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1.
Cell Rep ; 39(11): 110972, 2022 Jun 14.
Artigo em Inglês | MEDLINE | ID: mdl-35705043

RESUMO

The molecular mechanism underlying the functional interaction between H1R and TRPV1 remains unclear. We show here that H1R directly binds to the carboxy-terminal region of TRPV1 at residues 715-725 and 736-749. Cell-penetrating peptides containing these sequences suppress histamine-induced scratching behavior in a cheek injection model. The H1R-TRPV1 binding is kept at a minimum at rest in mouse trigeminal neurons due to TRPV1 SUMOylation and it is enhanced upon histamine treatment through a transient TRPV1 deSUMOylation. The knockin of the SUMOylation-deficient TRPV1K823R mutant in mice leads to constitutive enhancement of H1R-TRPV1 binding, which exacerbates scratching behaviors induced by histamine. Conversely, SENP1 conditional knockout in sensory neurons enhances TRPV1 SUMOylation and suppresses the histamine-induced scratching response. In addition to interfering with binding, TRPV1 SUMOylation promotes H1R degradation through ubiquitination. Our work unveils the molecular mechanism of histaminergic itch by which H1R directly binds to deSUMOylated TRPV1 to facilitate the transduction of the pruritogen signal to the scratching response.


Assuntos
Histamina , Receptores Histamínicos H1 , Animais , Histamina/metabolismo , Camundongos , Prurido/induzido quimicamente , Receptores Histamínicos H1/metabolismo , Células Receptoras Sensoriais/metabolismo , Sumoilação , Canais de Cátion TRPV/genética , Canais de Cátion TRPV/metabolismo
2.
Front Immunol ; 13: 879754, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35711438

RESUMO

Chronic spontaneous urticaria (CSU) is defined as recurrent episodes of spontaneous wheal development and/or angioedema for more than six weeks and at least twice a week. The core link in the pathogenesis of CSU is the activation of mast cells, T cells, eosinophils, and other immune cells infiltrating around the small venules of the lesion. Increased vascular permeability, vasodilatation, and recruitment of inflammatory cells directly depend on mast cell mediators' release. Complex regulatory systems tightly influence the critical roles of mast cells in the local microenvironment. The bias toward Th2 inflammation and autoantibodies derived from B cells, histamine expressed by basophils, and initiation of the extrinsic coagulation pathway by eosinophils or monocytes exerts powerful modulatory influences on mast cells. Cell-to-cell interactions between mast cells and eosinophils/T cells also are regulators of their function and may involve CSU's pathomechanism. This review summarizes up-to-date knowledge regarding the crosstalk between mast cells and other immune cells, providing the impetus to develop new research concepts and treatment strategies for CSU.


Assuntos
Urticária Crônica , Urticária , Basófilos/metabolismo , Histamina/metabolismo , Humanos , Mastócitos
3.
Int J Mol Sci ; 23(10)2022 May 23.
Artigo em Inglês | MEDLINE | ID: mdl-35628643

RESUMO

The naturally occurring dipeptide carnosine (ß-alanyl-L-histidine) specifically attenuates tumor growth. Here, we ask whether other small imidazole-containing compounds also affect the viability of tumor cells without affecting non-malignant cells and whether the formation of histamine is involved. Patient-derived fibroblasts and glioblastoma cells were treated with carnosine, L-alanyl-L-histidine (LA-LH), ß-alanyl-L-alanine, L-histidine, histamine, imidazole, ß-alanine, and L-alanine. Cell viability was assessed by cell-based assays and microscopy. The intracellular release of L-histidine and formation of histamine was investigated by high-performance liquid chromatography coupled to mass spectrometry. Carnosine and LA-LH inhibited tumor cell growth with minor effects on fibroblasts, and L-histidine, histamine, and imidazole affected viability in both cell types. Compounds without the imidazole moiety did not diminish viability. In the presence of LA-LH but not in the presence of carnosine, a significant rise in intracellular amounts of histidine was detected in all cells. The formation of histamine was not detectable in the presence of carnosine, LA-LH, or histidine. In conclusion, the imidazole moiety of carnosine contributes to its anti-neoplastic effect, which is also seen in the presence of histidine and LA-LH. Despite the fact that histamine has a strong effect on cell viability, the formation of histamine is not responsible for the effects on the cell viability of carnosine, LA-LH, and histidine.


