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Highlights: [•] Mammalian HDC enzymes are differentially processed in Cos7 cells. [•] Caspase-dependent and caspase-independent processing of rat and human HDCs’ occurs. [•] Caspase-dependent processing of rat and human HDCs’ occurs at divergent sites. [•] Caspase processing of rat and human HDCs’ in Cos7 cells is caspase-6 dependent. [•] Processing of the human HDC enzyme can be pharmacologically regulated. [ABSTRACT FROM AUTHOR]

Histidine decarboxylase (HDC), a histamine synthase, is expressed in various hematopoietic cells and is induced by hematopoietic cytokines such as granulocyte colony-stimulating factor (G-CSF). We previously showed that nitrogen-containing bisphosphonate (NBP)-treatment induces extramedullary hematopoiesis via G-CSF stimulation. However, the function of HDC in NBP-induced medullary and extramedullary hematopoiesis remains unclear. Here, we investigated changes in hematopoiesis in wild-type and HDC-deficient (HDC-KO) mice. NBP treatment did not induce anemia in wild-type or HDC-KO mice, but did produce a gradual increase in serum G-CSF levels in wild-type mice. NBP treatment also enhanced Hdc mRNA expression and erythropoiesis in the spleen and reduced erythropoiesis in bone marrow and the number of vascular adhesion molecule 1 (VCAM-1)-positive macrophages in wild-type mice, as well as increased the levels of hematopoietic progenitor cells and proliferating cells in the spleen and enhanced expression of bone morphogenetic protein 4 (Bmp4), CXC chemokine ligand 12 (Cxcl12), and hypoxia inducible factor 1 (Hif1) in the spleen. However, such changes were not observed in HDC-KO mice. These results suggest that histamine may affect hematopoietic microenvironments of the bone marrow and spleen by changing hematopoiesis-related factors in NBP-induced extramedullary hematopoiesis.

Histamine or scombrotoxin fish poisoning is caused by ingestion of bacterially produced histamine in fish. Histamine-producing bacteria generally contain the histidine decarboxylase gene (hdc). However, some strains of Photobacterium phosphoreum are known to produce significant levels of histamine, although the hdc gene in these strains has not been recognized. The objective of this study was to investigate a previously unidentified mechanism of histamine production by P. phosphoreum. We identified a protein with histidine decarboxylase (HDC) activity comparable to activity of the pyridoxal-5-phosphate (PLP) dependent HDC from P. kishitanii and M. morganii. The newly identified protein (HDC2) in P. phosphoreum and P. kishitanii strains, was approximately 2× longer than the HDC protein from other Gram-negative bacteria and had 12% similarity to previously identified HDCs. In addition, the hdc2 gene cluster in P. phosphoreum was identical to the hdc gene cluster in P. kishitanii. HDC2 had optimal activity at 20-35 °C, at pH 4, and was not affected by 0-8% NaCl concentrations. Compared to the hdc gene from P. kishitanii, expression of the hdc2 gene was constitutive and not affected by pH or excess histidine. This newly identified protein explains possible mechanisms of histamine production in P. phosphoreum. Characterization of this protein will help in designing control measures to prevent or reduce histamine production in fish., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Published by Elsevier B.V.)

