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1.
PLoS One ; 8(3): e57758, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-23505439

RESUMO

To pinpoint the exact location of the etiological variant/s present at 1q21.1 harboring FCRL1-5 and CD5L genes, we carried out a refined association study in the entire FCRL region in 1,536 patients with Graves' disease (GD) and 1,516 sex-matched controls by imputation analysis, logistic regression, and cis-eQTL analysis. Among 516 SNPs with P<0.05 in the initial GWAS scan, the strongest signals associated with GD and correlated to FCRL3 expression were located at a cluster of SNPs including rs7528684 and rs3761959. And the allele-specific effects for rs3761959 and rs7528684 on FCRL3 expression level revealed that the risk alleles A of rs3761959 and C of rs7528684 were correlated with the elevated expression level of FCRL3 whether in PBMCs or its subsets, especially in CD19(+) B cells and CD8(+) T subsets. Next, the combined analysis with 5,300 GD cases and 4,916 control individuals confirmed FCRL3 was a susceptibility gene of GD in Chinese Han populations, and rs3761959 and rs7528684 met the genome-wide association significance level (P(combined) = 2.27×10(-12) and 7.11×10(-13), respectively). Moreover, the haplotypes with the risk allele A of rs3761959 and risk allele C of rs7528684 were associated with GD risk. Finally, our epigenetic analysis suggested the disease-associated C allele of rs7528684 increased affinity for NF-KB transcription factor. Above data indicated that FCRL3 gene and its proxy SNP rs7528684 may be involved in the pathogenesis of GD by excessive inhibiting B cell receptor signaling and the impairment of suppressing function of Tregs.


Assuntos
Estudo de Associação Genômica Ampla , Doença de Graves/genética , Receptores Fc/genética , Cromossomos Humanos Par 1 , Epigênese Genética , Feminino , Perfilação da Expressão Gênica , Frequência do Gene , Haplótipos , Humanos , Desequilíbrio de Ligação , Masculino , Polimorfismo de Nucleotídeo Único , Locos de Características Quantitativas
2.
Gene ; 516(2): 345-50, 2013 Mar 10.
Artigo em Inglês | MEDLINE | ID: mdl-23291414

RESUMO

Mutations of CYP17A1 gene could cause complete or partial, combined or isolated 17α-hydroxylase/17,20-lyase enzyme deficiencies (17OHD). We intended to investigate the CYP17A1 mutation in five unrelated patients and analyze its possible influence on phenotype of an atypical 17OHD patient presented with micropenis, hypertension and intermittent hypokalemia. Steroid hormones were assayed in these patients. A novel missense mutation (c.1169C>G, p. Thr390Arg) located in exon 7 was detected in one of the patients. Homozygous c. 985_987delinsAA, p. Tyr329fs mutation was found in two patients, while compound heterozygous mutations (c. 985_987delinsAA, p. Tyr329fs/c. 932-939 del, p. Val311fs and c. 287G>A, p. Arg96Gln/c. 985_987delinsAA, p. Tyr329fs) were found in two other patients, respectively. Then, steric model analysis of CYP17A1 showed that the novel mutation T390R changed the local structure as well as the electrostatic potential of the nearby beta sheet. Finally, site-directed mutagenesis and in vitro expression were used to analyze the activity of novel mutant CYP17A1. It indicated the T390R mutant retained part of enzyme activity, which was consistent to the clinical features. In conclusion, we identified a novel missense mutation of CYP17A1 gene from a patient with micropenis, hypertension and intermittent hypokalemia, which varied from other four patients. It also expanded our understanding of genotype-phenotype correlation of the disease.


Assuntos
Hiperplasia Suprarrenal Congênita/genética , Grupo com Ancestrais do Continente Asiático/genética , Mutação de Sentido Incorreto , Esteroide 17-alfa-Hidroxilase/genética , Adolescente , Hiperplasia Suprarrenal Congênita/etnologia , Sequência de Aminoácidos , Sequência de Bases , Células Cultivadas , Consanguinidade , Análise Mutacional de DNA , Feminino , Humanos , Masculino , Modelos Moleculares , Dados de Sequência Molecular , Mutação de Sentido Incorreto/fisiologia , Esteroide 17-alfa-Hidroxilase/química , Adulto Jovem
3.
Transl Res ; 161(1): 44-9, 2013 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-23036723

