Neurokinin B and its receptor in idiopathic hypogonadotropic hypogonadism / 中华内分泌代谢杂志

Idiopathic hypogonadotropic hypogonadism (IHH) is characterized by delayed or absent puberty and lowered sexual function as a result of impaired pulsatile gonadotropin-realeasing hormone (GnRH) secretion.Identification of TAC3/TACR3 mutations as the culprits of IHH revealed that neurokinin B (NKB) signaling pathway was involved in the regulation of pulsatile GnRH secretion.This review focuses on the involvement of NKB signaling in pulsatile GnRH release,the discovery of TAC3/TACR3 mutations and the phenotypes,and treatment of patients who carry TAC3 or/and TACR3 mutations.

The role of neurokinin B and its receptor in hypothalamic-pituitary-gonad axis / 国际儿科学杂志

Kisspoptin signaling plays an essential role in the onset of puberty and reproductive development.Recently studies implicate that steroid-responsive NKB,kisspeptin,NK3 R,and estrogen receptor α (ERα) coexpress in arcuate nucleus of hypothalamus of variety of mammalian species and regulate the secretion of gonadotrophic hormone.The function of neurons in the hypothalamus is to regulate the estrogen negative feedback on gonadotropin-releasing hormone (GnRH) secretion.Loss of function of neurokinin B (NKB) or its receptor,the neurokinin-3 receptor produces idiopathic hypogonadotropic hypogonadism.These studies demonstrate NKB and neurokinin-3 receptor as the essential elements of the human reproductive axis.

Mutational analysis of TAC3 and TACR3 genes in patients with idiopathic central pubertal disorders / Análise de mutações nos genes TAC3 e TACR3 em pacientes com distúrbios puberais centrais idiopáticos

OBJECTIVE: To investigate the presence of variants in the TAC3 and TACR3 genes, which encode NKB and its receptor (NK3R), respectively, in a large cohort of patients with idiopathic central pubertal disorders. SUBJECTS AND METHODS: Two hundred and thirty seven patients were studied: 114 with central precocious puberty (CPP), 73 with normosmic isolated hypogonadotropic hypogonadism (IHH), and 50 with constitutional delay of growth and puberty (CDGP). The control group consisted of 150 Brazilian individuals with normal pubertal development. Genomic DNA was extracted from peripheral blood and the entire coding region of both TAC3 and TACR3 genes were amplified and automatically sequenced. RESULTS: We identified one variant (p.A63P) in NKB and four variants, p.G18D, p.L58L (c.172C>T), p.W275* and p.A449S in NK3R, which were absent in the control group. The p.A63P variant was identified in a girl with CPP, and p.A449S in a girl with CDGP. The known p.G18D, p.L58L, and p.W275* variants were identified in three unrelated males with normosmic IHH. CONCLUSION: Rare variants in the TAC3 and TACR3 genes were identified in patients with central pubertal disorders. Loss-of-function variants of TACR3 were associated with the normosmic IHH phenotype. Arq Bras Endocrinol Metab. 2012;56(9):646-52.

OBJETIVO: Investigar a presença de variantes nos genes TAC3 e TACR3, os quais codificam a NKB e seu receptor (NK3R), respectivamente, em uma coorte de pacientes com distúrbios puberais centrais idiopáticos. SUJEITOS E MÉTODOS: Duzentos e trinta e sete pacientes foram estudados: 114 com puberdade precoce central (PPC), 73 com hipogonadismo hipogonadotrófico isolado normósmico (HHI) e 50 com retardo constitucional do crescimento e desenvolvimento (RCCD). O grupo controle consistiu de 150 indivíduos brasileiros que apresentaram desenvolvimento puberal normal. O DNA genômico foi extraído de sangue periférico, e as regiões codificadoras dos genes TAC3 e TACR3 foram amplificadas e sequenciadas automaticamente. RESULTADOS: Uma variante (p.A63P) foi identificada na NKB, e quatro variantes, p.G18D, p.L58L (c.172C>T), p.W275X e p.A449S, foram identificadas no NK3R, as quais foram ausentes no grupo controle. A variante p.A63P foi identificada em uma menina com PPC, e a variante p.A449S, em uma menina com RCCD. As variantes previamente descritas, p.G18D, p.L58L e p.W275X, foram identificadas em três indivíduos com HHI normósmico do sexo masculino não relacionados. CONCLUSÃO: Variantes raras nos genes TAC3 e TACR3 foram identificadas em pacientes com distúrbios puberais centrais idiopáticos. Mutações de perda de função no gene TACR3 foram associadas com o fenótipo de HHI normósmico. Arq Bras Endocrinol Metab. 2012;56(9):646-52.

