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1.
Cell Physiol Biochem ; 47(3): 1133-1140, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29913443

RESUMO

BACKGROUND/AIMS: Serum procalcitonin (PCT) is elevated in acute liver failure (ALF), but the expression of PCT in the liver has not been elucidated. We aimed to clarify the regulation of hepatic PCT expression and the cell sources in ALF. METHODS: Human monocytic leukemia line U937 cells were treated with 12-O-tetradecanoylphorbol-l3-acetate (PMA) (100 ng/ mL) for 24 h to induce activated macrophages. In the presence of lipopolysaccharide (LPS, 1 µg/mL), activated macrophages and human hepatocyte line L02 cells were incubated with LPS or co-cultured for 0, 2, 6, and 24 h. In an in vivo experiment, male C57BL/6 mice were challenged with intraperitoneal LPS/D-galactosamine (LPS/D-GalN). Serum liver enzymes alanine aminotransferase (ALT) and aspartate aminotransferase (AST) were measured using an automatic chemical analyzer. Inflammatory mediators were measured by real-time PCR and liver histology was examined by hematoxylin-eosin (HE) staining and immunohistochemistry (IHC). RESULTS: LPS induced the upregulation of PCT mRNA in U937-activated macrophages but not in L02 cells. When co-cultured with L02 cells, the expression of PCT mRNA of activated macrophages was upregulated compared to controls; however, the activated macrophages did not induce the expression of PCT mRNA in L02 cells in the presence of LPS. Moreover, serum liver enzymes (ALT, AST), inflammation, necrosis, and hepatic expression of PCT were significantly elevated in the LPS/D-GalN-challenged ALF mouse model. IHC revealed that PCT expression was co-localized with hepatic macrophages. CONCLUSIONS: Hepatic PCT expression is upregulated in ALF. Hepatic macrophages but not hepatocytes are the cell source of hepatic PCT expression.


Assuntos
Calcitonina/biossíntese , Falência Hepática Aguda/metabolismo , Fígado/metabolismo , Macrófagos/metabolismo , Regulação para Cima , Animais , Humanos , Lipopolissacarídeos/toxicidade , Fígado/patologia , Falência Hepática Aguda/induzido quimicamente , Falência Hepática Aguda/patologia , Macrófagos/patologia , Masculino , Camundongos , Acetato de Tetradecanoilforbol/farmacologia , Células U937
2.
Endocr Pathol ; 28(4): 351-361, 2017 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-29063495

RESUMO

Increased levels of circulating calcitonin are a clue in the diagnosis of medullary thyroid carcinoma. However, hypercalcitoninemia can also be related to other pathological conditions, including pancreatic neuroendocrine neoplasms (PanNENs). Ectopic hormonal production is not unusual in both functioning and non-functioning PanNENs; however, little is known about the frequency of calcitonin expression in these neoplasms. The aims of this study were to assess the frequency of calcitonin immunoreactivity in PanNENs, independently from serum calcitonin levels, and to evaluate the clinicopathological and prognostic features of calcitonin-immunoreactive (Cal-IR) PanNENs, including a comparison with cases already reported in the literature. We screened 229 PanNENs for the immunohistochemical expression of calcitonin, including both functioning and non-functioning neoplasms, as well as both well-differentiated and poorly differentiated PanNENs. Both the clinicopathological data and the follow-up information were available and were compared with the immunohistochemical results. In addition, we reviewed the features of the calcitonin-producing PanNENs previously reported in the literature. Calcitonin was expressed in 25 of our 229 PanNENs (10.9%). Examples of well- and poorly differentiated, as well as both functioning and non-functioning PanNENs, were found to be calcitonin immunoreactive. Cal-IR PanNENs did not show any significant difference with the whole series of neoplasms included in the study, when the clinicopathological parameters were considered, except for a younger age at diagnosis and for a larger size of the tumor in non-functioning Cal-IR PanNENs. Taken together, our results show that calcitonin immunoreactivity is not an exceptional event in PanNENs. Furthermore, calcitonin expression does not identify a separate clinical entity, in contrast to other PanNENs with ectopic hormone production, such as adrenocorticotropic hormone (ACTH)-producing PanNENs, which show a distinctively more aggressive behavior.


Assuntos
Calcitonina/biossíntese , Tumores Neuroendócrinos/patologia , Neoplasias Pancreáticas/patologia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Tumores Neuroendócrinos/metabolismo , Neoplasias Pancreáticas/metabolismo , Adulto Jovem
3.
Anal Chem ; 89(13): 6992-6999, 2017 07 05.
Artigo em Inglês | MEDLINE | ID: mdl-28590120

RESUMO

The peptide hormone calcitonin is intimately connected with human cancer development and proliferation. Its biosynthesis is reasoned to proceed via glycine-, α-hydroxyglycine-, glycyllysine-, and glycyllysyllysine-extended precursors; however, as a result of the limitations of current analytical methods, until now, there has been no procedure capable of detecting these individual species in cell or tissue samples. Therefore, their presence and dynamics in cancer had not been established. Here, we report the first methodology for the separation, detection, and quantification of calcitonin and each of its precursors in human cancer cells. We also report the discovery and characterization of O-glycosylated calcitonin and its analogous biosynthetic precursors. Through direct and simultaneous analysis of the glycosylated and nonglycosylated species, we interrogate the hormone biosynthesis. This shows that the cellular calcitonin level is maintained to mitigate effects of biosynthetic enzyme inhibitors that substantially change the proportions of calcitonin-related species released into the culture medium.


