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1.
PLoS Comput Biol ; 16(1): e1007590, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31940345

RESUMO

Urticaria is a common skin disorder characterized by the rapid appearance and disappearance of local skin edema and flares with itching. It is characterized by various macroscopic skin eruptions unique to patients and/or subtypes of urticaria with respect to shape, size, color, and/or duration of eruptions. Nevertheless, the mechanism underlying multifarious eruptions in urticaria is largely unknown. The eruptions are believed to be evoked by histamine release from mast cells in the skin. However, the majority of visible characteristics of urticaria cannot be explained by a simple injection of histamine to the skin. To explain the multifarious eruptions of urticaria, we developed a single reaction-diffusion model suggesting the self-activation and self-inhibition regulation of histamine release from mast cells. Using the model, we found that various geometrical shapes of eruptions typically observed in patients can be explained by the model parameters and randomness or strength of the initial stimuli to mast cells. Furthermore, we verified that the wheal-expanding speed of urticaria, which is shown to be much smaller than that of the intradermal injection experimental system may be explained by our model and a simple diffusion equation. Our study suggests that the simple reaction-diffusion dynamics, including the independent self-activating and -inhibitory regulation of histamine release, may account for the essential mechanism underlying the formation of multifarious eruptions in urticaria.


Assuntos
Modelos Biológicos , Urticária , Biologia Computacional , Histamina/metabolismo , Liberação de Histamina/fisiologia , Humanos , Mastócitos/metabolismo , Pele/metabolismo , Pele/patologia , Pele/fisiopatologia , Urticária/metabolismo , Urticária/patologia , Urticária/fisiopatologia
2.
Proc Natl Acad Sci U S A ; 117(6): 3150-3156, 2020 02 11.
Artigo em Inglês | MEDLINE | ID: mdl-31992639

RESUMO

Heart failure and chronic kidney disease are major causes of morbidity and mortality internationally. Although these dysfunctions are common and frequently coexist, the factors involved in their relationship in cardiorenal regulation are still largely unknown, mainly due to a lack of detailed molecular targets. Here, we found the increased plasma histamine in a preclinical mouse model of severe cardiac dysfunction, that had been cotreated with angiotensin II (Ang II), nephrectomy, and salt (ANS). The ANS mice exhibited impaired renal function accompanied with heart failure, and histamine depletion, by the genetic inactivation of histidine decarboxylase in mice, exacerbated the ANS-induced cardiac and renal abnormalities, including the reduction of left ventricular fractional shortening and renal glomerular and tubular injuries. Interestingly, while the pharmacological inhibition of the histamine receptor H3 facilitated heart failure and kidney injury in ANS mice, administration of the H3 agonist immethridine (Imm) was protective against cardiorenal damages. Transcriptome analysis of the kidney and biochemical examinations using blood samples illustrated that the increased inflammation in ANS mice was alleviated by Imm. Our results extend the pharmacological use of H3 agonists beyond the initial purposes of its drug development for neurogenerative diseases and have implications for therapeutic potential of H3 agonists that invoke the anti-inflammatory gene expression programming against cardiorenal damages.


Assuntos
Anti-Inflamatórios/farmacologia , Insuficiência Cardíaca/metabolismo , Agonistas dos Receptores Histamínicos/farmacologia , Histamina/metabolismo , Nefropatias/metabolismo , Animais , Modelos Animais de Doenças , Coração/efeitos dos fármacos , Histamina/sangue , Rim/efeitos dos fármacos , Camundongos , Substâncias Protetoras/farmacologia , Receptores Histamínicos H3/metabolismo
3.
PLoS Pathog ; 15(12): e1008156, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31790497

RESUMO

Kaposi's sarcoma-associated herpesvirus (KSHV) causes several human cancers, such as Kaposi's sarcoma (KS) and primary effusion lymphoma (PEL). Current treatment options for KSHV infection and virus associated diseases are sometimes ineffective, therefore, more effectively antiviral agents are urgently needed. As a herpesvirus, lytic replication is critical for KSHV pathogenesis and oncogenesis. In this study, we have established a high-throughput screening assay by using an inducible KSHV+ cell-line, iSLK.219. After screening a compound library that consisted of 1280 Food and Drug Administration (FDA)-approved drugs, 15 hit compounds that effectively inhibited KSHV virion production were identified, most of which have never been reported with anti-KSHV activities. Interestingly, 3 of these drugs target histamine receptors or signaling. Our data further confirmed that antagonists targeting different histamine receptors (HxRs) displayed excellent inhibitory effects on KSHV lytic replication from induced iSLK.219 or BCBL-1 cells. In contrast, histamine and specific agonists of HxRs promoted viral lytic replication from induced iSLK.219 or KSHV-infected primary cells. Mechanistic studies indicated that downstream MAPK and PI3K/Akt signaling pathways were required for histamine/receptors mediated promotion of KSHV lytic replication. Direct knockdown of HxRs in iSLK.219 cells effectively blocked viral lytic gene expression during induction. Using samples from a cohort of HIV+ patients, we found that the KSHV+ group has much higher levels of histamine in their plasma and saliva than the KSHV- group. Taken together, our data have identified new anti-KSHV agents and provided novel insights into the molecular bases of host factors that contribute to lytic replication and reactivation of this oncogenic herpesvirus.


