Journal of Toxicological Sciences最新文献

{"title":"Evaluation of rewarding effects of nitazene analogs: results from conditioned place preference tests and in vivo microdialysis experiments in mice.","authors":"Kyoko Hataoka, Motoki Hojo, Sakiko Nomura, Yoshio Nakagawa, Ayaka Kawai, Mari Nakamura, Kiyomi Ikushima, David B Alexander, Jin Suzuki, Toshinari Suzuki, Akiko Inomata","doi":"10.2131/jts.50.33","DOIUrl":"https://doi.org/10.2131/jts.50.33","url":null,"abstract":"<p><p>In illicit drug markets, the most recently expanding new synthetic opioid subclass is benzimidazoles, also known as nitazenes, which were originally developed as analgesics in the 1950s. The emergence of this classical, potent drug family has attracted extensive research interest in the field of forensic toxicology; however, information on their psychological and physical dependence is very limited. Herein, we evaluated the rewarding effects of four nitazene analogs using a battery of in vivo experiments, with a positive control drug (isotonitazene). The four test materials, metonitazene, etodesnitazene, metodesnitazene, and flunitazene, were administered to male C57BL/6J mice by i.p. administration at 0.5, 2, 20, and 20 mg/kg, respectively. In comprehensive behavioral observation tests, representative opioid-related physiological and behavioral states, including analgesia, stereotypic circling behavior, hyperlocomotion, and Straub tail response, were observed. A set of conditioned place preference tests revealed that all the four analogs induced palatability in mice. Furthermore, measurements of dopamine levels in the nucleus accumbens shell by in vivo microdialysis resulted in significant elevations in all test material-treated groups, suggesting that the nitazenes elicit the rewarding effect through a neural circuit originating from the μ-opioid receptor activation at the ventral tegmental area. Our findings add important data regarding the psychological dependence of nitazenes and highlight the abuse potential of these four materials and other prevailing nitazene analogs.</p>","PeriodicalId":17654,"journal":{"name":"Journal of Toxicological Sciences","volume":"50 1","pages":"33-43"},"PeriodicalIF":1.8,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142950773","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":"Toxicity of nickel, copper, and selenium in medaka embryos (oryzias latipes): a comparative study.","authors":"Sylvester Addai-Arhin, Seiya Shino, Masaya Uchida, Hiroshi Ishibashi, Koji Arizono, Nobuaki Tominaga","doi":"10.2131/jts.50.23","DOIUrl":"https://doi.org/10.2131/jts.50.23","url":null,"abstract":"<p><p>The indispensability of biometals nickel, copper, and selenium in pharmaceutical, agricultural, and other industrial applications, coupled with their release from mining processes, has made them potent environmental contaminants, especially when present in aquatic ecosystems at levels above the essential range. The toxicity of these biometals in fish embryogenesis, including their toxicity levels, was studied using medaka embryos. Test solutions (0.001-10 ppm) of the biometals, along with an isotonic solution as a control, were introduced into the embryos using a nanosecond pulsed electric field application. The exposed embryos were cultured at 25 ± 1°C and microscopically observed daily for 14 days in an isotonic solution. Developmental abnormalities and toxicity were observed during the 14-day observation period. All biometals caused some abnormalities in developing embryos at all concentrations. Major abnormalities included delayed development; deformities such as curvature of bones or spines; abnormal formation of the hearts, eyes, and circulatory systems; and mortality. The toxicity of the biometals was significantly different (p < 0.05) from that of the control. Gene expression analysis revealed that 4747, 1961, and 1952 genes were affected by copper, nickel, and selenium, respectively. Copper affected the highest number of genes and caused the highest toxicity. These results indicate that nickel, copper, and selenium can cause toxicity in developing fish embryos at concentrations ranging from 0.01 ppb to 10 ppm. Therefore, there is a need to constantly monitor the levels of these biometals, particularly in aquatic ecosystems, to preserve aquatic life.