Effect of nephrotoxicants and hepatotoxicants on gene expression profile in human peripheral blood mononuclear cells

Dadarkar, Shruta S.; Fonseca, Lyle C.; Thakkar, Arvind; Mishra, Prabha B.; Rangasamy, Ashok K.; Padigaru, Muralidhara

doi:10.1016/j.bbrc.2010.09.039

Cited by 6 publications

(5 citation statements)

References 25 publications

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“…From the comparative point of view, transcriptional changes observed in the heart were mirrored by PBMCs. Today, these cells represent an alternative to invasive tissue sampling, as they have been shown to reflect the transcriptomic alterations elicited by xenobiotics on a number of target tissues (Cui and Paules, ; Dadarkar et al ., ; Rockett et al ., ). Thus, PBMCs might be considered as a potential surrogate tissue for the early detection and diagnosis of PLD in the heart of preclinical rodent model species.…”

Section: Discussionmentioning

confidence: 99%

“…Nonetheless, the accessibility of these and other target tissues is always difficult without sacrificing the animals and subjecting them to an invasive procedure. To overcome such a problem, an emerging area of interest in toxicogenomics is studying the xenobiotic‐induced responses in whole blood cells, particularly peripheral blood mononuclear cells (PBMCs), as they are (a) easily accessible, (b) interact continuously with the body and (c) changes in their gene profiling may reflect the xenobiotic‐induced genomic tissue perturbations (Dadarkar et al ., ). Thus, peripheral blood cells offer advantages as an alternative to invasive tissue sampling (Cui and Paules, ; Rockett et al ., ).…”

Section: Introductionmentioning

confidence: 97%

See 1 more Smart Citation

Molecular biomarkers of phospholipidosis in rat blood and heart after amiodarone treatment

Bocchini

Giantin

Crivellente

et al. 2014

J of Applied Toxicology

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Phospholipidosis (PLD) is characterized by an intracellular accumulation of phospholipids in lysosomes and concurrent development of concentric lamellar bodies. It is induced in humans and in animals by drugs with a cationic amphiphilic structure. The purpose of the present study was to identify a set of molecular biomarkers of PLD in rat blood and heart, hypotheticallya pplicable in preclinical screens within the drug development process. A toxicological study was set up in rats orally treated up to 11 days with 300 mg kg(–1) per day(–1) amiodarone (AMD). Light and transmission electron microscopy investigations were performed to confirm the presence of lamellar bodies indicative of phospholipid accumulation. The effects of AMD upon the transcriptome of these tissues were estimated using DNA microarray technology. Microarray data analysis showed that a total of 545 and 8218 genes were modulated by AMD treatment in heart and blood, respectively. Some genes implicated in the phospholipid accumulation in cells, such as phospholipase A2, showed similar alterations of gene expression. After transcriptome criteria of analysis and target selection, including also the involvement in the onset of PLD, 7 genes (Pla2g2a, Pla2g7, Gal, Il1b, Cebpb, Fcgr2b, Acer 2) were selected as candidate biomarkers of PLD in heart and blood tissues, and their potential usefulness as a sensitive screening test was screened and confirmed by quantitative Real-Time PCR analysis. Collectively, these data underscore the importance of transcriptional profiling in drug discovery and development, and suggest blood as a surrogate tissue for possible phospholipid accumulation in cardiomyocytes.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 97%

Molecular biomarkers of phospholipidosis in rat blood and heart after amiodarone treatment

Bocchini

Giantin

Crivellente

et al. 2014

J of Applied Toxicology

View full text Add to dashboard Cite

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“…Therefore, in spite of the limited number of chemicals tested in the study, our results suggested that the blood gene expression markers may be specific to the type of target organ toxicity involved. Dadarkar et al (2010b) performed gene expression analysis and hierarchical clustering in RNA samples obtained from human PBMCs treated with either hepatotoxic (acetaminophen, rosiglitazone, fluconazole and isoniazid) or nephrotoxic (cyclophosphamide, amphotericin B, gentamicin and cisplatin) drugs and identified a set of 365 genes that could discriminate the two classes of drugs. Further support to the specificity of blood gene expression markers to target organ toxicity is provided by Kim et al (2011) who investigated blood gene expression profiles in rats administered each of three different VOCs (dichloromethane, ethylbenzene and trichloroethylene).…”

Section: Blood Transcriptomics In Toxicology: Challengesmentioning

confidence: 99%

“…Dadarkar et al . () performed gene expression analysis and hierarchical clustering in RNA samples obtained from human PBMCs treated with either hepatotoxic (acetaminophen, rosiglitazone, fluconazole and isoniazid) or nephrotoxic (cyclophosphamide, amphotericin B, gentamicin and cisplatin) drugs and identified a set of 365 genes that could discriminate the two classes of drugs. Further support to the specificity of blood gene expression markers to target organ toxicity is provided by Kim et al .…”

