Publications by authors named "Daniela Pretti da Cunha Tirapelli"

32 Publications

Expression of MicroRNAs (miR-15b, miR-16, miR-138, miR-221, and miR-222) as Biomarkers of Endothelial Corpus Cavernosum Dysfunction in a Diabetic Alcoholic Murine Model.

Sex Med 2021 Apr 3;9(2):100326. Epub 2021 Mar 3.

Division of Urology, University of São Paulo, Ribeirão Preto Medical School, Surgery and Anatomy, Ribeirao Preto, São Paulo, Brazil.

Introduction: MicroRNAs (miRNAs) are short noncoding RNA molecules that regulate gene expression and are related to endothelial dysfunction (EnD). Recently, miRNAs have also been explored as potential biomarkers and target molecular therapy of erectile dysfunction (ED). Could the miRNAs be the tip of the iceberg of chronic arterial disease foreshadowed by the ED?

Aim: To investigate the expression of miR-15b, miR-16, miR-138, miR-221, and miR-222 in corpus cavernosum (CC) and peripheral blood in a rat model of endothelium dysfunction secondary to diabetes (DM) and alcohol consumption to assess potential endothelial lesion biomarkers.

Methods: Twenty males Wistar rats were divided into 4 groups: control group (C), alcohol consumption group (A), diabetic group (D), diabetic-alcohol consumption group (D + A). DM was alloxan-induced and alcohol consumption was through progressive increase of ethanol concentration in drinkable water. After 7 weeks, miRNAs expressions from CC and blood sample were evaluated by real-time PCR. Functional assessment of CC was performed in an acetylcholine endothelium-dependent relaxation pharmacological study.

Main Outcome Measure: miRNA expression in CC and blood were evaluated; pharmacological study in CC strips was conducted to validate EnD.

Results: We found that 3 miRNAs (miR-16, miR-221, and miR-222) were downregulated in the CC in the D+A group, while all 5 miRNAs were downregulated in the blood of D and D + A groups. The endothelium-dependent relaxation induced by acetylcholine was significantly decreased in groups A, D, and D + A. Diagnostic accuracy estimated by AUC, to discriminating groups A, D, and D + A from controls, was superior to >0.9 in all plasmatic miRNAs.

Conclusion: miRNAs downregulation was identified in both CC and blood notably in DM associated with alcohol consumption animals (D + A), the greatest endothelial injury potential group. Serum miRNAs have also demonstrated high diagnostic accuracy properties in predicting CC relaxation dysfunction labeling EnD. RB Tiraboschi, FSL Neto, DP da Cunha Tirapelli, et al. Expression of MicroRNAs (miR-15b, miR-16, miR-138, miR-221, and miR-222) as Biomarkers of Endothelial Corpus Cavernosum Dysfunction in a Diabetic Alcoholic Murine Model. Sex Med 2021;9:100326.
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http://dx.doi.org/10.1016/j.esxm.2021.100326DOI Listing
April 2021

Chronic alcoholism associated with diabetes induced apoptosis in the corpus cavernosum of rats.

Acta Cir Bras 2020 Sep 7;35(8):e202000805. Epub 2020 Sep 7.

PhD, Associate Professor, Department of Surgery and Anatomy, FMRP-USP, Ribeirao Preto-SP, Brazil. Conception and design of the study, critical revision, supervised all phases.

Purpose: To evaluate the effects of alcohol exposure and diabetes on apoptotic process in the corpus cavernosum.

Methods: Forty eight male Wistar rats were divided into four groups: control, diabetic, alcoholic and diabetic-alcoholic. Samples of the corpus cavernosum were prepared to study protein expression of apoptotic genes (Caspases-3 and 9) by immunohistochemistry and Real-Time PCR.

Results: The immunoreactivity of Caspases-3 and -9 was diffuse and higher in the treated groups though there was no significant difference between the experimental groups, only when compared with the control group. An increase was observed in the gene expression of Caspases-9 in the diabetic and ethanol-diabetic groups when compared with control and ethanol groups.

Conclusions: The association of these factors (ethanol and diabetes) probably can affect the apoptosis mechanism in lesions of the cavernous tissue in the rat penis. Both gene and protein expression of Caspase-9 in diabetic and ethanol-diabetic groups suggest the involvement of the apoptosis cascade from this study model.
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http://dx.doi.org/10.1590/s0102-865020200080000005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7478468PMC
September 2020

Increased HLA-G Expression in Tissue-Infiltrating Cells in Inflammatory Bowel Diseases.

Dig Dis Sci 2020 Aug 24. Epub 2020 Aug 24.

Division of Gastroenterology, Department of Medicine, Ribeirão Preto Medical School, University of São Paulo, Avenida Bandeirantes 3900, Ribeirão Preto, SP, 14049-900, Brazil.

Background: Since HLA-G is an immune checkpoint molecule and since Crohn's disease (CD) and ulcerative colitis (UC) exhibit deregulated immune-mediated mechanisms, we aimed to evaluate intestinal HLA-G expression and soluble HLA-G (sHLA-G) levels in CD/UC patients stratified according to the CD phenotype/localization and UC extension.

Methods: HLA-G tissue expression was assessed by immunohistochemistry in biopsies collected from 151 patients (90 CD, 61 UC) and in surgical resection specimens (28 CD, 12 UC). Surgical material from 24 healthy controls was also assessed. Plasma sHLA-G levels (97 CD, 81 UC, and 120 controls) were evaluated using ELISA.

Results: HLA-G expression was similarly observed in the intestinal epithelial cells of control and CD/UC specimens. However, in biopsies, the plasma cells/lymphocytes infiltrating the lamina propria in CD/UC presented (1) increased HLA-G expression compared to controls (P < 0.0001), (2) greater cell staining in UC cells than in CD cells irrespective of disease extent (P = 0.0011), and (3) an increased number of infiltrating cells in the inflammatory CD phenotype compared to that in the stenosing and fistulizing phenotypes (P = 0.0407). In surgical specimens, CD/UC patients exhibited higher infiltrating cell HLA-G expression in lesion areas than in margins. sHLA-G levels were higher in UC/CD patients (P < 0.0001) than in controls, but no difference was observed between diseases.

