Apigenin attenuates inflammatory response in allergic rhinitis mice by inhibiting the TLR4/MyD88/NF-κB signaling pathway.

BACKGROUND: Allergic rhinitis (AR) is an immunoglobulin E (IgE)-mediated immune inflammatory response that mainly affects the nasal mucosa. Currently, there is evidence that apigenin, as a flavonoid, has anti-allergic potential. MATERIAL/METHODS: In vitro, compound 48/80 and lipopolysaccharide (LPS) were used to induce mast cell activation and inflammation in HMC-1 cells. In vivo, ovalbumin (OVA) induced and stimulated AR in BALB/c mice. ELISA was used to detect the contents of ß-hexosaminidase, histamine, eosinophil cationic protein (ECP), OVA-specific IgE, IgG1, and IgG2a, inflammatory factors in cells and mouse serum. Cell viability and apoptosis were measured with MTT and flow cytometry. Toll like receptor 4 (TLR4)/myeloid differentiation factor88 (MyD88)/Nuclear transcription factor-κB (NF-κB) pathway-related proteins in cells and mouse nasal mucosa tissues were analyzed with Western blotting. The levels of Th1 (IFN-γ) and Th2 (IL-4, IL-5, and IL-13) cytokines and Th1 (T-bet) and Th2 (GATA-3) specific transcription factors were also assessed. The ratio of Th1 (CD4+ IFN-γ+ ) / Th2 (CD4+ IL-4+ ) cells in mouse peripheral blood mononuclear cells was evaluated by flow cytometry. RESULTS: Apigenin significantly inhibited compound 48/80-induced secretion of ß-hexosaminidase and histamine. Apigenin blocked LPS-induced decrease in cell viability and increase in cell apoptosis and inflammatory cytokine secretion by suppressing the activity of the TLR4/MyD88/NF-κB pathway. Apigenin treatment reduced the levels of OVA-specific IgE, IgG1 and IgG2a as well as ß-hexosaminidase, histamine and ECP levels in mouse serum. Moreover, administration with apigenin decreased Th2 cytokine and transcription factor levels and increased Th1 cytokine and transcription factor levels, and promoted the ratio of Th1/Th2 cells in AR mice. Additionally, apigenin significantly alleviated nasal symptoms and nasal eosinophil infiltration in AR mice. CONCLUSIONS: Apigenin alleviates the inflammatory response of allergic rhinitis by inhibiting the activity of the TLR4/MyD88/NF-κB signaling pathway.

FcεRI deficiency alleviates silica-induced pulmonary inflammation and fibrosis.

Silicosis is one of the most important occupational diseases worldwide, caused by inhalation of silica particles or free crystalline silicon dioxide. As a disease with high mortality, it has no effective treatment and new therapeutic targets are urgently needed. Recent studies have identified FCER1A, encoding α-subunit of the immunoglobulin E (IgE) receptor FcεRI, as a candidate gene involved in the biological pathways leading to respiratory symptoms. FcεRI is known to be important in allergic asthma, but its role in silicosis remains unclear. In this study, serum IgE concentrations and FcεRI expression were assessed in pneumoconiosis patients and silica-exposed mice. The role of FcεRI was explored in a silica-induced mouse model using wild-type and FcεRI-deficient mice. The results showed that serum IgE concentrations were significantly elevated in both pneumoconiosis patients and mice exposed to silica compared with controls. The mRNA and protein expression of FcεRI were also significantly increased in the lung tissue of patients and silica-exposed mice. FcεRI deficiency significantly attenuated the changes in lung function caused by silica exposure. Silica-induced elevations of IL-1ß, IL-6, and TNF-α were significantly attenuated in the lung tissue and bronchoalveolar lavage fluid (BALF) of FcεRI-deficient mice compared with wild-type controls. Additionally, FcεRI-deficient mice showed a significantly lower score of pulmonary fibrosis than wild-type mice following exposure to silica, with significantly lower hydroxyproline content and expression of fibrotic genes Col1a1 and Fn1. Immunofluorescent staining suggested FcεRI mainly on mast cells. Mast cell degranulation took place after silica exposure, as shown by increased serum histamine levels and ß-hexosaminidase activity, which were significantly reduced in FcεRI-deficient mice compared with wild-type controls. Together, these data showed that FcεRI deficiency had a significant protective effect against silica-induced pulmonary inflammation and fibrosis. Our findings provide new insights into the pathophysiological mechanisms of silica-induced pulmonary fibrosis and a potential target for the treatment of silicosis.