Diabetes has been reported to modulate the airway smooth muscle reactivity and lead to attenuation of allergic inflammatory response in the lungs. In this study, we aimed to study the effect of insulin on cell activation and airway responsiveness in patients with diabetes mellitus (DM). The airway contraction in rat model groups including a non-DM group, a non-DM+INDUCTION group, a DM+INDUCTION group and a DM+INDUCTION+INSULIN group was measured to observe the effect of insulin on airway responsiveness. Radioenzymatic assay was conducted to measure the levels of histamine, and ELISA assay was conducted to measure bronchial levels of interleukin (IL)-1b, tumour necrosis factor (TNF)-a, cytokine-induced neutrophil chemoattractant (CINC)-1, P-selectin and β-hexosaminidase. The tension in the main and intrapulmonary bronchi of DM+INDUCTION rats was lower than that of the non-DM+INDUCTION rats, whereas the treatment of insulin partly restored the normal airway responsiveness to OA in DM rats. The release of histamine was remarkably suppressed in DM+INDUCTION rats but was recovered by the insulin treatment. Also, OA significantly increased the levels of IL-1b, TNF-a, CINC-1 and P-selectin in non-DM rats, whereas insulin treatment in DM+INDUCTION rats partly restored the normal levels of IL-1b, TNF-a, CINC-1 and P-selectin in DM rats. Moreover, the expression of IR and IGF1R was evidently suppressed in DM rats, with the methylation of both IR and IGF1R promoters was aggravated in DM rats. Therefore, we demonstrated that DM-induced hypermethylation inhibited mast cell activation and airway responsiveness, which could be reversed by insulin treatment., (© 2020 The Authors. Journal of Cellular and Molecular Medicine published by Foundation for Cellular and Molecular Medicine and John Wiley & Sons Ltd.)

Huntingtin-associated protein 1 (HAP1) is a neuronal cytoplasmic protein that is predominantly expressed in the brain and spinal cord. In addition to the central nervous system, HAP1 is also expressed in the peripheral organs including endocrine system. Different types of enteroendocrine cells (EEC) are present in the digestive organs. To date, the characterization of HAP1-immunoreactive (ir) cells remains unreported there. In the present study, the expression of HAP1 in pyloric stomach in adult male rats and its relationships with different chemical markers for EEC [gastrin, marker of gastrin (G) cells; somatostatin, marker of delta (D) cells; 5-HT, marker of enterochromaffin (EC) cells; histamine, marker of enterochromaffin-like (ECL) cells] were examined employing single- or double-labelled immunohistochemistry and with light-, fluorescence- or electron-microscopy. HAP1-ir cells were abundantly expressed in the glandular mucosa but were very few or none in the surface epithelium. Double-labelled immunofluorescence staining for HAP1 and markers for EECs showed that almost all the G-cells expressed HAP1. In contrast, HAP1 was completely lacking in D-cells, EC-cells or ECL-cells. Our current study is the first to clarify that HAP1 is selectively expressed in G-cells in rat pyloric stomach, which probably reflects HAP1's involvement in regulation of the secretion of gastrin., (Copyright © 2020 Elsevier GmbH. All rights reserved.)

Histamine, one of the most toxic and commonly encountered biogenic amines (BA) in food, is produced by the microbial decarboxylation of histidine. It may accumulate at high concentrations in fish and fermented food. Cheese has some of the highest histamine concentrations, the result of the histidine-decarboxylase activity of certain lactic acid bacteria (LAB). The present work describes the nucleotide sequence and transcriptional organization of the gene cluster responsible for histamine biosynthesis (the HDC cluster) in Lactobacillus vaginalis IPLA 11064 isolated from cheese. The influence of histidine availability and pH on histamine production and the expression of the HDC cluster genes is also examined. As expected, the results suggest that the production of histamine under acidic conditions improves cell survival by maintaining the cytosol at an appropriate pH. However, the transcriptional regulation of the HDC cluster is quite different from that described in other dairy histamine-producing LAB, probably due to the lack of a termination-antitermination system in the histidyl-tRNA synthetase gene (hisS)., Competing Interests: Declaration of competing interest The authors declare no conflict of interest., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Aims: Quality evaluation of fresh whitemouth croaker (Micropogonias furnieri) by histamine determination using the HPLC-DAD method and quantification of histamine-forming bacteria using NGS and qPCR., Methods and Results: The histamine content of fresh whitemouth croaker was detected by high performance liquid chromatography with diode array detector with a concentration ranging from 258·52 to 604·62 mg kg -1 being observed. The number of histidine decarboxylase (hdc gene) copies from Gram-negative bacteria and the bacteria Morganella morganii and Enterobacter aerogenes were quantified by quantitative polymerase chain reaction. All samples were positive, with copy numbers of the hdc gene ranging from 4·67 to 12·01 log 10 per g. The microbial community was determined by sequencing the V4 region of the 16S rRNA gene using the Ion Torrent platform. The bioinformatics data generated by frog software showed that the phylum Proteobacteria was the most abundant, with the family Moraxellaceae being more prevalent in samples collected in the summer, whereas the Pseudomonadaceae was more present in the winter., Conclusions: All fish muscle samples analysed in this study presented histamine values higher than those allowed by CODEX Alimentarius. Additionally, a wide variety of spoilage micro-organisms capable of expressing the enzyme histidine decarboxylase were detected. Thus, improvements in handling and processing are required to minimize the prevalence of histamine-producing bacteria in fish., Significance and Impact of the Study: Global fish production in 2016 was 171 million tons, with the largest consumer being China, followed by Indonesia and the USA. In Brazil, 1·3 million tons of fish are consumed per year, with whitemouth croaker being the main fish landed. Notably, cases associated with histamine poisoning are quite common. According to the European Food Safety Authority and European Centre for Disease Prevention and Control, a total of 599 HFP outbreaks were identified in the European Union during the period 2010-2017. In the USA, there were 333 outbreaks with 1383 people involved between 1998 and 2008., (© 2019 The Society for Applied Microbiology.)

