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MSH or Melanocyte-Stimulating Hormone Basics
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MSH is an explosively new hormone that is deficient in many people due to inflammation, infections and possible toxin exposures of various kinds. Some feel it can even be permanently destroyed, but this is unfortunately usually due to very narrow and limited treatment abilities—fetish medical interests. According to the brilliant leader in MSH research, who has the two major textbooks on the topic, Dr. Cone, MSH has vast roles in the body—perhaps one reason it is being made all over the world with eagerness for many years.
He includes in his The Melanocortin System, from a paper by Hruby, Cai, et. al. (2002) that MSH has some of these sample effects:
- Heart Function Benefits
- Stress Coping Help
- Better Attention and Memory
- Cancer and UV Protection, e.g., skin cancer
- Addiction Treatment
- Neuron Repair
- Pain Control
- Anti-inflammatory Effects
- Weight Control or a Restoration of Normal Eating
- Normal Urination
- Fever Control
- Erection Benefits
Amusingly, some authors act like they have discovered MSH, when everything they say about MSH is well-known throughout the pharmaceutical and research world community. One just needs to read the basics in basic books and articles. Some feel they have discovered a link between Leptin and obesity and MSH. And while these things are related, there is no simplistic path, since as the article by Shimizu and others below shows Leptin and MSH are independent in a great many ways.
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Nat Neurosci. 2005 May;8(5):571-8.
Anatomy and regulation of the central melanocortin system.
Cone RD.
The central melanocortin system [which makes MSH] is perhaps the best-characterized neuronal pathway involved in the regulation of energy homeostasis. This collection of circuits is unique in having the capability of sensing signals from a staggering array of hormones, nutrients and afferent neural inputs. It is likely to be involved in integrating long-term adipostatic signals from leptin and insulin, primarily received by the hypothalamus, with acute signals regulating hunger and satiety, primarily received by the brainstem. The system is also unique from a regulatory point of view in that it is composed of fibers expressing both agonists and antagonists of melanocortin receptors. Given that the central melanocortin system is an active target for development of drugs for the treatment of obesity, diabetes and cachexia, it is important to understand the system in its full complexity, including the likelihood that the system also regulates the cardiovascular and reproductive systems.
J Endocrinol. 2007 Apr;193(1):1-9.
The leptin-dependent and -independent melanocortin signaling system: regulation of feeding and energy expenditure.
Shimizu H, Inoue K, Mori M.
The brain hypothalamus coordinates extra-hypothalamic regions to maintain energy homeostasis through the regulation of food intake and energy expenditure. A number of anorexigenic and orexigenic molecules in the hypothalamic nuclei participate in the control of energy homeostasis. Leptin and pro-opiomelanocortin (POMC)-derived alpha-melanocyte-stimulating hormone are key anorectic molecules, and the leptin receptor and POMC gene are both expressed in the hypothalamic arcuate nucleus. Although it has been considered that melanocortin signaling is localized downstream to leptin signaling, data have accumulated to support the concept of a leptin-independent melanocortin signaling system. We focus on and review the melanocortin signaling system that functions dependently or independently of leptin signaling in the regulation of energy homeostasis.
- 1: Gastroenterology. 2008 Jan;134(1):166-78. Epub 2007 Oct 17.
PepT1-mediated tripeptide KPV uptake reduces intestinal inflammation.
Dalmasso G, Charrier-Hisamuddin L, Thu Nguyen HT, Yan Y, Sitaraman S, Merlin D.
Department of Medicine, Division of Digestive Diseases, Emory University School of Medicine, Atlanta, Georgia, USA.
BACKGROUND & AIMS: KPV is a tripeptide (Lys-Pro-Val), which possesses anti-inflammatory properties; however, its mechanisms of action still remain unknown. PepT1 is a di/tripeptide transporter normally expressed in the small intestine and induced in colon during inflammatory bowel disease (IBD). The aim of this study was to 1) investigate whether the KPV anti-inflammatory effect is PepT1-mediated in intestinal epithelian and immune cells, and 2) examine the anti-inflammatory effects in two models of mice colitis. METHODS: Human intestinal epithelial cells Caco2-BBE, HT29-Cl.19A, and human T cells (Jurkat) were stimulated with pro-inflammatory cytokines in the present or absence of KPV. KPV anti-inflammatory effect was assessed using a NF-kappaB luciferase gene reporter, Western blot, real-time RT-PCR and ELISA. Uptake experiments were performed using cold KPV as a competitor for PepT1 radiolabelled substrate or using [(3)H]KPV to determine kinetic characteristics of KPV uptake. Anti-inflammatory effect of KPV was also investigated in DSS- and TNBS-induced colitis in mice. KPV was added to drinking water and inflammation was assessed at the histologic level and by proinflammatory cytokine mRNA expression. RESULTS: Nanomolar concentrations of KPV inhibit the activation of NF-kappaB and MAP kinase inflammatory signaling pathways, and reduce pro-inflammatory cytokine secretion. We found that KPV acts via PepT1 expressed in immune and intestinal epithelial cells. Furthermore, oral administration of KPV reduces the incidence of DSS- and TNBS-induced colitis indicated by a decrease in pro-inflammatory cytokine expression. CONCLUSIONS: This study indicates tht KPV is transported into cells by PepT1 and might be a new therapeutic agent for IBD.
Publication Types:
PMID: 18061177 [PubMed - indexed for MEDLINE]
- 2: Basic Clin Pharmacol Toxicol. 2007 Dec;101(6):416-20.
