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1.
Dis Model Mech ; 13(2)2019 12 03.
Artigo em Inglês | MEDLINE | ID: mdl-31666234

RESUMO

STIM and ORAI proteins play a fundamental role in calcium signaling, allowing for calcium influx through the plasma membrane upon depletion of intracellular stores, in a process known as store-operated Ca2+ entry. Point mutations that lead to gain-of-function activity of either STIM1 or ORAI1 are responsible for a cluster of ultra-rare syndromes characterized by motor disturbances and platelet dysfunction. The prevalence of these disorders is at present unknown. In this study, we describe the generation and characterization of a knock-in mouse model (KI-STIM1I115F) that bears a clinically relevant mutation located in one of the two calcium-sensing EF-hand motifs of STIM1. The mouse colony is viable and fertile. Myotubes from these mice show an increased store-operated Ca2+ entry, as predicted. This most likely causes the dystrophic muscle phenotype observed, which worsens with age. Such histological features are not accompanied by a significant increase in creatine kinase. However, animals have significantly worse performance in rotarod and treadmill tests, showing increased susceptibility to fatigue, in analogy to the human disease. The mice also show increased bleeding time and thrombocytopenia, as well as an unexpected defect in the myeloid lineage and in natural killer cells. The present model, together with recently described models bearing the R304W mutation (located on the coiled-coil domain in the cytosolic side of STIM1), represents an ideal platform to characterize the disorder and test therapeutic strategies for patients with STIM1 mutations, currently without therapeutic solutions.This article has an associated First Person interview with Celia Cordero-Sanchez, co-first author of the paper.

2.
Nutrients ; 11(10)2019 Oct 06.
Artigo em Inglês | MEDLINE | ID: mdl-31590434

RESUMO

BACKGROUND: The association between circulating levels of vitamin D and the incidence of chronic diseases is known. The identification of vitamin D as a biomarker of physiological/pathological ageing could contribute to expanding current knowledge of its involvement in healthy ageing. METHODS: According to PRISMA guidelines, a systematic review was conducted on cohorts studying the role of 25OH-Vitamin D [25(OH)D] and 1,25(OH)2-Vitamin D [1,25(OH)2D] concentrations as biomarkers of healthy ageing. We consulted MedLine, Scopus, and Web of Science to search for studies on the association between vitamin D status in populations of originally healthy adults, and outcomes of longevity, illness, and physical and cognitive functionality. The quality of the studies was assessed using the Newcastle Ottawa scale. RESULTS: Twenty cohorts from 24 articles were selected for this review. Inverse associations were found between low 25(OH)D levels and all-cause mortality, respiratory and cardiovascular events, as well as markers relating to hip and non-vertebral fractures. Associations between 1,25(OH)2D and healthy ageing outcomes gave similar results, although of lower clinical significance. CONCLUSIONS: This systematic review pinpoints peculiar aspects of vitamin D as a multidimensional predictor of ill health in the ageing process. Further well-designed controlled trials to investigate whether vitamin D supplement results in superior outcomes are warranted in the future.

3.
J Clin Endocrinol Metab ; 104(11): 5263-5273, 2019 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-31215990

RESUMO

BACKGROUND: GH deficiency (GHD) is characterized by a cluster of cardiovascular risk factors and subtle inflammation. We aimed to demonstrate, through a proteomic approach, molecules directly modulated by GHD and involved in the inflammatory state. METHODS: Ten children with isolated GHD were studied before and after 1 year of treatment with rhGH and compared with 14 matched controls. A two-dimensional electrophoresis plasma proteomics analysis was performed at baseline and after GH treatment to identify the top molecules modulated by GH. In vitro studies on human hepatoma (HepG2) cells were performed to validate the data. RESULTS: Twelve of 20 proteomic spots were predicted to be isoforms α and ß of haptoglobin (Hp) and confirmed by liquid chromatography tandem mass spectrometry and Western immunoblot analyses. Hp levels were higher in patients with GHD than controls at baseline (P < 0.001) and were reduced following GH treatment (P < 0.01). In HepG2 cells, both GH and IGF-1 were able to downregulate IL-6-induced Hp secretion. Moreover, Hp secretion was restored in pegvisomant-treated HepG2 cells. CONCLUSIONS: Hp is a molecule acting in the inflammatory state of GHD and a possible biomarker for GH treatment. Nevertheless, the contribution of other factors and the molecular pathways involved in the GH downregulation of Hp remain to be clearly defined.

