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  • Dexmedetomidine attenuates ethanol-induced inhibition of hippocampal neurogenesis in neonatal mice
    Toxicol. Appl. Pharmacol. (IF 3.585) Pub Date : 2020-01-16
    Keyi Lv; Congwen Yang; Rui Xiao; Ling Yang; Tianyao Liu; Ruiyu Zhang; Xiaotang Fan

    Background/Aims Ethanol (EtOH) exposure during a period comparable to the third trimester in human results in obvious neurotoxicity in the developing hippocampus and persistent deficits in hippocampal neurogenesis. Dexmedetomidine (DEX), a highly selective α-2-adrenergic agonist has been demonstrated to restore the impaired neurogenesis and neuronal plasticity in the dentate gyrus (DG) that follows neurological insult. However, the protective roles of DEX in the EtOH-induced deficits of postnatal neurogenesis in the hippocampus are still unknown. Methods Mice were pretreated with DEX prior to EtOH exposure to determine its protective effects on impaired postnatal hippocampal neurogenesis. Six-day-old neonatal mice were treated with DEX (125 μg/kg) or saline, followed by EtOH at a total of 5 g/kg or an equivalent volume of saline on P7. Immunohistochemistry and immunofluorescence were used to evaluate the neurogenesis and activated microglia in the DG. Quantitative real time PCR (qRT-PCR) was utilized to assess the expression of inflammatory factors in the hippocampus. Results DEX pretreatment attenuated the inhibition of EtOH-mediated hippocampal neurogenesis and the reduction of hippocampal neural precursor cells (NPCs). We further confirmed that DEX pretreatment reversed the EtOH-induced microglia activation in the DG as well as the upregulation of the hippocampal TNFα, MCP-1, IL-6, and IL-1β mRNA levels. Conclusion Our findings indicate that DEX pretreatment protects against EtOH-mediated inhibition of hippocampal neurogenesis in postnatal mice and reverses EtOH-induced neuroinflammation via repressing microglia activation and the expression of inflammatory cytokines.

    更新日期:2020-01-16
  • Nagilactone D ameliorates experimental pulmonary fibrosis in vitro and in vivo via modulating TGF-β/Smad signaling pathway
    Toxicol. Appl. Pharmacol. (IF 3.585) Pub Date : 2020-01-15
    Ao Li; Xiao Xiao; Zhe-Ling Feng; Xiuping Chen; Li-Juan Liu; Li-Gen Lin; Jin-Jian Lu; Le-Le Zhang
    更新日期:2020-01-15
  • 更新日期:2020-01-14
  • The antidotes atropine and pralidoxime distinctively recover cardiorespiratory components impaired by acute poisoning with chlorpyrifos in rats
    Toxicol. Appl. Pharmacol. (IF 3.585) Pub Date : 2020-01-10
    Igor Simões Assunção Felippe; Cláudia Janaína Torres Müller; Alciene Almeida Siqueira; Leonardo dos Santos; Alana Cavadino; Julian Francis Richmond Paton; Vanessa Beijamini; Karla Nívea Sampaio

    In a previous work we showed that the organophosphate pesticide (OP) chlorpyrifos (CPF) reduces the protective chemoreflex and baroreflex responses in rats. However, whether the antidotes atropine (ATR) and pralidoxime (2-PAM) are capable of restoring these reflex functions remains unexplored. Rats were poisoned with CPF (30 mg.Kg-1, i.p.) and one hour after the intoxication, ATR (10 mg.Kg−1, i.p.) and 2-PAM (40 mg.Kg−1, i.p.) were administrated separately or in combination. Cardiorespiratory parameters were recorded in awake rats 24 h after CPF. Systolic blood pressure (SBP) and heart rate (HR) variability and spontaneous baroreflex sensitivity (sBRS) were derived from 30 min undisturbed recordings and chemoreflex was assessed through potassium cyanide (KCN) i.v. injections (10, 20, 40, 80 μg/ rat). CPF poisoning increased SBP variability and low frequency/high frequency (LF/HF) ratio of HR spectrum, indicating autonomic imbalance with increased cardiac sympathetic tone. sBRS was not changed. Treatment with 2-PAM restored SBP variability, whilst both antidotes increased LF/HF ratio. CPF poisoning reduced the hypertensive, bradycardic and tachypneic chemoreflex responses. Chemoreflex-induced hypertensive response was restored by 2-PAM treatment, while ATR recovered the bradycardic response. Both antidotes restored the chemoreflex tachypneic response. Our data show distinct effects of ATR and 2-PAM on cardiorespiratory parameters affected by OP poisoning. While 2-PAM rescued the chemoreflex hypertensive response, ATR reversed chemoreflex bradycardic dysfunction. Although 2-PAM clinical use is questioned in some countries, our data indicate that summation of effects of both antidotes appears beneficial on the cardiorespiratory system and peripheral chemoreflex function.

    更新日期:2020-01-11
  • Resveratrol modulates the blood plasma levels of Cu and Zn, the antioxidant status and the vascular response of thoracic arteries in copper deficient Wistar rats
    Toxicol. Appl. Pharmacol. (IF 3.585) Pub Date : 2020-01-07
    Michał Majewski; Katarzyna Ognik; Michael Thoene; Aleksandra Rawicka; Jerzy Juśkiewicz
    更新日期:2020-01-07
  • Characterizing biopersistence potential of the metabolite 5:3 fluorotelomer carboxylic acid after repeated oral exposure to the 6:2 fluorotelomer alcohol
    Toxicol. Appl. Pharmacol. (IF 3.585) Pub Date : 2020-01-07
    Shruti V. Kabadi; Jeffrey W. Fisher; Daniel R. Doerge; Darshan Mehta; Jason Aungst; Penelope Rice

    Our previous report on pharmacokinetic (PK) evaluation of 6:2 fluorotelomer alcohol (6:2 FTOH) examined the biopersistence potential of its metabolites based on data published from single inhalation and occupational 6:2 FTOH exposure studies. We calculated internal exposure estimates of three key metabolites of 6:2 FTOH, of which 5:3 fluorotelomer carboxylic acid (5:3 acid) had the highest internal exposure and the slowest clearance. No oral repeated 6:2 FTOH exposure data were available at the time to fully characterize the biopersistence potential of the metabolite 5:3 acid. We recently received additional data on 6:2 FTOH and 5:3 acid, which included a 90-day toxicokinetic study report on repeated oral 6:2 FTOH exposure to rats. We reviewed the study and analyzed the reported 5:3 acid concentrations in plasma, liver, and fat using one-compartment PK modeling and calculated elimination rate constants (kel), elimination half-lives (t1/2) and times to steady state (tss) of 5:3 acid at three 6:2 FTOH doses. Our results showed that tss of 5:3 acid in plasma and evaluated tissues were approximately close to 1 year, such that the majority of highest values were observed at the lowest 6:2 FTOH dose, indicating its association with the biopersistence of 6:2 FTOH. The results of our PK analysis are the first to characterize biopersistence potential of the 5:3 acid after repeated oral exposure to the parent compound 6:2 FTOH based on steady state PK parameters, and therefore, may have an impact on future study designs when conducting toxicity assays for such compounds.

    更新日期:2020-01-07
  • Bioactivity screening of environmental chemicals using imaging-based high-throughput phenotypic profiling
    Toxicol. Appl. Pharmacol. (IF 3.585) Pub Date : 2019-12-30
    Johanna Nyffeler; Clinton Willis; Ryan Lougee; Ann Richard; Katie Paul-Friedman; Joshua A. Harrill

    The present study adapted an existing high content imaging-based high-throughput phenotypic profiling (HTPP) assay known as “Cell Painting” for bioactivity screening of environmental chemicals. This assay uses a combination of fluorescent probes to label a variety of organelles and measures a large number of phenotypic features at the single cell level in order to detect chemical-induced changes in cell morphology. First, a small set of candidate phenotypic reference chemicals (n = 14) known to produce changes in the cellular morphology of U-2 OS cells were identified and screened at multiple time points in concentration-response format. Many of these chemicals produced distinct cellular phenotypes that were qualitatively similar to those previously described in the literature. A novel workflow for phenotypic feature extraction, concentration-response modeling and determination of in vitro thresholds for chemical bioactivity was developed. Subsequently, a set of 462 chemicals from the ToxCast library were screened in concentration-response mode. Bioactivity thresholds were calculated and converted to administered equivalent doses (AEDs) using reverse dosimetry. AEDs were then compared to effect values from mammalian toxicity studies. In many instances (68%), the HTPP-derived AEDs were either more conservative than or comparable to the in vivo effect values. Overall, we conclude that the HTPP assay can be used as an efficient, cost-effective and reproducible screening method for characterizing the biological activity and potency of environmental chemicals for potential use in in vitro-based safety assessments.

    更新日期:2019-12-31
  • The effects of a phthalate metabolite mixture on antral follicle growth and sex steroid synthesis in mice
    Toxicol. Appl. Pharmacol. (IF 3.585) Pub Date : 2019-12-26
    Daryl D. Meling; Genoa R. Warner; Jason R. Szumski; Liying Gao; Andressa V. Gonsioroski; Saniya Rattan; Jodi A. Flaws

    Phthalates are used as solvents and plasticizers in a wide variety of consumer products. Most people are exposed to phthalates as parent compounds through ingestion, inhalation, and dermal contact. However, these parent compounds are quickly metabolized to more active compounds in several tissues. Although studies indicate that the phthalate metabolites reach the ovary, little is known about whether they are ovarian toxicants. Thus, this study tested the hypothesis that phthalate metabolites influence the expression of genes involved in sex steroid synthesis, cell cycle regulation, cell death, oxidative stress, and key receptors, as well as production of sex steroid hormones by mouse antral follicles. The selected metabolite mixture consisted of 36.7% monoethyl phthalate (MEP), 19.4% MEHP, 15.3% monobutyl phthalate (MBP), 10.2% monoisobutyl phthalate (MiBP), and 10.2% monoisononyl phthalate (MiNP), and 8.2% monobenzyl phthalate (MBzP). Antral follicles from adult CD-1 mice were cultured for 96 h with vehicle control (DMSO) or metabolite mixture (0.065–325 μg/ml). Growth of follicles in culture was monitored every 24 h. Total RNA was isolated after 24 and 96 h and used for gene expression analysis. Media were collected and subjected to hormone analysis. Exposure to the phthalate mixture inhibited follicle growth, decreased expression of steroidogenic enzymes, and altered the levels of sex steroids relative to control. The mixture, primarily at the two highest doses, also altered expression of cell cycle regulators, apoptotic factors, oxidative stress genes, and of some receptors. Collectively, these data suggest that mixtures of phthalate metabolites can directly impact follicle health.