Section: Introductionmentioning

confidence: 99%

Blood transcriptomics: applications in toxicology

Joseph

Umbright

Sellamuthu

2013

J of Applied Toxicology

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The number of new chemicals that are being synthesized each year has been steadily increasing. While chemicals are of immense benefit to mankind, many of them have a significant negative impact, primarily owing to their inherent chemistry and toxicity, on the environment as well as human health. In addition to chemical exposures, human exposures to numerous non-chemical toxic agents take place in the environment and workplace. Given that human exposure to toxic agents is often unavoidable and many of these agents are found to have detrimental human health effects, it is important to develop strategies to prevent the adverse health effects associated with toxic exposures. Early detection of adverse health effects as well as a clear understanding of the mechanisms, especially at the molecular level, underlying these effects are key elements in preventing the adverse health effects associated with human exposure to toxic agents. Recent developments in genomics, especially transcriptomics, have prompted investigations into this important area of toxicology. Previous studies conducted in our laboratory and elsewhere have demonstrated the potential application of blood gene expression profiling as a sensitive, mechanistically relevant and practical surrogate approach for the early detection of adverse health effects associated with exposure to toxic agents. The advantages of blood gene expression profiling as a surrogate approach to detect early target organ toxicity and the molecular mechanisms underlying the toxicity are illustrated and discussed using recent studies on hepatotoxicity and pulmonary toxicity. Furthermore, the important challenges this emerging field in toxicology faces are presented in this review article.

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“…Briefly, cells were seeded on 24-well culture plates in medium at an approximate density of 10 5 cells/cm 2 and, after 24 hrs stabilization, bladder urothelial cell line T24 were co-cultured with medium containing various concentrations of CP and BSO (200 and 800 µM) and Aloe vera plant extract (10, 50 and 100µM) for 24 hrs. The concentration of CP was selected based on previously reported cytotoxic levels in cultured cells [20]. For stock solution, CP and BSO were dissolved in MilliQ Plus sterilized water at the concentration of 800 mM and Aloe vera plant extract was dissolved in dimethyl sulfoxide (DMSO) to obtain a 100mM.…”

Section: Cell Culture and Peroxide Hydrogen Productionmentioning

confidence: 99%

Therapeutic Effects of Aloe Vera Plant Extract Against Cyclophosphamide and Buthionine Sulfoximine Induced Toxicities in the Bladder

Rouissi¹

2012

Biochem & Pharmacol

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Bladder toxicity is one of the most troublesome side effects associated with chemotherapeutic treatments of cancer involving the use of cyclophosphamide (CP) and buthionine-SR-sulfoximine (BSO). The present study was undertaken to investigate the effects of pre-treatment with an Aloe vera plant extract (AVE) on the urotoxicity induced by acute doses of CP and BSO using a Swiss albino mice model. The modulation of toxicity was evaluated by measuring lipid peroxidation (LPO), peroxide hydrogen production (H 2 O 2) and antioxidants in the urinary bladder of the animals. The findings revealed that Aloe vera induced remarkable protective effects in terms of both LPO and enzymatic antioxidant activities. The CP-treated mice were noted to undergo significant decreases in the activities of glutathione S-transferase (GST), glutathione reductase (GR), glutathione peroxidase (GP), and catalase (CAT) when compared to the controls. The levels of reduced glutathione (GSH) also decreased with an increase in LPO in the CP-treated animals and BSO treatment exerted an additive toxic effect in the CP-treated animals. Pre-treatment with the Aloe vera herbal extract restored all enzymatic activities back to normal, thus confirming its overall protective effect against the toxic effects of CP and BSO. The potential effect of AVE to prevent CP and BSO induced urotoxicity was also reflected by the histological analysis, indicative of its uroprotective effects. The restoration of GSH through treatment with Aloe vera may play an important role in the reversal of CP-induced apoptosis and free radical mediated LPO in urinary bladder. Due to its widespread availability in nature and relative lack of toxicity, the Aloe vera plant extract presented in the current study could be considered a potential strong candidate for future applications as an adjutant to cancer chemotherapies.

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Effect of nephrotoxicants and hepatotoxicants on gene expression profile in human peripheral blood mononuclear cells

Cited by 6 publications

References 25 publications

Molecular biomarkers of phospholipidosis in rat blood and heart after amiodarone treatment

Molecular biomarkers of phospholipidosis in rat blood and heart after amiodarone treatment

Blood transcriptomics: applications in toxicology

Therapeutic Effects of Aloe Vera Plant Extract Against Cyclophosphamide and Buthionine Sulfoximine Induced Toxicities in the Bladder

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