Functional evaluation of THIQ, a melanocortin 4 receptor agonist, in models of food intake and inflammation.
Muceniece R, Zvejniece L, Vilskersts R, Liepinsh E, Baumane L, Kalvinsh I, Wikberg JE, Dambrova M.
Faculty of Medicine, University of Latvia, Riga, Latvia.
The central melanocortinergic system plays an important role in regulating different aspects of energy homeostasis and the immunomodulatory response. In the present study, we evaluated the in vivo activities of food intake suppression and anti-inflammatory activity of THIQ, which has been proposed to possess high and selective melanocortin-4 receptor agonistic activity in vitro. The results showed that THIQ (0.1, 0.3 and 1 nmol/rat, intracerebroventricularly) is less effective in reducing food intake and body weights of rats than the non-selective melanocortin receptor agonist melanotan II. Electron paramagnetic resonance measurements in mice brain tissue showed that THIQ at doses of 0.001 and 0.01 nmol/mouse (intracisternally) increased the concentration of nitric oxide, which is not typical for melanocortin receptor agonists. In an experimental brain inflammation model, THIQ only weakly antagonized lipopolysaccharide-induced nitric oxide overproduction in brain tissue at a dose of 0.01 nmol/mouse. Our findings provide new insight into the in vivo pharmacological profile of the in vitro selective melanocortin-4 receptor agonist THIQ and give grounds for caution when interpreting and predicting melanocortin receptor selective agonist activity in vivo.
Publication Types:
PMID: 18028105 [PubMed - indexed for MEDLINE]
- 3: J Sex Med. 2007 Nov;4 Suppl 4:269-79.
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Bremelanotide: an overview of preclinical CNS effects on female sexual function.
Pfaus J, Giuliano F, Gelez H.
Concordia University-Psychology, Montreal, Canada. Jim.Pfaus@concordia.ca
INTRODUCTION: Bremelanotide is an analogue of the naturally occurring peptide alpha-melanocyte-stimulating hormone (alpha-MSH). It stimulates erection in men and male rats, and is currently in clinical trials for the treatment of erectile dysfunction. AIM: To review the effects of bremelanotide, an analogue of the naturally occurring peptide alpha-MSH, on the preclinical indices of sexual desire in female rats, and where in the brain these actions may occur. MAIN OUTCOME MEASURES: Appetitive sexual behaviors, such as solicitations, hops and darts, and pacing, were assessed along with consummatory behaviors such as lordosis. The involvement of brain regions was assessed following direct administration to the region, by the stimulation of molecular markers of neural activation, and using microdialysis to examine extracellular fluid for different neurotransmitters. METHODS: Using a model that allows ovariectomized, hormone-primed female rats to control the timing of sexual encounters with males, we tested the ability of bremelanotide to increase appetitive (proceptive) and/or consummatory sexual behaviors. RESULTS: Bremelanotide dramatically and selectively increased measures of solicitation in female rats, without altering pacing or lordosis, following both peripheral (subcutaneous) administration or infusions directly into the lateral ventricles or medial preoptic area (mPOA), but not the ventromedial hypothalamus. The mPOA is critical for the display of appetitive sexual behaviors in females and males of a variety of species. Peripheral administration of bremelanotide activates the mPOA and other hypothalamic and limbic regions of the brain involved in sexual behavior, and may work by activating dopamine terminals in the mPOA. CONCLUSIONS: To the extent that solicitations indicate the desire of female rats to engage in sexual activity, bremelanotide appears to possess the behavioral, pharmacological, and neuroanatomical specificity required of a drug in the treatment of hypoactive sexual desire disorders.
PMID: 17958619 [PubMed - indexed for MEDLINE]
- 4: Ann Rheum Dis. 2007 Nov;66 Suppl 3:iii52-5.
alpha-MSH related peptides: a new class of anti-inflammatory and immunomodulating drugs.
Luger TA, Brzoska T.
Department of Dermatology, University Clinics Münster, Von-Esmarch-Str. 58, D-48149 Münster, Germany. luger@uni-muenster.de
alpha-Melanocyte-stimulating hormone (alpha-MSH) is a tridecapeptide derived from the proopiomelanocortin by post-translational processing. In addition to its effects on melanocytes, alpha-MSH has potent anti-inflammatory effects when administered systemically or locally. The anti-inflammatory effects of alpha-MSH are mediated by direct effects on cells of the immune system as well as indirectly by affecting the function of resident non-immune cells. alpha-MSH affects several pathways implicated in regulation of inflammatory responses such as NF-kappaB activation, expression of adhesion molecules and chemokine receptors, production of pro-inflammatory cytokines and other mediators. Thus alpha-MSH may modulate inflammatory cell proliferation, activity and migration. The anti-inflammatory effects of alpha-MSH have been confirmed by means of animal models of inflammation such as irritant and allergic contact dermatitis, cutaneous vasculitis, asthma, inflammatory bowel disease, rheumatoid arthritis, ocular and brain inflammation. Most of the anti-inflammatory activities of alpha-MSH can be attributed to its C-terminal tripeptide KPV. K(D)PT, a derivative of KPV corresponding to the amino acid 193-195 of IL-1beta, is currently emerging as another tripeptide with potent anti-inflammatory effects. The anti-inflammatory potential together with the favourable physiochemical properties most likely will allow these agents to be developed for the treatment of inflammatory skin, eye and bowel diseases, allergic asthma and arthritis.
PMID: 17934097 [PubMed - indexed for MEDLINE]
- 5: Invest Ophthalmol Vis Sci. 2007 Nov;48(11):5112-7.
