovitine (IC ₅₀ = 0.716 µM) as the most potent inhibitor (IC ₅₀ = 0.536 µM), followed by compound 9 g (IC ₅₀ = 0.675 µM). SAR analysis showed that the observed activity was significantly influenced by the electronic nature of the added substituents as well as the orientation of the indole bond, with brominated derivatives exhibiting greater potency. The antiproliferative activity of the most potent compounds against the cancer cell lines HepG2, HCT‐116, and MCF‐7 was further assessed. In addition to having an enhanced selectivity index for normal MCF‐10A cells (SI = 8.00 vs. 4.96 for Roscovitine), compound 5 d had the greatest activity against MCF‐7 cells (IC ₅₀ = 6.78 µM), surpassing Roscovitine (IC ₅₀ = 8.11 µM). According to mechanistic investigations, compound 5 d significantly reduced the S‐phase population, markedly promoted apoptosis, and caused G1 and G2/M cell‐cycle arrest. Additionally, the consistent binding of compound 5 d within the ATP‐binding pocket of CDK‐2 was confirmed by molecular docking and molecular dynamics simulations, and attractive drug‐like and pharmacokinetic features, similar to those of Roscovitine, were demonstrated by in silico ADMET predictions. All of these results point to compound 5 d as a promising lead scaffold for developing potent CDK‐2‐targeted anticancer agents.

Ethnopharmacological relevance: Punica granatum (pomegranate) peel is traditionally used for its antimicrobial and health-promoting properties in several cultures. Rich in polyphenols, the peel has attracted interest for its potential applications in treating infections and cancer, particularly in integrative approaches for immunocompromised patients. Materials and methods: Pomegranate peel extracts were prepared using solvents of increasing polarity, with emphasis on the ethyl acetate fraction (PPE-EA). A nano-formulated version (n-PPE-EA) was developed using a standard nano-encapsulation technique. Cytotoxic activity was evaluated in THP-1 human leukemia cells using MTT assay, flow cytometry, and biochemical analyses. Antimicrobial activity was assessed against Streptococcus pyogenes via agar diffusion. Gene expression of BCL2, PI3K, and CDK8 was measured to elucidate mechanisms of action. Results: Among all tested extracts, PPE-EA showed the strongest dual activity, reducing THP-1 cell viability by over 50% at 100 µg/mL and inhibiting S. pyogenes with a 10.5 ± 1.1 mm zone. Nano-encapsulation enhanced both effects, reducing the IC₅₀ from 1.48 ± 0.03 µg/mL to 0.19 ± 0.01 µg/mL and increasing the bacterial inhibition zone to 15.6 ± 0.5 mm. n-PPE-EA induced apoptosis, cell cycle arrest, elevated catalase activity, and reduced malondialdehyde levels. It also downregulated BCL2, PI3K, and CDK8 expression. Conclusion: The nano-formulated PPE-EA demonstrated potent cytotoxic and antimicrobial activities, with enhanced efficacy attributed to improved bioavailability and modulation of apoptotic and cell cycle pathways. These findings support its potential as a multifunctional therapeutic agent in integrative cancer care.

The updated guidelines from the World Health Organization highlight that treatment options for multidrug-resistant tuberculosis (MDR-TB) remain limited due to the scarcity of effective drugs. As a result, there is an urgent necessity to develop novel or repurposed drugs that demonstrate efficacy against multidrug-resistant (MDR) strains. In this study, a new series of thiazole-pyridine hybrids were thoughtfully designed and synthesized to assess their potential as antitubercular agents. These compounds were specifically created to target enoyl acyl carrier protein reductase (InhA), a crucial enzyme in the pathogenesis of Mycobacterium tuberculosis. The majority of the compounds evaluated demonstrated substantial antitubercular activity, with minimum inhibitory concentrations (MIC) ranging from 0.5 to 3.9 μg mL⁻¹ against Mycobacterium tuberculosis H37Rv. Among them, compound 5a was the most effective, with an MIC of 0.5 μg mL⁻¹. Further evaluations of compound 5a demonstrated its ability to disrupt bacterial biofilms and its strong inhibition of InhA, with an IC₅₀ of 0.19 ± 0.008 μg ml⁻¹, demonstrating superior efficacy compared to triclosan, which was employed as the reference drug. Molecular docking and dynamics analyses demonstrated that the pyridine ring and thiazole group are essential for binding affinity, and the pyridine-thiazole framework in compound 5a formed stable interactions within the active site of InhA.

