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Protein & Cell ; (12): 788-809, 2021.
Article in English | WPRIM | ID: wpr-922475


Hepatocellular carcinoma (HCC) is the most common primary liver malignancy and is the fourth-leading cause of cancer-related deaths worldwide. HCC is refractory to many standard cancer treatments and the prognosis is often poor, highlighting a pressing need to identify biomarkers of aggressiveness and potential targets for future treatments. Kinesin family member 2C (KIF2C) is reported to be highly expressed in several human tumors. Nevertheless, the molecular mechanisms underlying the role of KIF2C in tumor development and progression have not been investigated. In this study, we found that KIF2C expression was significantly upregulated in HCC, and that KIF2C up-regulation was associated with a poor prognosis. Utilizing both gain and loss of function assays, we showed that KIF2C promoted HCC cell proliferation, migration, invasion, and metastasis both in vitro and in vivo. Mechanistically, we identified TBC1D7 as a binding partner of KIF2C, and this interaction disrupts the formation of the TSC complex, resulting in the enhancement of mammalian target of rapamycin complex1 (mTORC1) signal transduction. Additionally, we found that KIF2C is a direct target of the Wnt/β-catenin pathway, and acts as a key factor in mediating the crosstalk between Wnt/β-catenin and mTORC1 signaling. Thus, the results of our study establish a link between Wnt/β-catenin and mTORC1 signaling, which highlights the potential of KIF2C as a therapeutic target for the treatment of HCC.

Adult , Aged , Animals , Carcinoma, Hepatocellular/pathology , Cell Line, Tumor , Cell Movement , Cell Proliferation , Epithelial-Mesenchymal Transition/genetics , Female , Gene Expression Regulation, Neoplastic , Humans , Intracellular Signaling Peptides and Proteins/metabolism , /metabolism , Liver Neoplasms/pathology , Male , Mice , Mice, Inbred BALB C , Middle Aged , Neoplasm Staging , Prognosis , Protein Binding , RNA, Small Interfering/metabolism , Survival Analysis , Tumor Burden , Wnt Signaling Pathway , Xenograft Model Antitumor Assays , beta Catenin/metabolism
Braz. j. med. biol. res ; 52(6): e8399, 2019. graf
Article in English | LILACS | ID: biblio-1011582


Imatinib is the first line of therapy for patients with metastatic or gastrointestinal stromal tumors (GIST). However, drug resistance limits the long-term effect of imatinib. Long non-coding RNAs (lncRNAs) are emerging as key players in regulating drug resistance in cancer. In this study, we investigated the association between lncRNA CCDC26 and IGF-1R in GIST and their involvement in drug resistance. Considering the key role of lncRNAs in drug resistance in cancer, we hypothesized that IGF-1R is regulated by lncRNAs. The expression of a series of reported drug resistance-related lncRNAs, including CCDC26, ARF, H19, NBR2, NEAT1, and HOTAIR, in GIST cells treated with imatinib H19 was examined at various time-points by qRT-PCR. Based on our results and published literature, CCDC26, a strongly down-regulated lncRNA following imatinib treatment, was chosen as our research target. GIST cells with high expression of CCDC26 were sensitive to imatinib treatment while knockdown of CCDC26 significantly increased the resistance to imatinib. Furthermore, we found that CCDC26 interacted with c-KIT by RNA pull down, and that CCDC26 knockdown up-regulated the expression of IGF-1R. Moreover, IGF-1R inhibition reversed CCDC26 knockdown-mediated imatinib resistance in GIST. These results indicated that treatments targeting CCDC26-IGF-1R axis would be useful in increasing sensitivity to imatinib in GIST.

Humans , Receptors, Somatomedin/genetics , Drug Resistance, Neoplasm , Intracellular Signaling Peptides and Proteins/genetics , RNA, Long Noncoding/genetics , Imatinib Mesylate/pharmacology , Antineoplastic Agents/pharmacology , Signal Transduction , Down-Regulation/genetics , Gene Expression Regulation, Neoplastic , Receptors, Somatomedin/metabolism , Receptor, IGF Type 1 , Apoptosis , Cell Line, Tumor , Intracellular Signaling Peptides and Proteins/metabolism , RNA, Long Noncoding/metabolism , Flow Cytometry
Acta cir. bras ; 33(2): 117-124, Feb. 2018. tab, graf
Article in English | LILACS | ID: biblio-886260