4.
Acta Physiol (Oxf) ; 226(3): e13269, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-30834670

RESUMO

AIM: Loss of skeletal muscle is one of the main features of cancer cachexia. Vitamin D (VD) deficiency is associated with impairment of muscle mass and performance and is highly prevalent in cachectic patients; therefore, VD supplementation has been proposed to counteract cancer cachexia-associated muscle loss. However, in both cachectic cancer patients and tumour-bearing animals, VD supplementation led to disappointing results, urging the need for a better understanding of VD activity on skeletal muscle. METHODS: Cancer-associated muscle wasting was reproduced in vitro by treating C2C12 myotubes with cancer cell conditioned medium, a combination of TNF-α and IFNγ or IL-6 pro-cachectic cytokines. The biological effects and mechanisms of action of 1,25-dihydroxy VD (1,25 VD) and its precursor 25-hydroxy VD (25 VD) on myotubes were explored. RESULTS: We demonstrated that only 25 VD was able to protect from atrophy by activating Akt signalling, inducing protein synthesis, and stimulating the autophagic flux, while 1,25 VD had an atrophic activity per se, increasing FoxO3 levels, inducing the expression of atrogenes, and blocking the autophagic flux. Furthermore, we showed that the contrasting activities of these VD metabolites on C2C12 myotubes depend on a differential induction of VD-24-hydroxylase and transformation of VD metabolites in pro-atrophic 24-hydroxylated products, as silencing of VD-24-hydroxylase reduced the atrophic activity of 1,25 VD. CONCLUSIONS: Altogether these data might explain the lack of efficacy of VD treatment in vivo for the protection of muscle mass in cancer.

5.
Endocrine ; 62(1): 129-135, 2018 10.
Artigo em Inglês | MEDLINE | ID: mdl-29846901

RESUMO

PURPOSE: Muscle regeneration depends on satellite cells (SCs), quiescent precursors that, in consequence of injury or pathological states such as muscular dystrophies, activate, proliferate, and differentiate to repair the damaged tissue. A subset of SCs undergoes self-renewal, thus preserving the SC pool and its regenerative potential. The peptides produced by the ghrelin gene, i.e., acylated ghrelin (AG), unacylated ghrelin (UnAG), and obestatin (Ob), affect skeletal muscle biology in several ways, not always with overlapping effects. In particular, UnAG and Ob promote SC self-renewal and myoblast differentiation, thus fostering muscle regeneration. METHODS: To delineate the endogenous contribution of preproghrelin in muscle regeneration, we evaluated the repair process in Ghrl-/- mice upon CTX-induced injury. RESULTS: Although muscles from Ghrl-/- mice do not visibly differ from WT muscles in term of weight, structure, and SCs content, muscle regeneration after CTX-induced injury is impaired in Ghrl-/- mice, indicating that ghrelin-derived peptides actively participate in muscle repair. Remarkably, the lack of ghrelin gene impacts SC self-renewal during regeneration. CONCLUSIONS: Although we cannot discern the specific Ghrl-derived peptide responsible for such activities, these data indicate that Ghrl contributes to a proper muscle regeneration.


Assuntos
Grelina/metabolismo , Músculo Esquelético/metabolismo , Regeneração/fisiologia , Células Satélites de Músculo Esquelético/metabolismo , Animais , Grelina/genética , Masculino , Camundongos , Camundongos Knockout
6.
Oxid Med Cell Longev ; 2018: 6419805, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29682162

