Archives of Toxicology最新文献

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Intracellular hydrogen sulfide induces stress granule formation and translational repression through eIF2α phosphorylation. 细胞内硫化氢通过eIF2α磷酸化诱导应激颗粒形成和翻译抑制。
IF 4.8 2区 医学
Archives of Toxicology Pub Date : 2025-04-09 DOI: 10.1007/s00204-025-04026-y
S Kanno, S Hirano, J Monma-Otaki, H Kato, M Fukuta, H Takase, Y Nakamura, T Oshima
{"title":"Intracellular hydrogen sulfide induces stress granule formation and translational repression through eIF2α phosphorylation.","authors":"S Kanno, S Hirano, J Monma-Otaki, H Kato, M Fukuta, H Takase, Y Nakamura, T Oshima","doi":"10.1007/s00204-025-04026-y","DOIUrl":"https://doi.org/10.1007/s00204-025-04026-y","url":null,"abstract":"<p><p>Acute exposure to high concentrations of hydrogen sulfide (H<sub>2</sub>S), a toxic gaseous substance, can cause potentially lethal respiratory damages. Stress granules (SGs) are cytoprotective membrane-less intracellular organelles formed transiently in response to various stressors. We examined SG formation and the underlying molecular mechanism following exposure to high concentrations of H<sub>2</sub>S using human bronchial BEAS-2B (BEAS) and GFP-tagged G3BP1-stably transfected CHO cells. We first examined the changes in intracellular H<sub>2</sub>S concentration by NaHS exposure. Qualitative and quantitative analyses revealed that intracellular H<sub>2</sub>S levels rapidly increased after NaHS exposure and accumulated in cells dose dependently. In terms of the response to H<sub>2</sub>S taken up after exposure to 2.5-10 mM NaHS, both cell lines formed discrete SG assemblies within 1 h. SG formation induced by NaHS exposure was enhanced by treatment with glutathione (GSH) or thioredoxin (Trx) inhibitor but suppressed by treatment with a PERK inhibitor or integrated stress response inhibitor. Levels of phosphorylation of eIF2 α, which is essential for canonical SG formation, were significantly and dose-dependently increased in NaHS-exposed BEAS cells. Phosphorylation of eIF2α was further increased by GSH or Trx inhibitor treatment. These results suggest that GSH and Trx play protective roles in H<sub>2</sub>S-induced SG formation. PERK, a kinase of eIF2α, might activate the pathway partially. Levels of newly synthesized proteins were markedly reduced in NaHS-exposed cells. In summary, when humans inhale high concentrations of H<sub>2</sub>S, H<sub>2</sub>S is rapidly taken up by pulmonary cells and induces SG formation and translational repression via eIF2α phosphorylation, thereby protecting against cell death.</p>","PeriodicalId":8329,"journal":{"name":"Archives of Toxicology","volume":" ","pages":""},"PeriodicalIF":4.8,"publicationDate":"2025-04-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143810334","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
ITGA1, the alpha 1 subunit of integrin receptor, is a novel marker of drug-resistant senescent melanoma cells in vitro. 整合素受体α 1亚基ITGA1是体外耐药衰老黑色素瘤细胞的新标志物。
IF 4.8 2区 医学
Archives of Toxicology Pub Date : 2025-04-09 DOI: 10.1007/s00204-025-04028-w
Julia Słaby, Maciej Wnuk, Dominika Błoniarz, Paulina Stec, Tomasz Szmatoła, Ewa Kaznowska, Adam Reich, María Moros, Anna Lewińska
{"title":"ITGA1, the alpha 1 subunit of integrin receptor, is a novel marker of drug-resistant senescent melanoma cells in vitro.","authors":"Julia Słaby, Maciej Wnuk, Dominika Błoniarz, Paulina Stec, Tomasz Szmatoła, Ewa Kaznowska, Adam Reich, María Moros, Anna Lewińska","doi":"10.1007/s00204-025-04028-w","DOIUrl":"https://doi.org/10.1007/s00204-025-04028-w","url":null,"abstract":"<p><p>Chemotherapy-induced senescence may promote drug resistance and treatment failure. Precise detection and elimination of senescent cancer cells is considered as a novel promising anticancer strategy. However, data on senescence-associated skin cancer cell surface markers as potential therapeutic targets are limited. In the present study, we have established two models of drug-induced senescence in vitro using DNA damaging chemotherapeutics, namely etoposide (0.75-5 µM) and cisplatin (1.25-5 µM), and ten skin cancer cell lines, both melanoma (n = 8, A375, G-361, MM370, SH-4, SK-MEL-1, MeWo, MM127, RPMI-7951) and non-melanoma (n = 2, A431, MCC13), to investigate the levels of 97 cell surface markers. Initial gene expression analysis revealed the increasing tendency in the levels of seven transcripts (ITGA1, ITGA3, VAMP3, STX4, ARMCX3, ULBP2, and PLAUR) and five transcripts (ITGA1, ITGA3, STX4, ARMCX3, and PLAUR) in five etoposide and cisplatin-induced senescent melanoma cell lines, respectively, compared to corresponding proliferating cells. Elevated pools of integrin α1 (ITGA1) were confirmed at mRNA and protein levels in eight drug-induced senescent melanoma cell lines. Similar pattern of changes in integrin α1 levels was not observed in drug-induced senescent non-melanoma skin cancer cells. Analysis using clinical melanoma samples also showed that the levels of ITGA1 and ITGA3 were correlated with the presence of melanoma cells in a section. We document that integrin α1 can be considered as a novel marker of drug-induced senescent melanoma cells. Thus, we postulate that new integrin α1-based targeted therapies can be designed and tested against drug-induced senescent melanoma cells.</p>","PeriodicalId":8329,"journal":{"name":"Archives of Toxicology","volume":" ","pages":""},"PeriodicalIF":4.8,"publicationDate":"2025-04-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143810386","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Thalidomide-induced limb malformations: an update and reevaluation. 沙利度胺所致肢体畸形:更新与重新评估。
IF 4.8 2区 医学
Archives of Toxicology Pub Date : 2025-04-08 DOI: 10.1007/s00204-024-03930-z
Michael D Collins, William J Scott
{"title":"Thalidomide-induced limb malformations: an update and reevaluation.","authors":"Michael D Collins, William J Scott","doi":"10.1007/s00204-024-03930-z","DOIUrl":"https://doi.org/10.1007/s00204-024-03930-z","url":null,"abstract":"<p><p>Historically, thalidomide-induced congenital malformations have served as an important example of the enhanced susceptibility of developing embryos to chemical perturbation. The compound produced a wide variety of congenital malformations in humans, which were initially detected by an association with a relatively rare limb defect labeled phocomelia. Although true phocomelia in the most severe form is a transverse defect with intercalary absence of limb regions, it is proposed that thalidomide produces a longitudinal limb phenotype in humans under usual circumstances that can become transverse in severe cases with a preferential sensitivity of forelimb over hindlimb, preaxial over postaxial, and left more impacted than the corresponding non-autopod limb bones on the right. The thalidomide-induced limb phenotype in humans is described and followed by a hierarchical comparison with various laboratory animal species. Mechanistic studies have been hampered by the fact that only non-human primates and rabbits have malformations that are anatomically similar to humans. Included in this review are unpublished data on limb malformations produced by thalidomide in rhesus monkeys from experiments performed more than 50 years ago. The critical period in gestation for the induction of phocomelia may initiate prior to the development of the embryonic limb bud, which contrasts with other chemical and physical agents that are known to produce this phenotype. The importance of toxicokinetic parameters is reviewed including dose, enantiomers, absorption, distribution, and both non-enzymatic and enzymatic biotransformations. The limb embryopathy mechanism that provides a partial explanation of the limb phenotype is that cereblon binds to thalidomide creating a protein complex that ubiquitinates protein substrates (CRL4<sup>CRBN</sup>) that are not targets for the complex in the absence of the thalidomide. One of these neosubstrates is SALL4 which when mutated causes a syndrome that phenocopies aspects of thalidomide embryopathy. Other candidate neosubstrates for the complex that have been found in non-human species may contribute to an understanding of the limb defect including PLZF, p63, and various zinc finger transcription factors. It is proposed that it is important to consider the species-specificity of the compound when considering potential mechanistic pathways and that some of the more traditional mechanisms for explaining the embryopathy, such as anti-angiogenesis and redox perturbation, may contribute to a full understanding of this teratogen.</p>","PeriodicalId":8329,"journal":{"name":"Archives of Toxicology","volume":" ","pages":""},"PeriodicalIF":4.8,"publicationDate":"2025-04-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143810389","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Unraveling the Hsp70-ROS-autophagy axis in pentachlorophenol-challenged lung and liver epithelial cells. 揭示五氯酚挑战肺和肝上皮细胞的hsp70 - ros自噬轴。