Abstract Purpose: To observe the efficacy of phosphocreatine pre-administration (PCr-PA) on X-linked inhibitor of apoptosis protein (XIAP), the second mitochondia-derived activator of caspase (Smac) and apoptosis in the ischemic penumbra of rats with focal cerebral ischemia-reperfusion injury (CIRI). Methods: A total of 60 healthy male Sprague Dawley (SD) rats were randomly divided into three groups (n=20): group A (the sham operation group), group B <intraperitoneally injected with 20 mg/kg (10 mg/ml) of saline before preparing the ischemia-reperfusion (IR) model>, and group C <intraperitoneally injected with 20 mg/kg (10 mg/ml) of PCr immediately before preparing the IR model>. After 24 h for reperfusion, the neurological function was evaluated and the tissue was sampled to detect expression of XIAP, Smac and caspase-3 positive cells in the ischemic penumbra so as to observe the apoptosis. Results: Compared with group B, neurological deficit scores, numbers of apoptotic cells, expression of Smac,caspase-9 and the numbers of Caspase-3 positive cells were decreased while expression of XIAP were increased in the ischemic penumbra of group C. Conclusions: Phosphocreatine pre-administration may elicit neuroprotective effects in the brain by increasing expression of X-linked inhibitor of apoptosis protein, reducing expression of second mitochondia-derived activator of caspase, and inhibiting the apoptosis in the ischemic penumbra.

Humans , Animals , Male , Rats , Phosphocreatine/pharmacology , Cardiotonic Agents/pharmacology , Reperfusion Injury/metabolism , Brain Ischemia/metabolism , Mitochondrial Proteins/metabolism , Intracellular Signaling Peptides and Proteins/metabolism , X-Linked Inhibitor of Apoptosis Protein/metabolism , Random Allocation , Brain Ischemia/prevention & control , Rats, Sprague-Dawley , Apoptosis/drug effects , Neuroprotective Agents/pharmacology , Disease Models, Animal , Drug Evaluation, Preclinical , Apoptosis Regulatory Proteins , Caspase 3/metabolism
Rev. Assoc. Med. Bras. (1992) ; 62(1): 72-77, Jan.-Feb. 2016. graf
Article in English | LILACS | ID: lil-777437


SUMMARY Even though the physiological role of estrogen in the female reproductive cycle and endometrial proliferative phase is well established, the signaling pathways by which estrogen exerts its action in the endometrial tissue are still little known. In this regard, advancements in cell culture techniques and maintenance of endometrial cells in cultures enabled the discovery of new signaling mechanisms activated by estrogen in the normal endometrium and in endometriosis. This review aims to present the recent findings in the genomic and non-genomic estrogen signaling pathways in the proliferative human endometrium specifically associated with the pathogenesis and development of endometriosis.

RESUMO Embora esteja bem estabelecido o papel fisiológico do estrogênio no ciclo reprodutivo feminino e na fase proliferativa do endométrio, as vias de sinalização por meio das quais a ação do estrogênio é exercida no tecido endometrial são ainda pouco conhecidas. Nesse sentido, o avanço nas técnicas de cultura celular e a manutenção de células endometriais em cultivo possibilitaram a descoberta de novos mecanismos sinalizadores ativados pelo estrogênio no endométrio normal e na endometriose. Esta revisão tem o objetivo de apresentar as descobertas recentes envolvendo as vias de sinalização genômica e não genômica do estrogênio no endométrio proliferativo humano, especificamente associadas à patogênese e ao desenvolvimento da endometriose.

Humans , Female , Receptors, Estrogen/metabolism , Endometriosis/physiopathology , Endometriosis/metabolism , Endometrium/physiopathology , Endometrium/metabolism , Estrogens/metabolism , Signal Transduction , Receptors, Estrogen/genetics , Intracellular Signaling Peptides and Proteins/metabolism , Endometriosis/genetics , Estrogens/genetics
Rev. bras. enferm ; 68(2): 320-324, Mar-Apr/2015. tab
Article in Portuguese | LILACS, BDENF | ID: lil-752520


RESUMO Objetivo: investigar a presença de micro-organismos nas narinas dos profissionais de enfermagem de um hospital de ensino brasileiro. Método: estudo transversal, em duas unidades de internação especializadas em HIV/aids. Foram coletadas amostras de secreção nasal de profissionais de enfermagem no período de um mês. As amostras foram processadas no laboratório de microbiologia da instituição e a análise dos dados resultantes por meio do software Statistical Package for the Social Sciences (SPSS) versão 19.0. Os aspectos éticos foram contemplados. Resultados: dos 73 profissionais de enfermagem do serviço, foram coletadas amostras de secreção nasal de 61 (80,2%). Foram isolados seis tipos de micro-organismos em 22 (41,0%) culturas positivas. Destaca-se que o Staphylococcus aureus representou 22,9%, sendo quatro resistentes à oxacilina (MRSA). Conclusão: o Staphylococcus aureus foi o micro-organismo de maior prevalência nos indivíduos deste estudo. .

RESUMEN Objetivo: investigar la presencia de microorganismos en las fosas nasales del personal de enfermería de un hospital universitario brasileño. Método: estudio transversal en dos unidades de hospitalización especializados en VIH/SIDA. Muestras de secreción nasal de enfermeras fueron recolectados durante un mes. Las muestras fueron procesadas en el laboratorio de microbiología de la institución y se analizaron con el paquete estadístico para el software de Ciencias Sociales (SPSS) versión 19.0. Los aspectos éticos fueron cubiertos. Resultados: 73 de los profesionales de enfermería, se recogieron muestras de las secreciones nasales de 61 (80,2%). Se aislaron seis tipos de microorganismos en 22 (41,0%) cultivos positivos. Es de destacar que el Staphylococcus aureus representó el 22,9%, cuatro oxacilina-resistente (MRSA). Conclusión: Staphylococcus aureus fue la prevalencia más microorganismo en los individuos de este estudio. .

