Disease relevance of NMU

• In this study, we showed that airway eosinophilia was reduced in NMU-deficient mice in an allergen-induced asthma model [1].
• These data strongly implied that targeting the NMU signaling pathway would be a promising therapeutic strategy for the treatment of lung cancers [2].
• Neuromedin U: a Myb-regulated autocrine growth factor for human myeloid leukemias [3].
• Screening of neuromedin U2 receptor (NMU2R) ligands may be very useful to treat obesity for the reason that centrally administered neuromedin U affects feeding behavior, energy expenditure, and pituitary [4].
• Rats were first treated with a single dose of either 15 or 50 mg/kg body weight NMU and then fed Ro24-5531 (2.5 or 1.25 nmol/kg of diet) for 5-7 months [5].

Psychiatry related information on NMU

• NmU caused a marked increase in grooming and motor activity but did not affect PPI [6].
• These results suggest that NMU plays a role in feeding behavior and catabolic functions via CRH [7].
• The mean latency period was significantly lengthened in all the treated groups as compared to that in the only NMU-administered rats (P < 0.001) [8].

High impact information on NMU

• Peripheral activities of NMU include stimulation of smooth muscle, increase of blood pressure, alteration of ion transport in the gut, control of local blood flow and regulation of adrenocortical function [9].
• Intracerebroventricular administration of NMU markedly suppresses food intake in rats [9].
• NMU is expressed in the ventromedial hypothalamus in the rat brain, and its level is significantly reduced following fasting [9].
• To determine the cytotoxicity of 7,12-dimethylbenz[a]anthracene (DMBA) and N-nitroso-N-methylurea (NMU) on primary cultures of rat mammary cells, cultures were exposed to various concentrations of these carcinogens [10].
• Exposing Indo-1-labeled K562 cells to NmU induced an intracellular Ca(++) flux consistent with engagement of the NMU1R [3].

Chemical compound and disease context of NMU

• The principal site of action of these agents was the forestomach, squamous cell papillomas of this organ developing in 53 and 61% of the animals receiving the higher doses of NMU and N-nitroso-N-ethylurea, respectively [11].
• Recently, we have demonstrated the malignant transformation of HPV-18 C-1 cells after multiple exposures to the chemical carcinogen N-nitroso-N-methylurea (NMU) [12].
• Replacing the geminal methyl groups on the calcitriol-related side chain of these gemini compounds with trideuteriomethyl moieties further boosted the potency in the colon cancer model in mice some 10-fold, reduced NMU-induced breast cancer carcinogenesis in rats and decreased the IC(50) values for renin mRNA inhibition into the pM range [13].
• CONCLUSIONS: We propose that the local RAS in pineal gland is modified in rats with breast cancer induced by NMU through the inhibition of AspAP activity, which may lead to increased levels of Ang II [14].

Biological context of NMU

• Furthermore, NMU-R1 was also expressed in human peripheral blood eosinophils, and NMU induced cell adhesion in a dose-dependent manner [1].
• NMU-R1 was highly expressed in the eosinophil cell line, and NMU directly induced Ca(2+) mobilization and extracellular/signal-regulated kinase phosphorylation [1].
• Although its amino-acid sequence is highly conserved across species, the physiological effects of NMU are variable between species and little is known of its effects on human tissues [15].
• High-affinity binding sites for NmU were identified in canine bladder [16].
• In agreement, centrally administered NmU affects feeding behaviour, energy expenditure and pituitary output [6].

Anatomical context of NMU

• Neuromedin U (NMU) is a neuropeptide expressed not only in the central nervous system but also in various organs, including the gastrointestinal tract and lungs [1].
• These data indicate that NMU promotes eosinophil infiltration into inflammatory sites by directly activating eosinophils [1].
• Neuromedin U is a bioactive peptide isolated originally from the porcine spinal cord [17].
• TGR-1 mRNA was primarily expressed in the uterus, suggesting that TGR-1 mediates the contractile activity of neuromedin U in this tissue [17].
• Although NmU had no effect on canine uterus it did cause contraction of canine stomach, ileum, and colon [16].

Associations of NMU with chemical compounds

• We found that neuromedin U specifically and clearly elevated the extracellular acidification rates, arachidonic acid metabolite release, and intracellular Ca(2+) mobilization in Chinese hamster ovary cells expressing TGR-1 [17].
• NmU elevated levels of 5-HT in the frontal cortex and hypothalamus, with decreased levels of its metabolites in the hippocampus and hypothalamus, but did not affect dopamine function [6].
• Neuromedin U (NMU), an anorexigenic peptide, was originally isolated from porcine spinal cord in 1985 [18].
• However, leptin appears not to change NMU gene expression in either the mouse DMH or the rat pars tuberalis [19].
• In rats treated with the higher dose of NMU, Ro24-5531 was fed in combination with tamoxifen; in these experiments, Ro24-5531 significantly enhanced the ability of tamoxifen to reduce total tumor burden, as well as to increase the probability that an animal would be tumor free at the end of the experiment [5].

Physical interactions of NMU

• NMU binds to GPR66-expressing cells with high specificity to induce intracellular calcium mobilization [20].

Regulatory relationships of NMU

• Here we demonstrate that GPR66/FM-3 is specifically stimulated by NmU, causing the mobilization of intracellular calcium [21].
• 2. The prototype chemical carcinogens NMU and BP induce amplified expression of ras protooncogene in benign (noninvolved) human mammary TDLU [22].
• TAM suppressed carcinogenesis to 0% incidence like TAM+MEL in both the NMU and DMBA models [23].
• Neuromedin U and pituitary adenylate cyclase activating peptide (PACAP) have recently been demonstrated in gut nerves [24].

Other interactions of NMU

• We recently identified neuromedin U as the cognate ligand for the orphan G protein-coupled receptor FM-3 [17].
• The neuromedin u-growth hormone secretagogue receptor 1b/neurotensin receptor 1 oncogenic signaling pathway as a therapeutic target for lung cancer [2].
• We found that c-myb was elevated in AML and ALL samples, but NmU expression was increased only in AML cells [3].
• The LHbeta/FSHbeta ratio, which is an index of puberty onset, is high in young NMU-deficient mice [18].
• Two structurally related, G-protein-coupled receptors were identified as receptors for the neuropeptide, neuromedin U. This peptide is found in highest levels in the gut and genitourinary system where it potently contracts smooth muscle but is also expressed in the spinal cord and discrete regions of the brain [25].

Analytical, diagnostic and therapeutic context of NMU

• Using a genome-wide cDNA microarray to search for genes that were specifically up-regulated in non-small cell lung cancers (NSCLC), we identified an abundant expression of neuromedin U (NMU) in the great majority of lung cancers [2].
• Quantitative reverse transcriptase-polymerase chain reaction analysis of neuromedin U expression in a range of human tissues showed that the peptide is highly expressed in the intestine, pituitary, and bone marrow, with lower levels of expression seen in stomach, adipose tissue, lymphocytes, spleen, and the cortex [26].
• Sequence analysis revealed a 174 amino acid human precursor containing the 25 residue NmU peptide near the C terminus of the precursor [27].
• Furthermore, NMU-overexpressing xenografts were associated with lower animal body weight than control tumors, indicating a possible role of NMU in cancer cachexia [28].
• Molecular cloning of rat Krev-1 cDNA and analysis of the mRNA levels in normal and NMU-induced mammary carcinomas [29].

References