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1.
J Neurol Sci ; 420: 117276, 2021 01 15.
Artigo em Inglês | MEDLINE | ID: mdl-33360484

RESUMO

Sars-Cov-2 or Novel coronavirus infection (COVID-19) has become a global challenge, affecting elderly population at large, causing a burden on hospitals. It has been affecting the world from a health and economic perspective after its emergence since October 2019 at Wuhan province of China. Later on it became a pandemic, with aged people most affected. Surprisingly, the infants and children were not severely infected and mortality among them was reported infrequently. If they died it was due to some comorbidity or congenital heart problems. Why the rate of infection varies in different age groups around the world and what is the protective mechanism in children remains a mystery. Based on our neuropathological experience at the "Lino Rossi Research Center for the study and prevention of the unexpected perinatal death and Sudden Infant Death Syndrome (SIDS)" of the University of Milan, Italy, we hypothesize that the decreased severity of the disease in infants compared to the elderly may be due to alteration at neurotransmitter levels especially of the Substance P (SP) and of the spinal trigeminal nucleus in the brainstem that is responsible for its secretion. This neurotransmitter may be directly related to the respiratory illness as is in COVID-19 infection. It is responsible for the increased inflammation and the characteristic symptoms associated with this disease. It is the main switch that must be urgently turned off using the NK-1R antagonist which is the receptor of SP and responsible for its functionality, especially in the elderly.


Assuntos
/metabolismo , Substância P/metabolismo , /patologia , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Recém-Nascido , Masculino
2.
Orv Hetil ; 161(35): 1436-1440, 2020 08.
Artigo em Húngaro | MEDLINE | ID: mdl-32822321

RESUMO

Neuropeptides synthetised in the enteric nervous system can change the function of the immunocells and play a role in inflammatory processes. In our review the effects of inflammation on the neuropeptide content of nerves and immune cells were compared. Inflamed tissue samples (human gastritis and animal models with experimental colitis and streptozotocin-induced diabetes mellitus) were examined. The number and contacts of neuropeptide-containing nerves and immune cells were studied using immunohistochemistry, confocal laser microscopy and electronmicroscopy. In inflammation, the number of substance P, vasoactive intestinal polypeptide and neuropeptide Y nerve fibres was increased significantly in parallel with the strongly increased number of immunocompetent cells (p<0.001). In inflammatory diseases, a large number of lymphocytes and mast cells were also positive for these neuropeptides. Very close morphological relationship between substance P and neuropeptide Y immunoreactive nerve fibres and immunocells could be demonstrated only in inflamed mucosa. Some of the substance P immunoreactive immunocells were also immunoreactive for tumor necrosis factor alpha and nuclear factor kappa B in the case of inflammation. The increased number of tumor necrosis factor alpha and nuclear factor kappa B immunoreactive immune cells correlated with the increased number of substance P-containing nerve fibres. Substance P, vasoactive intestinal polypeptide and neuropeptide Y released from nerve fibres and immunocells can play a role in inflammation. Our results suggest that using substance P antagonists or vasoactive intestinal polypeptide and neuropeptide Y peptides might be a novel therapeutic concept in the management of inflammation. Orv Hetil. 2020; 161(35): 1436-1440.


Assuntos
Inflamação/terapia , Neuropeptídeo Y/metabolismo , Substância P/metabolismo , Substância P/uso terapêutico , Peptídeo Intestinal Vasoativo/metabolismo , Animais , Imuno-Histoquímica/métodos , Inflamação/imunologia , Inflamação/metabolismo , Fibras Nervosas/imunologia , Fibras Nervosas/metabolismo , Neuropeptídeo Y/imunologia , Neuropeptídeo Y/uso terapêutico , Substância P/imunologia , Peptídeo Intestinal Vasoativo/imunologia , Peptídeo Intestinal Vasoativo/uso terapêutico
3.
J Headache Pain ; 21(1): 105, 2020 Aug 26.
Artigo em Inglês | MEDLINE | ID: mdl-32842964

RESUMO

BACKGROUND: Different pain syndromes may be characterized by different profiles of mediators reflecting pathophysiological differences, and these alterations may be measured in a simple saliva sample. The aims of the current study were to compare concentration of glutamate, serotonin (5-HT), nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), and substance P (SP) in saliva and plasma from a well-defined group of patients with chronic temporomandibular disorders myalgia (TMD-myalgia) with a group of pain-free controls, and further investigate the relationship between these markers and clinical characteristics. METHODS: Patients diagnosed according to the diagnostic criteria for TMD (n = 39), and matched healthy pain-free controls (n = 39) were included. Stimulated whole saliva and plasma samples were collected in the morning. Glutamate was analysed using a colorimetric assay, and 5-HT and SP were analysed by commercially available ELISA. Levels of NGF and BDNF were determined using multiplex electrochemiluminescence assay panel. RESULTS: Patients expressed higher salivary and plasma levels of glutamate (saliva: 40.22 ± 13.23 µmol/L; plasma: 30.31 ± 18.73 µmol/L) than controls (saliva: 33.24 ± 11.27 µmol/L; plasma: 20.41 ± 15.96 µmol/L) (p < 0.05). Salivary NGF (0.319 ± 0.261 pg/ml) and BDNF (3.57 ± 1.47 pg/ml) were lower in patients compared to controls (NGF: 0.528 ± 0.477 pg/ml; BDNF 4.62 ± 2.51 pg/ml)(p's < 0.05). Contrary, plasma BDNF, was higher in patients (263.33 ± 245.13 pg/ml) than controls (151.81 ± 125.90 pg/ml) (p < 0.05). 5-HT was undetectable in saliva. Neither plasma 5-HT, nor SP levels differed between groups. BDNF and NGF concentrations correlated to levels of psychological distress (p < 0.0005). CONCLUSION: The higher levels of salivary and plasma glutamate in patients with TMD-myalgia compared to controls strengthens its importance in the pathophysiology of TMD-myalgia. However, the lack of correlation to pain levels question its role as a putative biomarker. Patients with TMD-myalgia further had lower levels of salivary NGF and BDNF, but higher plasma BDNF. These results and their correlations to psychological distress warrant further investigations.


