Melanocortin Peptides Research Articles

ACTH Enhances Lipid Accumulation in Bone-marrow derived Mesenchymal Stem Cells undergoing Adipogenesis

ACTH is a major hormone of the stress axis or hypothalamic-pituitary-adrenal (HPA) axis. It is derived from pro-opiomelanocortin (POMC) the precursor to the melanocortin family of peptides. POMC produces the biologically active melanocortin peptides via a series of enzymatic steps in a tissue-specific manner, yielding the melanocyte-stimulating hormones (MSHs), corticotrophin (ACTH) and ?-endorphin. The melanocortin system plays an imperative role in energy expenditure, insulin release and insulin sensitivity. Bone marrow derived mesenchymal stem cells circulate in the blood stream and as progenitor cells have the potential to differentiate into many cell types such as osteoblasts, chondrocytes and adipocytes. Here we examine the effects of ACTH on the mouse D1 bone-marrow derived MSC. ACTH significantly increased lipid accumulation during the adipogenic differentiation of D1 cells in a concentration- dependent manner. ACTH also shifts the temporal pattern of D1 adipogenic differentiation to the left i.e. differentiation occurs earlier with ACTH treatment. No significant differences in protein expression of peroxisome proliferator-activated receptor gamma (PPAR-?2), a regulating transcription factor of adipogenesis were found. Therefore the effects of ACTH are suggested to be mediated by an alternative pathway. Overall the results indicate a connection between increased adipose deposition and the elevated circulating ACTH associated with stress.

From adaption to death: endoplasmic reticulum stress as a novel target of selective neurodegeneration?

From adaption to death: endoplasmic reticulum stress as a novel target of selective neurodegeneration?

The Melanocortin-4 Receptor Is Expressed in Enteroendocrine L Cells and Regulates the Release of Peptide YY and Glucagon-like Peptide 1 In Vivo

The melanocortin-4 receptor (MC4R) is expressed in the brainstem and vagal afferent nerves and regulates a number of aspects of gastrointestinal function. Here we show that the receptor is also diffusely expressed in cells of the gastrointestinal system, from stomach to descending colon. Furthermore, MC4R is the second most highly enriched GPCR in peptide YY (PYY) and glucagon-like peptide 1 (GLP-1) expressing enteroendocrine L cells. When vectorial ion transport is measured across mouse or human intestinal mucosa, administration of α-MSH induces a MC4R-specific PYY-dependent antisecretory response consistent with a role for the MC4R in paracrine inhibition of electrolyte secretion. Finally, MC4R-dependent acute PYY and GLP-1 release from L cells can be stimulated in vivo by intraperitoneal (i.p.) administration of melanocortin peptides to mice. This suggests physiological significance for MC4R in L cells and indicates a previously unrecognized peripheral role for the MC4R, complementing vagal and central receptor functions.

Melanocortin peptides: potential targets in systemic lupus erythematosus.

Systemic lupus erythematosus (SLE) is a systemic autoimmune disease resulting in loss of self-tolerance with multiple organs, such as the kidney, skin, joints, and the central nervous system (CNS), being targeted. Numerous immunosuppressant therapies are currently being used for the treatment of SLE, but their clinical utility is somewhat variable because of the clinical heterogeneity. Melanocortins are a family of peptides derived from the common precursor protein pro-opiomelanocortin. These multifunctional peptides activate five subtypes of melanocortin receptors expressed on immune, skin, muscle, bone, and kidney cells and cells within the CNS. Melanocortin peptides have demonstrated a variety of biologic actions including immunomodulation, melanogenesis, and renoprotection. This review aims to introduce the melanocortin system and explore the mechanisms by which they may be beneficial in diseases such as SLE.

