Al Azhar University

Mosquitoes pose a significant global health threat due to their capacity to transmit fatal diseases and their growing resistance to conventional synthetic insecticides. This study synthesized and evaluated three novel 2,4thiazolidinedione (TZD) derivatives (TzTPOMe, TzTPCl, and TzTPNO2) as multi-target larvicides against the 3rd larval instar of Culex pipiens. The compounds were synthesized via Knoevenagel condensation and characterized by spectral analyses (IR, NMR, and mass) and DFT calculations at the B3LYP/6-31G(d,p) level to examine the electronic properties of their E and Z isomers. Biological evaluations demonstrated exceptional potency, with all compounds achieving up to 100% mortality at 1000 & micro;g/mL within 24 h. The nitro-substituted derivative, TzTPNO2, exhibited the highest toxicity, recording the lowest LC50 values at 24 and 48 h, respectively. Biochemical assays revealed a potent multi-target mechanism; the leading derivatives significantly inhibited neuro-enzymes (Acetylcholinesterase) and critical metabolic enzymes (GABA-T, amylase, and lipase) while simultaneously suppressing antioxidant defenses (SOD, GST, CAT, and GSH). This systemic collapse triggered catastrophic oxidative stress, evidenced by elevated lipid peroxidation and total protein carbonyl content. Safety assessments against non-target aquatic predators (Stratiomys longicornis, Cybister tripunctatus, Sphaerodema urinators, and Gambusia affinis) revealed a high selectivity toward mosquito larvae with minimal impact on predatory efficiency, supporting their environmental compatibility. These findings were robustly supported by computational modeling; molecular docking and 100 ns molecular dynamics (MD) simulations confirmed the formation of highly stable protein-ligand complexes, often exceeding the binding affinities of established inhibitors. Complemented by favorable ADMET profiling indicating high intestinal absorption and a safe, nonmutagenic profile, these TZD hybrids, particularly TzTPNO2 represent a promising strategy for developing new, resistance-breaking chemical larvicides through combined neurotoxicity, metabolic disruption, and severe oxidative damage, offering a sustainable and environmentally safe approach for integrated vector management programs.

This study evaluates the protective potential of Fondaparinux (Fond), a selective antithrombin-mediated Factor Xa inhibitor, in methotrexate-induced hepatotoxicity. The work explores its ability to correct coagulation imbalance, improve endothelial function, and attenuate oxidative and inflammatory cascades (TLR4/NLRP3, NF-κB p65/IL-1β/MCP-1). Animals were allocated into 4 groups. A control group was given distilled water via the intraperitoneal route (i.p.); an MTX group was given a single intraperitoneal injection of MTX (20 mg/kg) on the seventh experimental day; and two groups received prior prophylactic administration of Fondaparinux (at doses of 5 or 10 mg/kg, intraperitoneally) throughout seven consecutive days before as well as for an additional four-day period following MTX administration. MTX significantly elevated hepatic injury markers (AST, ALT, ALP), induced oxidative stress with depleted antioxidants (SOD, GSH), and activated TLR4/NLRP3 signaling, resulting in upregulation of inflammatory mediators (TNF-α, NF-κB p65, IL-18, IL-1β, MCP-1, caspase-1, iNOS, ICAM-1, MPO) and suppression of IL-10 (p < 0.05). Endothelial dysfunction was evidenced by reduced eNOS. MTX also triggered marked coagulation disturbances, including enhanced Factor Xa–dependent thrombin generation, increased tissue factor, fibrin deposition, and elevated PAI-1. Mitochondrial apoptotic signaling was promoted, as indicated by elevated expression of cytochrome c along with induced caspase-3 and caspase-9 activation . Histologically, MTX caused extensive hepatic damage characterized by periportal fibrosis, inflammatory infiltration, bile duct proliferation, hepatocellular necrosis, vacuolation, and vascular congestion. Fondaparinux pretreatment dose-dependently restored hemostatic balance, improved endothelial function, suppressed oxidative and inflammatory responses, attenuated apoptosis, and markedly ameliorated histopathological alterations. Fondaparinux limits methotrexate-associated liver damage through inhibition of Factor Xa–dependent coagulation pathways while providing antioxidant, anti-inflammatory, anti-apoptotic, and hepatoprotective actions.