Assuntos
Saliva/metabolismo , Transtornos da Articulação Temporomandibular/sangue , Transtornos da Articulação Temporomandibular/metabolismo , Adulto , Biomarcadores/metabolismo , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Feminino , Ácido Glutâmico/metabolismo , Humanos , Masculino , Pessoa de Meia-Idade , Mialgia/metabolismo , Fator de Crescimento Neural/metabolismo , Substância P/metabolismo , Adulto Jovem
4.
Am J Physiol Gastrointest Liver Physiol ; 319(1): G23-G35, 2020 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-32421358

RESUMO

Glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) are released from enteroendocrine cells (EECs) in response to nutrient ingestion and lower blood glucose levels by stimulation of insulin secretion and thus are defined as incretins. GLP-1 receptor (GLP-1R) expression has been identified on enteric neurons that include intrinsic afferent neurons, extrinsic spinal, and vagal sensory afferents but has not been shown to have an incretin effect through these nerves. GLP-1 and GIP enter the mesenteric lymphatic fluid (MLF) after a meal via the interstitial fluid (IF) from local tissue secretion and/or blood capillaries. We tested if MLF could induce diet-dependent intransient increases in intracellular calcium ([Ca2+]i) in cultured sensory neurons. Postprandial rat MLF, collected from the superior mesenteric lymphatic duct, induced a significant twofold higher intransient increase in [Ca2+]i in primary-cultured sensory neurons than MLF from fasted rats. Inhibition of transient receptor potential vanilloid 1 (TRPV1) and TRPV1 and ankyrin 1 cation channels (TRPA1) with ruthenium red eliminated the difference. Substance P (SP) (a peptide that stimulates insulin secretion) sensor cells cocultured with sensory neurons showed both the GLP-1R agonist exendin-4 (Ex-4) and GIP induced transient increases in [Ca2+]i directly coupled to SP secretion in the sensory nerves. Ex-4-induced release of SP required expression of either TRPA1 or TRPV1. These data identify unrecognized actions of GLP-1 and GIP as incretins by acting as neurolymphocrines and suggest a mechanism for sensory nerves to respond to the postprandial state through MLF.NEW & NOTEWORTHY Glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) are secreted upon eating to lower blood sugar. GLP-1 and GIP were found to induce the secretion of substance P (SP) from cultured sensory nerves. SP enhances insulin secretion. Mesenteric lymphatic fluid (MLF) also stimulates sensory neurons in a diet-dependent manner. These studies identify new actions of GLP-1 and GIP as incretins and suggest a mechanism for sensory nerves to respond to diet through MLF.


Assuntos
Polipeptídeo Inibidor Gástrico/metabolismo , Peptídeo 1 Semelhante ao Glucagon/metabolismo , Glucose/metabolismo , Substância P/metabolismo , Canal de Cátion TRPA1/metabolismo , Animais , Glicemia/metabolismo , Células Enteroendócrinas/metabolismo , Receptor do Peptídeo Semelhante ao Glucagon 1/metabolismo , Incretinas/metabolismo , Período Pós-Prandial , Ratos , Receptores dos Hormônios Gastrointestinais
5.
J Leukoc Biol ; 108(1): 267-281, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32421901

RESUMO

Psoriasis is a common, chronic multifactorial inflammatory skin disease with both genetic and environmental components. A number of studies have suggested that psoriasis episodes are often preceded by stressful life events. Nevertheless, the underline mechanisms of stress in psoriasis remain unexplored. To address this question, we established an emotional stress mouse model induced by empty bottle stimulation, and applied imiquimod (IMQ), a ligand of TLR7/8 and effective potent immune activator, on the dorsal skin to induce psoriasis-like lesions. We found that empty bottles induced emotional stress exaggerated and prolonged psoriasiform dermatitis, which appeared as more prominent epidermal hyperplasia in the emotional stress mice compared with the control mice. Higher mRNA expression of Il-1ß, Il-17a, and Il-22, as well as higher secretion of IL-1ß, IL-12p40, IL-17, and IL-22 were observed in the skin lesion of emotional stress mice. The emotional stress condition and IMQ treatment synergistically led to higher expression levels of neurotransmitters and their receptors in the skin, especially substance P (SP), we also found that SP could stimulate DCs to secrete more IL-23p40 in vitro. In addition, NK-1R antagonist partially abrogated enhanced epidermal thickness and the level of neurotransmitters in emotional stress mice. Taken together, these results indicate that stress exacerbates and prolongs psoriasiform dermatitis in mice by up-regulating IL-1ß and IL-23p40, which were related to local DCs stimulated by abnormal SP.


