Search Results (267)

Although ductal carcinoma in situ (DCIS) diagnoses continue to climb, patient management remains constrained by limitations in recurrence prediction. Conventional histopathology and existing prognostic parameters often inadequately predict local recurrence, leading to over- or under-treatment. Additionally, discourse remains over the clinical implications of margin width as a measure of recurrence risk, demonstrating the limitations of a margin-based model, and motivating our proposal that recurrence risk is dynamic and should be defined by patient-specific, spatially resolved diagnostic biomarkers. This review introduces field cancerization as a framework that may illuminate mechanisms underlying DCIS ipsilateral recurrence and improve clinical decision-making. We propose that the potential drivers of ductal field cancerization span two stages: pre-tumorigenesis and post-tumorigenesis. Pre-tumorigenic events include non-biological and biological exposome factors. Post-tumorigenic drivers include intratumoral and microenvironment-mediated remodeling of adjacent tissues that promote malignancy. This review bridges stage-specific molecular mechanisms to potentially actionable strategies for DCIS patient management—particularly margin assessment and recurrence risk prognostication—while highlighting the critical unmet need to identify biomarkers that measure high-risk field changes. We also emphasize the need to move beyond lesion-centric management toward multivariable prognostic models that include distance-mapped field biomarkers, enabling more precise surgery, improved selection of adjuvant therapy, and safer de-escalation for low-risk patients. Full article

Chromium (Cr) remains a significant environmental health concern, with exposure mainly through ingestion and inhalation. Its toxicological profile is driven by oxidation state: trivalent chromium [Cr(III)] shows low bioavailability, whereas hexavalent chromium [Cr(VI)] is highly bioavailable, crosses cell membranes, and generates reactive intermediates associated with oxidative and genotoxic effects. Several studies have highlighted the assessment of chromium exposure, particularly Cr(III) and Cr(VI), across different biological matrices as a key approach for accurate exposure characterization. This review synthesizes experimental and epidemiological evidence regarding urinary chromium (uCr) as a biomarker of exposure, alongside advances in analytical techniques and the emerging exposome framework. Although widely used due to non-invasive sampling and suitability for large studies, uCr primarily reflects recent exposure (<48 h), exhibits high intra- and inter-individual variability, and lacks routine Cr(VI)/Cr(III) speciation, limiting its value for low-level environmental exposure. Unlike urinary or whole blood chromium, chromium in red blood cells (RBCs) is specific to Cr(VI) exposure, since in vitro studies reveal selective, donor-independent accumulation of hexavalent chromium in RBCs. However, the current literature is primarily concerned with sampling strategies, pre-treatment procedures, and analytical validation, with comparatively little consideration given to chromium speciation and species interconversion in biological matrices, despite their essential significance for exposure assessment and toxicological interpretation. Full article

Metabolomic studies in COPD reveal systemic metabolic perturbations, yet sex is often treated as a covariate rather than a biological driver. We aimed to identify plasma metabolites differentiating COPD from controls and to define sex-specific metabolic signatures in both groups. Methods: In this controlled observational study (BIOMEPOC cohort), untargeted plasma metabolomics was performed by LC-MS/MS. Differential abundance was tested across four contrasts (COPD vs. controls; men vs. women within controls; men vs. women within COPD; sex-by-disease interaction) with a false discovery rate (FDR) correction. Because smoking history differed between COPD and controls, a post hoc ever-smokers analysis was conducted. Results: COPD differed from controls in nine metabolites (all decreased): DL-stachydrine, 3-methyl-L-histidine, fructose, pipecolinic and nipecotic acids, 5-nitro-o-toluidine, conjugated linoleic acid, aminoadipate, and creatinine. This pattern is compatible with metabolic depletion, remodeling, and/or altered flux across multiple compartments rather than simple substrate deficiency, spanning muscle-related pools, amino acid handling, carbohydrate-associated metabolism, and exposome-linked inputs. In ever-smokers, results were directionally consistent, with five metabolites remaining nominally significant. Among controls, five metabolites were higher in men after FDR correction (PABA, cis-4-hydroxy-D-proline, N-acetylasparagine, deoxycarnitine, and creatinine), consistent with physiological sex dimorphism in energy pathways, connective-tissue remodeling, and diet/microbiome-related metabolism. Within COPD, six metabolites differed by sex after FDR correction, defining three axes: creatine energy buffering (men: higher GAA/creatinine, lower creatine), purine/urate handling (men: higher urate), and conjugated bile acids (men: higher GCDCA), implicating muscle bioenergetics, redox/inflammatory tone, and gut–liver crosstalk. Conclusions: Plasma metabolomics identifies a pattern compatible with systemic remodeling in COPD and sex-associated divergences in creatine, purine/urate, and bile-acid pathways, supporting a sex-influenced view of systemic COPD heterogeneity and highlighting targets for mechanistic validation. Full article