Assuntos
Antivirais/farmacologia , Herpesvirus Humano 8/efeitos dos fármacos , Histamina/metabolismo , Sarcoma de Kaposi/virologia , Ativação Viral/efeitos dos fármacos , Avaliação Pré-Clínica de Medicamentos , Herpesvirus Humano 8/fisiologia , Ensaios de Triagem em Larga Escala , Humanos , Receptores Histamínicos/metabolismo , Transdução de Sinais/fisiologia , Ativação Viral/fisiologia , Latência Viral/efeitos dos fármacos , Latência Viral/fisiologia
4.
Pharm Res ; 36(11): 158, 2019 Sep 11.
Artigo em Inglês | MEDLINE | ID: mdl-31512001

RESUMO

PURPOSE: P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP) are xenobiotic transporters which pump out variety types of compounds, but information on their interaction with endogenous substrates in the skin is limited. The purpose of the present study was to clarify possible association of these transporters in dermal accumulation of inflammatory mediators. METHODS: Dermatitis model was constructed by repeated topical application of oxazolone in wild-type, and P-gp and BCRP gene triple knockout (Mdr1a/1b/Bcrp-/-) mice to observe difference in phenotype. Target metabolome analysis of 583 metabolites was performed using skin and plasma. RESULTS: Dermatitis and scratching behavior in dermatitis model of Mdr1a/1b/Bcrp-/- mice were more severe than wild-type mice, suggesting protective roles of these transporters. This hypothesis was supported by the metabolome analysis which revealed that concentration of histamine and other dermatitis-associated metabolites like urate and serotonin in the dermatitis skin, but not normal skin, of Mdr1a/1b/Bcrp-/- mice was higher than that of wild-type mice. Gene expression of P-gp and BCRP was reduced in oxazolone-treated skin and the skin of patients with atopic dermatitis or psoriasis. CONCLUSIONS: These results suggest possible association of these efflux transporters with dermal inflammatory mediators, and such association could be observed in the dermatitis skin.


Assuntos
Membro 1 da Subfamília B de Cassetes de Ligação de ATP/genética , Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/genética , Dermatite/metabolismo , Histamina/metabolismo , Metaboloma/efeitos dos fármacos , Proteínas de Neoplasias/genética , Pele/metabolismo , Animais , Deleção de Genes , Humanos , Masculino , Camundongos , Camundongos Knockout
5.
Mol Immunol ; 114: 362-368, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31450181

RESUMO

Madi-Ryuk (MDR) is a traditional Korean medicine and it has been widely used in Korea to treat arthritis and we previously reported the anti-allergic inflammatory effect of MDR in vitro model. However, therapeutic evidence of MDR on in vivo model of allergic inflammatory reaction has not yet been demonstrated. The research purpose was to investigate the efficacy of MDR and its active ingredient tannic acid (TA) in ovalbumin (OVA)-induced AR mice model. OVA-challenged AR mice orally medicated MDR or its active ingredient TA daily for ten days. In mice having a AR, MDR and TA prominently diminished number of rubs and levels of histamine, IgE, thymic stromal lymphopoietin, interleukin (IL)-1ß, IL-4, IL-5, IL-13, IL-33, and tumor necrosis factor-α. In addition, protein expression levels and activities of caspase-1 were declined by oral medication of MDR and TA. Decline in levels of macrophage inflammatory protein-2 and intercellular adhesion molecules-1 and reduction in penetrations of inflammatory cells into inflamed tissue were also noted in MDR and TA groups. Taken together, identification of MDR effect in preclinical models suggests that MDR may be a therapeutic drug for the treatment and prevention of AR.


