Search Results (2,325)

Pesticide exposure is a plausible but incompletely characterized contributor to kidney injury. This review integrates current clinical, epidemiologic, experimental, and mechanistic evidence on pesticide-related nephrotoxicity, focusing on glyphosate-based herbicides, paraquat, organophosphate insecticides, and atrazine. A structured search of PubMed and Web of Science identified English-language studies published between January 2015 and February 2026. Of 635 records screened, 61 human studies were retained for full-text evaluation, and relevant animal, in vitro, and regulatory sources were additionally reviewed for mechanistic interpretation. Across pesticide classes, the proximal tubule emerged as the most consistent renal target, although downstream pathways differed, including oxidative stress, mitochondrial dysfunction, transporter disruption, endoplasmic reticulum stress, inflammation, apoptosis, ferroptotic signaling, and fibrotic remodeling. Human evidence was strongest for acute kidney injury following severe poisoning, whereas associations between chronic occupational or environmental exposure and chronic kidney disease or end-stage renal disease were more limited and heterogeneous. Biomarkers including kidney injury molecule-1 (KIM-1), neutrophil gelatinase-associated lipocalin (NGAL), β₂-microglobulin, cystatin C, interleukin-18 (IL-18), cytochrome c, and 8-hydroxy-2′-deoxyguanosine (8-OHdG) often detected early tubular stress before abnormalities appeared in conventional renal indices. Overall, pesticide nephrotoxicity is best conceptualized as a spectrum of mechanism-specific tubular injury signatures, supporting a shift toward biomarker-informed early detection, improved hazard identification, and more mechanistically grounded risk assessment. Full article

Mediterranean meadows of Posidonia oceanica are chronically exposed to complex mixtures of environmental contaminants, including metals and trace elements derived from coastal urbanization, maritime traffic, and industrial activities. This study aimed to assess metal-related toxicity in P. oceanica by integrating multi-element burden analysis with a panel of oxidative stress biomarkers. Concentrations of a wide suite of elements were quantified in samples of internal (juvenile), intermediate, and external (adult) leaves, reflecting the ontogenetic structure of the plant. Oxidative responses were evaluated using five biomarkers [i.e., hydrogen peroxide (H₂O₂), lipid peroxidation (TBARS), superoxide dismutase (SOD), glutathione S-transferase (GST), and catalase (CAT)] measured on each leaf compartment. Biomarker data were standardized and integrated into a merged Stress Index summarizing overall physiological toxicity. Associations between individual elements, the sum of all measured elements (ΣallElements), the Stress Index, and single biomarkers were explored using Pearson correlation analysis. Juvenile leaves exhibited the highest Stress Index values, elevated H₂O₂ and TBARS, and marked activation of SOD and GST, indicating early oxidative toxicity. Intermediate leaves showed a trend toward increased CAT activity, not reaching statistical significance, along with minimal damage, suggesting effective detoxification, whereas adult leaves accumulated higher levels of Fe, Ni, and Pb, but displayed moderate stress responses. Overall, leaf-class structure strongly modulated both exposure and toxicological response. The integration of ΣAllElements with multi-biomarker indices provides a robust framework for diagnosing metal-related toxicity in P. oceanica under realistic multi-element exposure scenarios. Full article

Chlorpyrifos (CP) remains one of the most globally pervasive organophosphorus pesticides, and its toxicological profile continues to raise substantial public health and environmental concerns. While traditionally characterized by its potent acetylcholinesterase-inhibitory properties, accumulating evidence now shows that chlorpyrifos and its bioactive metabolite, chlorpyrifos-oxon (CPO), exert far broader toxic effects, including the induction of oxidative stress, enhancement of neuroinflammatory processes, and the triggering of persistent epigenetic alterations. In this review, we synthesize current findings to highlight the expanding spectrum of CP-induced toxicity, while also providing a multidisciplinary overview of chlorpyrifos characteristics, including its environmental fate, metabolism, and transformation pathways. The analysis encompasses not only classical neurotoxicity but also disruptions in neurodevelopment, endocrine signaling, gut microbiota composition, hepatic function, musculoskeletal integrity and carcinogenic pathways. By synthesizing results across human, animal, and environmental studies, this review offers a comprehensive overview of CP’s multidimensional toxicity and highlights the urgent need for improved biomonitoring, regulatory harmonization, and global strategies to reduce exposure. Full article