In vitro generated autoimmune regulatory T cells enhance intravitreous allogeneic retinal graft survival.
Ng TF, Kitaichi N, Taylor AW.
Schepens Eye Research Institute, Boston, MA 02114, USA.
PURPOSE: The authors demonstrated that in vitro-generated alpha-melanocyte stimulated hormone (MSH)-induced Treg cells specific to ocular autoantigen suppress ocular autoimmune disease in vivo when adoptively transferred. They examined the possibility of using these ocular autoantigen-specific Treg cells to promote the survival of a retinal allograft placed in the mouse vitreous. METHODS: Enhanced green fluorescent protein (eGFP)-C57BL/6 neonatal retinal microaggregates were injected into the vitreous of B10-RIII mice before the adoptive transfer of interphotoreceptor retinoid-binding protein (IRBP; an ocular antigen) or ovalbumin (OVA)-specific alpha-MSH-induced Treg cells. GFP transplants were imaged in vivo on days 7 and 12. In addition, on day 12, the eyes were cryosectioned and immunostained with a panel of neuronal and immune cell markers. RESULTS: GFP allografts underwent no detectable changes in size on days 7 and 12 in the B10-RIII mice injected with IRBP-specific Treg cells; however, mice that received OVA-specific Treg cells or no Treg cells experienced remarkable reductions in graft size on day 12. Only one quarter of the original size was seen. Using neuronal-specific markers, immunohistochemistry showed that the architecture of the retinal allografts in the IRBP Treg cell-injected group had intact rosettes and neuronal cells on the outermost layer, whereas the allografts in the OVA Treg cell-injected mice were disorganized. Immune cell-specific markers demonstrated that Treg cells and activated microglial cells were found in the retinal allografts of the mice injected with IRBP Treg cells, but not in the retinal allografts of the OVA Treg-injected mice. CONCLUSIONS: These results demonstrate that adoptive transfer of alpha-MSH-generated IRBP-specific Treg cells promotes retinal allograft survival and development.
PMID: 17962463 [PubMed - indexed for MEDLINE]
- 6: Peptides. 2007 Oct;28(10):2009-15. Epub 2007 Aug 1.
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MIF-1 and its peptidomimetic analogs attenuate haloperidol-induced vacuous chewing movements and modulate apomorphine-induced rotational behavior in 6-hydroxydopamine-lesioned rats.
Castellano JM, Batrynchuk J, Dolbeare K, Verma V, Mann A, Skoblenick KJ, Johnson RL, Mishra RK.
Department of Psychiatry and Behavioral Neurosciences, McMaster University, 1200 Main Street West, Hamilton, Ontario, Canada L8N 3Z5.
Two melanocyte-stimulating hormone release inhibiting factor-1 (MIF-1) also known as L-prolyl-L-leucyl-glycinamide (PLG) peptidomimetic analogs, 3(R)-[[[2(S)-pyrrolidinyl]carbonyl]-amino]-3-(butyl)-2-oxo-1-pyrrolidineacetamide trifluoroacetate (A) and 3(R)-[[[2(S)-pyrrolidinyl]carbonyl]amino]-3-(benzyl)-2-oxo-1-pyrrolidineacetamide trifluoroacetate (B), were evaluated for their ability to modulate dopaminergic activity by measuring apomorphine-induced rotations in 6-hydroxydopamine (6-OHDA)-lesioned rats, and haloperidol (HP)-induced vacuous chewing movements (VCMs) in rats; animal models of Parkinson's disease (PD) and human tardive dyskinesia (TD), respectively. In the 6-OHDA model, both analogs were found to potentiate the contralateral rotational behavior induced by apomorphine dose-dependently and with approximately the same potency. Furthermore, each analog was able to significantly attenuate HP-induced VCMs with almost equal efficacy. The potency and efficacy of these analogs were significantly greater than their parent compound, PLG. These results suggest that both analogs can modulate dopaminergic activity in vivo, likely by the same mechanisms recruited by PLG previously reported.
Publication Types:
PMID: 17766011 [PubMed - indexed for MEDLINE]
- 7: Am J Hypertens. 2007 Aug;20(8):862-5.
Prevention of salt-induced hypertension by an analog of gamma-melanocyte-stimulating hormone in the rat.
Ni XP, Humphreys MH.
Division of Nephrology, San Francisco General Hospital, and Department of Medicine, University of California at San Francisco, San Francisco, California 94143, USA.
BACKGROUND: Rats with suppression of pituitary intermediate lobe (IL) function by treatment with the dopaminergic agonist bromocriptine develop salt-sensitive hypertension accompanied by a deficiency of gamma-melanocyte-stimulating hormone (gamma-MSH). METHODS: To study the time course, and establish the causal role, of gamma-MSH deficiency in the development of salt-sensitive hypertension, we instrumented 12 male Sprague-Dawley rats with radiotelemetry transmitters to record intraaortic mean arterial pressure (MAP). One week later, they were placed on a high-sodium diet (8% NaCl, HSD) and received daily intraperitoneal injections of bromocriptine (5 mg/kg). The rats were also implanted with micro-osmotic pumps to deliver either a stable analog of gamma-MSH ([Nle3, D-Phe6]-gamma-MSH, NDP-gamma-MSH) at 12 pmol/h or normal saline vehicle. RESULTS: In vehicle-treated rats on the HSD and receiving bromocriptine injections, MAP rose so that it was significantly greater than that in NDP-gamma-MSH-treated animals by Day 4, and reached a stable plateau of approximately 135 mm Hg between Days 7 and 14. After Day 14, bromocriptine injections were stopped, and MAP in vehicle-infused rats fell progressively despite continued ingestion of the HSD, so that by Day 18, MAP was no longer different from NDP-gamma-MSH-infused animals. The MAP in the latter group did not vary significantly from the control level of 101+/-4 mm Hg throughout the 21 days of the experiment. CONCLUSIONS: These results indicate that gamma-MSH deficiency is a consequence of the bromocriptine treatment responsible for the salt-sensitive hypertension, and these results also identify the time course during which this hypertension develops.
