Search Results (321)

This study explores how aristolochic acid I (AAI) drives hepatocellular carcinoma (HCC). We first employ network toxicology and machine learning to map the key molecular target genes. Next, our research utilizes molecular docking to evaluate how AAI binds to these targets, and finally confirms the stability and dynamics of the resulting complexes through molecular dynamics simulations. We identified 193 overlapping target genes between AAI and HCC through databases such as PubChem, OMIM, and ChEMBL. Machine learning algorithms (SVM-RFE, random forest, and LASSO regression) were employed to screen 11 core genes. LASSO serves as a rapid dimension-reduction tool, SVM-RFE recursively eliminates the features with the smallest weights, and Random Forest achieves ensemble learning through decision trees. Protein–protein interaction networks were constructed using Cytoscape 3.9.1, and key genes were validated through GO and KEGG enrichment analyses, an immune infiltration analysis, a drug sensitivity analysis, and a survival analysis. Molecular-docking experiments showed that AAI binds to each of the core targets with a binding affinity stronger than −5 kcal mol⁻¹, and subsequent molecular dynamics simulations verified that these complexes remain stable over time. This study determined the potential molecular mechanisms underlying AAI-induced HCC and identified key genes (CYP1A2, ESR1, and AURKA) as potential therapeutic targets, providing valuable insights for developing targeted strategies to mitigate the health risks associated with AAI exposure. Full article

The use of opioids for cancer-related pain is essential but poses significant challenges due to the risk of misuse and the development of opioid use disorder (OUD). This review takes a multidisciplinary perspective based on the current scientific literature to analyze the pharmacological mechanisms, classification, and therapeutic roles of opioids in oncology. Key risk factors for opioid misuse—including psychiatric comorbidities, prior substance use, and insufficient clinical monitoring—are discussed in conjunction with validated tools for pain assessment and international guidelines. The review emphasizes the importance of integrating toxicological, pharmacological, physiological, and public health perspectives to promote rational opioid use. Pharmacogenetic variability is explored as a determinant of treatment response and addiction risk, underscoring the value of personalized medicine. Evidence-based strategies such as early screening, psychosocial interventions, and the use of buprenorphine-naloxone are presented as effective measures for managing OUD in cancer patients. Ultimately, this work advocates for safe, patient-centered opioid prescribing practices that ensure effective pain relief without compromising safety or quality of life. Full article

Euphorbia hirta L. is traditionally used to treat tumors and has demonstrated anticancer effects. This study evaluated the phytochemical composition, toxicity, and antitumor activity of saline extract (SE) from E. hirta leaves in mice. Phytochemical analysis included thin layer chromatography, high-performance liquid chromatography, and quantification of phenols, flavonoids, and proteins. Acute toxicity (2000 mg/kg) assessed mortality, hematological, biochemical, histological parameters, water/feed intake, and body weight. Genotoxicity was evaluated via comet and micronucleus assays. Antitumor activity was tested in vitro and in vivo on sarcoma 180. SE contained 107.3 mg GAE/g phenolics and 22.9 mg QE/g flavonoids; the presence of gallic and ellagic acids was detected. Protein concentration was 12.16 mg/mL with lectin activity present. No mortality, organ damage, or genotoxic effects occurred in toxicity tests. SE demonstrated in vitro cytotoxicity against sarcoma cells (IC₅₀: 10 µg/mL). In vivo, SE (50–200 mg/kg) reduced tumor weight by 70.2–72.3%. SE modulated IL-2, IL-4, IL-6, IL-17, IFN-γ, and TNF-α in tumor environment. Tumors showed inflammatory infiltrate, necrosis, and fibrosis after treatment. These findings position the extract as a promising candidate for further development as a safe, plant-based antitumor agent. Full article