5-Fluorouracil (5-FU) is a cornerstone chemotherapeutic agent that is extensively utilized in the management of malignancies; however, its clinical utility is constrained by its narrow therapeutic index and dose-limiting toxicities. The study aimed to study the hepato-nephroprotective effects of epigallocatechin gallate (EGCG) and EGCG mediated selenium nanoparticles and their effect in mitigating the toxicity induced by 5-FU. EGCG-functionalized selenium nanoparticles (EGCG-SeNPs) were produced by mixing sodium selenite, with EGCG acting as both the reducing and stabilizing agent. Nanoparticles were characterized using UV-vis spectroscopy, FT-IR, dynamic light scattering, zeta potential analysis, and transmission electron microscopy. 35 adult rats were randomly assigned to control, 5-FU, 5-FU + Na₂SeO₃, 5-FU + EGCG, and 5-FU + EGCG-SeNPs groups. Hepatorenal toxicity was induced by intraperitoneal 5-FU administration during the final five days of the experiment. Serum biochemical markers, tissue oxidative stress, antioxidant enzyme, inflammatory cytokine levels, and apoptosis-related gene expression were evaluated. Immunohistochemical analysis of Nrf2 and Keap1 and histopathological examination of tissues were performed. 5-FU induced severe hepatorenal toxicity, evidenced by marked elevations in liver and kidney function biomarkers, excessive oxidative stress, inflammatory cytokine overproduction, NF-κB activation, and apoptotic signaling. Treatment with EGCG-SeNPs markedly ameliorated 5-FU-induced hepatic and renal dysfunction, restoring liver enzyme and kidney biomarker levels to near-normal levels more effectively than EGCG or sodium selenite alone. EGCG-SeNPs significantly suppressed lipid peroxidation, NGAL, and inflammatory mediators while robustly enhancing antioxidant defenses and activating the Nrf2/HO-1 pathway with concomitant Keap-1 downregulation, strongly inhibited NF-κB signaling, normalized cytokine balance, reduced poly (ADP-ribose) (PAR) activation, and attenuated apoptosis. EGCG–SeNPs confer superior protection against 5-FU–induced hepatorenal toxicity compared to EGCG or inorganic selenium alone. The potent protective effects of EGCG–SeNPs are mediated through coordinated antioxidant, anti-inflammatory, and anti-apoptotic mechanisms, primarily via activation of the Nrf2/HO-1 axis and suppression of NF-κB signaling. Full article

Steatosis, characterized by excessive fat accumulation in the liver, is a significant precursor to chronic liver disease and hepatocarcinoma. This condition is influenced by multiple contributing factors such as obesity, alcohol consumption, and exposure to chemicals or drugs. Systems biology approaches including transcriptomics and metabolomics can aid in grouping chemicals according to their mode of action. In this study, we analyze transcriptomic and metabolomic data from primary human and transformed hepatocytes, respectively, to differentiate between steatotic and non-steatotic chemicals. Rather than assessing each steatotic compound individually, we pooled several steatotic chemicals in order to minimize compound-specific noise and better identify features associated with the underlying process of steatosis. Differential gene expression analysis revealed established mechanisms involved in steatosis, consistent with the recently updated adverse outcome pathway. Likewise, metabolomic data enabled clear discrimination between steatotic and non-steatotic chemicals. These findings highlight the potential of omics technologies to support chemical grouping based on insights into the molecular mechanisms that drive steatosis development. Full article

Metals are an essential part of the life of all organisms because they participate as an essential part of diverse components, especially as enzymatic cofactors. In humans, there are metals that are trace elements and therefore are required for the proper functioning of different biological processes, so they must be present in cells and tissues. However, when the organism is overexposed, those same essential metals—in high concentrations that become toxic—cause imbalances or overt pathologies. On the other hand, there are metals that are not essential in humans, so their presence and accumulation in the organism can cause adverse effects. In this review we focus on the essentiality and toxicity of the main trace metals such as iron, zinc, copper, manganese, chromium, cobalt, molybdenum, and nickel, as well as on the toxicity of metals such as vanadium, cadmium, and lead that are not essential for humans. In addition, the report describes the main mechanisms by which metals exert their toxic effects on the body, as well as the primary sources of pollution through which they are released into the environment. Full article