Assuntos
Epiderme/patologia , Imiquimode/efeitos adversos , Subunidade p40 da Interleucina-12/biossíntese , Interleucina-1beta/biossíntese , Psoríase/induzido quimicamente , Estresse Psicológico/complicações , Animais , Ansiedade/etiologia , Ansiedade/patologia , Células Dendríticas/efeitos dos fármacos , Células Dendríticas/patologia , Dermatite/etiologia , Dermatite/patologia , Emoções , Epiderme/efeitos dos fármacos , Hiperplasia , Inflamação/patologia , Masculino , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Antagonistas do Receptor de Neuroquinina-1/farmacologia , Neurotransmissores/metabolismo , Nociceptores/metabolismo , Psoríase/complicações , Psoríase/patologia , Receptores da Neurocinina-1/metabolismo , Substância P/metabolismo , Regulação para Cima/efeitos dos fármacos
6.
Eur J Histochem ; 64(2)2020 Apr 28.
Artigo em Inglês | MEDLINE | ID: mdl-32363847

RESUMO

To develop a new therapeutic strategy against thyroid cancer (TC), the expression of both substance P (SP) and neurokinin-1 receptor (NK-1R) must be demonstrated in TC cells. This study aims to examine by immunohistochemistry, the localization of SP and the NK-1R in human TC samples (papillary, follicular, medullary, anaplastic), in metastasis and in healthy thyroid samples. SP and the NK-1R were expressed in all normal and TC samples. In healthy glands, SP was located in follicular cells (nucleus) and colloid and NK-1R in follicular cells (cytoplasm) and stroma. In TC samples, SP was visualized in follicular cells (nucleus and cytoplasm), stroma and colloid and NK-1R in follicular cells (cytoplasm), stroma and colloid. A semiquantitative scoring system (Allred Unit Scoring System) was applied. The expression (Allred total score) of SP and NK-1R was weaker in normal thyroid glands than in TC. In comparison with TC samples, a lower intensity/proportion of SP (nucleus and cytoplasm of follicular cells; stroma) was observed in normal samples. By contrast, in the colloid of TC samples the presence of SP was lower than in normal samples. In comparison with TC samples, the presence of the NK-1R in the cytoplasm of follicular cells and colloid was lower in normal thyroid samples, whereas the expression of this receptor in the stroma was higher. The results reported in this study suggest that the NK-1R could be a new target for the treatment of TC and use of the NK-1R antagonists could serve as a new anti-TC therapeutic strategy.


Assuntos
Receptores da Neurocinina-1/metabolismo , Substância P/metabolismo , Neoplasias da Glândula Tireoide/metabolismo , Núcleo Celular/metabolismo , Citoplasma/metabolismo , Feminino , Humanos , Imuno-Histoquímica , Masculino , Estatísticas não Paramétricas , Células Epiteliais da Tireoide/metabolismo , Glândula Tireoide/citologia , Glândula Tireoide/patologia , Neoplasias da Glândula Tireoide/patologia
7.
Nat Commun ; 11(1): 2673, 2020 05 29.
Artigo em Inglês | MEDLINE | ID: mdl-32471973

RESUMO

Aldosterone, produced by the adrenals and under the control of plasma angiotensin and potassium levels, regulates hydromineral homeostasis and blood pressure. Here we report that the neuropeptide substance P (SP) released by intraadrenal nerve fibres, stimulates aldosterone secretion via binding to neurokinin type 1 receptors (NK1R) expressed by aldosterone-producing adrenocortical cells. The action of SP is mediated by the extracellular signal-regulated kinase pathway and involves upregulation of steroidogenic enzymes. We also conducted a prospective proof-of-concept, double blind, placebo-controlled clinical trial aimed to investigate the impact of the NK1R antagonist aprepitant on aldosterone secretion in healthy male volunteers (EudraCT: 2008-003367-40, ClinicalTrial.gov: NCT00977223). Participants received during two 7-day treatment periods aprepitant (125 mg on the 1st day and 80 mg during the following days) or placebo in a random order at a 2-week interval. The primary endpoint was plasma aldosterone levels during posture test. Secondary endpoints included basal aldosterone alterations, plasma aldosterone variation during metoclopramide and hypoglycaemia tests, and basal and stimulated alterations of renin, cortisol and ACTH during the three different stimulatory tests. The safety of the treatment was assessed on the basis of serum transaminase measurements on days 4 and 7. All pre-specified endpoints were achieved. Aprepitant decreases aldosterone production by around 30% but does not influence the aldosterone response to upright posture. These results indicate that the autonomic nervous system exerts a direct stimulatory tone on mineralocorticoid synthesis through SP, and thus plays a role in the maintenance of hydromineral homeostasis. This regulatory mechanism may be involved in aldosterone excess syndromes.


Assuntos
Aldosterona/sangue , Aprepitanto/farmacologia , Antagonistas do Receptor de Neuroquinina-1/farmacologia , Receptores da Neurocinina-1/metabolismo , Substância P/metabolismo , Adolescente , Córtex Suprarrenal/metabolismo , Glândulas Suprarrenais/metabolismo , Adulto , Aldosterona/metabolismo , Células Cultivadas , Humanos , Hipoglicemia/sangue , Masculino , Metoclopramida , Mineralocorticoides/biossíntese , Placebos/administração & dosagem , Estudo de Prova de Conceito , Estudos Prospectivos , Transaminases/sangue , Adulto Jovem
8.
Neuron ; 106(5): 855-869.e8, 2020 06 03.
Artigo em Inglês | MEDLINE | ID: mdl-32240599

RESUMO

Predictive learning exerts a powerful influence over choice between instrumental actions. Nevertheless, how this learning is encoded in a sufficiently stable manner to influence choices that can occur much later in time is unclear. Here, we report that the basolateral amygdala (BLA) encodes predictive learning and establishes the memory necessary for future choices by driving the accumulation of delta-opioid receptors (DOPRs) on the somatic membrane of cholinergic interneurons in the nucleus accumbens shell (NAc-S). We found that the BLA controls DOPR accumulation via its influence on substance P release in the NAc-S, and that although DOPR accumulation is not necessary for predictive learning per se, it is necessary for the influence of this learning on later choice between actions. This study uncovers, therefore, a novel GPCR-based form of memory that is established by predictive learning and is necessary for such learning to guide the selection and execution of specific actions.