    更新日期:2019-12-27
  • A toxicogenomic approach for the risk assessment of the food contaminant acetamide
    Toxicol. Appl. Pharmacol. (IF 3.585) Pub Date : 2019-12-24
    Rance Nault; Bryan Bals; Farzeneh Teymouri; Michael B. Black; Melvin E. Andersen; Patrick D. McMullen; Seetha Krishnan; Nagesh Kuravadi; Neetha Paul; Santhosh Kumar; Kamala Kannan; K.C. Jayachandra; Lakshmanan Alagappan; Bhavesh Dhirajlal Patel; Kenneth T. Bogen; Bhaskar B. Gollapudi; James E. Klaunig; Tim R. Zacharewski; Venkataraman Bringi

    Acetamide (CAS 60-35-5) is detected in common foods. Chronic rodent bioassays led to its classification as a group 2B possible human carcinogen due to the induction of liver tumors in rats. We used a toxicogenomics approach in Wistar rats gavaged daily for 7 or 28 days at doses of 300 to 1500 mg/kg/day (mkd) to determine a point of departure (POD) and investigate its mode of action (MoA). Ki67 labeling was increased at doses ≥750 mkd up to 3.3-fold representing the most sensitive apical endpoint. Differential gene expression analysis by RNA-Seq identified 1110 and 1814 differentially expressed genes in male and female rats, respectively, following 28 days of treatment. Down-regulated genes were associated with lipid metabolism while up-regulated genes included cell signaling, immune response, and cell cycle functions. Benchmark dose (BMD) modeling of the Ki67 labeling index determined the BMD10 lower confidence limit (BMDL10) as 190 mkd. Transcriptional BMD modeling revealed excellent concordance between transcriptional POD and apical endpoints. Collectively, these results indicate that acetamide is most likely acting through a mitogenic MoA, though specific key initiating molecular events could not be elucidated. A POD value of 190 mkd determined for cell proliferation is suggested for risk assessment purposes.

    更新日期:2019-12-25
  • Protective effect of resveratrol on obesity-related osteoarthritis via alleviating JAK2/STAT3 signaling pathway is independent of SOCS3
    Toxicol. Appl. Pharmacol. (IF 3.585) Pub Date : 2019-12-24
    Mengqi Jiang; Jianyi He; Hailun Gu; Yingchun Yang; Yue Huang; Xiaolei Xu; Li Liu

    Resveratrol (RES) has a protective effect on osteoarthritis (OA), nevertheless, the underlying mechanisms of RES towards obesity-related OA are still unclear. This study is aimed to determine whether leptin resistant mechanism presents in articular cartilage of obesity-related OA and whether the protective effect of RES is involved in the regulation of leptin signal by affecting suppressor of cytokine signaling 3 (SOCS3). Male C57BL/6 J mice were fed with standard chow diet, high fat diet (HFD) or high fat diet with RES (45 mg/kg.bw) for 22 weeks. Knee joints of mice were evaluated by histological and immunohistochemistry analysis. Serum level of leptin was measured by ELISA. The leptin, leptin receptor (OB-Rb), SOCS3 mRNA expression and JAK2, STAT3, OB-Rb and SOCS3 protein expression in cartilage were determined by real-time RT-PCR and western blot. In addition, SW1353 cells were pretreated with or without AG490, and stimulated with leptin in the presence or absence of RES to detect JAK2, STAT3, matrix metalloproteinase-13 (MMP-13) and SOCS3 expression. We found that HFD could induce obesity-related OA and RES prevented its progression. Serum leptin and mRNA expression in cartilage was up-regulated by HFD, while RES ameliorated the elevation. Besides, RES significantly inhibited the JAK2/STAT3 signaling pathway in cartilage, as well as SOCS3. In in vitro study, RES exhibited the same effect in SW1353 cells which stimulated with leptin. In conclusion, no significant leptin resistance existed in cartilage of obesity-related OA and the inhibitory effect of RES on obesity-related OA via alleviating JAK2/STAT3 signaling pathway is independent of SOCS3.

    更新日期:2019-12-25
  • p38 MAPK-DRP1 signaling is involved in mitochondrial dysfunction and cell death in mutant A53T α-synuclein model of Parkinson's disease
    Toxicol. Appl. Pharmacol. (IF 3.585) Pub Date : 2019-12-24
    Chen Gui; Yixian Ren; Jialong Chen; Xian Wu; Kanmin Mao; Huihui Li; Honglin Yu; Fei Zou; Wenjun Li

    Abnormal accumulation of α-synuclein and mitochondria dynamics dysfunction are considered to be implicated in the pathogenesis of Parkinson's disease. However, the underlying mechanisms how α-synuclein abnormal accumulation causes mitochondrial dynamics dysfunction remains unclear. Here, we demonstrate that dynamin-related protein 1(DRP1) is a substrate for p38 MAPK, mutant α-synuclein overexpression in SN4741 cell caused p38 MAPK activation, p38 MAPK-mediated phosphorylation DRP1 at serine 616 to activate DRP1 and is associated with increased mitochondrial fission, which resulted in mitochondrial dysfunction and neuronal loss. Inhibition of p38 MAPK or expression of a kinase death form of p38 MAPK not only attenuates DRP1-mediated mitochondrial fission,but also restores the mitochondrial dysfunction and cell death in α-synuclein A53T model. These findings showed that inhibition of p38 MAPK-DRP1 signaling pathway may be a viable therapeutic strategy of PD on maintenance of mitochondrial homeostasis.

    更新日期:2019-12-25
  • Transcriptomic modifications of the thyroid gland upon exposure to phytosanitary-grade fipronil: Evidence for the activation of compensatory pathways
    Toxicol. Appl. Pharmacol. (IF 3.585) Pub Date : 2019-12-24
    Pascal G.P. Martin; Véronique Dupouy; Julien Leghait; Thierry Pineau; Arnaud Polizzi; Frédéric Lasserre; Béatrice B. Roques; Catherine Viguié

    Fipronil is a phenylpyrazole insecticide used for the control of a variety of pest for domestic, veterinary and agricultural uses. Fipronil exposure is associated to thyroid disruption in the rat. It increases thyroid hormone (TH) hepatic clearance. The effect on thyroxine (T4) clearance is about four fold higher than the effect on T4 plasma concentrations suggesting that the thyroid gland might develop compensatory mechanisms. The aim of this study was to document the potential effects of fipronil treatment on the thyroid transcriptome together with its effects on TSH and TH blood levels under well characterized internal exposure to fipronil and its main metabolite fipronil sulfone. Fipronil (3 mg/kg/d by gavage for 14 days) clearance increased while its half-life decreased (about 10 fold) throughout treatment. Fipronil treatment in adult female rats significantly decreased total T4 and free triiodothyronine (T3) concentrations. Key genes related to thyroid hormone synthesis and/or cellular dynamic were modulated by fipronil exposure. RT-PCR confirmed that thyroglobulin gene expression was upregulated. A trend toward higher Na/I symporter expression was also noted, while sulfotransferase 1a1 gene expression was down-regulated. The expression of genes potentially involved in thyroid cell dynamic were upregulated (e.g. prostaglandin synthase 1, amphiregulin and Rhoa). Our results indicate that both pathways of TH synthesis and thyroid cell dynamics are transcriptional targets of fipronil and/or its main sulfone metabolite. The underlying mechanisms remain to be elucidated.

    更新日期:2019-12-25
  • Triptonide effectively suppresses gastric tumor growth and metastasis through inhibition of the oncogenic Notch1 and NF-κB signaling pathways
    Toxicol. Appl. Pharmacol. (IF 3.585) Pub Date : 2019-12-19
    Shufen Xiang; Zhe Zhao; Tong Zhang; Bin Zhang; Mei Meng; Zhifei Cao; Quansheng Zhou

    Gastric cancer ranks as the third leading cause of cancer-related death worldwide. The uncontrolled tumor growth and robust metastasis are key factors to cause the cancer patient death. Mechanistically, aberrant activation of Notch and NF-κB signaling pathways plays pivotal roles in the initiation and metastasis of gastric cancer. Despite great efforts have been made in recent decades, the effective drug against the advanced and metastatic gastric cancer is still lacking in the clinical setting. In this study, we found that triptonide, a small molecule (MW358) purified from the traditional Chinese medicinal herb Tripterygium wilfordii Hook F, effectively suppressed tumor growth and metastasis in xenograft mice without obvious toxicity at the doses we tested, resulting in potent anti-gastric cancer effect with low toxicity. Triptonide markedly inhibited human metastatic gastric cancer cell migration, invasion, proliferation, and tumorigenicity. Molecular mechanistic studies revealed that triptonide significantly reduced Notch1 protein levels in metastatic gastric cancer cells through degrading the oncogenic protein Notch1 via the ubiquitin-proteasome pathway. Consequently, the levels of Notch1 downstream proteins RBPJ, IKKα, IKKβ were significantly diminished, and nuclear factor-kappa B (NF-κB) phosphorylation was significantly reduced. Together, triptonide effectively suppresses gastric cancer growth and metastasis via inhibition of the oncogenic Notch1 and NF-κB signaling pathways. Our findings provide a new strategy and drug candidate for treatment of the advanced and metastatic gastric cancer.

    更新日期:2019-12-19
  • miR-187-5p/apaf-1 axis was involved in oxidative stress-mediated apoptosis caused by ammonia via mitochondrial pathway in chicken livers
    Toxicol. Appl. Pharmacol. (IF 3.585) Pub Date : 2019-12-18
    Yanmin Xu; Zhuo Li; Shuai Zhang; Hongfu Zhang; Xiaohua Teng

    Ammonia (NH3), a toxic gas, is an important cause of atmospheric haze and one of the main pollutants in air environment of poultry houses, threatening the health of human beings and poultry. However, little is known about the effect of NH3 on liver apoptotic damage. This study aimed to investigate the mechanism of oxidative stress-mediated apoptosis caused by NH3 in chicken livers and whether miR-187-5p/apaf-1 axis was involved in this mechanism. Here we duplicated NH3 poisoning model of chickens for fattening to study the ultrastructure of chicken livers, apoptosis rate, oxidative stress indexes, miR-187-5p, and apoptosis-related genes. Obvious apoptotic characteristics of liver tissues exposed to excess NH3 were observed, and the apoptosis rate increased. Excess NH3 decreased the activities of catalase (CAT), superoxide dismutase (SOD), total antioxidant capacity (T-AOC) and glutathione peroxidase (GSH-Px), and increased the content of malondialdehyde (MDA), suggesting that oxidative stress occurred. miR-187-5p decreased, and apoptotic protease activating factor-1 (apaf-1) increased, indicating that excess NH3 dysregulated miR-187-5p/apaf-1 axis. The expression of tumor protein p53 (p53), Bcl-2 associated X protein (Bax), Bcl-2 homologous antagonist/killer (Bak), Cytochrome-c (Cyt-c), Caspase-9, Caspase-8, and Caspase-3 was promoted, and the expression of B-cell lymphoma-2 (Bcl-2) was inhibited, resulting in apoptosis. Moreover, oxidative stress indexes, miR-187-5p, and apoptosis-related genes changed in dose- and time-dependent manner. Altogether, miR-187-5p/apaf-1 axis participated in oxidative stress-mediated apoptosis caused by NH3 via mitochondrial pathway in the livers of chickens for fattening. This study may provide new ideas to study the mechanism of liver apoptotic damage induced by NH3 exposure.

