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melanocortin receptor

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https://www.readbyqxmd.com/read/29783840/discovery-of-melanocortin-ligands-via-a-double-simultaneous-substitution-strategy-based-on-the-ac-his-dphe-arg-trp-nh-2-template
#1
Aleksandar Todorovic, Cody J Lensing, Jerry Ryan Holder, Joseph W Scott, Nicholas B Sorensen, Carrie Haskell-Luevano
The melanocortin system regulates an array of diverse physiological functions including pigmentation, feeding behavior, energy homeostasis, cardiovascular regulation, sexual function, and steroidogenesis. Endogenous melanocortin agonist ligands all possess the minimal messaging tetrapeptide sequence His-Phe-Arg-Trp. Based on this endogenous sequence, the Ac-His1-DPhe2-Arg3-Trp4-NH2 tetrapeptide has previously been shown to be a useful scaffold when utilizing traditional positional scanning approaches to modify activity at the various melanocortin receptors (MC1-5R)...
May 21, 2018: ACS Chemical Neuroscience
https://www.readbyqxmd.com/read/29780671/protection-of-cultured-brain-endothelial-cells-from-cytokine-induced-damage-by-%C3%AE-melanocyte-stimulating-hormone
#2
András Harazin, Alexandra Bocsik, Lilla Barna, András Kincses, Judit Váradi, Ferenc Fenyvesi, Vilmos Tubak, Maria A Deli, Miklós Vecsernyés
The blood-brain barrier (BBB), an interface between the systemic circulation and the nervous system, can be a target of cytokines in inflammatory conditions. Pro-inflammatory cytokines tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β) induce damage in brain endothelial cells and BBB dysfunction which contribute to neuronal injury. The neuroprotective effects of α-melanocyte stimulating hormone (α-MSH) were investigated in experimental models, but there are no data related to the BBB. Based on our recent study, in which α-MSH reduced barrier dysfunction in human intestinal epithelial cells induced by TNF-α and IL-1β, we hypothesized a protective effect of α-MSH on brain endothelial cells...
2018: PeerJ
https://www.readbyqxmd.com/read/29771759/finding-treatable-genetic-obesity-strategies-for-success
#3
Kristin Dayton, Jennifer Miller
PURPOSE OF REVIEW: Genetic obesity is responsible for up to 7% of severe childhood obesity. Although current Pediatric Endocrine Society guidelines recommend assessment of children with early-onset morbid obesity and hyperphagia for underlying genetic disorders, a vast majority of patients are not being appropriately screened for genetic obesity syndromes. RECENT FINDINGS: With advances in genetic testing, more genetic causes of obesity are being identified. Treatments are likely to be individualized, depending on the cause of the obesity, and must be targeted at addressing the underlying cause...
May 15, 2018: Current Opinion in Pediatrics
https://www.readbyqxmd.com/read/29742429/diet-induced-growth-is-regulated-via-acquired-leptin-resistance-and-engages-a-pomc-somatostatin-growth-hormone-circuit
#4
Heiko Löhr, Simon Hess, Mafalda M A Pereira, Philip Reinoß, Sandra Leibold, Christel Schenkel, Claudia M Wunderlich, Peter Kloppenburg, Jens C Brüning, Matthias Hammerschmidt
Anorexigenic pro-opiomelanocortin (Pomc)/alpha-melanocyte stimulating hormone (αMSH) neurons of the hypothalamic melanocortin system function as key regulators of energy homeostasis, also controlling somatic growth across different species. However, the mechanisms of melanocortin-dependent growth control still remain ill-defined. Here, we reveal a thus-far-unrecognized structural and functional connection between Pomc neurons and the somatotropic hypothalamo-pituitary axis. Excessive feeding of larval zebrafish causes leptin resistance and reduced levels of the hypothalamic satiety mediator pomca...