Assuntos
Calcitonina/análogos & derivados , Calcitonina/análise , Cromatografia Líquida de Alta Pressão/métodos , Glicopeptídeos/análise , Precursores de Proteínas/análise , Amidina-Liases/antagonistas & inibidores , Calcitonina/biossíntese , Calcitonina/metabolismo , Carboxipeptidase H/antagonistas & inibidores , Linhagem Celular Tumoral , Ácidos Graxos Monoinsaturados/farmacologia , Glicopeptídeos/biossíntese , Glicopeptídeos/química , Glicopeptídeos/metabolismo , Glicosilação , Humanos , Oxigenases de Função Mista/antagonistas & inibidores , Precursores de Proteínas/biossíntese , Precursores de Proteínas/química , Precursores de Proteínas/metabolismo , Extração em Fase Sólida/métodos , Succinatos/farmacologia
4.
Arch Oral Biol ; 74: 114-122, 2017 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-27930933

RESUMO

BACKGROUND: Extracellular matrix (ECM) secretion and osteogenic differentiation in periodontal ligament fibroblasts (PDLF) facilitate the neogenesis of alveolar bone, which is the cellular basis for alveolar bone repair. Calcitonin (CT) has been reported to play an important role in promoting ECM expression and inducing osteogenic differentiation in osteoblast, but its effects on PDLFs remain obscure. METHODS: The expression of CT, transforming growth factor-beta 1(TGF-ß1) and bone morphogenetic protein (BMP) in gingival crevicular fluid (GCF) was measured by ELISA. The effects of CT on collagen synthesis and osteogenic differentiation in hPDLFs were investigated by using the primarily cultured hPDLFs infected with adenovirus carrying the CT gene. Gene expression was measured by quantitative PCR and western blot. RESULTS: The expression of CT in gingival crevicular fluid (GCF) of patients with periodontitis was significantly higher than that of healthy subjects. In addition, CT expression correlated with the clinical indexes including probing pocket depth (PPD), clinical attachment level (CAL), and gingival index (GI). The in vitro study demonstrated that overexpression of CT by adenovirus infection increased the expression of TGF-ß1, collagen type I and III, and osteoblastic markers including BMP-2/-4, alkaline phosphatase and osteocalcin in human PDLFs. Moreover, CT-enhanced collagen synthesis was abrogated in hPDLFs transfected with TGF-ß1 siRNA, and CT-induced osteoblastic differentiation was blocked in hPDLFs by BMPs inhibitor noggin. CONCLUSIONS: These results suggest that CT promotes collagen synthesis and osteogenic differentiation in hPDLFs via the TGF-ß1 and BMPs signaling pathways, respectively.


Assuntos
Calcitonina/farmacologia , Diferenciação Celular/efeitos dos fármacos , Colágeno/biossíntese , Colágeno/efeitos dos fármacos , Fibroblastos/efeitos dos fármacos , Ligamento Periodontal/efeitos dos fármacos , Adenoviridae/genética , Fosfatase Alcalina/metabolismo , Proteína Morfogenética Óssea 2/metabolismo , Proteína Morfogenética Óssea 4/metabolismo , Proteína Morfogenética Óssea 7/metabolismo , Proteínas Morfogenéticas Ósseas/metabolismo , Calcitonina/biossíntese , Calcitonina/genética , Técnicas de Cultura de Células , China , Colágeno Tipo I/metabolismo , Colágeno Tipo III/metabolismo , Progressão da Doença , Matriz Extracelular/metabolismo , Feminino , Fibroblastos/metabolismo , Expressão Gênica , Líquido do Sulco Gengival/metabolismo , Humanos , Masculino , Pessoa de Meia-Idade , Osteoblastos/efeitos dos fármacos , Osteocalcina/metabolismo , Osteogênese/efeitos dos fármacos , Perda da Inserção Periodontal , Índice Periodontal , Ligamento Periodontal/metabolismo , Bolsa Periodontal , Periodontite/metabolismo , Proteínas Recombinantes , Fator de Crescimento Transformador beta1/metabolismo , Regulação para Cima
5.
Int J Surg Pathol ; 25(2): 191-194, 2017 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-27658647

RESUMO

Neuroendocrine tumors (NETs) of the thyroid are rare; the most common type is medullary thyroid carcinoma (MTC). They are derived from parafollicular cells (C-cells) that usually express calcitonin, chromogranin, and carcinoembryonic antigen. Calcitonin-negative NETs of the thyroid are extremely rare, and the origin of these tumors is unclear. Whereas some believe that these tumors are from follicular cells, recent reports have shown expression of calcitonin gene-related peptide in these tumors, indicating parafollicular C-cell origin. Here, we report a case of calcitonin-negative NET of the thyroid in a 74-year-old woman, with review of the literature.