Histamine food poisoning is a major safety concern related to seafood consumption worldwide. Morganella psychrotolerans is a novel psychrotolerant histamine-producer. In this study, the histamine production behaviors of M. psychrotolerans and two other major histamine-producers, mesophilic Morganella morganii and psychrotrophic Photobacterium phosphoreum, were compared in seafood products, and histamine accumulation by M. psychrotolerans was characterized at various pH and temperature levels in culture broth. The growth of M. psychrotolerans and P. phosphoreum increased similarly at 4 °C in canned tuna, but M. psychrotolerans produced much higher levels of histamine than P. phosphoreum. Histamine accumulation by M. psychrotolerans was induced at lower environmental pH condition at 4 and 20 °C. The optimal temperature and pH for producing histamine by crude histidine decarboxylase of M. psychrotolerans were 30 °C and pH 7, respectively. The activity of the crude HDC extracted from M. psychrotolerans cells at 10 °C retained 45% of the activity at 30 °C. Histidine decarboxylase gene expression of M. psychrotolerans was induced by low pH conditions. These results suggest that M. psychrotolerans are also a very important histamine-producer leading to histamine poisoning associated with seafood below the refrigeration temperature.

Mast cells have secretory granules containing chemical mediators such as histamine and play important roles in the immune system. Polyamines are essential factors for cellular processes such as gene expression and translation. It has been reported that secretory granules contain both histamine and polyamines, which have similar chemical structures and are produced from the metabolism of cationic amino acids. We investigated the effect of polyamine depletion on mast cells using bone marrow-derived mast cells (BMMCs). Polyamine depletion was induced using α-difluoromethylornithine (DFMO), an irreversible inhibitor of ornithine decarboxylase. DFMO treatment resulted in a significant reduction of cell number and abnormal secretory granules in BMMCs. Moreover, the cells showed a 2.3-fold increase in intracellular histamine and up-regulation of histidine decarboxylase (HDC) at the transcriptional level during BMMC differentiation. Levels of the transcription factor kruppel-like factor 4 (KLF4) greatly decreased upon DFMO treatment; however, Klf4 mRNA was expressed at levels similar to controls. We determined the translational regulation of KLF4 using reporter genes encoding Klf4-luc2 fusion mRNA, for transfecting NIH3T3 cells, and performed in vitro translation. We found that the efficiency of KLF4 synthesis in response to DFMO treatment was enhanced by the existence of a GC-rich 5'-untranslated region (5'-UTR) on Klf4 mRNA, regardless of the recognition of the initiation codon. Taken together, these results indicate that the enhancement of histamine synthesis by DFMO depends on the up-regulation of Hdc expression, achieved by removal of transcriptional suppression of KLF4, during differentiation., Competing Interests: The authors have declared that no competing interests exist.

