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1.
Theranostics ; 11(17): 8430-8447, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34373751

RESUMO

Self-assembly of solid organs from single cells would greatly expand applicability of regenerative medicine. Stem/progenitor cells can self-organize into micro-sized organ units, termed organoids, partially modelling tissue function and regeneration. Here we demonstrated 3D self-assembly of adult and induced pluripotent stem cell (iPSC)-derived fibroblasts, keratinocytes and endothelial progenitors into both, planar human skin in vivo and a novel type of spheroid-shaped skin organoids in vitro, under the aegis of human platelet lysate. Methods: Primary endothelial colony forming cells (ECFCs), skin fibroblasts (FBs) and keratinocytes (KCs) were isolated from human tissues and polyclonally propagated under 2D xeno-free conditions. Human tissue-derived iPSCs were differentiated into endothelial cells (hiPSC-ECs), fibroblasts (hiPSC-FBs) and keratinocytes (hiPSC-KCs) according to efficiency-optimized protocols. Cell identity and purity were confirmed by flow cytometry and clonogenicity indicated their stem/progenitor potential. Triple cell type floating spheroids formation was promoted by human platelet-derived growth factors containing culture conditions, using nanoparticle cell labelling for monitoring the organization process. Planar human skin regeneration was assessed in full-thickness wounds of immune-deficient mice upon transplantation of hiPSC-derived single cell suspensions. Results: Organoids displayed a distinct architecture with surface-anchored keratinocytes surrounding a stromal core, and specific signaling patterns in response to inflammatory stimuli. FGF-7 mRNA transfection was required to accelerate keratinocyte long-term fitness. Stratified human skin also self-assembled within two weeks after either adult- or iPSC-derived skin cell-suspension liquid-transplantation, healing deep wounds of mice. Transplant vascularization significantly accelerated in the presence of co-transplanted endothelial progenitors. Mechanistically, extracellular vesicles mediated the multifactorial platelet-derived trophic effects. No tumorigenesis occurred upon xenografting. Conclusion: This illustrates the superordinate progenitor self-organization principle and permits novel rapid 3D skin-related pharmaceutical high-content testing opportunities with floating spheroid skin organoids. Multi-cell transplant self-organization facilitates development of iPSC-based organ regeneration strategies using cell suspension transplantation supported by human platelet factors.

2.
Transl Neurodegener ; 9(1): 38, 2020 09 24.
Artigo em Inglês | MEDLINE | ID: mdl-32972456

RESUMO

BACKGROUND: Misfolded oligomeric α-synuclein plays a pivotal role in the pathogenesis of α-synucleinopathies including Parkinson's disease and multiple system atrophy, and its detection parallels activation of microglia and a loss of neurons in the substantia nigra pars compacta. Here we aimed to analyze the therapeutic efficacy of PD03, a new AFFITOPE® immunotherapy approach, either alone or in combination with Anle138b, in a PLP-α-syn mouse model. METHODS: The PLP-α-syn mice were treated with PD03 immunotherapy, Anle138b, or a combination of two. Five months after study initiation, the mice underwent behavioral testing and were sacrificed for neuropathological analysis. The treatment groups were compared to the vehicle group with regard to motor performance, nigral neuronal loss, microglial activation and α-synuclein pathology. RESULTS: The PLP-α-syn mice receiving the PD03 or Anle138b single therapy showed improvement of gait deficits and preservation of nigral dopaminergic neurons associated with the reduced α-synuclein oligomer levels and decreased microglial activation. The combined therapy with Anle138b and PD03 resulted in lower IgG binding in the brain as compared to the single immunotherapy with PD03. CONCLUSIONS: PD03 and Anle138b can selectively target oligomeric α-synuclein, resulting in attenuation of neurodegeneration in the PLP-α-syn mice. Both approaches are potential therapies that should be developed further for disease modification in α-synucleinopathies.