Background/Objectives: Substance use disorders, particularly opioid addiction, continue to pose a major global health and toxicological challenge. Morphine dependence represents a significant problem in both clinical practice and preclinical research, particularly in modeling the pharmacodynamics of withdrawal. Rodent models remain indispensable for investigating the neurotoxicological effects of chronic opioid exposure and withdrawal. However, conventional behavioral assessments rely on manual observation, limiting objectivity, reproducibility, and scalability—critical constraints in modern drug toxicity evaluation. This study introduces MWB_Analyzer, an automated and high-throughput system designed to quantitatively and objectively assess morphine withdrawal behaviors in rats. The goal is to enhance toxicological assessments of CNS-active substances through robust, scalable behavioral phenotyping. Methods: MWB_Analyzer integrates optimized multi-angle video capture, real-time signal processing, and machine learning-driven behavioral classification. An improved YOLO-based architecture was developed for the accurate detection and categorization of withdrawal-associated behaviors in video frames, while a parallel pipeline processed audio signals. The system incorporates behavior-specific duration thresholds to isolate pharmacologically and toxicologically relevant behavioral events. Experimental animals were assigned to high-dose, low-dose, and control groups. Withdrawal was induced and monitored under standardized toxicological protocols. Results: MWB_Analyzer achieved over 95% reduction in redundant frame processing, markedly improving computational efficiency. It demonstrated high classification accuracy: >94% for video-based behaviors (93% on edge devices) and >92% for audio-based events. The use of behavioral thresholds enabled sensitive differentiation between dosage groups, revealing clear dose–response relationships and supporting its application in neuropharmacological and neurotoxicological profiling. Conclusions: MWB_Analyzer offers a robust, reproducible, and objective platform for the automated evaluation of opioid withdrawal syndromes in rodent models. It enhances throughput, precision, and standardization in addiction research. Importantly, this tool supports toxicological investigations of CNS drug effects, preclinical pharmacokinetic and pharmacodynamic evaluations, drug safety profiling, and regulatory assessment of novel opioid and CNS-active therapeutics. Full article

Medetomidine, a veterinary α2-adrenergic agonist, has recently emerged as an adulterant in the non-medical opioid supply, yet human exposure has remained poorly characterized. We conducted a pragmatic retrospective cohort analysis utilizing chart review and liquid chromatography–tandem mass spectrometry (LC-MS/MS) toxicology testing on available urine samples from patients presenting to two hospitals in Philadelphia, PA, who fit two clinical phenotypes, intoxication or withdrawal. Samples also underwent glucuronidase pre-treatment to assess impact on the yield of medetomidine and xylazine metabolite detection. Testing identified universal exposure to medetomidine (58/58 samples) via the 3-hydroxy-medetomidine (3-OH-M) metabolite, post glucuronidase treatment and variable xylazine exposure (40/58 samples). Importantly, 32% of medetomidine exposures would have been missed without enzymatic pre-treatment. Patients exhibited two distinct clinical phenotypes: intoxication, characterized primarily by sedation; bradycardia; and often hypotension, and withdrawal, presenting with life-threatening tachycardia; hypertension and often encephalopathy. Notably, clinical phenotype correlated with urinary concentrations of 3-OH-M but not xylazine. These findings underscore the critical need for heightened clinical awareness and need for contemporaneous toxicologic screening mechanisms for medetomidine exposure, emphasizing its distinct clinical presentations and the potential public health implications posed by its widespread adulteration in illicit opioids. Full article

Nanodrugs hold great promise for targeted therapies, but their potential for cytotoxicity remains a major area of concern, threatening both patient safety and clinical translation. In this systematic review, we conducted a systematic investigation of nanotoxicity studies—identified through an AI-assisted screening procedure using Scopus, PubMed, and Elicit AI—to establish the molecular determinants of nanodrug-induced cytotoxicity. Our findings reveal three dominant and linked mechanisms that consistently act in a range of nanomaterials: oxidative stress, inflammatory signaling, and lysosomal disruption. Key nanomaterial properties like chemical structure, size, shape, surface charge, tendency to aggregate, and biocorona formation control these pathways, modulating cellular uptake, reactive oxygen species generation, cytokine release, and subcellular injury. Notably, the most frequent mechanism was oxidative stress, which often initiated downstream inflammatory and apoptotic signaling. By linking these toxicity pathways with particular nanoparticle characteristics, our review presents necessary guidelines for safer, more biocompatible nanodrug formulation design. This extensive framework acknowledges the imperative necessity for mechanistic toxicity assessment in nanopharmaceutical design and underscores the strength of AI tools in driving systematic toxicology studies. Full article