With an increase in atopic cases and owing to a significant role of mast cells in type I hypersensitivity, a therapeutic need to inhibit degranulation of mast cells has risen. Mast cells are notorious for IgE-mediated allergic response. Advancements have allowed researchers to improve clinical outcomes of already available therapies. Engineered peptides and antibodies can be easily manipulated to attain desired characteristics as per the biological environment. A number of these molecules are designed to target mast cells in order to regulate the release of histamine and other mediators, thereby controlling type I hypersensitivity response. The aim of this review paper is to highlight some of the significant molecules designed for the purpose., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

The author has described two new functions of endothelial cells for efficient delivery of drugs to tissues. First, it was indicated that tight junction (TJ)-associated protein, claudin-1, exerts potent paracellular barrier function in cultured mouse lung microvascular endothelial cells (LMECs). This barrier was instantly and reversibly opened by reduction of TJ proteins expression via histamine H 1 and H 2 receptors. Histamine was biosynthesized by l-histidine decarboxylase from uptaken l-histidine, and biotransformed by type B of monoamine oxidase, suggesting that histamine concentration is controlled in rat brain MECs (BMECs) and LMECs. Moreover, uptake of l-histidine into BMECs and LMECs markedly increased with addition of ZnSO 4 . Second, it was suggested that drug-metabolizing enzymes such as CYP and flavin-containing monooxygenase exist in vascular endothelial cells exposed to blood and to aerobic conditions. These cells have the same ability to metabolize drugs as hepatocytes, demonstrating that vascular endothelial cells are a metabolic barrier against tissue transfer of drugs. From these results, it was suggested that reversible opening of TJ and selective inhibition of drug metabolism in vascular endothelial cells may be efficient delivery strategies of drugs to tissues. Finally, I hope that this research will lead to development of new drugs and possible re-evaluation of discontinued drugs.

Histamine is a biogenic amine that is chiefly produced in mast cells and basophils and elicits an allergic response upon stimulation. Histidine decarboxylase (HDC) is a unique enzyme that catalyzes the synthesis of histamine. Therefore, the spatiotemporally specific Hdc gene expression profile could represent the localization of histamine-producing cells under various pathophysiological conditions. Although the bioactivity of histamine is well defined, the regulatory mechanism of Hdc gene expression and the distribution of histamine-producing cell populations in various disease contexts remains unexplored. To address these issues, we generated a histidine decarboxylase BAC (bacterial artificial chromosome) DNA-directed GFP reporter transgenic mouse employing a 293-kb BAC clone containing the entire Hdc gene locus and extended flanking sequences (Hdc-GFP). We found that the GFP expression pattern in the Hdc-GFP mice faithfully recapitulated that of conventional histamine-producing cells and that the GFP expression level mirrored the increased Hdc expression in lipopolysaccharide (LPS)-induced septic lungs. Notably, a CD11b + Ly6G + Ly6C low myeloid cell population accumulated in the lung during sepsis, and most of these cells expressed high levels of GFP and indeed contain histamine. This study reveals the accumulation of a histamine-producing myeloid cell population during sepsis, which likely participates in the immune process of sepsis.

Mast cells (MCs) are the principal effector cells of IgE-mediated allergy. IL-33 is released by resident skin cells as alarmin upon tissue damage or allergen contact. Owing to their pronounced receptor expression, MCs are important targets of IL-33 action, but consequences for skin MCs are ill-defined, especially upon chronic exposure to IL-33. Mimicking the inflammatory milieu of skin disorders, we found that persistent exposure to IL-33 (over a 5-week period) strengthened skin MC numbers through accelerated cell-cycle progression and restriction of apoptosis. Conversely, IL-33 attenuated degranulation and FcεRI expression, potentially as a feedback to chronic "alarmin" exposure. Interestingly, the negative impact on histamine release was counterbalanced by amplified histamine production. Considering the clinical significance of histamine and scarce information on its regulation, we explored the molecular underpinnings. IL-33 induced swift phosphorylation of p38 and JNK (but not of ERK1/2 or AKT), and stimulated histidine decarboxylase expression. Combining pharmacological inhibition and kinase elimination by Accell-facilitated RNA interference in skin MCs revealed a p38-dependent, but JNK-independent mechanism. Collectively, IL-33 exerts multifaceted effects on cutaneous MCs at a post-maturation stage. The IL-33-skin MC axis may contribute to and balance inflammation in chronic skin disorders., (Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.)