Assuntos
Benzodioxóis/administração & dosagem , Sistemas de Liberação de Medicamentos/métodos , Fatores Imunológicos/administração & dosagem , Atrofia de Múltiplos Sistemas/tratamento farmacológico , Atrofia de Múltiplos Sistemas/metabolismo , Pirazóis/administração & dosagem , alfa-Sinucleína/metabolismo , Animais , Feminino , Masculino , Camundongos , Camundongos Transgênicos , Atrofia de Múltiplos Sistemas/genética , Atrofia de Múltiplos Sistemas/patologia , Doenças Neurodegenerativas/tratamento farmacológico , Doenças Neurodegenerativas/genética , Doenças Neurodegenerativas/metabolismo , Doenças Neurodegenerativas/patologia , alfa-Sinucleína/genética
3.
Alzheimers Dement ; 15(9): 1133-1148, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31378574

RESUMO

INTRODUCTION: Immunotherapeutic approaches targeting amyloid ß (Aß) protein and tau in Alzheimer's disease and α-synuclein (α-syn) in Parkinson's disease are being developed for treating dementia with Lewy bodies. However, it is unknown if single or combined immunotherapies targeting Aß and/or α-syn may be effective. METHODS: Amyloid precursor protein/α-syn tg mice were immunized with AFFITOPEs® (AFF) peptides specific to Aß (AD02) or α-syn (PD-AFF1) and the combination. RESULTS: AD02 more effectively reduced Aß and pTau burden; however, the combination exhibited some additive effects. Both AD02 and PD-AFF1 effectively reduced α-syn, ameliorated degeneration of pyramidal neurons, and reduced neuroinflammation. PD-AFF1 more effectively ameliorated cholinergic and dopaminergic fiber loss; the combined immunization displayed additive effects. AD02 more effectively improved buried pellet test behavior, whereas PD-AFF1 more effectively improved horizontal beam test; the combined immunization displayed additive effects. DISCUSSION: Specific active immunotherapy targeting Aß and/or α-syn may be of potential interest for the treatment of dementia with Lewy bodies.


Assuntos
Peptídeos beta-Amiloides/imunologia , Imunoterapia , Doença por Corpos de Lewy/imunologia , alfa-Sinucleína/imunologia , Doença de Alzheimer , Animais , Humanos , Fatores Imunológicos , Camundongos , Doença de Parkinson
4.
Mol Neurodegener ; 10: 10, 2015 Mar 19.
Artigo em Inglês | MEDLINE | ID: mdl-25886309

RESUMO

BACKGROUND: Multiple system atrophy (MSA) is a neurodegenerative disease characterized by parkinsonism, ataxia and dysautonomia. Histopathologically, the hallmark of MSA is the abnormal accumulation of alpha-synuclein (α-syn) within oligodendroglial cells, leading to neuroinflammation, demyelination and neuronal death. Currently, there is no disease-modifying treatment for MSA. In this sense, we have previously shown that next-generation active vaccination technology with short peptides, AFFITOPEs®, was effective in two transgenic models of synucleinopathies at reducing behavioral deficits, α-syn accumulation and inflammation. RESULTS: In this manuscript, we used the most effective AFFITOPE® (AFF 1) for immunizing MBP-α-syn transgenic mice, a model of MSA that expresses α-syn in oligodendrocytes. Vaccination with AFF 1 resulted in the production of specific anti-α-syn antibodies that crossed into the central nervous system and recognized α-syn aggregates within glial cells. Active vaccination with AFF 1 resulted in decreased accumulation of α-syn, reduced demyelination in neocortex, striatum and corpus callosum, and reduced neurodegeneration. Clearance of α-syn involved activation of microglia and reduced spreading of α-syn to astroglial cells. CONCLUSIONS: This study further validates the efficacy of vaccination with AFFITOPEs® for ameliorating the neurodegenerative pathology in synucleinopathies.


