Journal of Applied Toxicology最新文献

{"title":"Effect of vehicle on the in vitro penetration and metabolism of genistein and daidzein in ex vivo skin explants and the Phenion full-thickness skin model.","authors":"Camille Géniès, Corinne Jeanjean, Abdulkarim Najjar, Andreas Schepky, Daniela Lange, Jochen Kühnl, Eric Fabian, Anne Zifle, Helene Duplan, Nicola J Hewitt, Carine Jacques","doi":"10.1002/jat.4693","DOIUrl":"10.1002/jat.4693","url":null,"abstract":"<p><p>In a read-across assessment of the safety of genistein and daidzein in cosmetic products, additional information was required to account for differences in their systemic exposure after topical application in a typical body lotion formulation. Therefore, we measured the penetration and metabolism of two doses (3 and 30 nmoles/cm²) of genistein and daidzein applied in ethanol and in a body formulation to fresh pig skin, fresh and frozen human skin, and PhenionFT models. Both chemicals readily penetrated all skin models when applied in ethanol. The same sulfate and glucuronide metabolites were formed in fresh pig skin, fresh human skin, and PhenionFT models, which also all demonstrated that (a) these pathways could be saturated between 3 and 30 nmoles/cm² and (b) the extent of metabolism of daidzein was lower than genistein. Although the relative amounts of radiolabeled chemical in human skin and medium compartments were altered by freezing, their overall bioavailability was not affected. The greatest impact on the bioavailability and distribution of both chemicals was observed when they were applied in the formulation. Most of the dose applied in the formulation was retained on the skin surface, especially at 30 nmoles/cm² (60%-90%), resulting in much lower amounts in the medium and/or skin. In conclusion, all four skin models demonstrated first-pass metabolism of genistein and daidzein and a marked alteration in their disposition by applying them in a body lotion formulation. This supports the use of fresh pig skin and PhenionFT models as alternatives to human skin for investigating skin metabolism and formulation effects for these two chemicals. The results were used to develop the dermal module of a PBPK model and dose setting for organ-on-chip experiments. They could also be used to refine internal exposure estimates in regulatory safety assessments.</p>","PeriodicalId":15242,"journal":{"name":"Journal of Applied Toxicology","volume":" ","pages":"210-221"},"PeriodicalIF":2.7,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142080427","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Long-term nanoplastics exposure contributes to impaired steroidogenesis by disrupting the hypothalamic-testis axis: Evidence from integrated transcriptome and metabolome analysis.","authors":"Qian He, Xin Li, Caiyan Xie, Mingzhe Zhang, Zebin Lai, Yan Zhou, Lei Luo, Yunxiao Yang, Mengyuan Qu, Kunming Tian","doi":"10.1002/jat.4696","DOIUrl":"10.1002/jat.4696","url":null,"abstract":"<p><p>Cumulative evidence suggested that nanoplastics (NPs) cause male toxicity, but the mechanisms of which are still misty. Steroidogenesis is a key biological event that responsible for maintaining reproductive health. However, whether dysregulated steroidogenesis is involved in NPs-induced impaired male reproductive function and the underlying mechanism remains unclear. In our study, Balb/c mice were continuously exposed to pristine-NPs or NH₂-NPs for 12 weeks, spanning the puberty and adult stage. Upon the long-term NPs treatment, the hypothalamus and testis were subjected to transcriptome and metabolome analysis. And the results demonstrated that both primitive-NPs and NH₂-NPs resulted in impaired spermatogenesis and steroidogenesis, as evidenced by a significant reduction in sperm quality, testosterone, FSH, and LH. The expression of genes involved in hypothalamic-pituitary-testis (HPT) axis, such as Kiss-1 and Cyp17a1 that encoded the key steroid hormone synthetase, was also diminished. Furthermore, the phosphatidylcholine and pantothenic acid that mainly enriched in glycerophospholipid metabolism were significantly reduced in the testis. Comprehensive analysis of the transcriptome and metabolome indicated that down-regulated Cyp17a1 was associated with decreased metabolites phosphatidylcholine and pantothenic acid. Overall, we speculate that the disturbed HPT axis induced by long-term NPs contributes to disordered glycerophospholipid metabolism and subsequently impaired steroidogenesis. Our findings deepen the understanding of the action of the mechanism responsible for NPs-induced male reproductive toxicology.