Search Results (51,848)

The rapid emergence of New Psychoactive Substances (NPS), particularly pyrrolidinophenone derivatives, poses a significant challenge for public health and forensic toxicology. While their neuropharmacological profiles as dopamine transporter inhibitors are well-documented, their cardiac toxicity remains poorly understood. This study employs a multiparametric New Approach Methodology (NAM) using zebrafish embryos to integrate neurobehavioral and cardiotoxic endpoints for comparative hazard prioritization. We evaluated nine pyrrolidine-containing cathinones, including α-PVP, MDPV, α-PiHP, MDPiHP, α-D2PV, 3-Cl-, 4-Cl-, and 3,4-Cl-α-PVP, and 4-F-3-Me-α-PVP, on locomotor activity and cardiac rhythmicity using high-speed video microscopy and dynamic pixel analysis. Across the series, compounds induced concentration-dependent negative chronotropy and, in most cases, locomotor suppression. Crucially, we identified a functional dissociation between atrial rate control and atrioventricular (AV) conduction. The 3,4-dichloro substitution (3,4-Cl-α-PVP) was the most potent inducer of negative chronotropy (EC₅₀ = 52.6 μM), whereas 4-Cl-α-PVP exhibited a distinct pro-arrhythmic liability, increasing the incidence of 2:1 AV block. Time-course locomotor profiling indicated that α-PVP and chlorinated analogs were among the most potent behavioral modifiers. Using a Functional Safety Index (AV block EC₅₀/locomotor EC₅₀-like), we show that most compounds exhibit wide separations between neurobehavioral inhibition and severe conduction impairment, while specific substitutions, particularly para-chlorination, are associated with comparatively reduced functional separation between these endpoints within the assay. Overall, these data demonstrate that subtle structural changes within the pyrrolidinophenone scaffold can shape distinct arrhythmic phenotypes and functional safety profiles, supporting zebrafish-based integrated screening as a rapid platform for prioritizing emerging synthetic cathinones with comparatively higher cardiac liability within this experimental framework. Full article

Traditional drug discovery processes are typically expensive, time-consuming, and have a very high failure rate. Artificial intelligence (AI) is currently reshaping this field in unprecedented ways, promising to significantly improve the efficiency and success rate of drug development. This article systematically compares and analyzes the application of AI for two major drug types: small molecule vs. peptide drugs. It explores their applications in several key stages of drug development, including virtual screening, lead compound optimization, de novo drug design, ADMET (absorption, distribution, metabolism, excretion, and toxicity) property prediction, and chemical synthesis planning. While both drug types benefit from AI-driven approaches, fundamental differences exist in molecular representation, data availability, key challenges, and model adaptability. For small molecule drugs, AI focuses on drug efficacy, synthetic feasibility, and accurate structure–activity relationship prediction. In contrast, for peptide drugs, AI faces more unique biological challenges, such as inherent flexibility, complex biological functions, stability, and immunogenicity. Finally, this article provides a forward-looking perspective on the future of AI-driven drug discovery, highlighting the immense potential of basic models, multimodal integrated systems, and autonomous discovery platforms, which will collectively drive the next wave of precision drug development. Full article

Predicting acute toxicity across species is essential for early-stage drug safety evaluation. While recent efforts have primarily focused on improving predictive accuracy, they often fail to address two critical issues: the substantial divergence in toxicity mechanisms among different species, and the inherent noise present in experimental data. To bridge this gap, we introduce a Probabilistic Multitask Active Learning (PMAL) framework for multi-species acute toxicity prediction. Our framework integrates two key modules: a Probabilistic Multitask Learning (PML) component which jointly models the predictive distributions of multiple toxicity endpoints from a probabilistic viewpoint, and an Uncertainty-based Active Learning (UAL) component which strategically selects the most informative compounds for experimental annotation based on predictive uncertainty. Empirical evaluations demonstrate that PMAL surpasses state-of-the-art methods and is capable of providing well-calibrated uncertainty estimates for small molecules across diverse toxicity endpoints. Beyond advancing multi-species toxicity prediction, the core design principles of PMAL offer a generalizable paradigm for learning in noisy multi-task environments. Full article