RESUMO

Cancer cachexia is a devastating syndrome occurring in the majority of terminally ill cancer patients. Notably, skeletal muscle atrophy is a consistent feature affecting the quality of life and prognosis. To date, limited therapeutic options are available, and research in the field is hampered by the lack of satisfactory models to study the complexity of wasting in cachexia-inducing tumors, such as pancreatic cancer. Moreover, currently used in vivo models are characterized by an explosive cachexia with a lethal wasting within few days, while pancreatic cancer patients might experience alterations long before the onset of overt wasting. In this work, we established and characterized a slow-paced model of pancreatic cancer-induced muscle wasting that promotes efficient muscular wasting in vitro and in vivo. Treatment with conditioned media from pancreatic cancer cells led to the induction of atrophy in vitro, while tumor-bearing mice presented a clear reduction in muscle mass and functionality. Intriguingly, several metabolic alterations in tumor-bearing mice were identified, paving the way for therapeutic interventions with drugs targeting metabolism.


Assuntos
Caquexia/fisiopatologia , Músculo Esquelético/fisiopatologia , Atrofia Muscular/fisiopatologia , Neoplasias Pancreáticas/fisiopatologia , Animais , Feminino , Camundongos , Camundongos Endogâmicos C57BL , Qualidade de Vida
7.
Cell Res ; 28(3): 265-280, 2018 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-29219147

RESUMO

Glycolysis has long been considered as the major metabolic process for energy production and anabolic growth in cancer cells. Although such a view has been instrumental for the development of powerful imaging tools that are still used in the clinics, it is now clear that mitochondria play a key role in oncogenesis. Besides exerting central bioenergetic functions, mitochondria provide indeed building blocks for tumor anabolism, control redox and calcium homeostasis, participate in transcriptional regulation, and govern cell death. Thus, mitochondria constitute promising targets for the development of novel anticancer agents. However, tumors arise, progress, and respond to therapy in the context of an intimate crosstalk with the host immune system, and many immunological functions rely on intact mitochondrial metabolism. Here, we review the cancer cell-intrinsic and cell-extrinsic mechanisms through which mitochondria influence all steps of oncogenesis, with a focus on the therapeutic potential of targeting mitochondrial metabolism for cancer therapy.


Assuntos
Carcinogênese , Transformação Celular Neoplásica , Mitocôndrias , Neoplasias/metabolismo , Animais , Antineoplásicos/uso terapêutico , Cálcio/metabolismo , Carcinogênese/imunologia , Carcinogênese/metabolismo , Transformação Celular Neoplásica/imunologia , Transformação Celular Neoplásica/metabolismo , Glicólise , Humanos , Mitocôndrias/imunologia , Mitocôndrias/metabolismo , Terapia de Alvo Molecular , Neoplasias/tratamento farmacológico , Oxirredução
8.
Curr Opin Support Palliat Care ; 11(4): 287-292, 2017 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-28922293

RESUMO

PURPOSE OF REVIEW: The possibility to use vitamin D supplementation to improve muscle wasting, with particular focus on cancer cachexia, is discussed. RECENT FINDINGS: Vitamin D exerts biological actions on myogenic precursor proliferation and differentiation, impinging on muscle regeneration. However, the effects of VitD supplementation in diseases associated with muscle atrophy, such as cancer cachexia, are poorly investigated. Data obtained in experimental models of cancer cachexia show that the administration of vitamin D to tumor-bearing animals is not able to prevent or delay both muscle wasting and adipose tissue depletion, despite increased expression of muscle vitamin D receptor. Not just vitamin D supplementation impairs muscle damage-induced regeneration, suggesting that upregulation of vitamin D receptor signaling could contribute to muscle wasting. SUMMARY: Vitamin D supplementation is likely beneficial to reduce or delay aging-related sarcopenia and osteoporosis, although the available data still put in evidence significant discrepancies. By contrast, VitD supplementation to tumor-bearing animals or to rats with arthritis was shown to be totally ineffective. In this regard, the adoption of VitD treatment in patients with cancer cachexia or other chronic diseases should be carefully evaluated, in particular whenever a regenerative process might be involved.