Assuntos
Doenças Desmielinizantes/prevenção & controle , Atrofia de Múltiplos Sistemas/patologia , Atrofia de Múltiplos Sistemas/prevenção & controle , Transtornos Parkinsonianos/patologia , alfa-Sinucleína/imunologia , Animais , Astrócitos/citologia , Astrócitos/imunologia , Astrócitos/metabolismo , Doenças Desmielinizantes/imunologia , Modelos Animais de Doenças , Camundongos Transgênicos , Microglia/citologia , Microglia/imunologia , Atrofia de Múltiplos Sistemas/imunologia , Neurônios/citologia , Neurônios/imunologia , Oligodendroglia/citologia , Oligodendroglia/imunologia , Transtornos Parkinsonianos/imunologia , Vacinação/métodos
5.
Oncoimmunology ; 1(5): 618-629, 2012 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-22934254

RESUMO

Although cure rates for acute lymphoblastic leukemia (ALL) have increased, development of resistance to drugs and patient relapse are common. The environment in which the leukemia cells are present during the drug treatment is known to provide significant survival benefit. Here, we have modeled this process by culturing murine Bcr/Abl-positive acute lymphoblastic leukemia cells in the presence of stroma while treating them with a moderate dose of two unrelated drugs, the farnesyltransferase inhibitor lonafarnib and the tyrosine kinase inhibitor nilotinib. This results in an initial large reduction in cell viability of the culture and inhibition of cell proliferation. However, after a number of days, cell death ceases and the culture becomes drug-tolerant, enabling cell division to resume. Using gene expression profiling, we found that the development of drug resistance was accompanied by massive transcriptional upregulation of genes that are associated with general inflammatory responses such as the metalloproteinase MMP9. MMP9 protein levels and enzymatic activity were also increased in ALL cells that had become nilotinib-tolerant. Activation of p38, Akt and Erk correlated with the development of environment-mediated drug resistance (EMDR), and inhibitors of Akt and Erk in combination with nilotinib reduced the ability of the cells to develop resistance. However, inhibition of p38 promoted increased resistance to nilotinib. We conclude that development of EMDR by ALL cells involves changes in numerous intracellular pathways. Development of tolerance to drugs such as nilotinib may therefore be circumvented by simultaneous treatment with other drugs having divergent targets.

6.
Mol Cancer ; 11: 42, 2012 Jun 21.
Artigo em Inglês | MEDLINE | ID: mdl-22721004

RESUMO

BACKGROUND: Treatment of Philadelphia chromosome-positive acute lymphoblastic leukemias (Ph-positive ALL) with clinically approved inhibitors of the Bcr/Abl tyrosine kinase frequently results in the emergence of a leukemic clone carrying the T315I mutation in Bcr/Abl, which confers resistance to these drugs. PHA-739358, an Aurora kinase inhibitor, was reported to inhibit the Bcr/Abl T315I mutant in CML cells but no preclinical studies have examined this in detail in human ALL. RESULTS: We compared the sensitivity of human Bcr/Abl T315I, Bcr/Abl wild type and non-Bcr/Abl ALL cells to this drug. PHA-739358 inhibited proliferation and induced apoptosis independently of Bcr/Abl, the T315I mutation, or presence of the tumor suppressor p53, but the degree of effectiveness varied between different ALL samples. Since short-term treatment with a single dose of drug only transiently inhibited proliferation, we tested combination treatments of PHA-739358 with the farnesyltransferase inhibitor Lonafarnib, with vincristine and with dasatinib. All combinations reduced viability and cell numbers compared to treatment with a single drug. Clonogenic assays showed that 25 nM PHA-739358 significantly reduced the colony growth potential of Ph-positive ALL cells, and combined treatment with a second drug abrogated colony growth in this assay. PHA-739358 further effectively blocked Bcr/Abl tyrosine kinase activity and Aurora kinase B in vivo, and mice transplanted with human Bcr/Abl T315I ALL cells treated with a 3x 7-day cycle of PHA-739358 as mono-treatment had significantly longer survival. CONCLUSIONS: PHA-739358 represents an alternative drug for the treatment of both Ph-positive and negative ALL, although combined treatment with a second drug may be needed to eradicate the leukemic cells.