May 8, 2018: Cell Reports
https://www.readbyqxmd.com/read/29736023/mc4r-agonism-promotes-durable-weight-loss-in-patients-with-leptin-receptor-deficiency
#5
Karine Clément, Heike Biebermann, I Sadaf Farooqi, Lex Van der Ploeg, Barbara Wolters, Christine Poitou, Lia Puder, Fred Fiedorek, Keith Gottesdiener, Gunnar Kleinau, Nicolas Heyder, Patrick Scheerer, Ulrike Blume-Peytavi, Irina Jahnke, Shubh Sharma, Jacek Mokrosinski, Susanna Wiegand, Anne Müller, Katja Weiß, Knut Mai, Joachim Spranger, Annette Grüters, Oliver Blankenstein, Heiko Krude, Peter Kühnen
Genetic defects underlying the melanocortin-4 receptor (MC4R) signaling pathway lead to severe obesity. Three severely obese LEPR-deficient individuals were administered the MC4R agonist setmelanotide, resulting in substantial and durable reductions in hyperphagia and body weight over an observation period of 45-61 weeks. Compared to formerly developed and tested MC4R agonists, setmelanotide has the unique capability of activating nuclear factor of activated T cell (NFAT) signaling and restoring function of this signaling pathway for selected MC4R variants...
May 7, 2018: Nature Medicine
https://www.readbyqxmd.com/read/29726959/melanocortin-4-receptor-pathway-dysfunction-in-obesity-patient-stratification-aimed-at-mc4r-agonist-treatment
#6
Kristin L Ayers, Benjamin S Glicksberg, Alastair S Garfield, Simonne Longerich, Joseph A White, Pengwei Yang, Lei Du, Thomas W Chittenden, Jeffery R Gulcher, Sophie Roy, Fred Fiedorek, Keith Gottesdiener, Sarah Cohen, Kari E North, Eric E Schadt, Shuyu D Li, Rong Chen, Lex H T Van der Ploeg
Context: The hypothalamic melanocortin 4 receptor (MC4R)-pathway serves a critical role in regulating bodyweight. Loss of function (LoF) mutations in the MC4R pathway including mutations in the POMC (1), PCSK1, LEPR (2) or the MC4R genes (3) have been shown to be causative of early-onset severe obesity. Methods: Through a comprehensive epidemiological analysis of known and predicted LoF variants in the POMC, PCSK1 and LEPR genes, we sought to estimate the number of US individuals with bi-allelic MC4R pathway LoF variants...
May 2, 2018: Journal of Clinical Endocrinology and Metabolism
https://www.readbyqxmd.com/read/29718699/effect-of-a-melanocortin-type-2-receptor-mc2r-antagonist-on-the-corticosterone-response-to-hypoxia-and-acth-stimulation-in-the-neonatal-rat
#7
Adam J Goldenberg, Ashley L Gehrand, Emily Waples, Mack Jablonski, Brian Hoeynck, Hershel Raff
The adrenal stress response in the neonatal rat shifts from ACTH-independent to ACTH-dependent between postnatal days 2 (PD2) and 8 (PD8). This may be due to an increase in an endogenous, bioactive, non-immunoreactive ligand to the MC2R. GPS1574 is a newly described MC2R antagonist that we have shown to be effective in vitro. Further experimentation with GPS1574 would allow better insight into this seemingly ACTH-independent steroidogenic response in neonates. We evaluated the acute corticosterone response to hypoxia or ACTH injection following pretreatment with GPS1574 (32 mg/kg) or Vehicle for GPS1574 in PD2, PD8, and PD15 rat pups...
May 2, 2018: American Journal of Physiology. Regulatory, Integrative and Comparative Physiology
https://www.readbyqxmd.com/read/29714486/melanoma-imaging-using-18-f-labeled-%C3%AE-melanocyte-stimulating-hormone-derivatives-with-positron-emission-tomography
#8
Chengcheng Zhang, Zhengxing Zhang, Kuo-Shyan Lin, Joseph Lau, Jutta Zeisler, Nadine Colpo, David M Perrin, Francois Benard
Melanocortin 1 receptor (MC1R) is specifically expressed in the majority of melanomas, a leading cause of death related to skin cancers. Accurate staging and early detection is crucial in managing melanoma. Based on the α-melanocyte-stimulating hormone (αMSH) sequence, MC1R-targeted peptides have been studied for melanoma imaging, predominately for use with single-photon emission computed tomography (SPECT), with few attempts made for positron emission tomography (PET). 18 F is a commonly used PET isotope due to readily available cyclotron production, pure positron emission and a favorable half-life (109...
