Chemical Research in Toxicology最新文献

{"title":"Environmental Stability Determines the Cytotoxicity of Metal-Organic Frameworks to a Nitrogen-Fixing Bacterium <i>Azotobacter vinelandii</i>.","authors":"Ziqi Tang, Chengzhuang Liang, Qinmei Zhong, Jinwei Yang, Yusen Ma, Yue Yuan, Yiming Zeng, Xian Wu, Sheng-Tao Yang","doi":"10.1021/acs.chemrestox.4c00385","DOIUrl":"https://doi.org/10.1021/acs.chemrestox.4c00385","url":null,"abstract":"<p><p>During widespread applications of metal-organic frameworks (MOFs), the environmental hazards and risks of MOFs have aroused great concerns. In this study, we aimed to reveal the importance of the environmental stability of MOFs on their toxicity. Two Zn-MOFs, namely, ZIF-8 with high aqueous stability and Zn-BDC with low aqueous stability, were compared directly in the toxicological evaluations of a nitrogen-fixing bacterium <i>Azotobacter vinelandii</i>. Zn-BDC showed strong cytotoxicity at 100 mg/L and higher, inducing growth inhibition, cell apoptosis, structural changes, oxidative damage, and, consequently, loss of nitrogen fixation ability. In contrast, ZIF-8 was nearly nontoxic to <i>A. vinelandii</i>. The transcriptome analysis showed that Zn-BDC directly disturbed the ribosome pathway and lowered the expression level of nitrogen-fixing <i>nif</i> cluster genes. On the other hand, ZIF-8 stress could regulate the flagellar assembly, siderophore group nonribosomal peptide biosynthesis, bacterial chemotaxis, and amino sugar and nucleotide sugar metabolism pathways to promote the cell growth of <i>A. vinelandii</i>. Beyond that, the toxicity of Zn-MOFs to <i>A. vinelandii</i> was associated with the release of Zn²⁺, but Zn-MOFs were less toxic than the mixtures of their starting materials. Overall, our results suggested that the environmental stability of Zn-MOFs determined their environmental toxicity through different molecular pathways. Designing stable MOFs is preferred due to environment-friendly considerations.</p>","PeriodicalId":31,"journal":{"name":"Chemical Research in Toxicology","volume":" ","pages":""},"PeriodicalIF":3.7,"publicationDate":"2024-11-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142666418","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Plant-Derived and Synthetic Nicotine in E-Cigarettes: Is Differentiation with NMR Spectroscopy Possible?","authors":"Yulia B Monakhova, Klaudia Adels, Bernd W K Diehl","doi":"10.1021/acs.chemrestox.4c00398","DOIUrl":"https://doi.org/10.1021/acs.chemrestox.4c00398","url":null,"abstract":"<p><p>To circumvent regulatory frameworks, many producers start to substitute plant-derived nicotine (tobacco-derived nicotine, TDN) by synthetic nicotine (tobacco-free nicotine, TFN) in e-cigarette products. Due to the higher costs of enantiomeric synthesis and purification of TFN, there is a need to develop an analytical method that clearly distinguishes between the two sources. To trace nicotine's origin, its enantiomeric purity can be postulated by ¹H NMR spectroscopy using (<i>R</i>)-(-)-1,1'-binaphthyl-2,2'-diyl hydrogen phosphate (BNPPA) as a chiral complexing agent. Low-field (LF) NMR conditions were optimized for this purpose even using a small amount of e-liquid sample (limit of quantification 8 mg/mL nicotine). All investigated products were found to contain one isomer (most likely (<i>S</i>)-(-)-nicotine). A direct ¹³C NMR method at natural abundance has been validated to differentiate (<i>S</i>)-TDN and (<i>S</i>)-TFN in e-cigarettes produced using nicotine of different origin. The method is based on calculation of the relative ¹³C content of 10 C-positions of the nicotine molecule with intraday and interday precisions below <0.2%. The method was applied to 12 commercial e-cigarette products labeled as containing TDN and TFN. Principal component analysis (PCA) was applied to the relative peak areas to visualize the difference between studied products. The LF ¹H NMR method is a good alternative to expensive high-field NMR to differentiate between a racemate mixture and single optical isomers, whereas only high-precision ¹³C NMR can be used to distinguish (<i>S</i>)-TDN and (<i>S</i>)-TFN in e-cigarettes after appropriate sample extraction.