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1.
J Oral Rehabil ; 47(7): 843-850, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32277715

RESUMO

The study aimed to investigate salivary levels of nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), substance P (SP) and glutamate at five time points from morning to afternoon in a well-characterised healthy and pain-free individuals. Ten young adults were included. Unstimulated and stimulated whole saliva were collected from each participant repeatedly across the day. Blood samples were drawn in connection with the first and last saliva sample as reference standard. Levels of NGF and BDNF were determined using gel-free Western blot technology, glutamate levels were analysed using a colorimetric assay, and SP was determined using a commercially available ELISA. Salivary NGF and BDNF showed significant differences between the different collection times in both unstimulated (NGF; P = .006; BDNF; P = .026) and stimulated whole saliva (NGF; P = .006; BDNF; P = .019). The highest concentrations of the neuropeptides were expressed in the early morning, and they thereafter decreased across the day. In contrast, the expression of salivary glutamate and SP did not show any significant changes across the day. Plasma levels of NGF were higher in the evening sample (P = .028); otherwise, there were no significant differences for any of the other markers between morning and evening samples. NGF and BDNF in whole saliva showed a significant variation across the day. On the contrary, no variation in the levels of SP and glutamate was detected. These findings highlight the importance of consistency in the collection time and approach in biomarker studies using saliva.


Assuntos
Dor , Saliva , Biomarcadores , Ácido Glutâmico , Humanos , Substância P , Adulto Jovem
2.
Menopause ; 27(5): 495, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32187135
3.
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
4.
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
5.
Int J Nanomedicine ; 15: 333-346, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32021183

RESUMO

Purpose: Wound healing, especially of extensive full-thickness wounds, is one of the most difficult problems in clinical studies. In this study, we prepared a novel substance P (SP)-delivery system using zeolite imidazolate framework-8 (ZIF-8) nanoparticles. Methods: We synthesized ZIF-8 nanoparticles using a modified biomimetic mineralization method. We then coated SP-loaded ZIF-8 nanoparticles (SP@ZIF-8) with polyethylene glycol-thioketal (PEG-TK) to fabricate SP@ZIF-8-PEG-TK nanoparticles, and encapsulated them in injectable hydrogel composed of sodium alginate and pectin and cross-linked using calcium chloride. The final hydrogel wound dressing containing SP@ZIF-8-PEG-TK nanoparticles was called SP@ZIF-8-PEG-TK@CA. Results: The fabricated ZIF-8 nanoparticles had high SP-loading efficiency. SP-release assay showed that the SP@ZIF-8-PEG-TK nanoparticles maintained drug activity and showed responsive release under stimulation by reactive oxygen species. The SP@ZIF-8-PEG-TK nanoparticles promoted proliferation of human dermal fibroblasts, up-regulated expression levels of inflammation-related genes in macrophages, and exhibited favorable cytocompatibility in vitro. Full-thickness excision wound models in vivo confirmed that SP@ZIF-8-PEG-TK@CA dressings had excellent wound-healing efficacy by promoting an early inflammatory response and subsequent M2 macrophage polarization in the wound-healing process. Conclusion: In conclusion, these findings indicated that SP@ZIF-8-PEG-TK@CA dressings might be useful for wound dressing applications in the clinic.


Assuntos
Bandagens , Nanopartículas/química , Espécies Reativas de Oxigênio/metabolismo , Substância P/administração & dosagem , Cicatrização/efeitos dos fármacos , Zeolitas/química , Alginatos/química , Animais , Cloreto de Cálcio/química , Proliferação de Células/efeitos dos fármacos , Reagentes para Ligações Cruzadas/química , Sistemas de Liberação de Medicamentos/métodos , Fibroblastos/citologia , Fibroblastos/efeitos dos fármacos , Humanos , Hidrogéis/química , Imidazóis/química , Camundongos Endogâmicos BALB C , Nanopartículas/administração & dosagem , Pectinas/química , Polietilenoglicóis/química , Substância P/farmacocinética
6.
PLoS One ; 15(1): e0227817, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31971954