Evaluation of the Relationship among Biogenic Amines, Nitrite and Microbial Diversity in Fermented Mustard.

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.

Histamine and Scombrotoxins.

Histamine intoxications result when histamine-metabolizing enzymes are compromised or overwhelmed by dietary histamine in the human body. This can occur either due to metabolic enzyme deficiencies, such as in histamine intolerance to wines, aged cheese and other foods or from high concentrations of histamine following ingestion of decomposed fish. The presence of histamine in decomposed fish and fish products results from bacterial decarboxylation of free L-histidine following product mishandling. Consequently, histamine intoxications from mishandled fish, commonly referred to as scombrotoxin fish poisoning (SFP) or scombroid poisoning, require high levels of free L-histidine only found in certain species of pelagic fish. Differential diagnosis is required of clinicians since dietary histamine intoxications produce the same symptoms typical of release of endogenous histamine due to IgE -mediated seafood allergies or anisakiasis. Although high levels of dietary histamine are responsible for SFP, histamine has important physiological functions and tends to exert toxic effects only at doses beyond the physiological range. Endogenous histamine is essential to local immune responses, regulation of gastric acid secretion in the gut, and neurotransmission in the central nervous system. Scombrotoxins, postulated to explain histamine's augmented toxicity in scombrotoxic fish, are a milieu of histamine and other bioactives. Since time-and-temperature abuse is required to produce high levels of histamine in fish, management consists of ensuring proper handling by identifying hazards and critical control points (HACCP) and maintaining a "cold chain" from catch to consumption. Reference methods for detecting histamine have received increased attention and the European Commission has validated a popular precolumn dansylation-based HPLC method through inter-laboratory collaboration and studied method equivalence with the AOAC fluorescence method 977.13 recognized by Codex Alimentarius. Much progress has been made during the last decade in the development and validation of rapid screening methods for detecting histamine in food and especially in fish products. These include many innovative sensors and several validated commercial test kits, many of them based on a recombinant form of the enzyme histamine dehydrogenase (HD).

Estrogens influence female itch sensitivity via the spinal gastrin-releasing peptide receptor neurons.

There are sex differences in somatosensory sensitivity. Circulating estrogens appear to have a pronociceptive effect that explains why females are reported to be more sensitive to pain than males. Although itch symptoms develop during pregnancy in many women, the underlying mechanism of female-specific pruritus is unknown. Here, we demonstrate that estradiol, but not progesterone, enhances histamine-evoked scratching behavior indicative of itch in female rats. Estradiol increased the expression of the spinal itch mediator, gastrin-releasing peptide (GRP), and increased the histamine-evoked activity of itch-processing neurons that express the GRP receptor (GRPR) in the spinal dorsal horn. The enhancement of itch behavior by estradiol was suppressed by intrathecal administration of a GRPR blocker. In vivo electrophysiological analysis showed that estradiol increased the histamine-evoked firing frequency and prolonged the response of spinal GRP-sensitive neurons in female rats. On the other hand, estradiol did not affect the threshold of noxious thermal pain and decreased touch sensitivity, indicating that estradiol separately affects itch, pain, and touch modalities. Thus, estrogens selectively enhance histamine-evoked itch in females via the spinal GRP/GRPR system. This may explain why itch sensation varies with estrogen levels and provides a basis for treating itch in females by targeting GRPR.

