Disorders of pigmentation
Rashmi Sarkar, Anupam Das, Sumit Sethi in Concise Dermatology, 2021
It has to be determined whether the pigmentation is due to melanin or some other pigment (Table 19.2). Generalized melanin hyperpigmentation is seen in Addison’s disease due to destruction of the adrenal cortex from tuberculosis, autoimmune influences, metastases, or amyloidosis. Pigmentation is marked in the flexures, sites of trauma, scars, and sun-exposed areas, but the mucosae and nails are also hyperpigmented. The pigmentation is mediated via activation of the melanocortin-1 receptor. The diagnosis is supported by hypotension, hyponatraemia, and extreme weakness. The hyperpigmentation is due to an excess of pituitary peptides resulting from the lack of adrenal steroids. After bilateral adrenalectomy, pigmentation may be extreme (Nelson’s syndrome). This is associated with an enlarged pituitary gland, elevated fasting plasma ACTH level, and neurologic symptoms. Pheochromocytoma is characterized by Addisonian pigmentation due to ectopic ACTH and MSH production. Carcinoid syndrome manifests with diffuse hyperpigmentation due to an MSH-secreting tumor; along with pellagroid dermatitis.
The melanocyte and melaninogenesis
Dimitris Rigopoulos, Alexander C. Katoulis in Hyperpigmentation, 2017
PKC-β is involved in the stabilization of tyrosinase and the increase of its enzymatic activity by phosphorylating serine residues on the cytoplasmic domain of tyrosinase. This process seems to lead to the formation of a complex between tyrosinase and TRP-1, which results, as mentioned in the previous paragraph, in the activation and stabilization of tyrosinase. Two further proteins that regulate melaninogenesis are the transcription factor MITF and the melanocortin 1 receptor (MC1R). MITF is very important for the survival of the melanocyte. It is a basic helix–loop–helix and leucine zipper transcription factor, and it has at least nine isoforms. MITF blocks the apoptotic process by enhancing the expression of BCL2, a major antiapoptotic protein in the cell.21 Additionally, it regulates the transcription of the most important melaninogenesis enzymes, PKC-β, tyrosinase, TRP-1, and TRP-2. More specifically, transcription of PKC-β and tyrosinase is controlled by the MITF-M isoform.22 MC1R is the first of the five proteins that belong to the family of the melanocortin receptors, which are G protein–coupled receptors.9 The remaining are MC2R, MC3R, MC4R, and MC5R. Each of them has seven transmembrane domains. MC1R is expressed mostly in melanocytes, but also in other types of cells (keratinocytes, fibroblasts, and endothelial cells).8 It is activated by the hormones ACTH and α-MSH. MC1R regulates melaninogenesis by activating PKA, which induces MITF transcription, and then MITF, by the processes mentioned above, promotes synthesis of eumelanin.15
Neuroendocrine Regulation of Food Intake
Emmanuel Opara in NUTRITION and DIABETES, 2005
The integrated physiology of the interactions of these opposing neuropeptides is evident from their weight-related alterations. Following weight loss, the deceasing levels of insulin and leptin lead to activation of NPY/AgRP neurons and inhibition of POMC neurons (23). These counterregulatory changes induce accelerated food intake and accumulation of fat. Defects along the melanocortin signaling pathway, such as those seen in transgenic mice with targeted disruption of the MC4 receptor (knock-outs), result in hyperphagic and massive obesity (24). Recently, fairly widespread functional mutations of the human MC4 receptor have been demonstrated in patients with severe childhood obesity (25) and also linked to binge-eating disorder (26). It should be noted, however, that the majority of obese patients have no demonstrable mutations in MC4, yet such persons may possibly benefit from future therapies targeting activation of MC4 pathways. Indeed, intransal administration of a melanocortin fragment (MSH/ACTH 4–10) looks promising in that regard by inducing modest weight loss (27).
