Abstract：
:Mechanisms of cyclosporine A (CsA)-induced nephrotoxicity were generally thought to be hemodynamic in origin; however, there is now accumulating evidence of a direct tubular effect. Although genomic and proteomic experiments by our group and others provided overall information on genes and proteins up- or down-regulated by CsA in proximal tubule cells (PTC), a comprehensive view of events occurring after CsA exposure remains to be described. For this purpose, we applied a pharmacologic approach based on the use of known activities of a large panel of potentially protective compounds and evaluated their efficacy in preventing CsA toxicity in cultured mouse PTC. Our results show that compounds that blocked protein synthesis and apoptosis, together with the CK2 inhibitor DMAT and the PI3K inhibitor apigenin, were the most efficient in preventing CsA toxicity. We also identified GSK3, MMPs and PKC pathways as potential targets to prevent CsA damage. Additionally, heparinase-I and MAPK inhibitors afforded partial but significant protection. Interestingly, antioxidants and calcium metabolism-related compounds were unable to ameliorate CsA-induced cytotoxicity. Subsequent experiments allowed us to clarify the hierarchical relationship of targeted pathways after CsA treatment, with ER stress identified as an early effector of CsA toxicity, which leads to ROS generation, phenotypical changes and cell death. In summary, this work presents a novel experimental approach to characterizing cellular responses to cytotoxics while pointing to new targets to prevent CsA-induced toxicity in proximal tubule cells.
journal_name
Toxicol Appl Pharmacoljournal_title
Toxicology and applied pharmacologyauthors
Sarró E,Jacobs-Cachá C,Itarte E,Meseguer Adoi
10.1016/j.taap.2011.11.007subject
Has Abstractpub_date
2012-01-15 00:00:00pages
275-87issue
2eissn
0041-008Xissn
1096-0333pii
S0041-008X(11)00443-1journal_volume
258pub_type
杂志文章abstract：:This study was designed to evaluate the developmental toxicity of nitrazepam (NZ) in Sprague-Dawley rats and ICR mice and to determine the metabolic factors which modulate susceptibility to the developmental effects of NZ. Rats were treated orally with a single dose of NZ at 300 mg/kg on Day 12 of gestation. Mice rece...
journal_title：Toxicology and applied pharmacology
pub_type： 杂志文章
doi：10.1006/taap.1993.1150
更新日期：1993-08-01 00:00:00
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journal_title：Toxicology and applied pharmacology
pub_type： 杂志文章
doi：10.1006/taap.1997.8309
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journal_title：Toxicology and applied pharmacology
pub_type： 杂志文章
doi：10.1016/j.taap.2008.05.022
更新日期：2008-09-15 00:00:00
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journal_title：Toxicology and applied pharmacology
pub_type： 杂志文章
doi：10.1016/j.taap.2003.10.009
更新日期：2004-02-15 00:00:00
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journal_title：Toxicology and applied pharmacology
pub_type： 杂志文章
doi：10.1016/j.taap.2014.04.021
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journal_title：Toxicology and applied pharmacology
pub_type： 杂志文章
doi：10.1016/j.taap.2006.10.026
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journal_title：Toxicology and applied pharmacology
pub_type： 杂志文章,评审
doi：10.1016/j.taap.2003.09.020
更新日期：2004-03-15 00:00:00
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journal_title：Toxicology and applied pharmacology
pub_type： 杂志文章,评审
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更新日期：2020-12-15 00:00:00
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journal_title：Toxicology and applied pharmacology
pub_type： 杂志文章
doi：10.1006/taap.1996.0254
更新日期：1996-11-01 00:00:00
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journal_title：Toxicology and applied pharmacology
pub_type： 杂志文章
doi：10.1016/0041-008x(88)90122-6
更新日期：1988-04-01 00:00:00
abstract：:Exposure to environmental contaminants such as activators of the aryl hydrocarbon receptor (AhR) leads to the induction of defense and detoxification mechanisms. While these mechanisms allow organisms to metabolize and excrete at least some of these environmental contaminants, it has been proposed that these mechanism...
journal_title：Toxicology and applied pharmacology
pub_type： 杂志文章
doi：10.1016/j.taap.2013.04.017
更新日期：2013-08-15 00:00:00
abstract：:Tolerance to several toxic effects of Cd, including lethality, has been shown following pretreatment with Cd. This study was designed to determine if tolerance also develops to Cd-induced hepatotoxicity. Rats were challenged with Cd (2.0, 3.0, 4.0, or 5.0 mg/kg, iv) 24 hr after pretreatment with saline (2 ml/kg, sc) o...
journal_title：Toxicology and applied pharmacology
pub_type： 杂志文章
doi：10.1016/0041-008x(84)90283-7
更新日期：1984-07-01 00:00:00
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journal_title：Toxicology and applied pharmacology
pub_type： 杂志文章
doi：10.1016/j.taap.2006.09.002
更新日期：2007-03-01 00:00:00
abstract：:Recently, Gray and Ostby (Toxicol. Appl. Pharmacol. 133, 285-294, 1995) reported that in utero and lactational TCDD exposure causes striking abnormalities in the rat female reproductive system, including reduced fecundity and vaginal threads. The mechanism by which TCDD induces such abnormalities is unknown. Thus, we ...
journal_title：Toxicology and applied pharmacology
pub_type： 杂志文章
doi：10.1006/taap.1997.8295
更新日期：1997-12-01 00:00:00
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journal_title：Toxicology and applied pharmacology
pub_type： 杂志文章
doi：10.1016/j.taap.2015.11.019
更新日期：2016-01-01 00:00:00
abstract：:Previous reports from our laboratory indicated that prophylactic protection against cyanide intoxication in mice can be enhanced by administration of chlorpromazine when it is given with sodium thiosulfate. The mechanism of potentiation of sodium thiosulfate by chlorpromazine was studied alone and in combination with ...