Assuntos
Caquexia/tratamento farmacológico , Caquexia/etiologia , Suplementos Nutricionais , Neoplasias/complicações , Vitamina D/uso terapêutico , Tecido Adiposo/efeitos dos fármacos , Animais , Humanos , Músculo Esquelético/efeitos dos fármacos , Atrofia Muscular/tratamento farmacológico , Atrofia Muscular/metabolismo , Vitamina D/farmacologia
9.
Stem Cells ; 35(7): 1733-1746, 2017 07.
Artigo em Inglês | MEDLINE | ID: mdl-28436144

RESUMO

Muscle regeneration depends on satellite cells (SCs), quiescent precursors that, in consequence of injury or in pathological states such as muscular dystrophies, activate, proliferate, and differentiate to repair the damaged tissue. A subset of SCs undergoes self-renewal, thus preserving the SC pool and its regenerative potential. Unacylated ghrelin (UnAG) is a circulating hormone that protects muscle from atrophy, promotes myoblast differentiation, and enhances ischemia-induced muscle regeneration. Here we show that UnAG increases SC activity and stimulates Par polarity complex/p38-mediated asymmetric division, fostering both SC self-renewal and myoblast differentiation. Because of those activities on different steps of muscle regeneration, we hypothesized a beneficial effect of UnAG in mdx dystrophic mice, in which the absence of dystrophin leads to chronic muscle degeneration, defective muscle regeneration, fibrosis, and, at later stages of the pathology, SC pool exhaustion. Upregulation of UnAG levels in mdx mice reduces muscle degeneration, improves muscle function, and increases dystrophin-null SC self-renewal, maintaining the SC pool. Our results suggest that UnAG has significant therapeutic potential for preserving the muscles in dystrophies. Stem Cells 2017;35:1733-1746.


Assuntos
Distrofina/genética , Grelina/genética , Músculo Esquelético/metabolismo , Distrofia Muscular Animal/metabolismo , Regeneração/genética , Células Satélites de Músculo Esquelético/metabolismo , Acilação , Animais , Contagem de Células , Diferenciação Celular , Distrofina/metabolismo , Fibrose , Regulação da Expressão Gênica , Grelina/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos mdx , Músculo Esquelético/patologia , Distrofia Muscular Animal/genética , Distrofia Muscular Animal/patologia , Fenótipo , Células Satélites de Músculo Esquelético/patologia , Transdução de Sinais , Proteínas Quinases p38 Ativadas por Mitógeno/genética , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo
10.
Diabetes ; 65(4): 874-86, 2016 04.
Artigo em Inglês | MEDLINE | ID: mdl-26822085

RESUMO

Excess reactive oxygen species (ROS) generation and inflammation may contribute to obesity-associated skeletal muscle insulin resistance. Ghrelin is a gastric hormone whose unacylated form (UnAG) is associated with whole-body insulin sensitivity in humans and may reduce oxidative stress in nonmuscle cells in vitro. We hypothesized that UnAG 1) lowers muscle ROS production and inflammation and enhances tissue insulin action in lean rats and 2) prevents muscle metabolic alterations and normalizes insulin resistance and hyperglycemia in high-fat diet (HFD)-induced obesity. In 12-week-old lean rats, UnAG (4-day, twice-daily subcutaneous 200-µg injections) reduced gastrocnemius mitochondrial ROS generation and inflammatory cytokines while enhancing AKT-dependent signaling and insulin-stimulated glucose uptake. In HFD-treated mice, chronic UnAG overexpression prevented obesity-associated hyperglycemia and whole-body insulin resistance (insulin tolerance test) as well as muscle oxidative stress, inflammation, and altered insulin signaling. In myotubes, UnAG consistently lowered mitochondrial ROS production and enhanced insulin signaling, whereas UnAG effects were prevented by small interfering RNA-mediated silencing of the autophagy mediator ATG5. Thus, UnAG lowers mitochondrial ROS production and inflammation while enhancing insulin action in rodent skeletal muscle. In HFD-induced obesity, these effects prevent hyperglycemia and insulin resistance. Stimulated muscle autophagy could contribute to UnAG activities. These findings support UnAG as a therapeutic strategy for obesity-associated metabolic alterations.