ABSTRACT Objective: to investigate the presence of microorganisms in the nostrils of the nursing professionals of a Brazilian teaching hospital. Method: cross-sectional study in two inpatient units specialized in HIV/AIDS. Nasal secretion samples of nursing professionals were collected in one month. The samples were processed at the microbiology laboratory of the institution and analyzed using the Statistical Package for the Social Sciences (SPSS) software, version 19.0. Ethical aspects were abided. Results: from the 73 members of the nursing staff, samples of nasal secretions were collected from 61 (80.2%). Six types of microorganisms were isolated in 22 (41.0%) positive cultures. It is noteworthy that Staphylococcus aureus accounted for 22.9%, four of them oxacillin-resistant (MRSA). Conclusion: Staphylococcus aureus microorganism accounted for the largest prevalence in individuals of this study. .

Humans , Animals , Mice , Biomarkers/metabolism , Gonorrhea/immunology , Inflammation Mediators/metabolism , Inflammation/etiology , Neisseria gonorrhoeae/pathogenicity , Neutrophils/immunology , Bacterial Adhesion , Carcinoembryonic Antigen/genetics , Carcinoembryonic Antigen/metabolism , Cytokines/metabolism , Enzyme-Linked Immunosorbent Assay , Gene Expression Profiling , Gonorrhea/metabolism , Gonorrhea/microbiology , Inflammation/metabolism , Inflammation/pathology , Intracellular Signaling Peptides and Proteins/metabolism , Mice, Transgenic , Neisseria gonorrhoeae/immunology , Neutrophils/microbiology , Oligonucleotide Array Sequence Analysis , Oxidative Stress , Phagocytosis/physiology , Protein-Tyrosine Kinases/metabolism , Signal Transduction
Article in English | WPRIM | ID: wpr-157207


The development of hepatocellular carcinoma (HCC) is a complex process, and HCC arises from the accumulation of multiple genetic alterations leading to changes in the genomic landscape. Current advances in genomic technologies have revolutionized the search for genetic alterations in cancer genomes. Recent studies in which all coding exons in HCC were sequenced have shed new light on the genomic landscape of this malignant disease. Catalogues of these somatic mutations and systematic analysis of catalogued mutations will lead us to uncover candidate HCC driver genes, although further functional validation is needed to determine whether these genes play a causal role in the development of HCC. This review provides an overview of previously known oncogenes and new oncogene candidates in HCC that were uncovered from recent exome or whole-genome sequencing studies. This knowledge provides direction for future personalized treatment approaches for patients with HCC.

Carcinoma, Hepatocellular/pathology , Humans , Intracellular Signaling Peptides and Proteins/metabolism , Liver Neoplasms/pathology , Mutation , Oxidative Stress , Precision Medicine , Telomerase/metabolism , Transcription Factors/genetics , Tumor Suppressor Protein p53/genetics
Braz. j. med. biol. res ; 47(4): 273-278, 8/4/2014. graf
Article in English | LILACS | ID: lil-705769


Overexpression of cytokine-induced apoptosis inhibitor 1 (CIAPIN1) contributes to multidrug resistance (MDR) in breast cancer. This study aimed to evaluate the potential of CIAPIN1 gene silencing by RNA interference (RNAi) as a treatment for drug-resistant breast cancer and to investigate the effect of CIAPIN1 on the drug resistance of breast cancer in vivo. We used lentivirus-vector-based RNAi to knock down CIAPIN1 in nude mice bearing MDR breast cancer tumors and found that lentivirus-vector-mediated silencing of CIAPIN1 could efficiently and significantly inhibit tumor growth when combined with chemotherapy in vivo. Furthermore, Western blot analysis showed that both CIAPIN1 and P-glycoprotein expression were efficiently downregulated, and P53 was upregulated, after RNAi. Therefore, we concluded that lentivirus-vector-mediated RNAi targeting of CIAPIN1 is a potential approach to reverse MDR of breast cancer. In addition, CIAPIN1 may participate in MDR of breast cancer by regulating P-glycoprotein and P53 expression.