    更新日期:2019-12-19
  • Autophagic HuR mRNA degradation induces survivin and MCL1 downregulation in YM155-treated human leukemia cells
    Toxicol. Appl. Pharmacol. (IF 3.585) Pub Date : 2019-12-16
    Jing-Ting Chiou; Yuan-Chin Lee; Chia-Hui Huang; Yi-Jun Shi; Liang-Jun Wang; Long-Sen Chang
    更新日期:2019-12-17
  • Application of cytochrome P450 reactivity on the characterization of chemical compounds and its association with repeated-dose toxicity
    Toxicol. Appl. Pharmacol. (IF 3.585) Pub Date : 2019-12-10
    Michiko Watanabe, Takamitsu Sasaki, Jun-ichi Takeshita, Madoka Kushida, Yuki Shimizu, Hitomi Oki, Yoko Kitsunai, Haruka Nakayama, Hitomi Saruhashi, Rui Ogura, Ryota Shizu, Takuomi Hosaka, Kouichi Yoshinari

    Repeated-dose toxicity (RDT) studies are one of the critical studies to assess chemical safety. There have been some studies attempting to predict RDT endpoints based on chemical substructures, but it remains very difficult to establish such a method, and a more detailed characterization of chemical compounds seems necessary. Cytochrome P450s (P450s) comprise multiple forms with different substrate specificities and play important roles in both the detoxification and metabolic activation of xenobiotics. In this study, we investigated possible use of P450 reactivity of chemical compounds to classify these compounds. A total of 148 compounds with available rat RDT data were used as test compounds and subjected to inhibition assays against 18 human and rat P450s. Among the tested compounds, 82 compounds inhibited at least one P450 form. Hierarchical clustering analyses using the P450 inhibitory profiles divided the 82 compounds into nine groups, some of which showed characteristic chemical and biological properties. Principal component analyses of the P450 inhibition data in combination with the calculated chemical descriptors demonstrated that P450 inhibition data were plotted differently than most chemical descriptors in the loading plots. Finally, association analyses between P450 inhibition and RDT endpoints showed that some endpoints related to the liver, kidney and hematology were significantly associated with the inhibition of some P450s. Our present results suggest that the P450 reactivity profiles can be used as novel descriptors for characterizing chemical compounds for the investigation of the toxicity mechanism and/or the establishment of a toxicity prediction model.

    更新日期:2019-12-11
  • Evaluation of the exposure, dose-response and fate in the lung and pleura of chrysotile-containing brake dust compared to TiO2, chrysotile, crocidolite or amosite asbestos in a 90-day quantitative inhalation toxicology study – Interim results part 1: Experimental design, aerosol exposure, lung burdens and BAL1
    Toxicol. Appl. Pharmacol. (IF 3.585) Pub Date : 2019-12-10
    D.M. Bernstein, B. Toth, R.A. Rogers, D. Kling, P. Kunzendorf, J.I. Phillips, H. Ernst

    This 90-day repeated-dose inhalation toxicology study of brake-dust (BD) (brakes manufactured with chrysotile) in rats provides a comprehensive understanding of the biokinetics and potential toxicology in the lung and pleura. Exposure was 6 h/d, 5d/wk., 13wks followed by lifetime observation. Control groups included TiO2, chrysotile, commercial crocidolite and amosite asbestos. Aerosol fiber distributions of the chrysotile, crocidolite and amosite were similar (fibers L > 20 μm/cm3: chrysotile-Low/High 29/72; crocidolite 24; amosite 47 fibers/cm3; WHO-fibers/cm3: chrysotile-Low/High 119/233; crocidolite 181; amosite 281 fibers/cm3). The number of particles/cm3 in the BD was similar to that in the chrysotile, crocidolite & amosite exposures (BD 470–715; chrysotile 495–614; crocidolite 415; amosite 417 particles/cm3). In the BD groups, few fibers L > 20 μm were observed in the lungs at the end of exposure and no fibers L > 20 μm at 90d post exposure. In the chrysotile groups, means of 204,000 and 290,000 f(L > 20 μm)/lung were measured at 89d. By 180d, means of 1 and 3.9 fibers were counted on the filter corresponding to 14,000 and 55,000 f(L > 20 μm)/lung. In the crocidolite and amosite groups mean lung concentrations were 9,055,000 and 11,645,000 f(L > 20 μm)/lung at 89d. At 180d the means remained similar with 8,026,000 and 11,591,000 f(L > 20 μm)/lung representing 10–13% of the total lung fibers. BAL determined the total number of macrophages, lymphocytes, neutrophils, eosinophils, epithelial-cells and IL-1 beta, TNF-alpha and TGF-beta. At the moderate aerosol concentrations used in this study, neutrophil counts increased ~5 fold in the amphibole asbestos exposure groups. All other groups and parameters showed no important differences at these exposure concentrations.

    更新日期:2019-12-11
  • Low doses of BPA induced abnormal mitochondrial fission and hypertrophy in human embryonic stem cell-derived cardiomyocytes via the calcineurin-DRP1 signaling pathway: A comparison between XX and XY cardiomyocytes
    Toxicol. Appl. Pharmacol. (IF 3.585) Pub Date : 2019-12-09
    Wei Cheng, Shoufei Yang, Xiaolan Li, Fan Liang, Ren Zhou, Hui Wang, Yan Feng, Yan Wang

    Humans are inevitably exposed to bisphenol A (BPA) via multiple exposure ways. Thus, attention should be raised to the possible adverse effects related to low doses of BPA. Epidemiological studies have outlined BPA exposure and the increased risk of cardiovascular diseases (such as cardiac hypertrophy), which has been confirmed to be sex-specific in rodent animals and present in few in vitro studies, although the molecular mechanism is still unclear. However, whether BPA at low doses equivalent to human internal exposure level could induce cardiac hypertrophy via the calcineurin-DRP1 signaling pathway by disrupting calcium homeostasis is unknown. To address this, human embryonic stem cell (H1, XY karyotype and H9, XX karyotype)-derived cardiomyocytes (CM) were purified and applied to study the low-dose effects of BPA on cardiomyocyte hypertrophy. In our study, when H1– and H9-CM were exposed to noncytotoxic BPA (8 ng/ml), markedly elevated hypertrophic-related mRNA expression levels (such as NPPA and NPPB), enhanced cellular area and reduced ATP supplementation, demonstrated the hypertrophic cardiomyocyte phenotype in vitro. The excessive fission produced by BPA was promoted by CnAβ-mediated dephosphorylation of DRP1. At the molecular level, the increase in cytosolic Ca2+ levels by low doses of BPA could discriminate between H1– and H9-CM, which may suggest a potential sex-specific hypertrophic risk in cardiomyocytes in terms of abnormal mitochondrial fission and ATP production by impairing CnAβ-DRP1 signaling. In CnAβ-knockdown cardiomyocytes, these changes were highly presented in XX-karyotyped cells, rather than in XY-karyotyped cells.

    更新日期:2019-12-11
  • Vanillin derivative VND3207 activates DNA-PKcs conferring protection against radiation-induced intestinal epithelial cells injury in vitro and in vivo
    Toxicol. Appl. Pharmacol. (IF 3.585) Pub Date : 2019-12-09
    Ming Li, Yue Lang, Meng-Meng Gu, Jianming Shi, Benjamin P.C. Chen, Lan Yu, Ping-Kun Zhou, Zeng-Fu Shang

    Vanillin is a natural compound endowed with antioxidant and anti-mutagenic properties. We previously identified the vanillin derivative VND3207 with strong radio-protective and antioxidant effects and found that VND3207 confers survival benefit and protection against radiation-induced intestinal injury (RIII) in mice. We also observed that VND3207 treatment enhanced the expression level of the catalytic subunit of the DNA-dependent protein kinase (DNA-PKcs) in human lymphoblastoid cells with or without γ-irradiation. DNA-PKcs is a critical component of DNA double strand break repair pathway and also regulates mitotic progression by stabilizing spindle formation and preventing mitotic catastrophe in response to DNA damage. In the present study, we found that VND3207 protected intestinal epithelial cells in vitro against ionizing radiation by promoting cell proliferation and inhibiting cell apoptosis. In addition, VND3207 promoted DNA-PKcs activity by increasing autophosphorylation at S2056 site. Consistent with this, VND3207 significantly decreased the number of γH2AX foci and mitotic catastrophe after radiation. DNA-PKcs deficiency abolished these VND3207 radio-protective effects, indicating that DNA-PKcs activation is essential for VND3207 activity. In conclusion, VND3207 promoted intestinal repair following radiation injury by regulating the DNA-PKcs pathway.

    更新日期:2019-12-11
  • Evaluation of the dose-response and fate in the lung and pleura of chrysotile-containing brake dust compared to TiO2, chrysotile, crocidolite or amosite asbestos in a 90-day quantitative inhalation toxicology study – Interim results Part 2: Histopathological examination, Confocal microscopy and collagen quantification of the lung and pleural cavity
    Toxicol. Appl. Pharmacol. (IF 3.585) Pub Date : 2019-12-09
    D.M. Bernstein, B. Toth, R.A. Rogers, D. Kling, P. Kunzendorf, J.I. Phillips, H. Ernst

    The interim results from this 90-day multi-dose, inhalation toxicology study with life-time post-exposure observation has shown an important fundamental difference in persistence and pathological response in the lung between brake dust derived from brake-pads manufactured with chrysotile, TiO2 or chrysotile alone in comparison to the amphiboles, crocidolite and amosite asbestos. In the brake dust exposure groups no significant pathological response was observed at any time. Slight macrophage accumulation of particles was noted. Wagner-scores, were from 1 to 2 (1 = air-control group) and similar to the TiO2 group. Chrysotile being biodegradable, shows a weakening of its matrix and brakeing into short fibers & particles that can be cleared by alveolar macrophages and continued dissolution. In the chrysotile exposure groups, particle laden macrophage accumulation was noted leading to a slight interstitial inflammatory response (Wagner-score 1–3). There was no peribronchiolar inflammation and occasional very slight interstitial fibrosis. The histopathology and the confocal analyses clearly differentiate the pathological response from amphibole asbestos, crocidolite and amosite, compared to that from the brake dust and chrysotile. Both crocidolite and amosite induced persistent inflammation, microgranulomas, and fibrosis (Wagner-scores 4), which persisted through the post exposure period. The confocal microscopy of the lung and snap-frozen chestwalls quantified the extensive inflammatory response and collagen development in the lung and on the visceral and parietal surfaces. The interim results reported here, provide a clear basis for differentiating the effects from brake dust exposure from those following amphibole asbestos exposure. The subsequent results through life-time post-exposure will follow.