Background/Objectives: A promising anticancer strategy is the simultaneous inhibition of the receptor tyrosine kinases VEGFR-2 and c-Met, which are essential for tumor angiogenesis, growth, and metastasis. In this study, a novel series of piperidinyl-based benzoxazole derivatives was designed and synthesized as potential dual VEGFR-2/c-Met inhibitors. Methods: The kinase inhibitory potential of the derivatives was evaluated in comparison to reference inhibitors, Sorafenib (VEGFR-2 inhibitor) and Staurosporine (c-Met inhibitor). Cytotoxicity was assessed across breast, prostate (PC-3), and lung (A549) cancer cell lines. Mechanistic studies included cell-cycle analysis, apoptosis assays, gene expression profiling of apoptosis-related markers, and molecular docking within the ATP-binding pockets of both kinases. Results: Compounds 5a, 5g, 5h, 11a, and 11b showed strong inhibition of both kinases (IC₅₀ = 0.145–0.970 μM for VEGFR-2 and 0.181–1.885 μM for c-Met). Selective cytotoxicity was observed against breast cancer cells, with compound 11b (p-fluorophenyl derivative) exhibiting high selectivity toward MCF-7 over normal breast cells (MCF-10A) and potency comparable to or exceeding Sorafenib. Mechanistically, 11b induced G₂/M cell-cycle arrest and apoptosis (total apoptosis = 48.34%), accompanied by upregulation of p53, BAX, and caspase-9 and downregulation of Bcl-2. Molecular docking confirmed stable binding within the ATP-binding sites of both kinases. Conclusions: Compound 11b was established as a novel, selective, dual VEGFR-2/c-Met inhibitor with strong potential for targeted breast cancer therapy.

Modulating the signaling axis between tumors and their environment is one of the key strategies to slow down the progression of hepatocellular carcinoma (HCC). In this study, we aimed to design a polyethylene glycolated liposome loaded with thymoquinone (PEG-TQ-LP) as a delivery system to investigate its effect on HCC progression and the underlying mechanisms in vitro and in vivo. The study revealed the inhibitory effects of PEG-TQ-LP on the proliferation of HCC cells and facilitated apoptosis. The observed effect can be explained by the increased expression of BAX and the decreased expression of BCL2. The activation of p38-MAPK has been implicated in the anti-oncogenic impact of PEG-TQ-LP. This activation was correlated with the dephosphorylation of MEK and ERK. The in vivo study confirmed that PEG-TQ-LP reduces the detrimental effects of free TQ on liver tissue, suppresses tumor growth, and reestablishes the oxidative state equilibrium. Molecular docking analysis demonstrated that TQ docked well with three key targets. The findings from current investigations may represent a novel strategy for the treatment of liver cancer, as PEG-TQ-LP potently promotes apoptosis. This is achieved via thymoquinone’s ability to bind to cancer protein targets' active sites, which indicates that it functions similarly to anticancer medications.

