This book represents the joint effort of an international group of scientists who are at the fore... more This book represents the joint effort of an international group of scientists who are at the forefront of research in the field. The volume spans information on chemistry, pharmacology, distribution, and therapeutic potential of melanocortins. A recurrent theme in this volume is the role played by distinct melanocortin receptors in mediating melanocortin effects. Although these receptors have been identified and well-characterized, information in the book indicates that definite categorization of their expression and function in different conditions still needs major work. For example, it is clear that control of food intake mainly depends on central MC4R subtypes and pigmentation is regulated by MC1R in melanocytes. On the other hand, it appears that the anti-inflammatory effects of melanocortins are orchestrated by multiple receptors in the brain and in peripheral cells. Several human disorders could benefit of melanocortin treatment. Obesity has become a major health problem in Western Countries. Synthetic MC4R agonists are very promising candidates to treat this disorder; clinical trials are already in progress. The anti-cytokine action and the inhibitory effect on inflammatory cell migration make melanocortins potential new drugs for treatment of acute, chronic, and systemic inflammation. The neuroprotective action in vascular and inflammatory brain injury is likewise well established. Melanocortins could form a novel class of therapeutic agents for several disorders of the nervous system. Through activation of MC1R, α-MSH confers photoprotection to human melanocytes and reduces DNA damage caused by exposure to solar ultraviolet radiation. Based on these actions, MC1R agonists are promising agents for melanoma prevention strategies. The severe disability caused by obesity, neurological, and inflammatory disorders has very high costs in terms of decrease in quality of life and ability to work. These conditions thus entail a heavy economic price for both the patients and the society. It is clear that effective treatments would be a beneficial response to significant needs. As research described in this book indicates, melanocortins have a remarkable potential for treatment of many dire conditions.
The natural antimicrobial peptides are ancient host defense effector molecules, present in organi... more The natural antimicrobial peptides are ancient host defense effector molecules, present in organisms across the evolutionary spectrum. Several properties of α-melanocyte stimulating hormone (α-MSH) suggested that it could be a natural antimicrobial peptide. α-MSH is a primordial peptide that appeared during the Paleozoic era, long before adaptive immunity developed and, like natural antimicrobial molecules, is produced by barrier epithelia, immunocytes, and within the central nervous system. α-MSH was discovered to have antimicrobial activity against two representative pathogens,Staphylococcus aureusandCandida albicans. The candidacidal influences of α-MSH appeared to be mediated by increases in cell cyclic adenosine monophosphate (cAMP). The cAMP-inducing capacity of α-MSH likely interferes with the yeast's own regulatory mechanisms of this essential signaling pathway. It is remarkable that this mechanism of action in yeast mimics the influences of α-MSH in mammalian cells in w...
Tumor necrosis factor (TNF-a) underlies pathological pro- cesses and functional disturbances in a... more Tumor necrosis factor (TNF-a) underlies pathological pro- cesses and functional disturbances in acute and chronic neurological disease and injury. The neuroimmunomodulatory peptide a-MSH modulates actions and production of proin- flammatory cytokines including TNF-a, but there is no prior evidence that it alters TNF-a induced within the brain. To test for this potential influence of the peptide, TNF-a was induced centrally
A B S T R A C T The increasing use of marginal lungs for transplantation encourages novel approa... more A B S T R A C T The increasing use of marginal lungs for transplantation encourages novel approaches to improve graft quality. Melanocortins and their receptors (MCRs) exert multiple beneficial effects in pulmonary inflammation. We tested the idea that treatment with the synthetic α-melanocyte-stimulating hormone analogue [Nle4,D-Phe7]-α-MSH (NDP-MSH) during ex vivo lung perfusion (EVLP) could exert positive influences in lungs exposed to different injuries. Rats were assigned to one of the following protocols (N = 10 each): 1) ischemia/reperfusion (IR) or 2) cardiac death (CD) followed by ex vivo perfusion. NDP-MSH treatment was performed in five rats of each protocol before lung procurement and during EVLP. Pulmonary function and perfusate concentration of gases, electrolytes, metabolites, nitric-oxide, mediators, and cells were assessed throughout EVLP. ATP content and specific MCR expression were investigated in perfused lungs and in biopsies collected from rats in resting conditions (Native, N = 5). NDP-MSH reduced the release of inflammatory mediators in perfusates of both the IR and the CD groups. Treatment was likewise associated with a lesser amount of leukocytes (IR: p = 0.034; CD: p = 0.002) and reduced lactate production (IR: p = 0.010; CD: p = 0.008). In lungs exposed to IR injury, the NDP-MSH group showed increased ATP content (p = 0.040) compared to controls. In CD lungs, a significant improvement of vascular (p = 0.002) and airway (Ppeak: p < 0.001, compliance: p < 0.050, pO2: p < 0.001) parameters was observed. Finally, the expression of MC1R and MC5R was detected in both native and ex vivo-perfused lungs. The results indicate that NDP-MSH administration preserves lung function through broad positive effects on multiple pathways and suggest that exploitation of the melanocortin system during EVLP could improve reconditioning of marginal lungs before transplantation.