Assuntos
Anti-Inflamatórios/farmacologia , Rinite Alérgica/tratamento farmacológico , Taninos/farmacologia , Animais , Caspase 1/metabolismo , Quimiocina CXCL2/metabolismo , Citocinas/metabolismo , Modelos Animais de Doenças , Eosinófilos/efeitos dos fármacos , Eosinófilos/metabolismo , Histamina/metabolismo , Imunoglobulina E/metabolismo , Inflamação/induzido quimicamente , Inflamação/tratamento farmacológico , Inflamação/metabolismo , Interleucina-1beta/metabolismo , Medicina Tradicional Coreana/métodos , Camundongos , Camundongos Endogâmicos BALB C , Mucosa Nasal/efeitos dos fármacos , Mucosa Nasal/metabolismo , Ovalbumina/farmacologia , Rinite Alérgica/metabolismo , Fator de Necrose Tumoral alfa/metabolismo
6.
West J Emerg Med ; 20(4): 587-600, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31316698

RESUMO

Angioedema is defined by non-dependent, non-pitting edema that affects several different sites and is potentially life-threatening due to laryngeal edema. This narrative review provides emergency physicians with a focused overview of the evaluation and management of angioedema. Two primary forms include histamine-mediated and bradykinin-mediated angioedema. Histamine-mediated forms present similarly to anaphylaxis, while bradykinin-mediated angioedema presents with greater face and oropharyngeal involvement and higher risk of progression. Initial evaluation and management should focus on evaluation of the airway, followed by obtaining relevant historical features, including family history, medications, and prior episodes. Histamine-mediated angioedema should be treated with epinephrine intramuscularly, antihistaminergic medications, and steroids. These medications are not effective for bradykinin-mediated forms. Other medications include C1-INH protein replacement, kallikrein inhibitor, and bradykinin receptor antagonists. Evidence is controversial concerning the efficacy of these medications in an acute episode, and airway management is the most important intervention when indicated. Airway intervention may require fiberoptic or video laryngoscopy, with preparation for cricothyrotomy. Disposition is dependent on patient's airway and respiratory status, as well as the sites involved.


Assuntos
Angioedema/etiologia , Angioedema/terapia , Serviço Hospitalar de Emergência , Manuseio das Vias Aéreas , Algoritmos , Anti-Inflamatórios não Esteroides/uso terapêutico , Fatores de Coagulação Sanguínea/uso terapêutico , Bradicinina/análogos & derivados , Bradicinina/metabolismo , Bradicinina/uso terapêutico , Antagonistas de Receptor B2 da Bradicinina/uso terapêutico , Broncodilatadores/uso terapêutico , Epinefrina/uso terapêutico , Glucocorticoides/uso terapêutico , Histamina/metabolismo , Antagonistas dos Receptores Histamínicos/uso terapêutico , Humanos , Peptídeos/uso terapêutico , Plasma , Urticária/etiologia
7.
J Physiol Pharmacol ; 70(2)2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-31356185

RESUMO

A suitable inflammatory signal influences extracellular matrix accumulation and determines the quality of the myocardial infarction scar. The aim of the present study was to determine the influence of mast cell sonicates or histamine on collagen accumulation in heart myofibroblast culture and on the deposition of collagen in the myocardial infarction scar. The histamine receptor involved in the process was investigated. Myocardial infarction was induced by ligation of the left coronary artery. Myofibroblasts were isolated from the scar of myocardial infarction. The effects of mast cell sonicates, histamine and its receptor antagonists, i.e. ketotifen (H1-receptor inhibitor), ranitidine (H2-receptor inhibitor), ciproxifan (H3-receptor inhibitor), JNJ7777120 (H4-receptor inhibitor), imetit (H3 receptor agonist), were investigated. The mast cell sonicates or histamine (10-10 - 10-5M) augmented collagen content in myofibroblast cultures; however, histamine-induced elevation was reduced by ciproxifan (10-5M, 10-6M). Imetit (10-9 - 10-5M) elevated collagen content in the culture. H3 receptor expression on myofibroblasts was confirmed. Our findings indicate that histamine increases the deposition of collagen in cultures of myofibroblasts isolated from the myocardial infarction scar. This effect is dependent on H3 receptor activation.


Assuntos
Cicatriz/metabolismo , Colágeno/metabolismo , Histamina/metabolismo , Miofibroblastos/metabolismo , Receptores Histamínicos/metabolismo , Animais , Células Cultivadas , Coração/efeitos dos fármacos , Imidazóis/farmacologia , Masculino , Mastócitos/efeitos dos fármacos , Mastócitos/metabolismo , Infarto do Miocárdio/tratamento farmacológico , Infarto do Miocárdio/metabolismo , Ratos , Ratos Wistar , Tioureia/análogos & derivados , Tioureia/farmacologia
8.
Food Chem ; 300: 125209, 2019 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-31344629

RESUMO

Turbot can induce allergy in susceptible individuals due to the presence of parvalbumin (PV), a major fish allergen. This study aimed at evaluating the digestibility and the ability of PV to elicit the release of cellular degranulation, following treatment with tyrosinase (PV-Tyr), caffeic acid (PV-CA) and in combination (PV-Tyr/CA), using in vitro digestion and RBL-2H3 (passive rat basophil leukemia) cell line. The digestion assay products revealed that the stability of PV in simulated gastric fluid (SGF) was stronger, while in simulated intestinal fluid (SIF) was rather weak. Western blot analysis revealed that the IgG-binding abilities of the cross-linked PV were markedly reduced. Moreover, crosslinking hampered the release of cellular degranulation process in RBL-2H3 cell lines. PV-Tyr/CA showed highly significant reduction in the release rate of ß-hexosaminidase (66.02%), histamine (35.01%), tryptase (29.25%), cysteinyl leukotrienes (29.72%), prostaglandin D2 (34.96%), IL-4 (43.99%) and IL-13 (38.93%) and shown potential in developing hypoallergenic fish products.