Effect of dietary histamine on intestinal morphology, inflammatory status, and gut microbiota in yellow catfish (Pelteobagrus fulvidraco).

The toxic effect of dietary histamine on the intestine of aquatic animals has been demonstrated, but reports on the morphological observation of the intestine are limited. Thus, a feeding trial was conducted to determine the effect of dietary histamine on intestinal histology, inflammatory status and gut microbiota of yellow catfish (Pelteobagrus fulvidraco). Here, we showed that histamine-rich diets caused severe abnormality and damage to the intestine, including a decreased villi length and reduced villi number. In addition, the quantitative real-time PCR (qRT-PCR) demonstrates that histamine-rich diets increased the expression of pro-inflammatory genes (Tnfα, Il1ß, and Il8) and decreased the expression of an anti-inflammatory gene (Il10). Furthermore, the alpha-diversity (observed OTUs, Chao1, Shannon and Simpson) and beta-diversity (non-metric multidimensional scaling, with the stress value of 0.17) demonstrated that histamine-rich diets caused alterations in gut microbiota composition and diversity. Co-occurrence networks analysis of the gut microbiota community showed that the histamine influenced the number and the relationship between bacteria species in the phyla of Acidobacteria, Proteobacteria, and Bacteroidetes, which caused the instability of the intestinal microbiota community. Additionally, random forest selected six bacterial species as the biomarkers to separate the three groups, which are Lachnospiraceae Blautia (V520), Bacteroidales S24.7 (V235), Chloroplast Streptophyta (V368), Actinomycetales Streptomycetaceae (V152), Clostridia Clostridiales (V491) and Paraprevotellaceae Prevotella (V245). Finally, Pearson correlation analysis demonstrated that V520, V235, and V491 were negatively correlated with pro-inflammatory factors (Tnfα, Il1ß, and Il8) and positively correlated with an anti-inflammatory factor (Il10), which indicated that V520, V235, and V491 might be anti-inflammatory. These findings improved our understanding of the toxic effect of dietary histamine to intestinal histological damage, the induction of mucosa inflammatory status, and the alteration of gut microbiota.

Pharmacological studies on aqueous extract of Launaea arborescens from southwest Algeria.

ETHNOPHARMACOLOGICAL RELEVANCE: Launaea arborescens, its vernacular name is Mol-albina belonging to asteracaea family origin of the southwest of Algeria. This plant is used in folk medicines to treat gastroenteritis, diabetes, child aliment and other diseases; it is taken macerated or boiled. AIM: This study aims to evaluate the anti-inflammation an analgesic activity of the aqueous extract of Launaea arborescens (AqELA) and its pathway of action. METHODS: the investigation of anti-inflammatory and analgesic effects were done using formalin test, acetic acid test. For mechanism investigation, it was used hot plate test to induce opioid receptors, a histamine and serotonin test to induce edema paw, finally, for the TRPV1 receptor, it was used the capsaicin test. RESULTS: The aqueous extract of Launaea arborescens showed a significant inhibition of abdominal writhing test 95% and 100% inhibition of licking paw using acid acetic test and formalin test respectively (EC: 47 mg/kg and 104 mg/kg). The analgesic effect of the aqueous extract of Launaea arborescens showed inhibition of sensation of pain after 120 min compared to morphine effect. The aqueous extract of Launaea arborescens reduced paw volume after 180 min and 120 min for histamine and serotonin respectively with dose-dependent. Concerning of TRPV1 receptors, the inhibition was showed at doses 100 mg and 300 mg. CONCLUSION: Our results contribute towards validation of the traditional use of Launaea arborescens for inflammation ailment.

Cannabis roots: Pharmacological and toxicological studies in mice.

