Qualitative and quantitative concentration-response modelling of gene co-expression networks to unlock hepatotoxic mechanisms for next generation chemical safety assessment_Suppl1 DOI Creative Commons
Steven J. Kunnen, Emma Arnesdotter,

Christian Tobias Willenbockel

et al.

ALTEX, Journal Year: 2024, Volume and Issue: unknown

Published: Jan. 1, 2024

Next generation risk assessment of chemicals revolves around the use mechanistic information without animal experimentation. In this regard, toxicogenomics has proven to be a useful tool elucidate underlying mechanisms adverse effects xenobiotics. present study, two widely used human in vitro hepatocyte culture systems, namely primary hepatocytes (PHH) and hepatoma HepaRG cells, were exposed liver toxicants known induce cholestasis, steatosis or necrosis. Benchmark concentration-response modelling was applied transcriptomics gene co-expression networks (modules) derive benchmark concentrations (BMCs) gain insight into hepatotoxic effects. BMCs derived by modules recapitulated individual genes. Although PHH cells showed overlap deregulated genes toxicants, demonstrated higher responsiveness, based on lower co-regulated modules. Such can as point departure (tPOD) for assessing module-associated cellular (stress) pathways/processes. This approach identified clear tPODs maximum systemic concentration (Cmax) levels tested drugs, while cosmetics ingredients 10-100-fold than estimated plasma concentrations. could serve next practice identify early responsive at low BMCs, that linked key events outcome pathways. turn, assist delineating potential hazards new test using systems when are paired with chemical exposure assessment. Plain language summaryRisk traditionally been focused experiments. contrast, uses biological obtained from experiments cell models animals hazards. Since is main target organ toxicity, many (hepatocyte) have developed hazard models, HepaRG, toxic chemicals. Biological changes expression measured range which response perturbed modelling. Genes belonging same process joined an average process. animal-free related expected

Language: Английский

Titanium dioxide nanoparticles: a promising candidate for wound healing applications DOI Creative Commons
Hamed Nosrati, Morteza Heydari

Burns & Trauma, Journal Year: 2025, Volume and Issue: 13

Published: Jan. 1, 2025

Abstract Effective wound management and treatment are crucial in clinical practice, yet existing strategies often fall short fully addressing the complexities of skin healing. Recent advancements tissue engineering have introduced innovative approaches, particularly through use nanobiomaterials, to enhance healing process. In this context, titanium dioxide nanoparticles (TiO2 NPs) garnered attention due their excellent biological properties, including antioxidant, anti-inflammatory, antimicrobial properties. Furthermore, these can be modified therapeutic benefits. Scaffolds dressings containing TiO2 NPs demonstrated promising outcomes accelerating enhancing regeneration. This review paper covers process, properties that make them suitable for promoting healing, methods synthesizing NPs, scaffolds application potential toxicity NPs.

Language: Английский

Citations

2

Application of AOPs to assist regulatory assessment of chemical risks – Case studies, needs and recommendations DOI Creative Commons
Lola Bajard, Ondřej Adamovský, Karine Audouze

et al.

Environmental Research, Journal Year: 2022, Volume and Issue: 217, P. 114650 - 114650

Published: Oct. 26, 2022

While human regulatory risk assessment (RA) still largely relies on animal studies, new approach methodologies (NAMs) based in vitro, silico or non-mammalian alternative models are increasingly used to evaluate chemical hazards. Moreover, epidemiological studies with biomarkers of effect (BoE) also play an invaluable role identifying health effects associated exposures. To move towards the next generation (NGRA), it is therefore crucial establish bridges between NAMs and standard approaches, processes for increasing mechanistically-based biological plausibility studies. The Adverse Outcome Pathway (AOP) framework constitutes important tool address these needs but, despite a significant increase knowledge awareness, use AOPs RA remains limited. objective this paper issues related using context from various perspectives as was discussed workshop organized within European Union partnerships HBM4EU PARC spring 2022. presents examples where AOP has been proven useful process, particularly hazard prioritization characterization, integrated approaches testing (IATA), identification validation BoE Nevertheless, several limitations were identified that hinder optimal usability acceptance by community including lack quantitative information response-response relationships efficient ways map data (exposure toxicity) onto AOPs. summarizes suggestions, ongoing initiatives third-party tools may help overcome obstacles thus assure better implementation NGRA.

Language: Английский

Citations

66

Oxidative Stress in Sepsis: A Focus on Cardiac Pathology DOI Open Access
Giuseppe Bertozzi, Michela Ferrara, Aldo Di Fazio

et al.

