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1.
J Cell Biochem ; 119(7): 5775-5787, 2018 07.
Artigo em Inglês | MEDLINE | ID: mdl-29537103

RESUMO

Ovarian cancer (OC) is the fourth most common gynecological malignancy due to its highly aggressive, recurrent, and drug-resistant nature. The last two features are rendered by the presence of cancer stem cells (CSCs). Factors like TGFß1 and their downstream signaling pathways are upregulated in most cancers and are known to induce EMT and stemness, but the exact mechanisms underlying the process remain unelucidated. In our study, TGFß1 induced enhanced stem-like properties like high expression of the pluripotent markers SOX2, OCT4a, and NANOG, along with CD44, and CD117 in the OC cells. In addition, increased activity of the aldehyde dehydrogenase enzyme, formation of compact spheroids, and a quiescent phenotype were observed. In deciphering the mechanism behind it, our data propose ZEB1 transcription factor to play a substantial role in inducing the EMT-mediated stemness and chemoresistance. Further, in our study, we elucidated the significant contribution of both Smad and non-Smad pathways like ERK, JNK, and P38 MAPK pathways in the induction of stem-like characteristics. The novelty of the study also resides with the fact in the expression of different lineage-specific markers, like CD31, CD45, and CD117 along with CD44 in the TGFß1-induced epithelial ovarian cancer spheroids. This suggests a tendency of the spheroidal cells towards differentiating into heterogenic populations, which is a distinctive feature of a stem cell. Taken together, the present study provides an insight to the molecular cues involved in the acquisition of stemness and chemoresistance along with tumor heterogeneity in TGFß1-induced OC cells.


Assuntos
Antineoplásicos/farmacologia , Resistencia a Medicamentos Antineoplásicos , Transição Epitelial-Mesenquimal , Células-Tronco Neoplásicas/patologia , Neoplasias Ovarianas/patologia , Fator de Crescimento Transformador beta1/metabolismo , Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/genética , Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/metabolismo , Feminino , Humanos , Proteínas de Neoplasias/genética , Proteínas de Neoplasias/metabolismo , Células-Tronco Neoplásicas/metabolismo , Neoplasias Ovarianas/genética , Neoplasias Ovarianas/metabolismo , Proteína Smad2/genética , Proteína Smad2/metabolismo , Fator de Crescimento Transformador beta1/genética , Células Tumorais Cultivadas , Homeobox 1 de Ligação a E-box em Dedo de Zinco/genética , Homeobox 1 de Ligação a E-box em Dedo de Zinco/metabolismo
2.
Gene ; 513(2): 268-71, 2013 Jan 25.
Artigo em Inglês | MEDLINE | ID: mdl-23124075

RESUMO

Chewing betel quid may release chemical carcinogens including xenobiotics resulting in oral malignancy cases preceded by potential malignant lesions and conditions - Oral Submucous Fibrosis (OSF) being one of them. The cytochrome P4501A1 (CYP1A1) enzyme is central to the metabolic activation of these xenobiotics, whereas CYP2E1 metabolizes the nitrosamines and tannins. The present study investigated the association of polymorphisms at CYP1A1m1 (T3801C), m2 (A2455G), and CYP2E1 PstI site (nucleotide 21259) with the risk of OSF. The study was conducted on 75 OSF patients and 150 controls from an eastern Indian population. The above polymorphisms were analyzed by PCR-RFLP method. Analyses of data show that polymorphisms in CYP1A1m2 [OR=8.25 (4.31-15.80)]; CYP1A1m1 [OR=2.88 (1.57-5.24)] and CYP2E1 PstI site [OR=3.16 (1.10-9.04)] revealed significant association with OSF. Our results suggest that polymorphism in CYP1A1 and CYP2E1 may confer an increased risk for Oral Submucous Fibrosis.