Background: Polysubstance use, particularly combining opioids with stimulants such as cocaine, is rising among individuals with substance use disorders. This practice aims to balance cocaine’s stimulant effects with opioids’ sedative effect, potentially decreasing adverse outcomes. We hypothesized that concurrent exposure to cocaine and opioids would reduce the risk of neonatal opioid withdrawal syndrome (NOWS) compared to opioid use alone. Methods: This analysis draws from an ongoing prospective study of maternal substance use (SUD) at Regional One Health’s perinatal center in Memphis, TN, and included mothers and their infants born between 2018 and 2022. Maternal SUD was identified via screening questionnaires, urine toxicology, or umbilical cord tissue analysis. Participants were grouped into using (a) opioids with cocaine (OwC) and (b) opioids without cocaine (OwoC). Univariate and regression analyses were conducted to assess the risk of NOWS. Results: A total of 353 infants were born to 342 mothers, with 31% (110/353) of the infants born to women who used cocaine along with opioids. While maternal demographics were similar, the OwC group had significantly lower rates of prenatal care, chronic pain history, and MOUD enrollment (p = 0.03). Infants in the OwC group had significantly higher rates of NOWS (p < 0.01), longer hospital stays (p < 0.01), and 6.5 times greater odds of developing NOWS (p < 0.001). NOWS was associated with an average 15-day increase in the length of stay for term infants (95% CI: 11.2, 18.8; p < 0.001). Conclusions: Contrary to our hypothesis, our study highlights the significant impact of maternal cocaine use on the increased likelihood of NOWS and extended hospital stays for affected infants. Full article

Lippia multiflora Moldenke is widely used in Angola, on the African continent, and beyond for the treatment of many health conditions such as hypertension, enteritis, colds, gastrointestinal disturbances, stomachaches, jaundice, coughs, fevers, nausea, bronchial inflammation, conjunctivitis, malaria, and venereal diseases. However, there is limited literature about the active compounds linked with the reported biological activities. This study aims to assess the chemical profiles, antioxidant properties, and the cytotoxicity effects of the roots, stem bark, and leaves of L. multiflora. Chemical characterization of the crude extracts was assessed through quantification of total phenolic and flavonoid contents followed by Q exactive plus orbitrap™ ultra-high-performance liquid chromatography-mass spectrometer (UHPLC-MS) screening. The correlation between the extracts and the correlation between the compounds were studied using the multivariate analysis. Principal component analysis (PCA) loading scores and principal component analysis (PCA) biplots and correlation plots were used to connect specific compounds with observed biological activities. The antioxidant activities of the crude extracts were carried out in vitro using DPPH (2,2-diphenyl-1-picrylhydrazyl) free radical scavenging and reducing power assays, while the in vitro toxicology of the crude extracts was evaluated using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. A total of twenty constituents were characterized and identified using the UHPLC–Q/Orbitrap/MS. The methanol leaf extract showed the highest antioxidant activity in the DPPH free radical scavenging activity (IC₅₀ = 0.559 ± 0.269 μg/mL); however, the stem bark extract had the highest reducing power (IC_0.5 = 0.029 ± 0.026 μg/mL). High phenolic and flavonoid content was found in the dichloromethane leaf extract (32.100 ± 1.780 mg GAE/g) and stem bark extract (624.153 ± 29.442 mg QE/g), respectively. The results show the stem bark, methanol leaf, and dichloromethane leaf extracts were well-tolerated by the Vero cell line at concentrations up to 50 µg/mL. However, at 100 µg/mL onward, some toxicity was observed in the root, methanol leaf, and dichloromethane leaf extracts. The UHPLC–Q/Orbitrap/MS profiles showed the presence of terpenoids (n = 5), flavonoids (n = 5), phenols (n = 4), alkaloids (n = 3), coumarins (n = 1), fatty acids (n = 1), and organic acids (n = 1). According to several studies, these secondary metabolites have been reported and proven to be the most abundant for antioxidant potential. The identified flavonoids (catechin, quercitrin, and (−)-epigallocatechin) and phenolic compound (6-gingerol) can significantly contribute to the antioxidant properties of different plant parts of L. multiflora. The research findings obtained in this study provide a complete phytochemical profile of various parts of L. multiflora that are responsible for the antioxidant activity using UHPLC–Q/Orbitrap/MS analysis. Furthermore, the results obtained in this study contribute to the scientific information or data on the therapeutic properties of Lippia multiflora and provide a basis for further assessment of its potential as a natural remedy. Full article