Assuntos
Carnosina , Glioblastoma , Alanina , Carnosina/metabolismo , Fibroblastos/metabolismo , Glioblastoma/tratamento farmacológico , Glioblastoma/metabolismo , Histamina/metabolismo , Histamina/farmacologia , Histidina/metabolismo , Humanos , Imidazóis/farmacologia , beta-Alanina
4.
Int J Mol Sci ; 23(7)2022 Mar 28.
Artigo em Inglês | MEDLINE | ID: mdl-35409071

RESUMO

Huangjiu usually caused rapid-drunkenness and components such as ß-benzyl ethanol (ß-be), isopentanol (Iso), histamine (His), and phenethylamine (PEA) have been reported linked with intoxication. However, the destructive effect of these components on gut microbiota and liver is unclear. In this study, we found oral treatment of these components, especially His, stimulated the level of oxidative stress and inflammatory cytokines in liver and serum of mice. The gut microbiota community was changed and the level of lipopolysaccharide (LPS) increased significantly. Additionally, cellular pyroptosis pathway has been assessed and correlation analysis revealed a possible relationship between gut microbiota and liver pyroptosis. We speculated oral His treatment caused the reprogramming of gut microbiota metabolism, and increased LPS modulated the gut-liver interaction, resulting in liver pyroptosis, which might cause health risks. This study provided a theoretical basis for the effect of Huangjiu, facilitating the development of therapeutic and preventive strategies for related inflammatory disorders.


Assuntos
Microbioma Gastrointestinal , Piroptose , Animais , Histamina/metabolismo , Lipopolissacarídeos/metabolismo , Fígado/metabolismo , Camundongos
5.
Biochem Biophys Res Commun ; 607: 166-173, 2022 06 04.
Artigo em Inglês | MEDLINE | ID: mdl-35381387

RESUMO

Von Willebrand Factor (VWF) can promote platelet adhesion to the post-atherosclerotic regions to initiate thrombosis. The synthesis and secretion of VWF are important functions of endothelial cells (ECs). However, the mechanism through which blood flow regulates endothelial secretion of VWF remains unclear. We utilized a parallel-plate flow apparatus to apply fluid shear stress to human umbilical vein endothelial cells (HUVECs). Compared with pulsatile shear stress that mimics laminar flow in the straight parts of arteries or upstream of atherosclerotic stenosis sites, short-term exposure to oscillatory shear stress (OS) that mimics disturbed flow increased VWF secretion independent of affecting synaptosomal-associated protein 23 (SNAP23) expression and promoted the translocation of SNAP23 to the cell membrane. Vimentin associated with SNAP23, and this association was enhanced by OS or histamine. Acrylamide, a reagent that disrupts vimentin intermediate filaments, prevented histamine/OS-induced SNAP23 translocation, as well as VWF secretion. Immunofluorescence analysis revealed that the polarity of the vimentin intermediate filament network decreased after stimulation with histamine or OS. In addition, inhibition of protein kinase A (PKA) or G protein coupled receptor 68 (GPR68) eliminated the histamine/OS-induced phosphorylation of vimentin at Ser38 and secretion of VWF. Furthermore, syntaxin 7 might assist with the translocation of SNAP23 to the cell membrane, thus playing a role in promoting VWF secretion. The GPR68/PKA/vimentin signaling pathway may represent a novel mechanism for the regulation of SNAP23-mediated VWF secretion by ECs under OS and provide strategies for the prevention of atherosclerosis-related thrombosis.


Assuntos
Trombose , Fator de von Willebrand , Histamina/metabolismo , Células Endoteliais da Veia Umbilical Humana/metabolismo , Humanos , Filamentos Intermediários/metabolismo , Mecanotransdução Celular , Proteínas Qb-SNARE/metabolismo , Proteínas Qc-SNARE/metabolismo , Receptores Acoplados a Proteínas G/metabolismo , Estresse Mecânico , Trombose/metabolismo , Vimentina/metabolismo , Fator de von Willebrand/metabolismo
6.
Head Neck ; 44(7): 1554-1562, 2022 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-35411649

