Chemical Research in Toxicology最新文献

{"title":"Role of Ferroptosis Regulation by Nrf2/NQO1 Pathway in Alcohol-Induced Cardiotoxicity In Vitro and In Vivo","authors":"Chunpu Song,&nbsp;Dongjie Li,&nbsp;Ling Huang,&nbsp;Jie Zhang* and Xiaoyan Zhao*,&nbsp;","doi":"10.1021/acs.chemrestox.4c00140","DOIUrl":"10.1021/acs.chemrestox.4c00140","url":null,"abstract":"<p >The aim of the present study was to evaluate the cardiotoxic effects of alcohol and its potential toxic mechanism on ferroptosis in mice and H9c2 cells. Mice were intragastrically treated with three different concentrations of alcohol, 7, 14, and 28%, each day for 14 days. Body weight and electrocardiography (ECG) were recorded over the 14 day period. Serum creatine kinase (CK), lactic dehydrogenase (LDH), MDA, tissue iron, and GSH levels were measured. Cardiac tissues were examined histologically, and ferroptosis was assessed. In H9c2 cardiomyocytes, cell viability, reactive oxygen species (ROS), labile iron pool (LIP), and mitochondrial membrane potential (MMP) were measured. The proteins of ferroptosis were evaluated by the western blot technique in vivo and in vitro. The results showed that serum CK, LDH, MDA, and tissue iron levels significantly increased in the alcohol treatment group in a dose-dependent manner. The content of GSH decreased after alcohol treatment. ECG and histological examinations showed that alcohol impaired cardiac function and structure. In addition, the levels of ROS and LIP increased, and MMP levels decreased after alcohol treatment. Ferrostatin-1 (Fer-1) protected cells from lipid peroxidation. Western blotting analysis showed that alcohol downregulated the expression of Nrf2, NQO1, HO-1, and GPX4. The expressions of P53 and TfR were upregulated in vivo and in vitro. Fer-1 significantly alleviated alcohol-induced ferroptosis. In conclusion, the study showed that Nrf2/NQO1-dependent ferroptosis played a vital role in the cardiotoxicity induced by alcohol.</p>","PeriodicalId":31,"journal":{"name":"Chemical Research in Toxicology","volume":null,"pages":null},"PeriodicalIF":4.1,"publicationDate":"2024-06-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141246835","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":"Protein Haptenation and Its Role in Allergy","authors":"Maja Aleksic*,&nbsp; and ,&nbsp;Xiaoli Meng*,&nbsp;","doi":"10.1021/acs.chemrestox.4c00062","DOIUrl":"10.1021/acs.chemrestox.4c00062","url":null,"abstract":"<p >Humans are exposed to numerous electrophilic chemicals either as medicines, in the workplace, in nature, or through use of many common cosmetic and household products. Covalent modification of human proteins by such chemicals, or protein haptenation, is a common occurrence in cells and may result in generation of antigenic species, leading to development of hypersensitivity reactions. Ranging in severity of symptoms from local cutaneous reactions and rhinitis to potentially life-threatening anaphylaxis and severe hypersensitivity reactions such as Stephen-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN), all these reactions have the same Molecular Initiating Event (MIE), i.e. haptenation. However, not all individuals who are exposed to electrophilic chemicals develop symptoms of hypersensitivity. In the present review, we examine common chemistry behind the haptenation reactions leading to formation of neoantigens. We explore simple reactions involving single molecule additions to a nucleophilic side chain of proteins and complex reactions involving multiple electrophilic centers on a single molecule or involving more than one electrophilic molecule as well as the generation of reactive molecules from the interaction with cellular detoxification mechanisms. Besides generation of antigenic species and enabling activation of the immune system, we explore additional events which result directly from the presence of electrophilic chemicals in cells, including activation of key defense mechanisms and immediate consequences of those reactions, and explore their potential effects. We discuss the factors that work in concert with haptenation leading to the development of hypersensitivity reactions and those that may act to prevent it from developing. We also review the potential harnessing of the specificity of haptenation in the design of potent covalent therapeutic inhibitors.