Animals , Female , Humans , Antibiotics, Antineoplastic/therapeutic use , Breast Neoplasms/drug therapy , Doxorubicin/therapeutic use , Drug Resistance, Neoplasm/genetics , Gene Silencing , Intracellular Signaling Peptides and Proteins/genetics , Blotting, Western , Breast Neoplasms/genetics , Carcinoma/drug therapy , Carcinoma/genetics , Disease Models, Animal , Genes, MDR , Genetic Vectors/genetics , Growth Inhibitors/genetics , Intracellular Signaling Peptides and Proteins/metabolism , Lentivirus/genetics , Mice, Inbred BALB C , Mice, Nude , ATP Binding Cassette Transporter, Subfamily B, Member 1/drug effects , RNA Interference , RNA, Small Interfering/genetics , /drug effects
Medicina (B.Aires) ; 73(5): 401-5, oct. 2013.
Article in Spanish | LILACS, BINACIS | ID: biblio-1165168


Glucocorticoids play an important role in adipogenesis via the glucocorticoid receptor (GR) that forms a heterocomplex with Hsp90-Hsp70 and a high molecular weight immunophilin FKBP51 or FKBP52. We have found that FKBP51 level of expression progressively increases, FKBP52 decreases, whereas Hsp90, Hsp70, and p23 remain unchanged when 3T3-L1 preadipocytes differentiate. Interestingly, FKBP51 translocates from mitochondria to the nucleus at the onset of adipogenesis. FKBP51 transiently concentrates in the nuclear lamina, at a time that this nuclear compartment undergoes its reorganization. FKBP51 nuclear localization is transient, after 48 h it cycles back to mitochondria. We found that the dynamic FKBP51 mitochondrial-nuclear shuttling is regulated by glucocorticoids and mainly on cAMP-PKA signaling since PKA inhibition by myristoilated-PKI, abrogated FKBP51 nuclear translocation induced by 3-isobutyl-1-methylxanthine (IBMX). It has been reported that PKA interacts with GR in a ligand dependent manner potentiating its transcriptional capacity. GR transcriptional capacity is reduced when cells are incubated in the presence of IBMX, forskolin or dibutyryl-cAMP, compounds that induced nuclear translocation of FKBP51, therefore PKA may exert a dual role in the control of GR. In summary, the presence of FKBP51 in the nucleus may be critical for GR transcriptional control, and possibly for the control of other transcription factors that are not members of the nuclear receptor family but are regulated by PKA signaling pathway, when transcription has to be strictly controlled to succeed in the acquisition of the adipocyte phenotype.

Adipogenesis/physiology , Adipocytes/cytology , Mitochondria/metabolism , Cell Nucleus/metabolism , Intracellular Signaling Peptides and Proteins/metabolism , Tacrolimus Binding Proteins/metabolism , Receptors, Glucocorticoid/metabolism , /metabolism , Humans , Tacrolimus Binding Proteins/analysis
Arq. bras. endocrinol. metab ; 56(8): 501-506, Nov. 2012. ilus, tab
Article in English | LILACS | ID: lil-660257


We present here the clinical and molecular data of two patients with acromegaly treated with octreotide LAR after non-curative surgery, and who presented different responses to therapy. Somatostatin receptor type 2 and 5 (SSTR2 and SSTR5), and aryl hydrocarbon receptor-interacting protein (AIP) expression levels were analyzed by qPCR. In both cases, high SSTR2 and low SSTR5 expression levels were detected; however, only one of the patients achieved disease control after octreotide LAR therapy. When we analyzed AIP expression levels of both cases, the patient whose disease was controlled after therapy exhibited AIP expression levels that were two times higher than the patient whose disease was still active. These two cases illustrate that, although the currently available somatostatin analogs bind preferentially to SSTR2, some patients are not responsive to therapy despite high expression of this receptor. This difference could be explained by differences in post-receptor signaling pathways, including the recently described involvement of AIP. Arq Bras Endocrinol Metab. 2012;56(8):501-6.

Apresentamos os dados clínicos e moleculares de dois pacientes com acromegalia tratados com octreotide LAR após cirurgia não curativa, com diferentes respostas a essa terapia medicamentosa. As expressões do receptor de somatostatina tipo 2 e 5 (SSTR2 e SSTR5) e da proteína de interação com o receptor aril hidrocarbono (AIP) foram analisadas por qPCR. Em ambos os casos, foi encontrada uma expressão elevada de SSTR2 e baixa do SSTR5. No entanto, o controle da doença foi obtido após tratamento com octreotide LAR em apenas um dos pacientes. Quando analisamos a expressão do AIP em ambos os casos, o paciente cuja doença foi controlada após a terapia medicamentosa apresentou uma expressão duas vezes maior do que a do paciente não controlado com o tratamento. Conclui-se que esses dois casos ilustram que, embora os análogos de somatostatina atualmente disponíveis se liguem preferencialmente ao SSTR2, alguns pacientes não respondem ao tratamento, apesar de uma elevada expressão desse receptor. Isso poderia ser explicado por alterações nas vias de sinalização pós-receptor, incluindo o envolvimento recentemente descrito da AIP. Arq Bras Endocrinol Metab. 2012;56(8):501-6.