ETHNOPHARMACOLOGICAL RELEVANCE: There are many studies and therapeutic properties attributed to the flowers and leaves of the Cannabis species, but even with few pharmacological studies, Cannabis sativa L. (Cannabaceae) roots presents several therapeutic indications in folk medicine. AIM OF THE STUDY: This study aimed to evaluate the anti-inflammatory and spasmolytic effects as well as the toxicological profile of the aqueous extract of Cannabis sativa roots (CsAqEx) in mice. MATERIALS AND METHODS: We assessed the anti-inflammatory effect with carrageenan-induced leukocyte migration assay, and carrageenan and histamine-induced paw edema methods; The spasmolytic effect was assessed through in vitro assays with isolated mice trachea. To assess motor coordination and mobility, mice went through the rotarod and open field tests, respectively. For the single-dose toxicity study, we administered CsAqEx at the dose of 1000 mg/kg by gavage. In a repeated dose toxicity study, animals received CsAqEx at doses of 25 mg or 100 mg/kg for 28 days. RESULTS: The CsAqEx inhibited the migration of leukocytes at the doses of 25, 50, and 100 mg/kg. The CsAqEx showed anti-inflammatory activity after the intraplantar injection of carrageenan, presenting a reduction in edema formation at all tested doses (12.5, 25, 50 and 100 mg/kg). The dose of 12.5 mg/kg of CsAqEx prevented edema formation after intraplantar injection of histamine. In an organ bath, 729 µg/mL of CsAqEx did not promote spasmolytic effect on isolated mice tracheal rings contracted by carbachol (CCh) or potassium chloride (KCl). We did not observe clinical signs of toxicity in the animals after acute treatment with CsAqEx, which suggested that the median lethal dose (LD50) is greater than 1000 mg/kg. Repeated dose exposure to the CsAqEx did not produce significant changes in hematological, biochemical, or organ histology parameters. CONCLUSIONS: The results suggest that the anti-inflammatory effect of CsAqEx is related to the reduction of vascular extravasation and migration of inflammatory cells, without effects on the central nervous system. Moreover, there was no spasmolytic effect on airway smooth muscle and no toxicity was observed on mice.

The TRPM3 ion channel mediates nociception but not itch evoked by endogenous pruritogenic mediators.

During the molecular transduction of itch, the stimulation of pruriceptors on sensory fibers leads to the activation or sensitization of ion channels, which results in a consequent depolarization of the neurons. These ion channels mostly belong to the transient receptor potential (TRP) channels, which are involved in nociception and thermosensation. In particular, TRPV1 and TRPA1 were described in the transduction of both thermal nociception as well as histaminergic and non-histaminergic itch. The thermosensitive TRPM3 plays an indispensable role in heat nociception together with TRPV1 and TRPA1. However, the role of TRPM3 in the development of pruritus has not been studied yet. Therefore, in this study we aimed at investigating the potential role of TRPM3 in the transduction of pruritus and pain by investigating itch- and nociception-related behavior of Trpm3+/+ and Trpm3-/- mice, and by studying the activation of somatosensory neurons isolated from trigeminal ganglia upon application of algogenic and pruritogenic substances. Activators of TRPM3 evoked only nocifensive responses, but not itch in Trpm3+/+ animals, and these nocifensive responses were abolished in the Trpm3-/- strain. Histamine and endogenous non-histaminergic pruritogens induced itch in both Trpm3+/+ and Trpm3-/- mice to a similar extent. Genetic deletion or pharmacological blockade diminished TRPM3 mediated Ca2+ responses of sensory neurons, but did not affect responses evoked by pruritogenic substances. Our results demonstrate that, in contrast to other thermosensitive TRP channels, TRPM3 selectively mediates nociception, but not itch sensation, and suggest that TRPM3 is a promising candidate to selectively target pain sensation.

Herb pair of Ephedrae Herba-Armeniacae Semen Amarum alleviates airway injury in asthmatic rats.