</p>","PeriodicalId":31,"journal":{"name":"Chemical Research in Toxicology","volume":null,"pages":null},"PeriodicalIF":4.1,"publicationDate":"2024-06-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://pubs.acs.org/doi/epdf/10.1021/acs.chemrestox.4c00062","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141246818","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The Selective SIRT3 Inhibitor 3-TYP Represses Primary Myeloma Growth by Reducing c-Myc Stability","authors":"Yindi Zeng,&nbsp;Yaxin zhang,&nbsp;Zeyu Cui,&nbsp;Jiwei Mao,&nbsp;Jinge Xu* and Ruosi Yao*,&nbsp;","doi":"10.1021/acs.chemrestox.4c00142","DOIUrl":"10.1021/acs.chemrestox.4c00142","url":null,"abstract":"<p >Multiple myeloma is a hematological cancer that can be treated but remains incurable. With the advancement of science and technology, more drugs have been developed for myeloma chemotherapy that greatly improve the quality of life of patients. However, relapse remains a serious problem puzzling patients and doctors. Thus, developing more highly active and specific inhibitors is urgent for myeloma-targeted therapy. In this study, we identified the SIRT3 inhibitor 3-TYP (3-(1<i>H</i>-1,2,3-triazol-4-yl) pyridine) after screening a histone modification compound library, which showed high cytotoxicity and induced DNA damage in myeloma cells. Furthermore, the inhibitory effect of 3-TYP in our xenograft tumor studies also confirmed that compound 3-TYP could inhibit primary myeloma growth by reducing c-Myc protein stability by decreasing c-Myc Ser62 phosphorylation levels. Taken together, the results of our study identified 3-TYP as a novel c-Myc inhibitor, which could be a potential chemotherapeutic agent to target multiple myeloma.</p>","PeriodicalId":31,"journal":{"name":"Chemical Research in Toxicology","volume":null,"pages":null},"PeriodicalIF":4.1,"publicationDate":"2024-05-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141178048","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":"Quantum Mechanical Assessment of Nitrosamine Potency","authors":"Sriman De,&nbsp;Bishnu Thapa,&nbsp;Fareed Bhasha Sayyed*,&nbsp;Scott A. Frank,&nbsp;Paul D. Cornwell and Robert A. Jolly*,&nbsp;","doi":"10.1021/acs.chemrestox.4c00087","DOIUrl":"10.1021/acs.chemrestox.4c00087","url":null,"abstract":"<p >Nitrosamines are in the cohort of concern (CoC) as determined by regulatory guidance. CoC compounds are considered highly potent carcinogens that need to be limited below the threshold of toxicological concern, 1.5 μg/day. Nitrosamines like NDMA and NDEA require strict control, while novel nitrosamine drug substance-related impurities (NDSRIs) may or may not be characterized as potent carcinogens. A risk assessment based on the structural features of NDSRIs is important in order to predict potency because they lack substance-specific carcinogenicity. Herein, we present a quantum mechanical (QM)-based analysis on structurally diverse sets of nitrosamines to better understand how structure influences the reactivity that could result in carcinogenicity. We describe the potency trend through activation energies corresponding to α-hydroxylation, aldehyde formation, diazonium intermediate formation, reaction with DNA base, and hydrolysis reactions, and other probable metabolic pathways associated with the carcinogenicity of nitrosamines. We evaluated activation energies for selected cases such as <i>N</i>-nitroso pyrrolidines, <i>N</i>-nitroso piperidines, <i>N</i>-nitroso piperazines, <i>N</i>-nitroso morpholines, <i>N</i>-nitroso thiomorpholine, <i>N</i>-methyl nitroso aromatic, fluorine-substituted nitrosamines, and substituted aliphatic nitrosamines. We compare these results to the recent framework of the carcinogenic potency characterization approach (CPCA) proposed by health authorities which is meant to give guidance on acceptable intakes (AI) for NDSRIs lacking substance-specific carcinogenicity data. We show examples where QM modeling and CPCA are aligned and examples where CPCA both underestimates and overestimates the AI. In cases where CPCA predicts high potency for NDSRIs, QM modeling can help better estimate an AI. Our results suggest that a combined mechanistic understanding of α-hydroxylation, aldehyde formation, hydrolysis, and reaction with DNA bases could help identify the structural features that underpin the potency of nitrosamines. We anticipate this work will be a valuable addition to the CPCA and provide a more analytical way to estimate AI for novel NDSRIs.