RESUMO

Besides monocyte (MO)-derived macrophages (MACs), self-renewing tissue-resident macrophages (trMACs) maintain the intracutaneous MAC pool in murine skin. Here, we have asked whether the same phenomenon occurs in human skin using organ-cultured, full-thickness skin detached from blood circulation and bone marrow. Skin stimulation ex vivo with the neuropeptide substance P (SP), mimicking neurogenic skin inflammation, significantly increased the number of CD68+MACs in the papillary dermis without altering intracutaneous MAC proliferation or apoptosis. Since intraluminal CD14+MOs were undetectable in the non-perfused dermal vasculature, new MACs must have differentiated from resident intracutaneous progenitor cells in human skin. Interestingly, CD68+MACs were often seen in direct cell-cell-contact with cells expressing both, the hematopoietic stem cell marker CD34 and SP receptor (neurokinin-1 receptor [NK1R]). These cell-cell contacts and CD34+cell proliferation were up-regulated in SP-treated skin samples. Collectively, our study provides the first evidence that resident MAC progenitors, from which mature MACs can rapidly differentiate within the tissue, do exist in normal adult human skin. That these NK1R+trMAC-progenitor cells quickly respond to a key stress-associated neuroinflammatory stimulus suggests that this may satisfy increased local MAC demand under conditions of wounding/stress.


Assuntos
Macrófagos/imunologia , Inflamação Neurogênica/imunologia , Pele/imunologia , Células-Tronco/imunologia , Substância P/imunologia , Adulto , Antígenos CD/imunologia , Antígenos CD34/imunologia , Antígenos de Diferenciação Mielomonocítica/imunologia , Apoptose , Diferenciação Celular , Feminino , Humanos , Macrófagos/citologia , Técnicas de Cultura de Órgãos , Pele/citologia , Células-Tronco/citologia
7.
Curr Med Chem ; 27(9): 1469-1500, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31142248

RESUMO

There is a huge need for pharmaceutical agents for the treatment of chronic Neuropathic Pain (NP), a complex condition where patients can suffer from either hyperalgesia or allodynia originating from central or peripheral nerve injuries. To date, the therapeutic guidelines include the use of tricyclic antidepressants, serotonin-noradrenaline reuptake inhibitors and anticonvulsants, beside the use of natural compounds and non-pharmacological options. Unfortunately, these drugs suffer from limited efficacy and serious dose-dependent adverse effects. In the last decades, the heptapeptide SP1-7, the major bioactive metabolite produced by Substance P (SP) cleavage, has been extensively investigated as a potential target for the development of novel peptidomimetic molecules to treat NP. Although the physiological effects of this SP fragment have been studied in detail, the mechanism behind its action is not fully clarified and the target for SP1-7 has not been identified yet. Nevertheless, specific binding sites for the heptapeptide have been found in brain and spinal cord of both mouse and rats. Several Structure-Affinity Relationship (SAR) studies on SP1-7 and some of its synthetic analogues have been carried out aiming to developing more metabolically stable and effective small molecule SP1-7-related amides that could be used as research tools for a better understanding of the SP1-7 system and, in a longer perspective, as potential therapeutic agents for future treatment of NP.


Assuntos
Neuralgia , Animais , Anticonvulsivantes , Hiperalgesia , Camundongos , Peptidomiméticos , Ratos , Substância P
8.
J Mass Spectrom ; 55(1): e4449, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31820512

RESUMO

Chemical cross-linking combined with mass spectrometry (XL-MS) and computational modeling has evolved as an alternative method to derive protein 3D structures and to map protein interaction networks. Special focus has been laid recently on the development and application of cross-linkers that are cleavable by collisional activation as they yield distinct signatures in tandem mass spectra. Building on our experiences with cross-linkers containing an MS-labile urea group, we now present the biuret-based, CID-MS/MS-cleavable cross-linker imidodicarbonyl diimidazole (IDDI) and demonstrate its applicability for protein cross-linking studies based on the four model peptides angiotensin II, MRFA, substance P, and thymopentin.