Assuntos
Complexo Nuclear Basolateral da Amígdala/fisiologia , Comportamento de Escolha/fisiologia , Neurônios Colinérgicos/metabolismo , Interneurônios/metabolismo , Memória/fisiologia , Núcleo Accumbens/metabolismo , Receptores Opioides delta/metabolismo , Substância P/metabolismo , Animais , Condicionamento Clássico/fisiologia , Condicionamento Operante/fisiologia , Aprendizagem/fisiologia , Camundongos , Receptores Acoplados a Proteínas-G/metabolismo , Estriado Ventral
9.
Invest Ophthalmol Vis Sci ; 61(4): 25, 2020 04 09.
Artigo em Inglês | MEDLINE | ID: mdl-32305043

RESUMO

Purpose: Severing corneal nerves during orthotopic corneal transplantation elicits the elaboration of the neuropeptide substance P (SP), which induces the generation of CD11c+ contrasuppressor (CS) cells. CS cells disable T regulatory cells (Tregs) that are induced when antigens enter the anterior chamber (AC), either by direct injection or by orthotopic corneal transplantation. This study examined the crucial cell surface molecules on Tregs that are adversely affected by CS cells that are generated by severing corneal nerves. Methods: CS cells were induced by producing shallow 2.0-mm circular incisions in the corneal epithelium in BALB/c mice. CD8+ Tregs were generated by injecting ovalbumin into the AC. The effects of CS cells and SP on the expression and function of two cell surface molecules (CD103 and the receptor of interferon-γ) that are crucial for the induction and function of CD8+ Tregs were analyzed. Results: SP converted CD11c+, but not CD11c- , dendritic cells (DCs) to CS cells. Severing corneal nerves resulted in a 66% reduction in the expression of CD103 on CD8+ AC-associated immune deviation (ACAID) Tregs, and a 50% reduction in the interferon-γ receptor (IFN-γR). These effects could be mimicked in vitro by coculturing CS cells with CD8+ ACAID Tregs. Conclusions: The elaboration of SP in response to corneal nerve ablation converts CD11c+ DCs to CS cells. CS cells disable CD8+ ACAID Tregs by downregulating two crucial cell surface molecules, CD103 and IFN-γR, by an SP-dependent pathway. Blocking this pathway may provide a means of restoring ocular immune privilege in corneas subjected to corneal nerve injury.


Assuntos
Antígenos CD/imunologia , Córnea/inervação , Transplante de Córnea/métodos , Privilégio Imunológico , Cadeias alfa de Integrinas/imunologia , Interferon gama/metabolismo , Animais , Câmara Anterior/imunologia , Células Cultivadas , Córnea/citologia , Córnea/cirurgia , Modelos Animais de Doenças , Rejeição de Enxerto , Sobrevivência de Enxerto , Tolerância Imunológica , Terapia a Laser/métodos , Camundongos , Camundongos Endogâmicos BALB C , Substância P/metabolismo , Linfócitos T Reguladores/imunologia
10.
Life Sci ; 249: 117472, 2020 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-32112870

RESUMO

Aim Determine changes in the expressions of the ion channel-TRPV1-and neuropeptides-NKA, NKB, calcitonin gene-related peptide (CGRP), and SP-in 14-, 21-, and 42-day-old rats after inhaling 1.5% and 2.6% sevoflurane. MAIN METHODS: A small in-house inhalation anesthesia chamber was designed to allow 14-, 21-, and 42-day-old rats inhale 1.5% and 2.6% sevoflurane, and rats in the control group inhaled carrier gas(1 L/min air +1 L/min O2). In addition, 14- and 21-day-old rats were pretreated with capsazepine, followed by inhalation of 1.5% and 2.6% sevoflurane or the carrier gas. The expression of TRPV1 in lung tissues was detected by Western blotting, whereas the expressions of NKA, NKB, CGRP, and SP in the trachea were detected by immunohistochemistry. KEY FINDINGS: After inhalation of 1.5% sevoflurane, the expression of TRPV1 in the lung tissues of 14- and 21-day-old rats was significantly increased compared with that in the control group, which was antagonized by capsazepine pretreatment. Moreover, inhalation of 1.5% sevoflurane markedly increased the expressions of NKA, NKB, CGRP, and SP in the trachea of 21-day-old rats and of NKB, CGRP, and SP in the trachea of 14-day-old rats. The expressions of these molecules were antagonized by capsazepine pretreatment. Conversely, inhalation of 2.6% sevoflurane decreased the expressions of NKA and NKB in the trachea of 42-day-old rats. SIGNIFICANCE: Sevoflurane did not upregulate the expression of TRPV1 in the airways of late-developing rats. This anesthetic may have a two-way effect on airways, resulting in considerable effects in pediatric clinical anesthesia management.


Assuntos
Anestésicos Inalatórios/administração & dosagem , Sevoflurano/administração & dosagem , Canais de Cátion TRPV/metabolismo , Traqueia/metabolismo , Administração por Inalação , Fatores Etários , Animais , Gasometria , Peso Corporal/efeitos dos fármacos , Peptídeo Relacionado com Gene de Calcitonina/metabolismo , Capsaicina/análogos & derivados , Capsaicina/farmacologia , Relação Dose-Resposta a Droga , Neurocinina A/metabolismo , Neurocinina B/metabolismo , Ratos , Ratos Sprague-Dawley , Respiração/efeitos dos fármacos , Substância P/metabolismo
11.
Sci Adv ; 6(12): eaaz1050, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-32206720

RESUMO

Behavioral and clinical studies suggest a critical role of substance P (SP)/neurokinin-1 receptor (NK-1R) signaling in alcohol dependence. Here, we examined regulation of GABA transmission in the medial subdivision of the central amygdala (CeM) by the SP/NK-1R system, and its neuroadaptation following chronic alcohol exposure. In naïve rats, SP increased action potential-dependent GABA release, and the selective NK-1R antagonist L822429 decreased it, demonstrating SP regulation of CeM activity under basal conditions. SP induced a larger GABA release in alcohol-dependent rats accompanied by decreased NK-1R expression compared to naïve controls, suggesting NK-1R hypersensitivity which persisted during protracted alcohol withdrawal. The NK-1R antagonist blocked acute alcohol-induced GABA release in alcohol-dependent and withdrawn but not in naïve rats, indicating that dependence engages the SP/NK-1R system to mediate acute effects of alcohol. Collectively, we report long-lasting CeA NK-1R hypersensitivity corroborating that NK-1Rs are promising targets for the treatment of alcohol use disorder.