A novel ocellatin-P1 isoform was isolated and purified from the skin secretion of the pepper frog Leptodactylus labyrinthicus. The crude skin secretion was fractionated by reversed-phase high-performance liquid chromatography (RP-HPLC) using a C₈ column and the peptide was subsequently purified on a reversed-phase C₁₈ column. Ocellatin-LB3 (as this isoform was named) was chemically sequenced by Edman degradation. This peptide is a linear C-terminally amidated molecule composed of 25 amino acid residues: ¹GLLDTLKGAAKNVVGGLASKVMEKL²⁵-NH₂. Synthetic ocellatin-LB3 was active against Escherichia coli, Klebsiella pneumoniae and Pseudomonas aeruginosa and inactive against Staphylococcus aureus, Staphylococcus epidermidis and Enterococcus faecalis. In addition, the peptide reduced the Trypanosoma cruzi infection in L6 cells. At 64 µM it did not reduce erythrocytes or polymorphonuclear leukocytes, but did reduce mononuclear leukocyte counts, as detected by flow cytometry. No hemolytic activity was observed in red blood cells even at 128 µM. The peptide exhibited limited antiproliferative activity against MCF-7 and HeLa tumor cells at 128 µM. Pre-incubation with the peptide appeared to enhance N-formylmethionine-leucyl-phenylalanine (fMLP)-induced migration, indicating a potential additive or synergistic effect on human neutrophils. The three-dimensional structure of ocellatin-LB3 was investigated by circular dichroism (CD) and nuclear magnetic resonance (NMR). In the presence of sodium dodecyl sulfate (SDS), the peptide adopts an α-helical structure spanning residues Leu³–Lys²⁴, which remains largely preserved even at 95 °C. NMR Hydrogen/Deuterium (H/D) exchange experiments suggest that ocellatin-LB3 adopts a preferential orientation when interacting with SDS micelles. Based on the similarity among ocellatins, and on the physicochemical and structural properties of this peptide, a possible membrane-mediated mode of action is proposed, although this remains to be experimentally validated. Full article

The degradation of plastic waste leads to the release of numerous chemical additives, including phthalate plasticizers, which have been implicated in the pathogenesis of metabolic disorders. Di (2-ethylhexyl) phthalate (DEHP) is a widely used plasticizer whose primary metabolite, mono (2-ethyl-5-carboxypentyl) phthalate (MECPP), has been associated with multiple metabolic diseases. In this study, we applied an integrated approach combining network toxicology and molecular docking to systematically investigate the potential mechanistic role of MECPP in metabolic dysregulation. Our strategy included multi-platform target prediction, disease gene association analysis, functional enrichment, protein–protein interaction network construction, and molecular docking analysis. The results suggested that MECPP may be associated with six common core targets, including BCL2, BCL2L1, MAPK14, MMP2, MMP9, and TNFRSF1A, which are mainly involved in apoptosis, inflammatory regulation, and extracellular matrix remodeling. Pathway enrichment analysis further indicated the potential involvement of several disease-overlapping pathways, including insulin resistance, neuroactive ligand–receptor interaction, efferocytosis, advanced glycation end product–receptor for advanced glycation end product (AGE–RAGE) signaling, phospholipase D signaling, and renin secretion. Overall, these findings suggest that MECPP may contribute to metabolic dysregulation through overlapping molecular mechanisms across multiple diseases. This study provides a computational basis for future experimental validation and environmental risk assessment. Full article

Ovarian cancer (OC) remains one of the leading causes of gynecologic cancer mortality, largely due to late diagnosis, frequent relapse, and the emergence of chemoresistance. An important but often-overlooked contributor to treatment failure is the heterogeneous penetration of anticancer drugs within tumors. Structural and biochemical barriers—including abnormal vasculature, elevated interstitial pressure, dense extracellular matrix, drug efflux transporters, and malignant ascites—generate steep intratumoral concentration gradients that conventional preclinical models fail to capture. As a result, systemic pharmacokinetic measurements frequently provide limited insight into tumor-level drug exposure. Patient-derived organoids (PDOs) have emerged as physiologically relevant 3D models that preserve the genetic, architectural, and functional characteristics of the original tumor. These systems enable controlled investigation of pharmacokinetic and pharmacodynamic processes, including drug penetration, metabolism, retention, and exposure–response relationships. Adding cell-free malignant ascites supernatant enhances PDOs’ ability to mimic the metastatic peritoneal microenvironment of OC. This review discusses recent advances in PDO technologies and examines how PDO-derived data can inform intratumoral pharmacokinetics and dosing strategies using physiologically based pharmacokinetic modeling and in vitro–in vivo extrapolation. Emerging hybrid platforms, including organoid-on-chip systems, vascularized co-cultures, and multi-omics integration, are crucial to improve translational prediction and support precision oncology. Full article