</p>","PeriodicalId":31,"journal":{"name":"Chemical Research in Toxicology","volume":null,"pages":null},"PeriodicalIF":4.1,"publicationDate":"2024-05-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141157087","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":"Aristolochic Acid Exposure via Dermal Contact or Inhalation of Herbal Powders: Evidence of Occupational Exposure in Herbalists with Urothelial Cancer","authors":"Hong-Ching Kwok,&nbsp; and ,&nbsp;Wan Chan*,&nbsp;","doi":"10.1021/acs.chemrestox.4c00157","DOIUrl":"10.1021/acs.chemrestox.4c00157","url":null,"abstract":"<p >Emerging evidence showing urothelial cancer in herbalists is linked to aristolochic acid (AA) exposure; however, the exposure pathway remains unclear. Here, we show that dermal contact and inhalation of fine powders of AA-containing herbs are significant occupational AA exposure pathways for herbalists. We initiated the study by quantifying the amount of AA in the AA-containing powder deposited on gloves and face masks worn by the operators of an AA-containing herb grinding machine. Then, we measured the kinetics of dermal absorption and dissolution of AA from fine powders of AA-containing herbs into artificial sweat and surrogate lung fluid. Lastly, we quantified the mutagenic AA-DNA adduct levels formed in the kidneys of mice exposed to AA-containing fine powders through dermal contact. Our findings highlight an urgent occupational risk that should demand implementation of safety standards for herbalists exposed to AA-containing fine powders.</p>","PeriodicalId":31,"journal":{"name":"Chemical Research in Toxicology","volume":null,"pages":null},"PeriodicalIF":4.1,"publicationDate":"2024-05-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141079553","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":"Enhancing hERG Risk Assessment with Interpretable Classificatory and Regression Models","authors":"Igor H. Sanches,&nbsp;Rodolpho C. Braga,&nbsp;Vinicius M. Alves and Carolina Horta Andrade*,&nbsp;","doi":"10.1021/acs.chemrestox.3c00400","DOIUrl":"10.1021/acs.chemrestox.3c00400","url":null,"abstract":"<p >The human Ether-à-go-go-Related Gene (hERG) is a transmembrane protein that regulates cardiac action potential, and its inhibition can induce a potentially deadly cardiac syndrome. <i>In vitro</i> tests help identify hERG blockers at early stages; however, the high cost motivates searching for alternative, cost-effective methods. The primary goal of this study was to enhance the Pred-hERG tool for predicting hERG blockage. To achieve this, we developed new QSAR models that incorporated additional data, updated existing classificatory and multiclassificatory models, and introduced new regression models. Notably, we integrated SHAP (SHapley Additive exPlanations) values to offer a visual interpretation of these models. Utilizing the latest data from ChEMBL v30, encompassing over 14,364 compounds with hERG data, our binary and multiclassification models outperformed both the previous iteration of Pred-hERG and all publicly available models. Notably, the new version of our tool introduces a regression model for predicting hERG activity (pIC50). The optimal model demonstrated an <i>R</i>² of 0.61 and an RMSE of 0.48, surpassing the only available regression model in the literature. Pred-hERG 5.0 now offers users a swift, reliable, and user-friendly platform for the early assessment of chemically induced cardiotoxicity through hERG blockage. The tool provides versatile outcomes, including (i) classificatory predictions of hERG blockage with prediction reliability, (ii) multiclassificatory predictions of hERG blockage with reliability, (iii) regression predictions with estimated pIC₅₀ values, and (iv) probability maps illustrating the contribution of chemical fragments for each prediction. Furthermore, we implemented explainable AI analysis (XAI) to visualize SHAP values, providing insights into the contribution of each feature to binary classification predictions. A consensus prediction calculated based on the predictions of the three developed models is also present to assist the user’s decision-making process. Pred-hERG 5.0 has been designed to be user-friendly, making it accessible to users without computational or programming expertise. The tool is freely available at http://predherg.labmol.com.br.