RESUMO

BACKGROUND: Tumor-associated macrophages in the tumor microenvironment (TME), as a factor affecting lymphocytes, have received much attention. Both lymphocytes and macrophages can switch the expression of histamine receptors. In this study, we investigated the role of histamine in the TME of tongue squamous cell carcinoma (SCC). METHODS: Sixty-seven patients with stage I tongue SCC were studied. Histamine was evaluated by the expression of L-histidine decarboxylase (HDC). Macrophages, T lymphocytes, and lymph vessel density, as well as the Ki-67 labeling index (LI) and depth of invasion (DOI), were compared with HDC expression. RESULTS: HDC expression was significantly affected by the TME. The DOI, worst pattern of invasion, and Ki-67 LI were associated with histamine expression. C-C motif chemokine ligand (CCL) 2 and CCL22 were co-expressed with histamine H1 and H2 receptors. Histamine expression was most affected by the DOI. CONCLUSIONS: Tongue SCC expressing histamine affected the TME via histamine receptors and chemokines.


Assuntos
Carcinoma de Células Escamosas , Neoplasias da Língua , Carcinoma de Células Escamosas/patologia , Quimiocinas , Histamina/metabolismo , Histidina Descarboxilase/genética , Histidina Descarboxilase/metabolismo , Humanos , Antígeno Ki-67 , Receptores Histamínicos , Língua/patologia , Microambiente Tumoral
7.
Neuropharmacology ; 212: 109065, 2022 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-35487272

RESUMO

Brain histamine acts as a neurotransmitter in the regulation of various brain activities. Previous studies have shown that histamine N-methyltransferase (HNMT), a histamine-metabolizing enzyme, controls brain histamine concentration and brain function. However, the relative contribution of astrocytic or neuronal HNMT to the regulation of the histaminergic system is still inconclusive. Here, we phenotyped astrocytes-specific HNMT knockout (cKO) mice to clarify the involvement of astrocytic HNMT in histamine clearance and brain function. First, we performed histological examinations using HNMT reporter mice and showed a wide distribution of HNMT in the brain and astrocytic HNMT expression. Then, we created cKO mice by Cre-loxP system and confirmed that HNMT expression in cKO primary astrocytes was robustly decreased. Although total HNMT level in the cortex was not substantially different between control and cKO brains, histamine concentration after histamine release was elevated in cKO cortex. In behavioral tests, impaired motor coordination and lower locomotor activity were observed in the cKO mice. However, anxiety-like behaviors, depression-like behaviors, and memory functions were not altered by astrocytic HNMT disruption. Although sleep analysis demonstrated that the quantity of wakefulness and sleep did not change, the increased power density of delta frequency during wakefulness indicated lower cortical activation in cKO mice. These results demonstrate that astrocytic HNMT contributes to histamine clearance after histamine release in the cortex and plays a role in the regulation of motor coordination, locomotor activity, and vigilance state.


Assuntos
Histamina N-Metiltransferase , Histamina , Animais , Astrócitos/metabolismo , Encéfalo/metabolismo , Histamina/metabolismo , Histamina N-Metiltransferase/genética , Histamina N-Metiltransferase/metabolismo , Camundongos , Vigília/fisiologia
8.
Curr Biol ; 32(9): 1937-1948.e5, 2022 05 09.
Artigo em Inglês | MEDLINE | ID: mdl-35338850

RESUMO

Novel targets for treating feeding-related diseases are of great importance, and histamine has long been considered an anorexigenic agent. However, understanding its functions in feeding in a circuit-specific way is still limited. Here, we report a medial septum (MS)-projecting histaminergic circuit mediating feeding behavior. This MS-projecting histaminergic circuit is functionally inhibited during food consumption, and bidirectionally modulates feeding behavior via downstream H2, but not H1, receptors on MS glutamatergic neurons. Further, we observed a pathological decrease of histamine 2 receptors (H2Rs) expression in MS glutamatergic neurons in diet-induced obesity (DIO) mice. Genetically, down-regulation of H2Rs expression in MS glutamatergic neurons accelerates body-weight gain. Importantly, chronic activation of H2Rs in MS glutamatergic neurons (with its clinical agonist amthamine) significantly slowed down the body-weight gain in DIO mice, providing a possible clinical utility to treat obesity. Together, our results demonstrate that this MS-projecting histaminergic circuit is critically involved in feeding, and H2Rs in MS glutamatergic neurons is a promising target for treating body-weight problems.