In a recent study, repeated cold application induced beiging in subcutaneous white adipose tissue (SC WAT) of humans independent of body mass index. To identify factors that promote or inhibit beiging, we performed multiplex analysis of gene expression with the Nanostring nCounter system (the probe set contained genes for specific immune cell markers, cytokines, and chemokines) on the SC WAT from lean subjects. Multiple correlations analysis identified mast cell tryptase and CCL26, a chemokine for mast cells, as genes whose change correlated positively with the change in UCP1 in SC WAT, leading to the hypothesis that mast cells promote SC WAT beiging in response to cold. We quantified mast cell recruitment into SC WAT and degranulation. Mast cells increased in number in SC WAT in lean subjects, and there was an increase in the number of degranulated mast cells in both lean subjects and subjects with obesity. We determined that norepinephrine stimulated mast cell degranulation and histamine release in vitro. In conclusion, cold stimulated adipose tissue mast cell recruitment in lean subjects and mast cell degranulation in SC WAT of all research participants independent of baseline body mass index, suggesting that mast cells promote adipose beiging through the release of histamine or other products.

Background: Histamine is an important immunomodulator influencing both the innate and adaptive immune system. Certain host cells express the histidine decarboxylase enzyme (HDC), which is responsible for catalysing the decarboxylation of histidine to histamine. We and others have shown that bacterial strains can also express HDC and secrete histamine; however, the influence of bacterial-derived histamine on the host immune responses distant to the gut is unclear., Methods: The Escherichia coli BL21 (E coli BL21) strain was genetically modified to express the Morganella morganii (M morganii)-derived HDC gene (E coli BL21_HTW). E coli BL21 and E coli BL21_HTW were gavaged to ovalbumin (OVA) sensitized and challenged mice to investigate the effect of bacterial-derived histamine on lung inflammatory responses., Results: Oral administration of E coli BL21_HTW, which is able to secrete histamine, to wild-type mice reduced lung eosinophilia and suppressed ex vivo OVA-stimulated cytokine secretion from lung cells in the OVA respiratory inflammation mouse model. In histamine receptor 2 (H2R)-deficient mice, administration of histamine-secreting bacteria also reduced inflammatory cell numbers in bronchoalveolar lavage (BAL). However, the suppressive effect of bacterial-derived histamine on BAL inflammation was lost in HDC-deficient mice. This loss of activity was associated with increased expression of histamine degrading enzymes and reduced histamine receptor expression., Conclusion: Histamine secretion from bacteria within the gut can have immunological consequences at distant mucosal sites, such as within the lung. These effects are influenced by host histamine receptor expression and the expression of histamine degrading enzymes., (© 2018 EAACI and John Wiley and Sons A/S. Published by John Wiley and Sons Ltd.)

Histaminol is a relatively rare metabolite most commonly resulting from histidine metabolism. Here we describe histaminol production and secretion into the culture broth by the methanogen Methanococcus maripaludis S2 as well as a number of other methanogens. This work is the first identification of this compound as a natural product in methanogens. Its biosynthesis from histidine was confirmed by the incorporation of 2 H3-histidine into histaminol by growing cells of M. maripaludis S2. Possible functions of this molecule could be cell signaling as observed with histamine in eukaryotes or uptake of metal ions.

