去甲肾上腺素及其受体在痛性糖尿病神经病变中的作用

去甲肾上腺素(NE)作为中枢神经系统和交感神经系统中广泛分布的一种单胺类神经递质,其在疼痛方面的调节作用不容忽视.NE及其受体系统与痛性糖尿病神经病变的发生密切相关,外周NE递质受体系统主要起促痛作用,中枢NE递质受体系统则主要起镇痛作用,有关NE及其受体系统的研究对痛性糖尿病神经病变的防治有重要意义.     

Ghrelin与消化系统疾病

Ghrelin是由Kojima等于1999年发现的一种28肽，该物质最初由大鼠胃组织提取物中分离得到，是生长激素促分泌物受体 （growth hormone secretagogue receptor, GHSR）的天然内源性配体，能促进生长激素（GH）释放。进一步的研究表明．ghrelin主要来源于胃肠道，也可由下丘脑、垂体和多种外周组织器官产生。其受体在体内广泛分布，具有调节GH分泌、摄食和能量平衡，影响神经内分泌以及胃肠功能、心血管系统、记忆、睡眠等多种生物学作用，是近年来研究的热点。     

抑瘤素M在心脏疾病中的研究进展

<正>抑瘤素M(oncostatin M,OSM)于1986年被Zarling等研究发现,可由U937淋巴细胞分泌,因其在体外可抑制黑素瘤细胞得名。OSM主要表达于造血细胞,依赖白细胞介素(interleukin,IL)6家族共有受体及信号转导因子糖蛋白130(glucoprotein 130,gp130),OSM受体及白血病抑制因子受体(leukemia inhibitory factor receptor,LIFR)参与细胞内信号转导。现有研究表明,当中性粒细胞、CD4阳性细胞、单     

肝硬化患者血清一氧化氮和几种白细胞介素检测的临床意义

目的 探讨肝硬化患者血清一氧化氮(NO)、白细胞介素-2(IL-2)、白细胞介素-6(IL-6)、白细胞介素-8(IL-8)及可溶性白细胞介素-2受体(sIL-2R)变化的临床意义.方法 应用ELISA法测定肝硬化患者及正常对照组的血清IL-6、IL-8及sIL-2R含量;应用MTT法检测血IL-2活性;应用荧光法检测血清NO水平.结果 肝硬化患者血清IL-2、sIL-2R、IL-6、IL-8及NO水平:(5741.53±4376.52)U/ml、(486.76±46.41)U/ml、(15.78±3.04)pg/ml、(23.89±2.13)pg/ml及(6.33±0.37)μmol/L,显著高于正常对照组:(173.88±92.21)U/ml、(242.36±35.78)U/ml、(6.14±3.12)pg/ml、(17.71±1.32)pg/ml及(3.68±0.34)μmol/L,并随肝功受损程度进行性增加.结论 肝硬化患者血清IL-2、sIL-2R、IL-6及IL-8增加可能为NO增多的诱发因素;肝功能损伤可能是白细胞介素活性增加的重要原因.     

神经肽受体与肺神经内分泌瘤

肺神经内分泌瘤是一类特殊的肿瘤,具有神经内分泌的功能表现,可以合成、贮存和分泌各种神经胺类及肽类化学递质,并引起相应的临床综合征.近年来研究表明肺神经内分泌瘤表面存在多种神经肽受体,它们在肺神经内分泌瘤的白分泌、旁分泌及内分泌调节中具有重要作用.本文综述了多种神经肽受体在肺神经内分泌瘤表面的分布及其生物学功能,并探讨了其在肺神经内分泌瘤临床诊治中的应用前景.     

摄食、肥胖与神经免疫内分泌系统

本文首先简述神经内分泌、免疫内分泌和神经免疫内分泌的相关进展,然后从神经免疫内分泌的角度认识摄食、超重和肥胖.     

肝硬化患者血清—氧化氮和几种白细胞介素检测的临床意义

目的　探讨肝硬化患者血清一氧化氮 (NO)、白细胞介素 2 (IL 2 )、白细胞介素 6 (IL 6 )、白细胞介素 8(IL 8)及可溶性白细胞介素 2受体 (sIL 2R)变化的临床意义。方法　应用ELISA法测定肝硬化患者及正常对照组的血清IL 6、IL 8及sIL 2R含量 ;应用MTT法检测血IL 2活性 ;应用荧光法检测血清NO水平。结果　肝硬化患者血清IL 2、sIL 2R、IL 6、IL 8及NO水平 :(5 741.5 3± 4376 .5 2 )U/ml、(486 .76± 46 .41)U/ml、(15 .78± 3.0 4) pg/ml、(2 3.89± 2 .13)pg/ml及 (6 .33± 0 .37) μmol/L ,显著高于正常对照组 :(173.88± 92 .2 1)U/ml、(2 42 .36± 35 .78)U/ml、(6 .14± 3.12 ) pg/ml、(17.71± 1.32 )pg/ml及 (3.6 8± 0 .34 ) μmol/L ,并随肝功受损程度进行性增加。 结论　肝硬化患者血清IL 2、sIL 2R、IL 6及IL 8增加可能为NO增多的诱发因素 ;肝功能损伤可能是白细胞介素活性增加的重要原因。     