Assuntos
Alcoolismo/etiologia , Alcoolismo/metabolismo , Núcleo Central da Amígdala/metabolismo , Receptores da Neurocinina-1/agonistas , Receptores da Neurocinina-1/metabolismo , Transdução de Sinais/efeitos dos fármacos , Substância P/metabolismo , Adaptação Fisiológica , Animais , Núcleo Central da Amígdala/fisiopatologia , Modelos Animais de Doenças , Suscetibilidade a Doenças , Expressão Gênica , Imuno-Histoquímica , Masculino , Ratos , Receptores da Neurocinina-1/genética , Síndrome de Abstinência a Substâncias , Ácido gama-Aminobutírico/metabolismo
12.
PLoS One ; 15(3): e0222072, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32210435

RESUMO

NR4A is a nuclear receptor protein family whose members act as sensors of cellular environment and regulate multiple processes such as metabolism, proliferation, migration, apoptosis, and autophagy. Since the ligand binding domains of these receptors have no cavity for ligand interaction, their function is most likely regulated by protein abundance and post-translational modifications. In particular, NR4A1 is regulated by protein abundance, phosphorylation, and subcellular distribution (nuclear-cytoplasmic translocation), and acts both as a transcription factor and as a regulator of other interacting proteins. SUMOylation is a post-translational modification that can affect protein stability, transcriptional activity, alter protein-protein interactions and modify intracellular localization of target proteins. In the present study we evaluated the role of SUMOylation as a posttranslational modification that can regulate the activity of NR4A1 to induce autophagy-dependent cell death. We focused on a model potentially relevant for neuronal cell death and demonstrated that NR4A1 needs to be SUMOylated to induce autophagic cell death. We observed that a triple mutant in SUMOylation sites has reduced SUMOylation, increased transcriptional activity, altered intracellular distribution, and more importantly, its ability to induce autophagic cell death is impaired.


Assuntos
Morte Celular Autofágica/genética , Membro 1 do Grupo A da Subfamília 4 de Receptores Nucleares/genética , Membro 1 do Grupo A da Subfamília 4 de Receptores Nucleares/metabolismo , Proteínas Modificadoras Pequenas Relacionadas à Ubiquitina/metabolismo , Sumoilação/genética , Núcleo Celular/metabolismo , Citoplasma/metabolismo , Células HEK293 , Humanos , Membro 2 do Grupo A da Subfamília 4 de Receptores Nucleares/metabolismo , Fosforilação/genética , Estabilidade Proteica , Receptores da Neurocinina-1/genética , Receptores da Neurocinina-1/metabolismo , Substância P/metabolismo , Fatores de Transcrição/metabolismo , Ativação Transcricional/genética , Transfecção
13.
Sci Rep ; 10(1): 4073, 2020 03 05.
Artigo em Inglês | MEDLINE | ID: mdl-32139801

RESUMO

Lipopolysaccharide (LPS) induces fever through cytokines like receptor-activator of nuclear factor κB ligand (RANKL), triggering mediators like prostaglandins (PG), endothelin-1 (ET-1), corticotrophin-releasing factor (CRF), substance P (SP) and endogenous opioids. LPS-induced fever is reduced in females compared with males except in ovariectomized (OVX) females which show increased fever mediated by PG. The present study aimed to identify the mediators involved in fever in intact and OVX female rats. Fever was induced with LPS (50 µg/kg) intraperitoneally or CRF (2.5 µg), ET-1 (1 pg), morphine (10 µg) and SP (500 ng) intracerebroventricularly in sham-operated and OVX rats. The role of RANKL was evaluated with osteoprotegerin (OPG, 1 µg, intracerebroventricularly). Expression of RANK, CRFI/II, ETB, µ-opioid (MOR) and NK1 receptors was evaluated by confocal microscopy. Besides LPS, only morphine induced fever in OVX rats while all mediators induced fever in sham-operated animals. OPG abolished LPS-induced fever in OVX but not sham-operated animals. Overall, fever involves similar central mediators in cycling females and males but only morphine induced fever in OVX females. Importantly, RANK/RANKL participates in LPS-induced fever in OVX females, as in males but not in cycling females.


