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1.
Naunyn Schmiedebergs Arch Pharmacol ; 394(11): 2273-2287, 2021 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-34468816

RESUMO

Morbidity and mortality risks are enhanced in preeclamptic (PE) mothers and their offspring. Here, we asked if sexual dimorphism exists in (i) cardiovascular and renal damage evolved in offspring of PE mothers, and (ii) offspring responsiveness to antenatal therapies. PE was induced by administering NG-nitro-L-arginine methyl ester (L-NAME, 50 mg/kg/day, oral gavage) to pregnant rats for 7 days starting from gestational day 14. Three therapies were co-administered orally with L-NAME, atrasentan (endothelin ETA receptor antagonist), terutroban (thromboxane A2 receptor antagonist, TXA2), or α-methyldopa (α-MD, central sympatholytic drug). Cardiovascular and renal profiles were assessed in 3-month-old offspring. Compared with offspring of non-PE rats, PE offspring exhibited elevated systolic blood pressure and proteinuria and reduced heart rate and creatinine clearance (CrCl). Apart from a greater bradycardia in male offspring, similar PE effects were noted in male and female offspring. While terutroban, atrasentan, or α-MD partially and similarly blunted the PE-evoked changes in CrCl and proteinuria, terutroban was the only drug that virtually abolished PE hypertension. Rises in cardiorenal inflammatory (tumor necrosis factor alpha, TNFα) and oxidative (isoprostane) markers were mostly and equally eliminated by all therapies in the two sexes, except for a greater dampening action of atrasentan, compared with α-MD, on tissue TNFα in female offspring only. Histopathologically, antenatal terutroban or atrasentan was more effective than α-MD in rectifying cardiac structural damage, myofiber separation, and cytoplasmic alterations, in PE offspring. The repair by antenatal terutroban or atrasentan of cardiovascular and renal anomalies in PE offspring is mostly sex-independent and surpasses the protection offered by α-MD, the conventional PE therapy.

2.
Br J Cancer ; 125(7): 983-993, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34253873

RESUMO

BACKGROUND: Breast cancer stem cells (BCSCs) are drivers of therapy-resistance, therefore are responsible for poor survival. Molecular signatures of BCSCs from primary cancers remain undefined. Here, we identify the consistent transcriptome of primary BCSCs shared across breast cancer subtypes, and we examine the clinical relevance of ITGA7, one of the genes differentially expressed in BCSCs. METHODS: Primary BCSCs were assessed using immunohistochemistry and fluorescently labelled using Aldefluor (n = 17). Transcriptomes of fluorescently sorted BCSCs and matched non-stem cancer cells were determined using RNA-seq (n = 6). ITGA7 expression was examined in breast cancers using immunohistochemistry (n = 305), and its functional role was tested using siRNA in breast cancer cells. RESULTS: Proportions of BCSCs varied from 0 to 9.4%. 38 genes were significantly differentially expressed in BCSCs; genes were enriched for functions in vessel morphogenesis, motility, and metabolism. ITGA7 was found to be significantly downregulated in BCSCs, and low expression significantly correlated with reduced survival in patients treated with chemotherapy, and with chemoresistance in breast cancer cells in vitro. CONCLUSIONS: This study is the first to define the molecular profile of BCSCs from a range of primary breast cancers. ITGA7 acts as a predictive marker for chemotherapy response, in accordance with its downregulation in BCSCs.

3.
Toxicol Appl Pharmacol ; 426: 115615, 2021 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-34102242

RESUMO

Current therapies for preeclampsia (PE) and its complications are limited and defective. Considering the importance of endothelin (ET) and thromboxane A2 (TXA2) signaling in PE pathophysiology, we tested the hypothesis that prenatal blockade of endothelin ETA or thromboxane TXA2 receptors favorably reprograms preeclamptic cardiovascular and renal insults. PE was induced by daily oral administration of L-NAME (50 mg/kg) to pregnant rats for 7 consecutive days starting from gestational day 14. The effects of co-exposure to atrasentan (ETA receptor blocker, 10 mg/kg/day) or terutroban (TXA2 receptor blocker, 10 mg/kg/day) on cardiovascular and renal anomalies induced by PE were assessed on gestational day 20 (GD20) and at weaning time and compared with those evoked by the sympatholytic drug α-methyldopa (α-MD, 100 mg/kg/day), a prototypic therapy for PE management. Among all drugs, terutroban was basically the most potent in ameliorating PE-evoked increments in blood pressure and decrements in creatinine clearance. Cardiorenal tissues of PE rats exhibited significant increases in ETA and TXA2 receptor expressions and these effects disappeared after treatment with atrasentan and to a lesser extent by terutroban or α-MD. Atrasentan was also the most effective in reversing the reduced ETB receptor expression in renal tissues of PE rats. Signs of histopathological damage in cardiac and renal tissues of PE rats were mostly improved by all therapies. Together, pharmacologic elimination of ETA or TXA2 receptors offers a relatively better prospect than α-MD in controlling perinatal cardiorenal irregularities sparked by PE.