白细胞介素36与肺部炎症性疾病的相关性研究

白细胞介素36是白细胞介素1家族成员,包括白细胞介素36α、白细胞介素36β、白细胞介素36γ和白细胞介素36受体拮抗剂,其共同受体是白细胞介素36受体.白细胞介素36与白细胞介素1家族具有同源性,可以激活丝裂原激活蛋白激酶、核因子-κB信号通路,参与肺部炎症性疾病的发生和发展过程.现对白细胞介素36的命名、生物学特点...     

衰老与白细胞介素2及其受体关系的研究进展

在衰老与免疫系统关系的研究中,发现衰老与机体的白细胞介素2(IL-2)产生和白细胞介素2受体(IL-2R)表达水平有较为密切关系。本文对衰老与白细胞介素2及其受体关系的研究进展作一综述。     

白细胞介素-6与中枢神经系统疾病

白细胞介素 6 (IL 6 )是重要的炎症细胞因子之一 ,也是神经保护和神经营养因子之一 ,在脑血管病、脑外伤、神经变性性疾病和癫等疾病中起一定作用。在不同的疾病和疾病的不同时期 ,IL 6可发挥神经毒性或神经保护作用。     

Neuromedin s is a novel anorexigenic hormone

A novel 36-amino acid neuropeptide, neuromedin S (NMS), has recently been identified in rat brain and has been shown to be an endogenous ligand for two orphan G protein-coupled receptors, FM-3/GPR66 and FM-4/TGR-1. These receptors have been identified as neuromedin U (NMU) receptor type 1 and type 2, respectively. In this study, the physiological role of the novel peptide, NMS, on feeding regulation was investigated. Intracerebroventricular (icv) injection of NMS decreased 12-h food intake during the dark period in rats. This anorexigenic effect was more potent and persistent than that observed with the same dose of NMU. Neuropeptide Y, ghrelin, and agouti-related protein-induced food intake was counteracted by coadministration of NMS. Icv administration of NMS increased proopiomelanocortin mRNA expression in the arcuate nucleus (Arc) and CRH mRNA in the paraventricular nucleus (PVN). Pretreatment with SHU9119 (antagonist for alpha-MSH) and alpha-helical corticotropin-releasing factor-(9-41) (antagonist for CRH) attenuated NMS-induced suppression of 24-h food intake. After icv injection of NMS, Fos-immunoreactive cells were detected in both the PVN and Arc. When neuronal multiple unit activity was recorded in the PVN before and after icv injection of NMS, a significant increase in firing rate was observed 5 min after administration, and this increase continued for 100 min. These results suggest that the novel peptide, NMS, may be a potent anorexigenic hormone in the hypothalamus, and that expression of proopiomelanocortin mRNA in the Arc and CRH mRNA in the PVN may be involved in NMS action on feeding.     

Endogenous neuromedin U has anorectic effects in the Japanese quail

Neuromedin U (NMU), which is a brain-gut peptide, was first isolated as a smooth-muscle-contracting peptide from the porcine spinal cord in 1985. Intracerebroventricular (icv) injection of NMU into rats significantly reduced the food intake during dark period, and increased oxygen consumption, locomotor activity, and body temperature suggested that NMU is an anorectic and catabolic signaling molecule in mammals. In this study, we elucidated the central role of NMU in avian species using Japanese quail. Gene cloning analysis revealed that the amino acid sequence of Japanese quail NMU has high homology with that of chick, and low homology with that of rat except the C-terminal biologically active region. RT-PCR analysis revealed that NMU mRNA was expressed in various central and peripheral tissues. Both intraperitoneal (ip) and icv administration of synthetic Japanese quail NMU resulted in a significant reduction in food intake and increase in body temperature and locomotor activity in Japanese quails. Conversely, the administration of rat NMU into Japanese quail resulted in the opposite effects on food intake, body temperature, and locomotor activity. These opposite results may indicate that rat NMU act as an antagonist toward the Japanese quail NMU receptor. These results suggest that endogenous NMU plays an important role in the regulation of food intake and body temperature in avian species.     