Conclusions: Increased infiltrating cell HLA-G expression associated with increased sHLA-G levels in CD/UC patients may reflect ongoing host strategies to suppress chronic inflammation.
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http://dx.doi.org/10.1007/s10620-020-06561-3DOI Listing
August 2020

PPARG expression in colorectal cancer and its association with staging and clinical evolution.

Acta Cir Bras 2020 17;35(7):e202000708. Epub 2020 Aug 17.

Department of Anatomy and Surgery, Medical School, USP, Ribeirao Preto, SP, Brazil.

Purpose To evaluate the gene expression of peroxisome proliferator activated receptors gamma (PPARG) in colorectal tumors and to correlate this data with clinical variables of the patients. Methods We analyzed the gene expression of PPARG in 50 samples of colorectal tumors using real-time reverse transcription polymerase chain reaction, and 20 adjacent normal tissue samples as control. The results of these quantifications were correlated with the respective patients' medical records' clinical information. Results PPARG expression was not different in the tumor tissue compared to the control tissue. Patients older than 60 years, histological type with mucinous differentiation, more advanced staging at the time of diagnosis, and patients who evolved with recurrence of the disease or death did not present higher PPARG expression. Conclusion Expression of PPARGD was not associated with worse prognosis.
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http://dx.doi.org/10.1590/s0102-865020200070000008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7433669PMC
October 2020

Apoptosis related microRNAs and MGMT in glioblastoma cell lines submitted to treatments with ionizing radiation and temozolomide.

Rep Pract Oncol Radiother 2020 Sep-Oct;25(5):714-719. Epub 2020 Jul 10.

Medical School of Ribeirão Preto, University of São Paulo (USP), Department of Surgery and Anatomy, 3900 Bandeirantes Avenue, Ribeirão Preto, 14049-900, Brazil.

Aim: To evaluate the effect of radiotherapy and temozolomide on the expression of miRNAs apoptotic (miRNAs-21, -221, -222 (anti-apoptotic) and miRNAs-15a, -16 (pro-apoptotic)) and the gene MGMT in glioblastoma cell lines.

Background: The limited knowledge of the molecular biology of malignant gliomas may hinder the development of therapeutic modalities. In this scenario, one of the greatest advances of recent years was the identification of microRNAs. These molecules have an important role in biological processes involving cancer, including glioblastoma.

Materials And Methods: Trypan blue was used to verify the cell viability, and real time PCR to quantify the expression of microRNAs and gene 24, 48 and 120 h after exposure to treatments.

Results: There was a statistically significant decrease of expression of miR-15a between 48 and 120 h in line T98 G treated with radiation, increased expression of miR-15a between 24 and 120 h in line U251 treated with radiation and temozolomide, and increased expression of miR-16 between 24 and 120 h in line U251 treated with radiation alone and when combined with temozolomide. There was a decrease in MGMT gene expression, between 24 and 48 h in U343 cells treated with temozolomide.

Conclusions: Ionizing radiation and temozolomide modified the expression of miRNAs studied and MGMT.
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http://dx.doi.org/10.1016/j.rpor.2020.06.007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7358627PMC
July 2020

Morphological and molecular analysis of apoptosis in the corpus cavernosum of rats submitted to a chronic alcoholism model.

Acta Cir Bras 2020 3;35(3):e202000305. Epub 2020 Jun 3.

PhD, Associate Professor, Department of Surgery and Anatomy, FMRP-USP, Ribeirao Preto-SP, Brazil. Final approval.

Purpose: To evaluate the effect of chronic alcoholism on morphometry and apoptosis mechanism and correlate with miRNA-21 expression in the corpus cavernosum of rats.

Methods: Twenty-four rats were divided into two experimental groups: Control (C) and Alcoholic group (A). After two weeks of an adaptive phase, rats from group A received only ethanol solution (20%) during 7 weeks. The morphometric and caspase-3 immunohistochemistry analysis were performed in the corpus cavernosum. The miRNA-21 expression was analyzed in blood and cavernous tissue.

Results: Chronic ethanol consumption decreased cavernosal smooth muscle area of alcoholic rats. The protein expression of caspase 3 in the corpus cavernosum was higher in A compared to the C group. There was no difference in the expression of miRNA-21 in serum and cavernous tissue between the groups.

Conclusion: Chronic ethanol consumption reduced smooth muscle area and increased caspase 3 in the corpus cavernosum of rats, without altered serum and cavernosal miR-21 gene expression.
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http://dx.doi.org/10.1590/s0102-865020200030000005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7282493PMC
June 2020

Modulation of NMDA receptor by miR-219 in the amygdala and hippocampus of patients with mesial temporal lobe epilepsy.

J Clin Neurosci 2020 Apr 25;74:180-186. Epub 2020 Feb 25.

Department of Surgery and Anatomy, Ribeirao Preto Medical School, University of Sao Paulo, Ribeirao Preto, SP, Brazil.

Mesial temporal lobe epilepsy with hippocampal sclerosis is the most frequent form of focal epilepsy in adults, and it is often refractory to drug treatment. Regardless of the efforts on developing new antiepileptic drugs for refractory cases, studies suggest a need for better understanding the molecular bases of epilepsy. The microRNAs have been progressively investigated as potential targets for both epilepsy mechanisms elucidation and treatment. Therefore, the goal of this study was to evaluate the differential expression of miR-219, miR-181b, and miR-195, previously described as regulators of the excitatory neurotransmitter receptors NMDA-R1 and AMPA-GluR2 and inhibitory neurotransmitter GABA (α2, β3, and γ2 subunits) in the amygdala and hippocampus of patients with mesial temporal lobe epilepsy. Based on genes and miRNAs' quantitative Polymerase Chain Reaction (qPCR) from 18 patients with epilepsy, our results showed an inverse relationship between miR-219 and NMDA-NR1 expression in both the amygdala and hippocampus in comparison to their expression in controls. NR1 and GluR2 were upregulated in the amygdala of epileptic patients. Low miR-195 expression was observed in the amygdala of patients with epilepsy. Our findings indicate that miR-219 has a possible regulatory role in excitatory neurotransmission in patients with epilepsy, contributing to the new avenue of miRNA biology in drug-resistant epilepsy, reserving huge potential for future applications and clinical interventions in conjunction with existing therapies.
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http://dx.doi.org/10.1016/j.jocn.2020.02.024DOI Listing
April 2020

Analysis of Caspase-9 protein and microRNAs miR-21, miR-126 and miR-155 related to the apoptosis mechanism in the cerebellum of rats submitted to focal cerebral ischemia associated with an alcoholism model.