Assuntos
Comportamento Alimentar , Histamina , Animais , Comportamento Alimentar/fisiologia , Histamina/metabolismo , Histamina/farmacologia , Camundongos , Neurônios/fisiologia , Obesidade/metabolismo , Ganho de Peso
9.
J Allergy Clin Immunol ; 149(6): 2053-2061.e6, 2022 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-35240143

RESUMO

BACKGROUND: Thymic stromal lymphopoietin (TSLP) promotes TH2 inflammation and is deeply intertwined with inflammatory dermatoses like atopic dermatitis. The mechanisms regulating TSLP are poorly defined. OBJECTIVE: We investigated whether and by what mechanisms mast cells (MCs) foster TSLP responses in the cutaneous environment. METHODS: Ex vivo and in vivo skin MC degranulation was induced by compound 48/80 in wild-type protease-activated receptor 2 (PAR-2)- and MC-deficient mice in the presence or absence of neutralizing antibodies, antagonists, or exogenous mouse MC protease 6 (mMCP6). Primary human keratinocytes and murine skin explants were stimulated with lysates/supernatants of human skin MCs, purified tryptase, or MC lysate diminished of tryptase. Chymase and histamine were also used. TSLP was quantified by ELISA, real-time quantitative PCR, and immunofluorescence staining. RESULTS: Mas-related G protein-coupled receptor X2 (Mrgprb2) activation elicited TSLP in intact skin, mainly in the epidermis. Responses were strictly MC dependent and relied on PAR-2. Complementarily, TSLP was elicited by tryptase in murine skin explants. Exogenous mMCP6 could fully restore responsiveness in MC-deficient murine skin explants. Conversely, PAR-2 knockout mice were unresponsive to mMCP6 while displaying increased responsiveness to other inflammatory pathways, such as IL-1α. Indeed, IL-1α acted in concert with tryptase. In primary human keratinocytes, MC-elicited TSLP generation was likewise abolished by tryptase inhibition or elimination. Chymase and histamine did not affect TSLP production, but histamine triggered IL-6, IL-8, and stem cell factor. CONCLUSION: MCs communicate with kerationocytes more broadly than hitherto suspected. The tryptase/PAR-2 axis is a crucial component of this cross talk, underlying MC-dependent stimulation of TSLP in neighboring kerationocytes. Interference specifically with MC tryptase may offer a treatment option for disorders initiated or perpetuated by aberrant TSLP, such as atopic dermatitis.


Assuntos
Dermatite Atópica , Receptor PAR-2 , Animais , Quimases/metabolismo , Citocinas/metabolismo , Histamina/metabolismo , Humanos , Queratinócitos/metabolismo , Mastócitos/metabolismo , Camundongos , Receptor PAR-2/genética , Receptor PAR-2/metabolismo , Triptases/metabolismo
10.
Nature ; 604(7904): 190-194, 2022 04.
Artigo em Inglês | MEDLINE | ID: mdl-35355020

RESUMO

Type A γ-aminobutyric acid receptors (GABAARs) are pentameric ligand-gated chloride channels that mediate fast inhibitory signalling in neural circuits1,2 and can be modulated by essential medicines including general anaesthetics and benzodiazepines3. Human GABAAR subunits are encoded by 19 paralogous genes that can, in theory, give rise to 495,235 receptor types. However, the principles that govern the formation of pentamers, the permutational landscape of receptors that may emerge from a subunit set and the effect that this has on GABAergic signalling remain largely unknown. Here we use cryogenic electron microscopy to determine the structures of extrasynaptic GABAARs assembled from α4, ß3 and δ subunits, and their counterparts incorporating γ2 instead of δ subunits. In each case, we identified two receptor subtypes with distinct stoichiometries and arrangements, all four differing from those previously observed for synaptic, α1-containing receptors4-7. This, in turn, affects receptor responses to physiological and synthetic modulators by creating or eliminating ligand-binding sites at subunit interfaces. We provide structural and functional evidence that selected GABAAR arrangements can act as coincidence detectors, simultaneously responding to two neurotransmitters: GABA and histamine. Using assembly simulations and single-cell RNA sequencing data8,9, we calculated the upper bounds for receptor diversity in recombinant systems and in vivo. We propose that differential assembly is a pervasive mechanism for regulating the physiology and pharmacology of GABAARs.