Isoflurane is a widely used volatile anesthetic with context-dependent effects on neuronal survival, particularly in neurodegenerative conditions. Increasing evidence suggests that brief, sublethal stress exposure can induce adaptive cellular responses through hormesis-based preconditioning mechanisms. In this study, we investigated whether isoflurane preconditioning enhances neuronal tolerance to amyloid-β (Aβ)-induced toxicity and explored the underlying redox-dependent molecular pathways. Using HT-22 murine hippocampal neuronal cells, we demonstrate that short-term exposure to low-dose isoflurane induces a delayed neuroprotective phenotype characterized by improved cell viability, reduced apoptotic signaling, and maintained mitochondrial membrane potential following Aβ challenge. Mechanistically, isoflurane preconditioning elicited a mild and transient increase in intracellular reactive oxygen species (ROS), which is critical for the activation of the PI3K/Akt signaling pathway. Pharmacological scavenging of reactive oxygen species abolished Akt phosphorylation and reduced the protective effects of preconditioning, supporting a hormetic signaling model rather than direct antioxidant action. Following Akt activation, isoflurane preconditioning promoted the inhibitory phosphorylation of glycogen synthase kinase-3β (GSK-3β), decreased Keap1 protein levels, and facilitated nuclear translocation and transcriptional activation of nuclear factor erythroid 2-related factor 2 (Nrf2). Consequently, the expression of Nrf2-regulated antioxidant genes, including heme oxygenase-1, NAD(P)H quinone dehydrogenase 1 (NQO1), superoxide dismutase 1 and 2 (SOD1/2), and catalase, was significantly upregulated. Collectively, these findings indicate that isoflurane preconditioning confers neuroprotection through hormesis-like mild oxidative signaling and coordinated activation of endogenous antioxidant defenses rather than via direct antioxidant scavenging. Full article

Through the combined lenses of ecofeminism, masculinity studies, and critical animal studies, this article examines the cultural functions of animal metamorphosis in two Walt Disney animated feature films, Beauty and the Beast and The Princess and the Frog. It argues that animality operates as a narrative and symbolic space in which dominant gender norms and human–animal hierarchies are temporarily destabilized and reconfigured. Drawing on film analysis, this study shows how the animal figure enables the emergence of alternative masculinities—sensitive, relational, and ecologically attuned—while simultaneously exposing the structural limits of this apparent subversion. Although these films challenge toxic masculinity and propose more egalitarian interspecific relationships, their narrative resolutions ultimately reinstate anthropocentric and heteronormative frameworks by reasserting human centrality and normative romantic closure. By situating Disney’s representations within broader Western dualistic logics of domination (culture/nature, masculine/feminine, human/animal), I demonstrate that animality functions less as an autonomous mode of existence than as a transitional narrative device facilitating human self-transformation. In doing so, this article contributes to current discussions on how culturally mediated representations of animals shape human social imaginaries, ethical frameworks, and understandings of interspecies relationships. Full article

Microphysiological systems (MPS) that recapitulate human organ functions have gained attention as alternatives to animal experiments in drug discovery, regenerative medicine, and toxicity assessments. However, preserving MPS with adherent cells remains a significant challenge. In this study, we developed a supercooling preservation method that enables the low-temperature storage of human-derived adherent cells without freezing. Using human hepatic sinusoidal endothelial cells (TMNK-1), we optimized the preservation conditions by assessing the temperature, cooling and rewarming rates, and preservation solutions. Under optimized conditions (preservation at −4 °C, −0.028 °C/min cooling, and +1.0 °C/min rewarming), high cell viability and preserved morphology were maintained for up to 7 days. When these conditions were applied to both two- and three-dimensional MPS containing TMNK-1 or HepG2 cells, post-preservation viability remained high, and no cell death or cytoskeletal disruption was observed. This supercooling preservation method has the potential to serve as a practical strategy for the temporary storage of MPS. Full article

The presence of an unbalanced gut microbiome and the dysregulation of bile acid signalling are considered pivotal causes of various inflammation-based diseases. The Takeda G protein-coupled receptor (TGR5), TGR5 is a bile acid-responsive receptor that modulates inflammatory signalling pathways, making it an enticing molecular target for the discovery of novel anti-inflammatory agents. Herein, a comprehensive in silico approach was employed to identify potential TGR5 agonists from sterol-rich phytocompounds present in Triphala, a traditional polyherbal formulation. Using in silico computational methods, such as molecular docking and molecular dynamics simulations (MDS), we screened the putative agonistic potential of 10 phytocompounds obtained from Terminalia chebula, Terminalia bellirica, and Phyllanthus emblica against the crystal structure of human TGR5 (PDB ID: 7XTQ). Based on binding energy and molecular interactions, ergosterol (−12.34 ± 0.17 kcal/mol) and stigmasterol (−10.35 ± 0.04 kcal/mol) were predicted to be the top and best compounds. Furthermore, the stability of these two compounds in the docked complex was analysed using MDS for 200 ns. The mean Cα RMSD values were 0.22 ± 0.02 nm for both ergosterol- and stigmasterol-bound complexes, compared to 0.21 ± 0.02 nm for the unbound apo protein. Further, the molecular mechanics/Poisson–Boltzmann surface area (MMPBSA) analysis revealed that ergosterol exhibited binding free energy (−139.868 ± 12.318 kJ/mol) comparable to that of the co-crystallised ligand R399 −93.424 ± 8.919 kJ/mol. In silico ADMET predictions indicated acceptable drug-like properties and low toxicity for both compounds. Collectively, these computational findings suggest that ergosterol is a promising putative TGR5 agonist, warranting further experimental validation of its potential role in modulating inflammation-related pathways. Full article