Assuntos
Antineoplásicos/farmacologia , Benzamidas/farmacologia , Leucemia-Linfoma Linfoblástico de Células Precursoras B/metabolismo , Inibidores de Proteínas Quinases/farmacologia , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Proteínas Serina-Treonina Quinases/metabolismo , Pirazóis/farmacologia , Animais , Antineoplásicos/administração & dosagem , Apoptose/efeitos dos fármacos , Apoptose/genética , Aurora Quinase B , Aurora Quinases , Benzamidas/administração & dosagem , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/genética , Sinergismo Farmacológico , Ativação Enzimática/efeitos dos fármacos , Proteínas de Fusão bcr-abl/antagonistas & inibidores , Proteínas de Fusão bcr-abl/genética , Humanos , Camundongos , Mutação , Leucemia-Linfoma Linfoblástico de Células Precursoras B/tratamento farmacológico , Leucemia-Linfoma Linfoblástico de Células Precursoras B/genética , Inibidores de Proteínas Quinases/administração & dosagem , Pirazóis/administração & dosagem , Vincristina/farmacologia
7.
Mol Cell Biol ; 29(21): 5742-50, 2009 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-19703997

RESUMO

Bcr and Abr are GTPase-activating proteins for the small GTPase Rac. Both proteins are expressed in cells of the innate immune system, including neutrophils and macrophages. The function of Bcr has been linked to the negative regulation of neutrophil reactive oxygen species (ROS) production, but the function of Abr in the innate immune system was unknown. Here, we report that mice lacking both proteins are severely affected in two models of experimental endotoxemia, including exposure to Escherichia coli lipopolysaccharide and polymicrobial sepsis, with extensive microvascular leakage, resulting in severe pulmonary edema and hemorrhage. Additionally, in vivo-activated neutrophils of abr and bcr null mutant mice produced excessive tissue-damaging myeloperoxidase (MPO), elastase, and ROS. Moreover, the secretion of the tissue metalloproteinase MMP9 by monocytes and ROS by elicited macrophages was abnormally high. In comparison, ROS production from bone marrow monocytes was not significantly different from that of controls, and the exocytosis of neutrophil secondary and tertiary granule products, including lactoferrin, was normal. These data show that Abr and Bcr normally curb very specific functions of mature tissue innate immune cells, and that each protein has distinct as well as partly overlapping functions in the downregulation of inflammatory processes.


Assuntos
Inflamação/metabolismo , Proteínas/metabolismo , Proteínas Proto-Oncogênicas c-bcr/metabolismo , Animais , Citocalasina B/farmacologia , Endotoxemia/microbiologia , Ativação Enzimática/efeitos dos fármacos , Escherichia coli , Proteínas Ativadoras de GTPase , Lipopolissacarídeos/farmacologia , Lesão Pulmonar/patologia , Camundongos , Modelos Biológicos , Mutação/genética , N-Formilmetionina Leucil-Fenilalanina/farmacologia , Neutrófilos/efeitos dos fármacos , Neutrófilos/enzimologia , Fagocitose/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-bcr/deficiência , Espécies Reativas de Oxigênio/metabolismo , Proteínas rac de Ligação ao GTP/metabolismo
8.
Handb Exp Pharmacol ; (194): 393-416, 2009.
Artigo em Inglês | MEDLINE | ID: mdl-19655113

RESUMO

This review examines our developing understanding of the families and activities of some of the best known sensory-nerve-derived inflammatory neuropeptides, namely substance P, calcitonin gene-related peptide and galanin. Evidence to date shows involvement of these transmitters in a wide range of systems that includes roles as inflammatory modulators. There is an increasing understanding of the mechanisms involved in the release of the peptides from sensory nerves and these are key in understanding the potential of neuropeptides in modulating inflammatory responses and may also provide novel targets for anti-inflammatory therapy. The neuropeptides released act via specific G protein coupled receptors, most of which have now been cloned. There is knowledge of selective agonists and antagonists for many subtypes within these families. The study of neuropeptides in animal models has additionally revealed pathophysiological roles that in turn have led to the development of new drugs, based on selective receptor antagonism.