Publication Types:
PMID: 17679034 [PubMed - indexed for MEDLINE]
- 8: Cancer Biother Radiopharm. 2007 Jun;22(3):333-41.
Therapeutic efficacy of a 177Lu-labeled DOTA conjugated alpha-melanocyte-stimulating hormone peptide in a murine melanoma-bearing mouse model.
Miao Y, Shelton T, Quinn TP.
College of Pharmacy, University of New Mexico, Albuquerque, NM, USA.
The aim of this study was to examine the therapeutic efficacy of (177)Lu-DOTA-Re(Arg(11))CCMSH in the B16/F1 murine melanoma-bearing mouse model. METHODS: (177)Lu-DOTA-Re(Arg(11))CCMSH was prepared in 0.5 M NH(4)OAc at a pH of 5.4. Two (2) treatment groups of 10 melanoma-bearing C57 mice were administrated with 2 x 18.5 MBq and 1 x 37.0 MBq of (177)Lu-DOTA-Re(Arg(11))CCMSH through the tail vein, respectively. One (1) group of 10 melanoma-bearing C57 mice was injected with saline placebos as untreated melanoma-bearing controls. RESULTS: In contrast to the untreated melanoma-bearing control group, (177)Lu-DOTA-Re(Arg(11))CCMSH administration yielded rapid and lasting therapeutic effects in the treatment groups. (177)Lu-DOTA-Re(Arg(11))CCMSH treatment decreased the tumor growth rate and significantly (p > 0.05) prolonged the survival time of melanoma-bearing C57 mice. Treatment with 2 x 18.5 MBq or 1 x 37.0 MBq of (177)Lu-DOTA-Re(Arg(11))CCMSH significantly extended the mean survival of tumor-bearing mice from 13.3 to 15.1 and 16.2 days, respectively. (177)Lu-DOTA-Re(Arg(11))CCMSH treatment produced no observed acute renal toxicity. CONCLUSIONS: The therapy study results revealed that (177)Lu-DOTA-Re(Arg(11))CCMSH yielded quantitative therapeutic effects in B16/F1 melanoma-bearing mice and appeared to be a promising radiolabeled peptide for the targeted radionuclide therapy of melanoma.
Publication Types:
PMID: 17651039 [PubMed - indexed for MEDLINE]
- 9: Curr Top Med Chem. 2007;7(11):1137-44.
Melanocortins in the treatment of male and female sexual dysfunction.
Shadiack AM, Sharma SD, Earle DC, Spana C, Hallam TJ.
Palatin Technologies, Inc., Cranbury, NJ 08512, USA. ashadiack@palatin.com
Melanocortinergic agents are currently being investigated for a possible therapeutic role in male and female sexual dysfunction. These investigations were sparked by findings that systemic administration of a synthetic analog of alpha-MSH, MT-II, causes penile erections in a variety of species, including humans. Several other melanocortinergic agents including HP-228, THIQ, and bremelanotide (PT-141) have since been shown to have erectogenic properties thought to be due to binding to melanocortin receptors in the central nervous system, particularly the hypothalamus. Bremelanotide, a nasally administered synthetic peptide, is the only melanocortinergic agent that has been clinically studied in both males and females. Data from Phase II clinical trials of bremelanotide support the use of melanocortin-based therapy for erectile dysfunction. Studies using animal models have demonstrated that pre-copulatory behaviors in female rats analogous to sexual arousal are evoked, and preliminary clinical data also suggest a role in promoting sexual desire and arousal in women. Based on bremelanotide clinical experience, administration of a melanocortin agonist is well tolerated and not associated the hypotension observed with phosphodiesterase-5 inhibitors currently used to treat erectile dysfunction. This review discusses investigations of melanocortin agonists for the treatment of sexual dysfunction with emphasis on proposed sites and mechanisms of action in the central nervous system that appear to be involved in melanocortinergic modulation of sexual function. Current research validates use of melanocortinergic agents for the treatment of both male and female sexual dysfunction.
Publication Types:
PMID: 17584134 [PubMed - indexed for MEDLINE]
- 10: Curr Top Med Chem. 2007;7(11):1107-19.
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Design, synthesis and biological evaluation of ligands selective for the melanocortin-3 receptor.
Hruby VJ, Cai M, Cain JP, Mayorov AV, Dedek MM, Trivedi D.