</p>","PeriodicalId":17654,"journal":{"name":"Journal of Toxicological Sciences","volume":"50 1","pages":"23-32"},"PeriodicalIF":1.8,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142950775","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":"Circ_0008272 facilitates cadmium-induced malignant transformation of bronchial epithelial cells through histone modification.","authors":"Hongyu Hao, Yanfang Yang, Jinjin Cui, Lihua Huang","doi":"10.2131/jts.50.263","DOIUrl":"https://doi.org/10.2131/jts.50.263","url":null,"abstract":"<p><p>Cadmium (Cd) exposure through the respiratory system is associated with various respiratory disorders, including lung cancer. Circular RNAs (circRNAs) are increasingly recognized as critical regulators in carcinogenesis. This study employed high-throughput RNA sequencing and quantitative real-time PCR (qRT-PCR) to identify differentially expressed circRNAs in 16HBE cells (Cd-T) after 30 weeks of cadmium chloride (CdCl₂, 5 μmol/L) exposure. Circ_0008272 knockdown inhibited migration, invasion, proliferation, and colony formation in Cd-T cells, whereas its overexpression enhanced these malignant phenotypes. Bioinformatics analyses and RNA-Protein Interaction Prediction (RPISeq) suggested that circ_0008272 promotes tumor-like behavior in Cd-T cells by modulating histone modification pathways. In conclusion, circ_0008272 acts as a tumor-promoting factor in the Cd-induced malignant transformation of 16HBE cells.</p>","PeriodicalId":17654,"journal":{"name":"Journal of Toxicological Sciences","volume":"50 6","pages":"263-272"},"PeriodicalIF":1.8,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144199548","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":"Differential response of SNU-1826 colon cells on the autophagy, ER stress, and inflammation during the regulation of microplastic internalization.","authors":"Ayun Seol, Ji Eun Kim, Hee Jin Song, Tae Ryeol Kim, Eun Seo Park, Ki Ho Park, Su Jeong Lim, Su Ha Wang, Seong Cheol Park, Youngwoo Choi, Hyesung Kim, Sungbaek Seo, Dae Youn Hwang","doi":"10.2131/jts.50.361","DOIUrl":"https://doi.org/10.2131/jts.50.361","url":null,"abstract":"<p><p>The internalization mechanism of microplastics (MPs) into human cells has attracted considerable attention because these mechanisms are closely related to the physical and chemical properties of MPs. This study examined the response of human colon cells to autophagy, ER stress, and inflammation during the regulation on the internalization of polystyrene (PS)-MPs (0.4-0.6 μm size). To achieve this, changes in their key markers were analyzed in MPs-treated SNU-1826 cells after a cotreatment with uptake inhibitors or stimulators. The internalization of MPs was significantly higher in SNU-1826 cells than in other cells originated from differential tissues, such as the small intestine, kidneys, and nerves. On the other hand, the internalization of MPs into SNU-1826 cells was suppressed by cytochalasin D (CD) but not by pitstop (Pt). During this inhibition, the levels of the key parameters for autophagy (Light Chain 3-I/II (LC3-I/II) and Beclin1), ER stress (eukaryotic translation initiation factor 2 subunit alpha (EIF2α) and inositol-requiring kinase 1 alpha (IRE1α)), and inflammation (inducible nitric oxide synthase (iNOS), cyclooxygenase 2 (COX-2), tumor necrosis factor alpha (TNF-α), and interleukin (IL)-6) were suppressed in MPs+CD-treated SNU-1826 cells. In addition, the internalization of MPs into SNU-1826 cells was stimulated by a ZnSO₄ treatment, not by CaCl₂. These stimulation effects were reflected in the alteration of the critical parameters for autophagy, ER stress, and inflammation. Furthermore, the positive correlation was detected between MPs internalization and most parameters for cellular responses although their inhibition is stronger than stimulation. These results suggest that the internalization of MPs into SNU-1826 cells may be strongly associated with the changes in autophagy, ER stress, and inflammation during the regulation of CD and ZnSO₄.