Development and maintenance of complex tissues depends on a number of coordinated steps from early development through adulthood. These processes are fundamentally controlled by highly regulated gene expression patterns. Although critical contributors during development, intrinsic changes in gene expression alone cannot fully explain the complicated pathways that control tissue homeostasis. Rather, tissues are continuously exposed to extrinsic factors that also influence essential cellular processes. These external environmental factors are collectively known as the exposome. Notably, how different exposures impact gene expression and protein function, as well as how certain exposures lead to disease states, is not well understood. To understand how internal and external factors influence organismal development and homeostasis, it is necessary to consider how genetic and nongenetic components interact to direct critical biochemical pathways. Doing so presents new avenues for precision medicine, understanding disease progression, identifying biological threats, and improving biological security concerns. In this review, we present recent advances in exposure biology, focusing on how these innovations can help identify novel biomarkers to better understand changing exposome components. We also discuss the need to integrate technologies and exposure research to better identify and predict threats. Full article

Intercellular communication is mediated by extracellular vesicles (EVs), particles released by all cell types that transfer bioactive cargo (proteins, lipids, nucleic acids) to recipient cells, influencing their function. Furthermore, the human population is simultaneously exposed to mixtures of endocrine-disrupting chemicals (EDCs), capable of altering hormonal homeostasis. Epidemiological and experimental evidence, in animal and cellular models, show that EDCs can contribute to the initiation, development, and progression of carcinogenesis. This review analyzes the EDC–EV–Cancer axis, connecting the biology of EVs to environmental toxicology and the processes that lead to tumor development. It has been examined how specific pollutants—arsenic, polycyclic aromatic hydrocarbons, bisphenol A, phthalates, particulate matter 2.5, and cigarette smoke—modify the secretion and content of EVs. These altered EVs may subsequently trigger critical oncogenic mechanisms in recipient cells, including proliferation, angiogenesis, migration, immunosuppression, and metastasis. Specific mechanisms, pathways, miRNAs, and proteins have been identified, following exposure to various EDCs that are capable of modulating cells and the tumor microenvironment to induce carcinogenesis and tumor progression. Therefore, EVs represent a promising platform for investigating the role of exposome in tumor development, serving as a real-time monitoring system that would allow tracking of combined and dynamic human environmental exposure and help in cancer prevention. Full article