Expression of neurokinin B in hypertensive disorder complicating pregnancy / 中华围产医学杂志

Objective To investigate the relationship between the genesis of hypertensive disorder complicating pregnancy and neurokinin B (NKB).Methods The serum NKB levels of 229 women including non-pregnant women (n = 62),normal pregnant women (n = 80) and pregnant women with preeclampsia (n=37) or gestational hypertension (n= 50) were examined by enzyme linked immunosorbent assay.The umbilical blood levels of NKB and the NKB mRNA expression in the pregnant women were also tested by fluorescent quantitative reverse transcription-polymerase chain reaction technique.ANOVA and paired t-test were applied.Results (1)The maternal plasma NKB levels of normal pregnant women,patients with gestational hypertension or preeclampsia were significantly higher than that of non-pregnant women,respectively [(28.2±6.6)μg/L,(31.5±5.2)μg/L,(70.5±8.9)μg/L vs(3.2±1.8)μg/L,P＜ 0.01].In preeclampsia,gestational hypertension and normal pregnancy group,the NKB level in umbilical blood [(121.4±9.3)μg/L,(60.5±7.2)μg/L,(40.8±6.3)μg/L] were significantly higher than that of maternal plasma(P＜0.01).(2) The maternal plasma NKB level in gestational hypertension group was higher than that in normal pregnancy group,while the difference had no statistical significance (P＞0.05).The maternal plasma NKB level in preeclampsia group was higher than that in gestational hypertension group and normal pregnancy group (P＜0.01).Forty-eight hours after delivery,the maternal plasma NKB levels significantly decreased in the normal pregnant,gestational hypertension and preeclampsia group [ (14.1±4.2) μg/L,(16.4±3.8) μg/L,(25.4±5.2) μg/L],compared to the values before delivery (P＜0.01).(3) The expression of NKB mRNA in placenta of preeclampsia group was significantly higher than that of gestational hypertension group and normal pregnancy group [(3.8±0.6) × 10-3 vs(1.7±0.4) × 10-3 and (1.6±0.3) × 10-3,P＜0.01].No statistical difference was found in the expression of NKB mRNA in placenta between gestational hypertension group and normal pregnancy group (P＞0.05).Conclusions Elevated NKB level in placenta and maternal or umbilical blood might play an important role in the development of hypertensive disorder complicating pregnancy.

Relationship between neurokinin B and endotbelin-1 and hypertensive disorders complicating pregnancy / 中华妇产科杂志

Objective To investigate the relationship between neurokinin B (NKB), endothelin-1 (ET-1) and the pathogenesis of hypertensive disorder complicating pregnancy (HDCP). Methods 22 HDCP, who received antenatal examination in the Department of Obstetrics and Gynecology of Union Hospital of Tongji Medical College in Huazhong University of Science and Technology from March to July in 2005, were selected for the study, including 12 gestational hypertension (gestational hypertension group) and 10 preeclampsia (preeclamptic group); 22 normal pregnant women in the same period were served as control. At different gestational weeks, maternal plasma levels of NKB and ET-1 in three groups were detected by enzyme-linked immunoassay technique, the expression and location of NKB in placenta were examined by immunohistochemical SP, and mRNA expressions of NKB and ET-1 in placenta were measured with RT-PCR method. Results (1) At 10 - 14, 20 - 24, and 30 - 34 gestational weeks, the plasma levels of NKB and ET-1 in preeclamptic group were ( 35. 6±5.2), ( 17. 9±4. 3), (39. 5±4. 3 ), (22. 7± 3.6), (47. 1±3. 3) and (27.5±3.5) μg/L, respectively; in the control group they were (22. 9±3. 3), (10.7±5.3), (30.2±3.4), (13.2±4.1), (34.6±4.3) and (16.6±4.8) μg/L, respectively. There was a significant difference between preeclamptic group and control group ( P < 0. 05), while there was no significant difference between gestational hypertension group and control group (P>0.05).(2) Immunohistochemical staining for NKB protein was observed in all groups and was located in the villous syncytintrophoblast and villous vascular endothelial cells as well as cytoplasm of stromal cells, mostly located in villous syncytiotrophoblast. The expressions of NKB in placenta of preeclamptic group (0.244±0.020) was significantly higher than that in control group (0. 160±0. 012), with a significant difference between the two groups (P<0.05 ). However, there was no significant difference between gestational hypertension group (0.162±0.019) and control group (P>0.05). (3) The transcription levels of the NKB mRNA (0. 97±0. 36) and ET-1 mRNA (0. 90±0. 36) in preeclamptic placentas were both significantly higher than those in control groups (0. 78±0. 54, 0. 65±0. 47, respectively ), with a significant difference between the two groups( P <0. 05 ). But there was no significant difference between gestational hypertension group (0. 80±0. 40, 0. 70±0. 32, respectively) and control group (P >0. 05). (4) There was an evident positive correlation between plasma NKB and ET-1 levels in preeclampsia ( r =0. 79, P < 0. 05 ). Conclusions The significantly increased maternal plasma levels of NKB and ET-1 of patients with preeclampsia occur at early pregnancy (10 -14 gestational weeks) before the onset of clinical symptoms. The change of maternal plasma levels of NKB and ET-1 is closely related to pathogenesis of HDCP.