</p>","PeriodicalId":17654,"journal":{"name":"Journal of Toxicological Sciences","volume":"50 7","pages":"361-378"},"PeriodicalIF":1.8,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144553834","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":"The degree of caspase-3 aggregation determines the selectivity of arsenic-induced cell death.","authors":"Yutaro Yamada, Ryo Ito, Takuya Noguchi, Shuhei Hamano, Kohei Otani, Takaya Komatsu, Yusuke Hirata, Atsushi Matsuzawa","doi":"10.2131/jts.50.351","DOIUrl":"https://doi.org/10.2131/jts.50.351","url":null,"abstract":"<p><p>It is well known that apoptosis is triggered by arsenic. Meanwhile, recent evidence has demonstrated that arsenic also induces a non-canonical form of regulated cell death (RCD) called parthanatos that is triggered by the overactivation of poly (ADP-ribose) polymerase-1 (PARP-1). Here, we provide evidence of a novel mechanistic link between parthanatos and apoptosis induced by arsenic. Exposure to sodium arsenite clearly induced parthanatos in typical cancer cell lines such as HeLa and HT1080 cells, without activation of the apoptotic cascade, including the caspase-3 activation. Of note, we observed aggregation of caspase-3 in response to sodium arsenite, which was abolished by treatment with 4-phenylbutyrate (4-PBA), a chemical chaperone that prevents protein aggregation. Interestingly, in the presence of 4-PBA, sodium arsenite induced apoptosis rather than parthanatos. These findings suggest that the disaggregation of caspase-3 allows arsenic to induce the caspase-3 activation, and subsequent apoptosis. Thus, our results show that the degree of the caspase-3 aggregation may be a critical determinant of the selectivity of sodium arsenite-induced cell death.</p>","PeriodicalId":17654,"journal":{"name":"Journal of Toxicological Sciences","volume":"50 7","pages":"351-359"},"PeriodicalIF":1.8,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144553837","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":"Spermidine alleviates sepsis-induced acute kidney injury by suppressing apoptosis and inflammation through modulation of TLR4-mediated signaling.","authors":"Yun Shen, Qinyi Shi, Ting Dai, Yi Cai, Mengting Sheng, Ying Qiu, Ming Yang, Sanhong Hu, Bo Cheng","doi":"10.2131/jts.50.555","DOIUrl":"https://doi.org/10.2131/jts.50.555","url":null,"abstract":"<p><p>Sepsis-associated acute kidney injury (AKI) remains a critical clinical challenge with limited therapeutic options. This study investigated the renoprotective effects of spermidine using sepsis-associated AKI models. In vitro, HK-2 cells were challenged with lipopolysaccharide (LPS) to establish an inflammatory injury model, followed by spermidine treatment (25-100 μM). In vivo, a cecal ligation and puncture (CLP)-induced septic AKI mouse model was employed. Key methodologies included CCK-8 viability assay, flow cytometry apoptosis analysis, western blotting (apoptotic proteins: Bcl-2/Bax/cleaved caspase-9; TLR4/MyD88/TRAF6/p-p65), ELISA (TNF-α/IL-6/IL-1β), TUNEL staining, and histopathological assessment, with spermidine doses of 25-100 μM (cells) and 50 mg/kg (mice). We found that spermidine treatment significantly mitigated renal histopathological damage and improved functional markers, including blood urea nitrogen, serum creatinine, and neutrophil gelatinase-associated lipocalin. Spermidine administration attenuated oxidative stress by restoring antioxidant enzyme activities while reducing lipid peroxidation in renal tissues. Spermidine suppressed apoptosis in both LPS-challenged HK-2 and CLP-injured kidneys, evidenced by reduced apoptotic markers and caspase activation. Furthermore, spermidine inhibited systemic and intrarenal inflammatory cytokine production through modulation of the TLR4/MyD88/NF-κB signaling axis. These findings collectively establish that spermidine alleviates sepsis-induced AKI through coordinated suppression of apoptosis and inflammation mediated by TLR4/MyD88/NF-κB pathway inhibition.