Assuntos
Neuropeptídeos/metabolismo , Receptores Acoplados a Proteínas G/metabolismo , Células Receptoras Sensoriais/metabolismo , Transdução de Sinais , Analgésicos/farmacologia , Animais , Anti-Inflamatórios/farmacologia , Peptídeo Relacionado com Gene de Calcitonina/metabolismo , Galanina/metabolismo , Humanos , Inflamação/metabolismo , Inflamação/prevenção & controle , Mediadores da Inflamação/metabolismo , Neuralgia/metabolismo , Neuralgia/prevenção & controle , Receptores Acoplados a Proteínas G/efeitos dos fármacos , Células Receptoras Sensoriais/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Substância P/metabolismo , Taquicininas/metabolismo
9.
J Mol Neurosci ; 37(2): 177-81, 2009 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-18679831

RESUMO

Neuropeptides released from cutaneous nerves are attracting interest as modulators of inflammation in the skin. Recently, we showed that the neuropeptides galanin and galanin-like peptide potently inhibit inflammatory edema by reduction of microvascular blood flow. Reverse transcription-polymerase chain reaction analysis of murine skin revealed the expression of galanin receptors 2 and 3. The aim of the present study was to elucidate which galanin receptor subtype mediates the galanin-evoked inhibition of inflammatory edema formation in the skin. In this study, we report that AR-M1896, a non-GalR1 agonist, inhibited plasma extravasation induced by substance P and calcitonin gene-related peptide in a manner similar to galanin, confirming a non-GalR1-mediated effect. SNAP 37889, a nonpeptidergic selective antagonist of galanin receptor 3 (GalR3), dose-dependently abolished the antiedema effect of galanin. Thus, we were able to show that SNAP 37889 selectively antagonized galanin in the periphery and suggest that GalR3 is the receptor subtype mediating galanin's effects on the dermal microvasculature.


Assuntos
Edema/metabolismo , Galanina/metabolismo , Receptor Tipo 3 de Galanina/metabolismo , Vasculite/metabolismo , Animais , Derme/irrigação sanguínea , Modelos Animais de Doenças , Edema/imunologia , Feminino , Galanina/farmacologia , Indóis/farmacologia , Camundongos , Camundongos Endogâmicos , Microcirculação/fisiologia , Fragmentos de Peptídeos/metabolismo , Fragmentos de Peptídeos/farmacologia , Receptor Tipo 3 de Galanina/antagonistas & inibidores , Vasculite/imunologia
10.
Cardiovasc Res ; 78(1): 139-47, 2008 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-18203709

RESUMO

AIMS: Activation of the transient receptor potential vanilloid receptor 1 (TRPV1) leads to release of potent microvascular vasodilator neuropeptides. This study was designed to investigate in vivo mechanisms involved in TRPV1-mediated peripheral vasodilatation. METHODS AND RESULTS: Wildtype (WT) and TRPV1 knockout (KO) mice were investigated in a model of peripheral vasodilatation. Blood flow was measured by laser Doppler flowmetry under anaesthesia and following local application of the TRPV1 agonist capsaicin. A sustained (60 min) increase in blood flow was observed in WT but not TRPV1 KO mouse ears. This response was resistant to blockers of classic vasodilators but inhibited in pharmacogenetic experiments that targeted blockade of the substance P (SP) and calcitonin gene-related peptide (CGRP) pathways. The TRPV1-mediated vasodilatation was also attenuated by treatment with superoxide dismutase and the hydrogen peroxide scavenger catalase, but not by deactivated enzymes, supporting a novel role for reactive oxygen species (ROS) generation. Furthermore, neurogenic vasodilatation was observed neither in the presence of the selective NADPH inhibitor apocynin, nor in gp91 phox KO mice, under conditions where prostaglandin E1-induced vasodilatation occurred. Finally, a role of neuropeptides in initiating a ROS-dependent component was verified as superoxide dismutase, catalase, and apocynin inhibited SP and CGRP vasodilatation. CONCLUSION: These studies provide in vivo evidence that ROS are involved in mediating TRPV1- and neuropeptide-dependent neurogenic vasodilatation. An essential role of NADPH oxidase-dependent ROS is revealed that may be of fundamental importance to the neurogenic vasodilator component involved in circulatory homeostasis and the pathophysiology of certain cardiovascular diseases.