Assuntos
Areca/efeitos adversos , Citocromo P-450 CYP1A1/genética , Sistema Enzimático do Citocromo P-450/genética , Fibrose Oral Submucosa/genética , Polimorfismo Genético , Adulto , Estudos de Casos e Controles , Família 2 do Citocromo P450 , Desoxirribonucleases de Sítio Específico do Tipo II/genética , Desoxirribonucleases de Sítio Específico do Tipo II/metabolismo , Feminino , Predisposição Genética para Doença , Humanos , Índia , Masculino , Mastigação , Pessoa de Meia-Idade
3.
Exp Suppl ; 103: 57-82, 2012.
Artigo em Inglês | MEDLINE | ID: mdl-22642190

RESUMO

The interest in gelatinases is increased because of their association in diverse human diseases, though the relationship between MMP expression and disease progression is very complex and varies in cell to cell. Targeting gelatinases in disease treatment is complicated by the fact that gelatinases are indispensable for normal development and physiology due to their multifunctionality, possible functional redundancy, context-dependent expression, and activity. They are secreted as inactive zymogens which are processed to become active by removal of N-terminal propeptide. The folded conformation of zymogen is required to keep the gelatinases in its latency. Acting on a broad spectrum of extracellular substrates, the gelatinases (both MMP-2 and MMP-9) are critical to the biological processes. Three-dimensional structures of gelatinase-inhibitor complexes and inhibition profiles of compounds screened on them provide an invaluable source to gain insight into the structural determinants as well as functional selectivity. The quest for selective MMP inhibitors (MMPIs) still remains a challenge in search of successful clinical candidates. An increased understanding of the structure, regulation, and function of the individual MMPs will likely lead to more effective strategies in the development of highly selective inhibitors for any given MMP that can then be exploited to achieve the desired drugs.


Assuntos
Inibidores Enzimáticos/farmacologia , Gelatinases/antagonistas & inibidores , Gelatinases/química , Gelatinases/metabolismo , Relação Estrutura-Atividade
4.
Tissue Cell ; 40(6): 425-35, 2008 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-18573513

RESUMO

Oral submucous fibrosis (OSF) is a precancerous condition of the oral cavity and oropharynx and a significant number of such cases transform into oral squamous cell carcinoma (OSCC). Presently, diagnosis of OSF is done mainly through qualitative histopathological techniques and in the level of diagnostic molecular biology no specific genetic marker is evident. Keeping these facts in mind this study evaluates histopathological changes in the epithelium and subepithelial connective tissue of OSF through quantitative digital image analysis in respect to specific candidate features and analyses null mutations in the GSTM1 and GSTT1 by PCR amplification. The analysis revealed that there are subtle quantitative differences in the histological images of OSF compared to NOM. The thickness of the epithelium and cell population in its different zones, radius of curvature of rete-ridges and connective tissue papillae were decreased but length of rete-ridges and connective tissue papillae, fibrocity and the number of cellular components (predominantly inflammatory cells) in the subepithelial connective tissue were increased in OSF. The PCR study revealed that there is no significant difference in the allelic variants in GSTM1 between OSF and normal, while GSTT1 null gene showed significantly higher frequencies in this precancerous condition. This study establishes a distinct quantitative difference between normal oral mucosa (NOM) and OSF in respect to their histological features and GST null gene frequencies.


Assuntos
Glutationa Transferase/genética , Modelos Biológicos , Lesões Pré-Cancerosas/metabolismo , Lesões Pré-Cancerosas/patologia , Adulto , Algoritmos , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Carcinoma de Células Escamosas/genética , Carcinoma de Células Escamosas/metabolismo , Carcinoma de Células Escamosas/patologia , Progressão da Doença , Células Epiteliais/metabolismo , Células Epiteliais/patologia , Fibrose , Regulação Neoplásica da Expressão Gênica , Predisposição Genética para Doença , Genótipo , Glutationa Transferase/metabolismo , Humanos , Processamento de Imagem Assistida por Computador , Pessoa de Meia-Idade , Mucosa Bucal/metabolismo , Mucosa Bucal/patologia , Neoplasias Bucais/genética , Neoplasias Bucais/metabolismo , Neoplasias Bucais/patologia , Lesões Pré-Cancerosas/genética
5.
Food Chem Toxicol ; 46(2): 740-51, 2008 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-17983699