Assuntos
Benzodiazepinas , Receptores de GABA-A , Transdução de Sinais , Benzodiazepinas/farmacologia , Sítios de Ligação , Microscopia Crioeletrônica , Histamina/metabolismo , Humanos , Ligantes , Subunidades Proteicas/química , Subunidades Proteicas/metabolismo , RNA-Seq , Receptores de GABA-A/química , Receptores de GABA-A/metabolismo , Receptores de GABA-A/ultraestrutura , Análise de Célula Única , Ácido gama-Aminobutírico/metabolismo
11.
Elife ; 112022 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-35229720

RESUMO

Neurotransmitters are generated by de novo synthesis and are essential for sustained, high-frequency synaptic transmission. Histamine, a monoamine neurotransmitter, is synthesized through decarboxylation of histidine by histidine decarboxylase (Hdc). However, little is known about how histidine is presented to Hdc as a precursor. Here, we identified a specific histidine transporter, TADR (torn and diminished rhabdomeres), which is required for visual transmission in Drosophila. Both TADR and Hdc localized to neuronal terminals, and mutations in tadr reduced levels of histamine, thus disrupting visual synaptic transmission and phototaxis behavior. These results demonstrate that a specific amino acid transporter provides precursors for monoamine neurotransmitters, providing the first genetic evidence that a histidine amino acid transporter plays a critical role in synaptic transmission. These results suggest that TADR-dependent local de novo synthesis of histamine is required for synaptic transmission.


Assuntos
Drosophila , Histidina , Animais , Drosophila/genética , Histamina/metabolismo , Histidina Descarboxilase/genética , Histidina Descarboxilase/metabolismo , Proteínas de Membrana Transportadoras/metabolismo , Neurotransmissores , Transmissão Sináptica
12.
Biomolecules ; 12(3)2022 03 15.
Artigo em Inglês | MEDLINE | ID: mdl-35327646

RESUMO

Histamine intolerance (HIT) is a common disorder associated with impaired histamine metabolism. Notwithstanding, it is often misdiagnosed as other diseases because of its lack of specific clinical manifestations. HIT did not gain traction until the early 21st century. In this review, we will focus on the latest research and elaborate on the clinical manifestations of HIT, including its manifestations in special populations such as atopic dermatitis (AD) and chronic urticaria (CU), as well as the latest understanding of its etiology and pathogenesis. In addition, we will explore the latest treatment strategies for HIT and the treatment of specific cases.


Assuntos
Amina Oxidase (contendo Cobre) , Dermatite Atópica , Hipersensibilidade , Amina Oxidase (contendo Cobre)/metabolismo , Dermatite Atópica/diagnóstico , Histamina/metabolismo , Humanos , Hipersensibilidade/diagnóstico
13.
Inflamm Res ; 71(4): 497-511, 2022 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-35303133

RESUMO

OBJECTIVE: To evaluate the contribution of endogenous diamine oxidase (DAO) in the inactivation of exogenous histamine, to find a mouse strain with increased histamine sensitivity and to test the efficacy of rhDAO in a histamine challenge model. METHODS: Diamine oxidase knockout (KO) mice were challenged with orally and subcutaneously administered histamine in combination with the ß-adrenergic blocker propranolol, with the two histamine-N-methyltransferase (HNMT) inhibitors metoprine and tacrine, with folic acid to mimic acute kidney injury and treated with recombinant human DAO. Core body temperature was measured using a subcutaneously implanted microchip and histamine plasma levels were quantified using a homogeneous time resolved fluorescence assay. RESULTS: Core body temperature and plasma histamine levels were not significantly different between wild type (WT) and DAO KO mice after oral and subcutaneous histamine challenge with and without acute kidney injury or administration of HNMT inhibitors. Treatment with recombinant human DAO reduced the mean area under the curve (AUC) for core body temperature loss by 63% (p = 0.002) and the clinical score by 88% (p < 0.001). The AUC of the histamine concentration was reduced by 81%. CONCLUSIONS: Inactivation of exogenous histamine is not driven by enzymatic degradation and kidney filtration. Treatment with recombinant human DAO strongly reduced histamine-induced core body temperature loss, histamine concentrations and prevented the development of severe clinical symptoms.