Assuntos
Atrasentana/uso terapêutico , Antagonistas do Receptor de Endotelina A/uso terapêutico , Cardiopatias/prevenção & controle , Nefropatias/prevenção & controle , Naftalenos/uso terapêutico , Pré-Eclâmpsia/tratamento farmacológico , Propionatos/uso terapêutico , Receptores de Tromboxano A2 e Prostaglandina H2/antagonistas & inibidores , Animais , Atrasentana/farmacologia , Antagonistas do Receptor de Endotelina A/farmacologia , Feminino , Regulação da Expressão Gênica/efeitos dos fármacos , Cardiopatias/genética , Cardiopatias/patologia , Cardiopatias/fisiopatologia , Hemodinâmica/efeitos dos fármacos , Rim/efeitos dos fármacos , Rim/metabolismo , Rim/patologia , Nefropatias/genética , Nefropatias/patologia , Nefropatias/fisiopatologia , Miocárdio/metabolismo , Miocárdio/patologia , Naftalenos/farmacologia , Pré-Eclâmpsia/genética , Pré-Eclâmpsia/patologia , Pré-Eclâmpsia/fisiopatologia , Gravidez , Propionatos/farmacologia , Ratos , Ratos Sprague-Dawley , Receptor de Endotelina A/genética , Receptores de Tromboxano A2 e Prostaglandina H2/genética
4.
Eur J Pharmacol ; 806: 96-104, 2017 Jul 05.
Artigo em Inglês | MEDLINE | ID: mdl-28416371

RESUMO

Cyclosporine (CSA) and nonsteroidal antiinflammatory drugs (NSAIDs) are used together to manage arthritic disorders with an immune component. Previous reports showed contrasting effects for NSAIDs on CSA nephrotoxicity and acute elevations in blood pressure. Both effects were ameliorated or exaggerated after selective cyclooxygenase-2 (COX2) and nonselective COX inhibition, respectively. Here we investigated: (i) the interaction of CSA with NSAIDs possessing variable COX1/COX2 selectivities on hemodynamic, left ventricular (LV) and cardiac autonomic and histologic profiles, and (ii) role of NADPH-oxidase (NOX)/Rho-kinase (ROCK) pathway in the interaction. Female rats were pre-instrumented with femoral catheters and treated for 10 days with CSA (25mg/kg/day), diclofenac (nonselective NSAIDs, 1mg/kg/day), celecoxib (COX2 inhibitor, 10mg/kg/day), or their combinations. CSA-mediated hypertension was maintained upon co-administration of either NSAID whereas the concomitant reductions in time- and frequency-domain indices of heart rate variability (HRV) were accentuated in presence of diclofenac but not celecoxib. The isovolumic relaxation time (Τau), a measure of diastolic function, was reduced by all regimens whereas LV contractility (dP/dtmax) remained unaffected. The CSA/diclofenac regimen, but not individual treatments, increased cardiac NOX2 expression and caused more cardiac structural damage. The inhibition of NOX by diphenyleneiodonium reversed CSA/diclofenac-evoked increases in MAP, decreases in HRV and Tau, cardiac structural damage, and increased NOX2 expression. No such effects were observed after ROCK inhibition by fasudil, despite concomitant decreases in NOX2 expression. In conclusion, CSA/diclofenac-treated female rats exhibit exacerbated hemodynamic, autonomic, LV, and histopathologic disturbances via ROCK-independent NOX2 upregulation.


Assuntos
Anti-Inflamatórios não Esteroides/farmacologia , Sistema Nervoso Autônomo/efeitos dos fármacos , Sistema Cardiovascular/efeitos dos fármacos , Ciclosporina/farmacologia , NADPH Oxidases/metabolismo , Animais , Sistema Nervoso Autônomo/fisiologia , Ciclo-Oxigenase 2/metabolismo , Inibidores de Ciclo-Oxigenase 2/farmacologia , Interações Medicamentosas , Feminino , Hemodinâmica/efeitos dos fármacos , Ratos , Ratos Wistar , Transdução de Sinais/efeitos dos fármacos , Fatores de Tempo , Quinases Associadas a rho/metabolismo
5.
Pathol Res Pract ; 210(11): 751-8, 2014 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-25242024

RESUMO

We explored the expression of the stem cell markers OCT4 and nestin in laryngeal squamous cell carcinoma (LSCC) and investigated their relationship to survivin expression. Eighty-five LSCC, and 62 non-neoplastic laryngeal tissues were analyzed immunohistochemically for the presence of OCT4, nestin and survivin. Marker expression was correlated to clinicopathological parameters. The positive detection rates of OCT4 (42.35%) and nestin (51.76%) in LSCC were higher than those of non-neoplastic mucosa (p<0.05). OCT4 expression was positively associated with nestin expression (p=0.0001). High expression of both OCT4 and nestin was associated with higher tumor grade (p=0.0001). Also, high OCT4 expression was related to higher T stage (p=0.0001). Co-expression of OCT4 and nestin was more significantly associated with glottic location, higher T stage and nodal metastasis than high expression of either marker (p=0.015, 0.006 and 0.008, respectively). Survivin expression was not significantly related to expression of OCT4 or nestin (p=0.094 and 0.266, respectively). OCT4 and nestin are overexpressed in LSCC and may contribute to laryngeal carcinogenesis. Their co-expression may help to predict the lymph node metastatic potential of LSCC. No relationship was detected between expression of survivin and OCT4 or nestin.