THE DISTRIBUTION OF NEUROKININ B IMMUNOREACTIVE NERVE FIBERS IN THE LOWER RESPIRATORY TRACT OF GUINEA PIG / 解剖学报

The distribution of neurokinin B (NKB) in the lower respiratory tract of 16 guinea pigs was investigated using radioimmunoassay. As a result, it is noted that the concentration of NKB is the highest in the lung (43.83?4.37), moderate in the bronchus (36.12?5.36) and lowest in the trachea (26.44?3.73 pg/g wet tissue). NKB-immunoreactive fibers were demonstrated by immunohistochemistry in the following locations of the lower respiratory tract: 1. within and beneath the lining epithelium, smooth muscle layer and tunica adventitia of the trachea and bronchus; 2. in the smooth muscle layer of the bronchus in the lung; 3. in the alveolar septurn; 4. within smooth muscle layer and the border between smooth muscle and tunica adventitia of the blood vessels and around the blood vessels in the lung. It is also discussed that there may be a significance about the results for exploring the function of NKB and its relationship with some respiratory diseases.

IMMUNOHISTOCHEMICAL LOCALIZATION OF NEUROKININ B RECEPTOR (NK3) IN THE CENTRAL NERVOUS SYSTEM OF THE MOUSE / 解剖学报

Objective To examine the localization of neurokinin B receptor (NK3)\|like immunoreactivity (\|LI) in the central nervous system of the mouse. Methods An immunohistochemcial staining method was used. Results NK3 receptor\|LI was localized in somatic and dendritic profiles in the most parts and in neuropil in a few regions of the mouse central nervous system. A large number of neurons with NK3\|LI was seen in the anterior olfactory nuclei, accumbens nucleus, septal area, ventral pallidum, pallidum, caudate putamen, nucleus of the stria terminalis, anterior hypothalamic area, tuber cincreum area, lateral hypothalamic area, perifornical nucleus, supraoptic nucleus, arcuate nucleus, mammillar nuclei, substatia nigra, ventral tegmental area, retrorubral area, superior and inferior colliculus, periaqueductal gray, nucleus of the solitary tract, and superficial layers of the medullary and spinal dorsal horns. The superfical layers of the cerebral cortex, piriform cortex, dorsal hippocampus, amygdal complex, reticular formation of the brainstem contained some neurons with NK3 receptor\|LI. In the ventral hippocampus, median and intralaminar nuclei of the thalamus and interpeduncular nuclei, NKR\|LI was localized in neuropil. Conclusion\ Neurons with NK3 receptor\|LI were widely distributed in the central nervous system. It may be involved in many physiological functions in the central nervous system of the mouse.\;[

DISTRIBUTION OF SP, NKA, NKB AND CGRP IMMUNOREACTIVE NERVE FIBERS IN THE TRACHEOBRONCHIAL LYMPH NODES OF GUINEA PIG / 解剖学报

Immunohistochemical study revealed the distributions of substance P, neurokinin A, neurokinin B and calcitonin gene related peptide immunoreactive nerve fibers in the medulla, cortex and capsule of tracheobronchial lymph nodes in 10 guinea pigs. More immunopositive fibers were found to be distributed in the area around the blood vessels and lymph sinuses, less in the area distant to blood vessels. The four kinds of positive immunoreactive nerve fibers were also seen within the wall of the blood vessels. The results provide some morphological basis for the study of neuroimmunomodulation.