Adrenocorticotropin hormone (ACTH), which is secreted in response to psychological stress, plays an important role in the hair cycle. This study examined the mechanism by which ACTH affects the hair cycle using mice d...Adrenocorticotropin hormone (ACTH), which is secreted in response to psychological stress, plays an important role in the hair cycle. This study examined the mechanism by which ACTH affects the hair cycle using mice deficient in melanocortin receptor-2(MC2R<sup>-/-</sup>), which is a main receptor for ACTH. We observed the hair cycle using female MC2R<sup>-/-</sup> mice at 15 weeks old and five days old to determine whether there were any age-dependent differences. The 15-week-old MC2R<sup>-/-</sup> mice showed the anagen phase for all mice. On the other hand, all of the MC2R<sup>+/+</sup> mice showed the telogen phase at the same age. Moreover, in the five-day-old mice, the hair growth of the MC2R<sup>-/-</sup> mice occurred earlier than in the MC2R<sup>+/+</sup> mice. Both the 15-week-old and five-day-old MC2R<sup>-/-</sup> mice had higher levels of ACTH and alpha-melanocyte stimulating hormone in the blood than did the MC2R<sup>+/+</sup> mice. In addition, in the 15-week-old MC2R<sup>-/-</sup> mice, the hair cycle shifted to the telogen phase following the administration of a cyclic guanosine monophosphate (cGMP) inhibitor and MC1R/MC5R inhibitor. In the five-day-old MC2R<sup>-/-</sup> mice, the hair growth was slowed by the administration of corticosterone. These results suggest that the ACTH/MC2R system has an important role in the hair cycle.展开更多
Background Infantile spasms is a severe epileptic encephalopathy, which is refractory to conventional antiepileptic drugs. Adrenocorticotropic hormone （ACTH） has been the major therapy for infantile spasms; however,...Background Infantile spasms is a severe epileptic encephalopathy, which is refractory to conventional antiepileptic drugs. Adrenocorticotropic hormone （ACTH） has been the major therapy for infantile spasms; however, ACTH therapy is ineffective for some patients. The variations in the receptor genes can contribute to antiepileptic drug resistance. This study was to elucidate the possible associations between the variations of the MC2R gene and ACTH responsiveness in patients with infantile spasms. Methods We screened for variations in the promoter and coding region of the MC2R gene in 91 Chinese patients with infantile spasms and 94 controls, using PCR and a direct sequencing method. The frequencies of the genotypes, alleles and reconstructed haplotypes were analyzed in the cases and controls. The association between ACTH responsiveness and genetic variations of the MC2R gene was also assessed. Results Four single nucleotide polymorphisms （SNPs） were identified in the MC2R promoter, one of which was a novel specimen at position-2 from the transcription start site ATT, -2T〉C. Three SNPs （rs1893220, rs2186944 and -2T〉C） showed a significant difference between the cases and controls （P 〈0.05 for all）. The frequency of the common TCCT haplotype carrying four-SNP major alleles was significantly lower in the cases （39%） than in the controls （60%） （P=-0.00003）. The homozygous carriers of the TCCT haplotype had a much lower relative risk than the non-carriers （RR=O.42, 95%C/ 0.26-0.70, P=-0.0001）. ACTH responsiveness was strongly associated with the TCCT haplotype （P=-0.000082）. Compared with non-carriers of the TCCT haplotype, the homozygous and heterozygous carriers were more responsive to ACTH therapy （P=0.0002; P=-0.0003, respectively）. Conclusions Our results indicated that the TCCT haplotype in the MC2R promoter is strongly associated with the responsiveness of the ACTH therapy performed on patients with infantile spasms. The polymorphisms of the MC2R promoter might be one important factor that influences the efficacy of ACTH therapy on infantile spasms.展开更多