Arq Neuropsiquiatr 2019 24;77(10):689-695. Epub 2019 Oct 24.

Universidade de São Paulo, Faculdade de Medicina de Ribeirão Preto, Departamento de Cirurgia e Anatomia, Ribeirão Preto SP, Brasil.

Objective: This study aimed to analyze the cerebellum of rats submitted to an experimental focal cerebral ischemia, by middle cerebral artery occlusion for 90 minutes, followed by reperfusion for 48 hours, associated with an alcoholism model.

Methods: Fifty adult Wistar rats were used, subdivided into five experimental groups: control group (C): animals submitted to anesthesia only; sham group (S): animals submitted to complete simulation of the surgical procedure; ischemic group (I): animals submitted to focal cerebral ischemia for 90 minutes followed by reperfusion for 48 hours; alcoholic group (A): animals that received daily absolute ethanol diluted 20% in water for four weeks; and, ischemic and alcoholic group (I + A): animals receiving the same treatment as group A and, after four weeks, submitted to focal cerebral ischemia for 90 minutes, followed by reperfusion for 48 hours. The cerebellum samples were collected and immunohistochemical analysis of Caspase-9 protein and serum analysis by RT-PCR of microRNAs miR-21, miR-126 and miR155 were performed.

Results: The expression of Caspase-9 was higher in groups I, A and I + A. In the microRNAs analyses, miR-126 was higher in groups A and I + A, miR-155 was higher in groups I and I + A.

Conclusions: We conclude that apoptosis occurs in the cerebellar cortex, even if it is distant from the ischemic focus, and that microRNAs 126 and 155 show a correlation with cellular apoptosis in ischemic rats and those submitted to the chronic alcohol model.
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http://dx.doi.org/10.1590/0004-282X20190126DOI Listing
July 2020

Expression of MicroRNAs miR-145, miR-181c, miR-199a and miR-1183 in the Blood and Hippocampus of Patients with Mesial Temporal Lobe Epilepsy.

J Mol Neurosci 2019 Dec 31;69(4):580-587. Epub 2019 Jul 31.

Department of Surgery and Anatomy, Ribeirao Preto Medical School, University of Sao Paulo, Ribeirao Preto, SP, Brazil.

The aim of this study was to analyze the expression profiles of the microRNAs (miRNAs) miR-145, miR-181c, miR-199a and miR-1183 in the hippocampus and blood of patients with mesial temporal lobe epilepsy with hippocampal sclerosis (MTLE-HS) and to investigate whether these can be used as diagnosis and prognosis biomarkers for epilepsy. Hippocampus and blood samples were collected from 20 patients with MTLE-HS, ten of whom had a favorable surgical outcome (Engel I) and ten with an unfavorable surgical outcome (Engel III-IV). Hippocampus samples from autopsied individuals with no neurological or psychiatric medical history (necropsy samples) and blood samples from healthy individuals were used as controls. Real-time quantitative PCR (RQ-PCR) was used to analyze miRNA expression. The results showed that the expressions of these miRNAs differed quantitatively in the hippocampus and blood of patients with MTLE-HS in comparison to the respective control. This difference was most pronounced for miR-145, which was hypo-expressed in the hippocampus and hyper-expressed in the blood of MTLE-HS patients. MiRNAs miR-145, miR-181c, miR-199a and miR-1183 were hyper-expressed in the blood of patients with MTLE-HS. No statistical differences in the levels of these miRNAs in the blood or hippocampus were found between Engel I patients and Engel III-IV patients. These results suggest that the analyzed microRNAs are potential circulating biomarkers for epilepsy diagnosis.
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http://dx.doi.org/10.1007/s12031-019-01386-wDOI Listing
December 2019

microRNA-181d associated with the methylation status of the MGMT gene in Glioblastoma multiforme cancer stem cells submitted to treatments with ionizing radiation and temozolomide.

Brain Res 2019 10 18;1720:146302. Epub 2019 Jun 18.

Ribeirão Preto Medical School, University of São Paulo, Department of Surgery and Anatomy, Av. Bandeirantes, 3900, Monte Alegre, Ribeirão Preto, São Paulo 14048-900, Brazil.

Despite the increased understanding of the oncological mechanisms underlying Glioblastoma multiforme (GBM) pathophysiology, and recent advances in therapeutic strategies such as maximal surgical resection and post-operative radiotherapy with concomitant and adjuvant temozolomide chemotherapy, the prognosis for patients with brain tumors remains limited. Evidences indicate that the assessment of DNA methylation status in cancer stem cells would allow identifying molecules expressed in these cells, to lead to targeted elimination of this critical population from brain tumors, making the glioblastoma treatment more effective. This study aimed to analyze the role of microRNA-181d associated with the methylation status of the O-methylguanine methyl transferase (MGMT) gene in Glioblastoma multiforme cancer stem cells subjected to treatment with temozolomide and ionizing radiation. Such responses were analyzed in terms of cell survival, evaluation of the MGMT gene methylation status by MS-HRM (Methylation-Sensitive High Resolution Melting), and analysis of miRNA-181d and MGMT gene expression by relative quantification of mRNA levels in cancer stem cells subjected to treatment with temozolomide and ionizing radiation, isolated or combined. We showed that ionizing radiation and temozolomide reduced the viability of cancer stem cells from GBM patients, as well as modified MGMT gene and miRNA-181d expression in cancer stem cells, suggesting that miRNA-181d interferes in the glioblastoma cancer stem cell response to treatment with temozolomide and ionizing radiation.
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http://dx.doi.org/10.1016/j.brainres.2019.146302DOI Listing
October 2019

Neurocytoma mimicking macroadenoma.

Surg Neurol Int 2019 21;10. Epub 2019 Jan 21.

Department of Surgery and Anatomy, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, Brazil.

Background: Intraventricular and extraventricular central neurocytomas (CN) are equally frequent among 20-40-year-old men and women. However, sellar and suprasellar extraventricular CN are extremely rare, with only 12 reported cases.