In this study, a series of novel thiadiazole derivatives (7a, 7b, 9a, 9b, and 9c) were rationally designed as potential VEGFR-2 inhibitors using a pharmacophore-guided strategy. The compounds were synthesized and assessed for their antiangiogenic and anticancer effects. Among them, compound 9b showed the strongest VEGFR-2 inhibition (IC50 = 0.030 ± 0.001 μM), outperforming the reference drug Sorafenib. Cytotoxicity tests revealed that 9b was highly effective against MCF-7 breast cancer cells (IC50 = 8.06 ± 0.7 μM) while exhibiting minimal toxicity toward normal WI-38 cells. Flow cytometry demonstrated that 9b induced significant G2/M cell cycle arrest and increased apoptosis, supported by molecular data showing upregulation of caspase-3 and Bax and downregulation of Bcl-2, indicating activation of the intrinsic apoptotic pathway. Extensive in silico studies-including molecular docking, 200 ns molecular dynamics simulations, interaction mapping, principal component analysis of trajectories, and free energy landscape analysis-confirmed that 9b binds stably and efficiently within the VEGFR-2 active site. Overall, these results highlight compound 9b as a promising VEGFR-2-targeted antiangiogenic agent with potent enzymatic and cellular activity, favorable selectivity, and mechanistic validation through combined experimental and computational approaches.

Abstract Background Stent retriever (SR), contact aspiration (CA), and combined treatment are vital mechanical thrombectomy (MT) techniques for acute ischemic stroke (AIS) patients. Aim This study aimed to compare and rank these three MT strategies for AIS caused by large vessel occlusion using a Frequentist network meta-analysis (NMA). Methods A systematic review and Frequentist NMA following PRISMA guidelines were conducted. Relevant randomized controlled trials (RCTs) and observational studies were identified from electronic databases from inception to March 2025. Random effect models were used to estimate odds ratios (ORs) and mean differences with 95% confidence interval (CI). Results A total of 55 studies was included in the current NMA study. CA showed significantly higher modified thrombolysis in cerebral infarction (mTICI) 2c/3 scores at the end of the procedure (OR = 1.99, 95% CI [1.04, 3.81]), higher favorable modified Rankin Scale (mRS 0–2) at 3 months (OR = 1.28, 95% CI [1.03, 1.58]), and fewer adverse events (OR = 0.70, 95% CI [0.50, 0.98]) compared to combined approach. No significant differences among groups regarding National Institute of Health Stroke Scale, symptomatic intracerebral hemorrhage, and all-cause mortality. Conclusions The CA group demonstrated superior outcomes in mTICI 2c/3 scores, mRS 0–2 and adverse event rates. However, no significant differences were found between CA, SR, or combined approaches for other outcomes. These findings can guide clinicians in selecting appropriate thrombectomy strategies for AIS patients.

Neltuma juliflora (Sw.) Raf. (syn. = Prosopis juliflora (Sw.) DC.) is among the world's most aggressive woody invaders, yet its ecological impacts remain poorly quantified in hyper-arid environments, where soils are calcareous and ecosystems recover slowly from disturbance. In this study, we tested two hypotheses: (1) the presence of N. juliflora changes native plant diversity, as well as soil and key physicochemical properties in hyper-arid Qatar, and (2) agricultural farms act as primary sources of N. juliflora invasion. Using a comparative observational design across 62 sites (45 invaded and 17 non-invaded), we applied a generalised additive model (GAM) and a generalised linear mixed model (GLMM) to quantify invasion drivers and the impact of invasion on perennial species diversity, respectively. Additionally, we used the Wilcoxon rank-sum test to compare the soil properties in the invaded and non-invaded sites. Our results indicate that N. juliflora is positively associated with farms, with the probability of occurrence declining by ca. 20% for each kilometre farther away from agricultural farms. This pattern suggests substantial propagule pressure from agricultural farms. Perennial species richness declined from 7.5 species at 0% N. juliflora cover to 4.8 species at full cover (36% reduction). Invaded sites were characterised by higher amounts of coarse sand (16%); reduced silt-clay fractions (5%); and elevated salinity indicators, including electrical conductivity (0.744 dS m-1) and total dissolved solids (476 mg L-1), while major N-P-K pools remained unchanged. These findings demonstrate measurable invasion-related changes in soil conditions and native perennial diversity in hyper-arid ecosystems and highlight the role of agricultural land use as a key driver of biological invasion. From a sustainability perspective, early detection, targeted control near agricultural and grazing zones, and integration of invasive species monitoring into land-use planning frameworks are essential to prevent further ecosystem degradation, protect biodiversity, and enhance the resilience of desert landscapes under increasing climate and land-use pressures.