Root-knot nematodes, Meloidogyne spp., are widespread phytoparasites that cause a significant reduction in the yield of tomato Solanum lycopersicum. In the Russian Federation, where the use of chemical nematicides is limited due to environmental and toxicological risks, the cultivation of resistant varieties and hybrids remains the most effective and environmentally safe method to control Meloidogyne. In the course of this study, the resistance screening of 20 tomato varieties/hybrids and 21 mutant lines from the collection of the FSBSI FRCBPP to M. hapla was carried out using a comprehensive approach that included morphological and biochemical analysis methods. Resistance was assessed by calculating the gall formation index, the degree of root system damage, and biochemical parameters of fruits—vitamin C content and titratable acidity. In addition, molecular screening was carried out using the SCAR marker Mi23 to identify the Mi-1.2 gene, known as a key factor in resistance to a number of Meloidogyne spp. Although Mi-1.2 is not typically associated with resistance to M. hapla, all genotypes carrying this gene showed phenotypic resistance. This unexpected correlation suggests the possible involvement of Mi-associated or parallel mechanisms and highlights the need for further investigation into noncanonical resistance pathways. It was found that when susceptible genotypes were infected with M. hapla, there was a tendency for the vitamin C content to decrease, while resistant lines retained values close to the control. The presence of the Mi-1.2 gene was confirmed in 9.5% of samples. However, the phenotypic resistance of some lines, such as Volgogradets, which do not contain a marker for the Mi-1.2 gene, indicates a polygenic nature of resistance, alternative genetic mechanisms, or the possible influence of epigenetic mechanisms. The obtained data highlight the potential of using the identified resistant genotypes in breeding programs and the need for further studies of the molecular mechanisms of resistance, including the search for new markers specific to M. hapla, to develop effective strategies for tomato protection in sustainable agriculture. Full article

Per- and polyfluoroalkyl substances (PFASs) are synthetic chemicals extensively used in various industries due to their unique physicochemical properties. Their persistence in the environment and potential for bioaccumulation have raised significant health concerns. This review aims to elucidate the sources, exposure pathways, toxicological effects, and regulatory measures related to PFASs, with a particular focus on pediatric populations and medical applications. A comprehensive narrative review was conducted using PubMed, Scopus, and Web of Science to identify peer-reviewed literature published between 2000 and 2025. The search focused on PFAS use in healthcare, environmental contamination, exposure pathways, health effects, and regulatory actions. Relevant studies, reports, and policy documents were screened and thematically synthesized by the authors to evaluate clinical and environmental risks, particularly in pediatric populations. PFAS exposure is linked to various adverse health effects, including immunotoxicity, endocrine disruption, metabolic disorders, and carcinogenicity. Children are particularly vulnerable due to developmental susceptibilities and exposure through medical devices and environmental sources. Regulatory measures are evolving, but gaps remain, especially concerning medical device applications. There is an urgent need for comprehensive strategies to monitor and mitigate PFAS exposure, particularly in vulnerable populations. Enhanced regulatory frameworks, safer alternatives in medical devices, and public health interventions are essential to address the challenges posed by PFASs. Full article

Background: Prostate cancer is the most common cancer in men, especially after the age of 50. It is a malignant disease that is increasing due to the increased life expectancy of the world population. Its development and progression are dependent on androgenic stimulation. Objectives: This study aimed to identify potential inhibitors with anti-prostate cancer activity through the application of chemoinformatics tools, exploring the Princeton (~1.2 million compounds) and Zinc Drug (~175 million compounds) databases. Methods: The methodology used several computational techniques, such as ROCS (Rapid Chemical Structure Superposition) and EON (Electrostatic Potential Screening), predictions of pharmacokinetic and toxicological properties, molecular docking, synthetic accessibility, biological activity, and molecular dynamics. Results: At the end of all these virtual screening steps, the study resulted in four promising potential candidates for the treatment of prostate cancer: the molecules ZINC34176694, ZINC03876158, ZINC04097308, and ZINC03977981, which exhibited all the desirable pharmacokinetic parameters (ADME/Tox) for a potential drug. Conclusions: Docking and molecular dynamics studies demonstrate stability and interaction with the androgen receptor of the selected compounds, showing them to be promising candidates for the development of new drugs. Full article

Nitazenes represent an emerging class of new synthetic opioids characterized by a high-potency μ-opioid receptor (MOR) agonist activity. Background: We report two 20-year-old males who presented with severe neurorespiratory depression with typical opioid syndrome, but no opioid identification based on routine blood and urine screening tests. The first patient recovered with supportive care, mechanical ventilation, and naloxone infusion, whereas the second patient developed post-anoxic cardiac arrest and died from brain death. Methods: A complementary comprehensive toxicological screening using liquid chromatography coupled with high-resolution mass spectrometry (LC-HRMS) was performed, and data were processed using a dedicated molecular network strategy to profile the metabolites. Results: Protonitazene and protonitazepyne, two nitazenes differing in their ethylamine moieties (i.e., a diethyl versus a pyrrolidine substitution, respectively), were identified. We found an extensive metabolism of protonitazene, leading to the identification of multiple phase I (resulting from hydroxylation, N-desethylation, and O-despropylation) and phase II (resulting from glucuronidation) metabolites. By contrast, protonitazepyne metabolism appeared limited, with one metabolite annotated confidently, protonitazepyne acid, which resulted from the oxidative pyrrolidine ring cleavage. Concusions: To conclude, nitazene detection is highly challenging due to its extensive structural and metabolic diversity. Our findings highlight the contribution of the untargeted LC-HRMS screening approach and suggest that diagnostic product ions can serve as robust markers for nitazene identification. Full article