Bisphenol A (BPA) has long been used in plastics, resins, and food packaging materials; however, extensive research has demonstrated its reproductive, developmental, and endocrine-disrupting effects. Consequently, BPA has been increasingly restricted and replaced with structural analogues. Among these, tetramethyl bisphenol F (TMBPF) has emerged as one of the most widely used substitutes, particularly in epoxy resins and food-can coatings. Although initially regarded as a safer alternative, accumulating evidence suggests that TMBPF may exert multiple toxicological effects, raising concerns about its potential developmental neurotoxicity. The present study aimed to investigate the neurodevelopmental effects of TMBPF using both in vitro and in vivo approaches. First, a developmental neurotoxicity assay employing Sox1−GFP mouse embryonic stem cells was used to evaluate cytotoxicity using the cell counting kit-8 assay and neural differentiation based on green fluorescent protein (GFP) fluorescence intensity. The results indicated developmental neurotoxic potential according to the established discrimination index. Subsequently, pregnant and lactating mice were exposed to TMBPF daily from gestational day 10.5 to postnatal day 20, and their offspring were assessed for behavioral performance as well as changes in the expression of neurodevelopment-related genes in the brain. Behavioral analyses encompassed multiple domains, including memory and learning, social behavior, anxiety-related responses, and spontaneous locomotor activity, suggesting alterations in these functional outcomes. Molecular analyses further demonstrated changes associated with dopaminergic and cholinergic signaling, synaptic plasticity, neuronal activity markers, neuropeptides, and inflammatory pathways. Collectively, these findings provide the first evidence in a mammalian model that maternal exposure to TMBPF may influence offspring neurodevelopment. These findings suggest potential implications for human exposure to TMBPF, particularly through food-contact materials, and warrant further mechanistic and dose–response studies. Full article

The anticancer ruthenium complex indazolium trans-[tetrachlorobis(1H-indazole) ruthenate (III)—also known as KP1019—inhibits cancer cell proliferation in vitro, causes tumor regression in animal models, and showed no dose-limiting toxicity in a phase I clinical trial. Previous studies found that KP1019 damages DNA in both cancer cells and the budding yeast Saccharomyces cerevisiae. To identify other potential targets of KP1019 along with pathways that modulate the drug’s cellular effects, we screened the yeast gene deletion strain library by quantitative high-throughput cell array phenotyping (Q-HTCP). Fitness differences, as judged by growth curve analysis, identified genes for which loss of function (gene deletion) interacts with (enhances or suppresses) KP1019 effects. Drug-enhancing deletions were enriched for DNA repair functions, consistent with DNA damage being a primary target of KP1019 in yeast. pH homeostasis also modified the effects of KP1019. Drug-suppressing deletions prominently involved ribosomal proteins. A mechanistic link between ribosomal protein function and KP1019 toxicity was supported by dose-dependent accumulation of Rpl7a-GFP in the nucleolus, which is a hallmark of ribosomal biogenesis stress. Furthermore, KP1019 acted synergistically with the TOR pathway inhibitor everolimus to inhibit cell proliferation. The resulting model, wherein KP1019 perturbs ribosome assembly, can inform the design of future combination therapies. Full article

Micro- and nanoplastics (MPs/NPs) have emerged as pervasive environmental contaminants with increasing implications for human health, particularly within the digestive system. This review critically examines the role of MPs/NPs as disruptors of gastrointestinal and liver homeostasis through the lens of the plastic–gut–liver axis. We synthesize current evidence on primary exposure routes—including ingestion, inhalation, dermal contact, and transplacental transfer—and highlight their intestinal uptake, systemic dissemination, and tissue accumulation. Mechanistically, MPs/NPs compromise intestinal barrier integrity, promote oxidative stress, and induce microbiota dysbiosis, facilitating the translocation of microbial-derived signals to the liver via the portal circulation. This process triggers inflammatory signaling cascades, metabolic reprogramming, and immune dysregulation, contributing to hepatic steatosis, insulin resistance, and potential carcinogenic processes. Emerging evidence also implicates pancreatic dysfunction and β-cell stress within a broader gut–liver axis context. We further discuss the systemic propagation of MPs/NPs-induced dysbiosis along multi-organ axes, including gut–lung and gut–brain interactions. Despite robust preclinical data, human evidence remains limited due to methodological heterogeneity and the lack of standardized biomarkers. This review underscores critical knowledge gaps and emphasizes the need for integrative, translational approaches to clarify long-term health risks and inform regulatory strategies within the environmental exposome framework. Full article