Rare earth elements (REEs) and technology-related trace elements are increasingly used in modern products and processes, but biomonitoring data in healthy children and adolescents remain scarce; scalp hair provides a practical, integrative matrix for assessing multi-element patterns over time. Scalp hair collected in April–May 2001 from children (6–9 years; n = 120) and adolescents (13–16 years; n = 97) living in Alcalá de Henares (Spain) was retrieved from archival storage and analysed in 2025 using a single QA/QC-controlled ICP–MS workflow. Seven REEs (Ce, La, Pr, Nd, Gd, Er, and Y) and nine technology-related trace elements (Bi, Sb, Th, U, Pd, Pt, Rh, Ir, and Rb) were quantified after rigorous decontamination; left-censored data were treated using Kaplan–Meier, regression on order statistics, and maximum-likelihood approaches, and population reference values were derived as percentile-based upper limits (P95, 95% CI). In children, REEs were frequently detected and showed strong within-suite covariation, with medians in the low ng g⁻¹ range (e.g., Ce ≈ 0.011 µg g⁻¹; La ≈ 0.007 µg g⁻¹), whereas in adolescents, most REEs were near reporting limits. Sb and U were ubiquitous in both age groups, while platinum-group elements were largely undetected. Shale-normalised REE patterns were subparallel across normalisers, La/Ce anomalies were centred below unity, and weak soil–hair correlations suggested multiple microenvironmental exposure pathways. These data provide a robust pre-diffusion baseline for REE metals in European youth, offering a benchmark for future urban exposome assessments. Full article

Background: Saliva has been identified as a valuable diagnostic biofluid due to its non-invasive collection and its capacity to reflect oral and systemic biological processes. Advances in analytical chemistry, biosensing technologies, and artificial intelligence (AI)-assisted data integration have broadened the applications of salivary diagnostics. Among salivary exposome components, heavy metals such as lead, cadmium, mercury, nickel, chromium, arsenic, and aluminum serve as biologically and clinically relevant indicators of environmental exposure, toxic burden, and disease-associated molecular disorders. Methods: This structured review integrates clinical, experimental, and translational studies published between January 2020 and January 2026 that examined salivary heavy metal profiling in relation to oral health. Evidence was identified using systematic searches of PubMed/MEDLINE and supplementary sources. Studies were qualitatively assessed regarding analytical methodologies, reported concentration ranges, biological mechanisms, disease associations, and the development of digital and AI-assisted diagnostic applications. Results: Thirteen human clinical studies and six animal or in vivo investigations met the inclusion criteria. Across these studies, altered salivary metal profiles were linked to oxidative stress, inflammatory signaling, immune dysregulation, microbiome disturbances, and genotoxic markers relevant to periodontal disease, oral mucosal pathology, and the risk of oral squamous cell carcinoma. Inductively coupled plasma mass spectrometry was the predominant analytical platform, while emerging biosensor technologies showed potential for rapid detection and monitoring. Digital and AI-based approaches were identified as promising tools for integrating metallomic data with clinical and molecular biomarkers to support exposure-informed risk stratification. Conclusions: Salivary heavy metal profiling represents a biologically informative, non-invasive method for exposure-aware risk assessment in oral health. Although current clinical translation is limited by methodological variability, small cohort sizes, and the lack of standardized reference ranges, integration with digital biosensing platforms and explainable AI frameworks might facilitate scalable, precision-oriented salivary diagnostics. Full article

Background: Skin cancer is the most common malignancy worldwide. Although photoprotection is the cornerstone of skin cancer prevention, evidence regarding the role of other radiations different from the ultraviolet radiation and the efficacy of sunscreens, oral supplements, DNA-repair enzymes, and antioxidants continues to evolve. Objectives: To review the current evidence on photoprotective strategies and assess their role in preventing actinic keratoses (AK), keratinocyte carcinomas and melanoma. Methods: A narrative review of the literature was conducted using PubMed (2010–2025), including studies in English and Spanish. Search terms comprised “photoprotection,” “sunscreen,” “oral photoprotection,” “skin cancer,” “melanoma,” “keratinocyte cancer,” “UV radiation,” “non-melanoma skin cancer” and related concepts. Articles were selected for clinical relevance. Results: Daily sunscreen use significantly reduces AK and cutaneous squamous cell carcinoma in high-risk individuals, although evidence for basal cell carcinoma and melanoma prevention remains heterogeneous. Balanced broad-spectrum protection, including UVA and visible light filtering, seems to be important, whereas high-energy visible light needs further investigation. DNA-repair enzymes have shown reductions in cyclobutane pyrimidine dimers and clinical improvement of AK. Antioxidants such as Polypodium leucotomos extract, topical and oral, exhibit preventive effects on actinic damage and carcinogenesis. Topical and especially oral nicotinamide demonstrate chemopreventive potential in immunocompetent patients. Vulnerable populations—including transplant recipients, XP patients, individuals with albinism, and outdoor workers—require tailored photoprotection strategies with demonstrated benefit. Conclusions: Photoprotection extends far beyond UV filters, encompassing biological ingredients, antioxidants, oral supplements, and broad-spectrum strategies that target the full exposome. Comprehensive, behaviour-based photoprotection programmes are essential for high-risk groups. Full article