IF 4.8 2区 医学
Archives of Toxicology Pub Date : 2025-04-07 DOI: 10.1007/s00204-025-03983-8
S Thota, R Begum, D Mutyala, N Bidarimath, M Thakur, B Sarkar, J Morehouse, S Yang, P K Deb, W Dorsey, S Batra
{"title":"Unraveling the Hsp70-ROS-autophagy axis in pentachlorophenol-challenged lung and liver epithelial cells.","authors":"S Thota, R Begum, D Mutyala, N Bidarimath, M Thakur, B Sarkar, J Morehouse, S Yang, P K Deb, W Dorsey, S Batra","doi":"10.1007/s00204-025-03983-8","DOIUrl":"https://doi.org/10.1007/s00204-025-03983-8","url":null,"abstract":"<p><p>Pentachlorophenol (PCP) was extensively utilized as an organochlorine pesticide and wood preservative in the United States from the 1930s until the Environmental Protection Agency (EPA) imposed restrictions due to concerns about its toxicity and potential carcinogenic properties. Although it is no longer widely used, PCP remains a concern due to its environmental persistence and potential for long-term health effects. Significant occupational and environmental exposures have likely occurred, with the health and economic costs of PCP exposure potentially being substantial given its known toxicity. Notably, PCP exhibits rapid absorption through both the skin and respiratory system and has been shown to cause hepatotoxicity, developmental toxicity, immunotoxicity, irritation, and carcinogenicity in laboratory animal studies. PCP exposure induces oxidative stress, a key mechanism underlying its inflammatory and toxic effects, which can activate cellular stress responses including upregulation of heat shock protein 70 (Hsp70). Previous studies in lung and liver epithelial cells have shown that Hsp70 and oxidative stress play pivotal roles in triggering autophagy. This study establishes the critical role of the Hsp70-reactive oxygen species (ROS)-autophagy axis in regulating cellular responses to PCP exposure in human alveolar (A549) and liver carcinoma (HepG2) epithelial cells. Our research elucidated the molecular mechanisms underlying PCP's cellular effects, demonstrating that its exposure resulted in increased expression of autophagy-related proteins (Beclin-1, LC3B, ATG12, and ATG16), subunits of NADPH oxidase (NCF-1, NCF-2, NOX2, and Rac), and antioxidant proteins (SOD and GPx) in both lung and liver cell types. Notably, PCP augmented the interaction between Hsp70 and the autophagy regulator Beclin-1. Pretreatment with the ROS inhibitor N-acetylcysteine or Hsp70 knockdown markedly reversed PCP-induced responses. Our in-silico protein-protein docking analysis and molecular dynamics simulation studies revealed enhanced interactions and/or stable confirmations maintained throughout the simulations for TLR4-Hsp70 and Hsp70-Beclin-1 complexes in the presence of PCP. These findings provide a strong foundation for future studies, employing in vivo experimental models and human populations to identify promising targets for PCP-induced toxicity and cellular injury. Furthermore, these findings may have far-reaching implications for public health and environmental policy, ultimately leading to the identification of biomarkers and the development of more effective interventions for environmentally induced toxicity and diseases.</p>","PeriodicalId":8329,"journal":{"name":"Archives of Toxicology","volume":" ","pages":""},"PeriodicalIF":4.8,"publicationDate":"2025-04-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143794528","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Dihydromyricetin restores lysosomal function in Schwann cells to alleviate bortezomib-induced peripheral neuropathy via ERK/TFEB signaling. 二氢杨梅素恢复雪旺细胞溶酶体功能,通过ERK/TFEB信号通路缓解硼替佐米诱导的周围神经病变。
IF 4.8 2区 医学
Archives of Toxicology Pub Date : 2025-04-06 DOI: 10.1007/s00204-025-04030-2