Adult , Female , Humans , Male , Middle Aged , Acromegaly/drug therapy , Antineoplastic Agents, Hormonal/therapeutic use , Drug Resistance, Neoplasm , Intracellular Signaling Peptides and Proteins/metabolism , Octreotide/therapeutic use , Pituitary Neoplasms/drug therapy , Acromegaly/metabolism , Pituitary Neoplasms/metabolism , Receptors, Somatostatin/metabolism
West Indian med. j ; 60(2): 107-113, Mar. 2011. ilus
Article in English | LILACS | ID: lil-672734


BACKGROUND AND AIMS: Interferon-α (IFN-α) treatment is associated with up-regulation of epidermal growth factor receptor (EGFR) expression and marked growth inhibition of colon cancer cell lines. We aimed to determine the effect of combining IFN-α and gefitinib in the growth of human colon cancer cell lines. METHODS: Two human colon cancer cell lines SW480 and LOVO were treated with IFN-α alone or gefitinib alone or IFN-α plus gefitinib. Proliferation of colon cancer cells was measured by methyl thiazolyl tetrazolium (MTT) assay; the apoptosis rate was analysed by flow cytometry (FCM). The expression of XIAP, XAF1 mRNA was detected by RT-PCR and the expression of XIAP, XAF1 protein was detected by western blotting. RESULTS: Methyl thiazolyl tetrazolium showed that IFN-α, gefitinib and IFN-α plus gefitinib significantly inhibited SW480 and LOVO cells in a dose-dependent manner (p < 0.05). The FCM revealed that IFN α, gefitinib and IFN-α plus gefitinib could markedly upgrade the apoptosis rate (p < 0.05). The expression of XIAP mRNA down-regulated markedly (p < 0.05) while the expression of XAF1 mRNA up-regulated significantly (p < 0.05). The expression of XIAP protein was down-regulated markedly (p < 0.05) while the expression of XAF1 protein was up-regulated significantly (p < 0.05). CONCLUSION: IFN-α promotes the antiproliferaative effect of gefitinib on human colon cancer cell lines and the mechanism may be related to up-regulation expression of EGFR by IFN-α.

ANTECEDENTES Y OBJETIVOS: El tratamiento con interferón α (IFN-α) se halla asociado con la regulación por incremento de la expresión del receptor del factor de crecimiento epidérmico y la acentuada inhibición del crecimiento de las líneas celulares del cáncer colorrectal. El presente trabajo tuvo por objetivo determinar el efecto que se produce al combinar el IFN-α y el gefitinib en el crecimiento de las líneas celulares del cáncer de colon. MÉTODOS: Dos líneas celulares de cáncer del colon en humanos - SW480 y LOVO - fueron tratadas con IFN-α solamente, gefitinib solamente, o IFN-α más gefitinib. La proliferación de las células cancerosas del colon se midió mediante ensayo de metil tiazolil tetrazolio (MTT); la tasa de apoptosis se analizó mediante citometría de flujo (CMF); la expresión de XIAP/XAF1 mRNA fue detectada mediante RT-PCR y la expresión de la proteína XIAP/XAF1 fue detectada mediante inmunoblot (western blot). RESULTADOS: El MTT mostró que el IFN-α, el gefitinib, y el IFN-α más gefitinib inhibían de forma significativa las células SW480 y LOVO en dependencia de la dosis (p < 0.05). La CMF reveló que el IFN-α, el gefitinib, y el IFN-α más gefitinib podían aumentar notablemente la tasa de apoptosis (p < 0.05). La expresión de XIAP mRNA tuvo una marcada regulación por decremento (p < 0.05) mientras que la expresión de XAF1 mRNA tuvo una significativa regulación por incremento (p < 0.05); la expresión de la proteína XIAP fue notablemente regulada por decremento (p < 0.05) mientras que la expresión de la proteína XAF1 fue regulada por incremento de manera significativa (p < 0.05). CONCLUSIÓN: El IFN-α promueve el efecto antiproliferativo del gefitinib sobre las líneas celulares del cáncer colorrectal, y el mecanismo puede hallarse relacionado con la expresión de la regulación por incremento del EGFR mediante el IFN-α.

Humans , Antineoplastic Agents/pharmacology , Colonic Neoplasms/pathology , Interferon-alpha/pharmacology , Quinazolines/pharmacology , ErbB Receptors/antagonists & inhibitors , Apoptosis/drug effects , Cell Line, Tumor/drug effects , Cell Proliferation/drug effects , Colonic Neoplasms/metabolism , Dose-Response Relationship, Drug , Intracellular Signaling Peptides and Proteins/metabolism , Neoplasm Proteins/metabolism , ErbB Receptors/metabolism
Clinics ; 65(8): 757-762, June 2010. ilus, graf, tab
Article in English | LILACS | ID: lil-557000