Objective: Hepatic ischemia–reperfusion injury (HIRI) is a common pathological condition in liver surgery and transplantation, and cellular pyroptosis plays a key role in its pathogenesis. However, the clinical application of curcumin is limited by its poor water solubility and low bioavailability. This study aims to develop mesenchymal stem cell (MSC)-derived exosomes loaded with curcumin (Exo-Cur). It also investigates the role and mechanism of Exo-Cur in inhibiting HIRI-related cellular pyroptosis. Methods: The preparation of Exo-Cur was optimized using orthogonal experimental design. Its solubility, stability, particle size distribution, and zeta potential were then evaluated. The morphology of Exo-Cur and its uptake in hepatocytes were observed using laser scanning confocal microscopy. The effect of Exo-Cur on HIRI was assessed through hematoxylin and eosin (HE) staining, ALT and AST measurements, TUNEL assay, CCK-8 assay, and lactate dehydrogenase (LDH) assay. Inflammatory cytokine protein levels were quantified by ELISA, and their mRNA expression was assessed by qRT-PCR. Pyroptosis was assessed by Western blot, immunohistochemistry, and flow cytometry. Additionally, protein expression changes in the PI3K/Akt/mTOR signaling pathway were analyzed using Western blot. Results: Orthogonal experiments determined that the optimal preparation method for Exo-Cur involves cell density at 95%, a curcumin concentration of 30 μg/mL, and a co-cultivation time of 12 h. Characterization results showed that Exo-Cur maintained its typical cup-shaped structure as well as stable particle size and zeta potential. Additionally, its water solubility and its stability in vitro were significantly improved compared to free curcumin. Further mechanistic studies indicated that Exo-Cur could ameliorate the abnormal morphology resulting from HIRI-induced hepatocyte pyroptosis, reduce the proportion of pyroptotic cells, and significantly downregulate the expression of NLRP3 inflammasome and downstream pyroptosis-related proteins (ASC, C-Caspase-1, GSDMD-N). Pathway analysis revealed that Exo-Cur activates the PI3K/Akt/mTOR axis, a pathway inhibited by HIRI. Moreover, rapamycin, an inhibitor of this pathway, reverses Exo-Cur’s anti-pyroptosis effect. Conclusions: This study develops an efficient and stable Exo-Cur delivery system, confirming its protective effect against HIRI by activating the PI3K/Akt/mTOR axis and inhibiting NLRP3-mediated cellular pyroptosis. This innovative combination of MSC-derived exosomes combined with curcumin overcomes the limitations in clinical application of curcumin, such as poor bioavailability and stability, and offers a novel nanotherapeutic strategy to treat HIRI clinically. Full article

Microextraction Technologies (METs) have emerged as pivotal exposomic sensors for the on-site monitoring of Volatile Organic Compounds (VOCs) in ambient air. By integrating sampling and sample preparation into a single step, METs provide solvent-free, miniaturized, and field-deployable solutions that align with the principles of green analytical chemistry. This review critically examines fourteen commercially available METs, selected for their demonstrated analytical performance, commercial accessibility, and validation in real-world environments. These devices represent the current state of practice in exposomics, enabling both short-term hotspot detection and long-term exposure assessment. Particular attention is given to their compatibility with transportable and portable detection platforms, including vehicle-mounted and hand-held gas chromatography/mass spectrometry systems, where METs function as front-end concentrators that enhance sensitivity and spatial resolution. This review further discusses emerging applications in wearable formats and unmanned aerial vehicles, underscoring the role of METs in bridging laboratory-grade precision with field-based exposome research. By situating METs within the broader exposomic workflow of sampling, detection, and interpretation, this work identifies current technological gaps and outlines priorities for advancing robust, scalable, and environmentally sustainable exposure assessment strategies. Full article