Assuntos
Tumores Neuroendócrinos/diagnóstico , Neoplasias da Glândula Tireoide/diagnóstico , Idoso , Biomarcadores Tumorais/análise , Calcitonina/análise , Calcitonina/biossíntese , Feminino , Humanos
6.
J Comp Pathol ; 155(4): 286-298, 2016 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-27567273

RESUMO

Expression of thyroid transcription factor (TTF)-1 corroborates a thyroid origin of neoplasms. Thyroglobulin and calcitonin immunohistochemistry (IHC) can distinguish between a follicular and C-cell origin of thyroid tumours, respectively. Pax8 (expressed by normal canine thyroid follicular cells) and napsin A (expressed mainly by C-cells) labelling was compared with labelling for TTF-1, thyroglobulin and calcitonin in 114 canine proliferative thyroid lesions. All 81 follicular tumours expressed thyroglobulin and were negative for calcitonin; 79/81 (98%) of these tumours expressed TTF-1 and Pax8 and 60/81 (74%) expressed napsin A. All 25 C-cell lesions expressed calcitonin and were negative for expression of thyroglobulin; 22 (88%) were positive for TTF-1, 13 (57%) for Pax8 and 24/24 for napsin A. Six mixed follicular-medullary carcinomas expressed all five markers. Both carcinosarcomas expressed TTF-1 and napsin A, and one each of these tumours expressed thyroglobulin, calcitonin or Pax8. Pax8 expression was also detected in epididymal cells, endometrial cells and vas deferens epithelium, in Sertoli-like ovarian cells, and in some cases of ovarian adenoma, pancreatic carcinoma, renal cell carcinoma and Sertoli cell tumour. Napsin A was also detected in adrenocortical cells, ovarian granulosa cells, epididymal and endometrial cells, as well as in some renal cell carcinomas, pulmonary adenocarcinomas and Sertoli cell tumours. In summary, Pax8 was as sensitive as TTF-1 and slightly less sensitive than thyroglobulin for identification of follicular tumours, but had low sensitivity for C-cell tumours. Napsin A was as sensitive as calcitonin for C-cell neoplasms, but was less sensitive than thyroglobulin for follicular neoplasms. Thus, these markers are sensitive and, except for renal cell carcinoma (for Pax8, napsin A) and pulmonary adenocarcinoma (for napsin A), are specific thyroid tumour markers.


Assuntos
Biomarcadores Tumorais/análise , Doenças do Cão/patologia , Neoplasias da Glândula Tireoide/veterinária , Animais , Ácido Aspártico Endopeptidases/análise , Ácido Aspártico Endopeptidases/biossíntese , Calcitonina/análise , Calcitonina/biossíntese , Cães , Imuno-Histoquímica , Proteínas Nucleares/análise , Proteínas Nucleares/biossíntese , Fator de Transcrição PAX8/análise , Fator de Transcrição PAX8/biossíntese , Sensibilidade e Especificidade , Tireoglobulina/análise , Tireoglobulina/biossíntese , Fator Nuclear 1 de Tireoide , Fatores de Transcrição/análise , Fatores de Transcrição/biossíntese
7.
J Biochem Mol Toxicol ; 30(12): 580-587, 2016 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-27271987

RESUMO

Kaliotoxin (KTX), a specific blocker of potassium channels, exerts various toxic effects due to its action on the central nervous system. Its use in experimental model could help the understanding of the cellular and molecular mechanisms involved in the neuropathological processes related to potassium channel dysfunctions. In this study, the ability of KTX to stimulate neuro-immuno-endocrine axis was investigated. As results, the intracerebroventricular injection of KTX leads to severe structural-functional alterations of both hypothalamus and thyroid. These alterations were characterized by a massive release of hormones' markers of thyroid function associated with damaged tissue which was infiltrated by inflammatory cell and an imbalanced redox status. Taken together, these data highlight that KTX is able to modulate the neuro-endocrine response after binding to its targets leading to the hypothalamus and the thyroid stimulation, probably by inflammatory response activation and the installation of oxidative stress in these organs.


Assuntos
Eosinófilos/efeitos dos fármacos , Hipotálamo/efeitos dos fármacos , Neutrófilos/efeitos dos fármacos , Venenos de Escorpião/toxicidade , Escorpiões/química , Glândula Tireoide/efeitos dos fármacos , Animais , Calcitonina/biossíntese , Calcitonina/metabolismo , Catalase/metabolismo , Eosinófilos/imunologia , Glutationa/metabolismo , Hipotálamo/imunologia , Hipotálamo/metabolismo , Injeções Intraventriculares , Malondialdeído/metabolismo , Camundongos , Infiltração de Neutrófilos/efeitos dos fármacos , Neutrófilos/imunologia , Nitrilos/metabolismo , Oxirredução , Estresse Oxidativo , Venenos de Escorpião/isolamento & purificação , Escorpiões/fisiologia , Glândula Tireoide/imunologia , Glândula Tireoide/metabolismo , Tireotropina/biossíntese , Tireotropina/metabolismo , Tiroxina/biossíntese , Tiroxina/metabolismo , Tri-Iodotironina/biossíntese , Tri-Iodotironina/metabolismo
8.
Microbes Infect ; 18(2): 102-8, 2016 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-26482503

RESUMO

Sepsis is a leading cause of mortality in clinical infection, early identification and intervention is critical to improve its outcomes. Nonetheless, it is difficult to determine whether the cause of inflammation in patients is of bacterial origin at early stage. Procalcitonin (PCT) is considered as a promising marker in clinical laboratory test of bacterial infection. But the details for the regulation of PCT expression are not fully understood. miR-125b is important to immune system development and immunological host defense, while its role in the regulation of PCT production remains unexplored. In this study, we demonstrate that the expression of PCT is regulated by miR-125b in human monocytes. miR-125b modulates PCT expression by manipulating the amount and transcriptional activity of Stat3.