Assuntos
Ácidos Cafeicos/química , Citocinas/metabolismo , Hipersensibilidade Alimentar/imunologia , Monofenol Mono-Oxigenase/química , Parvalbuminas/química , Alérgenos/química , Alérgenos/farmacocinética , Animais , Degranulação Celular/efeitos dos fármacos , Linhagem Celular , Digestão , Proteínas de Peixes da Dieta/química , Linguados , Suco Gástrico , Histamina/metabolismo , Humanos , Parvalbuminas/imunologia , Parvalbuminas/farmacologia , Ratos , beta-N-Acetil-Hexosaminidases/metabolismo
9.
J Mol Neurosci ; 69(2): 235-245, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31201657

RESUMO

Cancer pain induced by pancreatic carcinoma is one of the most common symptoms and is difficult to endure, especially in the advanced stage. Evidence suggests that mast cells are recruited and degranulate in enteric disease-related visceral hypersensitivity. However, whether mast cells promote the visceral pain induced by pancreatic carcinoma remains unclear. Here, using toluidine blue staining and western blotting, we observed that mast cells were dramatically recruited to tissues surrounding pancreatic carcinoma, but not inside the carcinoma in patients with severe visceral pain. The levels of mast cell degranulation products, including tryptase, histamine, and nerve growth factor, were significantly increased in pericarcinoma tissues relative to their levels in normal controls, as evidenced by enzyme-linked immunosorbent assay. We determined that systemic administration of mast cell secretagogue compound 48/80 exacerbated pancreatic carcinoma-induced visceral hypersensitivity in a male BALB/c nude mouse model as assessed by measuring the hunching behavior scores and mechanical withdrawal response frequency evoked by von Frey stimulation. In contrast, the mast cell stabilizer ketotifen dose-dependently alleviated pancreatic cancer pain. In addition, we observed incomplete development of abdominal mechanical hyperalgesia and hunching behavior in mast cell-deficient mice with pancreatic carcinoma. However, ketotifen did not further attenuate visceral hypersensitivity in mast cell-deficient mice with carcinoma. Finally, we confirmed that intraplantar injection of pericarcinoma supernatants from BALB/c nude mice but not mast cell-deficient mice caused acute somatic nociception. In conclusion, our findings suggest that mast cells contribute to pancreatic carcinoma-induced visceral hypersensitivity through enrichment and degranulation in pericarcinoma tissues. The inhibition of mast cell degranulation may be a potential strategy for the therapeutic treatment of pancreatic carcinoma-induced chronic visceral pain.


Assuntos
Dor do Câncer/tratamento farmacológico , Carcinoma/complicações , Degranulação Celular , Mastócitos/metabolismo , Neoplasias Pancreáticas/complicações , Dor Visceral/tratamento farmacológico , Adulto , Animais , Dor do Câncer/etiologia , Feminino , Histamina/metabolismo , Antagonistas dos Receptores Histamínicos H1/farmacologia , Antagonistas dos Receptores Histamínicos H1/uso terapêutico , Humanos , Cetotifeno/farmacologia , Cetotifeno/uso terapêutico , Masculino , Mastócitos/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Pessoa de Meia-Idade , Fator de Crescimento Neural/metabolismo , Secretagogos/farmacologia , Secretagogos/uso terapêutico , Triptases/metabolismo , Dor Visceral/etiologia
10.
Pharmacology ; 104(3-4): 166-172, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31212298

RESUMO

BACKGROUND: Sensitization of transient receptor potential (TRP) cation channels probably contributes to intestinal hypersensitivity, a hallmark of gastrointestinal disorders. Histamine acting via histamine 1 receptor (H1R) to open TRP cation channels might also be involved. METHOD: The enterochromaffin cell line P-STS, responsive to histamine via H1R, was used as model to study possible synergism between histamine and TRP vanilloid 4 (TRPV4) pathways. RESULTS: The TRPV4 antagonist RN-1734, but not HC-067047, inhibited the cytoplasmic calcium response to histamine in P-STS cells. However, also pre-incubation with the TRPV4 agonist RN-1747 strongly inhibited the calcium response to histamine in P-STS as well as HeLa cells. This inhibitory effect of RN-1747 was not due to its known TRP melastatin 8 (TRPM8) antagonism, as the TRPM8 antagonist RQ-00203078 showed no significant effect on the histamine-induced calcium response of P-STS or HeLa cells. CONCLUSION: The TRPV4 agonist RN-1747, and possibly also the structurally similar TRPV4 antagonist RN-1734, should be used with caution because of yet unidentified interference with histamine signaling via H1R.