Assuntos
Amina Oxidase (contendo Cobre) , Histamina , Injúria Renal Aguda/induzido quimicamente , Amina Oxidase (contendo Cobre)/genética , Amina Oxidase (contendo Cobre)/metabolismo , Animais , Histamina/administração & dosagem , Histamina/metabolismo , Histamina N-Metiltransferase/metabolismo , Camundongos , Camundongos Knockout
14.
J Pharm Pharmacol ; 74(4): 537-546, 2022 Apr 20.
Artigo em Inglês | MEDLINE | ID: mdl-35134225

RESUMO

OBJECTIVES: This study aimed to analyse the potential effect of rupatadine (RUP) on ulcerative colitis (UC) induced by acetic acid (AA). METHODS: Forty male adult Wistar rats were divided into five groups: Control group: received vehicles for 14 days; AA model group: received AA at the 13th day; Sulfasalazine (SLZ) + AA group: received SLZ (250 mg/kg) for 14 days and AA at the 13th day; RUP-3 + AA group: received RUP (3 mg/kg/day) for 14 days and AA at the 13th day; and RUP-6 + AA group: received RUP (6 mg/kg/day) for 14 days and AA at the 13th day. Evidence of UC was assessed both macroscopically and microscopically. Oxidative stress markers (total antioxidant capacity and malondialdehyde), antioxidant enzyme (superoxide dismutase), histamine and platelet-activating factor (PAF) were determined. Immunohistochemical estimations of vascular endothelial growth factor (VEGF) and interleukin-6 (IL-6) were done. KEY FINDINGS: The AA group showed evidence of UC that was associated with a significant increase in oxidative stress, histamine and PAF levels with significant elevation in colonic VEGF and IL-6 immuno-expressions. RUP, in a dose-dependent manner, significantly ameliorated UC. CONCLUSION: RUP protects against UC by reducing oxidative stress and by regulating the PAF/IL-6/VEGF pathway.


Assuntos
Colite Ulcerativa , Transdução de Sinais , Ácido Acético/farmacologia , Animais , Antioxidantes/metabolismo , Antioxidantes/farmacologia , Colite Ulcerativa/induzido quimicamente , Colite Ulcerativa/tratamento farmacológico , Colite Ulcerativa/metabolismo , Colo , Ciproeptadina/análogos & derivados , Histamina/metabolismo , Interleucina-6/metabolismo , Masculino , Fator de Ativação de Plaquetas/metabolismo , Ratos , Ratos Wistar , Fator A de Crescimento do Endotélio Vascular/metabolismo
15.
Int J Mol Sci ; 23(3)2022 Jan 26.
Artigo em Inglês | MEDLINE | ID: mdl-35163341

RESUMO

The histamine H1 receptor (H1R) is a G protein-coupled receptor (GPCR) and represents a main target in the treatment of allergic reactions as well as inflammatory reactions and depressions. Although the overall effect of antagonists on H1 function has been extensively investigated, rather little is known about the potential modulatory effect of ions or sequence variants on antagonist binding. We investigated the dynamics of a phosphate ion present in the crystal structure and of a sodium ion, for which we determined the position in the allosteric pocket by metadynamics simulations. Both types of ions exhibit significant dynamics within their binding site; however, some key contacts remain stable over the simulation time, which might be exploited to develop more potent drugs targeting these sites. The dynamics of the ions is almost unaffected by the presence or absence of doxepin, as also reflected in their small effect (less than 1 kcal·mol-1) on doxepin binding affinity. We also examined the effect of four H1R sequence variants observed in the human population on doxepin binding. These variants cause a reduction in doxepin affinity of up to 2.5 kcal·mol-1, indicating that personalized medical treatments that take into account individual mutation patterns could increase precision in the dosage of GPCR-targeting drugs.


Assuntos
Doxepina , Histamina , Sítios de Ligação , Doxepina/química , Doxepina/metabolismo , Histamina/metabolismo , Antagonistas dos Receptores Histamínicos H1 , Humanos , Íons , Receptores Acoplados a Proteínas G/metabolismo , Receptores Histamínicos/metabolismo , Receptores Histamínicos H1/metabolismo
16.
Biomed Pharmacother ; 148: 112698, 2022 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-35149385