Department of Chemistry, University of Arizona, Tucson, Arizona 85721, USA. hruby@u.arizona.edu
The processed products of the proopiomelanocortin gene (ACTH, alpha-MSH, beta-MSH, gamma-MSH, etc.) interact with five melanocortin receptors, the MC1R, MC2R, MC3R, MC4R, and MC5R to modulate and control many important biological functions crucial for good health both peripherally (as hormones) and centrally (as neurotransmitters). Pivotal biological functions include pigmentation, adrenal function, response to stress, fear/flight, energy homeostasis, feeding behavior, sexual function and motivation, pain, immune response, and many others, and are believed to be involved in many disease states including pigmentary disorders, adrenal disorders, obesity, anorexia, prolonged and neuropathic pain, inflammatory response, etc. The melanocortin-3 receptor (MC3R) is found primarily in the brain and spinal cord and also in the periphery, and its biological functions are still not well understood. Here we review some of the biological functions attributed to the MC3R, and then examine in more detail efforts to design and synthesize ligands that are potent and selective for the MC3R, which might help resolve the many questions still remaining about its function. Though some progress has been made, there is still much to be done in this critical area.
Publication Types:
PMID: 17584128 [PubMed - indexed for MEDLINE]
- 11: Physiol Behav. 2007 Sep 10;92(1-2):278-82. Epub 2007 May 21.
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Evidence for hypothalamic dysregulation in mouse models of anorexia as well as in humans.
Johansen JE, Fetissov SO, Bergström U, Nilsson I, Faÿ C, Ranscht B, Hökfelt T, Schalling M.
Karolinska Institutet, Department of Molecular Medicine and Surgery, L8:00, Karolinska University Hospital, S-171 76 Stockholm, Sweden. jeanette.johansen@ki.se
Eating disorders constitute major medical health problems in the western world. Even though little is known about the molecular mechanisms behind abnormal eating behavior, it has become clear that the central nervous system (CNS), particularly the hypothalamus, plays a significant role. The anorexic anx/anx mouse is a unique model for studying food intake and energy expenditure. The anx mutation is linked to marked alterations in hypothalamic distributions of signal substances known to have potent regulatory roles in the control of food intake. Another mouse model that displays an anorectic phenotype similar to the anx/anx mouse is the Contactin KO mouse. This model displays very similar hypothalamic alterations as seen in the anx/anx mouse, arguing for a role of these specific hypothalamic changes in an anorectic phenotype. In human eating disorders, hypothalamic systems corresponding to those defective in mouse models could be compromised since autoantibodies against melanocortin peptides have been detected in anorectic and bulimic patients. These findings represent research avenues that may lead to a better understanding of eating disorders and development of targeted therapeutic approaches.
Publication Types:
PMID: 17560618 [PubMed - indexed for MEDLINE]
- 12: Prog Retin Eye Res. 2007 Jul;26(4):323-58. Epub 2007 Jan 17.
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Tyrosinase and ocular diseases: some novel thoughts on the molecular basis of oculocutaneous albinism type 1.
Ray K, Chaki M, Sengupta M.
Molecular and Human Genetics Division, Indian Institute of Chemical Biology, 4 Raja S. C. Mullick Road, Jadavpur, Kolkata 700 032, India. thisiskr@rediffmail.com
Tyrosinase (TYR) is a multifunctional copper-containing glycoenzyme (approximately 80 kDa), which plays a key role in the rate-limiting steps of the melanin biosynthetic pathway. This membrane-bound protein, possibly evolved by the fusion of two different copper-binding proteins, is mainly expressed in epidermal, ocular and follicular melanocytes. In the melanocytes, TYR functions as an integrated unit with other TYR-related proteins (TYRP1, TYRP2), lysosome-associated membrane protein 1 (LAMP1) and melanocyte-stimulating hormone receptors; thus forming a melanogenic complex. Mutations in the TYR gene (TYR, 11q14-21, MIM 606933) cause oculocutaneous albinism type 1 (OCA1, MIM 203100), a developmental disorder having an autosomal recessive mode of inheritance. In addition, TYR can act as a modifier locus for primary congenital glaucoma (PCG) and it also contributes significantly in the eye developmental process. Expression of TYR during neuroblast division helps in later pathfinding by retinal ganglion cells from retina to the dorsal lateral geniculate nucleus. However, mutation screening of TYR is complicated by the presence of a pseudogene-TYR like segment (TYRL, 11p11.2, MIM 191270), sharing approximately 98% sequence identity with the 3' region of TYR. Thus, in absence of a full-proof strategy, any nucleotide variants identified in the 3' region of TYR could actually be present in TYRL. Interestingly, despite extensive search, the second TYR mutation in 15% of the OCA1 cases remains unidentified. Several possible locations of these "uncharacterized mutations" (UCMs) have been speculated so far. Based on the structure of TYR gene, its sequence context and some experimental evidences, we propose two additional possibilities, which on further investigations might shed light on the molecular basis of UCMs in TYR of OCA1 patients; (i) partial deletion of the exons 4 and 5 region of TYR that is homologous with TYRL and (ii) variations in the polymorphic GA complex repeat located between distal and proximal elements of the human TYR promoter that can modulate the expression of the gene leading to disease pathogenesis.
Publication Types:
PMID: 17355913 [PubMed - indexed for MEDLINE]
- 13: Br J Pharmacol. 2007 Mar;150(5):595-603. Epub 2007 Jan 22.
Selective melanocortin MC4 receptor agonists reverse haemorrhagic shock and prevent multiple organ damage.
Giuliani D, Mioni C, Bazzani C, Zaffe D, Botticelli AR, Capolongo S, Sabba A, Galantucci M, Iannone A, Grieco P, Novellino E, Colombo G, Tomasi A, Catania A, Guarini S.
Department of Biomedical Sciences, Section of Pharmacology, University of Modena and Reggio Emilia, Modena, Italy.