目的分离犬MC2R基因cDNA5′末端,分析其启动区域特点。方法采用了RNA连接酶介导的RACE(RLM-RACE)技术分离了犬MC2R基因和局部序列比对工具(Basic Local Alignment Search Tool,BLAST)对CDS区进行了初步验证。结果新分离了犬MC2RcDNA的5...目的分离犬MC2R基因cDNA5′末端,分析其启动区域特点。方法采用了RNA连接酶介导的RACE(RLM-RACE)技术分离了犬MC2R基因和局部序列比对工具(Basic Local Alignment Search Tool,BLAST)对CDS区进行了初步验证。结果新分离了犬MC2RcDNA的5′末端,并对其启动区序列作了初步分析。序列分析显示,该基因至少由两个外显子(exon1和exon2)组成,exon1和exon2的一部分编码5′非翻译区(5′-UTR),exon2其余的部分编码整个编码区。结论克隆了犬MC2R基因的5′末端,在其启动区发现了inr、SF-1、SP1、CRE、PPRE、AP-1等多个顺式作用元件,为犬MC2R表达调控研究奠定基础。展开更多
黑素皮质素受体-2(melanocortin2-receptor,MC2R)属于A类七个跨膜α螺旋G蛋白受体,具有通过CA/cAMP/PKA信号转导途径调节类固醇激素分泌的昼夜节律和应激引起变化的功能。MC2R基因表达障碍可导致一种常染色体隐性遗传疾病,即家族性糖皮...黑素皮质素受体-2(melanocortin2-receptor,MC2R)属于A类七个跨膜α螺旋G蛋白受体,具有通过CA/cAMP/PKA信号转导途径调节类固醇激素分泌的昼夜节律和应激引起变化的功能。MC2R基因表达障碍可导致一种常染色体隐性遗传疾病,即家族性糖皮质激素缺陷(FGD)。黑素皮质素受-体2(melanocortin2-receptor,MC2R)基因在特定组织中是否表达,表达丰度的高低是由多种调控因子相互作用决定的。本文就参与其表达调控的类固醇转录因子-1(steroidogenic factor-1,SF-1)、过氧化物增值物激活受体γ(PPARγ)、视黄酸X受体α(RXRα)、活化激活蛋白1(activatorprotein1,AP-1)DAX-1(dosage-sensitive sexreversal adrenal hypoplasia gene on the X chromosome,gene-1)和E-盒结合蛋白等因子做一综述。展开更多
In order to prepare a specific melanocortin type 2 receptor (MC2R) ligand, β1-24-corticotrophin was prepared in one-step reaction with [18F] SFB and β-1-24-corticotrophin pharmaceutical solution (1 mg/mL, pH=6.5). [...In order to prepare a specific melanocortin type 2 receptor (MC2R) ligand, β1-24-corticotrophin was prepared in one-step reaction with [18F] SFB and β-1-24-corticotrophin pharmaceutical solution (1 mg/mL, pH=6.5). [18F]SFB was prepared in a semi-automated module in two steps with an overall radiochemical yield of 47% to EOB (not-decay corrected) in 90 min. The 18F-labeled intermediates and 18F-labeled peptide was checked by RTLC and HPLC. The results show that the radiochemical purity is >95% and the yield to EOB (not-decay corrected) is 29% for final 18F-labeled peptide at optimized conditions. Preliminary in vivo studies in normal mice were performed to determine biodistribution of the 18F-labeled peptide for 150 min. The results show that the major tracer uptake is consistent with the natural distribution of MC2R receptors in mammals. Testes/blood and testes/muscle ratios for 18F-labeled peptide at 150 min were 184 and 1.56, respectively, and adipocyte/blood and adipocyte/muscle ratios at 120 min were 221 and 142, respectively. The data support the specific receptor binding of the radiolabeled peptide as reported for MC2R receptor accumulation in adipocytes and testes and demonstrates the retention of biological activity of the peptide. This tracer can be used in detection of MC2R distribution in malignancies and sex organ diseases.展开更多
文摘Adrenocorticotropin hormone (ACTH), which is secreted in response to psychological stress, plays an important role in the hair cycle. This study examined the mechanism by which ACTH affects the hair cycle using mice deficient in melanocortin receptor-2(MC2R<sup>-/-</sup>), which is a main receptor for ACTH. We observed the hair cycle using female MC2R<sup>-/-</sup> mice at 15 weeks old and five days old to determine whether there were any age-dependent differences. The 15-week-old MC2R<sup>-/-</sup> mice showed the anagen phase for all mice. On the other hand, all of the MC2R<sup>+/+</sup> mice showed the telogen phase at the same age. Moreover, in the five-day-old mice, the hair growth of the MC2R<sup>-/-</sup> mice occurred earlier than in the MC2R<sup>+/+</sup> mice. Both the 15-week-old and five-day-old MC2R<sup>-/-</sup> mice had higher levels of ACTH and alpha-melanocyte stimulating hormone in the blood than did the MC2R<sup>+/+</sup> mice. In addition, in the 15-week-old MC2R<sup>-/-</sup> mice, the hair cycle shifted to the telogen phase following the administration of a cyclic guanosine monophosphate (cGMP) inhibitor and MC1R/MC5R inhibitor. In the five-day-old MC2R<sup>-/-</sup> mice, the hair growth was slowed by the administration of corticosterone. These results suggest that the ACTH/MC2R system has an important role in the hair cycle.
基金This study was supported by the grants from the National Natural Science Foundation of China （No. 30770747）, the Beijing Municipal Natural Science Foundation （No. 7081002, No. 7042024） and the Capital Development Foundation of Beijing （No. 2003-2007）.