</p>","PeriodicalId":31,"journal":{"name":"Chemical Research in Toxicology","volume":" ","pages":""},"PeriodicalIF":3.7,"publicationDate":"2024-11-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142638018","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Metabolic Activation and Cytotoxicity of Donepezil Induced by CYP3A4.","authors":"Jiannan Zheng, Guode Zhao, Zixia Hu, Chenyang Jia, Weiwei Li, Ying Peng, Jiang Zheng","doi":"10.1021/acs.chemrestox.4c00357","DOIUrl":"https://doi.org/10.1021/acs.chemrestox.4c00357","url":null,"abstract":"<p><p>Donepezil (DNP) is a selective cholinesterase inhibitor widely used for the therapy of Alzheimer's disease. Instances of liver injury correlated with DNP treatment have been reported, yet the underlying hepatotoxic mechanism remains to be elucidated. This study aimed to explore the contribution of metabolic activation to the hepatotoxicity of DNP. The structure of 6-<i>O</i>-desmethyl DNP (M1), the oxidative metabolite of DNP, was characterized by chemical synthesis, LC-MS/MS, and nuclear magnetic resonance. A reactive quinone methide resulting from the metabolism of DNP was captured by glutathione (GSH) fortified in liver microsomal incubations after exposure to DNP, and the resulting GSH conjugate (M2) was detected in the bile of rats receiving DNP. Recombinant human P450 enzyme incubation studies demonstrated that CYP3A4 was the principal enzyme responsible for the production of M1 and M2. The generation of M2 declined in rat primary hepatocytes pretreated with ketoconazole, an inhibitor of CYP3A4, which also decreased the vulnerability of rat primary hepatocytes to DNP-caused cytotoxicity. These findings suggest that the quinone methide metabolite may contribute to the cytotoxicity and hepatotoxicity caused by the DNP.</p>","PeriodicalId":31,"journal":{"name":"Chemical Research in Toxicology","volume":" ","pages":""},"PeriodicalIF":3.7,"publicationDate":"2024-11-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142638017","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Capturing Differential Quality of Experimental Evidence in a Predictive Quantum-Mechanical Model for Respiratory Sensitization.","authors":"Jakub Kostal, Joshua Vaughan, Kamila Blum, Adelina Voutchkova-Kostal","doi":"10.1021/acs.chemrestox.4c00289","DOIUrl":"https://doi.org/10.1021/acs.chemrestox.4c00289","url":null,"abstract":"<p><p>Asthma is of concern in occupational toxicology with significant public-health and economic costs. In the absence of benchmark in vivo and in vitro tests, the use of mechanistically sound in silico models is critical to inform hazard and to protect workers from exposure to potentially harmful substances. We recently reported on the computer-aided discovery and REdesign (CADRE) model for respiratory sensitization, which relies on a tiered structure of expert rules, molecular simulations, quantum-mechanics calculations and advanced statistics to accurately identify respiratory sensitizers from first principles. Here, we present an update to this model based on two years of testing in the pharmaceutical space, where we captured the heterogeneity of the underlying experimental evidence in two predictive tiers, thus allowing the practitioner to select an outcome based on their expert assessment of the data reliability and relevance. This user-based tuning of predictive models is critical for end points that lack consensus on what constitutes satisfactory evidence to support a decision in the handling of chemicals for occupational safety.</p>","PeriodicalId":31,"journal":{"name":"Chemical Research in Toxicology","volume":" ","pages":""},"PeriodicalIF":3.7,"publicationDate":"2024-11-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142612678","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"JAK/STAT signaling maintains an intermediate cell population during prostate basal cell fate determination","authors":"Wangxin Guo, Xiaoyu Zhang, Lin Li, Pengfei Shao, Chao Liang, Hongjiong Zhang, Kuo Liu, Shuoming Wang, Yunyi Peng, Jun Luo, Yi Ju, Angelo M. De Marzo, Chen Yu, Luonan Chen, Bin Zhou, Dong Gao","doi":"10.1038/s41588-024-01979-1","DOIUrl":"https://doi.org/10.1038/s41588-024-01979-1","url":null,"abstract":"<p>Unipotent basal and luminal stem cells maintain prostate homeostasis, with an intermediate cell population emerging during prostate inflammation or cancer. However, the identities of basal stem cell and intermediate cell population remain unclear. Here we identified a rare intermediate cell population expressing luminal markers (termed Basal-B) with enhanced organoid formation capacity, and a larger basal population (termed Basal-A). Genetic lineage tracing revealed Basal-B cells represented a transient basal stem cell state during prostate homeostasis and androgen-mediated regeneration. Activated JAK/STAT signaling was identified in Basal-B cells, and its inhibition significantly reduced Basal-B markers expression. Inflammation increased Basal-B-to-luminal cell transdifferentiation, but JAK/STAT inhibition notably attenuated this effect. <i>Pten</i> gene deletion increased Nkx3.1-expressing Basal-B-like cell population and led to neoplasia. In humans, h-Basal-B cells were more prevalent in benign prostate hyperplasia. This study reveals the identities of intermediate Basal-B cells and underscores the role of JAK/STAT signaling in prostate cell fate determination.