    更新日期:2019-12-11
  • Gant61 ameliorates CCl4-induced liver fibrosis by inhibition of Hedgehog signaling activity
    Toxicol. Appl. Pharmacol. (IF 3.585) Pub Date : 2019-12-06
    Shen Jiayuan, Yan Junyan, Wei Xiangzhen, Liu Zuping, Ni Jian, Hu Baowei, Jin Lifang

    As an intercellular signaling molecule, Hedgehog (Hh) plays a critical role in liver fibrosis/regeneration. Transcription effectors Gli1 and Gli2 are key components of the Hh signaling pathway. However, whether inhibition of Gli1/2 activity can affect liver fibrogenesis is largely unknown. In the present study, we investigated the effect of Gant61 (a Gli1/2 transcription factor inhibitor) on liver fibrosis and its possible mechanism. Wild-type and Shh-EGFP-Cre male mice were exposed to CCl4, and then treated with or without Gant61 for four weeks. The level of liver injury/fibrosis and expression levels of mRNA and protein related to the Hh ligand/pathway were assessed. In our study, CCl4 treatment induced liver injury/fibrosis and promoted activation of hepatic stellate cells (HSCs). In addition, CCl4 induced the expression of Shh ligands in and around the fibrotic lesion, accompanied by induction of mRNA and protein expression of Hh components (Smo, Gli1 and Gli2). However, administration of Gant61 decreased liver fibrosis by reduction in HSC number, down-regulation of mRNA and protein expression of Hh components (Smo, Gli1 and Gli2), and cell-cycle arrest of HSCs. Our data highlight the importance of the Shh pathway for the development of liver fibrosis, and also suggest Glis as potential therapeutic targets for the treatment of liver fibrosis.

    更新日期:2019-12-07
  • Verteporfin inhibits lipopolysaccharide-induced inflammation by multiple functions in RAW 264.7 cells
    Toxicol. Appl. Pharmacol. (IF 3.585) Pub Date : 2019-12-05
    Yuting Wang, Lei Wang, James T.F. Wise, Xianglin Shi, Zhimin Chen

    Inflammation is a physiologic response to damage triggered by infection, injury or chemical irritation. Chronic inflammation produces repeated damage to cells and tissues, which can induce a variety of human diseases including cancer. Verteporfin, an FDA approved drug, is used for the treatment of age-related macular degeneration. The anti-tumor effects of verteporfin have been demonstrated by a number of studies. However, fewer studies focus on the anti-inflammatory functions of this drug. In this study, we investigated the anti-inflammatory effects and potential mechanisms of verteporfin. The classic lipopolysaccharide (LPS)-induced inflammation cell model was used. RAW 264.7 cells were pre-treated with verteporfin or vehicle control, followed by LPS stimulation. Verteporfin inhibited IL-6 and TNF-α at mRNA and protein expression levels. This effect was mediated through inhibition of the NF-κB and JAK/STAT pathways. Finally, verteporfin exhibited an anti-inflammation effect by crosslinking of protein such as NF-κB p65, JAK1, JAK2, STAT1, or STAT3 leading to inflammation. Taken together, these results indicate that verteporfin has the potential to be an effective therapeutic agent against inflammatory diseases.

    更新日期:2019-12-05
  • Thymoquinone promotes mouse mesenchymal stem cells migration in vitro and induces their immunogenicity in vivo
    Toxicol. Appl. Pharmacol. (IF 3.585) Pub Date : 2019-12-05
    Niloufar Rezaei, Tayebeh Sardarzadeh, Sajjad Sisakhtnezhad

    Mesenchymal stem cells (MSCs) have unique potentials, including migration and immunomodulation. Identification of the factors that enhance these activities can improve clinical applications of MSCs. This study aimed to investigate total antioxidant capacity (TAC) and migration potential of mouse MSCs exposed to thymoquinone (TQ) in vitro, and to examine the effect of TQ-treated MSCs on the expression of mouse immune cell markers. The results of total antioxidant capacity and wound healing assays showed that TQ increased the rate of MSCs TAC and migration in a dose- and time-dependent manner. The maximum TAC and migration were detected at 600 and 250 ng/ml of TQ, respectively. Functionally, the real-time PCR data analysis indicated that TQ induced c-Met and Cxcr4 expression and therefore, there may be a correlation between upregulation of these genes and increased MSCs migration. TQ also enhanced the up and down regulating impact of MSCs on Rorγt and Plzf expression and the expression of Tcf4 in mouse immune cells, respectively. Overall, this study declares that TQ increases the TAC of MSCs. It also proposes that TQ may, through activation of c-MET and CXCR4 signalling pathways, promote MSCs migration. TQ may also augment MSCs immunogenicity through its influence on the expression of genes involved in commitment of mouse immune system cells in vivo.

    更新日期:2019-12-05
  • Sesamin suppresses NSCLC cell proliferation and induces apoptosis via Akt/p53 pathway
    Toxicol. Appl. Pharmacol. (IF 3.585) Pub Date : 2019-12-03
    Yueming Chen, Huachao Li, Weinan Zhang, Wanchen Qi, Changpeng Lu, Huiliang Huang, Zhicheng Yang, Bing Liu, Luyong Zhang
    更新日期:2019-12-04
  • Mice deficient in pyruvate dehydrogenase kinase 4 are protected against acetaminophen-induced hepatotoxicity
    Toxicol. Appl. Pharmacol. (IF 3.585) Pub Date : 2019-12-03
    Luqi Duan, Anup Ramachandran, Jephte Y. Akakpo, Benjamin L. Woolbright, Yuxia Zhang, Hartmut Jaeschke

    Though mitochondrial oxidant stress plays a critical role in the progression of acetaminophen (APAP) overdose-induced liver damage, the influence of mitochondrial bioenergetics on this is not well characterized. This is important, since lifestyle and diet alter hepatic mitochondrial bioenergetics and an understanding of its effects on APAP-induced liver injury is clinically relevant. Pyruvate dehydrogenase (PDH) is critical to mitochondrial bioenergetics, since it controls the rate of generation of reducing equivalents driving respiration, and pyruvate dehydrogenase kinase 4 (PDK4) regulates (inhibits) PDH by phosphorylation. We examined APAP-induced liver injury in PDK4-deficient (PDK4−/−) mice, which would have constitutively active PDH and hence elevated flux through the mitochondrial electron transport chain. PDK4−/− mice showed significant protection against APAP-induced liver injury when compared to wild type (WT) mice as measured by ALT levels and histology. Deficiency of PDK4 did not alter APAP metabolism, with similar APAP-adduct levels in PDK4−/− and WT mice, and no difference in JNK activation and translocation to mitochondria. However, subsequent amplification of mitochondrial dysfunction with release of mitochondrial AIF, peroxynitrite formation and DNA fragmentation were prevented. Interestingly, APAP induced a rapid decline in UCP2 protein levels in PDK4-deficient mice. These data suggest that adaptive changes in mitochondrial bioenergetics induced by enhanced respiratory chain flux in PDK4−/− mice render them highly efficient in handling APAP-induced oxidant stress, probably through modulation of UCP2 levels. Further investigation of these specific adaptive mechanisms would provide better insight into the control exerted by mitochondrial bioenergetics on cellular responses to an APAP overdose.

    更新日期:2019-12-04
  • Anti-inflammatory effects of Aureusidin in LPS-stimulated RAW264.7 macrophages via suppressing NF-κB and activating ROS- and MAPKs-dependent Nrf2/HO-1 signaling pathways
    Toxicol. Appl. Pharmacol. (IF 3.585) Pub Date : 2019-11-29
    Jie Ren, Dan Su, Lixia Li, Heng Cai, Meiju Zhang, Jingchen Zhai, Minyue Li, Xinyue Wu, Kun Hu

    Aureusidin, a naturally-occurring flavonoid, is found in various plants of Cyperaceae such as Heleocharis dulcis (Burm. f.) Trin., but its pharmacological effect and active mechanism are rarely reported. This study aimed to investigate the anti-inflammatory effect and action mechanism of Aureusidin in LPS-induced mouse macrophage RAW264.7 cells. The results suggested that lipopolysaccharide (LPS)-induced nitric oxide (NO), tumor necrosis factor-α (TNF-α) and prostaglandin E2 (PGE2) production were obviously inhibited by Aureusidin. Moreover, Aureusidin also significantly decreased the mRNA expression of various inflammatory factors in LPS-stimulated RAW264.7 cells. Furthermore, mechanistic studies showed that Aureusidin significantly inhibited nuclear transfer of nuclear factor-κB (NF-κB), while increasing the nuclear translocation of nuclear factor E2-related factor 2 (Nrf2) as well as expression of Nrf2 target genes such as heme oxygenase (HO-1) and NAD(P)H:quinone oxidoreductase 1 (NQO1), but the addition of the HO-1 inhibitor Sn-protoporphyrin (Snpp) significantly abolished the anti-inflammatory effect of Aureusidin in LPS-stimulated RAW264.7 cells, confirming the view that HO-1 was involved in the anti-inflammatory effect. In addition, Aureusidin increased the levels of reactive oxygen species (ROS) and mitogen-activated protein kinase (MAPK) phosphorylation in RAW264.7 cells. Antioxidant N-acetylcysteine (NAC) or three MAPK inhibitors blocked the nuclear translocation of Nrf2 and HO-1 expression induced by Aureusidin, indicating that Aureusidin activated the Nrf2/HO-1 signaling pathway through ROS and MAPKs pathways. At the same time, co-treatment with the NAC blocked the phosphorylation of MAPKs. Results from molecular docking indicated that Aureusidin inhibited the NF-κB pathway by covalently binding to NF-κB. Thus, Aureusidin exerted the anti-inflammatory activity through blocking the NF-κB signaling pathways and activating the MAPKs and Nrf2/HO-1 signaling pathways. Based on the above results, Aureusidin may be an attractive therapeutic candidate for the inflammation-related diseases.