文摘Background Infantile spasms is a severe epileptic encephalopathy, which is refractory to conventional antiepileptic drugs. Adrenocorticotropic hormone （ACTH） has been the major therapy for infantile spasms; however, ACTH therapy is ineffective for some patients. The variations in the receptor genes can contribute to antiepileptic drug resistance. This study was to elucidate the possible associations between the variations of the MC2R gene and ACTH responsiveness in patients with infantile spasms. Methods We screened for variations in the promoter and coding region of the MC2R gene in 91 Chinese patients with infantile spasms and 94 controls, using PCR and a direct sequencing method. The frequencies of the genotypes, alleles and reconstructed haplotypes were analyzed in the cases and controls. The association between ACTH responsiveness and genetic variations of the MC2R gene was also assessed. Results Four single nucleotide polymorphisms （SNPs） were identified in the MC2R promoter, one of which was a novel specimen at position-2 from the transcription start site ATT, -2T〉C. Three SNPs （rs1893220, rs2186944 and -2T〉C） showed a significant difference between the cases and controls （P 〈0.05 for all）. The frequency of the common TCCT haplotype carrying four-SNP major alleles was significantly lower in the cases （39%） than in the controls （60%） （P=-0.00003）. The homozygous carriers of the TCCT haplotype had a much lower relative risk than the non-carriers （RR=O.42, 95%C/ 0.26-0.70, P=-0.0001）. ACTH responsiveness was strongly associated with the TCCT haplotype （P=-0.000082）. Compared with non-carriers of the TCCT haplotype, the homozygous and heterozygous carriers were more responsive to ACTH therapy （P=0.0002; P=-0.0003, respectively）. Conclusions Our results indicated that the TCCT haplotype in the MC2R promoter is strongly associated with the responsiveness of the ACTH therapy performed on patients with infantile spasms. The polymorphisms of the MC2R promoter might be one important factor that influences the efficacy of ACTH therapy on infantile spasms.
文摘目的分离犬MC2R基因cDNA5′末端,分析其启动区域特点。方法采用了RNA连接酶介导的RACE(RLM-RACE)技术分离了犬MC2R基因和局部序列比对工具(Basic Local Alignment Search Tool,BLAST)对CDS区进行了初步验证。结果新分离了犬MC2RcDNA的5′末端,并对其启动区序列作了初步分析。序列分析显示,该基因至少由两个外显子(exon1和exon2)组成,exon1和exon2的一部分编码5′非翻译区(5′-UTR),exon2其余的部分编码整个编码区。结论克隆了犬MC2R基因的5′末端,在其启动区发现了inr、SF-1、SP1、CRE、PPRE、AP-1等多个顺式作用元件,为犬MC2R表达调控研究奠定基础。
文摘黑素皮质素受体-2(melanocortin2-receptor,MC2R)属于A类七个跨膜α螺旋G蛋白受体,具有通过CA/cAMP/PKA信号转导途径调节类固醇激素分泌的昼夜节律和应激引起变化的功能。MC2R基因表达障碍可导致一种常染色体隐性遗传疾病,即家族性糖皮质激素缺陷(FGD)。黑素皮质素受-体2(melanocortin2-receptor,MC2R)基因在特定组织中是否表达,表达丰度的高低是由多种调控因子相互作用决定的。本文就参与其表达调控的类固醇转录因子-1(steroidogenic factor-1,SF-1)、过氧化物增值物激活受体γ(PPARγ)、视黄酸X受体α(RXRα)、活化激活蛋白1(activatorprotein1,AP-1)DAX-1(dosage-sensitive sexreversal adrenal hypoplasia gene on the X chromosome,gene-1)和E-盒结合蛋白等因子做一综述。
文摘In order to prepare a specific melanocortin type 2 receptor (MC2R) ligand, β1-24-corticotrophin was prepared in one-step reaction with [18F] SFB and β-1-24-corticotrophin pharmaceutical solution (1 mg/mL, pH=6.5). [18F]SFB was prepared in a semi-automated module in two steps with an overall radiochemical yield of 47% to EOB (not-decay corrected) in 90 min. The 18F-labeled intermediates and 18F-labeled peptide was checked by RTLC and HPLC. The results show that the radiochemical purity is >95% and the yield to EOB (not-decay corrected) is 29% for final 18F-labeled peptide at optimized conditions. Preliminary in vivo studies in normal mice were performed to determine biodistribution of the 18F-labeled peptide for 150 min. The results show that the major tracer uptake is consistent with the natural distribution of MC2R receptors in mammals. Testes/blood and testes/muscle ratios for 18F-labeled peptide at 150 min were 184 and 1.56, respectively, and adipocyte/blood and adipocyte/muscle ratios at 120 min were 221 and 142, respectively. The data support the specific receptor binding of the radiolabeled peptide as reported for MC2R receptor accumulation in adipocytes and testes and demonstrates the retention of biological activity of the peptide. This tracer can be used in detection of MC2R distribution in malignancies and sex organ diseases.