</p>","PeriodicalId":31,"journal":{"name":"Chemical Research in Toxicology","volume":null,"pages":null},"PeriodicalIF":4.1,"publicationDate":"2024-05-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://pubs.acs.org/doi/epdf/10.1021/acs.chemrestox.3c00400","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141089646","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Quantification of Free Radicals from Vaping Electronic Cigarettes Containing Nicotine Salt Solutions with Different Organic Acid Types and Concentrations","authors":"Lillian N. Tran,&nbsp;Guodong Rao,&nbsp;Nicholas E. Robertson,&nbsp;Haylee C. Hunsaker,&nbsp;Elizabeth Y. Chiu,&nbsp;Brett A. Poulin,&nbsp;Amy K. Madl,&nbsp;Kent E. Pinkerton,&nbsp;R. David Britt and Tran B. Nguyen*,&nbsp;","doi":"10.1021/acs.chemrestox.4c00065","DOIUrl":"10.1021/acs.chemrestox.4c00065","url":null,"abstract":"<p >Electronic (e-) cigarette formulations containing nicotine salts from a range of organic acid conjugates and pH values have dominated the commercial market. The acids in the nicotine salt formulations may alter the redox environment in e-cigarettes, impacting free radical formation in e-cigarette aerosol. Here, the generation of aerosol mass and free radicals from a fourth-generation e-cigarette device was evaluated at 2 wt % nicotine salts (pH 7, 30:70 mixture propylene glycol to vegetable glycerin) across eight organic acids used in e-liquids: benzoic acid (BA), salicylic acid (SLA), lactic acid (LA), levulinic acid (LVA), succinic acid (SA), malic acid (MA), tartaric acid (TA), and citric acid (CA). Furthermore, 2 wt % BA nicotine salts were studied at the following nicotine to acid ratios: 1:2 (pH 4), 1:1 (pH 7), and 2:1 (pH 8), in comparison with freebase nicotine (pH 10). Radical yields were quantified by spin-trapping and electron paramagnetic resonance (EPR) spectroscopy. The EPR spectra of free radicals in the nicotine salt aerosol matched those generated from the Fenton reaction, which are primarily hydroxyl (OH) radicals and other reactive oxygen species (ROS). Although the aerosol mass formation was not significantly different for most of the tested nicotine salts and acid concentrations, notable ROS yields were observed only from BA, CA, and TA under the study conditions. The e-liquids with SLA, LA, LVA, SA, and MA produced less ROS than the 2 wt % freebase nicotine e-liquid, suggesting that organic acids may play dual roles in the production and scavenging of ROS. For BA nicotine salts, it was found that the ROS yield increased with a higher acid concentration (or a lower nicotine to acid ratio). The observation that BA nicotine salts produce the highest ROS yield in aerosol generated from a fourth-generation vape device, which increases with acid concentration, has important implications for ROS-mediated health outcomes that may be relevant to consumers, manufacturers, and regulatory agencies.</p>","PeriodicalId":31,"journal":{"name":"Chemical Research in Toxicology","volume":null,"pages":null},"PeriodicalIF":4.1,"publicationDate":"2024-05-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://pubs.acs.org/doi/epdf/10.1021/acs.chemrestox.4c00065","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141079592","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Ozonolysis of Terpene Flavor Additives in Vaping Emissions: Elevated Production of Reactive Oxygen Species and Oxidative Stress","authors":"Wonsik Woo,&nbsp;Linhui Tian,&nbsp;Michael Lum,&nbsp;Alexa Canchola,&nbsp;Kunpeng Chen and Ying-Hsuan Lin*,&nbsp;","doi":"10.1021/acs.chemrestox.4c00051","DOIUrl":"10.1021/acs.chemrestox.4c00051","url":null,"abstract":"<p >The production of e-cigarette aerosols through vaping processes is known to cause the formation of various free radicals and reactive oxygen species (ROS). Despite the well-known oxidative potential and cytotoxicity of fresh vaping emissions, the effects of chemical aging on exhaled vaping