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1.
Food Chem ; 368: 130852, 2022 Jan 30.
Artigo em Inglês | MEDLINE | ID: mdl-34419792

RESUMO

In this work, we demonstrate a novel solid-state electrochemiluminescence (ECL) sensor based on the Ru(bpy)32+@terbium-guanosine monophosphate infinite coordination polymer network ((Ru(bpy)32+@Tb-GMP ICPn). Comparing with the traditional luminescence of Ru(bpy)32+ observed in a liquid system, the proposed method of encapsulating Ru(bpy)32+ into ICPn for immobilization greatly improves the ECL signal and efficiency, which is attributed to the unique porous structure and large specific surface area of ICPn. Moreover, the solid-state Ru(bpy)32+ ECL sensor has good biocompatibility and low toxicity. Taking histamine (HA) as a detection model, a good linear relationship between ECL intensity and logarithm of HA concentration was obtained with a low detection limit of 17 nM, and satisfactory results were obtained for detecting HA levels in fish samples as well. The proposed solid-state Ru(bpy)32+ ECL sensor has great application prospects in the safety of food.


Assuntos
Medições Luminescentes , Polímeros , Animais , Técnicas Eletroquímicas , Produtos Pesqueiros , Histamina , Luminescência
2.
Talanta ; 237: 122913, 2022 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-34736650

RESUMO

Sensitivity and credibility detecting histamine (HA) as an important neurotransmitter in biofluids is of importance in analytical science and physiology. Surface-enhanced Raman spectroscopy (SERS) is able to realize the high sensitivity with single molecules level, but providing the high sensitivity for HA with a small cross section remains a challenge. Here we develop the metal complex-based SERS nanoprobe nitrilotriacetic acid-Ni2+ (NTA-Ni2+) combined with self-assemble Au NPs active substrates for sensitive detection of HA. The NTA-Ni2+ can capture the HA molecules close to Au NPs substrates and then amplify the Raman signals of HA owing to the formation of a complex of NTA-Ni2+-HA. The self-assemble Au film through the evaporation-driven method can provide the high-density hot spots substrate with high stability and reproducibility. The NTA-Ni2+ decorated Au NPs as nanoprobe responds to HA with 1 µM level of sensitivity. More importantly, the developed SERS nanoprobe composing of NTA-Ni2+ and self-assemble Au NPs can be utilized to detect and monitor the HA spiked into serum, indicating the potential prospect in analysis of HA in complex specimen.


Assuntos
Ouro , Nanopartículas Metálicas , Histamina , Nanotecnologia , Reprodutibilidade dos Testes , Análise Espectral Raman
3.
Food Chem ; 369: 130971, 2022 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-34488130

RESUMO

A highly sensitive molecularly imprinted surface-enhanced Raman scattering (SERS) sensor was developed for selective detection of histamine. A combination of two semiconductors and Ag nanoparticles (NPs) was used as the SERS substrate. The SERS was induced by Ag NPs plasmon resonances as well as charge-transfer between the semiconductors and the Ag NPs. The Raman intensity and the logarithm of the histamine concentration were linear over the range 10-8-10-3 mol L-1. The sensor exhibited good selectivity and had a sensitivity limit of 3.088 × 10-9 mol L-1. Histamine was detected in a spiked liquor sample, and its recoveries were in the range of 89.89%-109.18%.


Assuntos
Nanopartículas Metálicas , Análise Espectral Raman , Histamina , Semicondutores , Prata
4.
Acta Derm Venereol ; 101(11): adv00587, 2021 Nov 10.
Artigo em Inglês | MEDLINE | ID: mdl-34724070