Case Description: The authors report the case of a Brazilian 27-year-old man who presented with progressive vision loss during the last 4 years and serious bilateral keratoconus. We also review the epidemiological, clinical, radiological, pathological, and treatment features of the 12 reported cases. The patient developed left amaurosis and right temporal hemianopsia after undergoing bilateral corneal transplantation, which was detected during campimetry testing, and subsequently underwent magnetic resonance imaging, which revealed a huge hypophyseal tumor. Endocrinological evaluation revealed complete loss of pituitary function. The patient was referred to our department and underwent a two-step surgery (using transsphenoidal approach and cranio-orbital zygomatic approach) based on the diagnosis of an extraventricular central nervous system neurocytoma. Tumor removal was successful, and the patient was discharged at 3 weeks after admission to our department.

Conclusion: Although extraventricular neurocytomas of the brain are rare, careful preoperative consideration of its anatomy, pathophysiological features, and radiological features can enhance the treatment outcomes.
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http://dx.doi.org/10.4103/sni.sni_387_18DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6357540PMC
January 2019

Morphological and immunohistochemical analysis of proteins CASPASE 3 and XIAP in rats subjected to cerebral ischemia and chronic alcoholism.

Acta Cir Bras 2018 Aug;33(8):652-663

Assistant Professor, Department of Surgery and Anatomy, Medical School, USP, Ribeirao Preto-SP, Brazil. Design of the study, manuscript writing.

Purpose: To evaluate histopathological and ultrastructural changes and expression of proteins related to apoptosis CASPASE 3 and XIAP after experimental induction of temporary focal cerebral ischemia (90 minutes) due to obstruction of the middle cerebral artery in alcoholism model.

Methods: Forty adult Wistar rats were used, subdivided into 5 experimental groups: control group (C); Sham group (S); Ischemic group (I); Alcoholic group (A); and Ischemic and Alcoholized group (I+A): animals submitted to the same treatment of group A and after four weeks were submitted to focal cerebral ischemia during 90 minutes, followed by reperfusion of 48 hours. Were processed for histopathological analysis and immunohistochemistry (for the protein expression of CASPASE -3 and XIAP).

Results: Greater histopathological changes were observed in the animals of groups I and I+A in the three areas analyzed. The neuronal loss was higher in the medial striatum region of the animals of groups I and I + A. The protein expression of CASPASE -3 was higher than that of XIAP in the groups I and I + A for both proteins.

Conclusion: The expression of XIAP was slightly higher where the histopathological changes and expression of CASPASE -3 was less evident.
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http://dx.doi.org/10.1590/s0102-865020180080000001DOI Listing
August 2018

Expression in Whole Blood Samples of miRNA-191 and miRNA-455-3p in Patients with AAA and Their Relationship to Clinical Outcomes after Endovascular Repair.

Ann Vasc Surg 2018 Jul 5;50:209-217. Epub 2018 Mar 5.

Division of Vascular and Endovascular Surgery, Department of Surgery and Anatomy, Ribeirão Preto Medical School, University of São Paulo, Ribeirao Preto, Sao Paulo, Brazil.

Background: The purpose of this study was to quantify and evaluate the expression response of miRNA-191 and miRNA-455-3p endovascular repair of abdominal aortic aneurysm (AAA) based in whole blood samples.

Methods: This report describes a prospective study of a single center of 30 patients with AAA who underwent endovascular repair. Blood samples were collected preoperatively and 6 months postoperatively. The differential expression of the miRNAs was performed by the real-time polymerase chain reaction method, after extraction of the RNA from the blood samples at the 2 moments. In addition, bioinformatic tools were used to determine pathophysiological pathways related to AAA.

Results: The miR-191 and miR-455-3p were overexpressed preoperatively. After 6 months postoperatively, miR-191 (median 0.98, IQR 0.5-2.1, P < 0.0001) and miR-455-3p (median 1.4, IQR 0.6-3.1, P = 0.0003) presented a significant reduction in their expressions. There was no correlation between the diameter of the aneurysm and the expression of the miRNAs studied. In addition, analysis of the influence of the various types of devices used for the endovascular treatment of AAA showed no significant differences in the expression of miR-191 and miR-455-3p.

Conclusions: Exclusion of the aneurysmal sac after endovascular treatment induces a decrease in the expression of the studied miRNAs in whole blood samples, which suggests a possible use of them as biomarkers of therapeutic success.
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http://dx.doi.org/10.1016/j.avsg.2018.01.086DOI Listing
July 2018

High expression of XIAP and Bcl-2 may inhibit programmed cell death in glioblastomas.

Arq Neuropsiquiatr 2017 Dec;75(12):875-880

Universidade de São Paulo, Departamento de Cirurgia e Anatomia, Ribeirão Preto SP, Brasil.

Glioblastoma (GBM) is the most malignant glioma and represents 29% of all brain tumors. Tumorigenesis is intimately connected with characteristics acquired in the physiologic pathway of cellular death.

Objective: In the present study, the expression of anti-apoptotic (XIAP and Bcl-2) and apoptotic (cytochrome C, caspase 9, APAF-1), caspase 3 and the Smac/DIABLO genes related to the apoptosis pathway were evaluated in 30 samples of glioblastoma.

Methods: The gene expression was evaluated in 30 glioblastomas (WHO grade IV) and compared to 10 white matter control samples with real-time PCR.

Results And Conclusion: There were higher expressions of XIAP (p = 0.0032) and Bcl-2 (p = 0.0351) in the glioblastoma samples compared to the control samples of normal brain. These results raise the question of whether Bcl-2 and XIAP genes can be responsible for the inhibition of programmed cell death in glioblastomas. Moreover, they provide additional information capable of allowing the development of new target therapy strategies.
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http://dx.doi.org/10.1590/0004-282X20170156DOI Listing
December 2017

Spontaneous subdural hematoma associated with microcystic meningioma: first case report in the literature.

Br J Neurosurg 2019 Aug 29;33(4):428-431. Epub 2017 Jun 29.

b Ribeirão Preto Medical School, Department of Surgery and Anatomy, University of São Paulo , São Paulo , Brazil.