Over the past two decades, advances in the understanding of epigenetic mechanisms—driven by the rapid expansion of omics technologies—have catalyzed a major paradigm shift in biology: from the genetic determinism and linear causality of the Central Dogma toward the dynamic, networked complexity of systems biology and multilevel regulation. This reconceptualization extends to inheritance itself, highlighting the crucial role of the epigenome as a molecular interface between the genome and the exposome—the cumulative set of internal and external environmental influences experienced across the lifespan. Within this evolving framework, neurodevelopmental disorders exemplify the deep entanglement between genetic predisposition, environmental exposure, and epigenetic modulation. Their increasing global prevalence and frequent comorbidities underscore the need for an integrated etiological understanding that transcends reductionist models. This review tries to synthesize current evidence on the shared molecular and systemic mechanisms underlying neurodevelopmental spectrum disorders and examines how environmental and epigenetic factors jointly shape neurodevelopmental trajectories across generations. Finally, it discusses the broader implications of this paradigm shift for early diagnosis, prevention, and public health policies aimed at fostering healthy brain development in future generations. Full article

Curcumin is the main active ingredient in Curcuma longa turmeric, with a wide range of biological effects. It shows significant therapeutic potential in the field of stem cell therapy. This article aims to explore the modulatory effects and underlying mechanisms of curcumin on mesenchymal stem cells (MSCs), providing a theoretical basis based on experimental evidence for its clinical application in regenerative medicine. First, the physicochemical properties, main pharmacological activities, and metabolic pathways of curcumin are described. Subsequently, the key molecular mechanisms by which curcumin regulates MSCs are analyzed in depth, demonstrating that curcumin can significantly promote MSC proliferation and inhibit apoptosis by modulating signaling pathways and gene expression. Additionally, curcumin directs the differentiation of MSCs into osteoblasts and chondrocytes. It also inhibits their differentiation into adipocytes, thereby regulating the physiological functions of MSCs such as proliferation, differentiation, and apoptosis. Finally, several main challenges in current research are highlighted. These include the low oral bioavailability of curcumin; the regulatory effects that vary depending on doses and microenvironmental conditions; the underlying mechanisms not being fully elucidated; the research being mostly limited to in vitro cell models and animal experiments; and the lack of quality standards and production process control systems for curcumin preparations. Full article

Diabetes develops through a mix of clinical, metabolic, lifestyle, demographic, and environmental factors. Most current classification models focus on traditional biomedical indicators and do not include environmental exposure biomarkers. In this study, we develop and evaluate a supervised machine learning classification framework that integrates heterogeneous demographic, anthropometric, clinical, behavioral, and environmental exposure features to classify physician-diagnosed diabetes using data from the National Health and Nutrition Examination Survey (NHANES). We analyzed NHANES 2017–2018 data for adults aged ≥18 years, addressed missingness using Multiple Imputation by Chained Equations, and corrected class imbalance via the Synthetic Minority Oversampling Technique. Model performance was evaluated using stratified ten-fold cross-validation across eight supervised classifiers: logistic regression, random forest, XGBoost, support vector machine, multilayer perceptron neural network (artificial neural network), k-nearest neighbors, naïve Bayes, and classification tree. Random Forest and XGBoost performed best on the balanced dataset, with ROC AUC values of 0.891 and 0.885, respectively, after imputation and oversampling. Feature importance analysis indicated that age, household income, and waist circumference contributed most strongly to diabetes classification. To assess out-of-sample generalization, we conducted an independent 80/20 hold-out evaluation. XGBoost achieved the highest overall accuracy and F1-score, whereas random forest attained the greatest sensitivity, demonstrating stable performance beyond cross-validation. These results indicate that incorporating environmental exposure biomarkers alongside clinical and metabolic features yields improved classification performance for physician-diagnosed diabetes. The findings support the inclusion of chemical exposure variables in population-level diabetes classification and underscore the value of integrating heterogeneous feature sets in machine learning-based risk stratification. Full article