Assuntos
Calcitonina/biossíntese , MicroRNAs/metabolismo , Monócitos/metabolismo , Precursores de Proteínas/biossíntese , Fator de Transcrição STAT3/metabolismo , Peptídeo Relacionado com Gene de Calcitonina , Linhagem Celular , Regulação da Expressão Gênica , Humanos
9.
Appl Microbiol Biotechnol ; 99(23): 10097-106, 2015 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-26254786

RESUMO

Calcitonin participates in controlling homeostasis of calcium and phosphorus and plays an important role in bone metabolism. The aim of this study was to endow an industrial strain of Saccharomyces cerevisiae with the ability to express chimeric human/salmon calcitonin (hsCT) without the use of antibiotics. To do so, a homologous recombination plasmid pUC18-rDNA2-ura3-P pgk -5hsCT-rDNA1 was constructed, which contains two segments of ribosomal DNA of 1.1 kb (rDNA1) and 1.4 kb (rDNA2), to integrate the heterologous gene into host rDNA. A DNA fragment containing five copies of a chimeric human/salmon calcitonin gene (5hsCT) under the control of the promoter for phosphoglycerate kinase (P pgk ) was constructed to express 5hsCT in S. cerevisiae using ura3 as a selectable auxotrophic marker gene. After digestion by restriction endonuclease HpaI, a linear fragment, rDNA2-ura3-P pgk -5hsCT-rDNA1, was obtained and transformed into the △ura3 mutant of S. cerevisiae by the lithium acetate method. The ura3-P pgk -5hsCT sequence was introduced into the genome at rDNA sites by homologous recombination, and the recombinant strain YS-5hsCT was obtained. Southern blot analysis revealed that the 5hsCT had been integrated successfully into the genome of S. cerevisiae. The results of Western blot and ELISA confirmed that the 5hsCT protein had been expressed in the recombinant strain YS-5hsCT. The expression level reached 2.04 % of total proteins. S. cerevisiae YS-5hsCT decreased serum calcium in mice by oral administration and even 0.01 g lyophilized S. cerevisiae YS-5hsCT/kg decreased serum calcium by 0.498 mM. This work has produced a commercial yeast strain potentially useful for the treatment of osteoporosis.


Assuntos
Calcitonina/biossíntese , Calcitonina/genética , DNA Ribossômico/genética , Expressão Gênica , Recombinação Homóloga , Saccharomyces cerevisiae/genética , Administração Oral , Animais , Southern Blotting , Western Blotting , Cálcio/análise , Cromossomos Fúngicos , Vetores Genéticos , Humanos , Camundongos , Plasmídeos , Proteínas Recombinantes de Fusão/biossíntese , Proteínas Recombinantes de Fusão/genética , Salmão , Soro/química
10.
Clin Biochem ; 48(16-17): 1079-82, 2015 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-26129881

RESUMO

OBJECTIVE: To compare the clinical utility of serum and cerebrospinal fluid (CSF) procalcitonin (PCT) for the diagnosis of bacterial meningitis (BM) among patients with suspected meningitis. METHODS: Patients with meningitis-like symptoms (n=120), admitted to the Second People's Hospital of Wuxi or the Changhai Hospital of Shanghai between January 2011 and December 2013, were prospectively and consecutively enrolled in this study. BM was finally diagnosed by CSF culture, Gram staining, quantitative polymerase chain reaction (qPCR), and treatment response. The diagnostic accuracy of the serum and CSF PCT was assessed by receiver operator characteristic (ROC) curve analysis. The relationship between CSF and serum PCT levels as well as the CSF leukocyte count and protein level was analyzed by Spearman's correlation analysis. RESULTS: PCT level in both the serum and CSF was significantly increased in the BM patients. The area under ROC curve of serum PCT for the diagnosis of BM was 0.96 (95% confidence interval (CI): 0.93-1.00), significantly higher than that of CSF PCT (0.90, 95% CI: 0.83-0.96). Using 0.88ng/mL as the threshold, the diagnostic sensitivity, specificity, and accuracy of serum PCT for the diagnosis of BM were 0.87 (95% CI, 0.73-0.95), 1.00 (95% CI, 0.95-1.00), and 95%, respectively. The serum PCT level was positively correlated with the CSF PCT level, leukocyte count, and protein level. CONCLUSION: Both the serum and CSF PCT had a high diagnostic value for BM among suspected meningitis patients, and serum PCT demonstrated a superior diagnostic value compared to CSF PCT.


Assuntos
Calcitonina/biossíntese , Calcitonina/líquido cefalorraquidiano , Líquido Cefalorraquidiano/metabolismo , Meningites Bacterianas/sangue , Meningites Bacterianas/metabolismo , Precursores de Proteínas/biossíntese , Precursores de Proteínas/líquido cefalorraquidiano , Peptídeo Relacionado com Gene de Calcitonina , China , Diagnóstico Diferencial , Feminino , Humanos , Contagem de Leucócitos/métodos , Masculino , Meningites Bacterianas/líquido cefalorraquidiano , Meningites Bacterianas/diagnóstico , Pessoa de Meia-Idade , Estudos Prospectivos , Curva ROC , Sensibilidade e Especificidade , Soro/metabolismo
11.
Minerva Anestesiol ; 81(2): 157-65, 2015 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-24994498

