Quinoxaline-based cyanoacrylate hybrids as multi-target anti-proliferative and anti-inflammatory agents with potent activity against hepatocellular carcinoma: induction of apoptosis and modulation of oxidative stress signaling
A set of quinoxaline-based derivatives incorporating a cyanoacrylate pharmacophore were designed, synthesized, and biologically evaluated for their dual anticancer and anti-inflammatory potential. Cytotoxic activity was assessed against HepG-2, HCT-116, MCF-7, and Panc-1 cancer cell lines using the MTT assay. Among the synthesized compounds, compound 9 exhibited the highest potency, particularly against HepG-2 cells (IC50 = 7.81 ± 1.1 µM), surpassing doxorubicin (IC50 = 15.96 ± 0.61 µM), and demonstrated improved selectivity toward WI-38 normal fibroblasts (IC50 = 67.21 µM; SI ≈ 7.81). Mechanistic investigations in HepG-2 cells revealed that compound 9 induced pronounced G0/G1 cell cycle arrest, increasing the cell population from 54.39% to 86.21% (∼1.6-fold), with a concomitant reduction in S-phase cells (∼3.1-fold decrease). Apoptosis analysis showed a significant increase in total apoptotic cells from 3.12% to 35.14% (∼11.3-fold), predominantly driven by late apoptosis (∼129-fold increase). These findings were supported by gene expression analysis, where compound 9 upregulated p53 (∼5.9-fold), BAX (∼3.7-fold), cytochrome c (∼3.9-fold), and caspase-7 (∼2.6-fold), while downregulating Bcl-2 (∼0.64-fold), indicating activation of the intrinsic mitochondrial apoptotic pathway. In LPS-stimulated RAW264.7 macrophages, compound 9 exhibited potent anti-inflammatory activity without significant cytotoxicity. The compound markedly reduced intracellular reactive oxygen species (ROS) levels in a dose-dependent manner (from 591.52 to 60.62 pg mL−1; ∼9.8-fold reduction) and significantly suppressed nitric oxide production. Furthermore, it downregulated key pro-inflammatory cytokines, including TNF-α (∼0.36-fold), IL-1β (∼0.47-fold), and IL-6 (∼0.51-fold), with effects comparable to celecoxib. Molecular docking studies indicated favorable binding of compound 9 within the active sites of IL-1β, TNF-α, and IL-6Rα, with the highest affinity toward IL-6Rα (−7.93 kcal mol−1). These interactions were further validated by 100 ns molecular dynamics simulations, which supported stable protein–ligand complexes, consistent RMSD profiles, preserved structural compactness, and persistent key interactions throughout the trajectories. Collectively, these findings identify compound 9 as a promising multi-target quinoxaline-based agent with dual antiproliferative and anti-inflammatory activities, mediated through induction of mitochondrial apoptosis and modulation of oxidative stress and cytokine signaling pathways.
This study constructed a pH-responsive P-TN/SF@Fe-Cur composite coating that demonstrated significant anti-infective, anti-inflammatory, antioxidant, pro-angiogenic, and pro-osteogenic effects in rat subcutaneous infection and femoral defect models.
ProteinReasoner is developed, a multimodal generative protein foundation model that sequentially connects amino acid sequence, evolutionary constraints and three-dimensional structure within a shared autoregressive architecture and suggests a general route towards reasoning across interdependent representations in other scientific domains.
