Jiawei guomin decoction regulates the degranulation of mast cells in atopic dermatitis mice via the HIS/PAR-2 pathway.

ETHNOPHARMACOLOGICAL RELEVANCE: Guomin decoction (GMD) is a traditional Chinese medicine commonly used in clinical practice. It has traditionally been used to treat all allergic diseases. Currently, Jiawei Guomin Decoction (JWGMD) is used to treat sensitive skin after initial therapy. Although it has a significant clinical therapeutic effect, the exact role of mast cell degranulation in treating atopic dermatitis (AD) is still unclear. AIM OF THE STUDY: GMD and JWGMD can both treat allergic diseases, while JWGMD focuses on skin allergies. This study aims to explore the potential effect of JWGMD on the degranulation of mast cells in an AD mouse model induced by 2,4-dinitrofluorobenzene (DNFB) and investigate the effectiveness of JWGMD in alleviating disease progression to further provide specific therapeutic targets for treating AD. MATERIALS AND METHODS: The scratching times and skin lesions of model mice induced by DNFB were observed, and skin tissues were collected for subsequent measurement. Histopathological changes in the back skin of mice were observed by haematoxylin eosin (H&E) staining, Toluidine blue staining was used to detect the degranulation of mouse skin mast cells, and the relationship between the expression of histamine (HIS), mast cell tryptase (MCT) and mast cell degranulation was analysed by enzyme-linked immunosorbent assay (ELISA). The expression of protease-activated receptor-2 (PAR-2), histamine 1 receptor (H1R), H2R, H4R and MCT proteins in AD mice was detected by Western blot (WB). Immunofluorescence assay (IFA) further confirmed the localization of PAR-2, H1R, H2R, H4R, and MCT proteins in the skin. Quantitative real-time PCR (qPCR) was used to determine PAR-2, H1R, H2R and H4R mRNA levels in skin lesions to further clarify the mechanism by which JWGMD amplifies mast cell degranulation in AD. In addition, a reliable ultrahigh-performance liquid chromatography-quadrupole electrostatic field orbitrap mass spectrometry (UPLC-QE-MS) nontargeted metabolomics analysis was performed to analyse the differences in metabolite abundance between GMD and JWGMD, and these results were used to identify the active components in JWGMD that may have antipruritic and anti-inflammatory properties and inhibit mast cell degranulation. RESULTS: After intermittent stimulation with DNFB, the skin lesions showed extensive desquamation, dryness, scabbing, skin thickening, and slight bleeding. Both treatments alleviated this phenomenon and reduced the number of scratches, with JWGMD being the most effective. JWGMD can significantly reduce inflammatory cell infiltration, oedema, and some capillary neogenesis in mice and reduce the degranulation of mast cells. The ELISA results showed that JWGMD can increase the levels of MCT and HIS proteins. The WB and IFA results demonstrated that JWGMD reduced the expression levels of PAR-2, H1R, H4R, and MCT proteins in skin lesions, with protein localization mainly in the epidermal layer, while H2R protein levels were increased and mainly localized in the dermis. In addition, JWGMD downregulates the mRNA expression of PAR-2, H1R, H2R, and H4R. Interestingly, through UPLC-QE-MS nontargeted metabolomic analysis, we detected the anti-inflammatory and antiallergy active substances in JWGMD, such as methyl eugenol, dictamnine and sinapine. CONCLUSIONS: JWGMD may alleviate itching through methyl syringol, dictamnine, sinapine and other substances, and its mechanism may be related to inhibiting the HIS/PAR-2 pathway in AD model mice and further regulating the self-amplification of mast cell degranulation. JWGMD is a potential drug for treating AD. Therefore, it deserves continuous attention and research.

Role of Histamine and Related Signaling in Kaposi's Sarcoma-Associated Herpesvirus Pathogenesis and Oncogenesis.