International Journal of Molecular Sciences, Journal Year: 2024, Volume and Issue: 25(5), P. 2912 - 2912

Published: March 2, 2024

This study aims to analyze post-mortem human cardiac specimens, verify and evaluate the existence or extent of oxidative stress in subjects whose cause death has been traced sepsis, through immunohistological oxidative/nitrosative markers. Indeed, present study, i-NOS, NOX2, nitrotyrosine markers were higher expressed septic group when compared control group, associated with also a significant increase 8-OHdG, highlighting pivotal role etiopathogenesis. In particular, 70% cardiomyocyte nuclei from specimens showed positivity for 8-OHdG. Furthermore, intense massive NOX2-positive myocyte immunoreaction was noticed as immunostaining reaction found cells. These results demonstrated correlation between nitrosative imbalance pathophysiology dysfunction documented cases sepsis. Therefore, subsequent studies will focus on expression other organs tissues, well involvement intracellular pattern apoptosis, better clarify complex pathogenesis multi-organ failure, leading support rationale including therapies targeting redox abnormalities management patients.

Language: Английский

Citations

12

Evidence linking cadmium and/or lead exposure to immunomodulatory effects in mammals based upon an adverse outcome pathways approach, and research perspectives DOI Creative Commons

Cloé Hadjadji,

Quentin Devalloir, Colette Gaillard

et al.

Chemosphere, Journal Year: 2025, Volume and Issue: 371, P. 144056 - 144056

Published: Jan. 4, 2025

For decades, studies have shown how exposure to non-essential trace metals such as lead (Pb) and cadmium (Cd) largely impact global wildlife. Ecoimmunotoxicology has emerged in the past two decades focuses on effects of pollutants immune system free-ranging organisms. Adverse outcome pathways (AOPs) represent a conceptual approach explore mechanistic linkage between molecular initiating event adverse outcomes, potentially at all biological levels organisation. The present paper proposes putative AOPs related Cd, Pb, mixture Cd-Pb, mammals address future questions ecoimmunotoxicology. Molecular Initiating Events for both relate entrance cells through Ca2+ channels or bond cell surfaces. Exposure Pb Cd-Pb share several similar Key (KEs), primarily an increase oxidative stress (OS) production reactive oxygen species. mixture, OS affects mitochondrial membranes, induces apoptosis, ultimately decreasing number. Both affect innate nuclear factor kappa B (NF-κB) mitogen-activated protein kinase (MAPK) inflammatory signalling pathways, leading upregulation markers mediators. Adaptive is also affected by though decrease CD4+/CD8+ ratio, MHCII, inactivation TH1 TH2 response, inhibition humoral response mediated various Ig. Mixture are less documented resulting more speculative AOP, but potential synergic antagonistic were identified. According our AOPs, further research ecoimmunotoxicology should focus KEs NF-κB/MAPK changes ratio MHCII complexes, AOs auto-immune disorders effective infection rate, particularly case metal mixtures.

Language: Английский

Citations

1

Adverse outcome pathways (AOPs) for radiation-induced reproductive effects in environmental species: state of science and identification of a consensus AOP network DOI Creative Commons
Knut Erik Tollefsen, Frédéric Alonzo, Nicholas A. Beresford

et al.

International Journal of Radiation Biology, Journal Year: 2022, Volume and Issue: 98(12), P. 1816 - 1831

Published: Aug. 17, 2022

Reproductive effects of ionizing radiation in organisms have been observed under laboratory and field conditions. Such assessments often rely on associations between exposure effects, thus lacking a detailed mechanistic understanding causality occurring at different levels biological organization. The Adverse Outcome Pathway (AOP), conceptual knowledge framework to capture, organize, evaluate visualize the scientific relevant toxicological has potential causal relationships molecular, cellular, individual, population effects. This paper presents first development set consensus AOPs for reproductive wildlife. work was performed by group experts formed during workshop organized jointly Multidisciplinary European Low Dose Initiative (MELODI) Radioecology Alliance (ALLIANCE) present AOP approach tools. series taxon-specific case studies that were used identify empirical evidence, common components propose could be into an network with broader taxonomic applicability.Expert consultation led identification key events description linkages radiation, impairment reduction fitness. study characterized domain AOPs, identified gaps pertinent reproductive-relevant reflected how assist applications (radioecological) research, environmental health assessment, radiological protection. Future advancement consolidation is planned include structured weight evidence considerations, formalized review critical assessment prior formal submission OECD sponsored program.