RESUMO

17α-hydroxylase/17,20-lyase deficiency (17OHD) is a rare autosomal recessive genetic disease that is characterized by low-renin hypertension, hypokalemia, and abnormal development of the genitalia. Mutations in the CYP17A1 gene account for this disease. We aim to investigate the CYP17A1 mutation and analyze its possible influence on phenotype in a Chinese patient with 17OHD. Steroid hormones were assayed. The 8 exons of the CYP17A1 gene were amplified and directly sequenced. Wild-type and mutant CYP17A1 cDNA were cloned into pcDNA3.1 expression vectors and transfected into 293T cells. Finally, 17-hydroxylase and 17,20-lyase activity were detected by using progesterone and 17-hydroxypregnenolone as the substrates. A novel missense mutation c.716 G>A located in exon 4 that changed the amino acid from arginine to glutamine (R239Q) was discovered in the patient. Steric model analysis of CYP17A1 showed that R239Q changed the local structure and the electrostatic potential. Functional study indicated that the R239Q mutant caused the complete loss of both 17α-hydroxylase and 17,20-lyase activities. Our study expanded the CYP17A1 mutation spectrum. With a functional study, we confirmed that the novel mutation caused the complete loss of both 17α-hydroxylase and 17,20-lyase activities.


Assuntos
Mutação de Sentido Incorreto , Esteroide 17-alfa-Hidroxilase/genética , Adulto , Sequência de Aminoácidos , China , Feminino , Humanos , Modelos Moleculares , Dados de Sequência Molecular , Fenótipo , Alinhamento de Sequência , Esteroide 17-alfa-Hidroxilase/química , Esteroide 17-alfa-Hidroxilase/metabolismo
4.
Mol Cell Endocrinol ; 341(1-2): 71-7, 2011 Jul 20.
Artigo em Inglês | MEDLINE | ID: mdl-21664248

RESUMO

Mimecan is a protein of unknown function that is expressed in the pituitary tissues of mouse and human. In this study, we observed the function of mimecan on the proopiomelanocortin (POMC) gene in the pituitary and the hypothalamo-pituitary-adrenal axis (HPAA). Incubating pituitary corticotroph AtT-20 cells with recombinant mimecan protein stimulated adrenocorticotrophic hormone (ACTH) secretion without significantly up-regulating POMC gene expression. In addition, pituitary corticotroph AtT-20 cell corticotropin-releasing hormone receptor 1 (CRHR1) gene expression was induced by mimecan. Interestingly, long-term mimecan overexpression in corticotroph cells increased CRHR1 mRNA levels while slightly decreasing POMC mRNA expression and ACTH secretion. Using mimecan knockout mice, we found that, although the serum ACTH concentration was not significantly different between wild type and mimecan knockout mice under basal conditions, the serum ACTH level was relatively lower in mimecan knockout mice after treatment with corticotropin-releasing hormone (CRH). Meanwhile, we observed that POMC and CRHR1 gene expression decreased in primary cultured knockout mouse pituitary cells compared with wild type cells. Taken together, these data suggest that mimecan expressed in pituitary corticotroph cells mainly regulates ACTH secretion in the pituitary and coordinates the HPAA.


Assuntos
Hormônio Adrenocorticotrópico/metabolismo , Corticotrofos/metabolismo , Sistema Hipotálamo-Hipofisário/metabolismo , Peptídeos e Proteínas de Sinalização Intercelular/farmacologia , Hipófise/citologia , Sistema Hipófise-Suprarrenal/metabolismo , Hormônio Adrenocorticotrópico/sangue , Animais , Linhagem Celular , Hormônio Liberador da Corticotropina/metabolismo , Expressão Gênica , Peptídeos e Proteínas de Sinalização Intercelular/genética , Peptídeos e Proteínas de Sinalização Intercelular/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Cultura Primária de Células , Pró-Opiomelanocortina/genética , Pró-Opiomelanocortina/metabolismo , Receptores de Hormônio Liberador da Corticotropina/genética , Receptores de Hormônio Liberador da Corticotropina/metabolismo
5.
Eur J Endocrinol ; 164(4): 627-33, 2011 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-21282350