Assuntos
Dieta Hiperlipídica/efeitos adversos , Grelina/farmacologia , Hiperglicemia/etiologia , Hiperglicemia/prevenção & controle , Inflamação/prevenção & controle , Músculo Esquelético/efeitos dos fármacos , Espécies Reativas de Oxigênio/metabolismo , Animais , Células Cultivadas , Regulação para Baixo/efeitos dos fármacos , Resistência à Insulina , Masculino , Camundongos , Camundongos Transgênicos , Músculo Esquelético/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Ratos , Ratos Wistar
12.
PLoS One ; 10(9): e0137999, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-26375957

RESUMO

A major obstacle to an effective myocardium stem cell therapy has always been the delivery and survival of implanted stem cells in the heart. Better engraftment can be achieved if cells are administered as cell aggregates, which maintain their extra-cellular matrix (ECM). We have generated spheroid aggregates in less than 24 h by seeding human cardiac progenitor cells (hCPCs) onto methylcellulose hydrogel-coated microwells. Cells within spheroids maintained the expression of stemness/mesenchymal and ECM markers, growth factors and their cognate receptors, cardiac commitment factors, and metalloproteases, as detected by immunofluorescence, q-RT-PCR and immunoarray, and expressed a higher, but regulated, telomerase activity. Compared to cells in monolayers, 3D spheroids secreted also bFGF and showed MMP2 activity. When spheroids were seeded on culture plates, the cells quickly migrated, displaying an increased wound healing ability with or without pharmacological modulation, and reached confluence at a higher rate than cells from conventional monolayers. When spheroids were injected in the heart wall of healthy mice, some cells migrated from the spheroids, engrafted, and remained detectable for at least 1 week after transplantation, while, when the same amount of cells was injected as suspension, no cells were detectable three days after injection. Cells from spheroids displayed the same engraftment capability when they were injected in cardiotoxin-injured myocardium. Our study shows that spherical in vivo ready-to-implant scaffold-less aggregates of hCPCs able to engraft also in the hostile environment of an injured myocardium can be produced with an economic, easy and fast protocol.


Assuntos
Coração/fisiologia , Miocárdio/citologia , Esferoides Celulares/citologia , Esferoides Celulares/transplante , Transplante de Células-Tronco , Células-Tronco/citologia , Engenharia Tecidual , Idoso , Idoso de 80 Anos ou mais , Animais , Western Blotting , Diferenciação Celular , Movimento Celular , Proliferação de Células , Células Cultivadas , Feminino , Imunofluorescência , Humanos , Técnicas Imunoenzimáticas , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Pessoa de Meia-Idade , Miocárdio/metabolismo , RNA Mensageiro/genética , Reação em Cadeia da Polimerase em Tempo Real , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Esferoides Celulares/metabolismo , Células-Tronco/metabolismo , Tecidos Suporte
13.
Nat Commun ; 6: 7388, 2015 Jun 11.
Artigo em Inglês | MEDLINE | ID: mdl-26066847

RESUMO

Functional screening of expression libraries in vivo would offer the possibility of identifying novel biotherapeutics without a priori knowledge of their biochemical function. Here we describe a procedure for the functional selection of tissue-protective factors based on the in vivo delivery of arrayed cDNA libraries from the mouse secretome using adeno-associated virus (AAV) vectors. Application of this technique, which we call FunSel, in the context of acute ischaemia, revealed that the peptide ghrelin protects skeletal muscle and heart from ischaemic damage. When delivered to the heart using an AAV9 vector, ghrelin markedly reduces infarct size and preserves cardiac function over time. This protective activity associates with the capacity of ghrelin to sustain autophagy and remove dysfunctional mitochondria after myocardial infarction. Our findings describe an innovative tool to identify biological therapeutics and reveal a novel role of ghrelin as an inducer of myoprotective autophagy.