Assuntos
Biureto/análogos & derivados , Biureto/química , Reagentes para Ligações Cruzadas/química , Peptídeos/química , Angiotensina II/química , Cromatografia Líquida de Alta Pressão , Imidazóis/química , Estudo de Prova de Conceito , Conformação Proteica , Substância P/química , Espectrometria de Massas em Tandem , Timopentina/química
9.
Aust Endod J ; 46(1): 73-81, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-31270901

RESUMO

One of the main objectives of root canal treatment is to alleviate the pain associated with irreversibly inflamed pulps. However, some patients may have moderate to severe pain following treatment. The aim of this study was to compare and assess the effect of ketorolac tromethamine on substance P expression in the pulp and periapical tissues when used as a root canal irrigant for single-visit root canal treatment in teeth with irreversible pulpitis. Thirty-six patients were randomly allotted to three irrigant groups - saline (n = 14), 3% sodium hypochlorite (n = 11) and ketorolac tromethamine (n = 11). Pulp blood samples (S1) were collected on gaining access to the pulp, and periapical blood samples (S2) were collected after root canal preparation. Quantification of substance P was done by ELISA test. The ketorolac tromethamine group had greater reduction in substance P expression (S2). Post-operative pain levels were not significantly influenced by the different root canal irrigants.


Assuntos
Anti-Inflamatórios , Pulpite , Irrigantes do Canal Radicular , Cavidade Pulpar , Humanos , Preparo de Canal Radicular , Tratamento do Canal Radicular , Hipoclorito de Sódio , Substância P
10.
Aust Endod J ; 46(1): 17-25, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-31270902

RESUMO

The aim of this study was to assess the influence of ketorolac tromethamine and dexamethasone on substance P and IL-8 expression when used as a root canal irrigant for single visit root canal treatment for acute irreversible pulpitis. A total of 42 patients with pain due to acute irreversible pulpitis in carious premolar and molar teeth were included in this study. The four irrigation groups were as follows: saline (n = 11), 3% sodium hypochlorite (n = 11), ketorolac tromethamine (n = 10) and dexamethasone (n = 10). Blood samples S1 and S2 were collected upon access opening and after canal preparation, respectively. Quantification of substance P and IL-8 were done using ELISA test. Post-operative pain was assessed by questioning the patients. The difference between S1 and S2 sample values for the four different irrigant groups was not significant. The sodium hypochlorite group had a higher mean expression of substance P and IL-8 values. Dexamethasone irrigation was more effective in controlling post-operative pain.


Assuntos
Pulpite , Cavidade Pulpar , Humanos , Interleucina-8 , Irrigantes do Canal Radicular , Preparo de Canal Radicular , Tratamento do Canal Radicular , Hipoclorito de Sódio , Substância P
11.
J Pharm Biomed Anal ; 178: 112953, 2020 Jan 30.
Artigo em Inglês | MEDLINE | ID: mdl-31718985

RESUMO

Recently, we developed a bradykinin reporter assay and demonstrated the differing protease activity in Complex Regional Pain Syndrome patients vs. controls. In order to further characterize CRPS pathophysiology, the neuropeptide substance P was evaluated as possible reporter substance, here. It was labeled with a chromophore at the lysine residue and generated two major fragments following incubation with serum (amino acid residues 3-8 and 3-11) which were reproducibly separated by thin-layer chromatography. Dabsylated substance P was shown to be a substrate of angiotensin-converting enzyme. The combination of both bradykinin and substance P reporter substances with specific enzyme inhibitors will shed more light on biochemical pathways in inflammatory processes and pain. Comparative clinical studies are now needed to define the application range of both assays in more detail.