The clinical hallmarks of infections caused by critical respiratory viruses consist of
pneumonia,... more The clinical hallmarks of infections caused by critical respiratory viruses consist of pneumonia, which can progress to acute lung injury (ALI), and systemic manifestations including hypercoagulopathy, vascular dysfunction, and endotheliitis. The disease outcome largely depends on the immune response produced by the host. The biomolecular mechanisms underlying certain dire consequences of the infection partly arise from an aberrant production of inflammatory molecules, an event denoted as “cytokine storm”. Therefore, in addition to antiviral therapies, molecules able to prevent the injury caused by cytokine excess are under investigation. In this perspective, taking advantage of melanocortin peptides and their receptors, components of an endogenous modulatory system that exerts marked anti-inflammatory and immunomodulatory influences, could be an effective therapeutic strategy to control disease evolution. Exploiting the melanocortin system using natural or synthetic ligands can form a realistic basis to counteract certain deleterious effects of respiratory virus infections. The central and peripheral protective actions exerted following melanocortin receptor activation could allow dampening the harmful events that trigger the cytokine storm and endothelial dysfunction while sustaining the beneficial signals required to elicit repair mechanisms. The long standing evidence for melanocortin safety encourages this approach.
This book represents the joint effort of an international group of scientists who are at the fore... more This book represents the joint effort of an international group of scientists who are at the forefront of research in the field. The volume spans information on chemistry, pharmacology, distribution, and therapeutic potential of melanocortins. A recurrent theme in this volume is the role played by distinct melanocortin receptors in mediating melanocortin effects. Although these receptors have been identified and well-characterized, information in the book indicates that definite categorization of their expression and function in different conditions still needs major work. For example, it is clear that control of food intake mainly depends on central MC4R subtypes and pigmentation is regulated by MC1R in melanocytes. On the other hand, it appears that the anti-inflammatory effects of melanocortins are orchestrated by multiple receptors in the brain and in peripheral cells. Several human disorders could benefit of melanocortin treatment. Obesity has become a major health problem in Western Countries. Synthetic MC4R agonists are very promising candidates to treat this disorder; clinical trials are already in progress. The anti-cytokine action and the inhibitory effect on inflammatory cell migration make melanocortins potential new drugs for treatment of acute, chronic, and systemic inflammation. The neuroprotective action in vascular and inflammatory brain injury is likewise well established. Melanocortins could form a novel class of therapeutic agents for several disorders of the nervous system. Through activation of MC1R, α-MSH confers photoprotection to human melanocytes and reduces DNA damage caused by exposure to solar ultraviolet radiation. Based on these actions, MC1R agonists are promising agents for melanoma prevention strategies. The severe disability caused by obesity, neurological, and inflammatory disorders has very high costs in terms of decrease in quality of life and ability to work. These conditions thus entail a heavy economic price for both the patients and the society. It is clear that effective treatments would be a beneficial response to significant needs. As research described in this book indicates, melanocortins have a remarkable potential for treatment of many dire conditions.
The natural antimicrobial peptides are ancient host defense effector molecules, present in organi... more The natural antimicrobial peptides are ancient host defense effector molecules, present in organisms across the evolutionary spectrum. Several properties of α-melanocyte stimulating hormone (α-MSH) suggested that it could be a natural antimicrobial peptide. α-MSH is a primordial peptide that appeared during the Paleozoic era, long before adaptive immunity developed and, like natural antimicrobial molecules, is produced by barrier epithelia, immunocytes, and within the central nervous system. α-MSH was discovered to have antimicrobial activity against two representative pathogens,Staphylococcus aureusandCandida albicans. The candidacidal influences of α-MSH appeared to be mediated by increases in cell cyclic adenosine monophosphate (cAMP). The cAMP-inducing capacity of α-MSH likely interferes with the yeast's own regulatory mechanisms of this essential signaling pathway. It is remarkable that this mechanism of action in yeast mimics the influences of α-MSH in mammalian cells in w...