RESUMO

BACKGROUND: Osteopontin (OPN) and soluble urokinase plasminogen activator receptor (suPAR) have been proposed as markers of disease severity and risk-stratification in infection and inflammation. In breast cancer, OPN and the membrane bound form of urokinase plasminogen activator receptor (uPAR) are functionally related, as OPN-induced cell migration depends on uPAR triggering by urokinase plasminogen activator (uPA). The aim of this study was to prospectively evaluate the kinetic of OPN and suPAR blood levels in patients developing septic shock (SS) compared to those not developing SS, and to investigate the relationships between these two biomarkers in immune cells in vitro. METHODS: We measured the levels of OPN and suPAR for 15 days in forty-three patients, defined a priory as at risk to develop septic shock. Moreover, we investigated in vitro the effect of recombinant OPN on uPAR and suPAR expression in monocytes. RESULTS: We found that OPN and suPAR levels were directly correlated to each other both at intensive care unit admission and on the day patients met SIRS/sepsis or septic shock criteria. In patients developing septic shock, OPN increased prior to suPAR and was already detectable up to 4 days before the shock development. In vitro, OPN induced suPAR production in monocytes by increasing both uPAR gene expression, and suPAR release from the cell surface. CONCLUSION: These data suggest that OPN is partly responsible for the increased plasma levels of suPAR and might be a valuable tool to predict the occurrence of septic shock.


Assuntos
Osteopontina/farmacologia , Receptores de Ativador de Plasminogênio Tipo Uroquinase/biossíntese , Adulto , Idoso , Biomarcadores , Calcitonina/biossíntese , Feminino , Expressão Gênica/efeitos dos fármacos , Humanos , Cinética , Masculino , Pessoa de Meia-Idade , Monócitos/efeitos dos fármacos , Monócitos/metabolismo , Estudos Prospectivos , Receptores de Ativador de Plasminogênio Tipo Uroquinase/genética , Proteínas Recombinantes/farmacologia , Choque Séptico/sangue
12.
Indian J Pathol Microbiol ; 57(4): 598-602, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-25308015

RESUMO

Papillary thyroid carcinoma (PTC) and medullary thyroid carcinoma (MTC) are two distinct types of thyroid carcinoma with considerable difference in terms of cellular origin, histopathological appearance, clinical course and prevalence. The histogenetic origin and possible molecular mechanisms responsible for the development of mixed medullary-papillary carcinoma of the thyroid are still unclear. The most widely accepted hypotheses considering co-occurrence of MTC and PTC are stem cell theory, collision effect theory and hostage theory. Herein we describe two rare cases of mixed medullary-papillary thyroid carcinoma with co-occurrence of MTC and PTC which developed with concomitant MEN 2A and different sites of lymph node metastasis in the first patient, while with atypical clinical presentation in the second patient. In conclusion, co-expression of thyroglobulin, synaptophysin and chromogranin by the papillary component of mixed tumor seems to support stem cell theory in our first case, whereas positive staining for calcitonin but not for thyroglobulin in the medullary component of the tumor along with separation of these two tumors from each other by a normal thyroid tissue seem to indicates the likelihood of collision effect theory in our second case.


Assuntos
Carcinoma/diagnóstico , Neoplasia Endócrina Múltipla Tipo 2a/diagnóstico , Proteínas Proto-Oncogênicas c-ret/genética , Neoplasias da Glândula Tireoide/diagnóstico , Adulto , Idoso , Calcitonina/biossíntese , Carcinoma/diagnóstico por imagem , Carcinoma/genética , Carcinoma Neuroendócrino , Carcinoma Papilar , Cromogranina A/biossíntese , Humanos , Neoplasias Pulmonares/secundário , Metástase Linfática , Masculino , Neoplasia Endócrina Múltipla Tipo 2a/diagnóstico por imagem , Polimorfismo de Nucleotídeo Único , Radiografia , Sinaptofisina/biossíntese , Tireoglobulina/biossíntese , Câncer Papilífero da Tireoide , Glândula Tireoide/patologia , Neoplasias da Glândula Tireoide/diagnóstico por imagem , Neoplasias da Glândula Tireoide/genética
13.
J Clin Endocrinol Metab ; 99(12): 4704-11, 2014 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-25215555

RESUMO

CONTEXT: Elevated calcitonin levels occur in up to 46% of patients with chronic hemodialysis (CHD) and frequently reflect benign C-cell hyperplasia rather than medullary thyroid carcinoma. For the differential diagnosis of hypercalcitoninemia, the pentagastrin-stimulated calcitonin test was used until its availability became restricted. OBJECTIVE: This study sought to compare calcium and pentagastrin in terms of their ability to stimulate calcitonin secretion and their side effects in patients with CHD. SETTING AND DESIGN: This prospective pilot study was conducted at the chronic hemodialysis unit of the Medical University of Vienna between December 2012 and September 2013. PATIENTS: We studied six male patients with CHD with elevated basal calcitonin levels. INTERVENTION: The stimulation test was performed first with 0.5 µg/kg pentagastrin and then with 1 mg/kg calcium after a median washout period of 7 (6-9) months. MAIN OUTCOME MEASURES: We measured calcitonin, serum ionized calcium, intact PTH (iPTH), and C-terminal fibroblast growth factor 23 levels before and 2, 5, and 10 minutes after iv infusion of the stimulant and assessed the tolerability of the two substances by a questionnaire. RESULTS: Both pentagastrin and calcium significantly stimulated calcitonin secretion at 2 and 5 minutes. Partial correlation analysis revealed a strong association between calcium- and pentagastrin-stimulated calcitonin levels (r=0.875, P < .0001). Only after calcium infusion serum ionized calcium levels increased from 1.09 (0.91-1.16) mmol/l to 1.4 (1.14-1.65) mmol/l at 2 minutes (P < .01) but returned to baseline levels at 5 minutes. Moreover, calcium infusion led to a significant decrease in iPTH levels from 315 (203-723) pg/ml to 182 (121-415) pg/ml at 5 minutes (P < .05) and 171 (91-346) pg/ml at 10 minutes (P < .001). In general, calcium caused fewer and less severe side effects than pentagastrin. CONCLUSIONS: In patients with CHD, the response of calcitonin to calcium and pentagastrin was comparable, making calcium a potential substitute for pentagastrin in these patients.