</p>","PeriodicalId":17654,"journal":{"name":"Journal of Toxicological Sciences","volume":"50 10","pages":"555-567"},"PeriodicalIF":1.5,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145206907","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":"Dihydropyrazine activates the CAMKK2-AMPK-ULK1 signaling pathway in human hepatoma HepG2 cells.","authors":"Madoka Sawai, Yuu Miyauchi, Hisao Kansui, Shinji Takechi","doi":"10.2131/jts.50.577","DOIUrl":"https://doi.org/10.2131/jts.50.577","url":null,"abstract":"<p><p>Dihydropyrazines (DHPs) are glycation intermediates produced by nonenzymatic glycation reactions in vivo and in foods. We previously reported that 3-hydro-2,2,5,6-tetramethylpyrazine (DHP-3) activates endoplasmic reticulum (ER) stress and inhibits autophagy, although its effect on autophagy initiation remained unclear. In this study, we examined the effect of DHP-3 on the autophagy initiation pathway in HepG2 cells. DHP-3 exposure resulted in activation of UNC-51-like kinase 1 (ULK1), the catalytic subunit of the ULK complex essential for autophagy initiation. Notably, phosphorylation of AMP-activated protein kinase (AMPK), an upstream activator of ULK1, was enhanced without a corresponding increase in the ADP/ATP ratio. Among the upstream kinases regulating AMPK, phosphorylation of calcium/calmodulin-dependent protein kinase kinase 2 (CAMKK2) was increased, whereas that of liver kinase B1 (LKB1) remained unchanged. These findings suggest that DHP-3 activates the CAMKK2-AMPK-ULK1 signaling pathway, thereby inducing autophagy initiation.</p>","PeriodicalId":17654,"journal":{"name":"Journal of Toxicological Sciences","volume":"50 10","pages":"577-582"},"PeriodicalIF":1.5,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145206843","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":"Paternal exposure to methylphenidate causes behavioral abnormalities in grandchildren.","authors":"Ryota Nakano, Riko Ikeda, Yoshitaka Yamazaki, Sakiko Munetomo-Aoki, Haruka Morinaka, Shohei Abe, Hikaru Isobe, Masahiro Hosonuma, Shotaro Kamijo, Asuka Kaizaki-Mitsumoto, Satoshi Numazawa","doi":"10.2131/jts.50.445","DOIUrl":"https://doi.org/10.2131/jts.50.445","url":null,"abstract":"<p><p>Attention-deficit/hyperactivity disorder (ADHD) is a neurodevelopmental disorder that is widely observed from childhood to adulthood and is treated with methylphenidate (MPH) as a first-line treatment. However, recent findings indicate that the paternal environment preceding conception may influence offspring health, potentially affecting subsequent generations. Moreover, we previously reported that MPH administration to sires reduced anxiety-related behaviors and induced memory impairments in the F1 generation. Therefore, in the present study, we investigated the effects of MPH exposure to sires on development, behavior, and brain gene expression in the F2 generation to extend our previous findings and examine the range of transgenerational effects. Although MPH exposure did not affect the number of births or survival rates, the body weight of mice in the MPH group was significantly lower than those in the control group. Additionally, motor development showed transient delays in early development but normalized by the age of weaning. Behavioral analysis further revealed a pronounced reduction in anxiety-like behaviors in the MPH group, particularly in female mice, with no effect on learning or memory. Finally, transcriptome analysis of the female cortex predicted the activation of neuroplasticity-related pathways, including the S100 family and CREB signaling. Notably, MPH was not administered to male F1 mice whose fathers had been administered MPH. Therefore, the ova of females mated with F1 males were not exposed to MPH. Nevertheless, the confirmation of behavioral abnormalities in the F2 generation strongly suggests that these abnormalities may have been induced by epigenetic changes in germ cells.