    更新日期:2019-11-30
  • Toxicokinetics of bisphenol S in rats for predicting human bisphenol S clearance from allometric scaling
    Toxicol. Appl. Pharmacol. (IF 3.585) Pub Date : 2019-11-28
    Véronique Gayrard, Marlène Z. Lacroix, Clémence A. Gély, Flore C. Grandin, Roger Léandri, Michèle Bouchard, Béatrice Roques, Pierre-Louis Toutain, Nicole Picard-Hagen

    Previous data obtained in piglets suggested that despite structural analogy with Bisphenol A (BPA), Bisphenol S (BPS) elimination may proceed more slowly, resulting in a much higher systemic exposure to unconjugated BPS than to BPA. Interspecies allometric scaling was applied to predict the toxicokinetic (TK) parameters of BPS, namely plasma clearance in humans from values obtained in animals, and thus contribute to assessment of the human internal exposure to BPS. Allometric scaling was performed using mean BPS plasma clearance values measured in rats after intravenous administration of 5 mg BPS /kg body weight (BW) and those previously obtained in piglets and sheep using identical IV BPS dosing and analytical procedures. The BPS plasma clearance, evaluated at 0.92 L/kg.h in rats, was proportional to species body weight, enabling the prediction of human BPS plasma clearance by extrapolating to a BW of 70 kg. The estimated BPS plasma clearance in humans was thus 0.92 L/min (0.79 L/kg.h), i.e. about two times lower than the previously estimated BPA clearance (1.79 L/min). By increasing systemic exposure to the active moiety of an environmental estrogenic chemical, this less efficient clearance of BPS in humans, as compared with BPA, might worsen the harmful consequences of replacing BPA by BPS.

    更新日期:2019-11-29
  • Low molecular polypeptide from oyster hydrolysate recovers photoaging in SKH-1 hairless mice
    Toxicol. Appl. Pharmacol. (IF 3.585) Pub Date : 2019-11-27
    Joon Sok Bang, Yu Jung Jin, Se-Young Choung

    When the human skin is chronically exposed to external stimuli such as ultraviolet (UV) radiation, the skin tissue suffers damage and the structure of the extracellular matrix (ECM) in the skin is disrupted. This eventually causes symptoms such as wrinkles loss of elasticity, skin sagging, and skin cancer. We previously found that hydrolysate extracted from pacific oyster (Crassostrea gigas) is effective in improving wrinkle formation. In this study, we selected a peptide that was expected to have the most wrinkle reduction effect among the various peptides in oyster hydrolysate through preliminary in vitro screening and examined whether the pentapeptide derived from oyster hydrolysate (OHP) is effective in reducing wrinkles in vivo. We investigated the wrinkle-reducing effect of the OHP through 18-week SKH-1 hairless mice model. Ouer results showed that the OHP reduces wrinkles lengths, depths, and epidermal thickness which were increased by UVB radiation, and restored the amount of collagen. The OHP recovered the activity of antioxidant enzymes and regulated the expression of proinflammatory cytokines. We also found that OHP increases the expression of type I collagen through stimulating TGFβ/Smad signaling pathway and inhibits the MMPs expression by regulating MAPK/AP-1 signaling pathway. This study has shown that the OHP plays crucial roles in collagen production and wrinkle reduction in hairless mice and we proved the possibility of the OHP as a component for inhibiting wrinkle formation which was induced by photoaging.

    更新日期:2019-11-28
  • The role of fit-for-purpose assays within tiered testing approaches: A case study evaluating prioritized estrogen-active compounds in an in vitro human uterotrophic assay
    Toxicol. Appl. Pharmacol. (IF 3.585) Pub Date : 2019-11-27
    Tyler Beames, Marjory Moreau, L. Avery Roberts, Kamel Mansouri, Saad Haider, Marci Smeltz, Chantel I. Nicolas, Daniel Doheny, Martin B. Phillips, Miyoung Yoon, Richard A. Becker, Patrick D. McMullen, Melvin E. Andersen, Rebecca A. Clewell, Jessica K. Hartman

    Chemical risk assessment relies on toxicity tests that require significant numbers of animals, time and costs. For the >30,000 chemicals in commerce, the current scale of animal testing is insufficient to address chemical safety concerns as regulatory and product stewardship considerations evolve to require more comprehensive understanding of potential biological effects, conditions of use, and associated exposures. We demonstrate the use of a multi-level new approach methodology (NAMs) strategy for hazard- and risk-based prioritization to reduce animal testing. A Level 1/2 chemical prioritization based on estrogen receptor (ER) activity and metabolic activation using ToxCast data was used to select 112 chemicals for testing in a Level 3 human uterine cell estrogen response assay (IKA assay). The Level 3 data were coupled with quantitative in vitro to in vivo extrapolation (Q-IVIVE) to support bioactivity determination (as a surrogate for hazard) in a tissue-specific context. Assay AC50s and Q-IVIVE were used to estimate human equivalent doses (HEDs), and HEDs were compared to rodent uterotrophic assay in vivo-derived points of departure (PODs). For substances active both in vitro and in vivo, IKA assay-derived HEDs were lower or equivalent to in vivo PODs for 19/23 compounds (83%). Activity exposure relationships were calculated, and the IKA assay was as or more protective of human health than the rodent uterotrophic assay for all IKA-positive compounds. This study demonstrates the utility of biologically relevant fit-for-purpose assays and supports the use of a multi-level strategy for chemical risk assessment.

    更新日期:2019-11-27
  • Applicability of the OECD 455 in-vitro assay for determination of hERa agonistic activity of isoflavonoids
    Toxicol. Appl. Pharmacol. (IF 3.585) Pub Date : 2019-11-20
    Darja Gramec Skledar, Václav Tvrdý, Maša Kenda, Anamarija Zega, Milan Pour, Pavel Horký, Přemysl Mladěnka, Marija Sollner Dolenc, Lucija Peterlin Mašič
    更新日期:2019-11-20
  • In vitro toxicity screening of polyglycerol esters of fatty acids as excipients for pulmonary formulations
    Toxicol. Appl. Pharmacol. (IF 3.585) Pub Date : 2019-11-19
    Eleonore Fröhlich, Kristin Öhlinger, Claudia Meindl, Carolina Corzo, Dirk Lochmann, Sebastian Reyer, Sharareh Salar-Behzadi

    One of the main problems for the development of pulmonary formulations is the low availability of approved excipients. Polyglycerol esters of fatty acids (PGFA) are promising molecules for acting as excipient for formulation development and drug delivery to the lung. However, their biocompatibility in the deep lung has not been studied so far. Main exposed cells include alveolar epithelial cells and alveolar macrophages. Due to the poor water-solubility of PGFAs, the exposure of alveolar macrophages is expected to be much higher than that of epithelial cells. In this study, two PGFAs and their mixture were tested regarding cytotoxicity to epithelial cells and cytotoxicity and functional impairment of macrophages. Cytotoxicity was assessed by dehydrogenase activity and lactate dehydrogenase release. Lysosome function, phospholipid accumulation, phagocytosis, nitric oxide production, and cytokine release were used to evaluate macrophage function. Cytotoxicity was increased with the increased polarity of PGFA molecules. At concentrations above 1 mg/ml accumulation in lysosomes, impairment of phagocytosis, secretion of nitric oxide, and increased release of cytokines were noted. The investigated PGFAs in concentrations up to 1 mg/ml can be considered as uncritical and are promising for advanced pulmonary delivery of high powder doses and drug targeting to alveolar macrophages.

    更新日期:2019-11-20
  • P-glycoprotein activation by 1-(propan-2-ylamino)-4-propoxy-9H-thioxanthen-9-one (TX5) in rat distal ileum: Ex vivo and in vivo studies
    Toxicol. Appl. Pharmacol. (IF 3.585) Pub Date : 2019-11-19
    Carolina Rocha-Pereira, Carolina Inés Ghanem, Renata Silva, Alfredo G. Casanova, Margarida Duarte-Araújo, Salomé Gonçalves-Monteiro, Emília Sousa, Maria de Lourdes Bastos, Fernando Remião
    更新日期:2019-11-20
  • Effects of physicochemical properties of TiO2 nanomaterials for pulmonary inflammation, acute phase response and alveolar proteinosis in intratracheally exposed mice
    Toxicol. Appl. Pharmacol. (IF 3.585) Pub Date : 2019-11-15
    Pernille Høgh Danielsen, Kristina Bram Knudsen, Janez Štrancar, Polona Umek, Tilen Koklič, Maja Garvas, Esa Vanhala, Sauli Savukoski, Yaobo Ding, Anne Mette Madsen, Nicklas Raun Jacobsen, Ingrid Konow Weydahl, Trine Berthing, Sarah Søs Poulsen, Otmar Schmid, Henrik Wolff, Ulla Vogel

    Nanomaterial (NM) characteristics may affect the pulmonary toxicity and inflammatory response, including specific surface area, size, shape, crystal phase or other surface characteristics. Grouping of TiO2 in hazard assessment might be challenging because of variation in physicochemical properties. We exposed C57BL/6 J mice to a single dose of four anatase TiO2 NMs with various sizes and shapes by intratracheal instillation and assessed the pulmonary toxicity 1, 3, 28, 90 or 180 days post-exposure. The quartz DQ12 was included as benchmark particle. Pulmonary responses were evaluated by histopathology, electron microscopy, bronchoalveolar lavage (BAL) fluid cell composition and acute phase response. Genotoxicity was evaluated by DNA strand break levels in BAL cells, lung and liver in the comet assay. Multiple regression analyses were applied to identify specific TiO2 NMs properties important for the pulmonary inflammation and acute phase response. The TiO2 NMs induced similar inflammatory responses when surface area was used as dose metrics, although inflammatory and acute phase response was greatest and more persistent for the TiO2 tube. Similar histopathological changes were observed for the TiO2 tube and DQ12 including pulmonary alveolar proteinosis indicating profound effects related to the tube shape. Comparison with previously published data on rutile TiO2 NMs indicated that rutile TiO2 NMs were more inflammogenic in terms of neutrophil influx than anatase TiO2 NMs when normalized to total deposited surface area. Overall, the results suggest that specific surface area, crystal phase and shape of TiO2 NMs are important predictors for the observed pulmonary effects of TiO2 NMs.