ETHNOPHARMACOLOGICAL RELEVANCE: Ephedrae Herba (EH, Ephedra sinica Stapf.) and Armeniacae Semen Amarum (ASA, Prunus armeniaca L. var. ansu Maxim.) have been used to treat asthma, cold, fever, and cough in China for thousands of years. AIM OF THE STUDY: In this study, we aimed to investigate the optimal ratio of EH and ASA compatibility (EAC) to reduce airway injury in asthmatic rats and its possible mechanism. METHODS: Rats were sensitized with a mixture of acetylcholine chloride and histamine bisphosphate 1 h before sensitization by intragastric administration of EAC or dexamethasone or saline for 7 days. Subsequently, the ultrastructure of rat airway epithelial tissue changes, apoptosis of the airway epithelial cells, and the expression of mRNA and protein of EGRF and Bcl-2 were detected. RESULTS: Transmission electron microscope: EAC (groups C and E) had the most prominent effect on repairing airway epithelial cells' ultrastructural changes in asthmatic rats. TUNEL: dexamethasone and EAC (groups B、C、E and F) inhibited the apoptosis of airway epithelial cells in asthmatic rats (P < 0.05). In situ hybridization: EAC (group E) inhibited the overexpression of EGFR and Bcl-2 mRNA (P < 0.05).Western Blotting: EAC (groups A、B、C、E and F) inhibited the upregulation of airway epithelial EGFR and Bcl-2 protein expression (P < 0.01). CONCLUSIONS: Our findings indicate that EAC can inhibit abnormal changes in airway epithelial structure and apoptosis of airway epithelial cells, thereby alleviating airway injury. In this study, the best combination of EH and ASA to alleviate airway epithelial injury in asthmatic rats was group E (EH: ASA = 8: 4.5).

Flare Size but Not Intensity Reflects Histamine-Induced Itch.

INTRODUCTION: Flare reactions arise due to the release of vasodilators from sensory nerves caused by antidromic transmission of action potentials after the induction of itch. OBJECTIVE: We investigated the link between flare and itch using 3 models of itch. METHODS: Skin provocations with histamine, capsaicin, and cowhage were performed in 31 subjects. Itch was quantified using the visual analog scale. Flare was assessed using laser speckle contrast imaging (LSCI) and digital photography. RESULTS: The duration, intensity, and area under the curve of histamine-induced itch correlated with the area of increased blood flow measured with LSCI (r = 0.545, p = 0.002; r = 0.575, p = 0.001; and r = 0.649, p < 0.001, respectively). Itch and skin blood flow in response to capsaicin or cowhage did not correlate. CONCLUSION: In histamine-induced skin inflammation, itch and increased blood flow are linked. Thus, the area of histamine-induced flare may be used as a surrogate marker for histamine-induced itch.

Perampanel attenuates scratching behavior induced by acute or chronic pruritus in mice.

An itch is defined as an unpleasant sensation that evokes a desire to scratch. Glutamate is a major excitatory neurotransmitter in the mammalian central nervous system and has a crucial role in pruriceptive processing in the spinal dorsal horn. It is well known that glutamate exerts its effects by binding to various glutamate receptors including α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors, and that AMPA/kainate receptors play a crucial role in pruriceptive processing; however, the precise role of AMPA receptors remains uncertain. Perampanel, an antiepileptic drug, is an antagonist of AMPA receptors. Pretreatment with perampanel dose-dependently attenuated the induction of scratching, a behavior typically associated with pruritus, by intradermal administration of the pruritogen chloroquine. In addition, the induction of scratching in mice painted with diphenylcyclopropenone and NC/Nga mice treated with Biostir AD, animal models of contact dermatitis and atopic dermatitis, respectively, was dose-dependently alleviated by administration of perampanel. These findings indicate that AMPA receptors play a crucial role in pruriceptive processing in mice with acute or chronic pruritus.

Histamine Intolerance: The Current State of the Art.