Although Kaposi's sarcoma-associated herpesvirus (KSHV) has been reported to cause several human cancers including Kaposi's sarcoma (KS) and primary effusion lymphoma (PEL), the mechanisms of KSHV-induced tumorigenesis, especially virus-host interaction network, are still not completely understood, which therefore hinders the development of effective therapies. Histamine, together with its receptors, plays an important role in various allergic diseases by regulating different inflammation and immune responses. Our previous data showed that antagonists targeting histamine receptors effectively repressed KSHV lytic replication. In the current study, we determined that histamine treatment increased cell proliferation and anchorage-independent growth abilities of KSHV-infected cells. Furthermore, histamine treatment affected the expression of some inflammatory factors from KSHV-infected cells. For clinical relevance, several histamine receptors were highly expressed in AIDS-KS tissues when compared to normal skin tissues. We determined that histamine treatment promoted KSHV-infected lymphoma progression in immunocompromised mice models. Therefore, besides viral replication, our data indicate that the histamine and related signaling are also involved in other functions of KSHV pathogenesis and oncogenesis.

Characteristics of histamine H4 receptor agonist-induced allergic conjunctivitis model in Guinea pigs.

Histamine is strongly associated with the onset of allergic conjunctivitis. The most recent cloned histamine H4 receptor antagonist is highly expected as a new therapeutic drug candidate. As a model for a therapeutic drug targeting the histamine H4 receptor, a mouse model in which conjunctivitis symptoms are induced by instilling 4-methylhistamine, a histamine H4 receptor agonist, has been reported. However, the affinity of the H4 receptor for histamine varies in species, and it is known that the histamine binding affinity for the guinea pig H4 receptor is closer to that for human receptor than mice receptor. In this paper, we investigated a possibility that a guinea pig model would become a drug efficacy evaluation model with higher evaluation accuracy than the mouse model. As a result, hyperemia was observed in the conjunctivae and iris of guinea pigs after instillation of 4-methylhistamine and specifically suppressed by the histamine H4 receptor antagonist. Unlikely to the previously reported mouse model, however, none of edema, increased vascular permeability or scratching behavior was observed, suggesting that there may be differences between mice and guinea pigs not only in the binding affinity of histamine to the H4 receptor but also in the biological reaction to 4-methylhistamine. Although the symptoms of allergic conjunctivitis do not appear comprehensively in the guinea pig model, results of this study indicated a possibility that this model can be used as a simple screening model in the early stages of drug development.

Regulación de las fases del ciclo vigilia-sueño por la histamina / Regulation of the phases of the sleep-wakefulness cycle with histamine

Redes neurales distribuidas en el encéfalo sustentan la generación de la vigilia y dos estados de sueño: sueño no REM y sueño REM. Estos tres estados comportamentales se engranan conjuntamente en una secuencia regular que constituye el ciclo vigilia-sueño. Este trabajo revisa y actualiza el conocimiento sobre la implicación del sistema histaminérgico en la organización del ciclo vigilia-sueño. Las neuronas histaminérgicas se localizan exclusivamente en el núcleo tuberomamilar hipotalámico, pero son el origen de proyecciones extensas a numerosas regiones encefálicas. Las neuronas histaminérgicas están activas durante la vigilia, especialmente con alta demanda atencional, y permanecen silentes en sueño no REM y sueño REM. Se han descrito cuatro receptores histaminérgicos metabotrópicos, de los cuales H1R, H2R y H3R están presentes en el sistema nervioso. H1R y H2R son fundamentalmente heterorreceptores postsinápticos, mientras que se piensa que H3R es mayormente un auto y heterorreceptor presináptico. Las neuronas histaminérgicas son activadas por las neuronas hipocretinérgicas y se cree que muchos de los efectos activadores de las hipocretinas se deben a acciones histaminérgicas. Las interacciones entre los axones histaminérgicos y los núcleos colinérgicos en el prosencéfalo y el troncoencéfalo son particularmente importantes para la activación cortical. Por el contrario, las neuronas histaminérgicas tuberomamilares, al igual que otras neuronas aminérgicas del locus coeruleus o del núcleo dorsal del rafe, son inhibidas por las neuronas del área preóptica promotoras de sueño no REM. Acciones inhibidoras adicionales sobre las neuronas histaminérgicas proceden de la liberación de adenosina en la región tuberomamilar. Finalmente, las neuronas histaminérgicas inhiben a las neuronas hipotalámicas REM-on que contienen hormona concentradora de melanina, apoyando así un papel permisivo del núcleo tuberomamilar en el sueño REM. De hecho, ratones deficientes para descarboxilasa de histidina, la enzima de síntesis de la histamina, muestran un aumento significativo de sueño REM (AU)