Melanocortin peptides protect chondrocytes from mechanically induced cartilage injury

IntroductionMechanical injury can greatly influence articular cartilage, propagating inflammation, cell injury and death – risk factors for the development of osteoarthritis. Melanocortin peptides and their receptors mediate anti-inflammatory and pro-resolving mechanisms in chondrocytes. This study aimed to investigate the potential chondroprotective properties of α-MSH and [DTRP8]-γ-MSH in mechanically injured cartilage explants, their ability to inhibit pro-inflammatory and stimulate anti-inflammatory cytokines in in situ and in freshly isolated articular chondrocytes. MethodsThe effect of melanocortins on in situ chondrocyte viability was investigated using confocal laser scanning microscopy of bovine articular cartilage explants, subjected to a single blunt impact (1.14N, 6.47kPa) delivered by a drop tower. Chondroprotective effects of α-MSH, [DTRP8]-γ-MSH and dexamethasone on cytokine release by TNF-α-activated freshly isolated articular chondrocytes/mechanically injured cartilage explants were investigated by ELISA. ResultsA single impact to cartilage caused discreet areas of chondrocyte death, accompanied by pro-inflammatory cytokine release; both parameters were modulated by α-MSH, [DTRP8]-γ-MSH and dexamethasone. Melanocortin pre-treatment of TNF-α-stimulated freshly isolated chondrocytes resulted in a bell-shaped inhibition in IL-1β, IL-6 and IL-8, and elevation of IL-10 production. The MC3/4 antagonist, SHU9119, abrogated the effect of [DTRP8]-γ-MSH but not α-MSH on cytokine release. ConclusionMelanocortin peptide pre-treatment prevented chondrocyte death following mechanical impact to cartilage and led to a marked reduction of pro-inflammatory cytokines, whilst prompting the production of anti-inflammatory/pro-resolving cytokine IL-10. Development of small molecule agonists towards melanocortin receptors could thus be a viable approach for preventing chondrocyte inflammation and death within cartilage and represent an alternative approach for the treatment of osteoarthritis.

Expression and colocalization patterns of calbindin-D28k, calretinin and parvalbumin in the rat hypothalamic arcuate nucleus

Calcium binding proteins (CaBPs) form a diverse group of molecules that function as signal transducers or as intracellular buffers of Ca2+ concentration. They have been extensively used to histochemically categorize cell types throughout the brain. One region which has not yet been characterized with regard to CaBP expression is the hypothalamic arcuate nucleus, which plays a vital role in neuroendocrine control and the central regulation of energy metabolism. Using in situ hybridization and immunofluorescence, we have investigated the cellular distribution of the three CaBPs, calbindin-D28k (CB), calretinin (CR) and parvalbumin (PV) in the rat arcuate nucleus. Both mRNA and immunoreactivity was detected in the arcuate nucleus for CB – located in the medial aspects – and CR – located ventrolaterally. No PV mRNA was detected in the arcuate nucleus. Immunofluorescence results for PV were ambiguous; while one antibody detected a group of cell somata, a different antibody failed to visualize any arcuate nucleus cell profiles. Using double-labeling, neither of the examined CaBPs were observed in cells immunoreactive for the signaling molecules agouti gene-related protein, tyrosine hydroxylase, neurotensin, growth hormone-releasing hormone, somatostatin, enkephalin, dynorphin or galanin. We did, however, observe CB- and CR-immunoreactivity, in two distinct populations of neurons immunoreactive for the melanocortin peptide α-melanocyte-stimulating hormone. These data identify distinct subpopulations of arcuate neurons defined by their expression of CaBPs and provide further support for differentiation between subpopulations of anorexigenic melanocortin neurons.

Decreased consumption of rewarding sucrose solutions after injection of melanocortins into the ventral tegmental area of rats.

The mesolimbic dopamine system is an important component of the neural circuitry controlling reward-related behavior. We have recently shown that the melanocortin peptides decrease normal homeostatic feeding through actions in the ventral tegmental area. It is unknown, however, whether melanocortin peptides can also act on dopamine pathways to regulate hedonic, reward-related aspects of feeding. In these studies, we tested whether injection of melanocortin receptor agonists directly into the ventral tegmental area (VTA) affected the intake of appetizing and rewarding sugar solutions in two-bottle choice tests. Varying doses of the melanocortin receptor agonist, MTII, were injected into the VTA, and the intake of different sugar solutions was measured in two-bottle choice tests to distinguish between potential effects on homeostatic versus hedonic aspects of feeding. In addition, 24-h food intake was measured throughout the experiments. Injection of MTII into the VTA dose dependently decreased the intake of 1 and 2 % sucrose solutions and 0.2 % saccharin solutions and decreased 24-h food intake in each study. Although MTII also decreased the intake of a 10 % sucrose solution, MTII appeared to be less potent in rats exposed to 10 % sucrose, as only the highest dose of MTII tested was effective at reducing 10 % sucrose intake and food intake in these rats. These studies demonstrate that melanocortins can act directly in the VTA to control reward-related feeding. Thus, these studies add to the growing body of evidence showing that melanocortins can interact with the mesolimbic dopamine system to regulate multiple reward-related behaviors.

