13 results on '"Karina G. Zecchin"'
Search Results
2. The Fatty Acid Synthase Inhibitor Orlistat Reduces the Growth and Metastasis of Orthotopic Tongue Oral Squamous Cell Carcinomas
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Fernanda Dos Santos Moreira, Michelle Agostini, Ricardo D. Coletta, Tuula Salo, Débora Campanella Bastos, Edgard Graner, Helena Fonseca Raposo, Rose Mara Ortega, Nivea Dias Amoedo, Karina G. Zecchin, Luciana Yamamoto Almeida, Fabiana Seguin, and Helena C. F. Oliveira
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Cancer Research ,medicine.medical_specialty ,Cell ,Apoptosis ,Metastasis ,Lactones ,Mice ,Prostate cancer ,Cell Line, Tumor ,Internal medicine ,medicine ,Carcinoma ,Animals ,Humans ,Cytotoxic T cell ,Neoplasm Metastasis ,Cell Proliferation ,Orlistat ,biology ,medicine.disease ,Xenograft Model Antitumor Assays ,Tongue Neoplasms ,Fatty Acid Synthase, Type I ,Fatty acid synthase ,medicine.anatomical_structure ,Endocrinology ,Oncology ,Cervical lymph nodes ,Tumor progression ,Carcinoma, Squamous Cell ,biology.protein ,Cancer research - Abstract
Fatty acid synthase (FASN) is the biosynthetic enzyme responsible for the endogenous synthesis of fatty acids. It is downregulated in most normal cells, except in lipogenic tissues such as liver, lactating breast, fetal lung, and adipose tissue. Conversely, several human cancers, including head and neck squamous cell carcinomas (HNSCC), overexpress FASN, which has been associated with poor prognosis and recently suggested as a metabolic oncoprotein. Orlistat is an irreversible inhibitor of FASN activity with cytotoxic properties on several cancer cell lines that inhibits tumor progression and metastasis in prostate cancer xenografts and experimental melanomas, respectively. To explore whether the inhibition of FASN could impact oral tongue squamous cell carcinoma (OTSCC) metastatic spread, an orthotopic model was developed by the implantation of SCC-9 ZsGreen LN-1 cells into the tongue of BALB/c nude mice. These cells were isolated through in vivo selection, show a more invasive behavior in vitro than the parental cells, and generate orthotopic tumors that spontaneously metastasize to cervical lymph nodes in 10 to 15 days only. SCC-9 ZsGreen LN-1 cells also exhibit enhanced production of MMP-2, ERBB2, and CDH2. The treatment with orlistat reduced proliferation and migration, promoted apoptosis, and stimulated the secretion of VEGFA165b by SCC-9 ZsGreen LN-1 cells. In vivo, the drug was able to decrease both the volume and proliferation indexes of the tongue orthotopic tumors and, importantly, reduced the number of metastatic cervical lymph nodes by 43%. These results suggest that FASN is a potential molecular target for the chemotherapy of patients with OTSCC. Mol Cancer Ther; 13(3); 585–95. ©2013 AACR.