RESUMO

Sensitive skin is a prevalent syndrome, characterized by discomfort in response to mild stimuli, which impacts on quality of life. Pruritus is one of the major symptoms of sensitive skin. However, the pathomechanism of sensitive skin is insufficiently understood. As an experimental model for pruritus, the cowhage skin prick test might provide insight into the understanding of sensitive skin. This study aimed to specify the characteristics of cowhage-induced pruritus in sensitive skin. Female volunteers, 20 with sensitive skin and 20 controls, were recruited. Self-report questionnaires were distributed and the responses evaluated; moreover, alongside assessments by dermatologists, skin physiology assessments, lactic acid sting test, capsaicin test and cowhage skin challenge were performed. Pruritus in sensitive skin was perceived as more intense and longer-lasting than in normal skin, with different qualities of accompanying sensations. Cowhage skin challenge results showed moderate consistency with clinical assessments. The results suggest that cowhage skin challenge could be a new tool for the assessment of sensitive skin.


Assuntos
Laboratórios , Mucuna , Histamina , Humanos , Prurido/diagnóstico , Qualidade de Vida , Pele
6.
Artigo em Inglês | MEDLINE | ID: mdl-34639461

RESUMO

Biogenic amines (BAs) are natural contaminants of wine that originate from decarboxylase microorganisms involved in fermentation processes. The primary relevance of biogenic amines in food could have both toxic effects on consumers' health (i.e., allergic reactions, nausea, tremors, etc.), if present at high concentrations, and concurrently it can be considered as a remarkable indicator of quality and/or freshness. Therefore, the presence of nine biogenic amines [Tryptamine (TRP), ß-phenylethylamine (ß-PEA), putrescine (PUT), cadaverine (CAD), histamine (HIS), serotonin (SER), tyramine (TYR), spermidine (SPD), and spermine (SPM)] was investigated in red and white wine samples, which differed in the winemaking processes. The qualitative-quantitative determination of BAs was carried out by chromatographic methods (HPLC-UV/Vis and LC-ESI-MS). The analysis showed that both winemaking processes had all the nine BAs considered in the study at different amounts. Data showed that red wines had a higher concentration of PUT (10.52 mg L-1), TYR (7.57 mg L-1), and HIS (6.5 mg L-1), the BAs most involved in food poisoning, compared to white wines, probably related to the different type of fermentation (alcoholic and malolactic).


Assuntos
Vinho , Aminas Biogênicas , Cadaverina/análise , Histamina/análise , Putrescina/análise , Vinho/análise
7.
Sensors (Basel) ; 21(19)2021 Oct 07.
Artigo em Inglês | MEDLINE | ID: mdl-34640978

RESUMO

Solid-contact ion-selective electrodes for histamine (HA) determination were fabricated and studied. Gold wire (0.5 mm diameter) was coated with poly(3,4-ethlenedioxythiophene) doped with poly(styrenesulfonate) (PEDOT:PSS) as a solid conductive layer. The polyvinyl chloride matrix embedded with 5,10,15,20-tetraphenyl(porphyrinato)iron(iii) chloride as an ionophore, 2-nitrophenyloctyl ether as a plasticizer and potassium tetrakis(p-chlorophenyl) borate as an ion exchanger was used to cover the PEDOT:PSS layer as a selective membrane. The characteristics of the HA electrodes were also investigated. The detection limit of 8.58 × 10-6 M, the fast response time of less than 5 s, the good reproducibility, the long-term stability and the selectivity in the presence of common interferences in biological fluids were satisfactory. The electrode also performed stably in the pH range of 7-8 and the temperature range of 35-41 °C. Additionally, the recovery rate of 99.7% in artificial cerebrospinal fluid showed the potential for the electrode to be used in biological applications.