Histamine intolerance, also referred to as enteral histaminosis or sensitivity to dietary histamine, is a disorder associated with an impaired ability to metabolize ingested histamine that was described at the beginning of the 21st century. Although interest in histamine intolerance has considerably grown in recent years, more scientific evidence is still required to help define, diagnose and clinically manage this condition. This article will provide an updated review on histamine intolerance, mainly focusing on its etiology and the existing diagnostic and treatment strategies. In this work, a glance on histamine intoxication will also be provided, as well as the analysis of some uncertainties historically associated to histamine intoxication outbreaks that may be better explained by the existence of interindividual susceptibility to ingested histamine.

Intranasal epinephrine effects on epinephrine pharmacokinetics and heart rate in a nasal congestion canine model.

BACKGROUND: Histamine release and vasodilation during an allergic reaction can alter the pharmacokinetics of drugs administered via the intranasal (IN) route. The current study evaluated the effects of histamine-induced nasal congestion on epinephrine pharmacokinetics and heart rate changes after IN epinephrine. METHODS: Dogs received 5% histamine or saline IN followed by 4 mg epinephrine IN. Nasal restriction pressure, epinephrine concentration, and heart rate were assessed. Maximum concentration (Cmax), area under plasma concentration-time curve from 1 to 90 min (AUC1-90), and time to reach Cmax (Tmax) were measured. Clinical observations were documented. RESULTS: In the 12 dogs in this study, nasal congestion occurred at 5-10 min after IN histamine administration versus no nasal congestion after IN saline. After administration of IN epinephrine, IN histamine-mediated nasal congestion was significantly reduced to baseline levels at 60, 80, and 100 min. There were no significant differences in Cmax and AUC1-90 between histamine and saline groups after IN epinephrine delivery (3.5 vs 1.7 ng/mL, p = 0.06, and 117 vs 59 ng/mL*minutes, p = 0.09, respectively). After receiving IN epinephrine, the histamine group had a significantly lower Tmax versus the saline group (6 vs 70 min, respectively; p = 0.02). Following IN epinephrine administration, the histamine group showed rapidly increased heart rate at 5 min, while there was a delayed increase in heart rate (occurring 30-60 min after administration) in the saline group. Clinical observations included salivation and emesis. CONCLUSION: IN histamine led to more rapid epinephrine absorption and immediately increased heart rate compared with IN saline. IN epinephrine decreased histamine-induced nasal congestion.

Complementary roles of murine NaV1.7, NaV1.8 and NaV1.9 in acute itch signalling.

Acute pruritus occurs in various disorders. Despite severe repercussions on quality of life treatment options remain limited. Voltage-gated sodium channels (NaV) are indispensable for transformation and propagation of sensory signals implicating them as drug targets. Here, NaV1.7, 1.8 and 1.9 were compared for their contribution to itch by analysing NaV-specific knockout mice. Acute pruritus was induced by a comprehensive panel of pruritogens (C48/80, endothelin, 5-HT, chloroquine, histamine, lysophosphatidic acid, trypsin, SLIGRL, ß-alanine, BAM8-22), and scratching was assessed using a magnet-based recording technology. We report an unexpected stimulus-dependent diversity in NaV channel-mediated itch signalling. NaV1.7-/- showed substantial scratch reduction mainly towards strong pruritogens. NaV1.8-/- impaired histamine and 5-HT-induced scratching while NaV1.9 was involved in itch signalling towards 5-HT, C48/80 and SLIGRL. Furthermore, similar microfluorimetric calcium responses of sensory neurons and expression of itch-related TRP channels suggest no change in sensory transduction but in action potential transformation and conduction. The cumulative sum of scratching over all pruritogens confirmed a leading role of NaV1.7 and indicated an overall contribution of NaV1.9. Beside the proposed general role of NaV1.7 and 1.9 in itch signalling, scrutiny of time courses suggested NaV1.8 to sustain prolonged itching. Therefore, NaV1.7 and 1.9 may represent targets in pruritus therapy.