Adrenocorticotropin hormone 1-39 promotes proliferation and differentiation of oligodendroglial progenitor cells and protects from excitotoxic and inflammation-related damage.

Oligodendroglia (OL) are highly susceptible to damage and, like neurons, are terminally differentiated. It is important to protect OL precursors (OPC) because they are reservoirs of differentiating cells capable of myelination following perinatal insult and remyelination in white matter diseases, including multiple sclerosis (MS). Patients with relapsing-remitting MS are commonly treated with high-dose corticosteroids (CS) when experiencing an exacerbation. Adrenocorticotropin hormone (ACTH), a primary component of another approved MS exacerbation treatment, is a melanocortin peptide that stimulates production of CS by the adrenals. Melanocortin receptors are also found in the central nervous system (CNS) and on immune cells. ACTH is produced within the CNS and may have CS-independent effects on glia. We found that ACTH 1-39 stimulated proliferation of OPC, and to a lesser extent astroglia (AS) and microglia (MG), in rat glial cultures. ACTH accelerated differentiation of PDGFRα(+) OPC to a later stage marked by galactolipid expression and caused greater expansion of OL myelin-like sheets compared with untreated cells. Protective effects of ACTH on OPC were assessed by treating cultures with selected toxic agents, with or without ACTH. At 200 nM, ACTH protected OPC from death induced by staurosporine, glutamate, NMDA, AMPA, kainate, quinolinic acid, H2 O2 , and slow NO release, but not against kynurenic acid or rapid NO release. These agents and ACTH were not toxic to AS or MG. Our findings indicate that ACTH 1-39 provides benefits by increasing the number of OPC, accelerating their development into mature OL, and reducing OPC death from toxic insults.

Targeting central melanocortin receptors: a promising novel approach for treating alcohol abuse disorders.

The melanocortin (MC) peptides are produced centrally by propiomelanocortin (POMC) neurons within the arcuate nucleus of the hypothalamus and act through five seven-transmembrane G-protein coupled melanocortin receptor (MCR) subtypes. The MC3R and MC4R subtypes, the most abundant central MCRs, are widely expressed in brain regions known to modulate neurobiological responses to ethanol, including regions of the hypothalamus and extended amygdala. Agouti-related protein (AgRP), also produced in the arcuate nucleus, is secreted in terminals expressing MCRs and functions as an endogenous MCR antagonist. This review highlights recent genetic and pharmacological findings that have implicated roles for the MC and AgRP systems in modulating ethanol consumption. Ethanol consumption is associated with significant alterations in the expression levels of various MC peptides/protein, which suggests that ethanol-induced perturbations of MC/AgRP signaling may modulate excessive ethanol intake. Consistently, MCR agonists decrease, and AgRP increases, ethanol consumption in mice. MCR agonists fail to blunt ethanol intake in mutant mice lacking the MC4R, suggesting that the protective effects of MCR agonists are modulated by the MC4R. Interestingly, recent evidence reveals that MCR agonists are more effective at blunting binge-like ethanol intake in mutant mice lacking the MC3R, suggesting that the MC3R has opposing effects on the MC4R. Finally, mutant mice lacking AgRP exhibit blunted voluntary and binge-like ethanol drinking, consistent with pharmacological studies. Collectively, these preclinical observations provide compelling evidence that compounds that target the MC system may provide therapeutic value for treating alcohol abuse disorders and that the utilization of currently available MC-targeting compounds- such as those being used to treat eating disorders- may be used as effective treatments to this end.