BACKGROUND AND PURPOSE: In circulatory shock, melanocortins have life-saving effects likely to be mediated by MC4 receptors. To gain direct insight into the role of melanocortin MC4 receptors in haemorrhagic shock, we investigated the effects of two novel selective MC4 receptor agonists. EXPERIMENTAL APPROACH: Severe haemorrhagic shock was produced in rats under general anaesthesia. Rats were then treated with either the non-selective agonist [Nle4, D-Phe7]-melanocyte-stimulating hormone (NDP--MSH) or with the selective MC4 agonists RO27-3225 and PG-931. Cardiovascular and respiratory functions were continuously monitored for 2 h; survival rate was recorded up to 24 h. Free radicals in blood were measured using electron spin resonance spectrometry; tissue damage was evaluated histologically 25 min or 24 h after treatment. Key results: All shocked rats treated with saline died within 30-35 min. Treatment with NDP--MSH, RO27-3225 and PG-931 produced a dose-dependent (13-108 nmol kg-1 i.v.) restoration of cardiovascular and respiratory functions, and improved survival. The three melanocortin agonists also markedly reduced circulating free radicals relative to saline-treated shocked rats. All these effects were prevented by i.p. pretreatment with the selective MC4 receptor antagonist HS024. Moreover, treatment with RO27-3225 prevented morphological and immunocytochemical changes in heart, lung, liver, and kidney, at both early (25 min) and late (24 h) intervals. Conclusions and Implications: Stimulation of MC4 receptors reversed haemorrhagic shock, reduced multiple organ damage and improved survival. Our findings suggest that selective MC4 receptor agonists could have a protective role against multiple organ failure following circulatory shock.
Publication Types:
PMID: 17245369 [PubMed - indexed for MEDLINE]
- 14: Exp Dermatol. 2007 Feb;16(2):104-9.
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Expression of the corticotropin-releasing hormone-proopiomelanocortin axis in the various clinical types of psoriasis.
Kim JE, Cho DH, Kim HS, Kim HJ, Lee JY, Cho BK, Park HJ.
Department of Dermatology, St Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Korea.
Psychological stress is known to aggravate inflammatory skin diseases such as atopic dermatitis, psoriasis and contact sensitivity by altering the cellular constituents of the immune system. The skin appendages function dually as prominent targets and sources of the peripheral corticotropin-releasing hormone-proopiomelanocortin (CRH-POMC) axis. In this study, we examined the expression level of CRH-POMC axis constituents in psoriasis, a well-known stress-related inflammatory skin disease. The 15 psoriasis patients and six normal controls were retrospectively selected after extensive review of their clinical records and skin biopsy specimens. We immunohistochemically analysed the expressivity of CRH, adrenocorticotrophic hormone (ACTH) and alpha-melanocyte-stimulating hormone (alpha-MSH) in various types of psoriatic lesions and control skin. A significant increase of CRH expression was observed in psoriatic lesions, which involved the entire epidermis (upper layer in particular), hair follicles and sweat glands compared with controls. Expression of ACTH and alpha-MSH was clearly stimulated in a subset of psoriasis patients compared with controls, but on the whole, lacked statistical significance. The immunoreactivity of CRH, ACTH and alpha-MSH in psoriasis was not dependent on its clinical subtype, duration or number of previous treatments. Compared with the definite increase of CRH expression in psoriasis, the expression of the POMC peptides was heterogenous with no overall significance. From the findings, we suggest that CRH, a key stress hormone, may play an important role in the pathomechanism of psoriasis.
Publication Types:
PMID: 17222223 [PubMed - indexed for MEDLINE]
- 15: J Appl Toxicol. 2007 Mar-Apr;27(2):183-8.
The effect of alpha-melanocyte stimulating hormone on gentamicin-induced acute nephrotoxicity in rats.
Kolgazi M, Arbak S, Alican I.
Department of Physiology, Marmara University, School of Medicine, 34668 Haydarpaşa, Istanbul, Turkey.
The effect of alpha-melanocyte stimulating hormone (alpha-MSH) was investigated on gentamicin-induced acute renal injury in rats. Sprague-Dawley rats (200-250 g; n = 8-10) were treated with gentamicin sulphate (GEN; 80 mg kg(-1)) or saline intraperitoneally for 7 consecutive days. alpha-MSH was administered at a dose of 25 microg rat(-1) day(-1) following GEN or saline injections. On day 8, all animals were decapitated. Trunk blood and 24 h urine were collected to measure the serum creatinine levels, blood urea nitrogen (BUN) levels and to calculate the creatinine clearance values. The kidneys were excised for histological evaluation and for the measurement of malondialdehyde (MDA) levels, glutathione (GSH) contents and myeloperoxidase (MPO) activity. Treatment with alpha-MSH reduced the severity of the renal lesions microscopically, decreased MDA content and MPO activity and restored GSH in kidney samples. However, it did not restore the impaired renal function tests due to GEN challenge. In conclusion, alpha-MSH treatment has a beneficial effect on GEN-induced acute nephrotoxicity, as confirmed by histological evaluation and biochemical assays; but it does not improve GEN-induced renal dysfunction. The mechanism of the protective effect could be attributed, at least in part, to decreased tissue leukocyte infiltration and thus, to decreased oxygen-derived reactive metabolite production.
PMID: 17216604 [PubMed - indexed for MEDLINE]
- 16: Life Sci. 2007 Feb 20;80(11):1040-5. Epub 2006 Nov 28.
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Gastric protection by alpha-melanocyte-stimulating hormone against ethanol in rats: involvement of somatostatin.
Jahovic N, Erkanli G, Işeri S, Arbak S, Alican I.