Assuntos
Histamina , Eletrodos Íon-Seletivos , Compostos Férricos , Ionóforos , Reprodutibilidade dos Testes
8.
Sheng Li Xue Bao ; 73(5): 821-827, 2021 Oct 25.
Artigo em Chinês | MEDLINE | ID: mdl-34708239

RESUMO

ß3-adrenergic agonists induce adaptive thermogenesis and promote beiging of white fat. However, it remains unclear which metabolites mediate the stimulatory effects of ß3-adrenergic agonists on thermogenesis of brown and beige fat. In this study, adipose tissue was isolated from 8-week-old C57/BL6J male mice by intraperitoneal administration of ß3-adrenergic agonist CL316,243 for RNA-Seq, which revealed that histidine decarboxylase, a key enzyme in histamine synthesis, was strongly induced in adipose by CL316,243. Therefore, we speculated that histamine might be involved in the process of thermogenesis in adipose tissue. We determined the physiological role and mechanism by which histamine promotes fat thermogenesis by intravenous administering histamine to C57BL/6J mice fed a normal or a high-fat diet. The results showed that intravenous injection of histamine into C57BL/6J mice fed a normal diet stimulated the expression of thermogenic genes, including peroxisome proliferator-activated receptor gamma coactivator-1α (PGC-1α) and uncoupling protein 1 (UCP1), in brown adipose tissue (BAT) and inguinal white adipose tissue (iWAT). H&E staining also suggested that histamine treatment decreased the size of lipid droplets in adipocytes. Moreover, histamine treatment also enhanced thermogenesis of fat in high-fat diet induced obese mice, and improved glucose intolerance and fatty liver phenotype. Finally, we demonstrated that the effects of histamine on the thermogenic program were cell autonomous. Our data suggest that histamine may mediate the effects of ß3-adrenergic agonists on thermogenesis of fat.


Assuntos
Tecido Adiposo Bege , Histamina , Tecido Adiposo Marrom , Animais , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Termogênese , Proteína Desacopladora 1/genética
9.
Nutrients ; 13(10)2021 Sep 29.
Artigo em Inglês | MEDLINE | ID: mdl-34684460

RESUMO

There is an ongoing need for new therapeutic modalities against SARS-CoV-2 infection. Mast cell histamine has been implicated in the pathophysiology of COVID-19 as a regulator of proinflammatory, fibrotic, and thrombogenic processes. Consequently, mast cell histamine and its receptors represent promising pharmacological targets. At the same time, nutritional modulation of immune system function has been proposed and is being investigated for the prevention of COVID-19 or as an adjunctive strategy combined with conventional therapy. Several studies indicate that several immunonutrients can regulate mast cell activity to reduce the de novo synthesis and/or release of histamine and other mediators that are considered to mediate, at least in part, the complex pathophysiology present in COVID-19. This review summarizes the effects on mast cell histamine of common immunonutrients that have been investigated for use in COVID-19.


Assuntos
COVID-19/imunologia , Histamina/imunologia , Sistema Imunitário/imunologia , Mastócitos/imunologia , Fenômenos Fisiológicos da Nutrição/imunologia , Transdução de Sinais/imunologia , Humanos , SARS-CoV-2
10.
Molecules ; 26(20)2021 Oct 13.
Artigo em Inglês | MEDLINE | ID: mdl-34684752

RESUMO

Biogenic amines (BAs) and nitrites are both considered harmful compounds for customer health, and are closely correlated with the microorganisms in fermented mustard (FM). In this study, BAs and nitrite contents in fifteen FM samples from different brands were analyzed. The concentrations of cadaverine in one sample and of histamine in one sample were above the toxic level. Moreover, five FM samples contained a high level of nitrite, exceeding the maximum residue limit (20 mg/kg) suggested by the National Food Safety Standard. Then, this study investigated bacterial and fungal communities by high-throughput sequencing analysis. Firmicutes and Basidiomycota were identified as the major bacteria and fungi phylum, respectively. The correlations among microorganisms, BAs and nitrite were analyzed. Typtamine showed a positive correlation with Lactobacillus and Pseudomonas. Cadaverine and nitrite is positively correlated with Leuconostoc. Furthermore, thirteen strains were selected from the samples to evaluate the accumulation and degradation properties of their BAs and nitrite. The results indicated that the Lactobacillus isolates, including L. plantarum GZ-2 and L. brevis SC-2, can significantly reduce BAs and nitrite in FM model experiments. This study not only assessed the contents of BAs and nitrite in FM samples, but also provided potential starter cultures for BAs and nitrite control in the FM products industry.