Endometrial organoids (EOs) have emerged as a powerful three-dimensional (3D) model for studying the human endometrium, offering new insights into infertility and reproductive disorders. These self-organizing miniature structures closely mimic the cellular composition, hormonal responsiveness, and functional characteristics of the endometrium, making them valuable preclinical tools for investigating implantation failure, endometrial receptivity, and disease pathophysiology. This review explores the role of EOs in reproductive medicine, with a focus on their applications in infertility research, environmental toxicology, and regenerative therapies. Traditional 2D cell cultures fail to capture the complexity of these physiological and pathological interactions, whereas organoids provide a physiologically relevant system for studying implantation mechanisms. Additionally, co-culture models incorporating stromal and immune cells have further enhanced our understanding of the maternal–fetal interface. Beyond modeling infertility, EOs hold significant promise for therapeutic applications. Advances in organoid transplantation have demonstrated potential for treating endometrial dysfunction-related infertility, including conditions such as Asherman’s syndrome and thin endometrium. Moreover, these models serve as a platform for drug screening and biomarker discovery, paving the way for personalized reproductive medicine. Despite their transformative potential, limitations remain, including the need for improved extracellular matrices, vascularization, and immune system integration. This review emphasizes the significant contributions of EOs to the field of infertility treatment and reproductive biology by examining recent advancements and emerging research. The continued refinement of these models would offer a paradigm for improving assisted reproductive technologies (ARTs) and regenerative medicine outcomes, offering new hope for individuals facing infertility challenges. Full article

Cytochrome P450 (CYP) enzymes are membrane-bound hemoproteins crucial for drug and xenobiotic metabolism. While more than 50 CYPs have been identified in humans, the isoforms from CYP1, 2, and 3 families contribute to the metabolism of about 80% of clinically approved drugs. To evaluate the effects of environmental chemicals on the activities of these important CYP enzyme families, we screened the Tox21 10K compound library to identify chemicals that inhibit CYP1A2, 2C9, 2C19, 2D6, and 3A4 enzymes. The data obtained from these five screenings were analyzed to reveal the structural classes responsible for inhibiting multiple and/or selective CYPs. Some known structural compound classes exhibiting pan-CYP inhibition, such as azole fungicides, along with established clinical inhibitors of CYPs, including erythromycin and verapamil inhibiting CYP3A4 and paroxetine and terbinafine inhibiting CYP2D6, were all confirmed in the current study. In addition, some selective CYP inhibitors, previously unknown but with potent activity (IC₅₀ values < 1 µM), were identified. Examples included yohimbine, an indole alkaloid, and loteprednol, a corticosteroid, which showed inhibitory activity in CYP2D6 and 3A4 assays, respectively. These findings suggest that assessment of a candidate compound’s impact on CYP function may allow pre-emptive mitigation of potential adverse reactions and toxicity during drug development or toxicological characterization of environmental chemicals. Full article

Background/Objectives: Perioperative strokes are a rare but recognized complication of cerebral aneurysm surgeries, often influenced by patient-specific factors. Amphetamine abuse, known for its vasospastic effects, is an underexplored risk factor in the neurosurgical setting. This report highlights the clinical and perioperative challenges associated with acute undisclosed amphetamine abuse in a patient undergoing elective clipping of an unruptured middle cerebral artery (MCA) aneurysm. Methods: A 46-year-old male presented with a 3 mm broad-based unruptured aneurysm in the proximal M1 segment of the right MCA. The patient reported a history of illicit drug use, including intravenous consumption. Upon further questioning, he admitted to intermittent use of amphetamines, although he denied any recent use. Elective aneurysm clipping via a transsylvian approach was performed after multidisciplinary consensus. Postoperatively, the patient developed anisocoria, prompting an emergency CT with perfusion and angiography, showing significant findings. Further imaging revealed a bilateral superior cerebellar artery territory infarction. Given the patient’s medical history, a toxicology screening later confirmed recent amphetamine use. Conclusions: This case highlights the need for preoperative evaluation, including routine toxicology screening, in patients with a history of substance abuse. Amphetamine use may present perioperative challenges and increase the risk of complications like vasospasm and stroke. Full article