- Published
- 2014
3. The fatty acid synthase inhibitor orlistat reduces experimental metastases and angiogenesis in B16-F10 melanomas
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Ricardo D. Coletta, Fabiana Seguin, Marco Aurélio de Carvalho, Miryam Paola Alvarez-Flores, Débora Campanella Bastos, Ana Marisa Chudzinski-Tavassi, Karina G. Zecchin, Edgard Graner, and Michelle Agostini
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Vascular Endothelial Growth Factor A ,Cancer Research ,medicine.medical_specialty ,Lung Neoplasms ,Cell Survival ,Angiogenesis ,Melanoma, Experimental ,Antineoplastic Agents ,Apoptosis ,Enzyme-Linked Immunosorbent Assay ,Lactones ,Mice ,angiogenesis ,Internal medicine ,melanoma ,medicine ,Animals ,Humans ,metastasis ,Enzyme Inhibitors ,RNA, Small Interfering ,neoplasms ,orlistat ,Cell Proliferation ,Mouth neoplasm ,fatty acid synthase ,Neovascularization, Pathologic ,biology ,Reverse Transcriptase Polymerase Chain Reaction ,Cell growth ,Melanoma ,vascular endothelial growth factor A (VEGFA) ,medicine.disease ,respiratory tract diseases ,Gene Expression Regulation, Neoplastic ,Mice, Inbred C57BL ,Fatty acid synthase ,Orlistat ,Vascular endothelial growth factor A ,Endocrinology ,Oncology ,Carcinoma, Squamous Cell ,biology.protein ,Cancer research ,Mouth Neoplasms ,Fatty Acid Synthases ,Translational Therapeutics ,medicine.drug - Abstract
Background: Fatty acid synthase (FASN) is overexpressed and associated with poor prognosis in several human cancers. Here, we investigate the effect of FASN inhibitors on the metastatic spread and angiogenesis in experimental melanomas and cultured melanoma cells. Methods: The lung colonisation assay and cutaneous melanomas were performed by the inoculation of mouse melanoma B16-F10 cells in C57BL6 mice. Blood vessel endothelial cells (RAEC and HUVEC) were applied to determine cell proliferation, apoptosis, and the formation of capillary-like structures. Vascular endothelial growth factor A (VEGFA) expression was evaluated by quantitative RT–PCR and ELISA in B16-F10, human melanoma (SK-MEL-25), and human oral squamous carcinoma (SCC-9) cells. Conditioned media from these cancer cell lines were used to study the effects of FASN inhibitors on endothelial cells. Results: B16-F10 melanoma-induced metastases and angiogenesis were significantly reduced in orlistat-treated mice. Fatty acid synthase inhibitors reduced the viability, proliferation, and the formation of capillary-like structures by RAEC cells, as well as the tumour cell-mediated formation of HUVEC capillary-like structures. Cerulenin and orlistat stimulated the production of total VEGFA in B16-F10, SK-MEL-25, and SCC-9 cells. Both drugs also enhanced VEGFA121, 165, 189, and 165b in SK-MEL-25 and SCC-9 cells. Conclusion: FASN inhibitors reduce metastasis and tumour-induced angiogenesis in experimental melanomas, and differentially modulate VEGFA expression in B16-F10 cells.
- Published
- 2012
4. Mutual paracrine effects of oral squamous cell carcinoma cells and normal oral fibroblasts: Induction of fibroblast to myofibroblast transdifferentiation and modulation of tumor cell proliferation
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Ricardo D. Coletta, L.P. Kowalski, Karina G. Zecchin, Sabrina Daniela da Silva, Michele Gassen Kellermann, Edgard Graner, Lays M. Sobral, and Márcio Ajudarte Lopes
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Adult ,Male ,Cancer Research ,Pathology ,medicine.medical_specialty ,Cell ,macromolecular substances ,Biology ,Paracrine signalling ,Stroma ,Transforming Growth Factor beta ,Paracrine Communication ,Tumor Cells, Cultured ,medicine ,Humans ,Aged ,Cell Proliferation ,Aged, 80 and over ,Cell growth ,Gene Expression Profiling ,Transdifferentiation ,Fibroblasts ,Middle Aged ,Immunohistochemistry ,stomatognathic diseases ,Cell Transformation, Neoplastic ,Phenotype ,medicine.anatomical_structure ,Oncology ,Cell Transdifferentiation ,Carcinoma, Squamous Cell ,Female ,Mouth Neoplasms ,Stromal Cells ,Oral Surgery ,Myofibroblast ,Transforming growth factor - Abstract
Several lines of evidence demonstrated that the stroma surrounding the tumors plays an important role in the growth and progression of several neoplasms, including oral squamous cell carcinomas (OSCC). We evaluated the presence of myofibroblasts in OSCC and determined whether their presence is associated with clinicopathological features of the tumors. We also investigated the mutual paracrine effects of tumor cells and myofibroblasts on fibroblast-myofibroblast transdifferentiation and tumor cell proliferation. Immunohistochemical analysis showed the approximately 60% of the OSCCs contained myofibroblasts in the stroma of the tumor. Abundant presence of myofibroblasts significantly correlated with N stage, disease stage, regional recurrence, and proliferative potential of the tumor cells. Using OSCC cell lines and primary oral normal fibroblasts (ONF), we demonstrated that tumor cells induced transdifferentiation of ONFs to myofibroblasts via secretion of transforming growth factor-beta 1 (TGF-beta 1). In turn, myofibroblasts secreted factors that stimulated OSCC cell proliferation, as revealed by measuring BrdU incorporation and Ki67 expression. The results of the study suggest that during tumor invasion OSCC-derived TGF-beta 1 promote fibroblast-myofibroblast transdifferentiation, and that tumor cellular proliferation can be induced by factors released from myofibroblasts, which may favor tumor growth.