Assuntos
Aminas Biogênicas/análise , Mostardeira/metabolismo , Mostardeira/microbiologia , Nitritos/análise , Bactérias/metabolismo , Aminas Biogênicas/química , Reatores Biológicos , Cadaverina/toxicidade , China , Fermentação , Alimentos e Bebidas Fermentados/análise , Fungos/metabolismo , Histamina/toxicidade , Lactobacillus/metabolismo , Microbiota/fisiologia , Mostardeira/química , Nitritos/química
11.
J Chromatogr A ; 1659: 462629, 2021 Dec 06.
Artigo em Inglês | MEDLINE | ID: mdl-34700182

RESUMO

Biogenic amines are quality control criteria for foods that are potentially toxic to humans. In this study, amidation derivatization for biogenic amines and liquid-solid phase transition microextraction were carried out simultaneously for food sample pretreatment. The derivatization reaction was executed in one pot with coumarin-3-carboxylic acid as the derivatizing reagent and (1-cyano-2-ethoxy-2-oxoethylidenaminooxy)dimethylamino-morpholino-carbenium hexafluorophosphate as the coupling agent. Liquid-solid phase transition microextraction was achieved by the salting-out effect, using a phase change salt (1 M disodium hydrogen phosphate) solution. The combined derivatization and microextraction process was completed within 3 min at 30 °C, and the liquid top phase was easily obtained by placing the tube in an ice bath. Finally, a narrowbore liquid chromatograph coupled with a UV detector was used to determine the levels of six biogenic amines. The coupling agent-assisted derivatization and liquid-solid phase transition microextraction parameters were also investigated. The quantitative linear ranges were 3-400 µM for histamine, putrescine, spermidine, cadaverine, and tyramine and 5-400 µM for spermine, and the detection limit was 1 µM. The relative standard deviations of the intra- and inter-batches were <5.3% and 8.4%, respectively, while the relative error was <4.5% for both. We successfully applied this simultaneous derivatization-microextraction method to determine the biogenic amines in fermented foods.


Assuntos
Aminas Biogênicas , Microextração em Fase Líquida , Aminas Biogênicas/análise , Cromatografia Líquida de Alta Pressão , Cromatografia Líquida , Histamina , Humanos , Microextração em Fase Sólida
12.
Prog Brain Res ; 266: 1-73, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34689857

RESUMO

Military personnel deployed in combat operations are highly prone to develop Parkinson's disease (PD) in later lives. PD largely involves dopaminergic pathways with hallmarks of increased alpha synuclein (ASNC), and phosphorylated tau (p-tau) in the cerebrospinal fluid (CSF) precipitating brain pathology. However, increased histaminergic nerve fibers in substantia nigra pars Compacta (SNpc), striatum (STr) and caudate putamen (CP) associated with upregulation of Histamine H3 receptors and downregulation of H4 receptors in human cases of PD is observed in postmortem cases. These findings indicate that modulation of histamine H3 and H4 receptors and/or histaminergic transmission may induce neuroprotection in PD induced brain pathology. In this review effects of a potent histaminergic H3 receptor inverse agonist BF-2549 or clobenpropit (CLBPT) partial histamine H4 agonist with H3 receptor antagonist, in association with monoclonal anti-histamine antibodies (AHmAb) in PD brain pathology is discussed based on our own observations. Our investigation shows that chronic administration of conventional or TiO2 nanowired BF 2649 (1mg/kg, i.p.) or CLBPT (1mg/kg, i.p.) once daily for 1 week together with nanowired delivery of HAmAb (25µL) significantly thwarted ASNC and p-tau levels in the SNpC and STr and reduced PD induced brain pathology. These observations are the first to show the involvement of histamine receptors in PD and opens new avenues for the development of novel drug strategies in clinical strategies for PD, not reported earlier.