OBJECTIVES: The aim of this study was to examine the expression of the N-myc downstream-regulated gene 1 protein in benign and malignant lesions of the thyroid gland by immunohistochemistry. INTRODUCTION: N-myc downstream-regulated gene 1 encodes a protein whose expression is induced by various stimuli, including cell differentiation, exposure to heavy metals, hypoxia, and DNA damage. Increased N-myc downstream-regulated gene 1 expression has been detected in various types of tumors, but the role of N-myc downstream-regulated gene 1 expression in thyroid lesions remains to be determined. METHODS: A tissue microarray paraffin block containing 265 tissue fragments corresponding to normal thyroid, nodular goiter, follicular adenoma, papillary thyroid carcinoma (classical pattern and follicular variant), follicular carcinoma, and metastases of papillary and follicular thyroid carcinomas were analyzed by immunohistochemistry using a polyclonal anti- N-myc downstream-regulated gene 1 antibody. RESULTS: The immunohistochemical expression of N-myc downstream-regulated gene 1 was higher in carcinomas compared to normal thyroid glands and nodular goiters, with higher expression in classical papillary thyroid carcinomas and metastases of thyroid carcinomas (P < 0.001). A combined analysis showed higher immunohistochemical expression of NDRG1 in malignant lesions (classical pattern and follicular variant of papillary thyroid carcinomas, follicular carcinomas, and metastases of thyroid carcinomas) compared to benign thyroid lesions (goiter and follicular adenomas) (P = 0.043). In thyroid carcinomas, N-myc downstream-regulated gene 1 expression was significantly correlated with a more advanced TNM stage (P = 0.007) and age, metastasis, tumor extent, and size (AMES) high-risk group (P = 0.012). CONCLUSIONS: Thyroid carcinomas showed increased immunohistochemical N-myc downstream-regulated gene 1 expression compared to normal and benign thyroid lesions and is correlated with more advanced tumor stages.

Adolescent , Adult , Aged , Aged, 80 and over , Female , Humans , Male , Middle Aged , Young Adult , Adenoma/metabolism , Cell Cycle Proteins/metabolism , Intracellular Signaling Peptides and Proteins/metabolism , Neoplasm Proteins/metabolism , Thyroid Neoplasms/metabolism , Adenoma/pathology , Immunohistochemistry , Lymphatic Metastasis , Microarray Analysis , Neoplasm Proteins/genetics , Paraffin Embedding , Thyroid Neoplasms/pathology
Article in English | IMSEAR | ID: sea-135443


Narcolepsy is a neurologic illness that typically begins in the second and third decades of life. It is chronic in nature and negatively impacts the quality of life of affected patients. The classic presentation is a tetrad of excessive daytime sleepiness, cataplexy, sleep paralysis, and hypnagogic hallucinations. The exact cause remains unknown, but there is significant evidence that hypocretin deficiency plays an integral role. Some primary conditions that result in secondary narcolepsy include traumatic brain injury, congenital disorders, tumours, and strokes. Some medical and psychiatric disorders share characteristics of narcolepsy, at times leading to diagnostic inaccuracy. Other sleep disorders are commonly co-morbid. Diagnosis relies on patient history and objective data gathered from polysomnography and multiple sleep latency testing. Treatment focuses on symptom relief through medication, education, and behavioural modification. Both classic pharmacological treatments as well as newer options have significant problems, especially because of side effects and abuse potential. Novel modalities are being examined to expand options for treatment.

Cataplexy/therapy , Comorbidity , Diagnosis, Differential , Disorders of Excessive Somnolence/diagnosis , Humans , Intracellular Signaling Peptides and Proteins/metabolism , Narcolepsy/complications , Narcolepsy/diagnosis , Narcolepsy/epidemiology , Narcolepsy/therapy , Neuropeptides/metabolism , Polysomnography/methods , Sleep Wake Disorders/diagnosis , Sleep Wake Disorders/therapy , Treatment Outcome
Article in English | WPRIM | ID: wpr-27757


As glucose is known to induce insulin secretion in pancreatic beta cells, this study investigated the role of a phospholipase D (PLD)-related signaling pathway in insulin secretion caused by high glucose in the pancreatic beta-cell line MIN6N8. It was found that the PLD activity and PLD1 expression were both increased by high glucose (33.3 mM) treatment. The dominant negative PLD1 inhibited glucose-induced Beta2 expression, and glucose-induced insulin secretion was blocked by treatment with 1-butanol or PLD1-siRNA. These results suggest that high glucose increased insulin secretion through a PLD1-related pathway. High glucose induced the binding of Arf6 to PLD1. Pretreatment with brefeldin A (BFA), an Arf inhibitor, decreased the PLD activity as well as the insulin secretion. Furthermore, BFA blocked the glucose-induced mTOR and p70S6K activation, while mTOR inhibition with rapamycin attenuated the glucose induced Beta2 expression and insulin secretion. Thus, when taken together, PLD1 would appear to be an important regulator of glucose-induced insulin secretion through an Arf6/PLD1/mTOR/p70S6K/Beta2 pathway in MIN6N8 cells.