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- 2008
5. Ovariectomy Reduces the Gelatinolytic Activity and Expression of Matrix Metalloproteinases and Collagen in Rat Molar Extraction Wounds
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R. D. Coletta, Karina G. Zecchin, Michele Conceição Pereira, Jacks Jorge, and Edgard Graner
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Molar ,medicine.medical_specialty ,Pathology ,medicine.drug_class ,Ovariectomy ,Endocrinology, Diabetes and Metabolism ,Blotting, Western ,Matrix metalloproteinase ,Collagen Type I ,Extracellular matrix ,Endocrinology ,Internal medicine ,medicine ,Animals ,Orthopedics and Sports Medicine ,RNA, Messenger ,Rats, Wistar ,DNA Primers ,Wound Healing ,Reverse Transcriptase Polymerase Chain Reaction ,Chemistry ,Granulation tissue ,Rats ,Blot ,Reverse transcription polymerase chain reaction ,Collagen Type III ,medicine.anatomical_structure ,Matrix Metalloproteinase 9 ,Estrogen ,Tooth Extraction ,Matrix Metalloproteinase 2 ,Female ,Wound healing - Abstract
Osteoporosis is commonly associated with estrogen deficiency. However, the mechanisms by which the lack of this hormone causes bone loss are poorly understood. The bone structure of the oral cavity seems to be affected by estrogen deficiency, since a delayed healing process after tooth extraction has been observed after ovariectomy in rats. The aim of this study was to describe the effect of the absence of estrogen on the expression and activity of matrix metalloproteinases (MMC)-2 and -9 and expression of types I and III collagens in the alveolar granulation tissue of young female rats after tooth extraction. Sixty-six, four-week-old female rats underwent bilateral ovariectomies (OVX) or sham operations. Three weeks later, both first and second mandibular molars were extracted and the animals were killed by cervical dislocation 3, 5, or 7 days after tooth extraction. The granulation tissues were collected from the extracted alveolar sockets and used for zymographic, Western blot, or reverse transcription polymerase chain reaction (RT-PCR) analysis. There was a gradual increase on the expression of all studied proteins as well as MMP-2 and -9 activities in the periods after surgery. In contrast, OVX animals showed a significant decrease in the gelatinolytic activities and expression of MMP-2 and -9 and types I and III collagens. The results presented here in suggest that the absence of estrogen may possibly contribute to the delayed alveolar wound healing by interfering with the extracellular matrix turnover.
- Published
- 2004
6. Smad7 blocks transforming growth factor-β1-induced gingival fibroblast-myofibroblast transition via inhibitory regulation of Smad2 and connective tissue growth factor
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Edgard Graner, Lays M. Sobral, Ricardo D. Coletta, Pablo Agustin Vargas, Patrick Franz Montan, Hercílio Martelli-Júnior, and Karina G. Zecchin
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Pathology ,medicine.medical_specialty ,medicine.medical_treatment ,Gingiva ,Connective tissue ,macromolecular substances ,SMAD ,Smad2 Protein ,Smad7 Protein ,Transforming Growth Factor beta1 ,Fibrosis ,medicine ,Humans ,Myofibroblasts ,integumentary system ,Chemistry ,Growth factor ,Connective Tissue Growth Factor ,Fibroblasts ,medicine.disease ,Hereditary gingival fibromatosis ,Cell biology ,CTGF ,medicine.anatomical_structure ,Gene Expression Regulation ,Cell Transdifferentiation ,Periodontics ,Myofibroblast ,Transforming growth factor ,Signal Transduction - Abstract