Central administration of neuromedin U activates neurons in ventrobasal hypothalamus and brainstem

Neuromedin U (NMU) is a peptide isolated from the porcine spinal cord. Recently, two receptors for NMU have been identified and characterized. A recent study indicated that NMU is an anorectic chemical in the brain. The present study shows that NMU has an action in the brain to inhibit food intake in rats. Intracerebroventricular injection of NMU inhibited dark-phase feeding. Animals injected with NMU showed a strong increase in Fos-immunoreactive nuclei in the paraventricular nucleus (PVN) and supraoptic nucleus (SON) of the hypothalamus, and in the parabrachial nucleus of the brain stem. Double immunohistochemistry revealed that a high number of oxytocin-immunoreactive neurons in the PVN and SON contained Fos after intracerebroventricular injection of NMU. In addition, a small proportion of vasopressinergic cells within the PVN and SON were found to contain Fos. The effect of NMU on the hypothalamus and brain stem contributes to the inhibitory effects of NMU on feeding behavior.     

Differential thresholds of neuromedins B-, C-, and bombesin-induced anorexia and crop-emptying rate in chicks

Neuromedin B (NMB) and neuromedin C (NMC) are homologs of bombesin and are distributed throughout both the brain and gastrointestinal tract. The physiological roles of these bombesin-like peptides in chicks (Gallus gallus) have not been documented. Therefore, the purpose of the present study was to measure the effects of these bombesin-like peptides on food intake, crop-emptying rate and body temperature in chicks, and then to compare these effects with those of bombesin. Intracerebroventricular (ICV, 5 nmol) and intraperitoneal (IP, 300 nmol/kg) injections of NMB, NMC, and bombesin significantly decreased food deprivation-induced food intake. When ICV injected (5 nmol), all three peptides significantly reduced crop-emptying rate. IP injection of NMC and bombesin (300 nmol/kg) also reduced crop-emptying rate while NMB did not. The magnitude of food intake suppression and crop-emptying rate reduction were greater for bombesin than NMB and NMC. ICV and IP injections of NMB, NMC and bombesin did not affect cloacal temperature. In sum, the present study suggests that central and peripheral NMB and NMC are associated with reduced food intake and crop-emptying of chicks, but these effects are weaker than those of bombesin.     

Combined blockade of both micro - and kappa-opioid receptors prevents the acute orexigenic action of Agouti-related protein

Agouti-related protein (AgRP) is an endogenous antagonist at the melanocortin 3 and 4 receptor in the hypothalamus. Central administration of AgRP produces a robust increase in food intake, and this effect can be blocked by administration of nonspecific opioid receptor antagonist. Such results implicate opioid receptors as critical to mediating the effects of AgRP. To determine which opioid receptor subtype is critical, we first determined the highest i3vt (administered into the third ventricle) dose of two specific opioid antagonists, nor-Binaltorphine or beta-funaltrexamine, that did not influence food intake on their own. Then, rats were pretreated with either of these two antagonists before i3vt AgRP and access to a high-fat diet. For neither the kappa- nor the micro -specific antagonist was there any effect to block the effects of AgRP on food intake. However, administration of both the kappa- and micro -receptor antagonists does significantly reduce the effect of AgRP. The current results implicate opioid receptors as critical downstream mediators of the potent effects of AgRP to increase food intake but indicate that either micro - or kappa-receptor activation is sufficient for AgRP's effect.     

Identification of a G protein-coupled receptor for pheromone biosynthesis activating neuropeptide from pheromone glands of the moth Helicoverpa zea

Pheromone biosynthesis-activating neuropeptide (PBAN), a peptide produced by the subesophageal ganglion, is used by a variety of moths to regulate pheromone production. PBAN acts directly on pheromone gland cells by using calcium and cAMP as second messengers. We have identified a gene encoding a G protein-coupled receptor (GPCR) from pheromone glands of the female moth Helicoverpa zea. The gene was identified based on sequence identity to a group of GPCRs from Drosophila that are homologous to neuromedin U receptors in vertebrates. The full-length PBAN receptor was subsequently cloned, expressed in Sf9 insect cells, and shown to mobilize calcium in response to PBAN. This response was dose-dependent (EC50 = 25 nM) with a maximum response at 300 nM and a minimal observable response at 10 nM. Four additional peptides produced by the PBAN-encoding gene were also tested for activity, and it was determined that three had similar activity to PBAN and the other was slightly less active. Peptides belonging to the same family as PBAN, namely pyrokinins, as well as the vertebrate neuromedin U peptide also induced a calcium response. We have identified a GPCR for the PBAN/pyrokinin family of peptides with a known function of stimulating pheromone biosynthesis in female moths. It is related to several receptors from insects (Drosophila and Anopheles) and to neuromedin U and ghrelin receptors from vertebrates.     