ADP-Ribosylation Factors/metabolism , Animals , Basic Helix-Loop-Helix Transcription Factors/metabolism , Cells, Cultured , Gene Expression Regulation, Enzymologic/drug effects , Glucose/pharmacology , Insulin/metabolism , Insulin-Secreting Cells/drug effects , Intracellular Signaling Peptides and Proteins/metabolism , Mice , Models, Biological , Oligodeoxyribonucleotides, Antisense/pharmacology , Phospholipase D/antagonists & inhibitors , Protein-Serine-Threonine Kinases/metabolism , Ribosomal Protein S6 Kinases, 70-kDa/metabolism , Signal Transduction/drug effects
Article in English | WPRIM | ID: wpr-112649


The aim of this study was to investigate the expression of Tspan-1, Jab1 and p27 in human hepatocellular carcinoma (HCC) and their clinicopathological significance. The expression of Tspan-1, Jab1 and p27 was detected in HCC tissues, the tissues around cancer (76 cases), and the normal tissues around the liver hemangiomas (10 cases). The overexpression of Tspan-1 and Jab1 was found in HCC tissues, positively correlated with clinical stage and negatively correlated with survival rate. The expression of p27 was found inversely linked to which of Tspan-1 and Jab1. In conclusion, the expression of Tspan-1, Jab1 and p27 is significantly associated with development of HCC. Overexpression of Tspan-1 and Jab1 suggests poor prognosis but overexpression of p27 may expect good prognosis for patients with HCC.

Adult , Aged , Carcinoma, Hepatocellular/metabolism , Cyclin-Dependent Kinase Inhibitor p27/metabolism , Female , Humans , Intracellular Signaling Peptides and Proteins/metabolism , Liver Neoplasms/metabolism , Male , Membrane Proteins/metabolism , Middle Aged , Peptide Hydrolases/metabolism , Prognosis , Survival Rate
Article in Korean | WPRIM | ID: wpr-194407


BACKGROUND/AIMS: DNA double strand break (DSB) is one of the critical types of DNA damage. When unrepaired DSB is accumulated in the nucleus of the cells having mutations in such genes as p53, it will lead to chromosomal instability and further more to mutation of tumor-activating genes resulting in tumorogenesis. Some of malignant cancers and its premalignant lesions were proven to have DSB in their nuclei. The aim of this study was to define the differences in expression of 53BP1 and gamma-H2AX, the markers of DSB, among normal, gastric adenoma, and gastric adenocarcinoma tissues. METHODS: Tissue microarray was made with the tissues taken from 121 patients who underwent gastrectomy for gastric adenocarcinoma, and 51 patients who underwent endoscopic mucosal resection for gastric adenoma. Immunochemical stain was performed for the marker of DSB, 53BP1 and gamma-H2AX in the tissue microarray. The normal tissues were collected from histologically confirmed tissues with no cellular atypia obtained from the patients with gastric adenocarcinoma. RESULTS: In gastric carcinoma cells, 53BP1 and gamma-H2AX were highly expressed as compared to normal epithelial cells and gastric adenoma (p<0.01). There were no differences in the expression of 53BP1 and gamma-H2AX between normal epithelium and gastric adenoma. The expression of 53BP1 in the adenoma with grade II and III atypism was more elevated than in those with grade I atypism. The expression of 53BP1 and gamma-H2AX were not significantly different according to the clinicopathologic parameters in the patients with gastric adenocarcinoma. CONCLUSIONS: The DSB in DNA seems to be associated with the development of gastric adenocarcinoma, but does not affect the premalignant adenoma cells.

Adenocarcinoma/genetics , Adenoma/genetics , Adult , Aged , Aged, 80 and over , Chromosomal Instability , DNA Breaks, Double-Stranded , Female , Histones/metabolism , Humans , Intracellular Signaling Peptides and Proteins/metabolism , Male , Middle Aged , Neoplasm Staging , Stomach Neoplasms/genetics
Rev. argent. microbiol ; 41(3): 134-140, jul.-sep. 2009. graf
Article in Spanish | LILACS | ID: lil-634627


El virus de la Lengua azul (VLA) es un ARN virus de doble cadena que induce apoptosis tanto en cultivos celulares como en tejidos blanco. Con el fin de dilucidar el mecanismo de apoptosis en la infección por el VLA, en el presente trabajo examinamos en detalle, por la técnica de Western blot, las señales celulares de caspasas, Bax, citocromo c, Smac/DIABLO y factor nuclear kappa B (NF-kB) que se activan en la infección viral. Hemos comprobado que luego de la infección in vitro con el VLA, se detectó la activación de la caspasa 8 y con ello el mecanismo extrínseco de la apoptosis. También detectamos por primera vez no sólo la activación de miembros de la familia Bcl-2 (Bax), sino también la liberación del citocromo c y la proteína Smac/DIABLO, confirmando que en la infección por el VLA está involucrado el mecanismo secuencial intrínseco de la apoptosis. Asimismo, demostramos que la infección por el VLA activa el NF-kB y que la apoptosis es sustancialmente reducida mediante la inhibición del mismo. La activación de las señales celulares tales como Bax, citocromo c, Smac/DIABLO y NF-kB presentados en este trabajo, esclarecen los mecanismos apoptóticos durante la infección por el VLA para una mayor comprensión del papel primario que juega la apoptosis en la patogénesis del virus.