Xiaoliang Liu, Xingxian Zhang, Xinhang Li, Chen Zhang, Huajing Cai, Jiayu Qi, Ke Wang, Xuyun Li, Xiuhua Wu, Ziqi Ye, Gang Chen, Xiangnan Zhang, Jiaying Wu
{"title":"Dihydromyricetin restores lysosomal function in Schwann cells to alleviate bortezomib-induced peripheral neuropathy via ERK/TFEB signaling.","authors":"Xiaoliang Liu, Xingxian Zhang, Xinhang Li, Chen Zhang, Huajing Cai, Jiayu Qi, Ke Wang, Xuyun Li, Xiuhua Wu, Ziqi Ye, Gang Chen, Xiangnan Zhang, Jiaying Wu","doi":"10.1007/s00204-025-04030-2","DOIUrl":"https://doi.org/10.1007/s00204-025-04030-2","url":null,"abstract":"<p><p>Bortezomib (BTZ) serves as a first-line drug for multiple myeloma (MM) treatment by reversibly inhibiting of the proteasomes. However, BTZ-induced peripheral neuropathy (BIPN) remains a significant toxicity concern, with its molecular mechanisms not fully elucidated, resulting in limited therapeutic options. Dihydromyricetin (DHM) has been shown to alleviate neuropathic pain, but its potential effect on BIPN has not been investigated. We found that oral administration of DHM (40 mg/kg/day, 200 mg/kg/day) for 2 weeks significantly improved mechanical allodynia, sciatic nerve conduction, and demyelination in a BIPN mouse model (BTZ 1.0 mg/kg, i.v.). BTZ (50 nmol/L) impaired lysosomal function and blocked autophagy flux in both primary cultured rat Schwann cells and RSC96 Schwann cells; these effects were reversed by DHM treatment (3 μmol/L, 10 μmol/L). Mechanistically, DHM facilitated the nuclear translocation of TFEB, a master regulator of lysosomal-related genes, and the protective effects of DHM on Schwann cells were abolished by Tfeb shRNA. Furthermore, BTZ treatment activated ERK signaling, leading to TFEB phosphorylation and impaired nuclear translocation. DHM treatment prevented the BTZ-induced ERK activation, and the protective effects of DHM were compromised by the ERK activator TBHQ. Importantly, DHM did not diminish the efficacy of BTZ against RPMI 8226 myeloma cells. This study demonstrates that DHM mitigates BTZ-induced toxicity on Schwann cells by restoring lysosome-autophagy activity through the ERK-TFEB pathway, highlighting DHM as a promising candidate for improving the adverse reaction of BTZ in the peripheral nervous system.</p>","PeriodicalId":8329,"journal":{"name":"Archives of Toxicology","volume":" ","pages":""},"PeriodicalIF":4.8,"publicationDate":"2025-04-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143794515","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Towards prospective identification of respiratory sensitizers: effects of piperazine, chloramine-T, and toluene-diisocyanate in an air-liquid interface model comprising human bronchial epithelial cells. 对呼吸道致敏剂的前瞻性鉴定:哌嗪、氯胺- t和甲苯二异氰酸酯在包括人支气管上皮细胞的气液界面模型中的作用。
IF 4.8 2区 医学
Archives of Toxicology Pub Date : 2025-04-06 DOI: 10.1007/s00204-025-04029-9
Evert Duistermaat, Véronique M P de Bruijn, Jolanda P Vermeulen, Eric R Gremmer, Rob J Vandebriel
{"title":"Towards prospective identification of respiratory sensitizers: effects of piperazine, chloramine-T, and toluene-diisocyanate in an air-liquid interface model comprising human bronchial epithelial cells.","authors":"Evert Duistermaat, Véronique M P de Bruijn, Jolanda P Vermeulen, Eric R Gremmer, Rob J Vandebriel","doi":"10.1007/s00204-025-04029-9","DOIUrl":"https://doi.org/10.1007/s00204-025-04029-9","url":null,"abstract":"<p><p>Exposure to respiratory sensitizers (RSs) is the leading cause of occupational asthma. Although the prospective identification of RSs is important, there currently exists no OECD-approved test guideline for this endpoint. The adverse outcome pathway for respiratory sensitization consists of key event (KE) 1: binding of the respiratory sensitizer to a protein, KE2: activation of lung epithelial cells, KE3: activation of dendritic cells, and KE4: T-cell response. Here, we focused on KE2 by investigating whether measuring this KE could contribute to prospectively identify respiratory sensitizers. To mimic real-life exposure, cells were exposed via the air. We used an air-liquid interface model comprising the human bronchial epithelial cell line Calu-3. Exposure to the RS piperazine (3, 18, and 100 mg/m<sup>3</sup>) dose-dependently increased IL-6 