Assuntos
Vasos Sanguíneos/inervação , Orelha/irrigação sanguínea , Neurônios Aferentes/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Canais de Cátion TRPV/metabolismo , Vasodilatação , Acetofenonas/farmacologia , Animais , Antioxidantes/metabolismo , Antioxidantes/farmacologia , Velocidade do Fluxo Sanguíneo , Peptídeo Relacionado com Gene de Calcitonina/genética , Peptídeo Relacionado com Gene de Calcitonina/metabolismo , Capsaicina/farmacologia , Catalase/metabolismo , Indometacina/farmacologia , Fluxometria por Laser-Doppler , Glicoproteínas de Membrana/antagonistas & inibidores , Glicoproteínas de Membrana/genética , Glicoproteínas de Membrana/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , NADPH Oxidase 2 , NADPH Oxidases/antagonistas & inibidores , NADPH Oxidases/genética , NADPH Oxidases/metabolismo , NG-Nitroarginina Metil Éster/farmacologia , Neurônios Aferentes/enzimologia , Receptores da Neurocinina-1/genética , Receptores da Neurocinina-1/metabolismo , Fluxo Sanguíneo Regional , Superóxido Dismutase/farmacologia , Canais de Cátion TRPV/agonistas , Canais de Cátion TRPV/genética , Tetraetilamônio/farmacologia , Fatores de Tempo , Vasodilatação/efeitos dos fármacos , Vasodilatadores/farmacologia
11.
J Mol Neurosci ; 34(2): 149-55, 2008 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-17999197

RESUMO

The release of neuropeptides from primary sensory nerve fibers has been implicated in the modulation of local immune responses in surface tissues, such as the skin and the gastrointestinal mucosa, thereby inducing neurogenic inflammation, which is characterized by plasma extravasation and vasodilatation. In addition, cytokines, either alone or in conjunction with neuropeptides, initiate recruitment of immunocompetent cells such as neutrophils during the initial phases of inflammation. Growing evidence suggests that the neuropeptide galanin plays an important role in skin immune defense and pathophysiology. In this paper, we report that adult mice carrying a loss-of-function mutation in the galanin gene (galanin knockout, Gal KO) demonstrate an absence of the normal neurogenic inflammatory response, upon treatment of the skin either with the vanilloid receptor 1 agonist capsaicin or noxious heat. Furthermore, a lack of an acute inflammatory edema induced by coinjection of substance P and calcitonin gene-related peptide was observed. In addition, Gal KO animals also exhibit a deficit in neutrophil accumulation in the skin after exposure to noxious heat, carrageenin, or tumor necrosis factor alpha. These data indicate that Gal KO mice demonstrate abnormal neurogenic inflammatory responses in murine skin compared to strain-matched wild-type mice.


Assuntos
Galanina , Marcação de Genes , Inflamação/metabolismo , Pele/metabolismo , Animais , Antipruriginosos/farmacologia , Peptídeo Relacionado com Gene de Calcitonina/metabolismo , Capsaicina/farmacologia , Carragenina/metabolismo , Galanina/genética , Galanina/metabolismo , Temperatura Alta , Humanos , Inflamação/genética , Camundongos , Camundongos Knockout , Neurotransmissores/metabolismo , Neutrófilos/metabolismo , Pele/efeitos dos fármacos , Pele/patologia , Substância P/metabolismo
12.
Proc Natl Acad Sci U S A ; 104(24): 10217-22, 2007 Jun 12.
Artigo em Inglês | MEDLINE | ID: mdl-17535903