Assuntos
Inibidores da Enzima Conversora de Angiotensina/química , Neuropeptídeos/química , Neuropeptídeos/metabolismo , Substância P/química , Substância P/metabolismo , Bradicinina/metabolismo , Cromatografia em Camada Delgada/métodos , Humanos , Peptidil Dipeptidase A/metabolismo
12.
Drug Deliv ; 27(1): 91-99, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31870182

RESUMO

Although cell-penetrating peptides (CPPs) has been proven to be efficient transporter for drug delivery, ideal peptide vectors for tumor therapy are still being urgently sought. Peptide antagonists have attracted substantial attention as targeting molecules because of their high tumor accumulation and antitumor activity compared with agonists. SPA, a derivative of substance P, is a potent antagonist that exhibits antitumor activity. Based on the amino acid composition of SPA, we speculate that it can translocate across cell membranes as CPPs do. In this study, our results demonstrated that SPA could enter cells similarly to a CPP. As a vector, SPA could efficiently deliver camptothecin and plasmids into cells. In addition, our results showed that SPA exhibited low toxicity to normal cells and high enzymatic stability. Taken together, our results validated the ability of SPA for efficient drug delivery. More importantly, our study opens a new avenue for designing ideal CPPs based on peptide antagonists.


Assuntos
Antineoplásicos Fitogênicos/farmacologia , Camptotecina/farmacologia , Peptídeos Penetradores de Células/química , Peptídeos Penetradores de Células/farmacocinética , Substância P/análogos & derivados , Animais , Antineoplásicos Fitogênicos/administração & dosagem , Antineoplásicos Fitogênicos/efeitos adversos , Células CHO , Camptotecina/administração & dosagem , Camptotecina/efeitos adversos , Peptídeos Penetradores de Células/administração & dosagem , Cricetulus , Sistemas de Liberação de Medicamentos
13.
Nat Commun ; 10(1): 5678, 2019 12 12.
Artigo em Inglês | MEDLINE | ID: mdl-31831729

RESUMO

As a protective mechanism, the cornea is sensitive to noxious stimuli. Here, we show that in mice, a high proportion of corneal TRPM8+ cold-sensing fibers express the heat-sensitive TRPV1 channel. Despite its insensitivity to cold, TRPV1 enhances membrane potential changes and electrical firing of TRPM8+ neurons in response to cold stimulation. This elevated neuronal excitability leads to augmented ocular cold nociception in mice. In a model of dry eye disease, the expression of TRPV1 in TRPM8+ cold-sensing fibers is increased, and results in severe cold allodynia. Overexpression of TRPV1 in TRPM8+ sensory neurons leads to cold allodynia in both corneal and non-corneal tissues without affecting their thermal sensitivity. TRPV1-dependent neuronal sensitization facilitates the release of the neuropeptide substance P from TRPM8+ cold-sensing neurons to signal nociception in response to cold. Our study identifies a mechanism underlying corneal cold nociception and suggests a potential target for the treatment of ocular pain.


Assuntos
Córnea/metabolismo , Nociceptividade/fisiologia , Células Receptoras Sensoriais/metabolismo , Substância P/metabolismo , Canais de Cátion TRPV/metabolismo , Sensação Térmica/fisiologia , Animais , Temperatura Baixa , Síndromes do Olho Seco , Regulação da Expressão Gênica , Hiperalgesia/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Células Receptoras Sensoriais/efeitos dos fármacos , Canais de Cátion TRPV/genética , Tamoxifeno/farmacologia
14.
Zhen Ci Yan Jiu ; 44(12): 906-10, 2019 Dec 25.
Artigo em Chinês | MEDLINE | ID: mdl-31867911