Assuntos
Citocinas/metabolismo , Febre/etiologia , Hipotálamo/imunologia , Hipotálamo/metabolismo , Lipopolissacarídeos/toxicidade , Ovariectomia/efeitos adversos , Analgésicos Opioides/metabolismo , Animais , Hormônio Liberador da Corticotropina/metabolismo , Endotelina-1/metabolismo , Feminino , Febre/metabolismo , Febre/patologia , Hipotálamo/efeitos dos fármacos , Prostaglandinas/metabolismo , Ligante RANK/metabolismo , Ratos , Ratos Wistar , Substância P/metabolismo
14.
BMC Oral Health ; 20(1): 27, 2020 01 30.
Artigo em Inglês | MEDLINE | ID: mdl-32000757

RESUMO

BACKGROUND: Both substance P and hypoxia-inducible factor 1 alpha (HIF-1α) are involved in inflammation and angiogenesis. However, the relationship between substance P and HIF-1α in rat periodontitis is still unknown. METHODS: Ligation-induced rat periodontitis was established to observe the distribution and expression of substance P and HIF-1α by immunohistochemistry. Rat gingival fibroblasts were cultured and stimulated with Porphyromonas gingivalis lipopolysaccharide (LPS). Recombinant substance P was applied to elaborate the relationship between substance P and HIF-1α in gingival fibroblasts in vitro. Primary mouse bone marrow-derived macrophages (BMMs) were isolated and cultured to observe the effect of substance P on receptor activator of NF-κB ligand (RANKL)-induced osteoclastogenesis by TRAP staining. Western blotting was used to investigate the expression of HIF-1α, osteoprotegerin (OPG) and RANKL. RESULTS: Rat experimental periodontitis was successfully established 6 weeks after ligation. Gingival inflammatory infiltration and alveolar bone loss were observed. Positive expression of substance P was found in the infiltrating cells. Higher HIF-1α levels were observed in periodontitis compared to that of normal tissues. Substance P upregulated the level of HIF-1α in gingival fibroblasts with or without 1 µg/ml LPS in vitro (*P < 0.05). Substance P upregulated the expression of HIF-1α in RANKL-stimulated BMMs in vitro. Substance P also increased the RANKL/OPG ratio in gingival fibroblasts (*P < 0.05). Both 10 nM and 50 nM substance P promoted RANKL-induced osteoclast differentiation (*P < 0.05). CONCLUSION: Substance P participates in periodontitis by upregulating HIF-1α and the RANKL/OPG ratio.


Assuntos
Subunidade alfa do Fator 1 Induzível por Hipóxia/genética , Osteoprotegerina/genética , Periodontite/metabolismo , Porphyromonas gingivalis/isolamento & purificação , Ligante RANK/genética , Substância P/genética , Animais , Regulação da Expressão Gênica , Gengiva/microbiologia , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Masculino , Camundongos , Osteoclastos , Osteoprotegerina/metabolismo , Periodontite/microbiologia , Porphyromonas gingivalis/genética , Ratos , Ratos Wistar , Substância P/metabolismo , Regulação para Cima/genética
15.
Chin Med J (Engl) ; 133(2): 190-197, 2020 Jan 20.
Artigo em Inglês | MEDLINE | ID: mdl-31929370

RESUMO

BACKGROUND: Pulsed radiofrequency (PRF), as a non-invasive treatment of neuropathic pain (NP), has been widely administered clinically. Previous studies have shown that PRF has the potential to improve hyperalgesia in animal models of NP. However, there have been few reports to clarify whether the mechanism of PRF treatment of NP involves intervention in the expression of substance P (SP). Therefore, this study administered PRF treatment to chronic constriction injury (CCI) model rats and observed the sciatic nerve mechanical pain threshold and SP expression in the spinal cord to explore the mechanism of PRF treatment. METHODS: A total of 96 Sprague-Dawley rats were randomly divided into the sham-surgery-sham-treatment group (S-S group), the sham-surgery-PRF group (S-P group), the CCI-sham-treatment group (C-S group), and the CCI-PRF group (C-P group). The C-S group and the C-P group underwent sciatic nerve CCI, while the other groups received a sham operation. At 14 days after the operation, the C-P group and the S-P group were treated with PRF for 300 s. We recorded the hindpaw withdrawal threshold (HWT) and the thermal withdrawal latency (TWL) of rats in the various groups at baseline, before treatment (0 days), and at 1, 7, 14, and 28 days after treatment. L4 to L6 spinal cord tissues were taken before treatment (0 days) and 1, 7, 14, and 28 days after treatment. The transcription and translation of SP were measured by quantitative polymerase chain reaction and Western blotting, respectively. RESULTS: The HWT and the TWL in the C-P group 28 days after PRF treatment were significantly higher than those in the C-S group (95% confidence interval [CI]: 5.84-19.50, P < 0.01; 95% CI: 2.58-8.69, P = 0.01). The expression of SP in the C-P group 28 days after PRF treatment was significantly lower than that in the C-S group (95% CI: 1.17-2.48, P < 0.01). CONCLUSIONS: PRF may alleviate CCI-induced NP by down-regulating the expression of SP in the spinal cord of CCI model rats.


Assuntos
Constrição Patológica/terapia , Neuralgia/terapia , Tratamento por Radiofrequência Pulsada/métodos , Substância P/metabolismo , Animais , Constrição Patológica/metabolismo , Modelos Animais de Doenças , Hiperalgesia/metabolismo , Hiperalgesia/terapia , Masculino , Neuralgia/metabolismo , Ratos , Ratos Sprague-Dawley
16.
J Immunol ; 204(4): 879-891, 2020 02 15.
Artigo em Inglês | MEDLINE | ID: mdl-31924647

RESUMO

Hematopoiesis is tightly regulated by the bone marrow (BM) niche. The niche is robust, allowing for the return of hematopoietic homeostasis after insults such as infection. Hematopoiesis is partly regulated by soluble factors, such as neuropeptides, substance P (SP), and neurokinin A (NK-A), which mediate hematopoietic stimulation and inhibition, respectively. SP and NK-A are derived from the Tac1 gene that is alternately spliced into four variants. The hematopoietic effects of SP and NK-A are mostly mediated via BM stroma. Array analyses with 2400 genes indicated distinct changes in SP-stimulated BM stroma. Computational analyses indicated networks of genes with hematopoietic regulation. Included among these networks is the high-mobility group box 1 gene (HMGB1), a nonhistone chromatin-associated protein. Validation studies indicated that NK-A could reverse SP-mediated HMGB1 decrease. Long-term culture-initiating cell assay, with or without NK-A receptor antagonist (NK2), showed a suppressive effect of HMGB1 on hematopoietic progenitors and increase in long-term culture-initiating cell assay cells (primitive hematopoietic cells). These effects occurred partly through NK-A. NSG mice with human hematopoietic system injected with the HMGB1 antagonist glycyrrhizin verified the in vitro effects of HMGB1. Although the effects on myeloid lineage were suppressed, the results suggested a more complex effect on the lymphoid lineage. Clonogenic assay for CFU- granulocyte-monocyte suggested that HMGB1 may be required to prevent hematopoietic stem cell exhaustion to ensure immune homeostasis. In summary, this study showed how HMGB1 is linked to SP and NK-A to protect the most primitive hematopoietic cell and also to maintain immune/hematopoietic homeostasis.