The Neuropeptide Y Y2 Receptor Is Coexpressed with Nppb in Primary Afferent Neurons and Y2 Activation Reduces Histaminergic and IL-31-Induced Itch.

Itch stimuli are detected by specialized primary afferents that convey the signal to the spinal cord, but how itch transmission is regulated is still not completely known. Here, we investigated the roles of the neuropeptide Y (NPY)/Y2 receptor system on scratch behavior. The inhibitory Y2 receptor is expressed on mouse primary afferents, and intrathecal administration of the Y2 agonist peptide YY (PYY)3-36 reduced scratch episode frequency and duration induced by compound 48/80, an effect that could be reversed by intrathecal preadministration of the Y2 antagonist BIIE0246. Also, scratch episode duration induced by histamine could be reduced by PYY3-36 In contrast, scratch behavior induced by α-methyl-5HT, protease-activated receptor-2-activating peptide SLIGRL, chloroquine, topical dust mite extract, or mechanical itch induced by von Frey filaments was unaffected by stimulation of Y2 Primary afferent neurons expressing the Npy2r gene were found to coexpress itch-associated markers such as natriuretic peptide precursor b, oncostatin M receptor, and interleukin (IL) 31 receptor A. Accordingly, intrathecal PYY3-36 reduced the scratch behavior induced by IL-31. Our findings imply that the NPY/Y2 system reduces histaminergic and IL-31-associated itch through presynaptic inhibition of a subpopulation of itch-associated primary afferents. SIGNIFICANCE STATEMENT: The spinal neuropeptide Y system dampens scratching behavior induced by histaminergic compounds and interleukin 31, a cytokine involved in atopic dermatitis, through interactions with the Y2 receptor. The Y2 receptor is expressed by primary afferent neurons that are rich in itch-associated neurotransmitters and receptors such as somatostatin, natriuretic peptide precursor b, and interleukin 31 receptors.

Determination of Histamine in Japanese Spanish Mackerel (Scomberomorus niphonius) Meat Implicated in a Foodborne Poisoning.

An incident of foodborne poisoning causing illness in seven victims due to ingestion of fried Japanese Spanish mackerel (JS mackerel; Scomberomorus niphonius) meat occurred in September 2014 in Hualien County, eastern Taiwan. Of the two suspected fish meats, one raw sample contained 3,318 ppm of histamine and one fried sample contained 1,906 ppm of histamine, levels which are greater than the potential hazard action level (500 ppm) in most illness cases. Given the allergy-like symptoms of the victims and the high histamine content in the suspected fish samples, this foodborne poisoning was strongly suspected to be caused by histamine intoxication. In addition, five histamine-producing bacterial strains isolated from suspected raw fish samples, capable of producing 152 to 1,020 ppm of histamine in Trypticase soy broth supplemented with 1.0% l-histidine, were identified as Hafnia alvei (one strain), Enterobacter aerogenes (two strains), Raoultella ornithinolytica (one strain), and Morganella morganii (one strain) by 16S rDNA sequencing with PCR amplification. Moreover, 12 raw fish samples and 39 fried fish samples from retail stores were collected and tested to determine the occurrence of histamine. Two of 12 commercial raw fish samples (16.7%) had histamine levels greater than the U.S. Food and Drug Administration guideline for decomposition of 50 ppm for scombroid fish or product or a combination of both. To our knowledge, this is the first report in Taiwan to demonstrate that the JS mackerel meat products could cause histamine intoxication.

Histamine and migraine revisited: mechanisms and possible drug targets.