</p>","PeriodicalId":15242,"journal":{"name":"Journal of Applied Toxicology","volume":" ","pages":"298-310"},"PeriodicalIF":2.7,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142347375","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Investigation of oral toxicity of WS₂ nanosheets to mouse intestine: Pathological injury, trace element balance, lipid profile changes, and autophagy.","authors":"Xianghao Zha, Sihuan Luo, Lianghuan Wei, Feixing Li, Youwen Li, Yi Cao","doi":"10.1002/jat.4701","DOIUrl":"10.1002/jat.4701","url":null,"abstract":"<p><p>The success of graphene oxides has gained extensive research interests in developing novel 2D nanomaterials (NMs). WS₂ nanosheets (NSs) are novel transition metal-based 2D NMs, but their toxicity is unclear. In this study, we investigated the oral toxicity of WS₂ NSs to mouse intestines. Male mice were administrated with vehicles, 1, 10, or 100 mg/kg NSs via intragastric route, once a day, for 5 days. The results indicate that the NSs did not induce pathological or ultrastructural changes in intestines. There were minimal changes of trace elements that the exposure did not induce W accumulation, and only Co levels were dose-dependently increased. Lipid droplets were observed in all groups of mice, but lipidomics data indicate that WS₂ NSs only significantly decreased four lipid species, all belonging to phosphatidylcholine (PC). The levels of proteins regulating autophagic lipolysis, namely, LC3, lysosomal associated membrane protein 2 (LAMP2) and perilipin 2 (PLIN2), were increased, but it was only statistically significantly different for LC3. The results of this study suggest that repeated intragastric exposure to WS₂ NSs only induced minimal influences on pathological injury, trace element balance, autophagy, and lipid profiles in mouse intestines, indicating relatively high biocompatibility of WS₂ NSs to mouse intestine via oral route.</p>","PeriodicalId":15242,"journal":{"name":"Journal of Applied Toxicology","volume":" ","pages":"311-321"},"PeriodicalIF":2.7,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142347374","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Gamma-Decanolactone Increases Stress Resistance and Improves Toxicity Parameters on the Caenorhabditis elegans Alternative Model.","authors":"Glaucia Maria Campos, Péterson Alves Santos, Mariana Uczay, Pricila Pflüger, Thaís Lemos Mendes, Jose Angel Fontenla, Patrícia Pereira","doi":"10.1002/jat.4705","DOIUrl":"10.1002/jat.4705","url":null,"abstract":"<p><p>Gamma-decanolactone (GD) is a monoterpene compound with anticonvulsant, antiparkinsonian, and neuroprotective effects in preclinical trials. This study aimed to evaluate the toxicity and antioxidant profile of GD in silico and in the Caenorhabditis elegans (C. elegans) experimental model. The C. elegans was used to determine the median lethal concentration (LC₅₀) of GD, as well as its effect on survival, development, reproduction, pharyngeal pumping, and stress resistance assays. The in silico study did not indicate hepatotoxic, cardiotoxic, or mutagenic potential to GD. It reduced the worms' survival, both at the L1 and L4 stages, in a concentration-dependent manner with an LC₅₀ value of 212.16 ± 5.56 μmol/mL. GD did not alter the development, reproduction, and pharyngeal pumping under normal experimental conditions in the three concentrations tested (25, 50, and 100 μmol/mL). In the thermal stress assay, GD did not change the survival pattern of the worms. Hydrogen peroxide (H₂O₂) reduced the survival of C. elegans and decreased the number of pharyngeal pumping, with these effects being reversed by GD. Also, GD presents an antioxidant activity by modulation the expression of the stress response genes such as sod-3, ctl-1,2,3, and gst-4. In conclusion, GD showed low toxicity in the C. elegans model and antioxidant profile both in the in silico study and in vivo assays.