Assuntos
Proteína HMGB1/metabolismo , Hematopoese/genética , Neuroimunomodulação/genética , Neurocinina A/metabolismo , Substância P/metabolismo , Adolescente , Adulto , Processamento Alternativo , Animais , Benzamidas/farmacologia , Biópsia , Medula Óssea/metabolismo , Medula Óssea/patologia , Transplante de Medula Óssea , Feminino , Perfilação da Expressão Gênica , Regulação da Expressão Gênica/efeitos dos fármacos , Regulação da Expressão Gênica/imunologia , Redes Reguladoras de Genes/efeitos dos fármacos , Redes Reguladoras de Genes/imunologia , Células HEK293 , Hematopoese/imunologia , Células-Tronco Hematopoéticas/metabolismo , Humanos , Camundongos , Neuroimunomodulação/imunologia , Neurocinina A/antagonistas & inibidores , Análise de Sequência com Séries de Oligonucleotídeos , Piperidinas/farmacologia , Cultura Primária de Células , Taquicininas/genética , Quimeras de Transplante , Adulto Jovem
17.
Exp Neurol ; 327: 113211, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-31987834

RESUMO

Transsynaptic anterograde and retrograde degeneration of neurons and neural fibers are assumed to trigger local excitotoxicity and inflammatory processes. These processes in turn are thought to drive exo-focal neurodegeneration in remote areas connected to the infarcted tissue after ischemic stroke. In the case of middle cerebral artery occlusion (MCAO), in which striato-nigral connections are affected, the hypothesis of inflammation-induced remote neurodegeneration is based on the temporal dynamics of an early appearance of inflammatory markers in midbrain followed by dopaminergic neuronal loss. To test the hypothesis of a direct transsynaptic mediation of secondary exo-focal post-ischemic neurodegeneration, we used a photochemical induction of a stroke (PTS) in Sprague-Dawley rats restricted to motor cortex (MC), thereby sparing the striatal connections to dopaminergic midbrain nuclei. To dissect the temporal dynamics of post-ischemic neurodegeneration, we analyzed brain sections harvested at day 7 and 14 post stroke. Here, an unexpectedly pronounced and widespread loss of dopaminergic neurons occurred 14 days after stroke also affecting dopaminergic nuclei that are not directly coupled to MC. Since the pattern of neurodegeneration in case of a pure motor stroke is similar to a major stroke including the striatum, it is unlikely that direct synaptic coupling is a prerequisite for delayed secondary exo-focal post ischemic neurodegeneration. Furthermore, dopaminergic neurodegeneration was already detected by Fluoro-Jade C staining at day 7, coinciding with a solely slight inflammatory response. Thus, inflammation cannot be assumed to be the primary driver of exo-focal post-ischemic cell death. Moreover, nigral substance P (SP) expression indicated intact striato-nigral innervation after PTS, whereas opposing effects on SP expression after striatal infarcts argue against a critical role of SP in neurodegenerative or inflammatory processes during exo-focal neurodegeneration.


Assuntos
Neurônios Dopaminérgicos/patologia , Mesencéfalo/patologia , Córtex Motor/patologia , Degeneração Neural/patologia , Acidente Vascular Cerebral/patologia , Animais , Neurônios Dopaminérgicos/metabolismo , Masculino , Mesencéfalo/metabolismo , Córtex Motor/metabolismo , Degeneração Neural/metabolismo , Ratos , Ratos Sprague-Dawley , Acidente Vascular Cerebral/metabolismo , Substância P/metabolismo , Substância Negra/metabolismo , Substância Negra/patologia
18.
Int Immunopharmacol ; 80: 106136, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31991372

RESUMO

Garlic (Allium sativum) - derived organosulfur compound diallyl disulfide (DADS) possesses antioxidant, anti-inflammatory and anti-cancer effects. This study was aimed to investigate the anti-inflammatory role and the underlying molecular mechanisms of DADS in cerulein-induced acute pancreatitis (AP) and associated lung injury. Administration of DADS significantly attenuated the severity of pancreatic and pulmonary inflammation by inhibiting cerulein induced serum amylase, myeloperoxidase activity (MPO) and histological changes in pancreas and lung. Furthermore, the anti-inflammatory effect of DADS was associated with the decrease in tumor necrosis factor (TNF)-α,cystathionine-γ-lyase (CSE), preprotachykinin A (PPTA), neurokinin-1-receptor (NK1R) expression and hydrogen sulfide (H2S) production in both pancreas and lung. In addition, DADS reduced caerulein-induced I-κB degradation and subsequent translocation of NF-κB in the pancreas and lung. These results show for the first time that in AP, DADS exhibits an anti-inflammatory effect by inhibiting CSE/H2S and SP/NK1R signaling and NF-кB pathway.