    更新日期:2019-11-15
  • CXCL14 downregulation in human keratinocytes is a potential biomarker for a novel in vitro skin sensitization test
    Toxicol. Appl. Pharmacol. (IF 3.585) Pub Date : 2019-11-14
    Eunyoung Lee, Sungjin Ahn, Sun Hee Jin, Moonyoung Lee, Jeong Joo Pyo, Jeayoung C. Shin, Seungchan An, Jaehyoun Ha, Minsoo Noh
    更新日期:2019-11-14
  • miR-181b-5p inhibits endothelial-mesenchymal transition in monocrotaline-induced pulmonary arterial hypertension by targeting endocan and TGFBR1
    Toxicol. Appl. Pharmacol. (IF 3.585) Pub Date : 2019-11-14
    Haiyan Zhao, Yang Wang, Xiaoli Zhang, Yingying Guo, Xiaofei Wang

    Endothelial-mesenchymal transition (EndMT) is a frequent event in endothelial dysfunction, which is associated with pulmonary arterial hypertension (PAH). MiR-181 family members exert diverse effects in multiple biological processes. However, the relationships between miR-181b-5p (miR-181b) and EndMT in PAH are not well understood. In this study, Sprague-Dawley (SD) rats were injected with monocrotaline (MCT) to establish PAH model, and primary rat pulmonary arterial endothelial cells (rPAECs) were treated with TNF-α, TGFβ1 and IL-1β in combination to induce EndMT (I-EndMT). Then we explored miR-181b expression and examined its functional role in PAH. Our data showed that miR-181b was down-expressed in PAH, and its overexpression attenuated the hemodynamics, pulmonary vascular hypertrophy, right ventricular remodeling and EndMT process in MCT-induced PAH rats. In I-EndMT rPAECs, we observed that inducing miR-181b reversed the decrease of endothelial markers and increase of mesenchymal markers. However, knockdown of miR-181b induced similar effects to EndMT. In addition, endocan and TGFBR1 levels were also increased in EndMT, which were negatively regulated by miR-181b. Luciferase activity results indicated that endocan and TGFBR1 were direct target genes of miR-181b. In summary, our findings firstly demonstrate that the beneficial effect of miR-181b on PAH may be associated with endocan/TGFBR1-mediated EndMT, providing a new insight into the diagnosis and treatment of PAH.

    更新日期:2019-11-14
  • 更新日期:2019-11-14
  • Use of a physiologically-based pharmacokinetic model to explore the potential disparity in nicotine disposition between adult and adolescent nonhuman primates
    Toxicol. Appl. Pharmacol. (IF 3.585) Pub Date : 2019-11-12
    Xiaoxia Yang, Jennifer Naylor, Katelin Matazel, Amy Goodwin, Cristina C. Jacob, Matthew Bryant, Lucie Loukotková, Gonçalo Gamboa da Costa, Susan Chemerynski, Ying Deng-Bryant, Chad Reissig, Kia Jackson, Jeffrey Fisher

    The widespread use and high abuse liability of tobacco products has received considerable public health attention, in particular for youth, who are vulnerable to nicotine addiction. In this study, adult and adolescent squirrel monkeys were used to evaluate age-related metabolism and pharmacokinetics of nicotine after intravenous administration. A physiologically-based pharmacokinetic (PBPK) model was created to characterize the pharmacokinetic behaviors of nicotine and its metabolites, cotinine, trans-3′-hydroxycotinine (3′-OH cotinine), and trans-3′-hydroxycotinine glucuronide (3′-OH cotinine glucuronide) for both adult and adolescent squirrel monkeys. The PBPK nicotine model was first calibrated for adult squirrel monkeys utilizing in vitro nicotine metabolic data, plasma concentration-time profiles and cumulative urinary excretion data for nicotine and metabolites. Further model refinement was conducted when the calibrated adult model was scaled to the adolescents, because adolescents appeared to clear nicotine and cotinine more rapidly relative to adults. More specifically, the resultant model parameters representing systemic clearance of nicotine and cotinine for adolescent monkeys were approximately two- to three-fold of the adult values on a per body weight basis. The nonhuman primate PBPK model in general captured experimental observations that were used for both model calibration and evaluation, with acceptable performance metrics for precision and bias. The model also identified differences in nicotine pharmacokinetics between adolescent and adult nonhuman primates which might also be present in humans.

    更新日期:2019-11-13
  • Pristimerin suppresses colorectal cancer through inhibiting inflammatory responses and Wnt/β-catenin signaling
    Toxicol. Appl. Pharmacol. (IF 3.585) Pub Date : 2019-11-09
    Qun Zhao, Yun Bi, Jing Zhong, Ziting Ren, Yingxiang Liu, Junjun Jia, Mengting Yu, Yan Tan, Qiufang Zhang, Xianjun Yu

    Pristimerin, a triterpenoid, has exhibited potential anti-inflammatory and anti-tumor activities. Nevertheless, the role and mechanism of pristimerin in intestinal inflammation and colon cancer require further investigation. Here, we found that pristimerin protected mice from dextran sulfate sodium (DSS)-induced colitis, restoring epithelial damage and reducing tissue inflammation and inflammatory cell infiltration. In addition, pristimerin dramatically reduced the number and size of the tumors in a azoxymethane (AOM)/DSS-induced colitis-associated colorectal cancer (CAC) model. Furthermore, we found that pristimerin suppressed Wnt/β-catenin signaling by RNA-Seq. Pristimerin inhibited Wnt/β-catenin signaling via activation of GSK3β, thereby suppressing Wnt target gene expression in colon cancer HCT116 and HT-29 cells. In HCT116 colon cancer xenografts and APCmin/+ mice, which undergo spontaneous intestinal tumorigenesis, administration of pristimerin reduced the tumor progression and decreased the expression of phosphorylated GSK3β Ser 9, β-catenin, cyclin D1 and c-Myc. These results suggest that pristimerin is a potent agent for preventing colon inflammation and carcinogenesis.

    更新日期:2019-11-11
  • Comparison of transcriptome expression alterations by chronic exposure to low-dose bisphenol A in different subtypes of breast cancer cells
    Toxicol. Appl. Pharmacol. (IF 3.585) Pub Date : 2019-11-09
    Hyelim Kim, Hoe Suk Kim, Woo Kyung Moon

    The impacts of chronic bisphenol A (BPA) exposure suspected to be a potential risk factor for breast cancer progression are not thoroughly understood in different subtypes of breast cancer cells (BCCs). This study aimed to compare the differentially expressed genes (DEGs) and biological functions in MCF-7 (luminal A), SK-BR3 (HER2–enriched) and MDA-MB-231 (triple–negative) cells exposed to BPA at an environmentally human-relevant low dose (10−8 M) for 30 days, by using the approach of RNA sequencing and online informatics tools. BPA-exposure resulted in 172, 137, and 139 DEGs in MCF-7/BPA, SK-BR3/BPA, and MDA-MB-231/BPA, respectively. The significantly enriched gene ontology terms of DEGs in each cell were different: cellular response to gonadotropin-releasing hormone, negative regulation of fibrinolysis, choline metabolism, glutamate signaling pathways and coagulation pathway in MCF-7/BPA; positive regulation of inflammatory response and VEGF/VEGFR signaling pathways in SK-BR3/BPA; negative regulation of keratinocyte proliferation and HIF signaling pathways in MDA-MB-231/BPA cells. The immune network analysis of DEGs across the breast cancer cells indicated NKT, NK and T cell activation and dendritic cell migration by regulating the expression of immunomodulatory genes. High expression of IL19, CA9 and SPARC identified in MCF-7/BPA, SK-BR3/BPA, and MDA-MB-231/BPA are detrimental gene signatures to predict poor overall survival in luminal A, HER2-enriched and triple–negative breast cancer patients, respectively. These findings indicate chronic BPA exposure has dissimilar impacts on the regulation of gene expression and diverse biological functions, including immune modulation, in different subtypes of BCCs.

    更新日期:2019-11-11
  • Chemerin-induced angiogenesis and adipogenesis in 3 T3-L1 preadipocytes is mediated by lncRNA Meg3 through regulating Dickkopf-3 by sponging miR-217
    Toxicol. Appl. Pharmacol. (IF 3.585) Pub Date : 2019-11-09
    Xianwei Huang, Caihua Fu, Wenhui Liu, Yansheng Liang, Peilun Li, Zhiquan Liu, Qiping Sheng, Ping Liu

    Purpose Obesity is often caused by the excess adipogenesis and regulated by long non-coding RNAs (lncRNAs) and microRNAs (miRNAs). We performed this study to investigate the influence of Meg3 expression on adipogenesis and also the Meg3/miR-217/Dkk3 axis-mediated molecular mechanism in adipogenesis and angiogenesis. Methods 3 T3-L1 preadipocytes were incubated with chemerin and transfected with Meg3-overexpressing (OE-Meg3) and Dkk3-overexpressing (OE-Dkk3) plasmids, siRNAs, and miR-217 mimics, inhibitor and scrambled sequences for 48 h or 72 h. The changes in cell proliferation, adipogenesis and angiogenesis ability in 3 T3-L1 preadipocytes was detected by using the corresponding assay. The expressions of related proteins were detected via western blot. Results Chemerin decreased miR-217 expression and increased Meg3 expression, meanwhile promoted the proliferation, adipogenesis and angiogenesis in 3 T3-L1 preadipocytes. Besides, OE-Meg3 exerted the synergistic effect on 3 T3-L1 preadipocytes when co-treated with chemerin. The target interactions between Meg3 and miR-217 as well as between miR-217 and Dkk3 were validated using dual-luciferase reporter system. SiMeg3 antagonized chemerin-induced changes, while the addition of miR-217 inhibitor attenuated siMeg3-induced changes in 3 T3-L1 preadipocytes. The proliferation, adipogenesis and angiogenesis in 3 T3-L1 preadipocytes were suppressed by miR-217 mimics, while promoted by the OE-Dkk3 Chemerin promoted the expression of fatty acid binding protein 4 and vascular endothelial growth factor (VEGF) proteins, and decreased the expression of cyclin D1, c-Myc, and β-catenin proteins. Meanwhile, these effects were further enhanced by OE-Meg3 or OE-Dkk3. However, the transfection of siMeg3, or miR-217 mimics, or siDkk3 reversed the previous changes. Conclusions Meg3/miR-217/Dkk3 induced adipogenesis and angiogenesis in 3 T3-L1 preadipocytes via activating VEGF signaling pathway and inhibiting Wnt/β-catenin signaling pathway.

