Archives of Toxicology最新文献

{"title":"Effects of metal oxide nanoparticles on healthy and psoriasis-like human epidermal keratinocytes in vitro","authors":"Li Yi Tan,&nbsp;Magdiel Inggrid Setyawati,&nbsp;Kee Woei Ng","doi":"10.1007/s00204-024-03848-6","DOIUrl":"10.1007/s00204-024-03848-6","url":null,"abstract":"<div><p>The use of metal oxide nanoparticles (NPs) in skincare products has significantly increased human skin exposure, raising safety concerns. Whilst NP’s ability to penetrate healthy skin is minimal, studies have demonstrated that metal oxide NPs can induce toxicity in keratinocytes through direct contact. Moreover, NP’s effect on common skin disorders like psoriasis, where barrier impairments and underlying inflammation could potentially increase NP penetration and worsen nanotoxicity is largely unstudied. In this paper, we investigated whether psoriasis-like human keratinocytes (Pso HKs) would exhibit heightened toxic responses to titanium dioxide (TiO₂), zinc oxide (ZnO), and/or silica (SiO₂) NPs compared to healthy HKs. Cells were exposed to each NP at concentrations ranging between 0.5 and 500 µg/ml for 6, 24, and 48 h. Amongst the metal oxide NPs, ZnO NPs produced the most pronounced toxic effects in both cell types, affecting cell viability, inducing oxidative stress, and activating the inflammasome pathway. Notably, only in ZnO NPs-treated Pso HKs, trappin-2/pre-elafin was cleaved intracellularly through a non-canonical process. In addition, tissue remodelling-related cytokines were upregulated in ZnO NP-treated Pso HKs. The full impact of the observed outcomes on psoriatic symptoms will need further evaluation. Nonetheless, our findings indicate the importance of understanding the sub-lethal impacts of NP exposures on keratinocytes, even though direct exposure may be low, particularly in the context of skin disorders where repeated and long-term exposures are anticipated.</p></div>","PeriodicalId":8329,"journal":{"name":"Archives of Toxicology","volume":"98 11","pages":"3689 - 3711"},"PeriodicalIF":4.8,"publicationDate":"2024-08-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142054786","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}

{"title":"Hepatic and metabolic outcomes induced by sub-chronic exposure to polystyrene microplastics in mice","authors":"Sheng-Han Lee,&nbsp;Ting-An Lin,&nbsp;Yuan-Horng Yan,&nbsp;Chu-Chun Chien,&nbsp;Tsun-Jen Cheng","doi":"10.1007/s00204-024-03847-7","DOIUrl":"10.1007/s00204-024-03847-7","url":null,"abstract":"<div><p>Microplastics (MPs) have attracted significant attention due to their global distribution in living environments. Although some studies have reported MP-induced hepatotoxicity in mouse models, a systematic approach to MP-mediated liver toxicity was still lacking. Therefore, we used a mouse model to study the sub-chronic effects of MP exposure on the liver. Female C57BL/6 mice, aged 6 weeks, received an oral administration of 0.3 mg of Nile Red-labeled polystyrene (PS) microplastics, with particle sizes of 0.5 µm (submicron) and 5 µm (micron), via gavage, while control mice received vehicle only. Each mouse was exposed to MPs twice a week for 12 weeks. After sacrifice, the levels of MP accumulation, oxidative stress, inflammation, and pathological changes were measured in the mouse liver, and blood samples were collected for serum biochemistry analysis. Our results demonstrated that 0.5 µm PS-MPs were accumulated in mouse livers post-MP exposure, but not in the 5 µm MP exposure group. Simultaneously, increased levels of glucose, triglyceride, alanine transaminase (ALT), aspartate transaminase (AST), superoxide dismutase, 4-hydroxy-2-nonenal-mercapturic acid (HNE-MA), interleukin-6, and lipid droplets were found in the 0.5 µm MP exposure group, while the fewer responses, including elevated liver weight index, glucose, high-density lipoprotein, AST, and decreased HNE-MA were observed in 5 µm MP exposure group. These results indicate that sub-chronic exposure to submicron MPs causes MP deposition in mouse livers, which further induces oxidative stress, increases inflammatory cytokines and perturbs glucose and lipid homeostasis, which might trigger more severe metabolic dysfunction or non-alcoholic steatohepatitis-like hepatotoxicity.</p></div>","PeriodicalId":8329,"journal":{"name":"Archives of Toxicology","volume":"98 11","pages":"3811 - 3823"},"PeriodicalIF":4.8,"publicationDate":"2024-08-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142054787","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}