Non traumatic subdural hematomas are rare, especially those associated with intracranial meningiomas. Among the most common meningiomas associated with spontaneous bleeding are angioblastic and malignant meningioma variants. The pathophysiological mechanisms of this association are not yet fully understood. The association of chronic subdural hematoma with microcystic meningioma histological subtype has not yet been described in the literature. The authors present a case report of a patient with a spontaneous non traumatic chronic subdural hematoma associated with a microcystic subtype grade I meningioma of the parietal convexity. Epidemiological, etiology, natural history, pathophysiology, risk factors of bleeding and treatment options are reviewed. Spontaneous subdural hematomas associated with meningiomas are rare, specially related to the microcystic variant of meningioma. Careful pre-operative consideration of specific anatomy and pathophysiological features are paramount to their full treatment.
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http://dx.doi.org/10.1080/02688697.2017.1346172DOI Listing
August 2019

Analysis of gene expression EGFR and KRAS, microRNA-21 and microRNA-203 in patients with colon and rectal cancer and correlation with clinical outcome and prognostic factors.

Acta Cir Bras 2017 Mar;32(3):243-250

Associate Professor, Coloproctology Division, Department of Surgery and Anatomy, School of Medicine of Ribeirao Preto, USP, Brazil. Concept, design, intellectual and scientific content of the study; supervision of all phases of the study, critical revision.

Purpose:: To evaluate the expression of EGFR, KRAS genes, microRNAs-21 and 203 in colon and rectal cancer samples, correlated with their age at diagnosis, histological subtype, value of pretreatment CEA, TNM staging and clinical outcome.

Methods: : Expression of genes and microRNAs by real time PCR in tumor and non-tumor samples obtained from surgical treatment of 50 patients.

Results: : An increased expression of microRNAs-21 and 203 in tumor samples in relation to non-tumor samples was found. There was no statistically significant difference between the expression of these genes and microRNAs when compared to age at diagnosis and histological subtype. The EGFR gene showed higher expression in relation to the value of CEA diagnosis. The expression of microRNA-203 was progressively lower in relation to the TNM staging and was higher in the patient group in clinical remission.

Conclusions: : The therapy of colon and rectum tumors based on microRNAs remains under investigation reserving huge potential for future applications and clinical interventions in conjunction with existing therapies. We expect, based on the exposed data, to stimulate the development of new therapeutic possibilities, making the treatment of these tumors more effective.
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http://dx.doi.org/10.1590/S0102-865020170030000009DOI Listing
March 2017

Expression signatures of DNA repair genes correlate with survival prognosis of astrocytoma patients.

Tumour Biol 2017 Apr;39(4):1010428317694552

1 Department of Clinical Analysis, Faculty of Pharmaceutical Sciences of Araraquara, University of São Paulo State, Araraquara, Brazil.

Astrocytomas are the most common primary brain tumors. They are very resistant to therapies and usually progress rapidly to high-grade lesions. Here, we investigated the potential role of DNA repair genes in astrocytoma progression and resistance. To this aim, we performed a polymerase chain reaction array-based analysis focused on DNA repair genes and searched for correlations between expression patters and survival prognoses. We found 19 genes significantly altered. Combining these genes in all possible arrangements, we found 421 expression signatures strongly associated with poor survival. Importantly, five genes (DDB2, EXO1, NEIL3, BRCA2, and BRIP1) were independently correlated with worse prognoses, revealing single-gene signatures. Moreover, silencing of EXO1, which is remarkably overexpressed, promoted faster restoration of double-strand breaks, while NEIL3 knockdown, also highly overexpressed, caused an increment in DNA damage and cell death after irradiation of glioblastoma cells. These results disclose the importance of DNA repair pathways for the maintenance of genomic stability of high-grade astrocytomas and suggest that EXO1 and NEIL3 overexpression confers more efficiency for double-strand break repair and resistance to reactive oxygen species, respectively. Thereby, we highlight these two genes as potentially related with tumor aggressiveness and promising candidates as novel therapeutic targets.
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http://dx.doi.org/10.1177/1010428317694552DOI Listing
April 2017

Expression profiles of eNOS, iNOS and microRNA-27b in the corpus cavernosum of rats submitted to chronic alcoholism and Diabetes mellitus.

Acta Cir Bras 2017 Jan;32(1):38-45

Associate Professor, Division of Urology, Department of Surgery and Anatomy, School of Medicine of Ribeirao Preto, USP, Ribeirao Preto-SP, Brazil. Concept, design, intellectual and scientific content of the study; critical revision; supervised all phases of the study.

Purpose: : To evaluate the expression of endothelial and inducible NOS in addition to the miRNA-27b in the corpus cavernosum and peripheral blood of healthy rats, diabetic rats, alcoholic rats and rats with both pathologies.

Methods: : Forty eight Wistar rats were divided into four groups: control (C), alcoholic (A), diabetic (D) and alcoholic-diabetic (AD). Samples of the corpus cavernosum were prepared to study protein expressions of eNOS and iNOS by immunohistochemistry and expression of miRNA-27b in the corpus cavernosum and peripheral blood.

Results: : Immunohistochemistry for eNOS and iNOS showed an increase in cavernosal smooth muscle cells in the alcoholic, diabetic and alcoholic-diabetic groups when compared with the control group. Similarly, the mRNA levels for eNOS were increased in cavernosal smooth muscle (CSM) in the alcoholic, diabetic and alcoholic-diabetic groups and miRNA-27b were decreased in CSM in the alcoholic, diabetic and alcoholic-diabetic groups.

Conclusion: : The major new finding of our study was an impairment of relaxation of cavernosal smooth muscle in alcoholic, diabetic, and alcoholic-diabetic rats that involved a decrease in the nitric oxide pathway by endothelium-dependent mechanisms accompanied by a change in the corpus cavernosum contractile sensitivity.
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http://dx.doi.org/10.1590/s0102-865020170105DOI Listing
January 2017

Morphological and immunohistochemical analysis of apoptosis in the cerebellum of rats subjected to focal cerebral ischemia with or without alcoholism model.

Acta Cir Bras 2016 Sep;31(9):629-637

Associate Professor, Department of Surgery and Anatomy, School of Medicine of Ribeirao Preto, USP, Brazil. Conception, design, intellectual and scientific content of the study; manuscript writing, critical revision; supervision of all phases of the study.