Assuntos
Apoptose/genética , Autofagia/genética , Grelina/genética , Mitocôndrias Cardíacas/metabolismo , Infarto do Miocárdio/genética , Animais , Animais Recém-Nascidos , Antibióticos Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Western Blotting , Dependovirus , Doxorrubicina/farmacologia , Perfilação da Expressão Gênica , Biblioteca Gênica , Técnicas de Transferência de Genes , Vetores Genéticos , Membro Posterior/irrigação sanguínea , Técnicas Imunoenzimáticas , Marcação In Situ das Extremidades Cortadas , Isquemia/genética , Isquemia/metabolismo , Camundongos , Microscopia Eletrônica de Transmissão , Microscopia de Fluorescência , Mitocôndrias Cardíacas/ultraestrutura , Músculo Esquelético/irrigação sanguínea , Infarto do Miocárdio/diagnóstico por imagem , Infarto do Miocárdio/metabolismo , Infarto do Miocárdio/patologia , Isquemia Miocárdica/genética , Isquemia Miocárdica/metabolismo , Miócitos Cardíacos/efeitos dos fármacos , Miócitos Cardíacos/metabolismo , Ratos , Ultrassonografia , Disfunção Ventricular Esquerda/diagnóstico por imagem , Disfunção Ventricular Esquerda/genética , Disfunção Ventricular Esquerda/metabolismo , Disfunção Ventricular Esquerda/patologia
14.
Int J Endocrinol ; 2015: 385682, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-25960743

RESUMO

Fibrosis can affect almost all tissues and organs, it often represents the terminal stage of chronic diseases, and it is regarded as a major health issue for which efficient therapies are needed. Tissue injury, by inducing necrosis/apoptosis, triggers inflammatory response that, in turn, promotes fibroblast activation and pathological deposition of extracellular matrix. Acylated and unacylated ghrelin are the main products of the ghrelin gene. The acylated form, through its receptor GHSR-1a, stimulates appetite and growth hormone (GH) release. Although unacylated ghrelin does not bind or activate GHSR-1a, it shares with the acylated form several biological activities. Ghrelin peptides exhibit anti-inflammatory, antioxidative, and antiapoptotic activities, suggesting that they might represent an efficient approach to prevent or reduce fibrosis. The aim of this review is to summarize the available evidence regarding the effects of acylated and unacylated ghrelin on different pathologies and experimental models in which fibrosis is a predominant characteristic.

15.
PLoS One ; 9(6): e97144, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-24887021

RESUMO

Diacylglycerol kinase α (DGKα), by phosphorylating diacylglycerol into phosphatidic acid, provides a key signal driving cell migration and matrix invasion. We previously demonstrated that in epithelial cells activation of DGKα activity promotes cytoskeletal remodeling and matrix invasion by recruiting atypical PKC at ruffling sites and by promoting RCP-mediated recycling of α5ß1 integrin to the tip of pseudopods. In here we investigate the signaling pathway by which DGKα mediates SDF-1α-induced matrix invasion of MDA-MB-231 invasive breast carcinoma cells. Indeed we showed that, following SDF-1α stimulation, DGKα is activated and localized at cell protrusion, thus promoting their elongation and mediating SDF-1α induced MMP-9 metalloproteinase secretion and matrix invasion. Phosphatidic acid generated by DGKα promotes localization at cell protrusions of atypical PKCs which play an essential role downstream of DGKα by promoting Rac-mediated protrusion elongation and localized recruitment of ß1 integrin and MMP-9. We finally demonstrate that activation of DGKα, atypical PKCs signaling and ß1 integrin are all essential for MDA-MB-231 invasiveness. These data indicates the existence of a SDF-1α induced DGKα - atypical PKC - ß1 integrin signaling pathway, which is essential for matrix invasion of carcinoma cells.


Assuntos
Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Quimiocina CXCL12/farmacologia , Diacilglicerol Quinase/metabolismo , Integrina beta1/metabolismo , Proteína Quinase C/metabolismo , Transdução de Sinais/efeitos dos fármacos , Linhagem Celular Tumoral , Feminino , Humanos , Metaloproteinase 9 da Matriz/metabolismo , Invasividade Neoplásica , Transporte Proteico/efeitos dos fármacos , Pseudópodes/efeitos dos fármacos , Pseudópodes/metabolismo , Proteínas rac de Ligação ao GTP/metabolismo
16.
Arch Immunol Ther Exp (Warsz) ; 62(5): 369-84, 2014 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-24728531

RESUMO

Ghrelin gene products--the peptides ghrelin, unacylated ghrelin, and obestatin--have several actions on the immune system, opening new perspectives within neuroendocrinology, metabolism and inflammation. The aim of this review is to summarize the available evidence regarding the less known role of these peptides in the machinery of inflammation and autoimmunity, outlining some of their most promising therapeutic applications.