Tumor necrosis factor (TNF-a) underlies pathological pro- cesses and functional disturbances in a... more Tumor necrosis factor (TNF-a) underlies pathological pro- cesses and functional disturbances in acute and chronic neurological disease and injury. The neuroimmunomodulatory peptide a-MSH modulates actions and production of proin- flammatory cytokines including TNF-a, but there is no prior evidence that it alters TNF-a induced within the brain. To test for this potential influence of the peptide, TNF-a was induced centrally
A B S T R A C T The increasing use of marginal lungs for transplantation encourages novel approa... more A B S T R A C T The increasing use of marginal lungs for transplantation encourages novel approaches to improve graft quality. Melanocortins and their receptors (MCRs) exert multiple beneficial effects in pulmonary inflammation. We tested the idea that treatment with the synthetic α-melanocyte-stimulating hormone analogue [Nle4,D-Phe7]-α-MSH (NDP-MSH) during ex vivo lung perfusion (EVLP) could exert positive influences in lungs exposed to different injuries. Rats were assigned to one of the following protocols (N = 10 each): 1) ischemia/reperfusion (IR) or 2) cardiac death (CD) followed by ex vivo perfusion. NDP-MSH treatment was performed in five rats of each protocol before lung procurement and during EVLP. Pulmonary function and perfusate concentration of gases, electrolytes, metabolites, nitric-oxide, mediators, and cells were assessed throughout EVLP. ATP content and specific MCR expression were investigated in perfused lungs and in biopsies collected from rats in resting conditions (Native, N = 5). NDP-MSH reduced the release of inflammatory mediators in perfusates of both the IR and the CD groups. Treatment was likewise associated with a lesser amount of leukocytes (IR: p = 0.034; CD: p = 0.002) and reduced lactate production (IR: p = 0.010; CD: p = 0.008). In lungs exposed to IR injury, the NDP-MSH group showed increased ATP content (p = 0.040) compared to controls. In CD lungs, a significant improvement of vascular (p = 0.002) and airway (Ppeak: p < 0.001, compliance: p < 0.050, pO2: p < 0.001) parameters was observed. Finally, the expression of MC1R and MC5R was detected in both native and ex vivo-perfused lungs. The results indicate that NDP-MSH administration preserves lung function through broad positive effects on multiple pathways and suggest that exploitation of the melanocortin system during EVLP could improve reconditioning of marginal lungs before transplantation.
The clinical hallmarks of infections caused by critical respiratory viruses consist of
pneumonia,... more The clinical hallmarks of infections caused by critical respiratory viruses consist of pneumonia, which can progress to acute lung injury (ALI), and systemic manifestations including hypercoagulopathy, vascular dysfunction, and endotheliitis. The disease outcome largely depends on the immune response produced by the host. The biomolecular mechanisms underlying certain dire consequences of the infection partly arise from an aberrant production of inflammatory molecules, an event denoted as “cytokine storm”. Therefore, in addition to antiviral therapies, molecules able to prevent the injury caused by cytokine excess are under investigation. In this perspective, taking advantage of melanocortin peptides and their receptors, components of an endogenous modulatory system that exerts marked anti-inflammatory and immunomodulatory influences, could be an effective therapeutic strategy to control disease evolution. Exploiting the melanocortin system using natural or synthetic ligands can form a realistic basis to counteract certain deleterious effects of respiratory virus infections. The central and peripheral protective actions exerted following melanocortin receptor activation could allow dampening the harmful events that trigger the cytokine storm and endothelial dysfunction while sustaining the beneficial signals required to elicit repair mechanisms. The long standing evidence for melanocortin safety encourages this approach.
Subarachnoid hemorrhage (SAH) is still a major cause of morbidity and mortality. α-Melanocyte sti... more Subarachnoid hemorrhage (SAH) is still a major cause of morbidity and mortality. α-Melanocyte stimulating hormone (α-MSH) and other melanocortin peptides exert potent neuroprotective action and they might modulate key molecules involved in SAH-induced vasospasm. The aim of this research was to determine whether treatment with the α-MSH analog Nle4,DPhe7-α-MSH (NDP-MSH) exerts protective effects in experimental SAH in the rat. Initial experiments examined effects of NDP-MSH on the basilar artery phenotype in the absence of injury. In these tests intrathecal injection of small concentrations (10 ng) of the peptide induced a tolerant phenotype similar to that observed after ischemic preconditioning. Then the effect of sys-temic treatment with NDP-MSH (100 μg i.v.) on experimental SAH was evaluated. SAH was induced by a single-blood injection into the cisterna magna. The basilar artery phenotype was examined at 4 h and the artery caliber at 5 days following SAH. Expression of 96 genes was analyzed by real-time reverse transcription polymerase chain reaction (RT-PCR) using Custom Taqman Low-Density Arrays. Four hours after SAH, the transcriptional profile of the basilar artery was deeply disrupted. Transcript alteration included genes involved in inflammation, stress response, apoptosis, and vascular remodeling. Treatment with NDP-MSH prevented most of these transcription changes and decreased phosphorylation of extracellular-signal-regulated kinases (ERK1/2) and inhibitor protein IκBα. Vasospasm on day 5 was significantly reduced by NDP-MSH administration. These results combine with others on CNS inflammation to suggest that the melanocortins could be safe and effective therapeutic candidates to treat SAH-related complications.