RESUMO

BACKGROUND: 17α-Hydroxylase/17,20-lyase deficiency (17OHD) caused by a mutation in the CYP17A1 gene is characterized by hypertension, hypokalemia, and abnormal development of the genitalia. The majority of CYP17A1 mutations are located in the coding sequence, and several intronic splicing site mutations have been reported. OBJECTIVE: A 2.5-year-old girl with 46,XY disordered sex development exhibited a nearly normal basal cortisol level and reduced sexual steroids. This study is aimed to explore the molecular basis and analyze its possible influence on the phenotype of the patient. METHODS AND RESULTS: Mutation analysis revealed compound heterozygous CYP17A1 mutations, with c.985_987delinsAA in one allele and a synonymous substitution (c.1263G>A) in another allele. In vitro expression analysis of the allelic minigene showed that the novel nucleotide variation located in exon 8 induces a splicing signal, which results in an aberrant splicing of CYP17A1 mRNA and a missing portion of exon 8. The translation product includes the deletion of six or seven amino acids from residue position 415 without causing a frameshift. Consistent with the result of molecular modeling, functional studies in transiently transfected HEK-293T cells with the aberrantly spliced enzyme proteins showed that the deleted proteins completely abolished the enzyme activity. However, RT-PCR indicated the existence of a small fraction of normal, functionally intact enzyme, which may explain the partial masculinization of this patient. CONCLUSION: This is the first description of an exonic splicing mutation in CYP17A1 relevant to the 17OHD phenotype. It also demonstrates the importance of studying synonymous change in such patients with less severe phenotype.


Assuntos
Esteroide 17-alfa-Hidroxilase/metabolismo , Pré-Escolar , Éxons/genética , Feminino , Humanos , Mutação , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Esteroide 17-alfa-Hidroxilase/genética
6.
Mol Cell Endocrinol ; 321(2): 239-44, 2010 Jun 10.
Artigo em Inglês | MEDLINE | ID: mdl-20178827

RESUMO

Mimecan is a protein of unknown function that is expressed in the pituitary. The aim of this study is to clarify the regulation and intracellular localisation of mimecan gene expression in the pituitary. With immunohistochemistry, we observed that mimecan protein was co-expressed with ACTH in pituitary corticotroph cells. Northern and Western blot analyses revealed that mimecan expression and secretion in corticotroph cells were up-regulated by treating AtT-20 cells with glucocorticoid. Meanwhile, mimecan expression in rat primary culture pituitary cells was also promoted by glucocorticoid. Co-incubation of AtT-20 cells with RU486 and glucocorticoid completely reversed the induction of mimecan gene expression by glucocorticoid. In addition, luciferase reporter assays showed that the -1474/+43 promoter region of mimecan was sufficient for glucocorticoid-responsive mimecan expression. These data collectively suggest that mimecan expressed in pituitary corticotroph cells is increased by glucocorticoid and that the up-regulation may be mediated by the classical GR pathways.


Assuntos
Corticotrofos/efeitos dos fármacos , Glucocorticoides/farmacologia , Glicoproteínas/metabolismo , Peptídeos e Proteínas de Sinalização Intercelular/metabolismo , Regulação para Cima/efeitos dos fármacos , Animais , Linhagem Celular , Células Cultivadas , Antagonistas de Hormônios/farmacologia , Imuno-Histoquímica , Mifepristona/farmacologia , Regiões Promotoras Genéticas , RNA Mensageiro/metabolismo , Ratos
7.
Clin Endocrinol (Oxf) ; 72(3): 312-9, 2010 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-19508587

RESUMO

OBJECTIVE: P450c17 deficiency (17alpha-hydroxylase/17,20-lyase deficiency, 17OHD) is a rare form of congenital adrenal hyperplasia caused by CYP17A1 gene mutations. The D487_F489 deletion in exon 8 and Y329fs in exon 6 are relatively frequent mutations of the CYP17A1 gene in China that completely abolish the enzyme activity of P450c17. However, little remains known about steroid biosynthetic functions in carriers with these mutations in a single allele of the CYP17A1 gene, who are assumed to have 50% P450c17 activity. We investigated adrenal steroidogenic function in genotype-proven heterozygotes carrying such mutations in the CYP17A1 gene in vivo. PATIENTS AND DESIGN: Eight patients and fourteen family members from five families with 17OHD were recruited. The mutations of the CYP17A1 gene in these individuals were screened by sequencing. The hormonal response to cosyntropin (ACTH) was evaluated in the 14 genotype-proven carriers and 45 age- and gender-matched normal controls. RESULTS: Fourteen carriers of the CYP17A1 mutation - seven with the D487_F489 deletion, six with Y329fs and one with H373L - were identified from the five families with 17OHD. Compared with normal controls, carriers showed lower basal and ACTH-stimulated cortisol levels but higher ACTH-stimulated corticosterone levels. The ratios of corticosterone to cortisol in the genotype-proven heterozygotes were higher than those of the normal controls at the baseline and after cosyntropin stimulation. Similarly, the progesterone levels and the ratios of progesterone to 17-hydroxyprogesterone in the male heterozygotes were also higher than those of the normal controls, both before and after ACTH stimulation. CONCLUSION: Genotype-proven carriers of the CYP17A1 mutation who lack apparent clinical symptoms exhibit decreased adrenal 17alpha-hydroxylase activity and altered adrenal gland reserve for steroid biosynthesis.