Biomaterials are engineered to interact with biological systems for therapeutic or diagnostic purposes. Among them, natural biomaterials offer important advantages over many synthetic polymers, including intrinsic biocompatibility, non-toxicity and biodegradability. Silk fibroin, a fibrous protein derived mainly from Bombyx mori cocoons, has re-emerged as a particularly versatile platform because it combines favourable mechanical, thermal, electrical and optical properties with aqueous processing and tuneable degradation. In this review, we first summarise the key structural, physicochemical and functional properties of regenerated silk fibroin, including its mechanical behaviour, thermal stability, dielectric and piezoelectric response, optical transparency and low autofluorescence. We then describe how extraction and regeneration protocols are used to produce defined material formats—fibres and nanofibrous mats, porous 3D scaffolds and hydrogels, sub-micron particles, thin films and microstructured devices—and outline major functionalisation strategies, ranging from physical blending and encapsulation to covalent chemistry, genetic engineering of recombinant silk variants, and enzyme-mediated conjugation approaches. Building on this foundation, we critically examine biomedical applications of silk fibroin with a particular emphasis on (i) hybrid silk–fluorophore systems for bioimaging and biosensing (nanodiamonds, quantum dots and organic dyes), (ii) optical fibre, wearable and edible sensors for health and food monitoring, (iii) wound dressings and wound-sensing platforms, and (iv) tissue engineering scaffolds and drug-delivery depots. Finally, we discuss current limitations, including process variability, the trade-offs introduced by blending and cross-linking, and the challenges posed by non-degradable inorganic fillers and clinical translation. Together, these perspectives highlight silk fibroin’s potential and constraints as a multifunctional biomaterial for next-generation biomedical devices and theranostic systems. Full article

Recent advances in enone chemistry have enabled the development of structurally optimized derivatives with improved anticancer selectivity. In this study, the cytotoxic activity and underlying mechanisms of sodium salts of four α,β-unsaturated enones (ES1–ES4), synthesized from vanillin-based scaffolds, were evaluated in human colorectal carcinoma (HCT-116), cervical adenocarcinoma (HeLa), and normal lung fibroblast (MRC-5) cell lines. All compounds exhibited concentration- and time-dependent cytotoxicity, with ES2 showing the highest potency (IC₅₀ = 14.25 μM in HCT-116 and 18.12 μM in HeLa at 72 h) and minimal toxicity toward MRC-5 cells (IC₅₀ > 90 μM). Although cisplatin demonstrated greater overall cytotoxicity, the enone salts displayed significantly higher selectivity indices, indicating a more favorable therapeutic window. Phase-contrast microscopy revealed characteristic morphological features of apoptosis, including cell rounding and membrane blebbing. Mechanistic investigations confirmed mitochondrial-mediated apoptosis, evidenced by increased early and late apoptotic populations, Bax upregulation, Bcl-2 downregulation, and caspase-3 activation. JC-10 staining demonstrated mitochondrial membrane depolarization accompanied by cytochrome c release. In addition, cell cycle analysis revealed pronounced G2/M phase arrest, particularly in HCT-116 cells. Collectively, these findings indicate that vanillin-derived enone sodium salts exert selective anticancer effects through mitochondrial apoptosis and cell cycle disruption, supporting their potential as low-toxicity anticancer candidates. Full article