Assuntos
Cálcio/metabolismo , Histamina/metabolismo , Sulfonamidas/farmacologia , Canais de Cátion TRPV/agonistas , Canais de Cátion TRPV/metabolismo , Linhagem Celular Tumoral , Células HeLa , Humanos , Morfolinas/farmacologia , Pirróis/farmacologia
11.
J Enzyme Inhib Med Chem ; 34(1): 1193-1198, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31237157

RESUMO

A series of histamine bis-Schiff bases and bis-spinaceamine derivatives were synthesised and investigated as activators of four human (h) carbonic anhydrase (CA, EC 4.2.1.1) isoforms, the cytosolic hCA I, II and VII, and the membrane-associated hCA IV. All isoforms were effectively activated by the new derivatives, with activation constants in the range of 4.73-10.2 µM for hCA I, 6.15-42.1 µM for hCA II, 2.37-32.7 µM for hCA IV and 32 nM-18.7 µM for hCA VII, respectively. The nature of the spacer between the two histamine/spinaceamine units of these molecules was the main contributor to the diverse activating efficacy, with a very different fine tuning for the diverse isoforms. As CA activators recently emerged as interesting agents for enhancing cognition, in the management of CA deficiencies, or for therapy memory and artificial tissues engineering, our compounds may be considered as candidates for such applications.


Assuntos
Aminas/metabolismo , Inibidores da Anidrase Carbônica/farmacologia , Histamina/metabolismo , Isoenzimas/antagonistas & inibidores , Bases de Schiff/metabolismo , Espectroscopia de Ressonância Magnética Nuclear de Carbono-13 , Humanos , Espectroscopia de Prótons por Ressonância Magnética , Espectroscopia de Infravermelho com Transformada de Fourier
12.
Food Chem ; 297: 124972, 2019 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-31253320

RESUMO

The aim of the present study was to evaluate Paralichthys olivaceus parvalbumin (PV) following treatment by laccase (LAC) in the presence of propyl gallate (PG) on the structure and potential allergenicity. The structure of LAC + PG treated PV was analyzed through SDS-PAGE, CD, fluorescence, and allergenicity was analyzed by immunological and cell model. Our results showed that LAC + PG treatment can induce structural changes through PV cross-linking. Western blotting and indirect ELISA analysis revealed the decrease in IgG binding capacity of PV, corresponding with the structural changes. The results of in vitro digestion illustrate that LAC + PG treated PV showed more resistance to gastrointestinal digestion compared to untreated PV. The release rate of ß-hexosaminidase and histamine decreased by 35.6% and 66.9%, respectively, with LAC + PG treatment by RBL-2H3 cell assay. Considering the wide utilization of LAC in food industry, our treatment reveals its potential for creation of hypoallergenic fish products under mild reaction conditions.


Assuntos
Alérgenos/imunologia , Proteínas de Peixes/imunologia , Linguados/imunologia , Lacase/metabolismo , Parvalbuminas/imunologia , Galato de Propila/química , Animais , Catálise , Reagentes para Ligações Cruzadas/química , Digestão , Ensaio de Imunoadsorção Enzimática , Proteínas de Peixes/química , Indústria Alimentícia , Histamina/metabolismo , Parvalbuminas/química , beta-N-Acetil-Hexosaminidases/metabolismo
13.
Neurochem Res ; 44(7): 1764-1772, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31093904

RESUMO

Ethanol is one of the most highly abused psychoactive compounds worldwide and induces sedation and hypnosis. The histaminergic system is involved in the regulation of sleep/wake function and is a crucial player in promoting wakefulness. To explore the role and mechanism of the histaminergic system in ethanol-induced sedation and hypnosis, we recorded locomotor activity (LMA) and electroencephalography (EEG)/electromyography (EMG) in mice using an infrared ray passive sensor recording system and an EEG/EMG recording system, respectively, after administration of ethanol. In vivo microdialysis coupled with high performance liquid chromatography and fluorometry technology were used to detect histamine release in the mouse frontal cortex (FrCx). The results revealed that ethanol significantly suppressed LMA of histamine receptor 1 (H1R)-knockout (KO) and wild-type (WT) mice in the range of 1.5-2.5 g/kg, but suppression was remarkably stronger in WT mice than in H1R-KO mice. At 2.0 and 2.5 g/kg, ethanol remarkably increased non-rapid eye movement sleep and decreased wakefulness, respectively. Neurochemistry experimental data indicated that ethanol inhibited histamine release in the FrCx in a dose-dependent manner. These findings suggest that ethanol induces sedation and hypnosis via inhibiting histamine release in mice.