Assuntos
Compostos Alílicos/farmacologia , Anti-Inflamatórios/farmacologia , Dissulfetos/farmacologia , Lesão Pulmonar/tratamento farmacológico , Pancreatite/tratamento farmacológico , Compostos Alílicos/uso terapêutico , Animais , Anti-Inflamatórios/uso terapêutico , Ceruletídeo/toxicidade , Cistationina gama-Liase/metabolismo , Modelos Animais de Doenças , Dissulfetos/uso terapêutico , Humanos , Sulfeto de Hidrogênio/metabolismo , Pulmão/efeitos dos fármacos , Pulmão/imunologia , Pulmão/patologia , Lesão Pulmonar/imunologia , Masculino , Camundongos , Pâncreas/efeitos dos fármacos , Pâncreas/imunologia , Pâncreas/patologia , Pancreatite/induzido quimicamente , Pancreatite/complicações , Pancreatite/imunologia , Receptores da Neurocinina-1/metabolismo , Índice de Gravidade de Doença , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/imunologia , Substância P/metabolismo , Fator de Necrose Tumoral alfa/metabolismo
19.
Am J Physiol Regul Integr Comp Physiol ; 318(4): R712-R721, 2020 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-31967860

RESUMO

Naked mole-rats (NMRs) live in large colonies within densely populated underground burrows. Their collective respiration generates significant metabolic carbon dioxide (CO2) that diffuses slowly out of the burrow network, creating a hypercapnic environment. Currently, the physiological mechanisms that underlie the ability of NMRs to tolerate environmental hypercapnia are largely unknown. To address this, we used whole-body plethysmography and respirometry to elucidate the hypercapnic ventilatory and metabolic responses of awake, freely behaving NMRs to 0%-10% CO2. We found that NMRs have a blunted hypercapnic ventilatory response (HCVR): ventilation increased only in 10% CO2. Conversely, metabolism was unaffected by hypercapnia. NMRs are insensitive to cutaneous acid-based pain caused by modified substance P (SP)-mediated peripheral neurotransmission, and SP is also an important neuromodulator of ventilation. Therefore, we re-evaluated physiological responses to hypercapnia in NMRs after an intraperitoneal injection of exogenous substance P (2 mg/kg) or a long-lived isoform of substance P {[pGlu5-MePhe8-MeGly9]SP(5-11), DiMe-C7; 40-400 µg/kg}. We found that both drugs restored hypercapnia sensitivity and unmasked an HCVR in animals breathing 2%-10% CO2. Taken together, our findings indicate that NMRs are remarkably tolerant of hypercapnic environments and have a blunted HCVR; however, the signaling network architecture required for a "normal" HCVR is retained but endogenously inactive. This muting of chemosensitivity likely suits the ecophysiology of this species, which presumably experiences hypercapnia regularly in their underground niche.


Assuntos
Dióxido de Carbono/farmacologia , Hipercapnia , Ratos-Toupeira , Receptores da Neurocinina-1/metabolismo , Fenômenos Fisiológicos Respiratórios , Substância P/metabolismo , Animais , Dióxido de Carbono/administração & dosagem , Masculino , Pletismografia , Substância P/deficiência
20.
Med Sci Monit ; 26: e920346, 2020 Jan 24.
Artigo em Inglês | MEDLINE | ID: mdl-31978040

RESUMO

BACKGROUND Osteoarthritis is a chronic degenerative disease of the joints that is common in older people worldwide. The characteristic features of osteoarthritis include cartilage degradation, synovitis, and remodelling of subchondral bone. The present study investigated the effect of 2-aminoquinoline on knee articular cartilage degradation in an osteoarthritis rat model. MATERIAL AND METHODS The rat model of osteoarthritis was established in Wistar rats by intra-articular injection of monosodium iodoacetate. The rats were randomly divided into 6 groups of 10 rats each: a normal control group, an untreated group, and 4 (5, 10, 15 and 20 mg/kg) treatment groups. The rats in treatment groups received 5, 10, 15, or 20 mg/kg doses of 2-aminoquinoline on day 2 of monosodium iodoacetate injection. RESULTS The 2-aminoquinoline treatment of monosodium iodoacetate-injected rats markedly decreased weight-bearing asymmetry, inhibited edema formation, and improved paw withdrawal thresholds. The expression of inflammatory cytokines was markedly higher in the osteoarthritis rats. Treatment with 2-aminoquinoline led to a significant reduction in inflammatory cytokine expression in osteoarthritis rats in a dose-dependent manner. In osteoarthritis rats, the expressions of prostaglandin E2 (PGE2), matrix metalloproteinase-13 (MMP-13), and substance P were also higher in comparison to the control group. The 2-aminoquinoline treatment supressed PGE2, MMP-13, and substance P levels in osteoarthritis rats. Moreover, the expression of phosphorylated nuclear factor kappaB (p-NF-kappaB) was markedly higher in the untreated rats. However, activation of NF-kappaB was downregulated in the osteoarthritis rats by treatment with 2-aminoquinoline. CONCLUSIONS The present study demonstrated that 2-aminoquinoline prevents articular cartilage damage in osteoarthritis rats through inhibition of inflammatory factors and downregulation of NF-kappaB activation, suggesting that 2-aminoquinoline would be effective in treatment of osteoarthritis.


Assuntos
Aminoquinolinas/farmacologia , Cartilagem Articular/patologia , NF-kappa B/metabolismo , Osteoartrite/patologia , Animais , Citocinas/biossíntese , Dinoprostona/metabolismo , Edema/patologia , Extremidades/patologia , Articulações/patologia , Masculino , Metaloproteinase 13 da Matriz/metabolismo , Fosforilação/efeitos dos fármacos , Ratos Wistar , Receptores Purinérgicos P2X7/metabolismo , Transdução de Sinais/efeitos dos fármacos , Substância P/metabolismo
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