</p>","PeriodicalId":15242,"journal":{"name":"Journal of Applied Toxicology","volume":" ","pages":"339-349"},"PeriodicalIF":2.7,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142375458","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Toxic Effects of 4-Bromodiphenyl Ether (BDE-3) on Antioxidant Enzymes, Cell Viability, Histology and Biomolecules in Zebrafish Embryo-Larvae.","authors":"Shiv Kumar, Pooja Chadha","doi":"10.1002/jat.4708","DOIUrl":"10.1002/jat.4708","url":null,"abstract":"<p><p>Polybrominated diphenyl ethers (PBDEs) are a class of flame retardants that are being used widely in industrial and consumers products such as plastics, electronics, furniture, textiles and so forth. They can undergo debromination process to form less brominated diphenyl ethers, which are bioaccumulative, more volatile and more toxic in nature. The current study was conducted to reveal the biochemical, apoptotic, histopathological, ultrastructural and biomolecular (ATR-FTIR) toxicity of 4-bromodiphenyl ether (BDE-3) in zebrafish larvae. After the 96-h LC₅₀ determination, the zebrafish embryos were exposed to sublethal concentrations of BDE-3, that is, 0.79 and 1.59 mg/L. The MDA content was found to be significantly increased in BDE-3 exposed larvae whereas the FRAP activity was found to be decreased. The catalase (CAT), glutathione-S-transferase (GST) and acetylcholinesterase (AChE) activity were observed to be significantly increased, and a decreased superoxide dismutase (SOD) activity was reported after the BDE-3 exposure in zebrafish larvae. The cell viability was reported to be decreased in zebrafish larvae after BDE-3 exposure. Histopathological and ultrastructural alterations were also observed in the BDE-3 exposed zebrafish larvae. The changes in the biomolecules such as DNA and protein were also revealed via ATR-FTIR analysis. The present investigation will help to understand the toxic nature of less brominated diphenyl ethers and could be utilised to assess environmental risk.</p>","PeriodicalId":15242,"journal":{"name":"Journal of Applied Toxicology","volume":" ","pages":"350-360"},"PeriodicalIF":2.7,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142375460","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Non-clinical safety evaluation of Yongdamsagan-tang water extract: A 13-week subchronic oral toxicity study in Sprague Dawley rats.","authors":"Woo-Young Jeon, Chang-Seob Seo, Hyekyung Ha, Hyeun-Kyoo Shin, Jae-Woo Cho, Mee-Young Lee","doi":"10.1002/jat.4703","DOIUrl":"10.1002/jat.4703","url":null,"abstract":"<p><p>Despite the continued clinical application of traditional herbal medicines, scientific evidence such as toxicological safety profile of Yongdamsagan-tang water extract (YSTW) has not yet been established. The purpose of this study was to investigate the potential toxicity profile of YSTW following a 13-week repeated oral administration at various concentrations to Sprague Dawley rats. YSTW was administered orally to rats once daily at doses of 0, 1000, 2000, and 5000 mg/kg bw/day for 13 weeks. During the experimental period, there were no significant toxicological changes related to YSTW treatment. These results indicate that the administration of YSTW for 13 weeks in the rat resulted in no signs of toxicity at up to 5000 mg/kg bw/day, which was considered the no-observed-adverse-effect level.</p>","PeriodicalId":15242,"journal":{"name":"Journal of Applied Toxicology","volume":" ","pages":"322-338"},"PeriodicalIF":2.7,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11738534/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142375459","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Melatonin intervention to prevent nanomaterial exposure-induced damages: A systematic review and meta-analysis of in vitro and in vivo studies.","authors":"Xuejiao Wang, Yang Zhou, Dongli Xie, Fei Yin, Yunxia Liang, Xiaogang Luo","doi":"10.1002/jat.4676","DOIUrl":"10.1002/jat.4676","url":null,"abstract":"<p><p>Given its antioxidant, anti-inflammatory, and antiapoptotic properties, melatonin (MEL), a health-caring food to improve sleep disorders, is hypothesized to protect against nanomaterial exposure-induced toxicity. However, the conclusion derived from different studies seemed