Assuntos
Etanol/farmacologia , Histamina/metabolismo , Hipnóticos e Sedativos/farmacologia , Sono/efeitos dos fármacos , Vigília/efeitos dos fármacos , Animais , Relação Dose-Resposta a Droga , Lobo Frontal/metabolismo , Locomoção/efeitos dos fármacos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Receptores Histamínicos H1/genética
14.
Cell Tissue Res ; 378(1): 33-48, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31049687

RESUMO

This paper provides quantitative data on the distributions of enteroendocrine cells (EEC), defined by the hormones they contain, patterns of colocalisation between hormones and EEC relations to nerve fibres in the rat gastric mucosa. The rat stomach has three mucosal types: non-glandular stratified squamous epithelium of the fundus and esophageal groove, a region of oxyntic glands in the corpus, and pyloric glands of the antrum and pylorus. Ghrelin and histamine were both contained in closed cells, not contacting the lumen, and were most numerous in the corpus. Gastrin cells were confined to the antrum, and 5-hydroxytryptamine (5-HT) and somatostatin cells were more frequent in the antrum than the corpus. Most somatostatin cells had basal processes that in the antrum commonly contacted gastrin cells. Peptide YY (PYY) cells were rare and mainly in the antrum. The only numerous colocalisations were 5-HT and histamine, PYY and gastrin and gastrin and histamine in the antrum, but each of these populations was small. Peptide-containing nerve fibres were found in the mucosa. One of the most common types was vasoactive intestinal peptide (VIP) fibres. High-resolution analysis showed that ghrelin cells were closely and selectively approached by VIP fibres. In contrast, gastrin cells were not selectively innervated by VIP or CGRP fibres. The study indicates that there are distinct populations of gastric EEC and selective innervation of ghrelin cells. It also shows that, in contrast to EEC of the small intestine, the majority of EEC within the stomach contained only a single hormone.


Assuntos
Células Enteroendócrinas , Mucosa Gástrica , Hormônios Gastrointestinais/metabolismo , Neuropeptídeos/metabolismo , Hormônios Peptídicos/metabolismo , Animais , Sistema Nervoso Entérico/citologia , Células Enteroendócrinas/citologia , Células Enteroendócrinas/metabolismo , Mucosa Gástrica/citologia , Mucosa Gástrica/inervação , Mucosa Gástrica/metabolismo , Histamina/metabolismo , Ratos , Ratos Sprague-Dawley
15.
Chem Biol Interact ; 308: 304-311, 2019 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-31132327

RESUMO

Polymyxin B (PMB) and polymyxin E (PME) are cyclic, peptide antibiotics which derived from various species of Paenibacillus (Bacillus) polymyxa. They are decapeptide antibiotics with an antimicrobial spectrum that includes Gram-negative bacteria, and reused as therapeutic agents due to the emergence of multidrug-resistant (MDR) Gram-positive bacteria. PMB or PME-induced anaphylactoid reactions in the clinic have been documented. However, the mechanism underlying anaphylactoid reaction induced by polymyxin has not yet been reported. Here, we report that human Mas-related G protein-coupled receptor X2 (MRGPRX2) and its mouse homologue Mas-related G protein-coupled receptor B2 (MrgprB2) are the receptors mediating the anaphylactoid response provoked by PMB and PME. We firstly investigated the anaphylactoid reactions induced by PMB and PME in LAD2 cells in vitro and in vivo, and found that treatment with PMB and PME led to significant release of mast cell granules such as histamine and ß-hexosaminidase, secretion of pro-inflammatory cytokines, such as TNF-α and PGD2, and provocation of calcium flux in LAD2 cells. Furthermore, treatment with PMB and PME led to reduced release of ß-hexosaminidase in MRGPRX2 knockdown-LAD2 cells, and obvious increased calcium release in MRGPRX2 overexpressing HEK293 cells, which suggested that MRGPRX2 are involved in mast cell activation provoked by PMB or PME. In vivo, MRGPRB2 knockout mice exhibited lower pseudo-allergic reactions than wild type mice. Activation of MrgprB2 also triggers increased capillary permeability and paw swelling. Our results elucidated the role of MRGPRX2 in PMB and PME-induced anaphylactoid response and suggested that MRGPRX2 as a potential therapeutic target to control the anaphylactoid reactions which triggered by PMB or PME.