Transforming growth factor-β1 (TGF-β1), its downstream signaling mediators (Smad proteins), and specific targets, including connective tissue growth factor (CTGF), play important roles in tissue remodeling and fibrosis via myofibroblast activation. We investigated the effect of overexpression of Smad7, a TGF-β1 signaling inhibitor, on transition of gingival fibroblast to myofibroblast. Moreover, we analyzed the participation of CTGF on TGF-β1-mediated myofibroblast transformation.To study the inhibitory effect of Smad7 on TGF-β1/CTGF-mediating gingival fibroblast transition into myofibroblasts, we stably overexpressed Smad7 in normal gingival fibroblasts and in myofibroblasts from hereditary gingival fibromatosis (HGF). Myofibroblasts were characterized by the expression of the specific marker isoform α of the smooth muscle actin (α-SMA) by Western blot, flow cytometry, and immunofluorescence. Enzyme-linked immunosorbent assay for type I collagen was performed to measure myofibroblast activity. CTGF's role on myofibroblast transformation was examined by enzyme-linked immunosorbent assay and small interference RNA.TGF-β1 induced the expression of α-SMA and CTGF, and small interference RNA-mediating CTGF silencing prevented fibroblast-myofibroblast switch induced by TGF-β1. In Smad7-overexpressing fibroblasts, ablation of TGF-β1-induced Smad2 phosphorylation marked decreased α-SMA, CTGF, and type I collagen expression. Similarly, HGF transfectants overexpressing Smad7 demonstrated low levels of α-SMA and phospho-Smad2 and significant reduction on CTGF and type I collagen production.CTGF is critical for TGF-β1-induced gingival fibroblast-myofibroblast transition, and Smad7 overexpression is effective in the blockage of myofibroblast transformation and activation, suggesting that treatments targeting myofibroblasts by Smad7 overexpression may be clinically effective in gingival fibrotic diseases, such as HGF.
- Published
- 2010
7. Mitochondrial ATP-sensitive K(+) channels as redox signals to liver mitochondria in response to hypertriglyceridemia
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Camila Campos Mantello, Bruno A. Paim, Karina G. Zecchin, Helena C. F. Oliveira, Alicia J. Kowaltowski, Amanda C. Augusto, Anibal E. Vercesi, Sonia A. Gurgueira, and Luciane C. Alberici
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Male ,medicine.medical_specialty ,Potassium Channels ,Mice, Transgenic ,Mitochondria, Liver ,Oxidative phosphorylation ,Mitochondrion ,Biochemistry ,chemistry.chemical_compound ,Mice ,Physiology (medical) ,Internal medicine ,medicine ,Animals ,Xanthine oxidase ,chemistry.chemical_classification ,Hypertriglyceridemia ,Reactive oxygen species ,NADPH oxidase ,biology ,Glutathione ,Disease Models, Animal ,Enzyme ,Endocrinology ,chemistry ,Mitochondrial matrix ,biology.protein ,Female ,Reactive Oxygen Species ,Oxidation-Reduction - Abstract
We have recently demonstrated that hypertriglyceridemic (HTG) mice present both elevated body metabolic rates and mild mitochondrial uncoupling in the liver owing to stimulated activity of the ATP-sensitive potassium channel (mitoK ATP ). Because lipid excess normally leads to cell redox imbalance, we examined the hepatic oxidative status in this model. Cell redox imbalance was evidenced by increased total levels of carbonylated proteins, malondialdehydes, and GSSG/GSH ratios in HTG livers compared to wild type. In addition, the activities of the extramitochondrial enzymes NADPH oxidase and xanthine oxidase were elevated in HTG livers. In contrast, Mn-superoxide dismutase activity and content, a mitochondrial matrix marker, were significantly decreased in HTG livers. Isolated HTG liver mitochondria presented lower rates of H 2 O 2 production, which were reversed by mitoK ATP antagonists. In vivo antioxidant treatment with N -acetylcysteine decreased both mitoK ATP activity and metabolic rates in HTG mice. These data indicate that high levels of triglycerides increase reactive oxygen generation by extramitochondrial enzymes that promote mitoK ATP activation. The mild uncoupling mediated by mitoK ATP increases metabolic rates and protects mitochondria against oxidative damage. Therefore, a biological role for mitoK ATP as a redox sensor is shown here for the first time in an in vivo model of systemic and cellular lipid excess.