RESUMO

OBJECTIVE: To observe the effect of acupoint application at bilateral "Tianshu" (ST25) on intestinal mobility and immunoactivity of vasoactive intestinal peptide (VIP) and substance P (SP) in colonic myenteric plexus of rats with functional constipation (FC), so as to analyze its mechanisms underlying improving FC. METHODS: Forty male SD rats were randomly divided into 4 groups, namely normal control, model, acupoint application and medication, with 10 rats in each group. The FC model was established by gavage of Loperamide Hydrochloride suspension fluid (0.5 mg/mL, 3 mg·kg-1·d-1) for 7 days. Herbal medicine paste (composed of Rheum Officinale, Sodium Sulfate, Mangnolia Officinalis, etc.) was applied to bilateral ST25 for 6 h, once daily for 4 weeks. Rats of the medication group were treated by gavage of Mosapride suspension fluid (0.15 mg/mL, 1.58 mg·kg-1·d-1) for 4 weeks. After the treatment, the rats were deprived of water for 12 hours, and then treated by gavage of 2 mL of activated carbon suspension, followed by recording the first black defecation time and the number of fecal particles and water content of feces within 6 h so as to assess the intestinal mobility. The immunoactivity and average surface density of VIP and SP positive granules in the colonic myenteric plexus were detected by immunohistochemistry. RESULTS: Compared with the normal control group, the first black defecation time was significantly prolonged, and the number and water content of fecal particles within 6 h, and the expression and the average surface density of VIP and SP were significantly reduced in the model group (P<0.01). After the treatment and compared with the model group, the first black defecation time was shortened, and the fecal water content and fecal particle number within 6 h, as well as the expression and the average surface density of VIP and SP were considerably increased in both acupoint application and medication groups (P<0.01). There were no significant differences between the acupoint application and medication groups in all the indexes mentioned above after the interventions (P>0.05). CONCLUSION: Acupoint application may improve the intestinal motility in FC rats, which may be asso-ciated with its effects in up-regulating the immunoactivity of VIP and SP in colonic myenteric plexus of the large intestine.


Assuntos
Plexo Mientérico , Peptídeo Intestinal Vasoativo , Pontos de Acupuntura , Animais , Constipação Intestinal , Medicina Herbária , Masculino , Ratos , Ratos Sprague-Dawley , Substância P
15.
Int J Mol Sci ; 20(21)2019 Oct 23.
Artigo em Inglês | MEDLINE | ID: mdl-31652731

RESUMO

The neuropeptide substance P (SP) contributes to neurogenic inflammation through the activation of human mast cells via Mas-related G protein-coupled receptor-X2 (MRGPRX2). Using pertussis toxins and YM-254890, we demonstrated that SP induces Ca2+ mobilization and degranulation via both the Gαi and Gαq family of G proteins in rat basophilic leukemia (RBL-2H3) cells stably expressing MRGPRX2. To determine the roles of MRGPRX2's transmembrane (TM) and intracellular domains on SP-induced responses, we utilized information obtained from both structural modeling and naturally occurring MRGPRX2 missense variants. We found that highly conserved residues in TM6 (I225) and TM7 (Y279) of MRGPRX2 are essential for SP-induced Ca2+ mobilization and degranulation in transiently transfected RBL-2H3 cells. Cells expressing missense variants in the receptor's conserved residues (V123F and V282M) as well as intracellular loops (R138C and R141C) failed to respond to SP. By contrast, replacement of all five Ser/Thr residues with Ala and missense variants (S325L and L329Q) in MRGPRX2's carboxyl-terminus resulted in enhanced mast cell activation by SP when compared to the wild-type receptor. These findings suggest that MRGPRX2 utilizes conserved residues in its TM domains and intracellular loops for coupling to G proteins and likely undergoes desensitization via phosphorylation at Ser/Thr residues in its carboxyl-terminus. Furthermore, identification of gain and loss of function MRGPRX2 variants has important clinical implications for SP-mediated neurogenic inflammation and other chronic inflammatory diseases.