Sa1725 Human Intestinal Fibroblasts Are Novel Target Cells for Alpha-Melanocyte-Stimulating Hormone -Possible Implications for the Treatment of Stricturing Crohn's Disease With Melanocortin Peptides and Derivatives

Sa1725 Human Intestinal Fibroblasts Are Novel Target Cells for Alpha-Melanocyte-Stimulating Hormone -Possible Implications for the Treatment of Stricturing Crohn's Disease With Melanocortin Peptides and Derivatives

Pharmacological activation of the melanocortin system limits plaque inflammation and ameliorates vascular dysfunction in atherosclerotic mice.

Melanocortin peptides have been shown to elicit anti-inflammatory actions and to promote vascular endothelial function by activating type 1 and 3 melanocortin receptors. Here, we addressed whether these favorable properties of melanocortins could reduce atherosclerotic plaque inflammation and improve vasoreactivity in atherosclerotic mice. Low-density lipoprotein receptor-deficient mice expressing only apolipoprotein B100 were fed a high-fat diet for 8 or 16 weeks and treated with either vehicle or a stable melanocortin analog, melanotan II (MT-II, 0.3 mg/kg per day, 4 weeks). We determined plaque uptake of fluorine-18-labeled fluorodeoxyglucose as a surrogate marker for atherosclerotic plaque inflammation and vascular function of the aorta by ex vivo analyses. MT-II had no effect on body weight or composition, or plasma cholesterol levels in atherosclerotic mice. Without attenuating atherosclerotic lesion size or lesional macrophage accumulation, MT-II treatment reduced fluorine-18-labeled fluorodeoxyglucose uptake in the atherosclerotic plaques. Resident macrophages in the lesions of MT-II-treated mice were polarized toward the anti-inflammatory M2 phenotype. Systemic inflammation was also attenuated by MT-II intervention as evidenced by decreased plasma levels of proinflammatory cytokines. In terms of aortic vasoreactivity, MT-II-treated mice showed enhanced endothelium-dependent relaxations, as well as promotion of vascular sensitivity to nitric oxide-mediated vasodilation, which were markedly impaired in control mice after prolonged duration of diet exposure. The present study demonstrates that pharmacological activation of the melanocortin system has therapeutic benefits in pre-established atherosclerosis by limiting plaque inflammation and promoting vascular endothelial function, which may provide a novel therapeutic approach for atherosclerosis.

Immunomodulatory effects of H.P. Acthar Gel on B cell development in the NZB/W F1 mouse model of systemic lupus erythematosus.

H.P. Acthar Gel® (Acthar) is a highly purified repository gel preparation of adrenocorticotropic hormone (ACTH1-39), a melanocortin peptide that can bind and activate specific receptors expressed on a range of systemic lupus erythematosus (SLE)-relevant target cells and tissues. This study was performed to evaluate the effects of Acthar in a mouse model of SLE, using an F1 hybrid of the New Zealand Black and New Zealand White strains (NZB/W F1). Twenty-eight week old NZB/W F1 mice with established autoimmune disease were treated with Acthar, Placebo Gel (Placebo), or prednisolone and monitored for 19 weeks. Outcomes assessed included disease severity (severe proteinuria, ≥ 20% body weight loss, or prostration), measurement of serial serum autoantibody titers, terminal spleen immunophenotyping, and evaluation of renal histopathology. Acthar treatment was linked with evidence of altered B cell differentiation and development, manifested by a significant reduction in splenic B cell follicular and germinal center cells, and decreased levels of circulating total and anti-double-stranded DNA (IgM, IgG, and IgG2a) autoantibodies as compared with Placebo. Additionally, Acthar treatment resulted in a significant decrease of proteinuria, reduced renal lymphocyte infiltration, and attenuation of glomerular immune complex deposition. These data suggest that Acthar diminished pathogenic autoimmune responses in the spleen, peripheral blood, and kidney of NZB/W F1 mice. This is the first preclinical evidence demonstrating Acthar's potential immunomodulatory activity and efficacy in a murine model of systemic lupus erythematosus.