Assuntos
11-Hidroxicorticosteroides/sangue , Hiperplasia Suprarrenal Congênita/genética , Esteroide 17-alfa-Hidroxilase/genética , Adolescente , Hiperplasia Suprarrenal Congênita/sangue , Adulto , Estudos de Casos e Controles , Cosintropina , Análise Mutacional de DNA , Feminino , Genótipo , Hormônios , Humanos , Masculino , Pessoa de Meia-Idade , Linhagem , Adulto Jovem
8.
Biochem Biophys Res Commun ; 390(4): 1208-13, 2009 Dec 25.
Artigo em Inglês | MEDLINE | ID: mdl-19878661

RESUMO

Obesity is frequently associated with malfunctions of the hypothalamus-pituitary-adrenal (HPA) axis and hyperaldosteronism, but the mechanism underlying this association remains unclear. Since the adrenal glands are embedded in adipose tissue, direct cross-talk between adipose tissue and the adrenal gland has been proposed. A previous study found that adiponectin receptor mRNA was expressed in human adrenal glands and aldosterone-producing adenoma (APA). However, the expression of adiponectin receptors in adrenal glands has not been confirmed at the protein level or in other species. Furthermore, it is unclear whether adiponectin receptors expressed in adrenal cells are functional. We found, for the first time, that adiponectin receptor (AdipoR1 and AdipoR2) mRNA and protein were expressed in mouse adrenal and adrenocortical Y-1 cells. However, adiponectin itself was not expressed in mouse adrenal or Y-1 cells. Furthermore, adiponectin acutely reduced basal levels of corticosterone and aldosterone secretion. ACTH-induced steroid secretion was also inhibited by adiponectin, and this was accompanied by a parallel change in the expression of the key genes involved in steroidogenesis. These findings indicate that adiponectin may take part in the modulation of steroidogenesis. Thus, adiponectin is likely to have physiological and/or pathophysiological significance as an endocrine regulator of adrenocortical function.


Assuntos
Adiponectina/fisiologia , Glândulas Suprarrenais/metabolismo , Aldosterona/biossíntese , Hidrocortisona/biossíntese , Receptores de Adiponectina/biossíntese , Adiponectina/farmacologia , Glândulas Suprarrenais/efeitos dos fármacos , Hormônio Adrenocorticotrópico/farmacologia , Animais , Linhagem Celular , Humanos , Masculino , Camundongos
9.
Hum Mutat ; 30(9): E855-65, 2009 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-19551906

RESUMO

Leydig cell hypoplasia (LCH) is a rare form of male pseudohermaphroditism caused by inactivating mutations in the luteinizing hormone receptor gene (LHCGR). The majority of LHCGR mutations are located in the coding sequence, resulting in impairment of either LH/CG binding or signal transduction. We report a Chinese family with two siblings (46, XY and 46, XX) carrying a missense mutation (c. 455 T>C, p. Ile152Thr) and a splice site mutation (c. 537-3 C>A). Computational analysis of the missense mutation in the three-dimensional structural model predicted it might influence the distribution of hydrogen bonds and intermolecular contacts between the hormone and receptor. Consistent with these findings, in vitro mutant analysis revealed a marked impairment of human chorionic gonadotropin binding and signal transduction. The splice-acceptor mutation (c. 537-3 C>A) resulted in abnormal splicing of LHCGR mRNA, skipping exon 7. This report expands the genotypic spectrum of LHCGR mutations, with relevant implications for the molecular analysis of this gene.