Purpose: : To evaluated histopathological changes, morphometric and expression of proteins CASPASE-3, BCL-2 and XIAP related to apoptosis in the cerebellum after induction of temporary focal cerebral ischemia followed by reperfusion, with or without a model of chronic alcoholism.

Methods: : Fifty Wistar rats were used and divided into: control group (C), sham group (S), ischemic group (I), alcoholic group (A), and ischemic and alcoholic group (IA). The cerebellum samples collected were stained for histopathological and morphometric analysis and immunohistochemistry study.

Results: : Histopathological changes were observed a greater degree in animals in groups A and IA. The morphometric study showed no difference in the amount of cells in the granular layer of the cerebellum between the groups. The expression of CASPASE-3 was higher than BCL-2 and XIAP in the groups A and IA.

Conclusion: : We observed correlation between histopathological changes and the occurrence of apoptosis in cerebellar cortex.
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http://dx.doi.org/10.1590/S0102-865020160090000009DOI Listing
September 2016

Comparative evaluation of oncologic outcomes in colon cancer.

Acta Cir Bras 2016 ;31 Suppl 1:34-9

Ribeirão Preto Medical School, University of São Paulo, Brazil.

Purpose: In this paper we report clinical variables on colon cancer series. Oncological outcomes were compared to low-income and high-income countries.

Methods: We analysed a prospective database of 51 colon cancer patients submitted to primary tumor resection between 2010 and 2011, showing clinical variables and oncologic outcomes.

Results: R0 resection obtained in 80.4%, 21.6% of patients was TNM stage IV, and only 13.7% showed TNM stage I. Disease-free survival was 32 months, overall survival was 46 months, and the tumoral recurrence rate was 9.8%. Univariate analysis showed association of serum CEA levels ≥ 5 ng/dl (p= 0.004), presence of metastasis at diagnosis (p= 0.012), compromised surgical margins (p < 0.001) and poorer tumor differentiation (p= 0.041) to death. Multivariate analysis identified compromised surgical margins as an independent risk factor for death due to colon cancer (P=0.003; odds ratio=0.36; 95% confidence interval=0.004-0.33). Nowadays, 62.7% of patients are alive.

Conclusion: Recurrence rate, disease-free survival and overall survival was similar to those observed in more developed countries. Serum CEA levels ≥ 5 ng/dl, the presence of metastasis at diagnosis, compromised surgical margins and poorer tumor differentiation were associated with death. A compromised surgical margin was the only independent risk factor for death.
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http://dx.doi.org/10.1590/S0102-86502016001300008DOI Listing
May 2017

Serological under expression of microRNA-21, microRNA-34a and microRNA-126 in colorectal cancer.

Acta Cir Bras 2016 ;31 Suppl 1:13-8

Department of Surgery and Anatomy, Ribeirão Preto Medical School, University of São Paulo, Brazil.

Purpose: This paper describes the ability of miRNA value predict oncological outcomes in CRC patients and correlates to clinical and pathologic variables.

Methods: We prospectively analyzed the serological expression of microRNA-21, microRNA-34a, and microRNA-126 in 37 stage II - IV CRC patients and correlate to seven fit counterparts. Serological microRNAs were extracted using the miRNeasy Mini Kit(r) (Qiagen, Hilden, Germany). Quantification of microRNAs was performed using TaqMan Master Mix(r) reagent (Applied Biosystems, USA).

Results: We obtained serological underexpression microRNA-21, microRNA-34a, and microRNA-126 in CRC group. However, miRNAs serological values do not impact prognosis. Furthermore, miRNAs was not influenced by CEA values, TNM staging, and histological subtype.

Conclusion: Despite lower expression of miR-21, miR-34a and miR-126 in the CRC group, no association with poor prognosis was found.
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http://dx.doi.org/10.1590/S0102-86502016001300004DOI Listing
May 2017

KRAS mutation associated with CD44/CD166 immunoexpression as predictors of worse outcome in metastatic colon cancer.

Cancer Biomark 2016 Mar;16(4):513-21

Internal Medicine Department, School of Medicine of Ribeirão Preto, University of São Paulo, São Paulo, Brazil.

Introduction: Multiple stages of carcinogenesis in colon cancer encompass subpopulations of cancer stem cells (CSC), responsible for tumor cell transformation, growth and proliferation. CD44 and CD166 proteins are CSC markers associated with cell signaling, adhesion, migration, metastasis and lymphocytic response. The expression of CSC may be modulated by some factors, such as the KRAS gene mutation.

Objective: Correlate the expression of CD44 and CD166 markers in metastatic colon adenocarcinoma and KRAS mutation status (wild-type/mutated) with clinical pathological features and patients' outcome.

Material And Methods: Fifty-eight samples of tumor tissue samples of metastatic colon adenocarcinoma were collected from patients treated with CapeOx at the HCFMRP-USP Clinical Oncology Service. Clinical and survival data were collected from medical records. KRAS status was determined by the polymerase chain reaction (PCR) technique, and analysis of immunohistochemical expression of CD44 and CD166 proteins was performed by tissue microarray.

Results: The expression of CD44 and CD166 were positive in 41% and 43% of patients, respectively, and mutated KRAS was detected in 48% of patients. A significant association was found between CD166 and CD44 expression (p= 0.016), mainly in the wild-type KRAS group (p= 0.042) and patients over 65 years (p= 0.001). CD44-positive patients had 3.7-fold and 5.3-fold greater risk of liver metastasis and lung metastasis, respectively (p< 0.01), compared with CD44-negative patients. CD166-negative patients had 2.7 greater risk of lymph node involvement (0.03), compared with CD166-positive patients. KRAS mutation increased the risk of liver metastasis by 8 times (p< 0.01), and the risk of lung metastasis by 5 times (p= 0.04) in CD44-positive patients. KRAS mutation increased the risk of lymph node involvement by 8 times in CD166-negative patients (p= 0.0007).