    更新日期:2019-11-11
  • Fibrin gels entrapment of a doxorubicin-containing targeted polycyclodextrin: Evaluation of in vivo antitumor activity in orthotopic models of human neuroblastoma
    Toxicol. Appl. Pharmacol. (IF 3.585) Pub Date : 2019-11-06
    Maurizio Viale, Graziella Vecchio, Irena Maric, Michele Cilli, Anna Aprile, Mirco Ponzoni, Vincenzo Fontana, Erica C. Priori, Vittorio Bertone, Mattia Rocco

    In vivo local antitumor activity of fibrin gels (FBGs) loaded with the poly-cyclodextrin oCD-NH2/Dox, compared to FBGs loaded with doxorubicin (Dox) or to free Dox, was evaluated in two mouse orthotopic neuroblastoma (NB) models, after positioning of the releasing devices in the visceral space. FBGs were prepared at the fibrinogen (FG) concentrations of 22 and 40 mg/ml clotted in the presence of 0.81 mM/mg FG Ca2+ and 1.32 U/mg FG thrombin. Our results indicate that FBGs loaded with oCD-NH2/Dox and applied as neoadjuvant loco-regional treatment, show an antitumor activity significantly greater than that displayed by the same FBGs loaded with identical dose of Dox or after free Dox administered intra venous (iv). In particular, FBGs prepared at 40 mg/ml showed a slightly lower antitumor activity, although after their positioning we observed a significant initial reduction of tumor burden lasting for several days after gel implantation. FBGs at 22 mg/ml loaded with oCD-NH2/Dox and applied after tumor removal (adjuvant treatment model) showed a significantly better antitumor activity than the iv administration of free Dox, with 90% tumor regrowth reduction compared to untreated controls. In all cases the weight loss post-treatment was limited after gel application, although in the adjuvant treatment the loss of body weight lasted longer than in the other treatment modality. In accordance with our recent published data on the low local toxic effects of FBGs, the present findings also underline an increase of the therapeutic index of Dox when locally administered through FBGs loaded with the oCD-NH2/Dox complex.

    更新日期:2019-11-06
  • Amlexanox ameliorates acetaminophen-induced acute liver injury by reducing oxidative stress in mice
    Toxicol. Appl. Pharmacol. (IF 3.585) Pub Date : 2019-11-05
    Jing Qi, Zixiong Zhou, Chae Woong Lim, Jong-Won Kim, Bumseok Kim

    Amlexanox, a clinically approved small-molecule therapeutic presently used to treat allergic rhinitis, ulcer, and asthma, is an inhibitor of the noncanonical IkB kinase-ε (IKKε) and TANK-binding kinase 1 (TBK1). This study was to investigate the protective mechanism of amlexanox in acetaminophen (APAP)-induced acute liver injury (ALI). Mice were intraperitoneally injected with APAP (300 mg/kg, 12 h) to induce ALI and were orally administrated with amlexanox (25, 50 and 100 mg/kg) one hour after APAP treatment. Inhibition of IKKε and TBK1 by treatment of amlexanox attenuated APAP-induced ALI as confirmed by decreased serum levels of aspartate aminotransferase and alanine aminotransferase. Furthermore, amlexanox significantly decreased hepatocellular apoptosis in injured livers of mice as evidenced by histopathologic observation. Consistently, reduced oxidative stress by amlexanox was observed by increased hepatic glutathione concomitant with decreased levels of malondialdehyde. Amlexanox also enhanced expression levels of nuclear factor erythroid 2-related factor 2 (Nrf2) target genes including heme oxygenase 1, NAD(P)H:quinone oxidoreductase 1, and glutamate-cysteine ligase in injured livers of mice. Mechanistic insights into the mode of action of amlexanox against APAP-induced hepatotoxicity were involved in increasing phosphorylation of AMP-activated protein kinase (AMPK) and nuclear translocation of Nrf2, both in vivo and in vitro. Furthermore, the protective effects of amlexanox on APAP-induced hepatotoxicity were abolished by compound C, an AMPK inhibitor. Taken together, our findings suggest that amlexanox exerts antioxidative activities against APAP-mediated hepatotoxicity via AMPK/Nrf2 pathway.

    更新日期:2019-11-06
  • Schisandrin B attenuates renal fibrosis via miR-30e-mediated inhibition of EMT
    Toxicol. Appl. Pharmacol. (IF 3.585) Pub Date : 2019-11-05
    Guangxu Cao, Shuang Li, Hezhan Shi, Peidi Yin, Jialing Chen, Huifeng Li, Ying Zhong, Li-Ting Diao, Bin Du
    更新日期:2019-11-06
  • 更新日期:2019-11-06
  • Polymer-coated nanoparticles and their effects on mitochondrial function in brain endothelial cells
    Toxicol. Appl. Pharmacol. (IF 3.585) Pub Date : 2019-11-01
    Aniela Bittner, Angélique Dominique Ducray, Michael Hubert Stoffel, Andrea Felser, Meike Mevissen

    Laser tissue soldering is a novel treatment method for injuries of hollow organs such as cerebrovascular aneurysms. Nanomaterials contained in the solder are foreign to the body. Hence, it is indispensable to carefully examine possible adverse effects prior to introducing this technique. The aim of this study was to characterize the impact of different concentrations of polymer-coated silica nanoparticles (NPs) on mitochondrial function and integrity of brain endothelial cells using the rat brain capillary endothelial cell line rBCEC4. At maximal capacity, NP exposure resulted in a decrease in the oxygen consumption rate whereas glycolysis was not affected. In combination with a stressor, i.e. lack of glucose in the medium, NP exposure interfered primarily with glycolytic ATP generation rather than oxidative phosphorylation. Furthermore, NPs caused a metabolic shift towards a stressed phenotype, exhibiting increased levels of the oxygen consumption rate and the extracellular acidification rate compared to untreated controls. Overall, mitochondrial mass, distribution and morphology as well as intracellular ATP content were not altered. The mitochondrial membrane potential was increased after exposure to the highest NP concentration and the content of proteins involved in mitochondrial dynamics was changed slightly, indicating possible modifications of the fusion / fission balance. In conclusion, PCL-NP exposure changed mitochondrial respiration, especially under glucose deprivation, but did not affect mitochondrial morphology and distribution. Further studies are needed to investigate whether the functional effects are transient or long-term as this will be crucial for the use of these NPs in laser tissue soldering.

    更新日期:2019-11-01
  • 更新日期:2019-11-01
  • Endocytosis mechanism in physiologically-based pharmacokinetic modeling of nanoparticles
    Toxicol. Appl. Pharmacol. (IF 3.585) Pub Date : 2019-10-31
    Linjing Deng, Hui Liu, Yongsheng Ma, Yufeng Miao, Xiaoli Fu, Qihong Deng

    Background The physiologically based pharmacokinetic (PBPK) model is a useful tool to predict the pharmacokinetics of various types of nanoparticles (NPs). The endocytosis mechanism plays a key role in pharmacokinetics of NPs. However, the effect of endocytosis mechanism both in the blood and tissue are seldom considered in PBPK model. Objectives To investigate the biodistribution of intravenously injected pegylated AuNPs in mice and human using PBPK model considering the endocytosis mechanism both in the blood and tissue. Methods Taking polyethylene glycol-coated gold nanoparticles (AuNPs) as an example, we developed a PBPK model to explore biodistribution of different size AuNPs. In the model, we considered the role of endocytosis mechanism both in the blood and tissue. In addition, the size-dependent permeability coefficient, excretion rate constant, phagocytic capacity, uptake rate, and release rate were derived from literatures. The mice PBPK model was extrapolated to the human by changing physiology parameters and the number of phagocytic cell (PCs). Results AuNPs were primarily distributed in the blood, liver, and spleen regardless of particle size, and almost all captured by the PCs in the liver and spleen, while few was captured in the blood. There are more organ distribution and longer circulation for smaller NPs. The 24-h accumulation of AuNPs decreased with increasing size in the most organ, while the accumulation of AuNPs showed an inverted U-shaped curve in the liver and slight U-shaped curve in the blood. The human results of model-predicted displayed a similar tendency with those in mice. Size, partition coefficients, and body weight were the key factors influencing the organ distribution of AuNPs. Conclusions The size played an important role on the distribution and accumulation of AuNPs in various tissues. Our PBPK model was well predicted the NPs distribution in mice and human. A better understanding of these mechanisms could provide effective guides for nanomedine delivery.

    更新日期:2019-11-01
  • Suppression of macrophages- Induced inflammation via targeting RAS and PAR-4 signaling in breast cancer cell lines
    Toxicol. Appl. Pharmacol. (IF 3.585) Pub Date : 2019-10-31
    Nadia A. Thabet, Nadia El-Guendy, Mona M. Mohamed, Samia A. Shouman
    更新日期:2019-11-01
  • 更新日期:2019-11-01
  • Development of organoid-based drug metabolism model
    Toxicol. Appl. Pharmacol. (IF 3.585) Pub Date : 2019-10-31
    Enoch Park, Han Kyung Kim, JooHyun Jee, Soojung Hahn, Sukin Jeong, Jongman Yoo
    更新日期:2019-11-01
  • Lung injury, oxidative stress and fibrosis in mice following exposure to nitrogen mustard
    Toxicol. Appl. Pharmacol. (IF 3.585) Pub Date : 2019-10-31
    Vasanthi R. Sunil, Kinal N. Vayas, Elena V. Abramova, Raymond Rancourt, Jessica A. Cervelli, Rama Malaviya, Michael Goedken, Alessandro Venosa, Andrew J. Gow, Jeffrey D. Laskin, Debra L. Laskin

    Nitrogen mustard (NM) is a cytotoxic vesicant known to cause acute lung injury which progresses to fibrosis. Herein, we developed a murine model of NM-induced pulmonary toxicity with the goal of assessing inflammatory mechanisms of injury. C57Bl6/J mice were euthanized 1–28 d following intratracheal exposure to NM (0.08 mg/kg) or PBS control. NM caused progressive alveolar epithelial thickening, perivascular inflammation, bronchiolar epithelial hyperplasia, interstitial fibroplasia and fibrosis, peaking 14 d post exposure. Enlarged foamy macrophages were also observed in the lung 14 d post NM, along with increased numbers of microparticles in bronchoalveolar lavage fluid (BAL). Following NM exposure, rapid and prolonged increases in BAL cells, protein, total phospholipids and surfactant protein (SP)-D were also detected. Flow cytometric analysis showed that CD11b+Ly6G+F4/80+Ly6Chi proinflammatory macrophages accumulated in the lung after NM, peaking at 3 d. This was associated with macrophage expression of HMGB1 and TNFα in histologic sections. CD11b+Ly6G+F4/80+Ly6Clo anti-inflammatory/pro-fibrotic macrophages also increased in the lung after NM peaking at 14 d, a time coordinate with increases in TGFβ expression and fibrosis. NM exposure also resulted in alterations in pulmonary mechanics including increases in tissue elastance and decreases in compliance and static compliance, most prominently at 14 d. These findings demonstrate that NM induces structural and inflammatory changes in the lung that correlate with aberrations in pulmonary function. This mouse model will be useful for mechanistic studies of mustard lung injury and for assessing potential countermeasures.