</p>","PeriodicalId":31,"journal":{"name":"Chemical Research in Toxicology","volume":"16 1","pages":""},"PeriodicalIF":30.8,"publicationDate":"2024-11-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142601020","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Growth hormone-releasing hormone and its analogues in health and disease","authors":"Riccarda Granata, Sheila Leone, Xianyang Zhang, Iacopo Gesmundo, Charlotte Steenblock, Renzhi Cai, Wei Sha, Ezio Ghigo, Joshua M. Hare, Stefan R. Bornstein, Andrew V. Schally","doi":"10.1038/s41574-024-01052-1","DOIUrl":"https://doi.org/10.1038/s41574-024-01052-1","url":null,"abstract":"<p>Growth hormone-releasing hormone (GHRH) and its ability to stimulate the production and release of growth hormone from the pituitary were discovered more than four decades ago. Since then, this hormone has been studied extensively and research into its functions is still ongoing. GHRH has multifaceted roles beyond the originally identified functions that encompass a variety of direct extrapituitary effects. In this Review, we illustrate the different biological activities of GHRH, covering the effects of GHRH agonists and antagonists in physiological and pathological contexts, along with the underlying mechanisms. GHRH and GHRH analogues have been implicated in cell growth, wound healing, cell death, inflammation, immune functions, mood disorders, feeding behaviour, neuroprotection, diabetes mellitus and obesity, as well as cardiovascular, lung and neurodegenerative diseases and some cancers. The positive effects observed in preclinical models in vitro and in vivo strongly support the potential use of GHRH agonists and antagonists as clinical therapeutics.</p>","PeriodicalId":31,"journal":{"name":"Chemical Research in Toxicology","volume":"196 1","pages":""},"PeriodicalIF":40.5,"publicationDate":"2024-11-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142601203","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Quantitative Structure-Activity Relationship Models to Predict Cardiac Adverse Effects.","authors":"Zhongyu Mou, Patra Volarath, Rebecca Racz, Kevin P Cross, Mounika Girireddy, Suman Chakravarti, Lidiya Stavitskaya","doi":"10.1021/acs.chemrestox.4c00186","DOIUrl":"https://doi.org/10.1021/acs.chemrestox.4c00186","url":null,"abstract":"<p><p>Drug-induced cardiotoxicity represents one of the most common causes of attrition of drug candidates in preclinical and clinical development. For this reason, the evaluation of cardiac toxicity is essential during drug development and regulatory review. In the present study, drug-induced postmarket adverse event combinations from the FDA Adverse Event Reporting System were extracted for 2002 drugs using 243 cardiac toxicity-related preferred terms (PTs). These PTs were combined into 12 groups based on their clinical relevance to serve as training sets. The optimal classification scheme was determined using a combination of data sources that included drug labeling information, published literature, clinical study data, and postmarket surveillance data. Two commercial QSAR platforms were used to construct 12 models, including general cardiac toxicity, cardiac ischemia, heart failure, cardiac valve disease, myocardial disease, pericardial disease, structural heart disease, cardiac arrhythmia, Torsades de Pointes, long QT syndrome, atrial fibrillation and ventricular arrhythmia, and cardiac arrest. The cross-validated performance for the new models reached a sensitivity of up to 80% and negative predictivity of up to 80%. These new models covering a wide range of cardiac endpoints will provide fast, reliable, and comprehensive predictions of potential cardiotoxic compounds in drug discovery and regulatory safety assessment.</p>","PeriodicalId":31,"journal":{"name":"Chemical Research in Toxicology","volume":" ","pages":""},"PeriodicalIF":3.7,"publicationDate":"2024-11-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142612685","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Chemical Composition of Aerosols from the E-Cigarette Vaping of Natural and Synthetic Cannabinoids.","authors":"Nicholas E Robertson, Jack Connolly, Nikolay Shevchenko, Mark Mascal, Kent E Pinkerton, Sascha C T Nicklisch, Tran B Nguyen","doi":"10.1021/acs.chemrestox.4c00326","DOIUrl":"https://doi.org/10.1021/acs.chemrestox.4c00326","url":null,"abstract":"<p><p>Vaping cannabinoids in electronic (e)-cigarette devices is rapidly increasing in popularity, particularly among adolescents, although the chemistry affecting the composition of the vape aerosol is not well