Bluetongue (BTV) is a double-stranded RNA virus that induces apoptosis both in mammalian cell cultures and in target tissues. To elucidate the apoptosis pathways in BTV infection, we have examined in detail the apoptosis mechanism by examination of caspases, Bax, cytochrome c, Smac/DIABLO and NF-kB signalling pathways. In this report, after cell infection with BTV, the activation of caspase 8 was detected, proving the extrinsic receptor binding apoptotic pathway. Apoptosis followed a sequential pathway involving the detection of activated Bcl-2 family members. Furthermore, its translocation to the mitochondria, as well as the release of cytochrome c and Smac/Diablo confirmed that BTV apoptosis involves the sequential intrinsic pathway. In addition, we demonstrated that NF-kB was activated following BTV infection and cell treatment with an inhibitor peptide before BTV infection, prevented NF-kB activation and substantially reduced cellular apoptosis. Our accumulating data concerning the activation of Bax, cytochrome c, Smac/DIABLO and NF-kB clarify the mechanism of apoptosis during BTV infection, and confer a better understanding of the primary role of apoptosis in BTV pathogenesis.

Humans , Apoptosis/physiology , Bluetongue virus/physiology , Signal Transduction/physiology , Cytopathogenic Effect, Viral , Caspases/metabolism , Cytochromes c/metabolism , Enzyme Activation , HeLa Cells/virology , Intracellular Signaling Peptides and Proteins/metabolism , Mitochondria/physiology , Mitochondrial Proteins/metabolism , NF-kappa B/antagonists & inhibitors , NF-kappa B/metabolism , Peptides/pharmacology
Biocell ; 33(2): 71-80, Aug. 2009. ilus
Article in English | LILACS | ID: lil-595031


The localization of GluR1 subunits of ionotropic glutamate receptors in the glial cells and inhibitory neurons of cerebellar cortex and their association with the climbing and parallel fibers, and basket cell axons were studied. Samples of P14 and P21 rat cerebellar cortex were exposed to a specific antibody against GluR1 subunit(s) ofAMPA receptors and were examined with confocal laser scanning microscopy. GluR1 strong immunoreactivity was confined to Purkinje cell and the molecular layer. Weak GluR1 immunoreactivity was observed surrounding some Golgi cells in the granule cell layer. Intense GluR1 immunoreactivity was localized around Purkinje, basket, and stellate cells. Purkinje cells expressed strong GluR1 immunoreactivity surrounding the cell body, primary dendritic trunk and secondary and tertiary spiny den dritic branches. Marked immunofluorescent staining was also detected in the Bergmann glial fibers at the level of middle and outer third molecular layer. Positive immunofluorescence staining was also observed surrounding basket and stellate cells, and in the capillary wall. These findings suggest the specific localization of GluR1 subunits ofAMPA receptors in Bergmann glial cells, inhibitory cerebellar neurons, and the associated excitatory glutamatergic circuits formed by climbing and parallel fibers, and by the inhibitory basket cell axons.

Animals , Rats , Purkinje Cells/cytology , Purkinje Cells/metabolism , Cerebellum/cytology , Intracellular Signaling Peptides and Proteins/metabolism , Membrane Proteins/metabolism , /metabolism , Neurons/cytology , Neurons/metabolism , Rats, Wistar , Receptors, AMPA/metabolism , Protein Subunits/metabolism
Article in English | WPRIM | ID: wpr-635141


The expression of endothelial nitric oxide synthase traffic inducer (NOSTRIN) was examined in the umbilical vessels of the patients with pre-eclampsia (PE) to explore its possible role in the pathogenesis of PE. The NOSTRIN mRNA in umbilical tissues was determined by RT-PCR. The eNOS activity in umbilical vessels was spectrophotometrically detected. NO2-/NO3-, the stable metabolic end products of NO, was measured by using nitrate reductase. RT-PCR showed that the expression level of NOSTRIN was significantly higher in women with PE than in the normal group (P<0.01). The activity of eNOS was significantly decreased in PE group [(12.83+/-3.61) U/mg] than in normal group [(21.72+/-3.83) U/mg] (P<0.01). The level of NO2-/NO3- in PE patients (27.53+/-7.48) micromol/mg was significantly lower than that of normal group (54.27+/-9.53) micromol/mg (P<0.01). The significant negative correlation existed between the expression of NOSTRIN and the activity of eNOS in umbilical vessels of women with PE (r=-0.58, P<0.01). It was concluded that the level of NOSTRIN expression was increased in umbilical vessel of women with PE, indicating that it may be involved in the pathogenesis of PE.

Intracellular Signaling Peptides and Proteins/genetics , Intracellular Signaling Peptides and Proteins/metabolism , Pre-Eclampsia/enzymology , Pre-Eclampsia/etiology , RNA, Messenger/genetics , RNA, Messenger/metabolism , Umbilical Arteries/cytology , Umbilical Arteries/enzymology , Umbilical Veins/cytology , Umbilical Veins/enzymology