production at dose levels that did not affect the other parameters tested (barrier integrity, cell metabolism, cytotoxicity, and IL-8 production). IL-6 has been linked to asthma in humans. Exposure to the RS chloramine-T (30, 300, and 3000 ng/cm<sup>2</sup>) showed only minor effects on the parameters tested. Exposure to the RS 2,4-toluene diisocyanate (10, 33, and 100 mg/m<sup>3</sup>) at the highest dose level clearly affected all parameters tested. Disrupted barrier function has been linked to asthma. In conclusion, this study may possibly suggest that different respiratory sensitizers may differentially impact KE2. Further research is needed to elucidate this.</p>","PeriodicalId":8329,"journal":{"name":"Archives of Toxicology","volume":" ","pages":""},"PeriodicalIF":4.8,"publicationDate":"2025-04-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143794519","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Biomarker-based approach to human exposure assessment of furan in food. 基于生物标志物的食品中呋喃人类暴露评估方法。
IF 4.8 2区 医学
Archives of Toxicology Pub Date : 2025-04-04 DOI: 10.1007/s00204-025-04022-2
C Kalisch, M Reiter, A Mally
{"title":"Biomarker-based approach to human exposure assessment of furan in food.","authors":"C Kalisch, M Reiter, A Mally","doi":"10.1007/s00204-025-04022-2","DOIUrl":"https://doi.org/10.1007/s00204-025-04022-2","url":null,"abstract":"<p><p>Humans are continuously exposed to furan, a hepatotoxic and carcinogenic process-related food contaminant. Considerable uncertainties associated with current exposure estimates based on the content of furan in food underscore the need to explore biomarker monitoring as an alternative or complementary approach to furan exposure assessment. Previous work in rats demonstrated a linear correlation between furan dose and several urinary furan metabolites, whereby N-[4-carboxy-4-(3-mercapto-1H-pyrrol-1-yl)-1-oxobutyl]-L-cysteinylglycine (GSH-BDA), the glutathione (GSH) conjugate of the reactive furan metabolite cis-2-butene-1,4-dial (BDA), was identified as a specific biomarker of exogenous furan exposure. To further test the validity of GSH-BDA as a biomarker of furan exposure, the present study was designed to monitor urinary excretion of furan metabolites in human volunteers after consumption of diets with low vs. high furan content using stable isotope dilution LC-MS/MS, and to investigate if analysis of GSH-BDA in human urine is suitable for translating biomarker levels into probable daily intakes. Ten healthy volunteers (n = 5/sex) consumed a low-furan diet for three days (day 1-3), followed by consumption of foods with high furan content for three days (day 4-6) and returned to a low-furan diet for a further three days (7-9). Urinary GSH-BDA excretion significantly increased during periods of a high-furan diet, and rapidly declined upon returning to a low-furan diet. Probable daily intakes estimated from GSH-BDA excretion in non-smoking subjects and excretion rates previously determined in F344/DuCrl rats ranged from 0.05 to 0.31 µg/kg bw/d during periods of low-furan diet and increased to 0.18-1.20 µg/kg bw/d during consumption of a high-furan diet. These estimates are in good agreement with exposures reported by the European Food Safety Authority (EFSA), which range between 0.11 to 0.75 µg/kg bw per day (minimum LB to maximum UB) for the average adult and 0.20 to 1.22 µg/kg bw per day (minimum LB to maximum UB) for highly exposed adult consumers (95th percentile). Interestingly, higher excretion of GSH-BDA was observed in smoking compared to non-smoking individuals, highlighting tobacco smoke as a significant source of furan exposure and confounding factor when estimating furan exposure via diet. In contrast to GSH-BDA, high urinary background levels of lysine adducts of BDA and BDA-derived cysteine-lysine crosslinks limit their suitability as biomarkers of exogenous furan exposure.</p>","PeriodicalId":8329,"journal":{"name":"Archives of Toxicology","volume":" ","pages":""},"PeriodicalIF":4.8,"publicationDate":"2025-04-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143778998","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Sex-specific differences in toxicology: does the sex make the poison? 毒理学上的性别差异:是性别制造毒素吗?