understood. This work investigates the formation of aerosol mass, bioactive hydroxyquinones, and harmful or potentially harmful carbonyls from the e-cigarette vaping of natural and synthetic cannabinoids e-liquids in propylene glycol and vegetable glycerin (PG/VG) solvent at a 50 mg/mL concentration in a commercial fourth-generation vaping device. The following cannabinoids were studied: cannabidiol (CBD), 8,9-dihydrocannabidiol (H2CBD), 1,2,8,9-tetrahydrocannabidiol (H4CBD), cannabigerol (CBG), and cannabidiolic acid (CBDA). Quantification of analytes was performed using liquid chromatography coupled to accurate mass spectrometry. The addition of cannabinoids significantly increased aerosol and carbonyl formation compared with the PG/VG solvent alone. All cannabinoids in the study formed hydroxyquinones during vaping (up to ∼1% mass conversion) except for CBDA, which primarily decarboxylated to CBD. Hydroxyquinone formation increased and carbonyl formation decreased, with a decreasing number of double bonds among CBD and its synthetic analogues (H2CBD and H4CBD). During the vaping process, ∼3-6% of the cannabinoid mass can be observed as carbonyls under the study conditions. Oxidation of the terpene moiety on the cannabinoids is proposed as a major contributor to carbonyl formation. CBD produced significantly higher concentrations of formaldehyde, acetaldehyde, acrolein, diacetyl, and methylglyoxal compared with the other cannabinoid samples. CBG produced significantly higher levels of acetone, methacrolein, and methylglyoxal. Conversion of CBD to tetrahydrocannabinol (THC) was not observed under the study conditions. The chemical mechanism basis for these observations is discussed. Compared with other modalities of use for CBD and other cannabinoids, vaping has the potential to adversely impact human health by producing harmful products during the heated aerosolization process.</p>","PeriodicalId":31,"journal":{"name":"Chemical Research in Toxicology","volume":" ","pages":""},"PeriodicalIF":3.7,"publicationDate":"2024-11-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142612681","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Engineering structural variants to interrogate genome function","authors":"Jonas Koeppel, Juliane Weller, Thomas Vanderstichele, Leopold Parts","doi":"10.1038/s41588-024-01981-7","DOIUrl":"https://doi.org/10.1038/s41588-024-01981-7","url":null,"abstract":"<p>Structural variation, such as deletions, duplications, inversions and complex rearrangements, can have profound effects on gene expression, genome stability, phenotypic diversity and disease susceptibility. Structural variants can encompass up to millions of bases and have the potential to rearrange substantial segments of the genome. They contribute considerably more to genetic diversity in human populations and have larger effects on phenotypic traits than point mutations. Until recently, our understanding of the effects of structural variants was driven mainly by studying naturally occurring variation. New genome-engineering tools capable of generating deletions, insertions, inversions and translocations, together with the discovery of new recombinases and advances in creating synthetic DNA constructs, now enable the design and generation of an extended range of structural variation. Here, we discuss these tools and examples of their application and highlight existing challenges that will need to be overcome to fully harness their potential.</p>","PeriodicalId":31,"journal":{"name":"Chemical Research in Toxicology","volume":"2 1","pages":""},"PeriodicalIF":30.8,"publicationDate":"2024-11-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142599616","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Toward advances in retinoblastoma genetics in Kenya","authors":"Helen Dimaras, Beatrice Omweri, Daniel Muema, Loice Kanda, Rosaline Wanjiru Macharia, John Gitau, Catherine Mutinda, Kahaki Kimani, Wairimu Waweru, Stephen Gichuhi, Marianne W. Mureithi, Lucy Njambi","doi":"10.1038/s41588-024-01974-6","DOIUrl":"https://doi.org/10.1038/s41588-024-01974-6","url":null,"abstract":"Despite extensive advancements in cancer genetics in North America and Europe, the African continent remains underrepresented in this vital research area. Here we highlight a pioneering collaborative project in Kenya, with a focus on expanding cancer genetics services and research into retinoblastoma, a prototypical heritable cancer syndrome.","PeriodicalId":31,"journal":{"name":"Chemical Research in Toxicology","volume":"14 1","pages":""},"PeriodicalIF":30.8,"publicationDate":"2024-11-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142598339","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}