Language: Английский

Citations

19

A metabolic shift to the serine pathway induced by lipids fosters epigenetic reprogramming in nontransformed breast cells DOI Creative Commons
Mariana Bustamante Eduardo, Gannon Cottone, Curtis W. McCloskey

et al.

Science Advances, Journal Year: 2025, Volume and Issue: 11(12)

Published: March 21, 2025

Lipid metabolism and the serine, one-carbon, glycine (SOG) methionine pathways are independently significantly correlated with estrogen receptor–negative breast cancer (ERneg BC). Here, we propose a link between lipid ERneg BC through phosphoglycerate dehydrogenase (PHGDH), rate-limiting enzyme in de novo serine pathway. We demonstrate that of paradigmatic medium-chain fatty acid octanoic leads to metabolic shift toward SOG pathways. PHGDH plays role both forward direction, contributing production S-adenosylmethionine, reverse generating oncometabolite 2-hydroxyglutarate, leading epigenomic reprogramming phenotypic plasticity. The cycle is closely linked transsulfuration Consequently, observe increases antioxidant glutathione, which mitigates reactive oxygen species (ROS), enabling survival subset cells have undergone DNA damage. These changes contribute several hallmarks cancer.

Language: Английский

Citations

0

Functional analysis of open stomata 1-slow anion channel associated 1–6 protein module in enhancing drought tolerance in tomato through stomatal regulation mechanisms DOI
Fulei Mo, Meiliang Wang,

Ruihua Gao

et al.

International Journal of Biological Macromolecules, Journal Year: 2025, Volume and Issue: unknown, P. 142591 - 142591

Published: March 1, 2025

Language: Английский

Citations

0

ROS scavenging enzyme-encoding genes play important roles in the desert moss Syntrichia caninervis response to extreme cold and desiccation stresses DOI

Haron Salih,

Wenwan Bai, Yuqing Liang

et al.

International Journal of Biological Macromolecules, Journal Year: 2023, Volume and Issue: 254, P. 127778 - 127778

Published: Nov. 4, 2023

Language: Английский

Citations

9

Beyond chemicals: Opportunities and challenges of integrating non-chemical stressors in adverse outcome pathways DOI Creative Commons
Laure‐Alix Clerbaux, Julija Filipovska, Penny Nymark

et al.

ALTEX, Journal Year: 2023, Volume and Issue: unknown

Published: Jan. 1, 2023

The adverse outcome pathways (AOPs) were developed to accelerate evidence-based chemical risk assessment by leveraging data from new approach methodologies. Thanks their stressor-agnostic approach, AOPs seen as instrumental in other fields. Here, we present that report non-chemical stressors along with the challenges encountered for development. Challenges regarding linked nanomaterials include non-specific molecular initiating events, limited understanding of nanomaterial biodistribution, and needs adaptations silico modeling testing systems. Development radiation face how incorporate ionizing events type, dose rate, energy deposition, account targeting multiple macromolecules. COVID-19 required inclusion SARS-CoV-2-specific replicative steps capture essential driving disease. Developing evaluate efficacy toxicity cell therapies necessitates addressing cellular nature therapeutic function stressor. Finally, emerging biological like microbial pesticides can learn AOPs. We further discuss needed expand AOP applicability beyond chemicals are mainly at levels while downstream key tissue or organ level, such inflammation, shared many initiated various stressors. In conclusion, although it is challenging integrate within AOPs, this expands opportunities real-world scenarios, identify vulnerable individuals, bridge knowledge on mechanisms adversity. Plain language summaryThe pathway (AOP) framework was help predict whether have toxic effects humans. Structuring available information an accessible database reduce animal testing. usually path interaction a stressor, chemical, human body outcome, e.g., disease symptom. concept has now been expanded nanomaterials, radiation, viruses, cells used treat patients, microorganisms employed pesticides. use these need be accommodated point out share inflammation By integrating into framework, scenarios where people may exposed different stressor types considered, individuals identified, compounded.

Language: Английский

Citations

9

A toxicological perspective on climate change and the exposome DOI Creative Commons
Robert Barouki

Frontiers in Public Health, Journal Year: 2024, Volume and Issue: 12

Published: April 8, 2024

Climate change is accompanied by changes in the exposome, including increased heat, ground-level ozone, and other air pollutants, infectious agents, pollens, psychosocial stress. These exposures alter internal component of exposome account for some health effects climate change. The adverse outcome pathways describe biological events leading to an unfavorable outcome. In this perspective study, I propose use toxicological framework better steps linking a stressor associated with Such also allows identification possible interactions between stressors related others, such as chemical pollution. More generally, call incorporation part improved involved its effects.

Language: Английский

Citations

2