A pilot study to determine the dose and effectiveness of adrenocorticotrophic hormone (H.P. Acthar(R) Gel) in nephrotic syndrome due to idiopathic membranous nephropathy

BackgroundH.P. Acthar® Gel is currently the only Food and Drug Administration therapy approved for the treatment of nephrotic syndrome. Active drug ingredients include structurally related melanocortin peptides that bind to cell surface G-protein-coupled receptors known as melanocortin receptors, which are expressed in glomerular podocytes. In animal models of membranous nephropathy, stimulation has been demonstrated to reduce podocyte injury and loss. We hypothesized that H.P. Acthar® Gel would improve symptoms of the nephrotic syndrome in patients with idiopathic membranous nephropathy.MethodsTwenty patients received a subcutaneous dose of 40 or 80 IU twice weekly. Changes in proteinuria, albumin, cholesterol profile, estimated glomerular filtration rate and serum anti-PLA2R antibodies were assessed at baseline and in response to treatment along with tolerance and safety.ResultsBaseline characteristics included mean proteinuria (9.1 ± 3.4 g/day), albumin (2.7 ± 0.8 g/dL), estimated glomerular filtration rate (77 ± 30 mL/min) along with elevated total and low-density lipoprotein (LDL) cholesterol. By 12 months of follow-up, there was a significant improvement in proteinuria in the entire cohort, decreasing to 3.87 ± 4.24 g/day (P < 0.001) with significant improvements in serum albumin, total and LDL cholesterol. A >50% decrease in proteinuria was noted in 65% of the patients with a trend toward better outcomes among patients who received greater cumulative doses. No significant adverse effects were documented. Clearing of serum anti-PLA2R antibodies prior to or in parallel with proteinuria improvement was noted in some, but not all patients.ConclusionsH.P. Acthar® Gel is a potential therapy for nephrotic syndrome secondary to idiopathic membranous nephropathy that deserves further study.

The melanocortin system in the male reproductive axis

Melanocortin receptors (MCS, MC1–MC5) are GPCRs, activated with different affinities by the melanocortin peptides (?-, ?-, ?-MSH and ACTH). They are widely distributed throughout the body displaying a multitude of actions however their role in reproductive physiology is unclear. Previously, we have shown a reduction of pituitary hormone content and abnormalities in testes morphology in male MC3 null mice. The aim of this study was to characterise MCS expression in the male mouse reproductive axis and to investigate the effects of MCS agonists/antagonists on in vitro testicular testosterone production (TP). MCS expression patterns were determined in mRNAs from hypothalami, pituitaries and testes of Balb/c and C57BL/6 male mice by two-step reverse transcriptase (RT) - quantitative (q) PCR and analysed using qBaseplus. To examine the functions of MCS in gonads, testes of Balb/c and C57BL/6 mice were hemi-sected and incubated with the potent MC3 and, to a lesser extent, MC4 agonist ([D-TRP8]-?2-MSH; 0.3–10 ?g/ml) in the presence or absence of hCG (50 mIU/ml) and/or a MC3/MC4 antagonist and MC1/MC5 agonist (SHU9119; 10 ?g/ml) for 5 h at 35 °C in air. There were no significant differences in the pattern of MCS expression between C57BL/6 and Balb/c. The most abundant MC in the hypothalamus and pituitary appears to be MC3 whilst in the testis it was MC2. TP in C57BL/6 mice is 50% less than in Balb/c: confirming published data that the former mice are hypoandrogenic. Activation of MC3 and MC4 using [D-TRP8]-?2-MSH had no or inhibitory effects on basal TP in Balb/c and C57BL/6, respectively. The same ligand decreased TP in both strains in the presence of hCG. In contrast, SHU9119±hCG increased TP threefold compared to basal levels independently of ligand dose in Balb/c. This study suggests that activation of specific MCS can alter TP however further work is required.

Mechanisms of action of ACTH in the management of relapsing forms of multiple sclerosis.