May 1, 2018: Molecular Pharmaceutics
https://www.readbyqxmd.com/read/29704154/pharmacological-effect-of-human-melanocortin-2-receptor-accessory-protein-2-variants-on-hypothalamic-melanocortin-receptors
#9
Jinye Liang, Lei Li, Xuanxuan Jin, Bingxin Xu, Linyu Pi, Shangyun Liu, Wei Zhu, Cong Zhang, Bing Luan, Lulu Gong, Chao Zhang
PURPOSE: Melanocortin-3 receptor (MC3R), melanocortin-4 receptor (MC4R), and a recently identified melanocortin-2 receptor accessory protein 2 (MRAP2), are highly expressed in hypothalamus and coordinately regulate energy homeostasis, but the single cellular transcriptome of melanocortin system remains unknown. Several infrequent MRAP2 variants are reported from severe obese human patients but the mechanisms on how they affect melanocortin signaling are unclear. METHODS: First, we performed in silico analysis of mouse hypothalamus RNA sequencing datasets at single-cell resolution from two independent studies...
April 27, 2018: Endocrine
https://www.readbyqxmd.com/read/29689050/activation-of-temperature-sensitive-trpv1-like-receptors-in-arc-pomc-neurons-reduces-food-intake
#10
Jae Hoon Jeong, Dong Kun Lee, Shun-Mei Liu, Streamson C Chua, Gary J Schwartz, Young-Hwan Jo
Proopiomelanocortin (POMC) neurons in the arcuate nucleus of the hypothalamus (ARC) respond to numerous hormonal and neural signals, resulting in changes in food intake. Here, we demonstrate that ARC POMC neurons express capsaicin-sensitive transient receptor potential vanilloid 1 receptor (TRPV1)-like receptors. To show expression of TRPV1-like receptors in ARC POMC neurons, we use single-cell reverse transcription-polymerase chain reaction (RT-PCR), immunohistochemistry, electrophysiology, TRPV1 knock-out (KO), and TRPV1-Cre knock-in mice...
April 2018: PLoS Biology
https://www.readbyqxmd.com/read/29688747/association-between-two-common-missense-substitutions-thr6lys-and-val81ile-in-mc3r-gene-and-childhood-obesity-a-meta-analysis
#11
Charita Koya, Tsung Yu, Carol Strong, Meng-Che Tsai
BACKGROUND: Two common missense variants in the melanocortin-3 receptor (MC3R) gene, Thr6Lys (T6K) and Val81Ile (V81I), are presumably correlated with pediatric obesity. This meta-analysis aimed to examine and synthesize evidence on the association between these two common MC3R polymorphisms and the development of childhood obesity. METHODS: A combination of words relevant to the research question was searched on PubMed, EMBASE, Scopus, and the Cochrane database...
April 24, 2018: Childhood Obesity
https://www.readbyqxmd.com/read/29679901/replacement-of-arg-with-nle-and-modified-d-phe-in-the-core-sequence-of-mshs-ac-his-d-phe-arg-trp-nh-2-leads-to-hmc1r-selectivity-and-pigmentation
#12
Saghar Mowlazadeh Haghighi, Yang Zhou, Jixun Dai, Jonathon R Sawyer, Victor J Hruby, Minying Cai
Melanoma skin cancer is the fastest growing cancer in the US [1]. A great need exists for improved formulations and mechanisms to prevent and protect human skin from cancers and other skin damage caused by sunlight exposure. Current efforts to prevent UV damage to human skin, which in many cases leads to melanoma and other skin cancers. The primordial melanocortin-1 receptor (MC1R) is involved in regulating skin pigmentation and hair color, which is a natural prevention from UV damage. The endogenous melanocortin agonists induce pigmentation and share a core pharmacophore sequence "His-Phe-Arg-Trp", and it was found that substitution of the Phe by D-Phe results in increasing melanocortin receptor potency...