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Several human disorders could benefit of melanocortin treatment. Obesity has become a major health problem in Western Countries. Synthetic MC4R agonists are very promising candidates to treat this disorder; clinical trials are already in progress. The anti-cytokine action and the inhibitory effect on inflammatory cell migration make melanocortins potential new drugs for treatment of acute, chronic, and systemic inflammation. The neuroprotective action in vascular and inflammatory brain injury is likewise well established. Melanocortins could form a novel class of therapeutic agents for several disorders of the nervous system. Through activation of MC1R, α-MSH confers photoprotection to human melanocytes and reduces DNA damage caused by exposure to solar ultraviolet radiation. Based on these actions, MC1R agonists are promising agents for melanoma prevention strategies.
The severe disability caused by obesity, neurological, and inflammatory disorders has very high costs in terms of decrease in quality of life and ability to work. These conditions thus entail a heavy economic price for both the patients and the society. It is clear that effective treatments would be a beneficial response to significant needs. As research described in this book indicates, melanocortins have a remarkable potential for treatment of many dire conditions.
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pneumonia, which can progress to acute lung injury (ALI), and systemic manifestations
including hypercoagulopathy, vascular dysfunction, and endotheliitis. The disease
outcome largely depends on the immune response produced by the host. The biomolecular
mechanisms underlying certain dire consequences of the infection partly arise
from an aberrant production of inflammatory molecules, an event denoted as “cytokine
storm”. Therefore, in addition to antiviral therapies, molecules able to prevent the injury
caused by cytokine excess are under investigation. In this perspective, taking advantage
of melanocortin peptides and their receptors, components of an endogenous modulatory
system that exerts marked anti-inflammatory and immunomodulatory influences, could be
an effective therapeutic strategy to control disease evolution. Exploiting the melanocortin
system using natural or synthetic ligands can form a realistic basis to counteract certain
deleterious effects of respiratory virus infections. The central and peripheral protective
actions exerted following melanocortin receptor activation could allow dampening the
harmful events that trigger the cytokine storm and endothelial dysfunction while sustaining
the beneficial signals required to elicit repair mechanisms. The long standing evidence for
melanocortin safety encourages this approach.
Keywords: respiratory viruses, SARS-CoV-2, acute lung injury, cytokine storm, endothelial dysfunction,
melanocortin receptors, adenocorticotropin, alpha melanocyte stimulating hormone
Several human disorders could benefit of melanocortin treatment. Obesity has become a major health problem in Western Countries. Synthetic MC4R agonists are very promising candidates to treat this disorder; clinical trials are already in progress. The anti-cytokine action and the inhibitory effect on inflammatory cell migration make melanocortins potential new drugs for treatment of acute, chronic, and systemic inflammation. The neuroprotective action in vascular and inflammatory brain injury is likewise well established. Melanocortins could form a novel class of therapeutic agents for several disorders of the nervous system. Through activation of MC1R, α-MSH confers photoprotection to human melanocytes and reduces DNA damage caused by exposure to solar ultraviolet radiation. Based on these actions, MC1R agonists are promising agents for melanoma prevention strategies.
The severe disability caused by obesity, neurological, and inflammatory disorders has very high costs in terms of decrease in quality of life and ability to work. These conditions thus entail a heavy economic price for both the patients and the society. It is clear that effective treatments would be a beneficial response to significant needs. As research described in this book indicates, melanocortins have a remarkable potential for treatment of many dire conditions.
pneumonia, which can progress to acute lung injury (ALI), and systemic manifestations
including hypercoagulopathy, vascular dysfunction, and endotheliitis. The disease
outcome largely depends on the immune response produced by the host. The biomolecular
mechanisms underlying certain dire consequences of the infection partly arise
from an aberrant production of inflammatory molecules, an event denoted as “cytokine
storm”. Therefore, in addition to antiviral therapies, molecules able to prevent the injury
caused by cytokine excess are under investigation. In this perspective, taking advantage
of melanocortin peptides and their receptors, components of an endogenous modulatory
system that exerts marked anti-inflammatory and immunomodulatory influences, could be
an effective therapeutic strategy to control disease evolution. Exploiting the melanocortin
system using natural or synthetic ligands can form a realistic basis to counteract certain
deleterious effects of respiratory virus infections. The central and peripheral protective
actions exerted following melanocortin receptor activation could allow dampening the
harmful events that trigger the cytokine storm and endothelial dysfunction while sustaining
the beneficial signals required to elicit repair mechanisms. The long standing evidence for
melanocortin safety encourages this approach.
Keywords: respiratory viruses, SARS-CoV-2, acute lung injury, cytokine storm, endothelial dysfunction,
melanocortin receptors, adenocorticotropin, alpha melanocyte stimulating hormone