Acute and subacute inflammation, the mechanisms by which demyelination and axonal loss occur in multiple sclerosis (MS), result from the migration of activated immune cells into the central nervous system parenchyma. The triggering antigen is unknown, but the process involves deregulated immune response of T and B lymphocytes, macrophages, and mediators with expansion of autoreactive T cells creating a shift in the balance of pro- and anti-inflammatory cytokines favoring inflammation. Ongoing disease activity and exacerbations early in the course of relapsing-remitting MS may prevent full remission and propagate future progressive disability. A key strategy of immune therapy is timely initiation of treatment to achieve remission, followed by maintenance of remission. In this context, treatment with high-dose methylprednisolone (MP) is currently recommended to induce a faster recovery from a clinical exacerbation that results from an acute inflammatory attack. Adrenocorticotropic hormone (ACTH or corticotropin) gel is an alternative for patients who do not respond to or do not tolerate corticosteroids. ACTH is a universal agonist in the melanocortin (MC) system and, as such, among other functions, stimulates the adrenal cortex to produce cortisol. MCs are a family of peptides that includes ACTH and other MC peptides. This system has five classes of receptors, all of which show a strong affinity for ACTH, suggesting a more complex and dynamic mechanism than only inducing endogenous corticosteroid production. ACTH and MCs regulate processes relevant to MS, including anti-inflammatory and immunomodulatory functions involving lymphocytes, macrophages, the sympathetic nervous system involved in inflammatory processes, and reduction of pro-inflammatory cytokines. The clinical implications of the mechanistic differences between corticosteroid and ACTH gel treatment remain to be elucidated. Recent data show that patients experiencing an acute exacerbation, who previously had suboptimal response to or were unable to tolerate MP treatment, showed positive clinical outcomes with fewer adverse events with ACTH gel.

Synaptic changes induced by melanocortin signalling

The melanocortin system has a well-established role in the regulation of energy homeostasis, but there is growing evidence of its involvement in memory, nociception, mood disorders and addiction. In this Review, we focus on the role of the melanocortin 4 receptor and provide an integrative view of the molecular mechanisms that lead to melanocortin-induced changes in synaptic plasticity within these diverse physiological systems. We also highlight the importance of melanocortin peptides and receptors in chronic pain syndromes, memory impairments, depression and drug abuse, and the possibility of targeting them for therapeutic purposes.

Complex structural and regulatory evolution of the pro-opiomelanocortin gene family

The melanocortin system is a neuroendocrine machinery that has been associated with phenotypic diversification in a number of vertebrate lineages. Central to the highly pleiotropic melanocortin system is the pro-opiomelanocortin (pomc) gene family, a family of pre-prohormones that each give rise to melanocyte stimulating hormone (MSH), adrenocorticotropic releasing hormone (ACTH), β-lipotropin hormone, and β-endorphin. Here we examine the structure, tissue expression profile, and pattern of cis transcriptional regulation of the three pomc paralogs (α1, α2, and β) in the model cichlid fish Astatotilapia burtoni and other cichlids, teleosts, and mammals. We found that the hormone-encoding regions of pomc α1, pomc α2 and pomc β are highly conserved, with a few notable exceptions. Surprisingly, the pomc β gene of cichlids and pomacentrids (damselfish) encodes a novel melanocortin peptide, ε-MSH, as a result of a tandem duplication of the segment encoding ACTH. All three genes are expressed in the brain and peripheral tissues, but pomc α1 and α2 show a more spatially restricted expression profile than pomc β. In addition, the promoters of each pomc gene have diverged in nucleotide sequence, which may have facilitated the diverse tissue-specific expression profiles of these paralogs across species. Increased understanding of the mechanisms regulating pomc gene expression will be invaluable to the study of pomc in the context of phenotypic evolution.

Activation of Melanocortin Receptor 3 as a new strategy to control experimental and rheumatoid arthritis