Assuntos
Calcitonina/biossíntese , Cálcio , Pentagastrina , Diálise Renal , Insuficiência Renal Crônica/tratamento farmacológico , Insuficiência Renal Crônica/metabolismo , Adulto , Idoso , Calcitonina/sangue , Cálcio/administração & dosagem , Cálcio/sangue , Relação Dose-Resposta a Droga , Fatores de Crescimento de Fibroblastos/sangue , Humanos , Infusões Intravenosas , Masculino , Pessoa de Meia-Idade , Hormônio Paratireóideo/sangue , Pentagastrina/administração & dosagem , Projetos Piloto
14.
Int J Surg Pathol ; 22(6): 530-5, 2014 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-24599901

RESUMO

In the thyroid, primary neuroendocrine tumors encompass medullary thyroid carcinoma (MTC) and, rarely, other tumors such as paragangliomas. MTCs are derived from C-cells and express calcitonin and neuroendocrine markers. Besides classic MTC, some reports have documented thyroid neuroendocrine tumors, which show no calcitonin expression and raise difficult diagnostic problems. A 76-year-old man presented with a mass in the left thyroid with neither serological calcitonin elevation nor familial history. A thorough clinico-laboratorial study did not disclose any other mass elsewhere. A left hemithyroidectomy was performed, and the histological examination revealed a neuroendocrine carcinoma resembling a paraganglioma-like MTC displaying unequivocal signs of vascular invasion. Immunohistochemically, the tumor cells showed reactivity for chromogranin A, synaptophysin, thyroid transcription factor-1 (TTF-1), paired box gene 8 (PAX8), cytokeratins (AE1/AE3 and CK8/18), and calcitonin gene-related peptide (CGRP) and negativity for calcitonin, carcinoembryonic antigen, TTF-2, thyroperoxidase, and thyroglobulin. In situ hybridization showed that the tumor cells lacked expression for calcitonin and thyroglobulin mRNA. Genetic analysis did not disclose any RET mutation. A diagnosis of C-cell-derived primary neuroendocrine carcinoma of the thyroid without calcitonin expression was made, and the patient remains free of metastasis or recurrence 18 months after surgery.


Assuntos
Carcinoma Neuroendócrino/diagnóstico , Neoplasias da Glândula Tireoide/diagnóstico , Idoso , Calcitonina/biossíntese , Humanos , Imuno-Histoquímica , Hibridização In Situ , Masculino
15.
Headache ; 54(3): 472-84, 2014 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-24512072

RESUMO

OBJECTIVE: To examine calcitonin gene-related peptide (CGRP) gene expression under inflammatory conditions using trigeminal ganglia organ cultures as an experimental system. These cultures have increased proinflammatory signaling that may mimic neurogenic inflammation in the migraine state. BACKGROUND: The trigeminal nerve sends peripheral pain signals to the central nervous system during migraine. Understanding the dynamic processes that occur within the trigeminal nerve and ganglion may provide insights into events that contribute to migraine pain. A neuropeptide of particular interest is CGRP, which can be elevated and play a causal role in migraine. However, most studies have overlooked a second splice product of the Calca gene that encodes calcitonin (CT), a peptide hormone involved in calcium homeostasis. Importantly, a precursor form of CT called procalcitonin (proCT) can act as a partial agonist at the CGRP receptor and elevated proCT has recently been reported during migraine. METHODS: We used a trigeminal ganglion whole organ explant model, which has previously been demonstrated to induce pro-inflammatory agents in vitro. Quantitative polymerase chain reaction and immunohistochemistry were used to evaluate changes in messenger ribonucleic acid (mRNA) and protein levels of CGRP and proCT. RESULTS: Whole mouse trigeminal ganglia cultured for 24 hours showed a 10-fold increase in CT mRNA, with no change in CGRP mRNA. A similar effect was observed in ganglia from adult rats. ProCT immunoreactivity was localized in glial cells. Cutting the tissue blunted the increase in CT, suggesting that induction required the close environment of the intact ganglia. Consistent with this prediction, there were increased reactive oxygen species in the ganglia, and the elevated CT mRNA was reduced by antioxidant treatment. Surprisingly, reactive oxygen species were increased in neurons, not glia. CONCLUSIONS: These results demonstrate that reactive oxygen species can activate proCT expression from the CGRP gene in trigeminal glia by a paracrine regulatory mechanism. We propose that this glial recruitment pathway may occur following cortical spreading depression and neurogenic inflammation to increase CGRP nociceptive actions in migraine.