Assuntos
Transtornos do Desenvolvimento Sexual/genética , Mutação de Sentido Incorreto , Sítios de Splice de RNA/genética , Receptores do LH/genética , Grupo com Ancestrais do Continente Asiático , Sequência de Bases , Criança , Família , Feminino , Heterozigoto , Humanos , Modelos Moleculares , Conformação Proteica , RNA Mensageiro/metabolismo , Receptores do LH/metabolismo
10.
Zhonghua Yi Xue Yi Chuan Xue Za Zhi ; 26(3): 282-7, 2009 Jun.
Artigo em Chinês | MEDLINE | ID: mdl-19504440

RESUMO

OBJECTIVE: To investigate the clinical and genetic characteristics of 7 patients from 5 families with 17a-hydroxylase/17,20 lyase deficiency (17OHD) and the CYP17A1 mutation in Chinese. METHODS: Clinical features and laboratory data were collected from 5 families with 17OHD. PCR direct sequencing was performed to screen the mutation of CYP17A1 gene of the patients. Polymerase chain reaction-restriction fragment length polymorphism(PCR-RFLP) and sequencing were performed to screen the mutations of CYP17A1 gene in 288 healthy individuals from Shandong province. RESULTS: Seven patients (5 of them were 46,XX; 2 were 46,XY) had typical clinical presentation of sexual infantilism, hypertension and hypokalemia. Hormone profile indicated decreased plasma cortisol and sex hormones, and elevated blood adrenocorticotrophic hormone (ACTH). TAC329AA and H373L in exon 6 and D487_F489del in exon 8 were identified from the patients. One heterozygote for D487_F489del was identified in 288 healthy controls. CONCLUSION: The TAC329AA and D487_F489del of the CYP17A1 gene were the most frequent mutations in Chinese with 17OHD.There might be certain frequency of heterozygotes for D487_F489del in Chinese population.


Assuntos
Esteroide 17-alfa-Hidroxilase/metabolismo , Esteroide 21-Hidroxilase/metabolismo , Adolescente , Adulto , Grupo com Ancestrais do Continente Asiático/genética , Éxons , Feminino , Frequência do Gene , Humanos , Hipertensão/genética , Hipopotassemia/genética , Masculino , Pessoa de Meia-Idade , Dados de Sequência Molecular , Mutação , Linhagem , Reação em Cadeia da Polimerase , Análise de Sequência de DNA , Infantilismo Sexual/genética , Infantilismo Sexual/metabolismo , Esteroide 17-alfa-Hidroxilase/genética , Esteroide 21-Hidroxilase/genética , Adulto Jovem
11.
Hum Mol Genet ; 18(6): 1156-70, 2009 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-19126779

RESUMO

Graves' disease (GD) is one of the most common human autoimmune diseases, and recent data estimated a prevalence of clinical hyperthyroidism of 0.25-1.09% in the population. Several reports have linked GD to the region 5q12-q33; and a locus between markers D5s436 and D5s434 was specifically linked to GD susceptibility in the Chinese population. In the present study, association analysis was performed using a large number of single-nucleotide polymorphisms (SNPs) at this locus in 2811 patients with GD recruited from different geographic regions of China. The strongest associations with GD in the combined Chinese Han cohorts were mapped to two SNPs in the promoter (pSNP) of SCGB3A2 [SNP76, rs1368408, P = 1.43 x 10(-6), odds ratio (OR) = 1.28 and SNP75, -623 - -622, P = 7.62 x 10(-5), OR = 1.32, respectively], a gene implicated in immune regulation. On the other hand, pSNP haplotypes composed of the SNP76 (rs1368408)+SNP74 (rs6882292) or SNP76+SNP75 (-623 approximately -622, AG/T) variants are correlated with high disease susceptibility (P = 0.0007, and P = 0.0192, respectively) in this combined Chinese Han cohort. Furthermore, these haplotypes were associated with reduced SCGB3A2 gene expression levels in human thyroid tissue, while functional analysis revealed a relatively low efficiency of SCGB3A2 promoters of the SNP76+SNP75 and SNP76+SNP74 haplotypes in driving gene expression. These results suggest that the SCGB3A2 gene may contribute to GD susceptibility.