Assuntos
Doenças Autoimunes/imunologia , Grelina/imunologia , Inflamação/imunologia , Fragmentos de Peptídeos/imunologia , Animais , Doenças Autoimunes/genética , Doença Crônica , Grelina/genética , Humanos , Inflamação/genética , Neuroendocrinologia/tendências , Fragmentos de Peptídeos/genética
17.
Curr Opin Clin Nutr Metab Care ; 17(3): 236-40, 2014 May.
Artigo em Inglês | MEDLINE | ID: mdl-24572833

RESUMO

PURPOSE OF REVIEW: Muscle wasting is a comorbidity often associated with a wide range of disorders that severely affects patient prognosis and quality of life. Ghrelin, through its receptor GHSR-1a, stimulates appetite and growth hormone (GH) release. Several studies indicate that ghrelin administration is a valid treatment for cachexia because it improves muscle mass and function, likely by restoring a positive energy balance. RECENT FINDINGS: In addition to its GHSR-1a-mediated effects on muscle mass, ghrelin acts directly on skeletal muscle, wherein it exerts a protective activity against muscle wasting. This direct activity is independent of GHSR-1a and is shared by the unacylated form of ghrelin, which does not bind GHSR-1a and is devoid of the effects on appetite and GH release. SUMMARY: Both the acylated and unacylated forms of ghrelin might have therapeutic potential for the treatment of skeletal muscle wasting.


Assuntos
Grelina/química , Grelina/uso terapêutico , Atrofia Muscular/tratamento farmacológico , Síndrome de Emaciação/tratamento farmacológico , Acilação , Caquexia/tratamento farmacológico , Humanos , Músculo Esquelético/efeitos dos fármacos , Músculo Esquelético/fisiopatologia , Atrofia Muscular/fisiopatologia , Receptores de Grelina/fisiologia
18.
Int Rev Neurobiol ; 108: 207-21, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-24083436

RESUMO

Promoting neuromuscular recovery after neural injury is a major clinical issue. While techniques for nerve reconstruction are continuously improving and most peripheral nerve lesions can be repaired today, recovery of the lost function is usually unsatisfactory. This evidence claims for innovative nonsurgical therapeutic strategies that can implement the outcome after neural repair. Although no pharmacological approach for improving posttraumatic neuromuscular recovery has still entered clinical practice, various molecules are explored in experimental models of neural repair. One of such molecules is the circulating peptide hormone ghrelin. This hormone has proved to have a positive effect on neural repair after central nervous system lesion, and very recently its effectiveness has also been demonstrated in preventing posttraumatic skeletal muscle atrophy. By contrast, no information is still available about its effectiveness on peripheral nerve regeneration although preliminary data from our laboratory suggest that this molecule can have an effect also in promoting axonal regeneration after nerve injury and repair. Should this be confirmed, ghrelin might represent an ideal candidate as a therapeutic agent for improving posttraumatic neuromuscular recovery because of its putative effects at all the various structural levels involved in this regeneration process, namely, the central nervous system, the peripheral nerve, and the target skeletal muscle.


Assuntos
Grelina/sangue , Fármacos Neuromusculares/sangue , Traumatismos dos Nervos Periféricos/sangue , Recuperação de Função Fisiológica/fisiologia , Animais , Axônios/metabolismo , Grelina/uso terapêutico , Humanos , Regeneração Nervosa/fisiologia , Fármacos Neuromusculares/uso terapêutico , Traumatismos dos Nervos Periféricos/tratamento farmacológico
19.
J Clin Invest ; 123(2): 611-22, 2013 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-23281394