Assuntos
Calcitonina/biossíntese , Neuroglia/metabolismo , Precursores de Proteínas/biossíntese , Espécies Reativas de Oxigênio/metabolismo , Gânglio Trigeminal/metabolismo , Animais , Peptídeo Relacionado com Gene de Calcitonina/metabolismo , Células Cultivadas , Imuno-Histoquímica , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Transtornos de Enxaqueca/metabolismo , Ratos , Ratos Sprague-Dawley , Reação em Cadeia da Polimerase Via Transcriptase Reversa
16.
Artigo em Chinês | MEDLINE | ID: mdl-25895305

RESUMO

OBJECTIVE: To investigate the expression and clinical significance of Ki67 and calcitonin in medullary thyroid carcinoma(MTC). METHOD: The expression level of Ki67 and calcitonin was studied in 44 cases of medullary thyroid carcinoma tissue and 20 cases of adjacent nontumor tissue by SP immunohistochemistry. RESULT: The positive expression of Ki67 and calcitonin in medullary thyroid carcinoma tissue were 86.36% (38/44) and 100.00% (44/44) respectively. There was a significant difference between carcinoma and normal thyroid tissue (P<0.01). The overexpression of Ki67 and calcitonin in medullary thyroid carcinoma had no relationship with gender and age of patients,but had relationship with size of tumor,clinical staging and lymph node metastasis (P<0.05). Meanwhile, Ki67 and calcitonon had no significant correlation with each other. CONCLUSION: The overexpression of Ki67 and calcitonin may play important role in occurrence, development and metastasis of medullary thyroid carcinoma. It may be used as an important judgement for the biological behavior of medullary thyroid carcinoma.


Assuntos
Calcitonina/biossíntese , Antígeno Ki-67/biossíntese , Neoplasias da Glândula Tireoide/metabolismo , Carcinoma Neuroendócrino , Humanos , Metástase Linfática
17.
Acta Biochim Biophys Sin (Shanghai) ; 45(5): 345-52, 2013 May.
Artigo em Inglês | MEDLINE | ID: mdl-23532063

RESUMO

Serotonin (5-HT) neurons synthesize a variety of peptides. How these peptides are controlled during development remains unclear. It has been reported that the co-localization of peptides and 5-HT varies by species. In contrast to the situations in the rostral 5-HT neurons of human and rat brains, several peptides do not coexist with 5-HT in the rostral 5-HT neurons of mouse brain. In this study, we found that the peptide substance P and peptide genes, including those encoding peptides thyrotropin-releasing hormone, enkephalin, and calcitonin gene-related peptide, were expressed in the caudal 5-HT neurons of mouse brain; these findings are in line with observations in rat and monkey 5-HT neurons. We also revealed that these peptides/peptide genes partially overlapped with the transcription factor Lmx1b that specifies the 5-HT cell fate. Furthermore, we found that the peptide cholecystokinin was expressed in developing dopaminergic neurons and greatly overlapped with Lmx1b that specifies the dopaminergic cell fate. By examining the phenotype of Lmx1b deletion mice, we found that Lmx1b was required for the expression of above peptides expressed in 5-HT or dopaminergic neurons. Together, our results indicate that Lmx1b, a key transcription factor for the specification of 5-HT and dopaminergic transmitter phenotypes during embryogenesis, determines some peptide phenotypes in these neurons as well.


Assuntos
Neurônios Dopaminérgicos/metabolismo , Proteínas com Homeodomínio LIM/fisiologia , Neurônios/metabolismo , Neurônios Serotoninérgicos/metabolismo , Fatores de Transcrição/fisiologia , Animais , Calcitonina/biossíntese , Colecistocinina/biossíntese , Encefalinas/biossíntese , Camundongos , Substância Cinzenta Periaquedutal/embriologia , Substância Cinzenta Periaquedutal/metabolismo , Fenótipo , Precursores de Proteínas/biossíntese , Núcleos da Rafe/embriologia , Núcleos da Rafe/metabolismo , Substância P/biossíntese , Hormônio Liberador de Tireotropina/biossíntese
18.
Virchows Arch ; 459(2): 147-54, 2011 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-21739268

RESUMO

We recently identified the transcription factor (TF) islet 1 gene product (ISL1) as a marker for well-differentiated pancreatic neuroendocrine tumors (P-NETs). In order to better understand the expression of the four TFs, ISL1, pancreatico-duodenal homeobox 1 gene product (PDX1), neurogenin 3 gene product (NGN3), and CDX-2 homeobox gene product (CDX2), that mainly govern the development and differentiation of the pancreas and duodenum, we studied their expression in hormonally defined P-NETs and duodenal (D-) NETs. Thirty-six P-NETs and 14 D-NETs were immunostained with antibodies against the four pancreatic hormones, gastrin, serotonin, calcitonin, ISL1, PDX1, NGN3, and CDX2. The TF expression pattern of each case was correlated with the tumor's hormonal profile. Insulin-positive NETs expressed only ISL1 (10/10) and PDX1 (9/10). Glucagon-positive tumors expressed ISL1 (7/7) and were almost negative for the other TFs. Gastrin-positive NETs, whether of duodenal or pancreatic origin, frequently expressed PDX1 (17/18), ISL1 (14/18), and NGN3 (14/18). CDX2 was mainly found in the gastrin-positive P-NETs (5/8) and rarely in the D-NETs (1/10). Somatostatin-positive NETs, whether duodenal or pancreatic in origin, expressed ISL1 (9/9), PDX1 (3/9), and NGN3 (3/9). The remaining tumors showed labeling for ISL1 in addition to NGN3. There was no association between a particular TF pattern and NET features such as grade, size, location, presence of metastases, and functional activity. We conclude from our data that there is a correlation between TF expression patterns and certain hormonally defined P-NET and D-NET types, suggesting that most of the tumor types originate from embryologically determined precursor cells. The observed TF signatures do not allow us to distinguish P-NETs from D-NETs.