Assuntos
Predisposição Genética para Doença , Doença de Graves/genética , Polimorfismo de Nucleotídeo Único/genética , Regiões Promotoras Genéticas , Proteínas/genética , Uteroglobina/genética , Animais , Pareamento de Bases/genética , Sequência de Bases , Sítios de Ligação , Sequência Conservada , Perfilação da Expressão Gênica , Regulação da Expressão Gênica , Ligação Genética , Marcadores Genéticos , Haplótipos , Humanos , Camundongos , Dados de Sequência Molecular , Proteínas/metabolismo , Receptores Imunológicos/genética , Receptores Imunológicos/metabolismo , Análise de Regressão , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Secretoglobinas , Uteroglobina/metabolismo
12.
J Mol Endocrinol ; 42(1): 67-74, 2009 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-18974228

RESUMO

Although circulating ghrelin levels correlate inversely with adiposity at baseline, little is known about the effect of percent visceral adipose tissue value (PVATV) on ghrelin expression and secretion in response to fasting. Our study demonstrated that ghrelin increased with 24-h fasting in rats with the lowest PVATV (less than 6%), after 3 days in rats with intermediate PVATV (6-9%) and 5 days in rats with the highest PVATV (greater than 9%). Ghrelin mRNA in the stomach was increased after 3 days in low-PVATV (5.8+/-0.9%) rats but not in high-PVATV (14+/-1.6%) rats. Therefore, both ghrelin secretion and mRNA were delayed in response to fasting in rats with increased visceral fat. In rats matched for PVATV, but with different body weights, the fasting induced similar levels of increased ghrelin while in rats with different PVATV ghrelin secretion was different in response to fasting, even when body weights were matched in two groups. These data suggested that the initial PVATV, not lean mass, was related to the pattern of plasma ghrelin in response to fasting in rats.


Assuntos
Adiposidade , Composição Corporal , Jejum , Grelina/metabolismo , Gordura Intra-Abdominal/metabolismo , Animais , Peso Corporal , Gorduras na Dieta , Grelina/sangue , Grelina/genética , Humanos , Leptina/sangue , Masculino , RNA Mensageiro/metabolismo , Distribuição Aleatória , Ratos , Ratos Sprague-Dawley , Estômago/anatomia & histologia , Estômago/fisiologia
13.
Biochem Biophys Res Commun ; 344(2): 562-70, 2006 Jun 02.
Artigo em Inglês | MEDLINE | ID: mdl-16620784

RESUMO

Ninety-eight genes/ESTs with differential expressions in epididymal adipose tissue of fed and 3-day fasting (F3) rats were identified by microarray analysis. Genes for lipogenesis, glycolysis, and glucose aerobic oxidation were decreased in response to starvation. Further study was performed to investigate the expression patterns of these genes in rat tissues after short- and long-term starvations. The results of the increased expression of the pyruvate dehydrogenase kinase 4 (PDK4) gene and decreased pyruvate dehydrogenase (PDH) in rat muscle together with decreased fatty acid synthase (FAS) in rat adipose tissue after 1 day of fasting (F1) suggested from transcriptional level that glucose aerobic oxidation was down-regulated in rat muscle and synthesis of saturated fatty acids was inhibited in rat adipose tissue after short-term fasting. It was noted that the transcriptions of genes involved in the fatty acid oxidation, such as very-long-chain Acyl-CoA dehydrogenase (LCAH), Acyl-CoA oxidase (ACO), carnitine palmitoyltransferase-I (CPT-I), and carnitine-acylcarnitine translocase (CAT)L, were greatly increased in F1 rat liver, then began to decrease in F3 and 5-day fasting (F5) rat liver, combined with significantly increased serum non-esterified fatty acids (NEFA) in F1 rats and increased urea in F5 rats, suggesting that inhibition of the oxidation of lipid and not the decreased availability of these fuels may play an important role in the phase II-phase III of fasting transition in the long-term fasting rats.


Assuntos
Metabolismo Energético/fisiologia , Jejum/metabolismo , Regulação da Expressão Gênica/fisiologia , Fatores de Transcrição/metabolismo , Transcrição Genética/fisiologia , Adaptação Fisiológica/fisiologia , Animais , Masculino , Ratos , Ratos Sprague-Dawley , Fatores de Tempo
14.
Zhongguo Yi Xue Ke Xue Yuan Xue Bao ; 28(6): 840-4, 2006 Dec.
Artigo em Chinês | MEDLINE | ID: mdl-17260479

RESUMO

Adipose tissue is not simply a depot of energy, but is an active endocrine organ. The adipokines play an important role in the pathogenesis of metabolic syndrome. The proinflammatory adipokines secreted from expanded visceral adipose tissue directly induce insulin resistance and vascular injuries. A better understanding of the endocrine function of adipose tissue may lead to more rational therapy for metabolic syndrome.