Heterogeneous catalytic degradation of organic dyes can effectively achieve the goals of reducing the chromaticity of aqueous solutions and completely removing pollutants. We here present a carbon-nitride-wrapped zero-valent Fe catalyst (CNFe), which can directly degrade Acid Red G (ARG) dye without additional oxidants. CNFe exhibited a nanotube-like morphology, wherein the zero-valent Fe (Fe⁰) was wrapped by a carbon layer to effectively enhance its dispersibility and prevent its oxidative deactivation. Meanwhile, the large specific surface area (169.19 m²/g), along with abundant active sites such as Fe and O, endowed CNFe with excellent activity. Under strongly acidic conditions, even in the presence of various anions, CNFe can still remove approximately 91.6% of ARG within 30 min. In a 10 h continuous flow column experiment, the removal efficiency of ARG consistently exceeded 67.6%, indicating that CNFe had great potential for treating actual dyeing wastewater. Catalytic mechanism studies showed that, under neutral conditions, CNFe mainly removed ARG through adsorption, whereas, under acidic conditions, the Fe⁰ in CNFe can not only activate molecular oxygen to generate HO· for the oxidative degradation of ARG but also remove ARG via reduction. Furthermore, CNFe can adsorb ARG through hydrogen bonding of surface hydroxyl groups. The developmental toxicity of the generated intermediates was effectively reduced, demonstrating lower environmental risks. Therefore, this study provided a simple, high-efficiency, and economical method for removing dyes from water, which can offer guidance for the treatment of practical dye wastewater. Full article

HIV latency, driven by a complex interplay of host factors, remains a key barrier to viral clearance. Current latency-reversing agents (LRAs) demonstrate limited efficacy and specificity, and none have been approved for clinical use. Although natural products have shown promise as LRAs, the therapeutic potential of fungal metabolites remains underexplored. Candida albicans, a prevalent human commensal and opportunistic pathogen, produces diverse secondary metabolites that can influence host pathways, affecting latency dynamics. This study aimed to investigate the latency-modulating potential of secondary metabolites of C. albicans using an integrative network pharmacology and computational pipeline. C. albicans secondary metabolites were retrieved from the literature, screened for drug-likeness, and mapped to human targets and biological pathways annotated in HIV latency. Key metabolites, hub genes, and pathways were systematically characterized through network and computational analyses. Six drug-like candidates, identified from 185 absorption, distribution, metabolism, excretion, and toxicity (ADMET)-screened metabolites, collectively mapped to 369 human genes with a 6.5% overlap in HIV latency (176 shared and 20 hub genes). These overlapping genes were significantly enriched for signal transduction, membrane localization, and adaptive responses to chemical stimuli. Kyoto encyclopedia of genes and genomes (KEGG) enrichment revealed oncogenic diseases (non-small cell lung, pancreatic, and prostate cancers) and latency-associated cascades, including PD-L1/PD-1, HIF-1, Ras, PI3K-Akt, calcium, and cAMP signaling. Six hub targets (MAPK1, PIK3CA, MAPK3, EGFR, MTOR, and AKT1) were consistently annotated within the top 30 KEGG pathways and displayed strong binding affinities for MET 15 and MET 119. Molecular dynamics (MD) simulations confirmed favorable binding free energies (BFEs) and stable conformational dynamics for the top-ranked metabolite MET 15. C. albicans secondary metabolites preferentially target oncogenic signaling networks central to HIV latency maintenance, notably PI3K/AKT/MTOR and MAPK/ERK, which regulate cell survival, metabolic homeostasis, and viral transcriptional repression. MET 15 is a top-ranked candidate metabolite for HIV latency-reversing therapeutics and warrants experimental validation in established latency models. Full article

Purpose: The objective of this study was to engineer and optimize a mucoadhesive, positively charged stearylamine-enriched liposomal platform, termed Aminosomes, to circumvent the biophysical barriers limiting the ocular bioavailability of Brimonidine Tartrate (BT), an alpha-2 adrenergic receptor agonist for glaucoma management. Methods: Aminosomes were synthesized using a tailored ethanol injection technique and optimized via a 3² × 2¹ full factorial design. Molecular integrity and crystallinity were assessed using Fourier-transform infrared spectroscopy (FTIR) and X-ray diffraction (XRD). The mucoadhesive potential was validated through a mucin interaction assay based on zeta potential shifts. In vitro release kinetics were evaluated using the dialysis membrane diffusion technique, while the therapeutic potential and ocular safety were validated through in vivo pharmacodynamic profiling of intraocular pressure (IOP) reduction, alongside comprehensive biocompatibility assessments via Draize irritancy protocol and histopathological examination. Results: The optimized Aminosomes exhibited nanometric dimensions, monodisperse size distribution, robust positive surface charge, and superior drug loading. FTIR and XRD analyses confirmed the chemical compatibility of the formulation components, as well as the successful encapsulation of BT and its transition to an amorphous state within the lipidic matrix. The mucoadhesion test demonstrated a high binding affinity for mucin. The in vitro release profile demonstrated a sustained-release pattern (78.8% over 12 h). Non-compartmental pharmacodynamic analysis of IOP-reduction data revealed a 2.8-fold increase in AUC_0–24h, 3.5-fold extension in t_1/2, and 5.2-fold prolongation in mean residence time (MRT) relative to the standard solution. Conclusions: The optimized Aminosomes demonstrated superior mucoadhesive anchoring, enhanced and sustained therapeutic flux without inducing ocular toxicity, offering a robust strategy for enhancing the pharmacodynamics of BT. Full article