Assuntos
Fármacos Neuroprotetores , Doença de Parkinson , Corpo Estriado , Histamina , Humanos , Imidazóis , Fármacos Neuroprotetores/farmacologia , Doença de Parkinson/tratamento farmacológico , Receptores Histamínicos H4 , Tioureia/análogos & derivados
13.
Nihon Yakurigaku Zasshi ; 156(5): 292-296, 2021.
Artigo em Japonês | MEDLINE | ID: mdl-34470934

RESUMO

Histamine is a biological amine that functions as a neurotransmitter in the brain to regulate arousal, appetite, and cognitive functions. Many pharmacological studies using histamine receptor agonists and antagonists have found that histamine promotes memory consolidation and retrieval. More recently, we have revealed that the activation of the brain histaminergic system by H3R antagonists/inverse agonists restores retrieval of forgotten long-term memory in mice and humans. The recovery of memory retrieval may involve histamine-induced excitatory effects. Histamine may increase neuronal excitability throughout the neural circuit, including both neurons that are and are not recruited into the memory trace, similar to noise added to the neural circuits for memory retrieval. Stochastic resonance can explain how adding noise to the circuit enhances memory retrieval. Memory is processed not only by consolidation and retrieval, but also by various processes such as maintenance, reconsolidation, extinction, and reinstatement. Further studies that separately analyze the memory processes are needed to elucidate the whole picture of the effects of histamine on learning and memory. Regarding the human histaminergic system, alterations in histamine signaling have been reported in several neuropsychiatric disorders, and these changes have been suggested to be involved in cognitive dysfunction in patients with the neuropsychiatric disorders. Therefore, the drugs that modulate histamine signaling, including H3R antagonists/inverse agonists, may be effective in the treatment of cognitive dysfunction, including Alzheimer's disease.


Assuntos
Histamina , Transtornos da Memória , Animais , Encéfalo , Humanos , Aprendizagem , Memória , Camundongos
14.
J Biotechnol ; 340: 39-46, 2021 Nov 10.
Artigo em Inglês | MEDLINE | ID: mdl-34474093

RESUMO

A putative diamine oxidase (DAO) from Yarrowia lipolytica PO1f (DAO-1) was homologously recombinantly integrated into the genome of Y. lipolytica PO1f using the CRISPR-Cas9 system for the subsequent DAO production in a bioreactor. Thereby, it was proven that the DAO-1 produced was indeed a functional DAO. The cultivation yielded 2343 ± 98 nkat/Lculture with a specific DAO activity of 1301 ± 54.2 nkat/gprotein, which was a 93-fold increase of specific DAO activity compared to the native Y. lipolytica PO1f DAO-1 production. The DAO-1 showed a broad substrate selectivity with tyramine, histamine, putrescine and cadaverine being the most favored substrates. It was most active at 40 °C, pH 7.2 in Tris-HCl buffer (50 mM) (with histamine as substrate), which is comparable to human and porcine DAOs. The affinity of DAO-1 towards histamine was lower compared to mammalian DAOs (Km = 2.3 ± 0.2 mM). Nevertheless, DAO-1 degraded around 75% of the histamine used in a bioconversion experiment with a food-relevant concentration of 150 mg/L. With its broad selectivity for the most relevant biogenic amines in foods, DAO-1 from Y. lipolytica PO1f is an interesting enzyme for application in the food industry for the degradation of biogenic amines.