IF 4.8 2区 医学
Archives of Toxicology Pub Date : 2025-04-03 DOI: 10.1007/s00204-025-04021-3
Charlotte Esser, Doreen Reichert
{"title":"Sex-specific differences in toxicology: does the sex make the poison?","authors":"Charlotte Esser, Doreen Reichert","doi":"10.1007/s00204-025-04021-3","DOIUrl":"https://doi.org/10.1007/s00204-025-04021-3","url":null,"abstract":"","PeriodicalId":8329,"journal":{"name":"Archives of Toxicology","volume":" ","pages":""},"PeriodicalIF":4.8,"publicationDate":"2025-04-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143771201","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Quantitative in vitro-to-in vivo extrapolation of human adrenergic and trace amine-associated receptor 1 potencies of pre-workout supplement ingredients using physiologically based kinetic modelling-based reverse dosimetry. 利用基于生理动力学模型的反向剂量法定量推断运动前补充成分的人肾上腺素能和微量胺相关受体1的效力。
IF 4.8 2区 医学
Archives of Toxicology Pub Date : 2025-04-03 DOI: 10.1007/s00204-025-03992-7
Nicole E T Pinckaers, W Matthijs Blankesteijn, Anastasiya Mircheva, Ans Punt, Antoon Opperhuizen, Frederik-Jan van Schooten, Misha Vrolijk
{"title":"Quantitative in vitro-to-in vivo extrapolation of human adrenergic and trace amine-associated receptor 1 potencies of pre-workout supplement ingredients using physiologically based kinetic modelling-based reverse dosimetry.","authors":"Nicole E T Pinckaers, W Matthijs Blankesteijn, Anastasiya Mircheva, Ans Punt, Antoon Opperhuizen, Frederik-Jan van Schooten, Misha Vrolijk","doi":"10.1007/s00204-025-03992-7","DOIUrl":"https://doi.org/10.1007/s00204-025-03992-7","url":null,"abstract":"<p><p>The present study predicts effective doses of a set of phenethylamine (PEA) analogues that are frequently present in pre-workout and weight-loss food supplements, to prioritize these compounds for further risk assessment. In vitro determined EC<sub>50</sub> values of PEA analogues for multiple human adrenergic receptor (ADR) subtypes (ADRα<sub>1A</sub>, α<sub>1B</sub>, α<sub>1D</sub>, α<sub>2A</sub>, β<sub>1</sub>, β<sub>2</sub>) and trace-amine associated receptor 1 (TAAR1) were extrapolated to human ED<sub>50</sub> values by using physiologically based kinetic (PBK) modelling-based reverse dosimetry combined with in silico and in vitro determined PBK model input parameters. The predicted ED<sub>50</sub> values of the studied PEAs for activation of ADRα<sub>1A/B/D</sub>, ADRα<sub>2A</sub>, ADRβ<sub>1</sub> and TAAR1 were within a range of 0.914-29.7 mg/kg body weight (bw), 139-234 mg/kg bw, 0.0839-38.8 mg/kg bw and 0.995-264 mg/kg bw, respectively. Comparison of the predicted ED<sub>50</sub> values with reported intake values revealed that particularly the exposure of the PEA analogues higenamine, isopropyloctopamine, β-methylphenethylamine and p-synephrine is in the same range or exceeds the predicted ED<sub>50</sub> values. This suggests that these PEAs can (in)directly affect the cardiovascular system after the intake of food supplements. These PEA analogues should therefore be considered as high priority compounds for further risk assessment. In conclusion, our study shows that the use of quantitative in vitro-to-in vivo extrapolation (QIVIVE) of adrenergic and TAAR1 potencies using a generic PBK model can serve as an efficient prioritization method for a whole set of chemical analogues.</p>","PeriodicalId":8329,"journal":{"name":"Archives of Toxicology","volume":" ","pages":""},"PeriodicalIF":4.8,"publicationDate":"2025-04-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143771199","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
A silence catalyst: CCL5-mediated intercellular communication in cancer. 沉默的催化剂:癌症中ccl5介导的细胞间通讯。
IF 4.8 2区 医学
Archives of Toxicology Pub Date : 2025-04-01 DOI: 10.1007/s00204-025-04036-w
Wei-Ting Hu, Ming Li, Pei-Jun Ma, Ding Yang, Xiao-Dong Liu, Yun Wang
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