Dental composites are widely used restorative materials but secondary caries to the restored tooth, polymerization shrinkage, and mechanical failure, limiting their longevity. Incorporating nanoparticles synthesized via eco-friendly methods offers a promising strategy to enhance composite performance. This study introduces a novel, eco-friendly strategy to enhance dental composite resins by incorporating TiO₂-NPs synthesized using Vitis vinifera extract. This study uniquely employs Vitis vinifera, rich in flavonoids and phenolics, as a reducing and capping agent, and for the first time integrates molecular docking analysis to explore the mechanistic antimicrobial interaction between TiO₂-NPs and Streptococcus mutans glucosyltransferase. The research evaluates the impact of these green-synthesized nanoparticles on antimicrobial properties, mechanical performance, polymerization shrinkage, and their molecular interactions with Streptococcus mutans glucosyltransferase via molecular docking analysis. The green-synthesized TiO₂-NPs were thoroughly characterized and integrated into dental composites at 10% and 20% by weight (Groups II and III, respectively), while Group I (control) contained only fumed silica fillers. The antimicrobial activity was assessed against S. mutans, S. sanguinis, and L. acidophilus, and mechanical properties (flexural strength and microhardness) were evaluated according to ISO standards. Polymerization shrinkage was measured using a strain gauge. Additionally, molecular docking analysis was performed to investigate the interaction of TiO₂-NPs with S. mutans glucosyltransferase. The modified composites exhibited significantly improved antimicrobial activity against key oral pathogens and superior mechanical properties compared to the control. Molecular docking studies provided insights into the potential antimicrobial mechanisms of TiO₂-NPs. These findings suggest that green-synthesized TiO₂-NPs offer a promising, eco-friendly approach to improve the performance and longevity of dental restorative materials.

The World Health Organization gave great attention to Mycobacterium tuberculosis, especially its zoonotic impact. Dromedary camels in Arabian countries are of great importance, as well as awareness of production and health. Little was known about the occurrence of M. tuberculosis among Arabian camels. Out of 88 samples were collected from necropsied male camels aged 5–6.5 years after the slaughter process resident in Cairo abattoir. Isolation of Mycobacteria was achieved on Middle Brook 7H10 agar with special supplements, and then the suspected colonies were assessed by their specific aspects. Lungs and lymph nodes were processed for histopathology. Molecular characterization was carried out by both conventional amplification (Mycobacterium bovis mpb70, M. tuberculosis- Pan Mycobacterium 16S rRNA) tracked by sanger sequencing; and bacterial 16S rRNA V3–V4 hypervariable region was amplified then it was followed by Mi-seq Ilumina. Moringa oliefera’s oil was analyzed by GC–MS. The antimycobacterial potential of M. oliefera was conducted by In vitro tetrazolium microplate assay (TEMA). In silico docking mode of action and prediction were studied. Mycobacterium was isolated from 9.4% (3/32) of the lung samples and 2.4% (1/41) of the recovered lymph node samples. The isolated strains had ideal culture characteristics of Mycobacterium. Sanger sequencing identified the M. tuberculosis variant bovis DRC-EG-CAMEL PQ036932. Mi-seq Illumina revealed abundant sequence readings belonging to ancestral Actinobacteria and Micromonosporaceae. In vitro testing showed that the Moringa oleifera methanol leaf extract had antimicrobial activity with MIC ranging from 7.8 to 32 µg/ml, and the seed oil showed inhibitory effects at 50% (v/v) (P value < 0.05). In silico docking of ferulic acid against M. tuberculosis variant bovis ribosomal protein S1 showed an affinity score of − 5.95 kcal/mol with one hydrogen bond. While squalene lipoprotein LprF exhibited a professional affinity score of − 6.11 kcal/mol with seventeen hydrophobic π-interactions. Mycobacterium tuberculosis variant bovis is measured to prevail in the Arabian camels. However, this study provided a detailed examination of Mycobacterium in camels, offering practical solutions to combat this pathogen and mitigate the effects of infection or zoonotic impacts on other animals and humans. Sanger sequencing is more recommended for Mycobacterium identification. Moringa oliefera’s potential anti-mycobacterial effect through either leaves or oil might be achieved for humans and animals as a different strategy for medicinal plants’ role. It might be a new insight into the struggle and the adverse effects of tuberculosis. In the upcoming research, therapeutic compounds could be separated from M. oliefera.