Assuntos
Anafilaxia/etiologia , Colistina/toxicidade , Polimixina B/toxicidade , Receptores Acoplados a Proteínas-G/metabolismo , Animais , Cálcio/metabolismo , Degranulação Celular/efeitos dos fármacos , Linhagem Celular , Células HEK293 , Histamina/metabolismo , Humanos , Mastócitos/citologia , Mastócitos/efeitos dos fármacos , Mastócitos/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Interferência de RNA , RNA Interferente Pequeno/metabolismo , Receptores Acoplados a Proteínas-G/antagonistas & inibidores , Receptores Acoplados a Proteínas-G/genética
16.
Neuroscience ; 410: 55-58, 2019 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-31047975

RESUMO

Acute cutaneous exposure to allergen often leads to itch, but seldom pain. The effect of mast cell activation on cutaneous C-fibers was studied using innervated isolated mouse skin preparation that allows for intra-arterial delivery of chemicals to the nerve terminals in the skin. Allergen (ovalbumin) injection into the isolated skin of actively sensitized mice strongly stimulated chloroquine (CQ)-sensitive C-fibers (also referred to as "itch" nerves); on the other hand, CQ-insensitive C-fibers were activated only modestly, if at all. The histamine H1 receptor antagonist pyrilamine abolished itch C-fibers response to histamine, but failed to significantly reduce the response to ovalbumin. Ovalbumin also strongly activated itch C-fibers in skin isolated from Mrgpr-cluster Δ-/- mice. When pyrilamine was studied in the Mrgpr-cluster Δ-/- mice thereby eliminating the influence of both histamine H1 and Mrgpr receptors (MrgprA3 and C11 are selectively expressed by itch nerves), the ovalbumin response was very nearly eliminated. The data indicate that the acute activation of itch C-fibers in mouse skin is largely secondary to the combined effect of activation of histamine H1 and Mrpgr receptors.


Assuntos
Alérgenos/toxicidade , Histamina/metabolismo , Terminações Nervosas/metabolismo , Fibras Nervosas Amielínicas/metabolismo , Prurido/metabolismo , Pele/metabolismo , Animais , Antagonistas dos Receptores Histamínicos H1/farmacologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Terminações Nervosas/efeitos dos fármacos , Fibras Nervosas Amielínicas/efeitos dos fármacos , Técnicas de Cultura de Órgãos , Prurido/induzido quimicamente , Pele/efeitos dos fármacos , Pele/inervação
17.
J Sep Sci ; 42(14): 2351-2359, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31050150

RESUMO

Saposhnikoviae Radix, the dried root of Saposhnikoviae divaricata, is commonly used in the traditional Chinese anti-allergic preparations, like Bofutsusho-san and Yupingfeng granules. A high-expression Mas-related G protein-coupled receptor X2 cell membrane chromatography coupled online with high-performance liquid chromatography combined with an ion trap time-of-flight multistage mass spectrometry system was established and used for screening and identifying the anti-allergic components in Saposhnikoviae Radix. The system was validated for excellent specificity and suitability using the appropriate standards. Two retained fractions were obtained on the cell membrane chromatography column, and three main components were identified as prim-O-glucosylcimifugin, cimifugin, and 4'-O-ß-d-glucosyl-5-O-methylvisamminol. Next, the molecular docking study was conducted, which confirmed that these three components could effectively bind to MRGPRX2 through hydrogen bonds with its amino acid residues. Finally, histamine release assay was performed to investigate the bioactivities of prim-O-glucosylcimifugin, cimifugin, and 4'-O-ß-d-glucosyl-5-O-methylvisamminol. Results showed that these three components could exert anti-allergic effects by inhibiting the histamine release in a dose-dependent manner (from 10 to 100 µM). In conclusion, the high-expression Mas-related G protein-coupled receptor X2 cell membrane chromatography is an effective tool for discovering the anti-allergic components in Saposhnikoviae Radix.


Assuntos
Antialérgicos/análise , Apiaceae/química , Membrana Celular/química , Avaliação Pré-Clínica de Medicamentos , Proteínas do Tecido Nervoso/química , Receptores Acoplados a Proteínas-G/química , Receptores de Neuropeptídeos/química , Antialérgicos/farmacologia , Cromatografia Líquida de Alta Pressão , Relação Dose-Resposta a Droga , Composição de Medicamentos , Histamina/metabolismo , Humanos , Espectrometria de Massas , Simulação de Acoplamento Molecular
18.
Mol Immunol ; 111: 118-127, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31051313