Assuntos
Carcinoma de Células Escamosas/metabolismo , Proteínas Inibidoras de Apoptose/metabolismo , Neoplasias Laríngeas/metabolismo , Nestina/metabolismo , Fator 3 de Transcrição de Octâmero/metabolismo , Idoso , Idoso de 80 Anos ou mais , Biomarcadores/metabolismo , Carcinoma de Células Escamosas/patologia , Feminino , Humanos , Neoplasias Laríngeas/patologia , Linfonodos/patologia , Masculino , Pessoa de Meia-Idade , Prognóstico , Células-Tronco/metabolismo , Survivina
6.
Turk Patoloji Derg ; 29(3): 193-200, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-24022309

RESUMO

OBJECTIVE: Poor immunogenicity has been described in breast carcinoma although dendritic cells, the major antigen presenters, are known to infiltrate the tumor. Vascular endothelial growth factor has been proposed to reduce local immune response in tumors. We investigated the maturation status of dendritic cells in invasive ductal carcinoma of the breast in relation to vascular endothelial growth factor expression and clinicopathological parameters. MATERIAL AND METHOD: Fifty invasive ductal carcinomas of the breast were immunostained with CD1a (marker of immature dendritic cells); CD83 (marker of mature dendritic cells), vascular endothelial growth factor, estrogen receptor and progesterone receptor. RESULTS: Mature dendritic cells were detected in 36 cases (72%), and correlated with smaller tumor size, negative lymph nodes, positive steroid receptor status, and lower grade (P < 0.001). Immature dendritic cells were found in 100% of cases and correlated only with negative steroid receptor expression (estrogen receptor and progesterone receptor) (P=0.006 and 0.020 respectively). Vascular endothelial growth factor expression was detected in 44 cases (88%), and correlated directly with positive nodal metastases (P=0.014), correlated inversely with mature dendritic cell count (P=0.005); and did not correlate with immature dendritic cell count (P=0.104). CONCLUSION: Mature dendritic cell count correlates with good prognostic features in invasive ductal carcinoma of the breast, suggesting their role in initiating primary anti-tumor immune response. Vascular endothelial growth factor expression may play a role in inhibition of dendritic cell maturation sequence in the tumor microenvironment.


Assuntos
Neoplasias da Mama/imunologia , Carcinoma Ductal de Mama/imunologia , Células Dendríticas/imunologia , Fator A de Crescimento do Endotélio Vascular/biossíntese , Adulto , Idoso , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Carcinoma Ductal de Mama/metabolismo , Carcinoma Ductal de Mama/patologia , Células Dendríticas/metabolismo , Feminino , Humanos , Imuno-Histoquímica , Pessoa de Meia-Idade
7.
ScientificWorldJournal ; 2013: 375139, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-24459428

RESUMO

OBJECTIVE: This work was designed to study the biological and demographic characteristics of meningiomas and their impact on tumor recurrence in Egyptian patients. MATERIAL AND METHODS: A cohort of 265 Egyptian patients with meningioma was studied. Immunohistochemistry for VEGF, Ki67, PR, CD20, and CD3 was performed. Statistical analysis was used to detect independent predictors of recurrence. RESULTS: Adults represented 98.9% of cases, with female preponderance (M : F ratio = 1 : 2.4). Histologically, 78.10% of cases were grade I, 19.20% were grade II, and 2.60% were grade III. Transitional variant was the most common (43.40%). VEGF expression (38.50% of cases) correlated positively with perifocal edema, tumor size, and proliferative index (PI). PR expression (64.5% of cases) correlated inversely with the PI (mean 3.75). Lymphocytic aggregates were detected in 7.20% of cases, with a mean CD20 : CD3 ratio of 1 : 10.1. In a multivariate analysis, only tumor size, PR expression and necrosis predicted recurrence independently. Using ROC curve, size was the best predictor of tumor recurrence with a cut-off point of >6 cm and an excellent negative predictive value (97.6%). CONCLUSIONS: Meningiomas in our region showed some distinctive clinicopathological and demographic criteria. Tumor size was found to be the best recurrence predictor factor of meningioma.


Assuntos
Biomarcadores Tumorais/metabolismo , Neoplasias Meníngeas/epidemiologia , Neoplasias Meníngeas/metabolismo , Meningioma/epidemiologia , Meningioma/metabolismo , Recidiva Local de Neoplasia/epidemiologia , Recidiva Local de Neoplasia/metabolismo , Adolescente , Adulto , Distribuição por Idade , Idoso , Idoso de 80 Anos ou mais , Criança , Estudos de Coortes , Egito/epidemiologia , Feminino , Humanos , Incidência , Masculino , Neoplasias Meníngeas/diagnóstico , Meningioma/diagnóstico , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/diagnóstico , Fatores de Risco , Distribuição por Sexo , Adulto Jovem
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