{"title":"Proteomic diversity of Russell's viper venom: exploring PLA2 isoforms, pharmacological effects, and inhibitory approaches","authors":"Kishore Srinivasan,&nbsp;Madhavan Nampoothiri,&nbsp;Shweta Khandibharad,&nbsp;Shailza Singh,&nbsp;Akshatha Ganesh Nayak,&nbsp;Raghu Chandrashekar Hariharapura","doi":"10.1007/s00204-024-03849-5","DOIUrl":"10.1007/s00204-024-03849-5","url":null,"abstract":"<div><p>Snakebite envenomation is a serious health concern in tropical regions, resulting in high mortality. The World Health Organization (WHO) has declared it a neglected tropical disease and is working on strategies to reduce mortality. Russell’s viper (<i>Daboia russelii</i>) is one of the most abundant venomous snakes found across Southeast Asia. Proteomic analysis of Russell’s viper venom has demonstrated variation, with phospholipase A2 (PLA2) being the most abundant toxin across geographic boundaries. PLA2, a major constituent of the low-molecular-weight fraction of snake venom, hydrolyses phospholipids at the sn-2 position, releasing arachidonic acid and lysophospholipids. They are reported to cause various pharmacological effects, including hemolysis, anticoagulation, neurotoxicity, myotoxicity, and oedema. Though administration of antivenoms (ASV) is the primary treatment for envenomation, it has many drawbacks. Besides causing hypersensitivity reactions and life-threatening anaphylaxis, treatment with ASV is further complicated due to its inability to neutralize low-molecular-weight toxins. Thus, there is a greater need to produce next-generation antivenoms that can target specific toxins in the venom. In this review, we explored the classification of Russell’s viper and the variation in its proteomic profile across Southeast Asia to date. In addition, we have also summarized the mechanism of action of PLA2 and discussed various isoforms of PLA2 found across different regions with their respective pharmacological effects. Finally, the drawbacks of commercially available antivenoms and the molecules investigated for inhibiting the low-molecular-weight toxin, PLA2 are discussed.</p></div>","PeriodicalId":8329,"journal":{"name":"Archives of Toxicology","volume":"98 11","pages":"3569 - 3584"},"PeriodicalIF":4.8,"publicationDate":"2024-08-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://link.springer.com/content/pdf/10.1007/s00204-024-03849-5.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142054788","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Genotoxicity of selected cannabinoids in human lymphoblastoid TK6 cells","authors":"Nicol Kolar,&nbsp;Ezgi Eyluel Bankoglu,&nbsp;Helga Stopper","doi":"10.1007/s00204-024-03826-y","DOIUrl":"10.1007/s00204-024-03826-y","url":null,"abstract":"<div><p>Natural non-psychoactive cannabinoids such as cannabigerol (CBG), cannabidiol (CBD), cannabichromene (CBC), cannabidivarin (CBDV), and cannabinol (CBN) are increasingly consumed as constituents of dietary products because of the health benefits claims. Cannabinoids may reduce certain types of pain, nausea, and anxiety. Anti-inflammatory and even anti-carcinogenic properties have been discussed. However, there are insufficient data available regarding their potential (geno-)toxic effects. Therefore, we tested CBG, CBD, CBC, CBDV, and CBN for their genotoxic potential and effects on mitosis and cell cycle in human lymphoblastoid TK6 cells. The selected cannabinoids (except CBDV) induced increased micronuclei formation, which was reduced with the addition of a metabolic activation system (S9 mix). CBDV induced micronuclei only after metabolic activation. Mitotic disturbances were observed with all tested cannabinoids, while G1 phase accumulation of cells was observed for CBG, CBD and CBDV. The genotoxic effects occurred at about 1000-fold higher concentrations than are reported as blood levels from human consumption. However, the results clearly indicate a need for further research into the genotoxic effects of cannabinoids. The mechanism of the mitotic disturbance, the shape of the dose–response curves and the possible effects of mixtures of cannabinoids are aspects which need clarification.</p></div>","PeriodicalId":8329,"journal":{"name":"Archives of Toxicology","volume":"98 10","pages":"3439 - 3451"},"PeriodicalIF":4.8,"publicationDate":"2024-08-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11402852/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142016185","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Monitoring of per- and polyfluoroalkyl substances (PFAS) in human blood samples collected in three regions with known PFAS releases in the environment and three control regions in South Germany","authors":"Lorena M. Cursino Hron,&nbsp;Mandy Wöckner,&nbsp;Veronika Fuchs,&nbsp;Ludwig Fembacher,&nbsp;Bettina Aschenbrenner,&nbsp;Caroline Herr,&nbsp;Wolfgang Schober,&nbsp;Stefanie Heinze,&nbsp;Wolfgang