May 10, 2018: European Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/29679223/association-between-lepr-fto-mc4r-and-pparg-2-polymorphisms-with-obesity-traits-and-metabolic-phenotypes-in-school-aged-children
#13
Sílvia M Almeida, José M Furtado, Paulo Mascarenhas, Maria E Ferraz, José C Ferreira, Mariana P Monteiro, Manuel Vilanova, Fernando P Ferraz
PURPOSE: Evaluate the relationship of leptin receptor (LEPR) rs1137101, fat mass obesity-associated (FTO) receptors 9939609, melanocortin-4 receptors (MC4R) rs2229616 and rs17782313, and proliferator-activated receptor-gamma (PPARG) rs1801282 with clinical and metabolic phenotypes in prepubertal children. RESEARCH QUESTION: What is the effect of polymorphisms on clinical and metabolic phenotypes in prepubertal children? METHODS: A cross-sectional descriptive study was performed to evaluate anthropometric features, percentage body fat (%BF), biochemical parameters, and genotype in 773 prepubertal children...
April 20, 2018: Endocrine
https://www.readbyqxmd.com/read/29678289/pathophysiology-of-melanocortin-receptors-and-their-accessory-proteins
#14
REVIEW
T V Novoselova, L F Chan, A J L Clark
The melanocortin receptors (MCRs) and their accessory proteins (MRAPs) are involved in regulation of a diverse range of endocrine pathways. Genetic variants of these components result in phenotypic variation and disease. The MC1R is expressed in skin and variants in the MC1R gene are associated with ginger hair color. The MC2R mediates the action of ACTH in the adrenal gland to stimulate glucocorticoid production and MC2R mutations result in familial glucocorticoid deficiency (FGD). MC3R and MC4R are involved in metabolic regulation and their gene variants are associated with severe pediatric obesity, whereas the function of MC5R remains to be fully elucidated...
April 2018: Best Practice & Research. Clinical Endocrinology & Metabolism
https://www.readbyqxmd.com/read/29669202/developing-a-biased-unmatched-bivalent-ligand-bumbl-design-strategy-to-target-the-gpcr-homodimer-allosteric-signaling-camp-over-%C3%AE-arrestin2-recruitment-within-the-melanocortin-receptors
#15
Cody J Lensing, Katie T Freeman, Sathya M Schnell, Robert C Speth, Adam T Zarth, Carrie Haskell-Luevano
Understanding the functional relevance of G protein-coupled receptor (GPCR) homodimerization has been limited by the insufficient tools to assess asymmetric signaling occurring within dimers comprised of the same receptor type. We present unmatched bivalent ligands (UmBLs) to study the asymmetric function of melanocortin homodimers. UmBLs contain one agonist and one antagonist pharmacophore designed to target a melanocortin homodimer such that one receptor is occupied by an agonist and the other receptor by an antagonist pharmacophore...
April 18, 2018: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/29660981/development-of-macrocyclic-peptidomimetics-containing-constrained-%C3%AE-%C3%AE-dialkylated-amino-acids-with-potent-and-selective-activity-at-human-melanocortin-receptors
#16
Francesco Merlino, Yang Zhou, Minying Cai, Alfonso Carotenuto, Ali Munaim Yousif, Diego Brancaccio, Salvatore Di Maro, Silvia Zappavigna, Antonio Limatola, Ettore Novellino, Paolo Grieco, Victor J Hruby
We report the development of macrocyclic melanocortin derivatives of MT-II and SHU-9119, achieved by modifying the cycle dimension, and incorporating constrained amino acids in ring-closing. This study culminated in the discovery of novel agonists/antagonists with an unprecedented activity profile, by adding pieces to the puzzle of the melanocortin receptor selec-tivity. Finally, the resulting 19- and 20-membered rings represent a suitable frame for the design of further therapeutic ligands as selective modulators of the melanocortin system...