- Published
- 2009
8. Myofibroblasts in the stroma of oral squamous cell carcinoma are associated with poor prognosis
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Lays M. Sobral, Inês Nobuko Nishimoto, Michele Gassen Kellermann, Luiz Paulo Kowalski, S. D. Da Silva, Márcio Ajudarte Lopes, Edgard Graner, Karina G. Zecchin, and Ricardo D. Coletta
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Oncology ,Adult ,Male ,medicine.medical_specialty ,Poor prognosis ,Pathology ,Histology ,Pathology and Forensic Medicine ,Stroma ,Tongue ,Internal medicine ,Carcinoma ,medicine ,Humans ,Basal cell ,Neoplasm Staging ,business.industry ,General Medicine ,Fibroblasts ,medicine.disease ,Prognosis ,Immunohistochemistry ,Actins ,Tongue Neoplasms ,Carcinoma, Squamous Cell ,Neoplasm staging ,Female ,Stromal Cells ,business ,Myofibroblast ,Precancerous Conditions - Published
- 2007
9. Differential expression of fatty acid synthase (FAS) and ErbB2 in nonmalignant and malignant oral keratinocytes
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Michelle Agostini, Ricardo D. Coletta, Luiz Paulo Kowalski, Sabrina Daniela da Silva, Isabela Werneck da Cunha, Karina G. Zecchin, Ana Lúcia Carrinho Ayrosa Rangel, Jacks Jorge, and Edgard Graner
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Keratinocytes ,Male ,Pathology ,medicine.medical_specialty ,Receptor, ErbB-2 ,Cell ,Epithelium ,Pathology and Forensic Medicine ,Cell Line, Tumor ,Keratin ,Carcinoma ,medicine ,Humans ,skin and connective tissue diseases ,neoplasms ,Molecular Biology ,Cells, Cultured ,Cell Proliferation ,chemistry.chemical_classification ,Mouth ,Tissue microarray ,biology ,Cell growth ,Cell Biology ,General Medicine ,medicine.disease ,Gene Expression Regulation, Neoplastic ,stomatognathic diseases ,medicine.anatomical_structure ,chemistry ,Gene Expression Regulation ,Cell culture ,Head and Neck Neoplasms ,Ki-67 ,biology.protein ,Carcinoma, Squamous Cell ,Female ,Mouth Neoplasms ,Fatty Acid Synthases - Abstract
The aim of this study was to investigate fatty acid synthase (FAS) and ErbB2 expression in nonmalignant oral epithelium and oral or head and neck squamous cell carcinomas (OSCC/HNSCC). Morphologically normal, hyperkeratotic, and dysplastic oral epithelium as well as well-differentiated and poorly differentiated OSCC were immunohistochemically evaluated for FAS, ErbB2, and Ki-67. These proteins were also analyzed in a tissue microarray with 55 HNSCC. SCC-9 cells were used to study FAS and ErbB2 during differentiation. FAS expression was higher in hyperkeratosis, dysplasias, and OSCC than in normal epithelium. Well-differentiated OSCC/HNSCC were more positive for FAS than the poorly differentiated tumors. ErbB2 was observed at the surface of nonmalignant and well-differentiated OSCC/HNSCC keratinocytes and in the cytoplasm of poorly differentiated cells. Ki-67 index was progressively higher from normal oral epithelium to OSCC, inversely correlated with cell surface ErbB2, and positively correlated with intracytoplasmic ErbB2. Finally, SCC-9 cell cultures were enriched in membrane ErbB2-positive cells after differentiation by anchorage deprivation. In conclusion, FAS is overexpressed in OSCC/HNSCC and hyperkeratotic oral epithelium and ErbB2 is found at the cell surface of differentiating keratinocytes and in the cytoplasm of poorly differentiated tumor cells. Ki-67 index is higher in epithelial dysplasias and OSCC than in morphologically normal oral epithelium.