aerosols by indoor atmospheric oxidants are yet to be elucidated. Terpenes are commonly found in e-liquids as flavor additives. In the presence of indoor ozone (O₃), e-cigarette aerosols that contain terpene flavorings can undergo chemical transformations, further producing ROS and reactive carbonyl species. Here, we simulated the aging process of the e-cigarette emissions in a 2 m³ FEP film chamber with 100 ppbv of O₃ exposure for an hour. The aged vaping aerosols, along with fresh aerosols, were collected to detect the presence of ROS. The aged particles exhibited 2- to 11-fold greater oxidative potential, and further analysis showed that these particles formed a greater number of radicals in aqueous conditions. The aging process induced the formation of various alkyl hydroperoxides (ROOH), and through iodometric quantification, we saw that our aged vaping particles contained significantly greater amounts of these hydroperoxides than their fresh counterparts. Bronchial epithelial cells exposed to aged vaping aerosols exhibited an upregulation of the oxidative stress genes, <i>HMOX-1</i> and <i>GSTP1</i>, indicating the potential for inhalation toxicity. This work highlights the indirect danger of vaping in environments with high ground-level O₃, which can chemically transform e-cigarette aerosols into new particles that can induce greater oxidative damage than fresh e-cigarette aerosols. Given that the toxicological characteristics of e-cigarettes are mainly associated with the inhalation of fresh aerosols in current studies, our work may provide a perspective that characterizes vaping exposure under secondhand or thirdhand conditions as a significant health risk.</p>","PeriodicalId":31,"journal":{"name":"Chemical Research in Toxicology","volume":null,"pages":null},"PeriodicalIF":4.1,"publicationDate":"2024-05-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://pubs.acs.org/doi/epdf/10.1021/acs.chemrestox.4c00051","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141079555","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Tox24 Challenge","authors":"Igor V. Tetko*,&nbsp;","doi":"10.1021/acs.chemrestox.4c00192","DOIUrl":"10.1021/acs.chemrestox.4c00192","url":null,"abstract":"","PeriodicalId":31,"journal":{"name":"Chemical Research in Toxicology","volume":null,"pages":null},"PeriodicalIF":4.1,"publicationDate":"2024-05-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141069532","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":"Cel-CS1K: A Celastrol–Chitosan Conjugate for Treating Diet-Induced Obesity","authors":"Huahui Zeng,&nbsp;Qikang Tian,&nbsp;Can Wang,&nbsp;Xin Zhu,&nbsp;Wenyang Li,&nbsp;Hang Guo,&nbsp;Zhenqiang Zhang* and Xiangxiang Wu*,&nbsp;","doi":"10.1021/acs.chemrestox.4c00018","DOIUrl":"10.1021/acs.chemrestox.4c00018","url":null,"abstract":"<p >Celastrol (Cel), extracted from <i>Tripterygium wilfordii</i> <i>Hook</i>, is a potential antiobesity drug, except for its adverse reactions in clinic. In the present study, we synthesized a promising celastrol–chitosan conjugate (Cel-CS1K) and evaluated its antiobesity effect and biological safety in diet-induced obese mice. Cel-CS1K showed higher drug loading (over 10 wt %), good solubility (18–19 mg/mL) in water, slower peak time (<i>T</i>_max = 4 h), and clearance (<i>T</i>_1/2 = 8.97 h) in rats. Cel-CS1K effectively attenuated the cytotoxicity, celastrol-induced apoptosis, and fat accumulation of hepatocytes. Cel-CS1K reduced body weight and dietary amount same as the free Cel but with lower toxicity in blood, liver, and testis. Cel-CS1K improved the glucose homeostasis, HDL-C level, insulin sensitivity, and leptin sensitivity, while it significantly reduced the gene expression levels of LDL-C, TG, and TC in obese mice. Furthermore, the adipose-related gene expression levels provided evidence in support of a role for Cel-CS1K in losing weight by the multimode regulation. Overall, Cel-CS1K provides a translatable therapeutic strategy for the treatment of diet-induced obese humans.</p>","PeriodicalId":31,"journal":{"name":"Chemical Research in Toxicology","volume":null,"pages":null},"PeriodicalIF":4.1,"publicationDate":"2024-05-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141074633","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}