Assuntos
Mutação com Ganho de Função , Mutação com Perda de Função , Mastócitos/metabolismo , Proteínas do Tecido Nervoso/química , Receptores Acoplados a Proteínas-G/química , Receptores de Neuropeptídeos/química , Substância P/metabolismo , Animais , Cálcio/metabolismo , Linhagem Celular Tumoral , Sequência Conservada , Humanos , Mutação de Sentido Incorreto , Proteínas do Tecido Nervoso/genética , Proteínas do Tecido Nervoso/metabolismo , Domínios Proteicos , Ratos , Receptores Acoplados a Proteínas-G/genética , Receptores Acoplados a Proteínas-G/metabolismo , Receptores de Neuropeptídeos/genética , Receptores de Neuropeptídeos/metabolismo
16.
Rev Assoc Med Bras (1992) ; 65(9): 1188-1192, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31618336

RESUMO

OBJECTIVE: We aimed to explore the effects of neuropeptides ghrelin, obestatin, and vasoactive intestinal peptide (VIP) on seizures and plasma concentrations of neuroinflammation biomarkers including calcitonin gene-related peptide (CGRP), substance-P (SP), and interleukin-1 beta (IL-1ß) in pentylenetetrazol-induced seizures in rats. METHODS: Ghrelin (80 µg/kg), obestatin (1 µg/kg), VIP (25 ng/kg) or saline were administered to rats intraperitoneally 30 min before pentylenetetrazole (PTZ, 50 mg/kg) injections. Stages of epileptic seizures were evaluated by Racine's scale, and plasma CGRP, SP, and IL-1ß concentrations were measured using ELISA. RESULTS: Both obestatin and VIP shortened onset-time of generalized tonic-clonic seizure, respectively, moreover VIP also shortened the onset-time of first myoclonic-jerk induced by PTZ. While PTZ increased plasma CGRP, SP and IL-1ß concentrations, ghrelin reduced the increases evoked by PTZ. While VIP further increased PTZ-evoked CGRP levels, it diminished IL-1ß concentrations. However, obestatin did not change CGRP, SP, and IL-1ß concentrations. CONCLUSION: Our results suggest that ghrelin acts as an anticonvulsant, obestatin acts as a proconvulsant, and VIP has dual action on epilepsy. Receptors of those neuropeptides may be promising targets for epilepsy treatment.


Assuntos
Convulsivantes/efeitos adversos , Neuropeptídeos/efeitos dos fármacos , Pentilenotetrazol/efeitos adversos , Hormônios Peptídicos/farmacologia , Convulsões/induzido quimicamente , Animais , Biomarcadores/sangue , Peptídeo Relacionado com Gene de Calcitonina/sangue , Peptídeo Relacionado com Gene de Calcitonina/efeitos dos fármacos , Modelos Animais de Doenças , Grelina/farmacologia , Inflamação , Interleucina-1beta/sangue , Interleucina-1beta/efeitos dos fármacos , Masculino , Mioclonia , Distribuição Aleatória , Ratos Wistar , Convulsões/metabolismo , Substância P/sangue , Substância P/efeitos dos fármacos , Fatores de Tempo , Peptídeo Intestinal Vasoativo/farmacologia
17.
Endocrinology ; 160(10): 2453-2463, 2019 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-31504389

RESUMO

The tachykinin neurokinin B (NKB, Tac2) is critical for proper GnRH release in mammals, however, the role of the other tachykinins, such as substance P (SP) and neurokinin A (NKA) in reproduction, is still not well understood. In this study, we demonstrate that NKA controls the timing of puberty onset (similar to NKB and SP) and stimulates LH release in adulthood through NKB-independent (but kisspeptin-dependent) mechanisms in the presence of sex steroids. Furthermore, this is achieved, at least in part, through the autosynaptic activation of Tac1 neurons, which express NK2R (Tacr2), the receptor for NKA. Conversely, in the absence of sex steroids, as observed in ovariectomy, NKA inhibits LH through a mechanism that requires the presence of functional receptors for NKB and dynorphin (NK3R and KOR, respectively). Moreover, the ability of NKA to modulate LH secretion is absent in Kiss1KO mice, suggesting that its action occurs upstream of Kiss1 neurons. Overall, we demonstrate that NKA signaling is a critical component in the central control of reproduction, by contributing to the indirect regulation of kisspeptin release.