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- 2007
10. A central role for neuronal adenosine 5'-monophosphate-activated protein kinase in cancer-induced anorexia
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Joseane Morari, José Rodrigo Pauli, Licio A. Velloso, Karina G. Zecchin, Mario J.A. Saad, Mirian Ueno, José B.C. Carvalheira, Eduardo R. Ropelle, Cláudio T. De Souza, and Marcel C. Faria
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Adenosine monophosphate ,Male ,medicine.medical_specialty ,AICA ribonucleotide ,Hypothalamus ,Anorexia ,Biology ,AMP-Activated Protein Kinases ,Deoxyglucose ,Protein Serine-Threonine Kinases ,Energy homeostasis ,chemistry.chemical_compound ,Endocrinology ,Multienzyme Complexes ,Internal medicine ,Neoplasms ,medicine ,Tumor Cells, Cultured ,Animals ,Phosphorylation ,Rats, Wistar ,Protein kinase A ,Neurons ,Drug Administration Routes ,digestive, oral, and skin physiology ,AMPK ,Ribonucleotides ,Aminoimidazole Carboxamide ,Adenosine ,Survival Analysis ,Metformin ,Rats ,chemistry ,medicine.symptom ,Neoplasm Transplantation ,medicine.drug - Abstract
The pathogenesis of cancer anorexia is multifactorial and associated with disturbances of the central physiological mechanisms controlling food intake. However, the neurochemical mechanisms responsible for cancer-induced anorexia are unclear. Here we show that chronic infusion of 5-amino-4imidazolecarboxamide-riboside into the third cerebral ventricle and a chronic peripheral injection of 2 deoxy-d-glucose promotes hypothalamic AMP-activated protein kinase (AMPK) activation, increases food intake, and prolongs the survival of anorexic tumor-bearing (TB) rats. In parallel, the pharmacological activation of hypothalamic AMPK in TB animals markedly reduced the hypothalamic production of inducible nitric oxide synthase, IL-1β, and TNF-α and modulated the expression of proopiomelanocortin, a hypothalamic neuropeptide that is involved in the control of energy homeostasis. Furthermore, the daily oral and intracerebroventricular treatment with biguanide antidiabetic drug metformin also induced AMPK phosphorylation in the central nervous system and increased food intake and life span in anorexic TB rats. Collectively, the findings of this study suggest that hypothalamic AMPK activation reverses cancer anorexia by inhibiting the production of proinflammatory molecules and controlling the neuropeptide expression in the hypothalamus, reflecting in a prolonged life span in TB rats. Thus, our data indicate that hypothalamic AMPK activation presents an attractive opportunity for the treatment of cancer-induced anorexia.
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- 2007
11. Defective insulin and acetylcholine induction of endothelial cell-nitric oxide synthase through insulin receptor substrate/Akt signaling pathway in aorta of obese rats
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Licio A. Velloso, Henrique Gottardello Zecchin, José B.C. Carvalheira, Mario J.A. Saad, Patrícia O. Prada, Fernanda B.M. Priviero, Edson Antunes, Cláudio T. De Souza, and Karina G. Zecchin
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MAPK/ERK pathway ,Male ,medicine.medical_specialty ,Nitric Oxide Synthase Type III ,Endocrinology, Diabetes and Metabolism ,Rats, Mutant Strains ,chemistry.chemical_compound ,Internal medicine ,Insulin receptor substrate ,Internal Medicine ,medicine ,Animals ,Insulin ,Obesity ,Rats, Wistar ,Protein kinase A ,Protein kinase B ,Janus kinase 2 ,biology ,Akt/PKB signaling pathway ,Tyrosine phosphorylation ,Janus Kinase 2 ,Dietary Fats ,Acetylcholine ,Receptor, Insulin ,Rats ,Endocrinology ,chemistry ,Enzyme Induction ,biology.protein ,Endothelium, Vascular ,Signal transduction ,Energy Intake ,Proto-Oncogene Proteins c-akt ,Signal Transduction - Abstract
The actions of acetylcholine (ACh) on endothelium mainly are mediated through muscarinic receptors, which are members of the G protein–coupled receptor family. In the present study, we show that ACh induces rapid tyrosine phosphorylation and activation of Janus kinase 2 (JAK2) in rat aorta. Upon JAK2 activation, tyrosine phosphorylation of insulin receptor substrate (IRS)-1 is detected. In addition, ACh induces JAK2/IRS-1 and IRS-1/phosphatidylinositol (PI) 3-kinase associations, downstream activation of Akt/protein kinase B, endothelial cell–nitric oxide synthase (eNOS), and extracellular signal–regulated kinase (ERK)-1/2. The pharmacological blockade of JAK2 or PI 3-kinase reduced ACh-stimulated eNOS phosphorylation, NOS activity, and aorta relaxation. These data indicate a new signal transduction pathway for IRS-1/PI 3-kinase/Akt/eNOS activation and ERK1/2 by means of JAK2 tyrosine phosphorylation stimulated by ACh in vessels. Moreover, we demonstrate that in aorta of obese rats (high-fat diet), there is an impairment in the insulin- and ACh-stimulated IRS-1/PI 3-kinase pathway, leading to reduced activation with lower protein levels of eNOS associated with a hyperactivated ERK/mitogen-activated protein kinase pathway. These results suggest that in aorta of obese rats, there not only is insulin resistance but also ACh resistance, probably mediated by a common signaling pathway that controls the activity and the protein levels of eNOS.