RESUMO

BACKGROUND: Arsenic is ubiquitous in the environment, and chronic or acute exposure through food and water as well as occupational sources can contribute to a well-defined spectrum of disease. Despite arsenic being a health hazard and a well-documented human carcinogen, a safe, effective and specific preventive or therapeutic measure for treating arsenic induced toxicity still eludes us. OBJECTIVE: This study was undertaken to evaluate the therapeutic efficacy of aqueous garlic (Allium sativum L.) extract (AGE) in terms of normalization of altered biochemical parameters particularly indicative of oxidative stress following sodium arsenite (NaAsO(2)) exposure and depletion of inorganic arsenic burden, in vitro and in vivo. RESULTS: AGE (2mg/ml) co-administered with 10 microM NaAsO(2) attenuated arsenite induced cytotoxicity, reduced intracellular reactive oxygen species (ROS) level in human malignant melanoma cells (A375), human keratinocyte cells (HaCaT) and in cultured human normal dermal fibroblast cells. Moreover, AGE application in NaAsO(2) intoxicated Sprague-Dawley rats resulted in a marked inhibition of tissue lipid peroxide generation; enhanced level of total tissue sulfhydryl groups and glutathione; and also increased the activities of antioxidant enzymes, superoxide dismutase and catalase to near normal. An increase in blood ROS level and myeloperoxidase activity in arsenic-intoxicated rats was effectively prevented by AGE administration. AGE was also able to counter arsenic mediated incongruity in blood hematological variables and glucose level. CONCLUSIONS: The restorative property of AGE was attributed to its antioxidant activity, chelating efficacy, and/or oxidizing capability of trivalent arsenic to its less toxic pentavalent form. Taken together, evidences indicate that AGE can be a potential protective regimen for arsenic mediated toxicity.


Assuntos
Arsenitos/antagonistas & inibidores , Inibidores Enzimáticos/toxicidade , Fibroblastos/efeitos dos fármacos , Alho , Estresse Oxidativo/efeitos dos fármacos , Extratos Vegetais/farmacologia , Compostos de Sódio/antagonistas & inibidores , Animais , Arsenitos/farmacocinética , Arsenitos/toxicidade , Catalase/metabolismo , Feminino , Fibroblastos/metabolismo , Humanos , Técnicas In Vitro , Masculino , Ratos , Ratos Sprague-Dawley , Espécies Reativas de Oxigênio/metabolismo , Compostos de Sódio/farmacocinética , Compostos de Sódio/toxicidade , Superóxido Dismutase/metabolismo , Distribuição Tecidual , Células Tumorais Cultivadas
6.
Indian J Clin Biochem ; 17(1): 49-57, 2002 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-23105337

RESUMO

Pretreatment of an ethanolic extract of leaf ofPiper betle linn at a dose of 200mg/kg body weight, orally administered to rats for ten consecutive days, was found to possess a significant protective action against gastric lesions induced by indomethacin. The extract pretreatment resulted in significant increase in superoxide dismutase (SOD) and catalase (CAT) activity, increase in mucus, hexosamine and total thiol group content, but marked reduction in oxidatively damaged protein and peroxidised lipid levels as compared to untreated ulcerated control. The extract was also found to possess both superoxide and hydroxyl free radical scavenging action. The present observations establish the efficacy of the extract in prevention of experimentally induced peptic ulcer by indomethacin and antioxidant property appears to be predominantly responsible for such cytoprotective activity in the experimental model.

7.
Indian J Clin Biochem ; 17(2): 44-51, 2002 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-23105349

RESUMO

Oral administration of ethanol extract of the rhizome ofPirorhiza kurroa at a dose of 20mg/kg body weight, for 10 consecutive days, was found to enhance the rate of healing on Indomethacin-induced gastric ulcer in rats, compared to the ulcerated group without treatment. The level of peroxidised lipid, in terms of thiobarbituric acid reactive species (TBARS), in gastric tissue, was increased in ulcerated rats which was restored to near normalcy on treatment with ethanol extract. The specific activity ofin vivo antioxidant enzymes, viz SOD and catalase and total tissue sulfhydryl (thiol) group, which were markedly decreased in ulcerated group, were found to be significantly elevated (p<0.05), on treatment with the above extract, at the specified dose, compared to the indomethacin-induced ulcerated group without any supporting treatment. The present study thus suggests that the ethanol extract of rhizome ofPicrorhiza kurroa, at the dose of 20mg/kg body weight, accelerated the healing of stomach wall of indomethacin induced gastric ulcerated rats by anin vivo free radical scavenging action.

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