Völkel","doi":"10.1007/s00204-024-03843-x","DOIUrl":"10.1007/s00204-024-03843-x","url":null,"abstract":"<div><p>Per- and polyfluoroalkyl substances (PFAS) are known as persistent and bioaccumulative chemicals. The present paper describes the analysis of 969 human blood samples collected in South Germany aiming to determine whether there are statistic significant differences in internal PFAS burden between three regions with known PFAS releases in the environment (study regions) and three regions without known PFAS releases in the environment (control regions). Nine environmental relevant PFAS were analyzed, including the perfluorooctanoic acid (PFOA) substitute 3H-perfluoro-3-[(3-methoxy-propoxy)propanoic acid] ammonium salt (ADONA). We found that concentrations of PFOA and perfluorooctane sulfonate (PFOS) were higher than for all other PFAS in all of the six regions, but all medians of PFOA (between 0.8 and 0.9 ng/ml for the study and control regions) and PFOS (between 1.3 and 1.5 ng/ml for the study regions and between 1.4 and 1.5 ng/ml for the control regions) were below the human biomonitoring values (HBM) I for PFOA (2 ng/ml) und for PFOS (5 ng/ml) derived by the German HBM Commission. Concentrations of ADONA were below the limit of quantification in all samples. Minor differences were observed in PFAS blood levels between study and control regions. Especially for PFOS and PFOA the medians for women are slightly lower compared to men. In summary, individuals living in regions with known environmental PFAS contaminations show no higher internal PFAS exposure to controls and in comparison to other studies in the literature.</p></div>","PeriodicalId":8329,"journal":{"name":"Archives of Toxicology","volume":"98 11","pages":"3727 - 3738"},"PeriodicalIF":4.8,"publicationDate":"2024-08-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142016186","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}

{"title":"Optimized methods for measuring competitive binding of chemical substances to thyroid hormone distributor proteins transthyretin and thyroxine binding globulin","authors":"Yang Shen,&nbsp;Toine F. H. Bovee,&nbsp;Douwe Molenaar,&nbsp;Yoran Weide,&nbsp;Antsje Nolles,&nbsp;Carmen Braucic Mitrovic,&nbsp;Stefan P. J. van Leeuwen,&nbsp;Jochem Louisse,&nbsp;Timo Hamers","doi":"10.1007/s00204-024-03842-y","DOIUrl":"10.1007/s00204-024-03842-y","url":null,"abstract":"<div><p>Transthyretin (TTR) and thyroxine-binding globulin (TBG) are two major thyroid hormone (TH) distributor proteins in human plasma, playing important roles in stabilizing the TH levels in plasma, delivery of TH to target tissues, and trans-barrier transport. Binding of xenobiotics to these distributor proteins can potentially affect all these three important roles of distributor proteins. Therefore, fast and cost-effective experimental methods are required for both TTR and TBG to screen both existing and new chemicals for their potential binding. In the present study, the TTR-binding assay was therefore simplified, optimized and pre-validated, while a new TBG-binding assay was developed based on fluorescence polarization as a readout. Seven model compounds (including positive and negative controls) were tested in the pre-validation study of the optimized TTR-binding assay and in the newly developed TBG-binding assay. The dissociation constants of the natural ligand (thyroxine, T4) and potential competitors were determined and compared between two distributor proteins, showing striking differences for perfluorooctanesulfonic acid (PFOS) and perfluorooctanoic acid (PFOA).</p></div>","PeriodicalId":8329,"journal":{"name":"Archives of Toxicology","volume":"98 11","pages":"3797 - 3809"},"PeriodicalIF":4.8,"publicationDate":"2024-08-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://link.springer.com/content/pdf/10.1007/s00204-024-03842-y.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142016187","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Effects of chronic insecticide exposure on neuronal network development in vitro in rat cortical cultures","authors":"Lennart V. J. van Melis,&nbsp;Anneloes M. Peerdeman,&nbsp;Celia Arenas González,&nbsp;Regina G. D. M. van Kleef,&nbsp;J. Pepijn Wopken,&nbsp;Remco H. S. Westerink","doi":"10.1007/s00204-024-03840-0","DOIUrl":"10.1007/s00204-024-03840-0","url":null,"abstract":"<div><p>Developmental exposure to carbamates, organophosphates, and pyrethroids has been associated with impaired neurodevelopmental outcomes. Sex-specific differences following chronic insecticide exposure are rather common in vivo. Therefore, we assessed the chronic effects of in vitro exposure to different carbamates (carbaryl, methomyl and aldicarb), organophosphates [chlorpyrifos (CPF), chlorpyrifos-oxon (CPO), and 3,5,6,trichloropyridinol (TCP)], and pyrethroids [permethrin, alpha-cypermethrin and 3-phenoxy benzoic acid (3-PBA)] on neuronal network development in sex-separated rat primary cortical cultures using micro-electrode array (MEA) recordings. Our results indicate that exposure for 1 week to carbaryl inhibited neurodevelopment in male cultures, while a hyperexcitation was observed in female cultures. Methomyl and aldicarb evoked a hyperexcitation after 2 weeks of exposure, which was more pronounced in female cultures. In contrast to acute MEA results, exposure to ≥ 10 µM CPF caused hyperexcitation in both sexes after 10 days. Interestingly, exposure to 10 µM CPO induced a clear hyperexcitation after 10 days of exposure in male but not female cultures. Exposure to 100 µM CPO strongly inhibited neuronal development. Exposure to the type I pyrethroid permethrin resulted in a hyperexcitation at 10 µM and a decrease in neuronal development at 100 µM. In comparison, exposure to ≥ 10 µM of the type II pyrethroid alpha-cypermethrin decreased neuronal development. In female but not in male cultures, exposure to 1 and 10 µM permethrin changed (network) burst patterns, with female cultures having shorter (network) bursts with fewer spikes per (network) burst. Together, these results show that MEA recordings are suitable for measuring sex-specific developmental neurotoxicity in vitro. Additionally, pyrethroid exposure induced effects on neuronal network development at human-relevant concentrations. Finally, chronic exposure has different effects on neuronal functioning compared to acute exposure, highlighting the value of both exposure paradigms.</p></div>","PeriodicalId":8329,"journal":{"name":"Archives of Toxicology","volume":"98 11","pages":"3837 - 3857"},"PeriodicalIF":4.8,"publicationDate":"2024-08-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://link.springer.com/content/pdf/10.1007/s00204-024-03840-0.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142003489","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"How contaminated is flatfish living near World Wars’ munition dumping sites with energetic compounds?","authors":"Edmund Maser,&nbsp;Tobias H. Buenning,&nbsp;Jennifer S. Strehse","doi":"10.1007/s00204-024-03834-y","DOIUrl":"10.1007/s00204-024-03834-y","url":null,"abstract":"<div><p>Seas worldwide are threatened by an emerging source of pollution as millions of tons of warfare materials were dumped after the World Wars. As their metal shells are progressively corroding, energetic compounds (EC) leak out and distribute in the marine environment. EC are taken up by aquatic organisms and pose a threat to both the marine ecosphere and the human seafood consumer because of their toxicity and potential carcinogenicity. Here, sediment samples and fish from different locations in the German North Sea of Lower Saxony were examined to determine whether EC transfer to fish living close to munition dumping areas. EC were found in sediments with a maximum concentration of 1.5 ng/kg. All analyzed fish muscle tissues/fillets and bile samples were positive for EC detection. In bile, the max. EC concentrations ranged between 0.25 and 1.25 ng/mL. Interestingly, while detected TNT metabolites in the muscle tissues were in concentrations of max. 1 ng/g (dry weight), TNT itself was found in concentrations of up to 4 ng/g (dry weight). As we found considerable higher amounts of non-metabolized TNT in the fish muscle, rather than TNT metabolites, we conclude an additional absorption route of EC into fish other than per diet. This is the first study to detect EC in the edible parts of fish caught randomly in the North Sea.</p></div>","PeriodicalId":8329,"journal":{"name":"Archives of Toxicology","volume":"98 11","pages":"3825 - 3836"},"PeriodicalIF":4.8,"publicationDate":"2024-08-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://link.springer.com/content/pdf/10.1007/s00204-024-03834-y.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141999376","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Mono-n-hexyl phthalate: exposure estimation and assessment of health risks based on levels found in human urine samples","authors":"Ralph Pirow,&nbsp;Ulrike Bernauer,&nbsp;Annegret Blume,&nbsp;Adrian Cieszynski,&nbsp;Gabriele Flingelli,&nbsp;Astrid Heiland,&nbsp;Matthias Herzler,&nbsp;Bettina Huhse,&nbsp;Christian Riebeling,&nbsp;Esther Rosenthal,&nbsp;Moustapha Sy,&nbsp;Thomas Tietz,&nbsp;Achim Trubiroha,&nbsp;Andreas Luch","doi":"10.1007/s00204-024-03835-x","DOIUrl":"10.1007/s00204-024-03835-x","url":null,"abstract":"<div><p>Mono-n-hexyl phthalate (MnHexP) is a primary metabolite of di-n-hexyl phthalate (DnHexP) and other mixed side-chain phthalates that was recently detected in urine samples from adults and children in Germany. DnHexP is classified as toxic for reproduction category 1B in Annex VI of Regulation (EC) 1272/2008 and listed in Annex XIV of the European chemical legislation REACH; thereby, its use requires an authorisation. Health-based guidance values for DnHexP are lacking and a full-scale risk assessment has not been carried out under REACH. The detection of MnHexP in urine samples raises questions about the sources of exposure and concerns of consumer safety. Here, we propose the calculation of a provisional oral tolerable daily intake value (TDI) of 63 µg/kg body weight/day for DnHexP and compare it to intake levels corresponding to levels of MnHexP found in urine. The resulting mean intake levels correspond to less than 0.2% of the TDI, and maximum levels to less than 5%. The TDI was derived by means of an approximate probabilistic analysis using the credible interval from benchmark dose modelling of published ex vivo data on reduced foetal testosterone production in rats. Thus, for the dose associated to a 20% reduction in testosterone production, a lower and upper credible interval of 14.9 and 30.0 mg/kg bw/day, respectively, was used. This is considered a conservative approach, since apical developmental endpoints (e.g. changed anogenital distance) were only observed at higher doses. In addition, we modelled various scenarios of the exposure to the precursor substance DnHexP from different consumer products, taking measured contamination levels into account, and estimated systemic exposure doses. Of the modelled scenarios including the application of sunscreen (as a lotion or pump spray), the use of lip balm, and the wearing of plastic sandals, and considering conservative assumptions, the use of DnHexP-contaminated sunscreen was highlighted as a major contributing factor. A hypothetical calculation using conservative assumptions for the latter resulted in a margin of safety in relation to the lower credible interval of 3267 and 1007 for adults and young children, respectively. Most importantly, it was found that only a fraction of the TDI is reached in all studied exposure scenarios. Thus, with regard to the reported DnHexP exposure, a health risk can be considered very unlikely.</p></div>","PeriodicalId":8329,"journal":{"name":"Archives of Toxicology","volume":"98 11","pages":"3659 - 3671"},"PeriodicalIF":4.8,"publicationDate":"2024-08-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://link.springer.com/content/pdf/10.1007/s00204-024-03835-x.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141995153","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Unraveling the AKT/ERK cascade and its role in Parkinson disease","authors":"Priyanka Kumari Keshri,&nbsp;Surya Pratap Singh","doi":"10.1007/s00204-024-03829-9","DOIUrl":"10.1007/s00204-024-03829-9","url":null,"abstract":"<div><p>Parkinson disease represents a significant and growing burden on global healthcare systems, necessitating a deeper understanding of their underlying molecular mechanisms for the development of effective treatments. The AKT and ERK pathways play crucial roles in the disease, influencing multiple cellular pathways that support neuronal survival. Researchers have made notable progress in uncovering how these pathways are controlled by upstream kinases and how their downstream effects contribute to cell signalling. However, as we delve deeper into their intricacies, we encounter increasing complexity, compounded by the convergence of multiple signalling pathways. Many of their targets overlap with those of other kinases, and they not only affect specific substrates but also influence entire signalling networks. This review explores the intricate interplay of the AKT/ERK pathways with several other signalling cascades, including oxidative stress, endoplasmic reticulum stress, calcium homeostasis, inflammation, and autophagy, in the context of Parkinson disease. We discuss how dysregulation of these pathways contributes to disease progression and neuronal dysfunction, highlighting potential therapeutic targets for intervention. By elucidating the complex network of interactions between the AKT/ERK pathways and other signalling cascades, this review aims to provide insights into the pathogenesis of Parkinson disease and describe the development of novel therapeutic strategies.</p></div>","PeriodicalId":8329,"journal":{"name":"Archives of Toxicology","volume":"98 10","pages":"3169 - 3190"},"PeriodicalIF":4.8,"publicationDate":"2024-08-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141970509","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}