Publications (69) View all
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Article: Cilastatin protects against cisplatin-induced nephrotoxicity without compromising its anticancer efficiency in rats.
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ABSTRACT: Cisplatin is an anticancer agent marred by nephrotoxicity; however, limiting this adverse effect may allow the use of higher doses to improve its efficacy. Cilastatin, a small molecule inhibitor of renal dehydropeptidase I, prevents proximal tubular cells from undergoing cisplatin-induced apoptosis in vitro. Here, we explored the in vivo relevance of these findings and the specificity of protection for kidney cells in cisplatin-treated rats. Cisplatin increased serum blood urea nitrogen and creatinine levels, and the fractional excretion of sodium. Cisplatin decreased the glomerular filtration rate, promoted histological renal injury and the expression of many pro-apoptotic proteins in the renal cortex, increased the Bax/Bcl2 ratio, and oxidative stress in kidney tissue and urine. All these features were decreased by cilastatin, which preserved renal function but did not modify the pharmacokinetics of cisplatin area under the curve. The cisplatin-induced death of cervical, colon, breast, and bladder-derived cancer cell lines was not prevented by cilastatin. Thus, cilastatin has the potential to prevent cisplatin nephrotoxicity without compromising its anticancer efficacy.Kidney International advance online publication, 20 June 2012; doi:10.1038/ki.2012.199.Kidney International 06/2012; · 6.61 Impact Factor -
Article: Changes in leukocyte gene expression profiles induced by antineoplastic chemotherapy.
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ABSTRACT: In the present study, we studied changes in gene expression induced by chemotherapy (CT) on normal peripheral blood leukocytes (PBLs), at baseline and following three CT cycles, in order to identify which genes were specifically affected and were potentially useful as biomarkers for a personalised prognosis and follow-up. A PBL subtraction cDNA library was constructed from four patients undergoing CT with paclitaxel and carboplatin (PC). mRNA from the PBLs was isolated prior to the patients receiving the first cycle and following the completion of the third cycle. The library was screened and the expression of the identified genes was studied in PBLs obtained from patients suffering from cancer prior to and following three cycles of PC and a reference group of patients undergoing treatment with Adriamycin-cyclophosphamide (AC). From the 1,200 screened colonies, 65 positive clones showed varied expression intensity and were sequenced; 27 of these were mitochondrial DNA and 38 clones (27 different) were coded for cytosolic and nuclear proteins. The genes that were studied in patients undergoing CT were ATM (ataxia-telangiectasia mutated gene), eIF4B (translation initiation factor 4B), MATR3 (Matrin 3), MORC3 (microrchidia 3), PCMTD2 (protein-L-isoaspartate O-methyltransferase), PDCD10 (programmed cell death gene 10), PSMB1 (proteasome subunit type β), RMND5A (required for meiotic nuclear division 5 homologue A), RUNX2 (runt-related transcription factor 2), SACM1L (suppressor of actin mutations 1-like), TMEM66 (transmembrane protein 66) and ZNF644 (zinc finger protein 644). Certain variations were observed in the expression of the genes that are involved in drug resistance mechanisms, some of which may be secondary to non-desirable effects and others of which may cause the undesired effects of CT. The expression of genes with a dynamic cellular role showed a marked positive correlation, indicating that their upregulation may be involved in a specific pattern of cell survival versus apoptosis in response to the cell damage induced by CT. Whether these CT-induced changes are random or directed in a specific selection-evolution manner needs to be elucidated.Oncology letters 06/2012; 3(6):1341-1349. · 0.11 Impact Factor -
Article: Na(+), K(+)-ATPase Subunit Composition in a Human Chondrocyte Cell Line; Evidence for the Presence of α1, α3, β1, β2 and β3 Isoforms.