Conclusion: An association between CD44 and CD166 expression was demonstrated in this study. Analysis of KRAS mutation combined with immunohistochemical expression of CD44 and CD166 identified subgroups of patients with colon adenocarcinoma at higher risk of lymph node involvement by the tumor and development of liver and lung metastasis.
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http://dx.doi.org/10.3233/CBM-160592DOI Listing
March 2016

Molecular Profiling Reveals Biologically Discrete Subsets and Pathways of Progression in Diffuse Glioma.

Cell 2016 Jan;164(3):550-63

Department of Genomic Medicine, Department of Bioinformatics and Computational Biology, Department of Biostatistics, Department of Neuro-Oncology, Department of Neurosurgery, Department of Pathology, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA. Electronic address:

Therapy development for adult diffuse glioma is hindered by incomplete knowledge of somatic glioma driving alterations and suboptimal disease classification. We defined the complete set of genes associated with 1,122 diffuse grade II-III-IV gliomas from The Cancer Genome Atlas and used molecular profiles to improve disease classification, identify molecular correlations, and provide insights into the progression from low- to high-grade disease. Whole-genome sequencing data analysis determined that ATRX but not TERT promoter mutations are associated with increased telomere length. Recent advances in glioma classification based on IDH mutation and 1p/19q co-deletion status were recapitulated through analysis of DNA methylation profiles, which identified clinically relevant molecular subsets. A subtype of IDH mutant glioma was associated with DNA demethylation and poor outcome; a group of IDH-wild-type diffuse glioma showed molecular similarity to pilocytic astrocytoma and relatively favorable survival. Understanding of cohesive disease groups may aid improved clinical outcomes.
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http://dx.doi.org/10.1016/j.cell.2015.12.028DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4754110PMC
January 2016

The expression of LEP, LEPR, IGF1 and IL10 in obesity and the relationship with microRNAs.

PLoS One 2014 1;9(4):e93512. Epub 2014 Apr 1.

Department of Surgery and Anatomy of the Faculty of Medicine of Ribeirão Preto, University of São Paulo, Ribeirao Preto, SP, Brazil.

Obesity is a multifactorial disease, with epigenetic alterations. Have been described modifications in the expression of some microRNAs, and some proteins related to obesity. The objective was to determine and correlate, in obese patients, the gene expression of LEP, LEPR, IGF1, IL10 and of miR-27a, miR-27b, miR-143 and miR-145. RNA was extracted from biopsies of subcutaneous fat, liver and visceral fat of 15 obese subjects submitted to bariatric surgery and of 15 non-obese subjects submitted to cholecystectomy for cDNA synthesis and for RT-PCR. The microRNAs were chosen using the TargetScan software. An increased expression of LEP and IGF1 was detected in the subcutaneous fat of the obese group compared to control, while the expression of IGF1 was higher in the control group than in the obese one. MiRNA-27a had a higher expression in the omentum of the obese patients and there was also a correlation in the expression of miRNA-145 and LEPR in the omentum of this group.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0093512PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3972109PMC
December 2015

Clinical-Pathological Correlation of KRAS Mutation Status in Metastatic Colorectal Adenocarcinoma.

World J Oncol 2013 Oct 27;4(4-5):179-187. Epub 2013 Sep 27.

Clinical Oncology, FMRP-USP (SP), Clinical Oncology Service, FMRP-USP (SP), Brazil.

Background: KRAS gene mutations play an important role in the carcinogenesis of colorectal tumors. However, studies that have assessed the association between KRAS gene mutation status and disease characteristics report conflicting results. To assess KRAS gene status (mutated or wild-type) and its association with the clinical, epidemiological, and histopathological features of metastatic colorectal adenocarcinoma as well its association with clinical outcomes.

Methods: Cross-sectional descriptive study in which clinical and histopathological data were collected from the medical records of 65 patients diagnosed with metastatic colorectal adenocarcinoma at the Clinical Oncology Service of the Teaching Hospital of the School of Medicine of Ribeirao Preto, University of Sao Paulo (Hospital das Clinicas da Faculdade de Medicina de Ribeirao Preto, Universidade de Sao Paulo -HCFMRP-USP) between 2005 and 2012 and analyzed based on their KRAS gene status.

Results: KRAS gene mutations were found in 49.2% of the tumors, and G/A (25.5%) and Gly12Asp (34.37%) were the most frequent mutations. Among the investigated clinical features (gender, ECOG (Eastern Cooperative Oncology Group), histology, degree of cell differentiation, lymph node ratio, primary tumor site, staging, presence of synchronous metastasis, lung metastasis, and liver metastasis), the association between age less than 65 years with KRAS mutation was statistically significant (P = 0.046). KRAS mutation status did not exhibit a significant correlation with the overall survival of the patients (P = 0.078); however, the cases with KRAS mutation exhibited shorter survival. In the multivariate analysis, synchronous metastasis (P = 0.03) and liver metastasis (P = 0.008) behaved as independent factors of poor prognosis relative to the overall survival of the patients.

Conclusion: The KRAS mutation status did not exhibit prognostic value in the investigated sample. Among the older patients (> 65 years old), wild-type KRAS was more frequently observed compared to mutated KRAS.
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http://dx.doi.org/10.4021/wjon719wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5649925PMC
October 2013

Modulation of HJURP (Holliday Junction-Recognizing Protein) levels is correlated with glioblastoma cells survival.

PLoS One 2013 25;8(4):e62200. Epub 2013 Apr 25.

Department of Clinical Analysis, Faculty of Pharmaceutical Sciences of Araraquara, University of São Paulo State (UNESP), Araraquara, Brazil.

Background: Diffuse astrocytomas are the most common type of primary brain cancer in adults. They present a wide variation in differentiation and aggressiveness, being classified into three grades: low-grade diffuse astrocytoma (grade II), anaplastic astrocytoma (grade III) and glioblastoma multiforme (grade IV), the most frequent and the major lethal type. Recent studies have highlighted the molecular heterogeneity of astrocytomas and demonstrated that large-scale analysis of gene expression could help in their classification and treatment. In this context, we previously demonstrated that HJURP, a novel protein involved in the repair of DNA double-strand breaks, is highly overexpressed in glioblastoma.