inconsistent. A meta-analysis of all available preclinical studies was performed to examine the effects of MEL on nanomaterial-induced damages. Eighteen relevant studies were retrieved through searching five electronic databases up to December 2023. The meta-analysis showed that relative to control, MEL treatment significantly increased cell viability (standardized mean difference [SMD = 1.27]) and alleviated liver function (lowered AST [SMD = -3.89] and ALT [SMD = -5.89]), bone formation (enhanced BV/TV [SMD = 4.13] and lessened eroded bone surface [SMD = -5.40]), and brain nerve (inhibition of AChE activity [SMD = -3.60]) damages in animals. The protective mechanisms of MEL against damages caused by nanomaterial exposure were associated with its antiapoptotic (decreased Bax/Bcl-2 ratio [SMD = -4.50] and caspase-3 levels [dose <100 μM: SMD = -3.66]), antioxidant (decreased MDA [in vitro: SMD = -2.84; in vivo: SMD = -4.27]), and anti-inflammatory (downregulated TNF-α [in vitro: SMD = -5.41; in vivo: SMD = -3.21] and IL-6 [in vitro: SMD = -5.90; in vivo: SMD = -2.81]) capabilities. In conclusion, our study suggests that MEL should be supplemented to prevent damages in populations exposed to nanomaterials.</p>","PeriodicalId":15242,"journal":{"name":"Journal of Applied Toxicology","volume":" ","pages":"179-199"},"PeriodicalIF":2.7,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141874888","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Concentration-dependent effects of the nerve agents cyclosarin and VX on cytochrome P450 in a HepaRG cell-based liver model.","authors":"Gabriele Horn, Franziska Frielingsdorf, Tobias Demel, Simone Rothmiller, Franz Worek, Niko Amend","doi":"10.1002/jat.4694","DOIUrl":"10.1002/jat.4694","url":null,"abstract":"<p><p>The exposure to highly toxic organophosphorus (OP) compounds, including pesticides and nerve agents, is an ongoing medical challenge. OP can induce the uncontrolled overstimulation of the cholinergic system through inhibition of the enzyme acetylcholinesterase (AChE). The cytochrome P450 (CYP) enzymes in the liver play a predominant role in the metabolism of xenobiotics and are involved in the oxidative biotransformation of most clinical drugs. Previous research concerning the interactions between OP and CYP has usually focused on organothiophosphate pesticides that require CYP-mediated bioactivation to their active oxon metabolites to act as inhibitors of AChE. Since there has been little data available concerning the effect of nerve agents on CYP, we performed a study with cyclosarin (GF) and O-ethyl-S-[2-(diisopropylamino)-ethyl]-methylphosphonothioate (VX) by using a well-established, metabolically competent in vitro liver model (HepaRG cells). The inhibitory effect of the nerve agents GF and VX on the CYP3A4 enzyme was investigated showing a low CYP3A4 inhibitory potency. Changes on the transcription level of CYP and associated oxygenases were evaluated by quantitative reverse transcription polymerase chain reaction (qRT-PCR) using the two nerve agent concentrations 250 nM and 250 μM. In conclusion, the results demonstrated various effects on oxygenase-associated genes in dependence of the concentration and the structure of the nerve agent. Such information might be of relevance for potential interactions between nerve agents, antidotes or other clinically administered drugs, which are metabolized by the affected CYP, for example, for the therapy with benzodiazepines, that are used for the symptomatic treatment of OP poisoning and that require CYP-mediated biotransformation.</p>","PeriodicalId":15242,"journal":{"name":"Journal of Applied Toxicology","volume":" ","pages":"222-229"},"PeriodicalIF":2.7,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142125847","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Characterization of the in vitro penetration and first-pass metabolism of genistein and daidzein using human and pig skin explants and Phenion full-thickness skin models.","authors":"Camille Géniès, Corinne Jeanjean, Abdulkarim Najjar, Andreas Schepky, Daniela Lange, Jochen Kühnl, Eric Fabian, Anne Zifle, Hélène Duplan, NIcola J Hewitt, Carine Jacques","doi":"10.1002/jat.4689","DOIUrl":"10.1002/jat.4689","url":null,"abstract":"<p><p>OECD