RESUMO

Cachexia is a wasting syndrome associated with cancer, AIDS, multiple sclerosis, and several other disease states. It is characterized by weight loss, fatigue, loss of appetite, and skeletal muscle atrophy and is associated with poor patient prognosis, making it an important treatment target. Ghrelin is a peptide hormone that stimulates growth hormone (GH) release and positive energy balance through binding to the receptor GHSR-1a. Only acylated ghrelin (AG), but not the unacylated form (UnAG), can bind GHSR-1a; however, UnAG and AG share several GHSR-1a-independent biological activities. Here we investigated whether UnAG and AG could protect against skeletal muscle atrophy in a GHSR-1a-independent manner. We found that both AG and UnAG inhibited dexamethasone-induced skeletal muscle atrophy and atrogene expression through PI3Kß-, mTORC2-, and p38-mediated pathways in myotubes. Upregulation of circulating UnAG in mice impaired skeletal muscle atrophy induced by either fasting or denervation without stimulating muscle hypertrophy and GHSR-1a-mediated activation of the GH/IGF-1 axis. In Ghsr-deficient mice, both AG and UnAG induced phosphorylation of Akt in skeletal muscle and impaired fasting-induced atrophy. These results demonstrate that AG and UnAG act on a common, unidentified receptor to block skeletal muscle atrophy in a GH-independent manner.


Assuntos
Grelina/química , Grelina/farmacologia , Atrofia Muscular/prevenção & controle , Acilação , Animais , Caquexia/metabolismo , Caquexia/prevenção & controle , Linhagem Celular , Grelina/metabolismo , Sistema de Sinalização das MAP Quinases , Masculino , Alvo Mecanístico do Complexo 2 de Rapamicina , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Transgênicos , Complexos Multiproteicos/metabolismo , Denervação Muscular , Músculo Esquelético/efeitos dos fármacos , Músculo Esquelético/metabolismo , Músculo Esquelético/patologia , Atrofia Muscular/metabolismo , Atrofia Muscular/patologia , Ligação Proteica , Proteínas Proto-Oncogênicas c-akt/metabolismo , Receptores de Grelina/metabolismo , Transdução de Sinais , Serina-Treonina Quinases TOR/metabolismo
20.
J Immunol ; 187(11): 5941-51, 2011 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-22048771

RESUMO

Diacylglycerol kinases (DGKs) metabolize diacylglycerol to phosphatidic acid. In T lymphocytes, DGKα acts as a negative regulator of TCR signaling by decreasing diacylglycerol levels and inducing anergy. In this study, we show that upon costimulation of the TCR with CD28 or signaling lymphocyte activation molecule (SLAM), DGKα, but not DGKζ, exits from the nucleus and undergoes rapid negative regulation of its enzymatic activity. Inhibition of DGKα is dependent on the expression of SAP, an adaptor protein mutated in X-linked lymphoproliferative disease, which is essential for SLAM-mediated signaling and contributes to TCR/CD28-induced signaling and T cell activation. Accordingly, overexpression of SAP is sufficient to inhibit DGKα, whereas SAP mutants unable to bind either phospho-tyrosine residues or SH3 domain are ineffective. Moreover, phospholipase C activity and calcium, but not Src-family tyrosine kinases, are also required for negative regulation of DGKα. Finally, inhibition of DGKα in SAP-deficient cells partially rescues defective TCR/CD28 signaling, including Ras and ERK1/2 activation, protein kinase C membrane recruitment, induction of NF-AT transcriptional activity, and IL-2 production. Thus SAP-mediated inhibition of DGKα sustains diacylglycerol signaling, thereby regulating T cell activation, and it may represent a novel pharmacological strategy for X-linked lymphoproliferative disease treatment.


Assuntos
Diacilglicerol Quinase/metabolismo , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Ativação Linfocitária/imunologia , Receptores de Antígenos de Linfócitos T/imunologia , Transdução de Sinais/imunologia , Western Blotting , Diglicerídeos/metabolismo , Imunofluorescência , Humanos , Imunoprecipitação , Peptídeos e Proteínas de Sinalização Intracelular/imunologia , Células Jurkat , Transporte Proteico/imunologia , Receptores de Antígenos de Linfócitos T/metabolismo , Proteína Associada à Molécula de Sinalização da Ativação Linfocitária , Linfócitos T/imunologia , Linfócitos T/metabolismo , Transfecção
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