Assuntos
Amina Oxidase (contendo Cobre) , Yarrowia , Amina Oxidase (contendo Cobre)/genética , Animais , Cadaverina , Histamina , Humanos , Putrescina , Suínos , Yarrowia/genética
15.
J Environ Pathol Toxicol Oncol ; 40(3): 63-73, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34587405

RESUMO

Allergic rhinitis (AR) is a common type of inflammatory disease with symptoms including rhinorrhea, fatigue, sneezing, and disturbed sleep. AR affects nearly 40% of peoples worldwide with the increased numbers of new cases. In this work, the study was conducted to disclose the anti-inflammatory and antiallergic properties of cirsilineol against the ovalbumin (OVA)-sensitized AR in mice. AR was provoked in BALB/c mice through the OVA challenge 30 days along with 10 and 20 mg/kg of cirsilineol treatment. The nasal symptoms, i.e., rubbing and sneezing was monitored after the final OVA challenge. The status of OVA-specific IgE, PGD2, and LTC4 was investigated using assay kits. The status of pro-inflammatory markers also examined using assay kits. The levels of oxidative markers, SOD activity, and pro-inflammatory markers in the spleen mononuclear cells (SMEs) were studied by using respective assay kits. The mRNA expression of TXNIP was assessed using RT-PCR study. The 10 and 20 mg/kg of cirsilineol treatment effectively decreased the sneezing and nasal rubbings in OVA-provoked mice. Cirsilineol also decreased the IgE, PGD2, and LTC4 status in the AR animals. The status of pro-inflammatory markers, i.e., IL-4, IL-5, IL-6, IL-33 and TNF-α was found to be decreased in the cirsilineol administered AR mice. Cirsilineol effectively reduced the ROS and MDA and improved SOD in the OVA-challenged SMCs. The mRNA expression of TXNIP was appreciably suppressed by the cirsilineol treatment. Altogether, these findings proved the beneficial actions of cirsilineol against the OVA-triggered AR in mice. The additional studies on the cirsilineol could lead to the development of new drug for AR management.


Assuntos
Antialérgicos/farmacologia , Flavonas/farmacologia , Rinite Alérgica/prevenção & controle , Animais , Biomarcadores/metabolismo , Proteínas de Transporte/genética , Células Cultivadas , Modelos Animais de Doenças , Eosinófilos/efeitos dos fármacos , Histamina/sangue , Imunoglobulina E/sangue , Imunoglobulina E/metabolismo , Leucotrieno C4/metabolismo , Camundongos Endogâmicos BALB C , Líquido da Lavagem Nasal , Ovalbumina/toxicidade , Estresse Oxidativo/efeitos dos fármacos , Prostaglandina D2/metabolismo , Rinite Alérgica/induzido quimicamente , Rinite Alérgica/imunologia , Baço/citologia , Tiorredoxinas/genética
16.
BMC Genomics ; 22(1): 695, 2021 Sep 26.
Artigo em Inglês | MEDLINE | ID: mdl-34563136

RESUMO

BACKGROUND: Biogenic histamine plays an important role in immune response, neurotransmission, and allergic response. Although endogenous histamine production has been extensively studied, the contributions of histamine produced by the human gut microbiota have not been explored due to the absence of a systematic annotation of histamine-secreting bacteria. RESULTS: To identify the histamine-secreting bacteria from in the human gut microbiome, we conducted a systematic search for putative histamine-secreting bacteria in 36,554 genomes from the Genome Taxonomy Database and Unified Human Gastrointestinal Genome catalog. Using bioinformatic approaches, we identified 117 putative histamine-secreting bacteria species. A new three-component decarboxylation system including two colocalized decarboxylases and one transporter was observed in histamine-secreting bacteria among three different phyla. We found significant enrichment of histamine-secreting bacteria in patients with inflammatory bowel disease but not in patients with colorectal cancer suggesting a possible association between histamine-secreting bacteria and inflammatory bowel disease. CONCLUSIONS: The findings of this study expand our knowledge of the taxonomic distribution of putative histamine-secreting bacteria in the human gut.