RESUMO

In patients with histamine intolerance accumulated or ingested histamine causes a broad range of undesirable symptoms. Food-derived histamine is degraded by intestinal diamine oxidase (DAO) and histamine-N-methyltransferase (HNMT), while the organic cation transporter 3 (OCT3) contributes to the transcellular flux of histamine. Anecdotal evidence from patients with HIT suggests an improvement of symptoms related to histamine intolerance after intake of Ze 339, a lipophilic CO2-extract prepared from the leaves of Petasites hybridus. Thus, it was the aim of this study to investigate the influence of Ze 339 on DAO, HNMT and OCT3 using Caco-2 and MDCKII cells. Even though Ze 339 reduced mRNA levels of HNMT and DAO, there was no change in protein expression. Ze 339 changed neither the basal release nor the enzymatic activity of DAO. Testing the interaction of Ze 339 with the transcellular histamine transport, we observed a significant increase in the basal to apical flux in presence of high Ze 339 concentrations at the early phases of the experiment. Testing the influence of Ze 339 on OCT3-mediated histamine uptake in overexpressing MDCKII cells revealed a dose-dependent inhibition with an estimated IC50 of 26.9 ug/mL for the extract. In conclusion, we report an effect of Ze 339 on transcellular histamine transport, where inhibition of OCT3 may contribute.


Assuntos
Petasites , Células CACO-2 , Histamina/metabolismo , Humanos , Petasites/metabolismo , Extratos Vegetais/farmacologia
17.
J Ethnopharmacol ; 290: 115077, 2022 May 23.
Artigo em Inglês | MEDLINE | ID: mdl-35131339

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: As a common medicinal and edible plant, Zingiber officinale Roscoe (ginger) is often used for the prevention of motion sickness. However, the mechanism of its anti-motion sickness remains to be elucidated. AIM OF THE STUDY: To explore novel treatment for motion sickness with less side effects, anti-motion sickness effect of ginger (Zingiber officinale) extract (GE) and the possible molecular mechanisms were investigated. MATERIALS AND METHODS: The anti-motion sickness effect of ginger was evaluated through mice animal experimental models. Components of ginger that might contribute to the anti-motion sickness effect were analyzed by LC-MS/MS. Subsequently, biochemical analysis integrated with serum metabolomic profiling were performed to reveal the systematic response of motion sickness mice to ginger extract's amelioration effect. RESULTS: Exhaustive swimming time of mice in the GE group reached 8.9 min, which was 52.2% longer than that in the model group. Motion sickness index scores and time taken traversing balance beam of mice in the GE group were decreased by 53.2% and 38.5%, respectively. LC-MS/MS analysis suggested that various active ingredients in GE, such as gingerol, ginger oil and terpenoids, might contribute to its appealing anti-motion sickness activity. Biochemical analysis revealed that GE can relieve motion sickness through reducing histamine and acetylcholine release in vestibular system, regulating fatty acid oxidation, sugar metabolism and bile acid metabolism in mice. CONCLUSION: Gavage of mice with GE can effectively relieve the symptoms of autonomic nervous system dysfunction, improve the balance and coordination ability and ameliorate the ability to complete complex work after rotation stimulation. GE has attractive potential for development and utilization as novel anti-motion sickness food or drugs.


Assuntos
Gengibre/química , Enjoo devido ao Movimento/patologia , Extratos Vegetais/farmacologia , Acetilcolina/metabolismo , Animais , Animais não Endogâmicos , Comportamento Animal/efeitos dos fármacos , Ácidos e Sais Biliares/metabolismo , Catecóis/farmacologia , Cromatografia Líquida , Relação Dose-Resposta a Droga , Ácidos Graxos/metabolismo , Álcoois Graxos/farmacologia , Histamina/metabolismo , Masculino , Camundongos , Óleos Vegetais/farmacologia , Açúcares/metabolismo , Espectrometria de Massas em Tandem , Terpenos/farmacologia
18.
J Cell Sci ; 135(6)2022 03 15.
Artigo em Inglês | MEDLINE | ID: mdl-35107584

RESUMO

Kinases play key roles in signaling networks that are activated by G-protein-coupled receptors (GPCRs). Kinase activities are generally inferred from cell lysates, hiding cell-to-cell variability. To study the dynamics and heterogeneity of ERK and Akt proteins, we employed high-content biosensor imaging with kinase translocation reporters. The kinases were activated with GPCR ligands. We observed ligand concentration-dependent response kinetics to histamine, α2-adrenergic and S1P receptor stimulation. By using G-protein inhibitors, we observed that Gq mediated the ERK and Akt responses to histamine. In contrast, Gi was necessary for ERK and Akt activation in response to α2-adrenergic receptor activation. ERK and Akt were also strongly activated by S1P, showing high heterogeneity at the single-cell level, especially for ERK. Cluster analysis of time series derived from 68,000 cells obtained under the different conditions revealed several distinct populations of cells that display similar response dynamics. ERK response dynamics to S1P showed high heterogeneity, which was reduced by the inhibition of Gi. To conclude, we have set up an imaging and analysis strategy that reveals substantial cell-to-cell heterogeneity in kinase activity driven by GPCRs.