Assuntos
Adiponectina/fisiologia , Leptina/fisiologia , Síndrome Metabólica/fisiopatologia , Resistina/fisiologia , Tecido Adiposo/fisiopatologia , Desenho de Fármacos , Síndrome Metabólica/tratamento farmacológico , Fator de Necrose Tumoral alfa/fisiologia
15.
Acta Pharmacol Sin ; 26(8): 976-81, 2005 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-16038631

RESUMO

AIM: To investigate the expression of feeding-related peptide receptors mRNA in GT1-7 cell line and roles of leptin and orexins in the control of GnRH secretion. METHODS: Receptors of bombesin3, cholecystokinin (CCK)-A, CCK-B, glucagon-like peptide (GLP)1, melanin-concentrating hormone (MCH)1, orexin1, orexin2, neuromedin-B, neuropeptide Y (NPY)1 and NPY5, neurotensin (NT)1, NT2, NT3, and leptin receptor long form mRNA in GT1-7 cells were detected by reversed transcriptase-polymerase chain reaction. GT1-7 cells were treated with leptin, orexin A and orexin B at a cohort of concentrations for different lengths of time, and GnRH in medium was determined by radioimmunoassay (RIA). RESULTS: Receptors of bombesin 3, CCK-B, GLP1, MCH1, orexin1, neuromedin-B, NPY1, NPY5, NT1, NT3, and leptin receptor long form mRNA were expressed in GT1-7 cells, of which, receptors of GLP1, neuromedin-B, NPY1, and NT3 were highly expressed. No amplified fragments of orexin2, NT2, and CCK-A receptor cDNA were generated with GT1-7 RNA, indicating that the GT1-7 cells did not express mRNA of them. Leptin induced a significant stimulation of GnRH release, the results being most significant at 0.1 nmol/L for 15 min. In contrast to other studies in hypothalamic explants, neither orexin A nor orexin B affected basal GnRH secretion over a wide range of concentrations ranging from 1 nmol/L to 500 nmol/Lat 15, 30, and 60 min. CONCLUSION: Feeding and reproductive function are closely linked. Many orexigenic and anorexigenic signals may control feeding behavior as well as alter GnRH secretion through their receptors on GnRH neurons.


Assuntos
Hormônio Liberador de Gonadotropina/metabolismo , Leptina/farmacologia , Neuropeptídeos/farmacologia , RNA Mensageiro/metabolismo , Receptores de Peptídeos/genética , Animais , Linhagem Celular , Relação Dose-Resposta a Droga , Ingestão de Alimentos/genética , Expressão Gênica , Receptor do Peptídeo Semelhante ao Glucagon 1 , Peptídeos e Proteínas de Sinalização Intracelular/farmacologia , Receptores de Orexina , Orexinas , RNA Mensageiro/genética , Radioimunoensaio , Receptor de Colecistocinina B/genética , Receptores da Bombesina/genética , Receptores de Superfície Celular/genética , Receptores Acoplados a Proteínas G , Receptores de Glucagon/genética , Receptores para Leptina , Receptores de Neuropeptídeos/genética , Receptores de Neuropeptídeo Y/genética , Receptores de Neurotensina/genética , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Fatores de Tempo
16.
Zhonghua Nei Ke Za Zhi ; 43(7): 515-8, 2004 Jul.
Artigo em Chinês | MEDLINE | ID: mdl-15312406

RESUMO

OBJECTIVE: To investigate the circadian rhythmicity of adiponectin in patients with Cushing's syndrome and obesity, as well as in normal subjects. The effects of glucocorticoids, insulin and leptin on the secretion of adiponectin were also explored. METHODS: 15 patients with Cushing's syndrome and 10 with obesity as well as 9 normal subjects were recruited and their serum adiponectin, glucocorticoids, insulin and leptin levels were determined 6 times a day (8:00, 12:00, 16:00, 20:00, 24:00, 3:00). RESULTS: Circadian rhythmicity of adiponectin was not observed, but the adiponectin levels in patients with obesity were lower than those in the normal subjects at all 6 time spots. The area under curve (AUC) of serum adiponectin concentrations were significantly negatively correlated with body mass index (BMI, r = 0.46, P < 0.01), waist circumference (r = -0.33, P < 0.05) and insulin AUC (r = -0.36, P < 0.05). A multiple linear regression analysis revealed that BMI and waist circumference were two significant independent parameters of the plasma adiponectin level. The adiponectin levels did not manifest any change after short term dexamethasone administration with both high and low doses, but were obviously decreased after surgery. CONCLUSIONS: Neither long-term endogenous hyperglucocorticoidism nor short-term dexamethasone administration affects the serum adiponectin levels and the serum adiponectin concentrations remain unchanged even with elevated postprandial insulin levels.