- Published
- 2007
12. Oral Malignant Melanoma: A Case Report and Literature Review
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Pablo Agustin Vargas, Camilla Borges Ferreira Gomes, Alan Roger dos Santos Silva, Oslei Paes de Almeida, Karina G. Zecchin, and Márcio Ajudarte Lopes
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medicine.medical_specialty ,business.industry ,Melanoma ,medicine ,Radiology, Nuclear Medicine and imaging ,Dentistry (miscellaneous) ,Surgery ,Oral Surgery ,medicine.disease ,business ,Dermatology ,Pathology and Forensic Medicine - Published
- 2015
13. Heterogeneous presence of myofibroblasts in hereditary gingival fibromatosis
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Lays M. Sobral, Ricardo D. Coletta, Michele Gassen Kellermann, Hercílio Martelli-Júnior, Karina G. Zecchin, Carolina Cavalcante Bitu, and Edgard Graner
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Pathology ,medicine.medical_specialty ,medicine.medical_treatment ,Blotting, Western ,Gingiva ,Connective tissue ,Biology ,Immediate-Early Proteins ,Transforming Growth Factor beta1 ,Transforming Growth Factor beta ,medicine ,Humans ,Fibroblast ,Fibromatosis, Gingival ,Analysis of Variance ,Reverse Transcriptase Polymerase Chain Reaction ,Growth factor ,Transdifferentiation ,Connective Tissue Growth Factor ,Fibroblasts ,medicine.disease ,Hereditary gingival fibromatosis ,Actins ,CTGF ,medicine.anatomical_structure ,Periodontics ,Intercellular Signaling Peptides and Proteins ,Myofibroblast ,Type I collagen - Abstract
Background/Aim: Hereditary gingival fibromatosis (HGF) fibroblasts are characterized by an increased production of collagen and transforming growth factor-β1 (TGF-β1), resulting in a fibrotic enlargement of the gingiva of affected patients. A common feature of interstitial fibrosis is the occurrence of myofibroblasts, which are regarded as the predominant cells in matrix synthesis. The goal of this article is to describe the presence of myofibroblasts in HGF in order to elucidate the mechanisms underlying HGF gingival overgrowth. Materials and Methods: Fibroblast cell lines and gingival samples from patients of two distinct families affected by HGF and from normal gingiva (NG) were included in this study. To characterize the presence of myofibroblasts, the expression of specific myofibroblast marker smooth muscle isoform of α-actin (α-SMA) was examined by semi-quantitative reverse transcriptase-polymerase chain reaction (RT-PCR), Western blot, immunofluorescence, and flow cytometric analysis. Immunohistochemistry against the α-SMA antigen was performed in the gingival tissue samples. Results: Our results demonstrated a significant increase in the expression of the myofibroblast marker α-SMA in cells from one HGF family (designed as HGF Family 2), which are also characterized by an elevated expression of type I collagen, TGF-β1 and connective tissue growth factor (CTGF). Additionally, α-SMA-positive cells were broadly detected in the gingival tissue samples from HGF Family 2 patients. In contrast, α-SMA expression by HGF Family 1 cells was quite similar to NG cells and no myofibroblasts were detected immunohistochemically, despite the higher levels of TGF-β1 and type I collagen in HGF Family 1 fibroblasts than in NG cells. The expression of CTGF, which has been considered a key molecule to promote the transdifferentiation of myofibroblasts via TGF-β1 activation, by HGF Family 1 cultures was significantly lower compared with HGF Family 2 and similar to NG control cells. Conclusions: Our results suggest that the presence of myofibroblasts in HGF could be dependent on CTFG expression levels, and different biological mechanisms may account for the gingival overgrowth observed in HGF patients. This could be an underlying reason for the high variable clinical expressivity of disease.
- Published
- 2006
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