Assuntos
Proteínas Proto-Oncogênicas c-akt , Receptores Acoplados a Proteínas G , Ativação Enzimática , Histamina/metabolismo , Histamina/farmacologia , Ligantes , Fosforilação , Proteínas Proto-Oncogênicas c-akt/metabolismo , Receptores Acoplados a Proteínas G/metabolismo , Transdução de Sinais
19.
Mar Drugs ; 20(2)2022 Jan 27.
Artigo em Inglês | MEDLINE | ID: mdl-35200634

RESUMO

Glycation, and the resulting buildup of advanced glycation end products (AGEs), is recognized as a key driver of cumulative skin damage and skin aging. Dunaliella salina is a halophile microalga adapted to intense solar radiation through the production of carotenoids. We present a natural supercritical CO2 extract of Dunaliella salina rich in the colorless carotenoids phytoene and phytofluene. The extract exhibited antiglycation and anti-inflammatory activities in ex vivo testing, showing strongly reduced formation of N-ε-carboxy-methyl-lysine with exposure to methylglyoxal, reduced AGE receptor levels, and significantly reduced interleukins 6 and 8. In a placebo-controlled clinical study under intense solar exposure, the extract significantly reduced the skin's glycation scores and its sensitivity to histamine; key skin aging parameters were also significantly improved vs. placebo, including wrinkle counts and spots. These results demonstrate the value of this Dunaliella salina extract, rich in colorless carotenoids, as an antiglycative, anti-inflammatory, and antiaging active ingredient, including in high-irradiation contexts.


Assuntos
Anti-Inflamatórios/farmacologia , Produtos Biológicos/farmacologia , Microalgas/química , Envelhecimento da Pele/efeitos dos fármacos , Adulto , Método Duplo-Cego , Feminino , Produtos Finais de Glicação Avançada/efeitos dos fármacos , Histamina/metabolismo , Humanos , Pessoa de Meia-Idade
20.
Int J Mol Sci ; 23(4)2022 Feb 18.
Artigo em Inglês | MEDLINE | ID: mdl-35216402

RESUMO

Several of the drugs currently available for the treatment of premature ejaculation (PE) (e.g., local anesthetics or antidepressants) are associated with numerous safety concerns and exhibit weak efficacy. To date, no therapeutics for PE have been approved in the United States, highlighting the need to develop novel agents with sufficient efficacy and fewer side effects. In this study, we focused on the histamine H3 receptor (H3R) as a potential target for the treatment of PE and evaluated the effects of imetit (an H3R/H4R agonist), ciproxifan (an H3R antagonist), and JNJ-7777120 (an H4R antagonist) in vivo. Our in vivo electrophysiological experiments revealed that imetit reduced mechanical stimuli-evoked neuronal firing in anesthetized rats. This effect was inhibited by ciproxifan but not by JNJ-7777120. Subsequently, we evaluated the effect of imetit using a copulatory behavior test to assess ejaculation latency (EL) in rats. Imetit prolonged EL, although this effect was inhibited by ciproxifan. These findings indicate that H3R stimulation suppresses mechanical stimuli-evoked neuronal firing in the spinal-penile neurotransmission system, thereby resulting in prolonged EL. To our knowledge, this is the first report to describe the relationship between H3R and PE. Thus, H3R agonists may represent a novel treatment option for PE.


Assuntos
Agonistas dos Receptores Histamínicos/farmacologia , Histamina/metabolismo , Ejaculação Precoce/tratamento farmacológico , Ejaculação Precoce/metabolismo , Receptores Histamínicos H3/metabolismo , Animais , Imidazóis/farmacologia , Masculino , Piperidinas/farmacologia , Ratos , Ratos Wistar , Tioureia/análogos & derivados , Tioureia/farmacologia
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