Assuntos
Gonadotropinas/metabolismo , Neurocinina A/metabolismo , Animais , Feminino , Kisspeptinas , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Neurocinina A/genética , Neurocinina B/genética , Neurocinina B/metabolismo , Precursores de Proteínas , Receptores da Neurocinina-2/genética , Receptores da Neurocinina-2/metabolismo , Maturidade Sexual , Substância P/genética , Substância P/metabolismo , Taquicininas
18.
Endocr Regul ; 53(3): 165-177, 2019 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-31517634

RESUMO

OBJECTIVE: The aim of the present study was to demonstrate the spatial relationship between the c-Fos immunoreactive cells elicited by an acute treatment with neuroleptics including amisulpride (AMI), olanzapine (OLA), quetiapine (QUE), and aripiprazole (ARI) and enkephalinergic (ENK), substance P (SP), and tyrosine hydroxylase (TH) innervation fields in the rat septum. METHODS: Male Sprague Dawley rats received a single injection of OLA (5 mg), ARI (10 mg), AMI (20 mg), QUE (15 mg/kg/b.w.). Ninety min after antipsychotics administration, the animals were transcardially perfused with a fixative and the brains cryocut into serial coronal sections of 35 µm thickness. The sections were processed for c-Fos staining using an avidin-biotin-peroxidase complex and visualized by nickel intensified diaminobenzidine to reach black endproduct. Afterwards, the sections were exposed to ENK, SP, and TH antibodies and the reaction product visualized by biotin-labeled fluorescent AlexaFluor 564 dye. The data were evaluated from the sections either simultaneously illuminated with fluorescent and transmission microscope beams or after merging the separately illuminated sections in the Adobe Photoshop 7.0 software. RESULTS: ENK, SP, and TH displayed characteristic spatial images formed by a dense accumulation of immunoreactive fibers and terminals on the both sides of the septum. A dense plexus of axons formed by ENK and SP immunopositive terminals were situated predominantly in the lateral, while TH ones more medial portion of the septum. QUE and AMI activated distinct amount of c-Fos expression in cells located within the SP-immunoreactive principal innervation field. The OLA effect on the c-Fos expression was very pronounced in the ventral TH-labeled principal innervation field including the space between the ENK field ventral portion and the dorsal margin of the accumbens nucleus shell. Generally, the occurrence of c-Fos cells in the ENK-immunoreactive principal innervation field, in comparison with the surrounding septal area, was less abundant after all of the four antipsychotics treatments. CONCLUSION: The data of the present study indicate that ENK, SP, and TH innervation fields may influence separate populations of septal cells activated by AMI, OLA, QUE, and ARI and that each of these region-differently innervated cells may be associated with the functional heterogeneity of the individual lateral septal nuclei.


Assuntos
Antipsicóticos/farmacologia , Encefalinas/metabolismo , Proteínas Proto-Oncogênicas c-fos/metabolismo , Septo do Cérebro/efeitos dos fármacos , Substância P/metabolismo , Tirosina 3-Mono-Oxigenase/metabolismo , Amissulprida/farmacologia , Animais , Aripiprazol/farmacologia , Imuno-Histoquímica , Masculino , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Olanzapina/farmacologia , Proteínas Proto-Oncogênicas c-fos/efeitos dos fármacos , Fumarato de Quetiapina/farmacologia , Ratos , Ratos Sprague-Dawley , Septo do Cérebro/metabolismo , Distribuição Tecidual/efeitos dos fármacos
19.
Int J Oral Sci ; 11(3): 24, 2019 09 10.
Artigo em Inglês | MEDLINE | ID: mdl-31501412