Assuntos
Microbioma Gastrointestinal , Microbiota , Bactérias/genética , Bactérias/metabolismo , Transporte Biológico , Histamina , Humanos
17.
Sci Rep ; 11(1): 17935, 2021 09 09.
Artigo em Inglês | MEDLINE | ID: mdl-34504120

RESUMO

Designer receptor activated by designer drugs (DREADDs) techniques are widely used to modulate the activities of specific neuronal populations during behavioural tasks. However, DREADDs-induced modulation of histaminergic neurons in the tuberomamillary nucleus (HATMN neurons) has produced inconsistent effects on the sleep-wake cycle, possibly due to the use of Hdc-Cre mice driving Cre recombinase and DREADDs activity outside the targeted region. Moreover, previous DREADDs studies have not examined locomotor activity and aggressive behaviours, which are also regulated by brain histamine levels. In the present study, we investigated the effects of HATMN activation and inhibition on the locomotor activity, aggressive behaviours and sleep-wake cycle of Hdc-Cre mice with minimal non-target expression of Cre-recombinase. Chemoactivation of HATMN moderately enhanced locomotor activity in a novel open field. Activation of HATMN neurons significantly enhanced aggressive behaviour in the resident-intruder test. Wakefulness was increased and non-rapid eye movement (NREM) sleep decreased for an hour by HATMN chemoactivation. Conversely HATMN chemoinhibition decreased wakefulness and increased NREM sleep for 6 h. These changes in wakefulness induced by HATMN modulation were related to the maintenance of vigilance state. These results indicate the influences of HATMN neurons on exploratory activity, territorial aggression, and wake maintenance.


Assuntos
Agressão/efeitos dos fármacos , Antipsicóticos/administração & dosagem , Clozapina/análogos & derivados , Vetores Genéticos/administração & dosagem , Histamina/metabolismo , Região Hipotalâmica Lateral/metabolismo , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Vigília/efeitos dos fármacos , Vigília/genética , Animais , Comportamento Animal/efeitos dos fármacos , Clozapina/administração & dosagem , Locomoção/efeitos dos fármacos , Locomoção/genética , Masculino , Camundongos , Camundongos Transgênicos , Sono de Ondas Lentas/efeitos dos fármacos , Sono de Ondas Lentas/genética
18.
Int J Mol Sci ; 22(18)2021 Sep 17.
Artigo em Inglês | MEDLINE | ID: mdl-34576210

RESUMO

G protein-coupled receptors (GPCRs) are targets of extracellular stimuli and hence occupy a key position in drug discovery. By specific and not yet fully elucidated coupling profiles with α subunits of distinct G protein families, they regulate cellular responses. The histamine H2 and H4 receptors (H2R and H4R) are prominent members of Gs- and Gi-coupled GPCRs. Nevertheless, promiscuous G protein and selective Gi signaling have been reported for the H2R and H4R, respectively, the molecular mechanism of which remained unclear. Using a combination of cellular experimental assays and Gaussian accelerated molecular dynamics (GaMD) simulations, we investigated the coupling profiles of the H2R and H4R to engineered mini-G proteins (mG). We obtained coupling profiles of the mGs, mGsi, or mGsq proteins to the H2R and H4R from the mini-G protein recruitment assays using HEK293T cells. Compared to H2R-mGs expressing cells, histamine responses were weaker (pEC50, Emax) for H2R-mGsi and -mGsq. By contrast, the H4R selectively bound to mGsi. Similarly, in all-atom GaMD simulations, we observed a preferential binding of H2R to mGs and H4R to mGsi revealed by the structural flexibility and free energy landscapes of the complexes. Although the mG α5 helices were consistently located within the HR binding cavity, alternative binding orientations were detected in the complexes. Due to the specific residue interactions, all mG α5 helices of the H2R complexes adopted the Gs-like orientation toward the receptor transmembrane (TM) 6 domain, whereas in H4R complexes, only mGsi was in the Gi-like orientation toward TM2, which was in agreement with Gs- and Gi-coupled GPCRs structures resolved by X-ray/cryo-EM. These cellular and molecular insights support (patho)physiological profiles of the histamine receptors, especially the hitherto little studied H2R function in the brain, as well as of the pharmacological potential of H4R selective drugs.