</p>","PeriodicalId":17654,"journal":{"name":"Journal of Toxicological Sciences","volume":"50 9","pages":"445-457"},"PeriodicalIF":1.5,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144959005","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":"Prolonged QRS duration in patients with acute poisoning occurs both xenobiotics and with low level of potassium: a single-center retrospective case control study.","authors":"Hironori Katsuki, Tetsuhisa Yamada, Katsuhiko Ayukawa","doi":"10.2131/jts.50.117","DOIUrl":"10.2131/jts.50.117","url":null,"abstract":"<p><p>Prolongation of QRS duration (prolonged QRS) is associated with severe outcomes in non-tricyclic antidepressant poisoning. However, factors other than xenobiotics affecting QRS duration have not yet been investigated. Hence, this study aimed to identify factors contributing to prolonged QRS. This study was a single-center retrospective case control study. Patients who had overdosed on drugs or orally ingested xenobiotics that they would not normally ingest orally were included in the study. Patients were divided into two groups: prolonged QRS and normal QRS. Subsequently, these groups were compared. We performed a logistic regression analysis with the factors extracted by comparison as explanatory variables and prolonged QRS as the objective variable. In total, 108 patients were analyzed; 19 belonged to the prolonged QRS group. In the prolonged QRS group, factors such as male sex, low level of potassium, and xenobiotic ingestion resulted in prolonged QRS. In a logistic regression analysis, significant differences were observed in terms of male sex (odds ratio [OR], 27.00; 95% confidence interval [CI], 5.93-123.00; p<0.001), xenobiotics ingested that resulted in prolonged QRS (OR, 8.55; 95% CI, 1.84-39.70; p<0.001), and potassium levels (OR, 0.15; 95% CI, 0.03-0.88; p=0.035). Ingestion of sodium channel blockers, male sex, and low level of potassium may contribute to prolonged QRS.</p>","PeriodicalId":17654,"journal":{"name":"Journal of Toxicological Sciences","volume":"50 3","pages":"117-123"},"PeriodicalIF":1.8,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143537435","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":"Diphenylarsinic acid induced astrocyte-preferential cell-type-specific aberrant activation of signal transduction related to oxidative stress, MAP kinase activation, transcription factor regulation, and glutathione metabolism.","authors":"Takayuki Negishi, Daiki Yoshioka, Ami Kajiura, Daiki Suzuki, Runa Tasaki, Shoto Sasaki, Takamasa Tsuzuki, Kazunori Yukawa","doi":"10.2131/jts.50.293","DOIUrl":"https://doi.org/10.2131/jts.50.293","url":null,"abstract":"<p><p>Diphenylarsinic acid (DPAA) was responsible for the 2003 arsenic poisoning incident in Japan, in which DPAA-exposed individuals experienced cerebellum-related neurological symptoms. We previously reported that DPAA targets cerebellar astrocytes rather than neurons in rats in vivo and induced the aberrant activation of particular signal transduction pathways, such as the MAP kinase and transcription factor pathway, as well as the oxidative stress response in cultured normal rat cerebellar astrocytes (NRA). Here, we examined the effects of 10 µM DPAA exposure for 96 hr in a panel of nine cell lines (HepG2, U251MG, T98G, 1321N1, SK-N-SH, SH-SY5Y, MCF7, A549, and C6) as well as NRA, and examined the DPAA-susceptible signal transduction pathways: oxidative-stress responsive factors [heme oxygenase-1 (HO-1), Hsp70, superoxide dismutase-1, and catalase), MAP kinases (ERK1/2, p38MAPK, and SAPK/JNK), transcription factors (CREB, c-Jun, and c-Fos), glutathione (GSH), and GSH-related enzymes (glutamate-cysteine ligase and glutathione synthetase). In NRA, DPAA significantly activated these signal transduction pathways. Although there were cell-type specificities in susceptibility to DPAA, multivariate clustering analyses classified NRA, rat glioma-derived C6, and two human glioma-derived cell lines, U251MG and 1321N1, into an identical group. These results suggest that DPAA might affect cellular signal transduction preferentially in astrocytes among the diverse types of cells.</p>","PeriodicalId":17654,"journal":{"name":"Journal of Toxicological Sciences","volume":"50 6","pages":"293-308"},"PeriodicalIF":1.8,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144199550","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}