In the course of analyzing amino acid sequence of an allergen (≈20 kDa), we found this protein has a homology with the amino acid sequence of putative α-Dioxygenase fragment (ADF). Allergy caused by many allergens having an enzymatic activity have been reported previously, but allergenicity to neither α-Dioxygenase enzyme nor to it's any constituents has been reported. We sought to purify an ADF (≈19.5 kDa) from chickpea to investigate it's inherent allergic potential in BALB/c mice. The ADF showed IgE-affinity in sera of sensitized BALB/c mice and allergic patients. Enhanced levels of histamine, specific IgE as well as IgG1, IL-4, IL-17, IL-6, IL-2 and IL-10 were observed in the sera of mice treated with ADF allergen. A positive skin Type 1 test and elevated number of mast cells were found in the treated mice. Apart from this, enhanced number of immune cells i.e. CD19+ and CD4+ were also noticed in the ADF treated group. Higher expressions of IL-4 as well as GATA-3 and prominent histological changes were observed in tissues of treated animals. Furthermore, expressions of Th2 cytokines, associated transcription factors and mast cell signaling proteins were also increased at mRNA and protein levels in the intestines of ADF treated mice. Conclusively, present study demonstrated that ADF with molecular weight of 19.5 kDa is a clinical relevant allergen which causes allergic immune responses in BALB/c mice and may play a pivotal role in allergy caused by food containing α-Dioxygenase enzyme in sensitive individuals., (Copyright © 2018 Elsevier GmbH. All rights reserved.)

Histamine in foods with a high histidine content may be produced by bacteria with histidine decarboxylase activity. Consumption of food enriched in histamine can produce symptoms of histamine poisoning that include flushing, headache, and urticaria. The number of histamine poisoning cases in Japan has decreased with developments in food hygiene management technology. However, approximately 10 cases are still reported each year. In addition, there have been cases where histamine was detected in the end products, prompting large product recalls. To prevent and identify causes of histamine toxicity, manufacturers must identify the bacteria causing the illness. A simple method of identification is needed, since sequence-based identification is complicated to perform and the analysis takes a long time. High-Resolution Melting Analysis (HRMA) is a method that detects differences in the base sequences of PCR products manifested as varied melting temperatures of double-stranded DNA. The present study was intended to develop a rapid identification method for major histamine-producing bacteria using HRMA. Species-specific HRMA primers were designed that specifically targeted the hdcA gene of 20 Gram-negative histamine-producing bacterial strains. The designed primers were used for HRM analysis of the 20 histamine-producing bacterial strains. The strains were divided into three groups (A, B, and C) based on differences in melting temperature values obtained by T m Calling analysis program. Group A comprised terrestrial bacteria, such as Morganella, Enterobacter, and Raoultella, while Groups B and C comprised marine bacteria, such as those belonging to the genera Vibrio and Photobacterium. The melting profiles obtained in Group A by HRMA were used to identify the aforementioned terrestrial bacteria. The findings indicated that HRMA can easily identify the major gram-negative histamine-producing bacteria. A flow chart was created to identify histamine-producing bacterial species. This method enables the identification of histamine-producing bacterial species more quickly and easily than conventional sequence-based methods. Therefore, the method could be valuable for food companies to screen raw materials and products and track the source of contamination, which will in turn contribute to the prevention of histamine-food poisoning and investigation of its causes.