A review on pharmacological options for the treatment of erectile dysfunction: state of the art and new strategies
Published in Expert Opinion on Pharmacotherapy, 2023
Mattia Longoni, Alessandro Bertini, Nicolò Schifano, Emanuele Zaffuto, Paolo Maggio, Rossi Piercarlo, Sara Baldini, Giulio Carcano, Gabriele Antonini, Andrea Salonia, Francesco Montorsi, Federico Dehò, Paolo Capogrosso
The contribution of the melanocortin system to sexual function is well known and pro-erectile functions of spinal melanocortin receptors, such as MC4R, have been proposed in multiple studies [103,104]. Indeed, intrathecal injection of melanocortin agonist (i.e. MT-II) to male rats’ lumbar spinal cord increases spontaneous erections [105]. Differently from ‘peripherical’ molecular pathways targeted by conventional drugs, MT-II manipulation of melanocortinergic receptors elicits a centrally-mediated erection by modulating the sympathetic efferent nerves to the pelvis, with little effect on the parasympathetics [106]. In a double-blind placebo-controlled study, MT-II peptide (0.025 mg/Kg) subcutaneous injection to 20 patients affected by psychogenic and organic ED was able to elicit significant erection in 17/20 men without video sex stimulation. Therefore, contrary to PDE5Is, MT-II agonist seems to induce spontaneous erection in absence of sexual stimulation [107]. Further clinical studies led to the development of PT−141, a cyclic heptapeptide melanocortin analog with improved tolerability, a more rapid onset of action compared to MT-II, and equal efficacy. In the phase IIA study, PT−141 intranasal administration induced a clinically significant erectile response compared to placebo [108,109]. Finally, in a pilot study the administration of a selective melanocortin−4 receptor agonist displayed a similar number of clinical responses to sildenafil [110]. Despite these preliminary promising results, which indicate melanocortin system as a novel target for ED treatment, further studies are needed.
Relationship Between Appetite-Related Peptides and Frailty in Older Adults
Published in Endocrine Research, 2023
Burcu Candemir, İbrahim İleri, Mehmet Muhittin Yalçın, Aydın Tuncer Sel, Berna Göker, Özlem Gülbahar, İlhan Yetkin
Peptide YY is a peptide that is secreted from the ileum and colon in response to nutrition and reduces appetite and hence called “ileal brake.” It inhibits the secretion of ghrelin, delays gastric emptying, and suppresses the secretory function of the pancreas and stomach.30 It also works centrally by inhibiting mRNA expression of NPY and AgRP in the arcuate nucleus.30 Alpha MSH, which is the product of the POMC gene, has a significant impact on food intake and energy balance. The effects of α-MSH on food intake and body weight are mediated in the brain via two melanocortin receptors (MCR), MC3-R and MC4-R. Melanocortin receptor-4 is localized primarily in the central nervous system and is responsible for the appetite-reducing effects of α -MSH. Functional mutations of MC4-R have been associated with hyperphagia and obesity in mice.31 CART is an anorexigenic hormone that shows its anorexigenic effect through the inhibition of NPY neurons and central release of glucagon-like peptide-1.32 Some authors reported increased CART mRNA expression with aging, while others found no changes.33–35 In the present study, our results suggested that α-MSH and CART levels were independent predictors of frailty. However, small predictive values raise the question of whether our findings are of any possible clinical significance. Nevertheless, the results of this study, which have a novel premise, will shed light on future studies.
Effects of Subcutaneous Repository Corticotropin Gel Injection on Regulatory T Cell Population in Noninfectious Retinal Vasculitis
Published in Ocular Immunology and Inflammation, 2023
Stephen D. Anesi, Peter Y. Chang, Arash Maleki, Ambika Manhapra, Sydney Look-Why, Soheila Asgari, Marisa Walsh, Kayla Drenen, C. Stephen Foster
The melanocortin pathway is thought to suppress inflammation by inhibiting both the innate and adaptive immune systems.13 Through negative control, the pathway blocks the proinflammatory interleukin-1 (IL-1) and tumor necrosis factor (TNF-) -α receptors in effector cells.14 These changes suppress the production of interferon (IFN-) -γ by effector T cells, while increasing the levels of transforming growth factor (TGF-) -β, and subsequently, increasing the regulatory functions of T-cells. These induced T cells are CD4 +T cells that express CD25 as well at the same level of CD4 on their surface in contrary to effector T cells.15,16 These induced T cells are referred to as T regulatory cells or Tregs. It has been shown that Treg cells are CD25+ CD4 + T cells that share similar surface markers as effector T cells, except that they also express the surface latency-associated peptide (LAP).13 Additionally, melanocortins promote FoxP3 messaging in effector T cells and subsequently increase the regulatory activities of the CD25 + T-cell population.13