Two chicken neuromedin U receptors: characterization of primary structure, biological activity and tissue distribution

Neuromedin U (NMU) is a bioactive peptide that is involved in a variety of physiological functions. Two of its receptors, NMUR1 and NMUR2, have been identified and characterized in mammals. In this study, we performed cDNA cloning of chicken NMUR1 and NMUR2, and characterized their primary structure, biological activity, and expression patterns in chicken tissues. The chicken NMUR1 and NMUR2 cDNAs encoded 438 and 395 amino acid sequences, respectively. Chicken NMUR1 showed 54.8%-56.5% sequence identity with human, rat, and mouse NMUR1, and NMUR2 shared 67.3%-70.1% sequence identity with mammalian orthologs. Both chicken receptors have typical characteristics of G-protein-coupled receptors with seven transmembrane domains and the D/ERY motif. An increase in intracellular Ca²⁺ mobilization was observed in HEK293 cells transfected with chicken NMUR1 or NMUR2 cDNA and treated with chicken or rat NMU. Real-time PCR analysis revealed that NMUR1 mRNA was preferentially expressed in the intestinal tissues such as the duodenum, jejunum, ileum, cecum, and colon/rectum, and brain regions such as the midbrain and optic lobe, and the ovary in adult hens. NMUR2 mRNA was exclusively expressed in the brain regions such as the cerebrum and midbrain. These results indicate that NMUR1 and NMUR2 mRNAs, which encode functional receptor proteins, are expressed in chicken tissues with different distribution patterns.     

Studies of the neuromedin U-2 receptor gene in human obesity: evidence for the existence of two ancestral forms of the receptor

Central administration of neuromedin U (NMU) suppresses food intake acting through the NMU-2 receptor (NMU2R), which is expressed in the hypothalamus. We screened the NMU2R gene in 96 patients with severe early-onset obesity. A common variant haplotype was found (f-0.21). This common variant haplotype was unusual in nature, consisting of four non-contiguous missense changes in complete linkage disequilibrium, and across two separate exons. The variant haplotype resulted in four amino acid substitutions (S295T/F312L/P380L/ M385 V) and was present in several other Europid populations and in subjects of South Asian, East Asian and African American origin, but not in eleven African Pygmies. This variant haplotype was not associated with obesity or related traits in 500 subjects from a prospective population-based cohort. In summary, we have identified two markedly different isoforms of the NMU-2 receptor, presumably arising through an ancient and complex mutational event; no genetic associations between this haplotype and obesity-related traits were, however, discerned. Further investigation of the pharmacogenomic consequences of NMU2R variation in humans is warranted.     

Appetite suppression based on selective inhibition of NPY receptors

AIM: The aim of this review is to critically assess available evidence that blockade of the actions of NPY at one of the five NPY receptor subtypes represents an attractive new drug discovery target for the development of an appetite suppressant drug. RESULTS: Blockade of the central actions of NPY using anti-NPY antibodies, antisense oligodeoxynucleotides against NPY and NPY receptor antagonists results in a decrease in food intake in energy-deprived animals. These results appear to show that endogenous NPY plays a role in the control of appetite. The fact that NPY receptors exist as at least five different subtypes raises the possibility that the actions of endogenous NPY on food intake can be adequately dissociated from other effects of the peptide. Current drug discovery has produced a number of highly selective NPY receptor antagonists which have been used to establish the NPY Y(1) receptor subtype as the most critical in regulating short-term food intake. However, additional studies are now needed to more clearly define the relative contribution of NPY acting through the NPY Y2 and NPY Y5 receptors in the complex sequence of physiological and behavioral events that underlie the long-term control of appetite. CONCLUSIONS: Blockade of the NPY receptor may produce appetite-suppressing drugs. However, it is too early to state with certainty whether a single subtype selective drug used alone or a combination of NPY receptor selective antagonists used in combination will be necessary to adequately influence appetite regulation.     

Transgenic overexpression of neuromedin U promotes leanness and hypophagia in mice

Recent work has shown that neuromedin U (NmU), a peptide initially identified as a smooth muscle contractor, may play a role in regulating food intake and energy homeostasis. To further evaluate this putative function, we measured food intake, body weight, energy expenditure and glucose homeostasis in transgenic mice that ubiquitously overexpress murine proNmU. NmU transgenic mice were lighter and had less somatic and liver fat, were hypophagic, and had improved insulin sensitivity as judged by an intraperitoneal insulin tolerance test. Transgenic mice had higher levels of hypothalamic NPY, POMC and MCH mRNA. There was no difference in O2 consumption between genotypes; however, NmU transgenic mice displayed a modest increase in respiratory quotient during food deprivation and refeeding. There were no behavioral disturbances in the NmU transgenic mice that could account for the results (e.g. changes in locomotor activity). When placed on a high-fat diet, transgenic mice remained lighter than wild-type mice and ate less, but gained weight at a rate similar to wild-type mice. Despite the increased weight gain with high-fat feeding, glucose tolerance was significantly improved in the transgenic mice. These findings support the hypothesized role of NmU as an endogenous anorexigenic peptide.