Assuntos
Ritmo Circadiano , Síndrome de Cushing/sangue , Hidrocortisona/sangue , Insulina/sangue , Peptídeos e Proteínas de Sinalização Intercelular/sangue , Leptina/sangue , Adiponectina , Adolescente , Adulto , Área Sob a Curva , Índice de Massa Corporal , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Obesidade/sangue
17.
Zhonghua Yi Xue Za Zhi ; 83(4): 338-40, 2003 Feb 25.
Artigo em Chinês | MEDLINE | ID: mdl-12812656

RESUMO

OBJECTIVE: To observe the effect of berberine on the differentiation of 3T3-L1 preadipocytes into adipocytes and to elucidate its mechanism. METHODS: 3T3-L1 preadipocytes were cultured and then divided into 7 groups into whose media were added berberine of the concentrations of 0, 0.1, 1, 10, and 100 micro mol/L, 100 nmol/Linsulin, and 10 micro mol/L berberine + 100 nmol/L insulin. The proliferation of 3T3-L1 preadipocytes was detected by MTT method. The accumulation of lipid in the cytoplasm of differentiated adipocytes was observed by oil red O staining. The peroxisome proliferation activated receptor gamma2 (PPARgamma2) mRNA and protein were detected by RT-PCR and Western blotting respectively. RESULTS: MTT method showed that the absorbance at 570 nm of 3T3-L1 preadipocytes increased by 17% (P < 0.01), 36% (P < 0.001), and 22% (P < 0.05) in the groups of 1, 10, and 100 micro mol/L berberine, by 53% (P < 0.0001)in the group of 100 nmol/L insulin, and by 66% in the group of 10 micro mol/L berberine + 100 nmol/L insulin. There were less and smaller lipid droplets in the 3T3-L1 adipocytes treated with berberine as compared with the untreated control cells and only 10% - 20% of the treated cells displayed big lipid drops. RT-PCR showed that berberine significantly reduced the expression of PPARgamma2 mRNA by 48% (P < 0.01) in the course of 3T3-L1 adipocyte differentiation. Western blotting showed that berberine inhibited the expression of PPARgamma2 protein. CONCLUSION: Berberine promotes the proliferation of 3T3-L1 preadipocytes, decreases the accumulation of lipid drops therein, and inhibits the terminal differentiation of adipocyte, which may be associated with its effect on decreasing the expression of PPARgamma2 mRNA and protein, suggesting that berberine has advantages in the treatment of obesity patients with type 2 diabetes.


Assuntos
Adipócitos/citologia , Berberina/farmacologia , Células 3T3-L1 , Animais , Diferenciação Celular/efeitos dos fármacos , Divisão Celular/efeitos dos fármacos , Camundongos , RNA Mensageiro/análise , Receptores Citoplasmáticos e Nucleares/análise , Receptores Citoplasmáticos e Nucleares/genética , Células-Tronco/citologia , Fatores de Transcrição/análise , Fatores de Transcrição/genética
19.
Zhong Xi Yi Jie He Xue Bao ; 1(1): 9-11, 2003 May.
Artigo em Chinês | MEDLINE | ID: mdl-15339602

RESUMO

In July 2002, the Women's Heath Initiative (WHI) clinical trial, designed to clarify the risks and benefits of combination hormone replacement therapy (HRT) to the postmenopausal women declared that interim safety review after an average follow-up of 5.2 years found that a combination of estrogen and progestin frequently prescribed to postmenopausal women in USA increased the risk of invasive breast cancer, heart disease, stroke, and pulmonary embolism while reduced bone fractures and colorectal cancer. The overall risks of HRT outweigh the benefits, which provides an opportunity for traditional Chinese medicine (TCM) going abroad. A variety of clinical and experimental evidences have showed that TCM exerts quite satisfactory effect on relieving postmenopausal symptoms with little adverse effect, hence a potential role to replace or to improve HRT or to reduce the side effect induced by HRT.


Assuntos
Terapia de Reposição Hormonal/efeitos adversos , Medicina Tradicional Chinesa , Pós-Menopausa , Neoplasias da Mama/induzido quimicamente , Estrogênios/efeitos adversos , Feminino , Humanos , Menopausa , Pessoa de Meia-Idade , Fatores de Risco
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