Over the last 15 years, mixture risk assessment for food xenobiotics has evolved from conceptual discussions and simple screening tools, such as the Hazard Index (HI), towards operational, component-based and probabilistic frameworks embedded in major food-safety institutions. This review synthesizes methodological and regulatory advances in cumulative risk assessment for dietary “cocktails” of pesticides, contaminants and other xenobiotics, with a specific focus on food-relevant exposure scenarios. At the toxicological level, the field is now anchored in concentration/dose addition as the default model for similarly acting chemicals, supported by extensive experimental evidence that most environmental mixtures behave approximately dose-additively at low effect levels. Building on this paradigm, a portfolio of quantitative metrics has been developed to operationalize component-based mixture assessment: HI as a conservative screening anchor; Relative Potency Factors (RPF) and Toxic Equivalents (TEQ) to express doses within cumulative assessment groups; the Maximum Cumulative Ratio (MCR) to diagnose whether risk is dominated by one or several components; and the combined Margin of Exposure (MOET) as a point-of-departure-based integrator that avoids compounding uncertainty factors. Regulatory frameworks developed by EFSA, the U.S. EPA and FAO/WHO converge on tiered assessment schemes, biologically informed grouping of chemicals and dose addition as the default model for similarly acting substances, while differing in scope, data infrastructure and legal embedding. Implementation in food safety critically depends on robust exposure data streams. Total Diet Studies provide population-level, “as eaten” exposure estimates through harmonized food-list construction, home-style preparation and composite sampling, and are increasingly combined with conventional monitoring. In parallel, human biomonitoring quantifies internal exposure to diet-related xenobiotics such as PFAS, phthalates, bisphenols and mycotoxins, embedding mixture assessment within a dietary-exposome perspective. Across these developments, structured uncertainty analysis and decision-oriented communication have become indispensable. By integrating advances in toxicology, exposure science and regulatory practice, this review outlines a coherent, tiered and uncertainty-aware framework for assessing real-world dietary mixtures of xenobiotics, and identifies priorities for future work, including mechanistically and data-driven grouping strategies, expanded use of physiologically based pharmacokinetic modelling and refined mixture-sensitive indicators to support public-health decision-making. Full article

Oxidative stress (OS) reflects a pathologic imbalance between excessive production of reactive oxygen species (ROS) and insufficient antioxidant defenses. Growing evidence indicates that a healthy gut microbiota (GM) is essential for regulating redox homeostasis, whereas gut dysbiosis contributes to elevated ROS levels and oxidative damage in DNA, lipids, and proteins. This redox disequilibrium initiates a cascade of cellular disturbances—including synaptic dysfunction, altered receptor activity, excitotoxicity, mitochondrial disruption, and chronic neuroinflammation—that can, in turn, impair cognitive and social functioning in metabolic and neuropsychiatric disorders via epigenetic mechanisms. In this review, we synthesize current knowledge on (1) how OS contributes to cognitive and social deficits through epigenetic dysregulation; (2) the role of disrupted one-carbon metabolism in epigenetically mediated neurological dysfunction; and (3) mechanistic links between leaky gut, OS, altered GM composition, and GM-derived epigenetic metabolites. We also highlight emerging microbiota-based therapeutic strategies capable of mitigating epigenetic abnormalities and improving cognitive and social outcomes. Understanding the OS–microbiota–epigenetic interplay may uncover new targetable pathways for therapies aimed at restoring brain and behavioral health. Full article