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ABSTRACT: Membrane transport systems participate in fundamental activities such as cell cycle control, proliferation, survival, volume regulation, pH maintenance and regulation of extracellular matrix synthesis. Multiple isoforms of Na(+), K(+)-ATPase are expressed in primary chondrocytes. Some of these isoforms have previously been reported to be expressed exclusively in electrically excitable cells (i.e., cardiomyocytes and neurons). Studying the distribution of Na(+), K(+)-ATPase isoforms in chondrocytes makes it possible to document the diversity of isozyme pairing and to clarify issues concerning Na(+), K(+)-ATPase isoform abundance and the physiological relevance of their expression. In this study, we investigated the expression of Na(+), K(+)-ATPase in a human chondrocyte cell line (C-20/A4) using a combination of immunological and biochemical techniques. A panel of well-characterized antibodies revealed abundant expression of the α1, β1 and β2 isoforms. Western blot analysis of plasma membranes confirmed the above findings. Na(+), K(+)-ATPase consists of multiple isozyme variants that endow chondrocytes with additional homeostatic control capabilities. In terms of Na(+), K(+)-ATPase expression, the C-20/A4 cell line is phenotypically similar to primary and in situ chondrocytes. However, unlike freshly isolated chondrocytes, C-20/A4 cells are an easily accessible and convenient in vitro model for the study of Na(+), K(+)-ATPase expression and regulation in chondrocytes.International Journal of Molecular Sciences 01/2012; 13(4):5019-34. · 2.60 Impact Factor -
Article: Patients with endometriosis and patients with poor ovarian reserve have abnormal follicle-stimulating hormone receptor signaling pathways.
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ABSTRACT: To study the integrity of the FSH receptor (FSHR) signaling pathway in granulosa-lutein cells at the time of egg retrieval and its relationship with the infertility diagnosis. In vitro assays. University laboratory and private IVF center. Patients undergoing IVF: 35 controls (no ovarian factor, NOF), 28 poor responders (PR), 32 patients with endometriosis (EM), and 22 patients with polycystic ovary syndrome (PCOS). Quantitative reverse transcriptase-polymerase chain reaction (PCR) in granulosa-lutein cells from pooled follicles. Correlation between expression of FSHR and FSH-regulated genes PAPP/Cyp19A1. Positive correlations among FSHR, PAPP, and Cyp19A1 expression levels are observed in NOF and are lost, with different patterns, in poor responder patients and those with endometriosis. Patients with endometriosis are an heterogeneous group including patients with poor ovarian reserve who behave like other poor responders patients (endometriosis-A) and patients with good response to ovarian stimulation (endometriosis-B) who show a specific alteration of the FSHR signaling pathway. These preliminary data suggest that the different signaling pathways activated through the FSHR in normal ovaries (NOF) are disrupted in poor responders and in patients with endometriosis. A better knowledge of the molecular origin of these errors may guide clinicians in the choice of personalized ovulation induction protocols for each type of ovarian dysfunction.Fertility and sterility 06/2011; 95(7):2373-8. · 3.97 Impact Factor -
Article: Expression and distribution of Na, K-ATPase isoforms in the human uterus.
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ABSTRACT: Na, K-ATPase activity relies on the composition of its catalytic alpha, beta, and FXYD constituents, all of which are expressed as multiple isoforms (4alpha, 4beta, and 7 FXYD). We used reverse transcription polymerase chain reaction (RT-PCR) and immunohistochemistry to study Na, K-ATPase expression in uterine samples from nonlaboring elective and laboring emergency caesarean sections (CSs). Transcripts of alpha1 to 3, beta1 to 3, and FXYD1 isoforms were detected in all samples, but FXYD2 was only present in hysterectomy samples. Abundant immunoreactivity of alpha1 and moderate alpha2 was localized in myometrial smooth muscle and secretory glands of all groups. Smooth muscle and gland epithelia showed diffuse cytoplasmic alpha3 immunoreactivity. beta isoforms were detected in all groups but beta3 showed much denser immunoreactivity in myometrial samples taken from women in labor. In pregnancy, there was a switch in isoform expression, resulting in increased beta3 and decreased FXYD2 at the protein and messenger RNA (mRNA) levels. Na, K-ATPase isoform alterations may modulate uterine contractility during labor.Reproductive sciences (Thousand Oaks, Calif.) 04/2010; 17(4):366-76. · 2.31 Impact Factor