Marmara University, School of Medicine, Department of Physiology, Haydarpasa, 34668, Istanbul, Turkey.
The proopiomelanocortin-derived tridecapeptide alpha-melanocyte-stimulating hormone (alpha-MSH) is a neuropeptide that exerts broad anti-inflammatory actions in mammals. This study aimed to investigate the effect of alpha-MSH on ethanol-induced gastric ulcer in rats and to evaluate the involvement of endogenous somatostatin in the actions of the peptide. The rats received 1 mL 75% ethanol or saline orally. alpha-MSH was given (25 micro g/rat; i.p.) alone or following the somatostatin antagonist cyclo-(7-aminoheptanoyl-PH-E-d-Trp-Lys-THR) (10 microM/kg; i.p.) administration. Gastric lesions were scored macroscopically and microscopically following decapitation at 30 min after ethanol challenge. Gastric malondialdehyde (MDA) level, myeloperoxidase (MPO) activity and mast cell counts were assessed. Ethanol-induced gastric hemorrhagic lesions were characterized by increased gastric MDA level, MPO activity and mast cell counts. alpha-MSH treatment decreased the extent of tissue injury and reversed tissue MDA level, MPO activity and mast cell counts. The effect of the peptide on the severity of gastric lesions, MDA level and MPO activity was reversed by the somatostatin antagonist. In conclusion, alpha-MSH is beneficial in a rat model of gastric ulcer via mechanisms which partly involve the endogenous somatostatin.
Publication Types:
PMID: 17188307 [PubMed - indexed for MEDLINE]
- 17: Gene Ther. 2007 Mar;14(5):383-95. Epub 2006 Oct 26.
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Prevention and treatment of experimental autoimmune encephalomyelitis with recombinant adeno-associated virus-mediated alpha-melanocyte-stimulating hormone-transduced PLP139-151-specific T cells.
Han D, Tian Y, Zhang M, Zhou Z, Lu J.
Institute of Immunology, Second Military Medical University, Shanghai, People's Republic of China. yptianimmu@126.com
The aim of this study was to investigate the immunomodulatory effects and mechanism of action of alpha-melanocyte-stimulating hormone (alpha-MSH) gene modified proteolipid protein (PLP) 139-151-specific T cells (T(PLP-alpha-MSH)) in the SJL mouse model of experimental autoimmune encephalomyelitis (EAE). PLP139-151-specific T cells (T(PLP) cells) were transduced with a recombinant adeno-associated virus 2 (rAAV2) encoding alpha-MSH. After activation with PLP139-151 in vitro, T(PLP-alpha-MSH) cells secreted high levels of alpha-MSH and also demonstrated an altered Th1-like cytokine pattern as well as a high frequency of CD4(+)CD25(+)Treg cells. Transfer studies showed that T(PLP-alpha-MSH) cells could suppress the induction of adoptive transfer EAE. More importantly, our studies demonstrated that T(PLP-alpha-MSH) cells had preventive and therapeutic effect on active relapse-remitting EAE (REAE) in an antigen-inducible manner. Suppression of REAE by T(PLP-alpha-MSH) cells was associated with a general reduction of inflammatory central nervous system (CNS) infiltrates, a pronounced decrease in Th1 cytokines and chemokines expression and an increase in Th2 cytokines. These data strongly suggested that local delivery of alpha-MSH by rAAV2-mediated alpha-MSH-transduced PLP139-151-specific T cells (T(PLP-alpha-MSH)) would be a desirable new approach to the treatment of autoimmune disease in the CNS.
Publication Types:
PMID: 17066098 [PubMed - indexed for MEDLINE]
- 18: Cancer Res. 2006 Oct 1;66(19):9483-91.
In melanoma, RAS mutations are accompanied by switching signaling from BRAF to CRAF and disrupted cyclic AMP signaling.
Dumaz N, Hayward R, Martin J, Ogilvie L, Hedley D, Curtin JA, Bastian BC, Springer C, Marais R.
Signal Transduction Team, The Institute for Cancer Research, Cancer Research UK Centre of Cell and Molecular Biology, London, United Kingdom.
Melanocytes require the RAS/RAF/MEK/ERK and the cyclic AMP (cAMP) signaling pathways to maintain the fine balance between proliferation and differentiation. We have investigated how cross-talk between these pathways affects melanoma progression. We show that cAMP suppresses CRAF activity in melanocytes and that this is essential to suppress the oncogenic potential of CRAF in these cells. As a consequence, BRAF alone is responsible for signaling to MEK. However, when RAS is mutated in melanoma, the cells switch their signaling from BRAF to CRAF. This switch is accompanied by dysregulated cAMP signaling, a step that is necessary to allow CRAF to signal to MEK. Thus, a fundamental switch in RAF isoform usage occurs when RAS is mutated in melanoma, and this occurs in the context of disrupted cAMP signaling. These data have important implications for the development of therapeutic strategies to treat this life-threatening disease.
Publication Types:
PMID: 17018604 [PubMed - indexed for MEDLINE]
- 19: Nat Clin Pract Endocrinol Metab. 2006 Aug;2(8):459-66.
Comment in:
Therapy insight: Use of melanocortin antagonists in the treatment of cachexia in chronic disease.
DeBoer MD, Marks DL.
Department of Pediatrics, Oregon Health and Science University, Portland, OR 97239-2901, USA.