April 16, 2018: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/29659163/synthesis-characterization-and-initial-biological-evaluation-of-99mtc-tc-tricarbonyl-labeled-dpa-%C3%AE-msh-peptide-derivatives-for-potential-melanoma-imaging
#17
Feng Gao, Wiebke Sihver, Ralf Bergmann, Birgit Belter, Cristina Bolzati, Nicola Salvarese, Jörg Steinbach, Jens Pietzsch, Hans-Jürgen Pietzsch
α-Melanocyte stimulating hormone (α-MSH) derivatives target the melanocortin-1 receptor (MC1R) specifically and selectively. In this study, the α-MSH derived peptide NAP-NS1 (Nle-Asp-His-D-Phe-Arg-Trp-Gly-NH2) with and without linkers was conjugated with 5-(bis(pyridin-2-yl)methyl)amino)pentanoic acid (DPA-COOH) and labeled with [99mTc]Tc-tricarbonyl by two methods. With the one-pot method the labeling was faster than with the two-pots method, however obtaining similarly high yields. Negligible transchelation and high stability in physiological solutions was determined for the [99mTc]Tc-tricarbonyl-peptide conjugates...
April 16, 2018: ChemMedChem
https://www.readbyqxmd.com/read/29642894/activation-of-melanocortin-receptor-4-with-ro27-3225-attenuates-neuroinflammation-through-ampk-jnk-p38-mapk-pathway-after-intracerebral-hemorrhage-in-mice
#18
Shengpan Chen, Lianhua Zhao, Prativa Sherchan, Yan Ding, Jing Yu, Derek Nowrangi, Jiping Tang, Ying Xia, John H Zhang
BACKGROUND: Neuroinflammation plays an important role in the pathogenesis of intracerebral hemorrhage (ICH)-induced secondary brain injury. Activation of melanocortin receptor 4 (MC4R) has been shown to elicit anti-inflammatory effects in many diseases. The objective of this study was to explore the role of MC4R activation on neuroinflammation in a mouse ICH model and to investigate the contribution of adenosine monophosphate-activated protein kinase (AMPK)/c-Jun N-terminal kinase (JNK)/p38 mitogen-activated protein kinase (p38 MAPK) pathway in MC4R-mediated protection...
April 11, 2018: Journal of Neuroinflammation
https://www.readbyqxmd.com/read/29642438/sesamol-inhibited-melanogenesis-by-regulating-melanin-related-signal-transduction-in-b16f10-cells
#19
Po-Yuan Wu, Ya-Jhen You, Yi-Jung Liu, Chien-Wei Hou, Chin-Sheng Wu, Kuo-Ching Wen, Chien-Yih Lin, Hsiu-Mei Chiang
Melanin is synthesized through a series of interactions catalyzed by melanogenic enzymes such as tyrosinase, dopachrome tautomerase (tyrosinase-related protein-2; TRP-2), and tyrosinase-related protein-1 (TRP-1). Tyrosinase plays a key role in catalysing the initial and limiting steps of melanogenesis. The melanin that results from melanogenesis has the protective effect of absorbing ultraviolet radiation. However, overproduction of melanin, in addition to altering the appearance of skin, may lead to skin disorders such as melasma, solar lentigo, and postinflammatory hyperpigmentation...
April 7, 2018: International Journal of Molecular Sciences
https://www.readbyqxmd.com/read/29625570/the-inhibition-of-human-lung-fibroblast-proliferation-and-differentiation-by-gs-coupled-receptors-is-not-predicted-by-the-magnitude-of-camp-response
#20
Maxine J Roberts, Rebecca E Broome, Toby C Kent, Steven J Charlton, Elizabeth M Rosethorne
BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is a chronic and progressive fibrotic lung disease for which there is no cure. Current therapeutics are only able to slow disease progression, therefore there is a need to explore alternative, novel treatment options. There is increasing evidence that the 3', 5' cyclic adenosine monophosphate (cAMP) pathway is an important modulator in the development of fibrosis, with increasing levels of cAMP able to inhibit cellular processes associated with IPF...
April 7, 2018: Respiratory Research
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