Study ObjectiveThe anti‐inflammatory properties of melanocortin peptides have long been established, though their main molecular target(s) is still elusive. Two receptors (MC1R and MC3R) have been suggested as their main target, but the patho‐physiological impact of this important homeostatic anti‐inflammatory system is unclear: we focused here on experimental and rheumatoid (RA) arthritis.MethodsMouse Studies (1) Arthritis was induced by K/BxN serum transfer (200 μl) into wild type (WT), recessive yellow e/e (Mc1r inactive mutant) and Mc3r−/− mice and disease profiles monitored. (2) Gene expression analysis was performed in arthritic paw joints using qPCR. (3) Daily treatment with vehicle or D[Trp8]‐γ‐MSH (MC3R agonist) was given to WT and Mc3r−/− mice (20 μg) induced with K/BxN arthritis and disease profiles assessed. Human Studies qPCR was used to analyse MCR and/or pro‐inflammatory cytokine mRNA levels in RA synovium transplanted into SCID mice treated with D[Trp8]‐γ‐MSH.ResultsUpon K/BxN serum transfer, Mc3r−/− mice displayed a marked disease exacerbation whereas no different profile of disease development was displayed by the Mc1r mutant and WT mice. This heightened presence of disease in Mc3r−/− null mice was confirmed by histological analysis of paw joints. At peak of arthritic profile (D6), mRNA analysis revealed up‐regulation of Rankl, Mcp‐1, Nos2 and Il‐1β, Il‐6 in Mc3r−/− mice compared to WT. Treatment of arthritic mice with D[Trp8]‐γ‐MSH significantly attenuated disease. In another preclinical model, stimulation of human MC3R with D[Trp8]‐γ‐MSH inhibited human IL‐1β, IL‐6, TNF‐α and RANKL gene expression in RA synovium transplanted into SCID mice.ConclusionsThese findings identify MC3R‐mediated signaling as a novel anti‐inflammatory pathway for innovative therapeutic targeting in RA.

Cellular mechanisms of developmental and sex differences in the rapid hormonal modulation of a social communication signal

Some gymnotiform electric fish species rapidly modify their electric signal waveforms by altering the action potential (AP) waveforms of their electrocytes, the excitable cells that produce the electric organ discharge (EOD). The fish Brachyhypopomus gauderio alters EOD amplitude and pulse duration as a social signal in accordance with the prevailing social conditions, under the dual regulation of melanocortins and androgens. We show here that B. gauderio uses two distinct cellular mechanisms to change signal amplitude, and its use of these two mechanisms varies with age and sex of the signaler. EOD amplitude and waveform are regulated by the coordinated timing and shaping of two APs generated from two opposing excitable membranes in each electrocyte. The two membranes fire in sequence within 100μs of each other with the second AP being broader than the first. We have shown previously that mature males increase EOD amplitude and duration when melanocortin peptide hormones act directly on electrocytes to selectively broaden the second AP and increase the delay between the two APs by approximately 25μs. Here we show that females selectively broaden only the second AP as males do, but increase amplitude of both APs with no change in delay between them, a previously unreported second mechanism of EOD amplitude change in B. gauderio. Juvenile fish broaden both APs and increase the delay between the APs. Cellular mechanisms of EOD plasticity are therefore shaped during development, presumably by sex steroids, becoming sexually dimorphic at maturity.

The Synthetic Melanocortin (CKPV)2 Exerts Anti-Fungal and Anti-Inflammatory Effects against Candida albicans Vaginitis via Inducing Macrophage M2 Polarization

In this study, we examined anti-fungal and anti-inflammatory effects of the synthetic melanocortin peptide (Ac-Cys-Lys-Pro-Val-NH2)2 or (CKPV)2 against Candida albicans vaginitis. Our in vitro results showed that (CKPV)2 dose-dependently inhibited Candida albicans colonies formation. In a rat Candida albicans vaginitis model, (CKPV)2 significantly inhibited vaginal Candida albicans survival and macrophages sub-epithelial mucosa infiltration. For mechanisms study, we observed that (CKPV)2 inhibited macrophages phagocytosis of Candida albicans. Meanwhile, (CKPV)2 administration inhibited macrophage pro-inflammatory cytokines (TNF-α, IL-1β and IL-6) release, while increasing the arginase activity and anti-inflammatory cytokine IL-10 production, suggesting macrophages M1 to M2 polarization. Cyclic AMP (cAMP) production was also induced by (CKPV)2 administration in macrophages. These above effects on macrophages by (CKPV)2 were almost reversed by melanocortin receptor-1(MC1R) siRNA knockdown, indicating the requirement of MC1R in the process. Altogether, our results suggest that (CKPV)2 exerted anti-fungal and anti-inflammatory activities against Candida albicans vaginitis probably through inducing macrophages M1 to M2 polarization and MC1R activation.