    更新日期:2019-11-01
  • Dipeptidyl peptidase-4 inhibitor sitagliptin induces vasorelaxation via the activation of Kv channels and PKA
    Toxicol. Appl. Pharmacol. (IF 3.585) Pub Date : 2019-10-31
    Hongliang Li, Mi Seon Seo, Jin Ryeol An, Hee Seok Jung, Kwon-Soo Ha, Eun-Taek Han, Seok-Ho Hong, Young Min Bae, Sung Hun Na, Won Sun Park
    更新日期:2019-11-01
  • Increasing ERK phosphorylation by inhibition of p38 activity protects against cadmium-induced apoptotic cell death through ERK/Drp1/p38 signaling axis in spermatocyte-derived GC-2spd cells
    Toxicol. Appl. Pharmacol. (IF 3.585) Pub Date : 2019-10-30
    Jung Bae Seong, Yong Chul Bae, Hyun-Shik Lee, Jae-Won Huh, Sang-Rae Lee, Hong Jun Lee, Dong-Seok Lee

    Many studies report that cadmium chloride (CdCl2)-induces oxidative stress is associated with male reproductive damage in the testes. CdCl2 also induces mitochondrial fission by increasing dynamin-related protein 1 (Drp1) expression as well as the mitochondria-dependent apoptosis pathway by extracellular signal-regulated kinase (ERK) activation. However, it remains unclear whether mechanisms linked to the mitochondrial damage signal via CdCl2-induced mitogen-activated protein kinases (MAPK) cause damage to spermatocytes. In this study, increased intracellular and mitochondrial reactive oxygen species (ROS) levels, mitochondrial membrane potential (∆Ψm) depolarization, and mitochondrial fragmentation and swelling were observed at 5 μM of CdCl2 exposure, resulting in increased apoptotic cell death. Moreover, CdCl2-induced cell death is closely associated with the ERK/Drp1/p38 signaling axis. Interestingly, SB203580, a p38 inhibitor, effectively prevented CdCl2-induced apoptotic cell death by reducing ∆Ψm depolarization and intracellular and mitochondrial ROS levels. Knockdown of Drp1 expression diminished CdCl2-induced mitochondrial deformation and ROS generation and protected GC-2spd cells from apoptotic cell death. In addition, electron microscopy showed that p38 inhibition reduced CdCl2-induced mitochondrial interior damage more effectively than N-acetyl-L-cysteine (NAC), an ROS scavenger; ERK inhibition; or Drp1 knockdown. Therefore, these results demonstrate that inhibition of p38 activity prevents CdCl2-induced apoptotic GC-2spd cell death by reducing depolarization of mitochondrial membrane potential and mitochondrial ROS levels via ERK phosphorylation in a signal pathway different from the CdCl2-induced ERK/Drp1/p38 axis and suggest a therapeutic strategy for CdCl2-induced male infertility.

    更新日期:2019-11-01
  • Alpinetin improves intestinal barrier homeostasis via regulating AhR/suv39h1/TSC2/mTORC1/autophagy pathway
    Toxicol. Appl. Pharmacol. (IF 3.585) Pub Date : 2019-10-30
    Yumeng Miao, Qi Lv, Simiao Qiao, Ling Yang, Yu Tao, Wenxin Yan, Pengfei Wang, Na Cao, Yue Dai, Zhifeng Wei
    更新日期:2019-11-01
  • Bisphenol A at a low concentration boosts mouse spermatogonial cell proliferation by inducing the G protein-coupled receptor 30 expression.
    Toxicol. Appl. Pharmacol. (IF 3.585) Pub Date : 2013-01-01
    Zhi-Guo Sheng,Wei Huang,Yu-Xiang Liu,Ben-Zhan Zhu

    Bisphenol A (BPA) is one of the most prevalent chemicals in daily-use materials, therefore, human exposure to BPA is ubiquitous. We found that low concentrations of BPA stimulate the spermatogonial GC-1 cells proliferation by G protein-coupled receptor 30 (GPR30)-mediated epidermal growth factor receptor (EGFR)-extracellular regulated kinase (ERK)-c-Fos pathway. However, through the same pathway GPR30 expression has been shown to be induced by EGF, an EGFR ligand. Thus, we want to know if low concentrations of BPA are able to induce the GPR30 expression and the possible mechanism(s) in GC-1 cells. By transient transfection with expression plasmids, 10(-9)M BPA significantly transactivates the Gpr30-5'-flanking region through activating the GPR30, cGMP-dependent protein kinase (PKG), estrogen receptor-α (ER-α), and EFGR-ERK pathways. Furthermore, an activator protein-1 (AP-1) site located within this region is found to be responsible for the transactivation of BPA. Expectedly, through the same pathways, BPA significantly induces the gene and protein expression of GPR30. c-Fos is further observed to be strongly recruited to the AP-1 site in a chromatin immunoprecipitation assay and its dysfunction on the AP-1 site markedly suppresses the expression of GPR30, p-ERK1/2, p-Ser118-ER-α and cell proliferation by BPA. Our results demonstrate that a low-concentration BPA induces GPR30 expression through the GPR30-EFGR-ERK-c-Fos, ER-α, and PKG pathways, presumably boosting the cells proliferation via a regulatory loop. The present study provides a novel insight into the potential role of GPR30 in the initiation and progression of male germ cell cancer induced by environmentally relevant BPA.

    更新日期:2019-11-01
  • Corrigendum to "Fullerene (C60) particle size implications in neurotoxicity following infusion into the hippocampi of Wistar rats" [Toxicology and Applied Toxicology 338 (2018) 197-203].
    Toxicol. Appl. Pharmacol. (IF 3.585) Pub Date : 2019-11-08
    Ândrea Barbosa Kraemer,Gustavo Morrone Parfitt,Daiane da Silva Acosta,Gisele Eva Bruch,Marcos Freitas Cordeiro,Luis Fernando Marins,Juliane Ventura-Lima,José María Monserrat,Daniela Martí Barros

    更新日期:2019-11-01
  • Corrigendum to "Wogonin inhibits tumor angiogenesis via degradation of HIF-1α protein" [Toxicology and Applied Pharmacology 271 (2013) 144-145].
    Toxicol. Appl. Pharmacol. (IF 3.585) Pub Date : 2019-09-19
    Xiuming Song,Jing Yao,Fei Wang,Mi Zhou,Yuxin Zhou,Hu Wang,Libin Wei,Li Zhao,Zhiyu Li,Na Lu,Qinglong Guo

    更新日期:2019-11-01
  • A comprehensive review of metal-induced cellular transformation studies.
    Toxicol. Appl. Pharmacol. (IF 3.585) Pub Date : 2017-05-17
    Qiao Yi Chen,Max Costa

    In vitro transformation assays not only serve practical purposes in screening for potential carcinogenic substances in food, drug, and cosmetic industries, but more importantly, they provide a means of understanding the critical biological processes behind in vivo cancer development. In resemblance to cancer cells in vivo, successfully transformed cells display loss of contact inhibition, gain of anchorage independent growth, resistant to proper cell cycle regulation such as apoptosis, faster proliferation rate, potential for cellular invasion, and ability to form tumors in experimental animals. Cells purposely transformed using metal exposures enable researchers to examine molecular changes, dissect various stages of tumor formation, and ultimately elucidate metal induced cancer mode of action. For practical purposes, this review specifically focuses on studies incorporating As-, Cd-, Cr-, and Ni-induced cell transformation. Through investigating and comparing an extensive list of studies using various methods of metal-induced transformation, this review serves to bridge an information gap and provide a guide for avoiding procedural discrepancies as well as maximizing experimental efficiency.

    更新日期:2019-11-01
  • Selectivity of natural, synthetic and environmental estrogens for zebrafish estrogen receptors.
    Toxicol. Appl. Pharmacol. (IF 3.585) Pub Date : 2014-08-12
    Caroline Pinto,Marina Grimaldi,Abdelhay Boulahtouf,Farzad Pakdel,François Brion,Sélim Aït-Aïssa,Vincent Cavaillès,William Bourguet,Jan-Ake Gustafsson,Maria Bondesson,Patrick Balaguer

    Zebrafish, Danio rerio, is increasingly used as an animal model to study the effects of pharmaceuticals and environmental estrogens. As most of these estrogens have only been tested on human estrogen receptors (ERs), it is necessary to measure their effects on zebrafish ERs. In humans there are two distinct nuclear ERs (hERα and hERβ), whereas the zebrafish genome encodes three ERs, zfERα and two zfERβs (zfERβ1 and zfERβ2). In this study, we established HeLa-based reporter cell lines stably expressing each of the three zfERs. We first reported that estrogens more efficiently activate the zfERs at 28°C as compared to 37°C, thus reflecting the physiological temperature of zebrafish in wildlife. We then showed significant differences in the ability of agonist and antagonist estrogens to modulate activation of the three zfER isotypes in comparison to hERs. Environmental compounds (bisphenol A, alkylphenols, mycoestrogens) which are hER panagonists and hERβ selective agonists displayed greater potency for zfERα as compared to zfERβs. Among hERα selective synthetic agonists, PPT did not activate zfERα while 16α-LE2 was the most zfERα selective compound. Altogether, these results confirm that all hER ligands control in a similar manner the transcriptional activity of zfERs although significant differences in selectivity were observed among subtypes. The zfER subtype selective ligands that we identified thus represent new valuable tools to dissect the physiological roles of the different zfERs. Finally, our work also points out that care has to be taken in transposing the results obtained using the zebrafish as a model for human physiopathology.

    更新日期:2019-11-01
  • Differential effects of five 'classical' scorpion beta-toxins on rNav1.2a and DmNav1 provide clues on species-selectivity.
    Toxicol. Appl. Pharmacol. (IF 3.585) Pub Date : 2006-11-23
    Frank Bosmans,Marie-France Martin-Eauclaire,Jan Tytgat

    In general, scorpion beta-toxins have been well examined. However, few in-depth studies have been devoted to species selectivity and affinity comparisons on the different voltage-activated Na(+) channels since they have become available as cloned channels that can be studied in heterologous expression systems. As a result, their classification is largely historical and dates from early in vivo experiments on mice and cockroach and fly larvae. In this study, we aimed to provide an updated overview of selectivity and affinity of scorpion beta-toxins towards voltage-activated Na(+) channels of vertebrates or invertebrates. As pharmacological tools, we used the classic beta-toxins AaHIT, Css II, Css IV, Css VI and Ts VII and tested them on the neuronal vertebrate voltage-activated Na(+) channel, rNa(v)1.2a. For comparison, its invertebrate counterpart, DmNav1, was also tested. Both these channels were expressed in Xenopus laevis oocytes and the currents measured with the two-electrode voltage-clamp technique. We supplemented this data with several binding displacement studies on rat brain synaptosomes. The results lead us to propose a general classification and a novel nomenclature of scorpion beta-toxins based on pharmacological activity.

    更新日期:2019-11-01
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