RESUMO

Phenothiazines are a class of antipsychotics that share the same tricyclic structure and are widely used in clinical settings. Adverse reactions from these drugs, however, have been regularly reported, with allergic skin reactions noted in some cases. Nevertheless, the mechanisms underlying anaphylaxis by these drugs have not been described. In the present study, we found that phenothiazine antipsychotics increased calcium mobilization and activated mast cells to release ß-hexosaminidase, histamine, and tumor necrosis factor-α via Mas-related G-protein-coupled receptor member X2 (MRGPRX2) in vitro. In addition, they induced histamine release in serum via Mrgprb2 in C57BL/6 mice without Evans blue extravasation or paw swell. Further experiments indicated these drugs had good interaction with the histamine H1 receptor (H1R) and show an anti-calcium mobilization effect on H1R-HEK293 cells, which confirmed a potential antagonist effect of these drugs on the H1R. The molecular docking and activity experiments indicated that the N-methyl substitution on the side chain of these drugs played a significant role in activating MRGPRX2, while the phenothiazine tricyclic ring was associated with the inhibiting effect on the H1R. Therefore, due to their dual properties of increasing histamine levels without obvious allergic symptoms, clinicians should be highly vigilant for damage from histamine accumulation and long-term inflammatory reactions during the clinical use of phenothiazine antipsychotics.


Assuntos
Antipsicóticos/efeitos adversos , Hipersensibilidade/imunologia , Fenotiazinas/efeitos adversos , Receptores Acoplados a Proteínas-G/imunologia , Receptores Histamínicos H1/imunologia , Anafilaxia/imunologia , Animais , Linhagem Celular , Células HEK293 , Histamina/metabolismo , Liberação de Histamina/efeitos dos fármacos , Liberação de Histamina/imunologia , Humanos , Masculino , Mastócitos/efeitos dos fármacos , Mastócitos/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Simulação de Acoplamento Molecular
19.
Int J Mol Sci ; 20(10)2019 May 17.
Artigo em Inglês | MEDLINE | ID: mdl-31108898

RESUMO

BACKGROUND: Studies on the regulation of gastric and pancreatic secretion began more than 100 years ago. Secretin was the first hormone postulated to exist, initiating the field of endocrinology. Gastrin produced in the antral mucosa was the second postulated hormone, and together with histamine and acetylcholine, represent the three major gastric acid secretagogues known since 1920. For a long time, the mast cell was the only recognized histamine-producing cell in the oxyntic mucosa and, in the mid-1980s, the ECL cell was recognized as the cell producing histamine, taking part in the regulation of gastric acid secretion. METHODS: This review is based upon literature research and personal knowledge. RESULTS: The ECL cell carries the gastrin receptor, and gastrin regulates its function (histamine release) as well as proliferation. Long-term hypergastrinemia results in gastric neoplasia of variable malignancies, implying that gastric hypoacidity resulting in increased gastrin release will induce gastric neoplasia, including gastric cancer. CONCLUSIONS: The trophic effect of gastrin on the ECL cell has implications to the treatment with inhibitors of acid secretion.


Assuntos
Celulas Tipo Enterocromafim/metabolismo , Mucosa Gástrica/metabolismo , Gastrinas/metabolismo , Acetilcolina/metabolismo , Animais , Celulas Tipo Enterocromafim/patologia , Mucosa Gástrica/patologia , Histamina/metabolismo , Humanos , Receptor de Colecistocinina B/metabolismo
20.
Int J Mol Sci ; 20(7)2019 Apr 08.
Artigo em Inglês | MEDLINE | ID: mdl-30965592

RESUMO

Mast cells play a critical role in the pathogenesis of allergic asthma. Histamine is a central mediator released from mast cells through allergic reactions. Histamine plays a role in airway obstruction via smooth muscle contraction, bronchial secretion, and airway mucosal edema. However, previous clinical trials of H1 receptor antagonists (H1RAs) as a treatment for asthma were not successful. In recent years, type 2 innate immunity has been demonstrated to be involved in allergic airway inflammation. Allergic asthma is defined by IgE antibody-mediated mast cell degranulation, while group 2 innate lymphoid cells (ILC2) induce eosinophilic inflammation in nonallergic asthma without allergen-specific IgE. Anti-IgE therapy has demonstrated prominent efficacy in the treatment of severe allergic asthmatics sensitized with specific perennial allergens. Furthermore, recent trials of specific cytokine antagonists indicated that these antagonists were effective in only some subtypes of asthma. Accordingly, H1RAs may show significant clinical efficacy for some subtypes of allergic asthma in which histamine is deeply associated with the pathophysiology.


Assuntos
Asma/metabolismo , Asma/fisiopatologia , Histamina/metabolismo , Animais , Antagonistas dos Receptores Histamínicos/uso terapêutico , Antagonistas dos Receptores Histamínicos H1/uso terapêutico , Humanos , Hipersensibilidade/tratamento farmacológico , Hipersensibilidade/imunologia , Hipersensibilidade/metabolismo , Linfócitos/efeitos dos fármacos , Linfócitos/imunologia , Linfócitos/metabolismo , Mastócitos/efeitos dos fármacos , Mastócitos/metabolismo
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