Chaozhong Liu, Linlin Chao, Shaomin Ji et al.· bioRxiv· 1 citation
Due to its importance and wide adoption, wheat cultivation is promptly required to shift towards sustainable practices, reducing the dependency on chemical components. Among bio-based solutions aimed at securing the sustainability of wheat cultivation, biostimulants offer a versatile platform of eco-friendly tools assuring sustainability and profitability. Microalgae present a concrete example of a biostimulant source due to their richness in metabolites and high value products. Therefore, this study evaluated the biostimulant potential of eleven eco-extracts prepared from soil-isolated microalgae strains. Eco-extracts applied via soil drench at low dose (0.1 g/L) were investigated for their biostimulant effects on wheat growth, physiology, yield, and quality under controlled conditions. Results demonstrated significant ameliorations in treated plants as compared to the control, with no phytoinhibitory effects. Remarkable enhancements were notable in growth parameters such as shoot and root lengths (+40-70%), physiological traits such as total chlorophyll and stomatal conductance (+7-52%), yield components in the example of grain number per spike and thousand grain weight (+17-103%), and grain quality namely protein and polyphenol content (+2-fold to 4-fold). Similarly, phosphorus accumulation and uptake were significantly improved, while soil physicochemical status was ameliorated, indicating enhanced fertility. Multivariate analysis and composite index ranking marked Chlorella sp. GA18, Chlorella sp. GA65, Scenedesmus sp. GA69, and Chlorococcum sp. GA63 as eco-extracts with consistent performances across all plant traits. These findings highlighted the promising potential of integrating microalgae-based eco-friendly extracts in sustainable wheat cultivation.
Amer Chabili, Z. Hakkoum, F. Minaoui et al.· Plant Science· 1 citation
Effective control of fluid flows is critical across transportation, energy and medicine, where it can increase lift, reduce drag, enhance mixing and attenuate noise1-3. Yet fluids are notoriously difficult to control because they involve high-dimensional, nonlinear and multiscale dynamics that resist conventional approaches4-6. Reinforcement learning has driven remarkable progress in fields such as protein folding and complex games, which have shared benchmarks and standardized environments7-10. Fluid dynamics has lacked such infrastructure, so each controller is typically tuned to a single geometry and operating condition, making progress difficult to accumulate, transfer and compare11-13. Here we introduce HydroGym, a solver-independent reinforcement learning platform providing more than 60 validated, openly available flow control environments spanning from canonical laminar flows to complex turbulent flows, with systematic progression in the Reynolds number up to Re = 4 × 105, and Mach number variations in two and three dimensions. Across these environments, agents repeatedly discover robust control principles, including boundary layer manipulation, disruption of acoustic feedback and reorganization of turbulent wakes. Critically, we demonstrate a proof of concept for zero-shot transfer, in which agents that are trained exclusively in inexpensive surrogate environments are deployed to challenging real-world scenarios such as a three-dimensional wing section. We achieve a 38% reduction in local skin friction while reducing exploration costs by four orders of magnitude compared with direct on-wing optimization. As this transfer exploits shared near-wall physics, the breadth of generalization remains open, suggesting a new pathway for research toward policy generalization across computationally prohibitive simulation environments. By offering a common, extensible foundation for reproducible research, HydroGym moves flow control from isolated case studies toward a cohesive community effort.
Christian Lagemann, Sajeda Mokbel, Miro Gondrum et al.· Nature· 1 citation
ABSTRACT Microplastics (MPs) accumulation in ecosystem and human organs poses urgent environmental and health risks, yet few enzymes efficiently degrade polyethylene terephthalate (PET) under physiological conditions. We leveraged deep learning to mine unexplored sequence space across 246 million proteins, discovering AhPETase, an evolutionarily distinct hydrolase with low homology (<50% sequence identity) to known PET‐degrading enzymes. This noncanonical biocatalyst efficiently depolymerizes PET at 37°C, outperforming all typical PETases and achieving a 7.76‐fold enhancement over IsPETase, one of the most representative mesophilic PETases. Additionally, engineered variant AhPETaseM1 retains functional activity for over 20 days under physiological conditions and can degrade post‐consumer PET MPs 34‐fold faster than recombinant human‐derived enzyme MG8 (rMG8) under equal enzyme loading. Critically, it reversed PET‐induced toxicity in human lung and colon cells, establishing the first proof‐of‐concept for enzymatic MPs detoxification.
Yuxuan Wang, Shijie He, Yuheng Chang et al.· Advancement of science· 0 citations
Current evidence linking mitochondrial dysfunction, ER stress, and ER-mitochondrial crosstalk to the pathogenesis of chronic pain is summarized and their potentials as therapeutic targets are discussed.
A. Yadawa, Sufang Liu, F. Tao· Brain Science· 0 citations