Assuntos
Proteínas de Ligação ao GTP/química , Ligantes , Simulação de Dinâmica Molecular , Engenharia de Proteínas/métodos , Receptores Histamínicos/química , Simulação por Computador , Microscopia Crioeletrônica , Sistemas de Liberação de Medicamentos , Células HEK293 , Histamina/química , Humanos , Luciferases/metabolismo , Distribuição Normal , Ligação Proteica , Conformação Proteica , Estrutura Secundária de Proteína , Receptores Histamínicos H2/metabolismo , Receptores Histamínicos H4/metabolismo , Transdução de Sinais , Raios X
19.
Nutrients ; 13(9)2021 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-34579083

RESUMO

Histamine is a natural amine derived from L-histidine. Although it seems that our knowledge about this molecule is wide and diverse, the importance of histamine in many regulatory processes is still enigmatic. The interplay between different types of histamine receptors and the compound may cause ample effects, including histamine intoxication and so-called histamine intolerance or non-allergic food intolerance, leading to disturbances in immune regulation, manifestation of gastroenterological symptoms, and neurological diseases. Most cases of clinical manifestations of histamine intolerance are non-specific due to tissue-specific distribution of different histamine receptors and the lack of reproducible and reliable diagnostic markers. The diagnosis of histamine intolerance is fraught with difficulties, in addition to challenges related to the selection of a proper treatment strategy, the regular course of recovery, and reduced amelioration of chronic symptoms due to inappropriate treatment prescription. Here, we reviewed a history of histamine uptake starting from the current knowledge about its degradation and the prevalence of histamine precursors in daily food, and continuing with the receptor interactions after entering and the impacts on the immune, central nervous, and gastrointestinal systems. The purpose of this review is to build an extraordinarily specific method of histamine cycle assessment in regard to non-allergic intolerance and its possible dire consequences that can be suffered.


Assuntos
Intolerância Alimentar , Gastroenteropatias/metabolismo , Histamina/metabolismo , Regulação da Expressão Gênica , Humanos
20.
Int J Mol Sci ; 22(18)2021 Sep 09.
Artigo em Inglês | MEDLINE | ID: mdl-34575903

RESUMO

G protein activation represents an early key event in the complex GPCR signal transduction process and is usually studied by label-dependent methods targeting specific molecular events. However, the constrained environment of such "invasive" techniques could interfere with biological processes. Although histamine receptors (HRs) represent (evolving) drug targets, their signal transduction is not fully understood. To address this issue, we established a non-invasive dynamic mass redistribution (DMR) assay for the human H1-4Rs expressed in HEK cells, showing excellent signal-to-background ratios above 100 for histamine (HIS) and higher than 24 for inverse agonists with pEC50 values consistent with literature. Taking advantage of the integrative nature of the DMR assay, the involvement of endogenous Gαq/11, Gαs, Gα12/13 and Gßγ proteins was explored, pursuing a two-pronged approach, namely that of classical pharmacology (G protein modulators) and that of molecular biology (Gα knock-out HEK cells). We showed that signal transduction of hH1-4Rs occurred mainly, but not exclusively, via their canonical Gα proteins. For example, in addition to Gαi/o, the Gαq/11 protein was proven to contribute to the DMR response of hH3,4Rs. Moreover, the Gα12/13 was identified to be involved in the hH2R mediated signaling pathway. These results are considered as a basis for future investigations on the (patho)physiological role and the pharmacological potential of H1-4Rs.


Assuntos
Proteínas de Ligação ao GTP/metabolismo , Receptores Histamínicos/metabolismo , Transdução de Sinais , Expressão Gênica , Inativação Gênica , Células HEK293 , Histamina/metabolismo , Humanos , Marcação por Isótopo , Modelos Biológicos , Receptores Acoplados a Proteínas G/genética , Receptores Acoplados a Proteínas G/metabolismo , Receptores Histamínicos/genética
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