Introduction: Chemotherapy-induced peripheral neuropathy (CIPN) is a dose-limiting toxicity affecting many patients treated with neurotoxic agents, leading to persistent pain and impaired quality of life. Methods: In our trial, Trial ID: NCT06091553, 160 patients met the eligibility criteria and were randomized into three groups. First, Arm D (duloxetine). Second, Arm (D + A): duloxetine is augmented with amitriptyline. Third, Arm (D + G): duloxetine is augmented with gabapentin. The primary outcome is the difference in Pain Inventory—Short Form (BPI-SF) measured during the final follow-up week (Week 4 and Week 8) between the treatments. Results: All groups showed significant within-group reductions in pain scores from baseline to Weeks 4 and 8. Meanwhile, all groups exhibited numerical improvements for the average pain by Week 8. No statistically significant differences were found between groups at either Week 4 (p = 0.161) or Week 8 (p = 0.868). Similarly, the proportion of responders was comparable across treatment arms at both time points, with 74.5–82.8% achieving a clinically meaningful reduction in pain by Week 8 (p = 0.566). Conclusions: These findings support duloxetine as an evidence-based first-line therapy for painful CIPN, while combination regimens may be reserved for individualized use in patients with inadequate response, pending confirmation in larger multicenter trials. Full article

The use of agro-industrial waste to obtain biochar has emerged as an environmentally friendly, low-cost, effective, profitable, and sustainable strategy for the removal of aflatoxin B1 (AFB1), a highly toxic and carcinogenic mycotoxin of importance in poultry production systems because it can cause serious economic losses, affect hatchability, egg production, and the growth of birds, and can cause their death. In this sense, the objective of the present study was to obtain a sustainable and low-cost biochar derived from agro-industrial coconut shell waste (BCS) and evaluate its AFB1 adsorption capacity using a conventional method based on buffer solutions and an in vitro avian digestion model that simulates the conditions of the gastrointestinal tract of the broiler chicken. The results showed that the adsorption capacity of BCS on AFB1 (250 ng/mL) at both pH 5.0 and 1.2 was close to 100%, while at pH 6.8, the adsorption of AFB1 was 86.24%. However, in the in vitro avian digestibility model, the adsorption capacity of BSC on AFB1 was 32.96%, thus highlighting the importance of considering factors that can affect the adsorption capacity of materials before in vivo studies, as this can lead to overestimations of results and, therefore, ineffective treatments or unexpected results in animals. Full article

Spent coffee grounds (SCG) are the main by-product generated by the coffee industry, with an estimated annual production of approximately 7 million tons. Although commonly treated as waste, SCG constitute a valuable source of phenolic compounds, particularly chlorogenic acid, which has been associated with antimicrobial, antioxidant, antimutagenic, anti-inflammatory, and cardioprotective properties. These bioactive compounds are of interest as functional ingredients for food, cosmetic, and pharmaceutical applications. However, their recovery by conventional extraction methods often depends on volatile, flammable, or toxic organic solvents. In this context, hydrophobic eutectic solvents (HES) have emerged as a greener and more sustainable alternative. In the present study, phenolic compounds were extracted from SCG using HES combined with microwave-assisted extraction (MAE). Sixteen terpene-based HES formulated with fatty acids and fatty alcohols were evaluated. Among them, camphor:dodecanoic acid and borneol:dodecanoic acid gave the highest total phenolic contents. Process optimization showed that the borneol:dodecanoic acid system, under 12% water content, a 1:10 solid-to-liquid ratio, 57 °C, and 120 min, reached 80.94 ± 4.44 mg GAE g⁻¹ by MAE. HPLC analysis revealed chlorogenic, caffeic, and ferulic acids as the main phenolic compounds, while the extracts also displayed high antioxidant activity. Overall, these findings demonstrate that HES-MAE is a promising and sustainable strategy for the recovery of value-added phenolics from SCG. Full article