journal_title：Toxicology and applied pharmacology
pub_type： 杂志文章
doi：10.1016/0041-008x(83)90028-5
更新日期：1983-12-01 00:00:00
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journal_title：Toxicology and applied pharmacology
pub_type： 杂志文章
doi：10.1016/j.taap.2005.06.012
更新日期：2006-01-01 00:00:00
abstract：:The aryl hydrocarbon receptor (AhR) and AhR nuclear translocator (ARNT) are transcription factors that express Per-Arnt-Sim (PAS) DNA-binding motifs and mediate the metabolism of drugs and environmental toxins in the liver. Because these transcription factors interact with other PAS genes in molecular feedback loops f...
journal_title：Toxicology and applied pharmacology
pub_type： 杂志文章
doi：10.1016/j.taap.2008.10.016
更新日期：2009-02-01 00:00:00
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journal_title：Toxicology and applied pharmacology
pub_type： 杂志文章
doi：10.1016/j.taap.2017.02.011
更新日期：2017-04-01 00:00:00
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journal_title：Toxicology and applied pharmacology
pub_type： 杂志文章
doi：10.1006/taap.2001.9341
更新日期：2002-02-01 00:00:00
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journal_title：Toxicology and applied pharmacology
pub_type： 杂志文章
doi：
更新日期：2002-10-15 00:00:00
abstract：:This study was undertaken to determine the ability of a series of 19 compounds representing different chemical classes of carcinogens to induce lung tumors in strain A/J mice after either ip or po administration. Aflatoxin B1, dibutylnitrosamine, 1,2-dimethylhydrazine, and methylnitrosourea induced a significant incre...
journal_title：Toxicology and applied pharmacology
pub_type： 杂志文章
doi：10.1016/0041-008x(86)90433-3
更新日期：1986-01-01 00:00:00
abstract：:Carbon disulfide is present in exposed subjects in free and bound or acid-labile forms. Sensitivities of the blood acid-labile CS2 (AL CS2) concentration and the modified iodine-azide test (IAT) were compared as indicators of CS2 exposure. Rats were exposed to 15 (approximately 5 ppm), 30, 60, or 120 mg/m3 of CS2. Exp...
journal_title：Toxicology and applied pharmacology
pub_type： 杂志文章
doi：10.1016/0041-008x(83)90158-8
更新日期：1983-09-30 00:00:00
abstract：:Targeting excessive production of reactive oxygen species (ROS) could be an effective therapeutic strategy to prevent oxidative stress-associated gastrointestinal inflammation. NADPH oxidase (NOX) and mitochondrial complexes (I and II) are the major sources of ROS production contributing to TNF-α/cycloheximide (CHX)-i...
journal_title：Toxicology and applied pharmacology
pub_type： 杂志文章
doi：10.1016/j.taap.2015.07.007
更新日期：2015-10-15 00:00:00
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journal_title：Toxicology and applied pharmacology
pub_type： 杂志文章
doi：10.1016/0041-008x(90)90101-y
更新日期：1990-10-01 00:00:00
abstract：:Previous studies from this laboratory have demonstrated that the addition of methyl groups at the 3 and 4 positions of the 2,5-hexanedione (2,5-HD) molecule results both in more rapid pyrrole formation and in enhanced neurotoxicity. In order to define more clearly the relationship between rates of pyrrole formation an...
journal_title：Toxicology and applied pharmacology
pub_type： 杂志文章
doi：10.1016/0041-008x(87)90296-1
更新日期：1987-02-01 00:00:00
abstract：:Information presented at this symposium indicates that modulation of Th cell responses is one means by which xenobiotics may cause immunotoxicity. A shift from Th1 to Th2 responses can enhance both infectious and allergic disease. Hence, in some cases, a common mechanism may be responsible for effects that are general...
journal_title：Toxicology and applied pharmacology
pub_type： 杂志文章,评审
doi：10.1006/taap.1997.8142
更新日期：1997-07-01 00:00:00
abstract：:Aromatase inhibitors like anastrozole play an undisputed key role in the treatment of breast cancer, but on the other hand, various side effects like osteoporosis and increased risk of bone fracture accompany the chronic administration of these drugs. Here we show for the first time that selenium nanoparticles, when g...
journal_title：Toxicology and applied pharmacology
pub_type： 杂志文章
doi：10.1016/j.taap.2013.01.028
更新日期：2013-04-15 00:00:00
abstract：:Air pollution, especially fine particulate matter (PM2.5, particles <2.5 μm in size), induces adverse health effects on the respiratory system. Uncontrolled proliferation of bronchial epithelial cells, resulting from deregulated cell cycle progression, contributes to pulmonary homeostatic imbalance. Although dysregula...
journal_title：Toxicology and applied pharmacology
pub_type： 杂志文章
doi：10.1016/j.taap.2019.114616
更新日期：2019-08-15 00:00:00
abstract：:Two hours after a four-hour exposure to hexamethylene diisocyanate trimer (HDIt) aerosol between 2.5 and 39 mg/m3, mice were injected iv with 51Cr-EDTA (chromium ethylenediaminetetraacetate). Ten minutes later the lung was lavaged. A larger amount of 51Cr-EDTA was detected in the lung lavage of HDIt mice than of contr...
journal_title：Toxicology and applied pharmacology
pub_type： 杂志文章
doi：10.1016/0041-008x(83)90269-7
更新日期：1983-07-01 00:00:00