test guideline compliant skin penetration studies, which also comply with the SCCS basic criteria, are lacking for genistein and daidzein. Therefore, we have measured their penetration and metabolism using ex vivo explants of fresh (i.e., metabolically viable) pig skin, fresh and frozen human skin, and Phenion full-thickness (FT) models. Preliminary studies using fresh pig skin helped to define the optimal experimental conditions. The dermal absorption of 10 nmoles/cm² genistein and daidzein in ethanol was comparable in all four models. A first-pass metabolism in skin to glucuronide and sulfate metabolites was demonstrated for both chemicals in all models except frozen human skin. The main difference between fresh skin models was the overall extent of metabolism and the relative ratio of each metabolite, for example, much lower sulfate conjugates were formed in pig skin incubations. The extent of parent chemical metabolized and the contribution of the glucuronide pathway were relatively lower in PhenionFT models than in fresh human skin, possibly due to a higher penetration rate in this model and differences in the expression of functional metabolizing enzymes. When metabolism in human skin was abolished by freezing, more radiolabelled chemical remained in the skin tissue but the overall dermal absorption was unchanged. In conclusion, this initial characterization study showed that all models tested indicated that genistein and daidzein extensively penetrated the skin when applied to skin in ethanol. All fresh skin models produced the same metabolites, with the known species difference in the sulfation pathway demonstrated in pig skin.</p>","PeriodicalId":15242,"journal":{"name":"Journal of Applied Toxicology","volume":" ","pages":"200-209"},"PeriodicalIF":2.7,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142080426","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Dose-Dependent Hepatorenal Damage Induced by Erythrosine: A Study of Biochemical, Oxidative Stress, DNA Damage, and Histopathological Effects in Wistar Rats.","authors":"Mandeep Singh, Pooja Chadha","doi":"10.1002/jat.4754","DOIUrl":"https://doi.org/10.1002/jat.4754","url":null,"abstract":"<p><p>This study aimed to provide insights into the hepatorenal toxicity induced by erythrosine, a synthetic red dye commonly used in food and pharmaceuticals, which has raised concerns over its potential health risks. Twenty-four rats were randomly divided into four groups (n = 6). The first group was the control group and the other group received one of three doses of erythrosine based on acceptable daily intake (¼ ADI, ½ ADI, and ADI, 0.1 mg/kg body weight). This study examined biological activity via biochemical enzyme analysis, oxidative stress indices, DNA damage, and histopathology. Compared with the control group, erythrosine administration increased the serum alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, total bilirubin, total protein, urea, creatinine, and uric acid at the highest erythrosine dose. The catalase and the superoxide dismutase activity decreased in both tissues at the highest dose. The glutathione-S-transferase activity increased at the ¼ ADI dose and decreased at higher doses in both tissues. In contrast, acetylcholinesterase activity was greater in erythrosine-treated rats than in control rats. Oxidative stress indices indicated increased lipid peroxidation, hydrogen peroxide content, and lactate dehydrogenase activity. The comet assay was used to assess DNA damage, revealing significant damage in the erythrosine-treated groups. Histopathological examination revealed necrotic and degenerative changes in the liver and kidney tissues. The findings underscore dose-dependent hepatorenal toxicity and highlight the novelty of demonstrating a comprehensive link between erythrosine exposure, oxidative stress, and DNA damage. These results emphasize the need for cautious evaluation of synthetic dye consumption due to potential health risks.</p>","PeriodicalId":15242,"journal":{"name":"Journal of Applied Toxicology","volume":" ","pages":""},"PeriodicalIF":2.7,"publicationDate":"2025-01-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143023443","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}