Cachexia is a process that accompanies many chronic diseases, and consists of a combination of wasting of lean body mass, increased energy expenditure, and a paradoxical loss of appetite. Cachexia both worsens quality of life and negatively affects treatment of the underlying disease. Conditions as diverse as cancer, renal failure, and heart failure show a remarkable similarity in their associated cachexia, exhibiting changes in metabolism and endocrinology, including marked increases in levels of cytokines that accompany these diseases. So far, it has been difficult to treat disease-associated cachexia successfully. One treatment that has shown promise in animal trials, however, involves antagonism of the central melanocortin system, an anorexigenic pathway in the hypothalamus and brainstem. Humans who have genetic mutations involving pro-opiomelanocortin or the melanocortin 4 receptor in this pathway exhibit increased appetite and increased lean body mass. Recent research has shown that in rodent models of cancer and renal failure, administration of melanocortin 4 receptor antagonists results in an attenuation of symptoms of cachexia, including maintenance of appetite, lean body mass, and basal energy expenditure. Although this research needs to be substantiated in humans, it provides a promising direction for treating the wasting that is associated with a variety of disease states.
Publication Types:
PMID: 16932335 [PubMed - indexed for MEDLINE]
- 20: Cell Mol Biol (Noisy-le-grand). 2006 May 30;52(2):47-52.
Proopiomelanocortin heterozygous and homozygous null mutant mice develop pituitary adenomas.
Karpac J, Ostwald D, Li GY, Bui S, Hunnewell P, Brennan MB, Hochgeschwender U.
Molecular, Cell and Developmental Biology Program, Oklahoma Medical Research Foundation, 825 NE 13th Street, Oklahoma City, OK 73104, USA.
Mice lacking all pro-opiomelanocortin (POMC)-derived peptides have been created by gene targeting of the POMC locus in embryonic stem cells. Phenotypes of the POMC null homozygous mutants include obesity, pigmentation defects, and adrenal insufficiency. Here, we report that both POMC null homozygous and heterozygous mutants also develop pituitary gland tumors, which result in their premature death. The tumors occur with 100% penetrance in both POMC heterozygous and homozygous genotypes. Histological examinations reveal that tumors start from hyperplastic focal points of melanotrophic cells within the intermediate lobe. Based on the morphological and immunohistological features, we have classified the tumors as non-invasive, non-secreting, intermediate lobe adenomas. These findings uncover potential novel roles of melanocortins in the regulation of cell proliferation.
PMID: 16914086 [PubMed - indexed for MEDLINE]
- 21: C R Biol. 2006 Aug;329(8):608-22; discussion 653-5. Epub 2006 May 15.
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Genetics of human obesity.
Clément K.
INSERM, U755 & IFR58, université Pierre-et-Marie Curie (Paris-6), 75004 Paris, France. karine.clement@htd.aphp.fr
We present the knowledge acquired in the field of the genetics of human obesity. The molecular approach proved to be powerful to define new syndromes associated to obesity. The pivotal role of leptin and melanocortin pathways were recognized but in rare obesity cases. In the commoner form of obesities, a multitude of polymorphisms located in genes and candidate regions participate in an individual susceptibility to weight gain in a permissive environment. The effects are often uncertain and the results not always confirmed. It is now necessary to integrate data of various origins (environment, genotype, expression) to clarify the domain.
Publication Types:
PMID: 16860279 [PubMed - indexed for MEDLINE]
- 22: Endocrinology. 2006 Sep;147(9):4438-44. Epub 2006 Jun 1.
Retinoic acid as a novel medical therapy for Cushing's disease in dogs.
Castillo V, Giacomini D, Páez-Pereda M, Stalla J, Labeur M, Theodoropoulou M, Holsboer F, Grossman AB, Stalla GK, Arzt E.
Unidad de Endocrinología, Hospital Escuela, Facultad de Ciencias Veterinarias, Universidad de Buenos Aires, 1428 Buenos Aires, Argentina.
Cushing's disease is almost always caused by an ACTH-secreting pituitary tumor, but effective medical therapy is currently limited. Because retinoic acid has been shown to be potentially useful in decreasing corticotroph secretion and proliferation in rodent models, we have studied its action in dogs with Cushing's disease. A randomized treatment with retinoic acid (n = 22) vs. ketoconazole (n = 20) in dogs with Cushing's disease was assigned for a period of 180 d. Clinical signs, plasma ACTH and alpha-MSH, the cortisol/creatinine urine ratio, and pituitary magnetic resonance imaging were assessed and compared at different time points. We recorded a significant reduction in plasma ACTH and alpha-MSH, and also in the cortisol/creatinine urine ratio, of the dogs treated with retinoic acid. Pituitary adenoma size was also significantly reduced at the end of retinoic acid treatment. Survival time and all the clinical signs evaluated showed an improvement in the retinoic-acid-treated dogs. No adverse events or signs of hepatotoxicity were observed, suggesting that the drug is not only effective but also safe. Retinoic acid treatment controls ACTH and cortisol hyperactivity and tumor size in dogs with ACTH-secreting tumors, leading to resolution of the clinical phenotype. This study highlights the possibility of using retinoic acid as a novel therapy in the treatment of ACTH-secreting tumors in humans with Cushing's disease.
Publication Types:
PMID: 16740975 [PubMed - indexed for MEDLINE]
- 23: FASEB J. 2006 Jul;20(9):1561-3. Epub 2006 May 24.
Melanoma prevention strategy based on using tetrapeptide alpha-MSH analogs that protect human melanocytes from UV-induced DNA damage and cytotoxicity.
Abdel-Malek ZA, Kadekaro AL, Kavanagh RJ,