RESUMO

Galanin-like peptide (GALP) is a hypothalamic neuropeptide belonging to the galanin family of peptides. The GALP gene is characterized by extensive differential splicing in a variety of murine tissues. One splice variant excludes exon 3 and results in a frame shift leading to a novel peptide sequence and a stop codon after 49 aa. In this peptide, which we termed alarin, the signal sequence of the GALP precursor peptide and the first 5 aa of the mature GALP are followed by 20 aa without homology to any other murine protein. Alarin mRNA was detected in murine brain, thymus, and skin. In accordance with its vascular localization, the peptide exhibited potent and dose-dependent vasoconstrictor and anti-edema activity in the cutaneous microvasculature, as was also observed with other members of the galanin peptide family. However, in contrast to galanin peptides in general, the physiological effects of alarin do not appear to be mediated via the known galanin receptors. Alarin adds another facet to the surprisingly high-functional redundancy of the galanin family of peptides.


Assuntos
Peptídeo Semelhante a Galanina/farmacologia , Peptídeos/farmacologia , Pele/irrigação sanguínea , Vasodilatadores/farmacologia , Sequência de Aminoácidos , Animais , Derme/metabolismo , Relação Dose-Resposta a Droga , Edema/tratamento farmacológico , Edema/etiologia , Edema/patologia , Feminino , Mutação da Fase de Leitura , Peptídeo Semelhante a Galanina/química , Peptídeo Semelhante a Galanina/genética , Peptídeo Semelhante a Galanina/metabolismo , Humanos , Hipotálamo/química , Imuno-Histoquímica , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos , Dados de Sequência Molecular , Peptídeos/química , Peptídeos/genética , Peptídeos/metabolismo , Sinais Direcionadores de Proteínas , Splicing de RNA , RNA Mensageiro/metabolismo , Fluxo Sanguíneo Regional , Pele/citologia , Distribuição Tecidual , Vasodilatadores/química , Vasodilatadores/metabolismo
13.
J Invest Dermatol ; 127(3): 716-21, 2007 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-17024098

RESUMO

The cutaneous vasculature plays a key role in the pathophysiology of inflammatory skin diseases. The vascular activity is under the control of the peripheral nervous system that includes locally released neuropeptides. Recently, we detected receptors for the neuropeptide galanin in association with dermal blood vessels, suggesting a role of the galanin-peptide-family in the regulation of the cutaneous microvasculature. Therefore, we have investigated galanin and galanin-like peptide (GALP), a neuropeptide previously only considered to be involved in metabolism and reproduction in the central nervous system, for vaso-modulatory activity in the murine skin in vivo. Picomole amounts of intradermally injected galanin and GALP decreased cutaneous blood flow and inhibited inflammatory edema formation. Both the full-length GALP (1-60) and the putative smaller proteolytic fragment GALP (3-32) showed similar effects. These activities are most likely mediated by galanin receptors galanin receptor subtype 2 (GalR2) and/or galanin receptor subtype 3 (GalR3), because reverse transcription-PCR analysis of murine skin revealed messenger RNA (mRNA) expression of GalR2 and GalR3 but not of galanin receptor subtype 1. The lack of galanin receptor mRNAs in endothelial and smooth muscle cells indicates a neuronal localization of these receptors around the vessels. These results indicate functional activity of GALP in the periphery in vivo and suggest a potential role as an inflammatory modulator.


Assuntos
Peptídeo Semelhante a Galanina/metabolismo , Galanina/química , Peptídeos/química , Vasodilatadores/farmacologia , Animais , Vasos Sanguíneos/metabolismo , Peptídeo Relacionado com Gene de Calcitonina/química , Edema/patologia , Células Endoteliais/metabolismo , Feminino , Peptídeo Semelhante a Galanina/química , Inflamação , Camundongos , Neuropeptídeos/química , Peptídeos/farmacologia , RNA Mensageiro/metabolismo , Pele/metabolismo
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