OBJECTIVE: To review the existing literature on histamine and migraine with a focus on the molecule, its receptors, its use in inducing migraine, and antihistamines in the treatment of migraine. BACKGROUND: Histamine has been known to cause a vascular type headache for almost a hundred years. Research has focused on antihistamines as a possible treatment and histamine as a migraine provoking agent but there has been little interest in this field for the last 25 years. In recent years two additional histamine (H3 and H4) receptors have been discovered and a series of non-sedating antihistamines have been developed. It is therefore timely to review the field again. METHODS: For this review the PubMed/MEDLINE database was searched for eligible studies. We searched carefully for all articles on histamine, antihistamines and histamine receptors in relation to migraine and the nervous system. The following search terms were used: histamine, migraine disorders, migraine, headache, antihistamines, histamine antagonists, clinical trials, induced headache, histamine H3 receptor, histamine H4 receptor and pharmacology. Four hundred thirty-six titles were read, 135 abstracts were read, 112 articles were read in full and 53 articles were used in this review. Review process resulted in 12 articles added to a total of 65. FINDINGS: Early studies of H1 and H2 antihistamines lack scientific strength and show conflicting results. Most of the antihistaminic drugs used in these trials bind also to other receptors which makes it difficult to conclude on the antihistaminic effect. Histamine is an efficient inducer of migraine attacks in migraine patients by an H1 mechanism most likely extracerebrally. These findings merit further investigation of antihistamines in clinical drug trials. The H3 and H4 receptors are found in primarily in CNS and immune tissues, respectively. H3 is likely to be involved in antinociception and has been linked with cognitive, neurodegenerative and sleep disorders. The only marketed H3 agent, pitolisant, is a brain penetrant H3 antagonist/inverse agonist which increases central histamine and causes headache. The experimental H3 agonist Nα-methylhistamine has shown promising results as a migraine preventative in studies of uncertain quality. With the current limited knowledge of the H4 receptor it is questionable whether or not the receptor is involved in migraine. CONCLUSION: There is insufficient support for first generation antihistamines (both H1 and H2) as preventive migraine medications and sedation and weight gain are unacceptable side effects. Non-sedating H1 antihistamines need to be appropriately tested. Central H3 receptors seem to have a role in migraine that merit further investigation. The histaminergic system may be a goal for novel migraine drugs.

In vitro and in vivo performance of epinastine hydrochloride-releasing contact lenses.

A number of drug-releasing contact lenses are currently being studied to address issues inherent in eye drops as a drug delivery method. In this study, we developed epinastine hydrochloride-releasing daily soft contact lenses for treatment of allergic conjunctivitis and examined their in vitro and in vivo performance. Preformed soft contact lenses with/without ionic functional groups were soaked in a solution of epinastine hydrochloride in phosphate-buffered saline to prepare epinastine hydrochloride-releasing soft contact lenses. Among these contact lenses with different ionicities, anionic lenses demonstrated the maximum, relatively linear epinastine hydrochloride release, in vitro. The amount of epinastine hydrochloride release was directly proportional to the concentration of the epinastine hydrochloride solution used to prepare the contact lens. The epinastine hydrochloride-releasing anionic soft contact lens also demonstrated prolonged drug release and significantly greater efficacy compared with epinastine hydrochloride eye drops 12 h after treatment, in vivo. Further studies are required to determine the appropriate amount of epinastine hydrochloride to be contained in the anionic soft contact lenses.

Effects of Medium Molecular Weight Heparinyl Phenylalanine on Type I Hypersensitivity.

BACKGROUND/AIM: We investigated the inhibitory action of medium molecular weight heparinyl phenylalanine (MHF) on type I hypersensitivity in comparison with medium molecular weight heparinyl arginine (MHR). MATERIALS AND METHODS: MHF and MHR were synthesized from heparin (HE) to decrease the side-effect of HE based on its anticoagulant action and used in this study. RESULTS: MHF demonstrated a significant inhibitory action on 48-h homologous passive cutaneous anaphylaxis in rats. Although MHF did not affect the death of mice injected with a lethal dose of histamine, it significantly prolonged the survival time of mice administered a lethal dose of compound 48/80. On the other hand, MHR did not inhibit type I hypersensitivity. CONCLUSION: The inhibitory action of MHF on the type I allergic reaction was due to a reduction or delay in histamine release from mast cells. MHF may be a potent anti-allergic agent.