Bisphenol S (BPS) is widely used as a replacement for bisphenol A, yet accumulating evidence suggests that it has comparable endocrine and cardiovascular toxicity. Here, we investigated whether prolonged low-dose BPS exposure induces subtle but classifiable phenotypic alterations in human coronary artery endothelial cells (HCAEC), using an end-to-end experimental and ML pipeline that spans cell culture, high-content imaging, feature extraction, and robust classification. Cells were exposed to 0.1 µM BPS for 96 h and profiled using a cell painting assay and high-content microscopy. Image segmentation yielded ~2500 quantitative features per cell across four compartments—Membrane, Cytoplasm, Ring region (i.e., perinuclear region), and Nucleus—for multiple fluorophores. We systematically compared different classifiers (Random Forest, XGBoost, LASSO logistic regressor) using feature selection (MRMR, ReliefF, LASSO) or transformation-based dimensionality reduction (PCA, autoencoders). Tree-based ensembles robustly handled high-dimensional inputs, with XGBoost combined with ReliefF-selected features achieving the best performance. The most informative descriptors predominantly mapped to mitochondrial and nuclear channels, indicating early alterations in mitochondrial organisation and chromatin-related features. These findings show that chronic low-dose BPS exposure elicits a distinct endothelial phenotype, consistent with early endothelial dysfunction, and demonstrate that integrating high-content imaging with machine learning provides a sensitive, scalable framework for vascular toxicity assessment of environmental contaminants. Full article

Polyethylene terephthalate microplastics (PET-MPs) are emerging environmental pollutants, but the molecular mechanisms underlying their hepatotoxicity remain poorly understood. Here, we combined network toxicology with experimental validation to investigate how PET-MPs induce liver injury. In silico, we investigated the PET-repeating unit as the molecular basis for target interactions. We identified 59 overlapping genes between 157 putative PET-MPs targets and 1693 liver injury-associated genes. Protein–protein interaction analysis revealed six hub genes (AKT1, PIK3CA, PIK3CB, PIK3CD, PIK3R1, and SRC), all components of the PI3K/AKT signaling pathway. Gene ontology analysis showed that PET-MPs affect cellular stress responses and kinase activities, while pathway enrichment analysis identified PI3K-Akt, Ras, and reactive oxygen species pathways as primary targets. Molecular docking demonstrated strong binding affinity between PET-MPs and these core targets (binding free energies <−5 kcal/mol). In vitro, PET-MPs induced mitochondrial depolarization, oxidative stress, upregulation of TNF-α and IL-6, and decreased p-AKT/AKT ratio, accompanied by increased apoptosis; the apoptotic effect was reversed by the AKT agonist SC79. In vivo experiments confirmed that AKT activation reduced PET-MP-induced liver injury, evidenced by decreased inflammation, lower serum transaminases, and restored oxidative balance. These protective effects were abolished by PI3K/AKT pathway inhibitors. Our study identifies potential therapeutic targets and strategies for PET-MP-induced liver injury. Full article

Excessive alcohol consumption causes millions of deaths annually, yet current pharmacological treatments for alcohol use disorders show limited efficacy and poor adherence, creating an urgent need for new therapeutic alternatives. Aldehyde dehydrogenase 2 (ALDH2) metabolizes acetaldehyde, a key mediator of the rewarding effects of alcohol in the brain, making ALDH2 activation a promising therapeutic target. This study investigated whether flurbiprofen, an FDA-approved nonsteroidal anti-inflammatory drug that activates ALDH2, reduces alcohol intake compared to the experimental ALDH2 activator Alda-1 and the structurally similar NSAID ibuprofen. Male alcohol-preferring UChB rats received oral flurbiprofen (2.5–10 mg/kg), Alda-1 (5 mg/kg), or ibuprofen (5 mg/kg) during acquisition and chronic phases of voluntary alcohol consumption under a two-bottle free-choice paradigm. Both flurbiprofen and Alda-1 reduced alcohol intake by approximately 60% and similarly increased ALDH2 activity 3–4-fold in brain and liver tissues. Ibuprofen showed modest effects (25% alcohol intake reduction). In vitro assays confirmed that flurbiprofen and Alda-1, but not ibuprofen, activated ALDH2 in PC-12 cells. Enzymatic assays and molecular docking revealed that Alda-1 lacks cyclooxygenase-inhibitory activity, unlike flurbiprofen, suggesting that ALDH2 activation is the primary mechanism underlying reduced alcohol consumption. These findings identify flurbiprofen as a clinically available ALDH2 activator with significant translational potential for treating alcohol use disorders. Full article