Methodology/principal Findings: Here we show that HJURP is remarkably overexpressed in a cohort composed of 40 patients with different grade astrocytomas. We also observed that tumors presenting the higher expression levels of HJURP are associated with poor survival prognosis, indicating HJURP overexpression as an independent prognostic factor of death risk for astrocytoma patients. More importantly, we found that HJURP knockdown strongly affects the maintenance of glioblastoma cells in a selective manner. Glioblastoma cells showed remarkable cell cycle arrest and premature senescence that culminated in elevated levels of cell death, differently from non-tumoral cells that were minimally affected.

Conclusions: These data suggest that HJURP has an important role in the maintenance of extremely proliferative cells of high-grade gliomas and point to HJURP as a potential therapeutic target for the development of novel treatments for glioma patients.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0062200PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3636219PMC
November 2013

Apoptosis in glioma cells treated with PDT.

Photomed Laser Surg 2011 May 23;29(5):305-9. Epub 2011 Jan 23.

Department of Surgery and Anatomy, University of São Paulo (USP), Brazil.

Background: Despite significant advances in neurosurgical techniques, the median survival time of patients with glioblastoma has improved little over the past 50 years and remains less than one year. Photodynamic therapy (PDT) is presently established as a widely accepted modality for the treatment of a variety of solid tumors.

Objectives: This study evaluated the effect of PDT-Photogem(®) on five glioma cell lines (U87, U138, U251, U343, and T98G).

Methods: The experiments were carried out in 25-cm(3) flasks with different groups of cells seeded at a density of 1 × 10(5) cells per flask. After 3 h, the medium was removed, and the cells were incubated for 4 h with Photogem (5 μg/mL). After the incubation time, the photosensitizer-containing medium was removed and the cells were irradiated with LED (630 nm, 25 mW/cm(2), 25 J/cm(2)) devices for 17 min. For the final steps of the PDT, the cells were returned to the incubator and kept at 37°C with 5% CO(2) for 24 h, the cell viability assay was assessed using the trypan blue method, and the expression of Caspase 3 mRNA levels was assessed by real-time quantitative PCR.

Results: Upon PDT-Photogem(®) treatment, viable cells, as evaluated by the trypan blue dye-exclusion method, decreased in two cell lines (U87 and U138) but not in the other three. Apoptosis, as assessed by the expression of caspase-3 mRNA levels, was at least partly involved in the death mechanism of the cell lines.

Conclusions: Collectively, our results indicated that PDT-Photogem(®) can act in glioma cells, thus encouraging new experiments in this field.
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http://dx.doi.org/10.1089/pho.2009.2649DOI Listing
May 2011

Caspase-3 and Bcl-2 expression in glioblastoma: an immunohistochemical study.

Arq Neuropsiquiatr 2010 08;68(4):603-7

Department of Surgery and Anatomy, Medicine School of Ribeirão Preto, University of São Paulo, Ribeirão Preto, SP, Brazil.

The unfavorable prognosis of malignant gliomas can also be explained by the incomplete knowledge of their molecular pathways. Studies regarding the regulatory process of apoptosis in glioblastoma (GBM), the most common malignant glioma, are few, and better knowledge of the expression of pro and anti-apoptotic proteins could collaborate with the development of new treatments founded on molecular basis. The objective of this study was to evaluate by immunohistochemistry the expression of caspase-3 and Bcl-2 in 30 samples of GBMs. The expression of caspase-3 (mean 17.67%) was lower than Bcl-2 (mean 30.92%), a statistically significant result (p<0.0001), suggesting low apoptotic activity in these tumors. Other studies of proteins related to the intrinsic and extrinsic pathway of apoptosis are required to provide additional information of this mechanism in GBMs.
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http://dx.doi.org/10.1590/s0004-282x2010000400023DOI Listing
August 2010

Expression of HSP70 in cerebral ischemia and neuroprotetive action of hypothermia and ketoprofen.

Arq Neuropsiquiatr 2010 08;68(4):592-6

Departament of Surgery and Anatomy, Medicine School of Ribeirão Preto, University of São Paulo, Ribeirão Preto, SP, Brazil.

Heat shock proteins (HSPs) are molecular chaperones that bind to other proteins to shepherd them across membranes and direct them to specific locations within a cell. Several injurious stimuli can induce Hsp70 expression, including ischemia. This study aimed to investigate the pattern of expression of protein (immunohistochemistry) and gene (real-time PCR) Hsp70 in experimental focal cerebral ischemia in rats by occlusion of the middle cerebral artery for 1 hour and the role of neuroprotection with hypothermia (H) and ketoprofen (K). The infarct volume was measured using morphometric analysis defined by triphenyl tetrazolium chloride. It was observed increases in the protein (p=0.0001) and gene (p=0.0001) Hsp70 receptor in the ischemic areas that were reduced by H (protein and gene: p<0.05), K (protein: p<0.001), and H+K (protein: p<0.01 and gene: p<0.05). The Hsp70 increases in the ischemic area suggests that the Hsp70-mediated neuroexcitotoxicity plays an important role in cell death and that the neuroprotective effect of both, H and K are directly involved with the Hsp70.
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http://dx.doi.org/10.1590/s0004-282x2010000400021DOI Listing
August 2010

Expression of apoptosis in human saphenous vein grafts in restoration of blood flow through coronary bypass surgery.

Rev Bras Cir Cardiovasc 2009 Jul-Sep;24(3):312-7

FMRP - USP.

Objective: To investigate the possible role of apoptosis on brief distensions of human saphenous veins at different pressures.

Methods: Fresh isolated grafts of human saphenous vein were assigned as control or distended (D) for fifteen seconds at 100, 200 and 300 mmHg. The degree of apoptotic caspases 3, 8, 9 and anti-apoptotic protein Bcl-2 expression were assessed by immunohistochemistry.

Results: Fresh isolated segments of distended human saphenous veins presented similar apoptotic protein expression when compared with control veins. However, the Bcl-2 expression was significantly higher in the 300 mmHg distended segments compared with the control vein.

Conclusion: These findings show that intact segments of human saphenous veins submitted to distensions at different pressures have similar apoptotic proteins expression when compared with non-distended control veins. Therefore, brief distensions commonly performed during surgical harvesting do not trigger apoptosis, and probably are not involved on the physiopathological mechanisms that lead to graft failure.
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http://dx.doi.org/10.1590/s0102-76382009000400009DOI Listing
June 2010