RESUMO

Inflammatory orofacial pain, in which substance P (SP) plays an important role, is closely related to the cross-talk between trigeminal ganglion (TG) neurons and satellite glial cells (SGCs). SGC activation is emerging as the key mechanism underlying inflammatory pain through different signalling mechanisms, including glial fibrillary acidic protein (GFAP) activation, phosphorylation of mitogen-activated protein kinase (MAPK) signalling pathways, and cytokine upregulation. However, in the TG, the mechanism underlying SP-mediated orofacial pain generated by SGCs is largely unknown. In this study, we investigated whether SP is involved in inflammatory orofacial pain by upregulating interleukin (IL)-1ß and tumour necrosis factor (TNF)-α from SGCs, and we explored whether MAPK signalling pathways mediate the pain process. In the present study, complete Freund's adjuvant (CFA) was injected into the whisker pad of rats to induce an inflammatory model in vivo. SP was administered to SGC cultures in vitro to confirm the effect of SP. Facial expression analysis showed that pre-injection of L703,606 (an NK-1 receptor antagonist), U0126 (an inhibitor of MAPK/extracellular signal-regulated kinase [ERK] kinase [MEK] 1/2), and SB203580 (an inhibitor of P38) into the TG to induce targeted prevention of the activation of the NK-1 receptor and the phosphorylation of MAPKs significantly suppressed CFA-induced inflammatory allodynia. In addition, SP promoted SGC activation, which was proven by increased GFAP, p-MAPKs, IL-1ß and TNF-α in SGCs under inflammatory conditions. Moreover, the increase in IL-1ß and TNF-α was suppressed by L703, 606, U0126 and SB203580 in vivo and in vitro. These present findings suggested that SP, released from TG neurons, activated SGCs through the ERK1/2 and P38 pathways and promoted the production of IL-1ß and TNF-α from SGCs, contributing to inflammatory orofacial pain associated with peripheral sensitization.


Assuntos
Proteínas Quinases Ativadas por Mitógeno , Neurônios/metabolismo , Substância P/metabolismo , Gânglio Trigeminal/fisiopatologia , Animais , Inflamação , Neuroglia , Ratos , Gânglio Trigeminal/metabolismo , Proteínas Quinases p38 Ativadas por Mitógeno
20.
J Med Food ; 22(10): 1009-1021, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31536448

RESUMO

Constipation is a common gastrointestinal disorder characterized by changes in intestinal habits. Increasing evidence indicates that long-term use of irritant laxatives causes serious side effects. Meanwhile, more than 50% of patients are dissatisfied with sense of use of non-prescriptional laxatives. ß-glucans are natural polysaccharides widely found in yeast, fungus, and plants, which have been reported to exhibit various pharmacological effects. The aim of this study was to characterize the effect of ß-glucans extracted from the bread yeast cell wall on loperamide-induced constipation mice. Forty mice were fed with loperamide (10 mg/kg) to make the constipation model and a diet supplemented with 2.5, 5, and 10 mg/kg ß-glucan. We assessed the defecation frequency, intestinal transit function of mice, as well as used high-throughput sequencing to analyze the intestinal microbiota composition and functional biological profiles data. Meanwhile, we detected expression of neurotransmitters including acetylcholinesterase, substance P, and serotonin (5-HT) and expression of tight junction protein (TJP) including zonula occludens-1 and mucin-2 in distal colon to characterize the possible molecular mechanisms. ß-glucans significantly enhanced intestinal motility and provided a possibility to regulate the expression of neurotransmitters and TJP in mice. The intestinal microecological portion of the treatment group partially recovered and was closer to the normal group. This study showed that ß-glucans can influence the intestinal microbiota and restore microecological balance to regulate the express of neurotransmitters and TJP to recover intestinal epithelial mechanical barrier. We suggested that ß-glucans could be used as an active nutritional supplement to protect the damaged intestinal barrier and help patients who have constipation complications and dysbiosis.


Assuntos
Constipação Intestinal/tratamento farmacológico , Microbioma Gastrointestinal , Loperamida/efeitos adversos , Saccharomyces cerevisiae/química , beta-Glucanas/farmacologia , Acetilcolinesterase/metabolismo , Animais , Constipação Intestinal/induzido quimicamente , Defecação/efeitos dos fármacos , Trânsito Gastrointestinal/efeitos dos fármacos , Masculino , Metagenoma , Camundongos , Camundongos Endogâmicos BALB C , Mucina-2/metabolismo , Serotonina/metabolismo , Substância P/metabolismo , Proteína da Zônula de Oclusão-1/metabolismo
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