Distributed neural networks in the brain sustain generation of wakefulness and two sleep states: non-REM sleep and REM sleep. These three behavioral states are jointly ingrained in a rhythmic sequence that constitutes the sleepwakefulness cycle. This paper reviews and updates knowledge about the involvement of the histaminergic system in sleep-wakefulness cycle organization. Histaminergic neurons are exclusively located in the hypothalamic tuberomammillary nucleus, but are the source of a widespread projection system to many brain regions. Histamine neurons are active during waking, especially with high attention need, and remain silent in both non-REM and REM sleep. There have been described four metabotropic histamine receptors, of which H1R, H2R and H3R are present in the nervous system. H1R and H2R are mainly postsynaptic heteroreceptors, whereas H3R is thought to be mostly a presynaptic auto- and hetero-receptor. Histaminergic neurons are excited by hypocretinergic neurons and most of the arousing hypocretin effects are thought to depend on histaminergic actions. Interactions among histaminergic axons and cholinergic nuclei within forebrain and brainstem are particularly important for cortical activation. In contrast, histaminergic tuberomammillary neurons, similarly to other aminergic neurons in locus coeruleus or dorsal raphe nucleus, are inhibited by non-REM sleep-promoting neurons of the preoptic region. Further inhibitory actions on histamine neurons come from adenosine release on tuberomammillary region. Finally, histaminergic neurons inhibit REM-on hypothalamic neurons containing melanine-concentrating hormone, thus supporting a permissive role of tuberomammillary nucleus in REM sleep. Actually, knockout mice for histidine decarboxylase, the enzyme synthetizing histamine, show a significant REM sleep increase (AU)

Histamine scavenging attenuates endotoxin-induced acute lung injury.

Histamine is an important mediator of early and late inflammatory responses. Here we asked whether scavenging of endogenous histamine by the arthropod-derived histamine binding protein EV131 diminishes acute respiratory distress syndrome (ARDS) induced by inhaled endotoxin. We demonstrate that EV131 (360 microg given intranasally) reduced endotoxin-induced bronchoconstriction and recruitment of neutrophils. Furthermore, EV131 administration diminished TNF-alpha and protein leak in the bronchoalveolar lavage fluid. The data suggest that histamine attenuates endotoxin-induced bronchoconstriction and neutrophil recruitment. Therefore, scavenging of histamine by EV131 may represent a novel therapeutic strategy in ARDS.

Evaluación del extracto acuoso liofilizado de Boerhavia erecta L. sobre la transmisión colinérgica e histaminérgica / Evaluation of the frozen-dried aqueous extract from Boerhavia erecta L. on the cholinegic and histaminergic transmission

Se evaluó el extracto acuoso liofilizado de Boerhavia erecta L. sobre la transmisión colinérgica e histaminérgica, se emplearon cobayos Hartley para la extracción de porciones de íleon que fueron estimulados con histamina y acetilcolina con y sin la presencia del extracto, también se provocó un previo bloqueo de los receptores histaminérgicos y colinérgicos presentes en el órgano para después estimular el mismo con el extracto de B. erecta. En todos los casos se determinó la amplitud de las contracciones del órgano; los registros se realizaron mediante un transductor isotónico acoplado a un polígrafo Nihon Kodhen. El extracto acuoso liofilizado de B. erecta a concentraciones entre 0,1 mg/mL y 1 mg/mL no presentó actividad antimuscarínica y si mostró efecto antihistamínico in vitro. El extracto de B. erecta a concentraciones entre 1 y 10 mg/mL administrada de forma conjunta con acetilcolina 3x10-3 M provocó una contracción mayor que las inducidas por la B. erecta administrada de forma independiente y menor que la provocada por la acetilcolina, un comportamiento similar se obtuvo tras la administración conjunta de B. erecta e histamina 10-5 M. Cuando los receptores muscarínicos e histamínicos fueron bloqueados con atropina y difenhidramina respectivamente y posteriormente se añadió B. erecta, las contracciones provocadas por esta última fueron menores que las provocadas por el extracto sin previo bloqueo de los receptores. Estos resultados indicaron que el extracto acuoso de B. erecta. tiene tanto efecto agonista como antagonista para la histamina en dependencia de la concentración a la que se utilice y no presenta actividad antimuscarínica(AU)