Assuntos
Fatores de Transcrição Hélice-Alça-Hélice Básicos/biossíntese , Neoplasias Duodenais/metabolismo , Proteínas de Homeodomínio/biossíntese , Proteínas do Tecido Nervoso/biossíntese , Tumores Neuroendócrinos/metabolismo , Neoplasias Pancreáticas/metabolismo , Transativadores/biossíntese , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores Tumorais/análise , Fator de Transcrição CDX2 , Calcitonina/biossíntese , Neoplasias Duodenais/patologia , Feminino , Gastrinas/biossíntese , Glucagon/biossíntese , Humanos , Imuno-Histoquímica , Insulina/biossíntese , Proteínas com Homeodomínio LIM , Masculino , Pessoa de Meia-Idade , Tumores Neuroendócrinos/patologia , Neoplasias Pancreáticas/patologia , Polipeptídeo Pancreático/biossíntese , Somatostatina/biossíntese , Fatores de Transcrição , Adulto Jovem
19.
Cephalalgia ; 31(5): 614-24, 2011 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-21216873

RESUMO

BACKGROUND: The neuropeptide calcitonin gene-related peptide (CGRP) plays a key role in migraine. CGRP gene expression involves an enhancer that is active in neurons, yet inactive in glia. In this report, we analyze epigenetic modifications that allow enhancer activation in glia. METHODS: DNA methylation and histone acetylation states were measured in rat and human- model cell lines and primary cultures of rat trigeminal ganglia glia. The functional consequence of altering the chromatin state was determined by quantitative measurements of both calcitonin (CT) and CGRP mRNAs. RESULTS: A hypermethylated CpG island flanking the enhancer was identified in glia and non-expressing cell lines. In addition, the chromatin was hypoacetylated. Treatment with the DNA methylation inhibitor 5-aza-2'-deoxycytidine induced CT mRNA ~30-fold in glial cultures. Treatment with a histone deacetylase inhibitor alone had little effect; however, the combination of inhibitors yielded a synergistic ~80-fold increase in CT and ~threefold increase in CGRP mRNA. Treated glia contained CT precursor (pro-CT) immunoreactivity. CONCLUSIONS: Epigenetic modulation is sufficient to induce the CGRP gene in glia. Because the CGRP gene is systemically activated by inflammatory conditions, this suggests that glial pro-CT may be an unexplored biomarker during migraine.


Assuntos
Calcitonina/genética , Epigênese Genética , Regulação da Expressão Gênica/genética , Neuroglia/metabolismo , Precursores de Proteínas/genética , Animais , Calcitonina/biossíntese , Peptídeo Relacionado com Gene de Calcitonina/biossíntese , Peptídeo Relacionado com Gene de Calcitonina/genética , Células Cultivadas , Imunoprecipitação da Cromatina , Elementos Facilitadores Genéticos/genética , Expressão Gênica , Humanos , Imuno-Histoquímica , Precursores de Proteínas/biossíntese , RNA Mensageiro/análise , Ratos , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Gânglio Trigeminal/metabolismo
20.
Spinal Cord ; 49(6): 715-20, 2011 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-21243003

RESUMO

STUDY DESIGN: Prospective, nonrandomized, observational cohort study. OBJECTIVES: To analyze procalcitonin (PCT) level in acute traumatic spinal cord injury patients with and without postoperative infectious complications, and to determine whether PCT is a prognostic parameter of infectious complications in the early postoperative period compared with other inflammatory markers. SETTING: Spine center of Chongqing, China; Trauma center of Chinese People's Liberation Army, China. METHODS: A total of 339 consecutive patients with acute spinal cord injury undergone surgery were evaluated. All patients underwent measurement of leukocyte count, erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), and serum PCT preoperatively and 24-48 h postoperatively. RESULTS: In all, 26 (7.7%) of 339 participants experienced postoperative infectious complication. Patients with infection exhibited significantly higher PCT and CRP levels compared with noninfection (both P<0.01). Multivariate logistic regression analysis showed that PCT and CRP levels were independent predicators for postoperative infection. The area under the receiver operating characteristics curve of PCT and CRP were 0.82 (95% confidence intervals (CI) 0.74-0.91) and 0.68 (95%CI, 0.57-0.78), respectively. A PCT cutoff of 0.1 ng ml(-1) had a reasonable sensitivity of 92% to exclude an infection and antibiotics can be initially withheld. However, in patients with PCT level above 0.5 ng ml(-1), a rapid initiation of antibiotics may be warranted. CONCLUSIONS: Serum PCT is a more reliable biologic marker for the early prediction of postoperative infectious complications in patients with acute traumatic spinal cord injury compared with CRP. PCT can early identify postoperative infections for establishing effective antibiotic therapy.


Assuntos
Calcitonina/sangue , Precursores de Proteínas/sangue , Traumatismos da Medula Espinal/sangue , Traumatismos da Medula Espinal/complicações , Infecção da Ferida Cirúrgica/sangue , Infecção da Ferida Cirúrgica/etiologia , Adulto , Biomarcadores/sangue , Proteína C-Reativa/biossíntese , Proteína C-Reativa/metabolismo , Calcitonina/biossíntese , Peptídeo Relacionado com Gene de Calcitonina , Estudos de Coortes , Diagnóstico Precoce , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Procedimentos Neurocirúrgicos/efeitos adversos , Procedimentos Neurocirúrgicos/métodos , Valor Preditivo dos Testes , Estudos Prospectivos , Precursores de Proteínas/biossíntese , Traumatismos da Medula Espinal/cirurgia , Infecção da Ferida Cirúrgica/epidemiologia
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