Background: Hepoxilins are biologically active metabolites of arachidonic acid that are formed through the 12-lipoxygenase pathway. Hepoxilin A 3 is now known to be an important regulator of mucosal inflammation in response to infection by bacterial pathogens and was recently identified as a potent neutrophil chemoattractant in the intestinal mucosa. Our goal in this study was to determine if airway infection with Chlamydia in a murine model of allergic airway disease (AAD) induces hepoxilin secretion along with airway neutrophilia. Methods: We utilized an AAD adult Balb/c mouse model to evaluate airway pathology and immune response by assaying bronchoalveolar lavage (BAL) fluid cytokine, cellularity, histidine decarboxylase (HDC) as well as histamine released in response to in-vivo chlamydial antigen stimulation of purified airway neutrophils. Hepoxilin A 3 production was determined by Western blot identification of 12-lipoxygenase precursor (12-LO). Results: Chlamydial infection induced increased production of IL-2, IL-12, TNF-α, and IFN-γ in BAL fluid compared to uninfected animals. Chlamydia -infected mice responded with robust airway neutrophil infiltration and upon induction of AAD increased their production of IL-4, IL-5, and IL-13 by >3 fold compared to unsensitized groups. In addition, 12-LO mRNA was upregulated in infected, but not in uninfected AAD mice, suggesting the production of hepoxilin A 3 . mRNA expression of HDC was induced only in neutrophils from the airways of Chlamydia -infected mice, but was not seen in AAD only or uninfected controls. When purified neutrophils from infected animals were challenged with chlamydial antigen in vitro there was significant histamine release. Conclusions: Our data confirms the production and release of hepoxilin A 3 in the murine airways concomitant with airway neutrophilia in response to chlamydial infection. We further confirmed that Chlamydia provokes the production and release of histamine by these neutrophils. These findings suggest that neutrophils, provoked by Chlamydia infection can synthesize and release histamine, thereby contributing directly to airway inflammation.

Among traditional Chinese medicine injections, intravenous Shuang-Huang-Lian (IV-SHL) has the highest incidence of injection-induced immediate hypersensitivity reactions (IHRs). The precise mechanisms of IV-SHL-induced IHRs remain ambiguous. In this study, we investigated the mechanisms of SHL injection (SHLI)-induced IHRs. Our data showed that serum total IgE and mouse mast cell protease 1 (MMCP1) levels were higher in the SHLI antiserum; however, these effects of SHLI disappeared in the antibiotic-treated mice. SHLI caused intraplantar vasopermeability and shock during the first local or systemic injection. SHLI-induced nonallergic IHRs were attributed to its intermediate fraction F2 (the extract of Lonicerae Japonicae Flos and Fructus forsythiae), and could be blocked by antagonists for histamine or C5a, rather than PAF or C3a. Eight constituents of F2 were able to directly activate C5 to promote local vasopermeability at the mg/mL level. In conclusion, SHLI-induced IHRs are not mediated by IgE. SHLI or its F2 can directly activate blood C5. Subsequently, C5a is likely to provoke histamine release from its effector cells (e.g., mast cells and basophils), indicating that histamine is a principal effector of IHRs induced by SHLI.

Background: Histamine (HA), a small molecule that is synthesized from the amino acid histidine, plays an important role in the immune system where it is associated with allergies, inflammation, and T-cell regulation. In the brain, histamine is stored in mast cells and other non-neuronal cells and also acts as a neurotransmitter. The histamine neuron cell bodies are in the tuberomammillary (TM) nucleus of the hypothalamus and these neurons send projections throughout the central nervous system (CNS), in particular to the cerebral cortex, amygdala, basal ganglia, hippocampus, thalamus, retina, and spinal cord. HA neurons make few synapses, but release HA from the cell bodies and from varicosities when the neurons fire. Thus the HA neural system seems to modulate and control the HA concentration in projection regions. It is known that high HA levels in the extracellular space inhibit serotonin release, so HA may play a role in the etiology of depression., Results: We compare model predictions to classical physiological experiments on HA half-life, the concentration of brain HA after histidine loading, and brain HA after histidine is dramatically increased or decreased in the diet. The model predictions are also consistent with in vivo experiments in which extracellular HA is measured, using Fast Scan Cyclic Voltammetry, in the premammillary nucleus (PM) after a 2 s antidromic stimulation of the TM, both without and in the presence of the H 3 autoreceptor antagonist thioperamide. We show that the model predicts well the temporal behavior of HA in the extracellular space over 30 s in both experiments., Conclusions: Our ability to measure in vivo histamine dynamics in the extracellular space after stimulation presents a real opportunity to understand brain function and control. The observed extracellular dynamics depends on synthesis, storage, neuronal firing, release, reuptake, glial cells, and control by autoreceptors, as well as the behavioral state of the animal (for example, depression) or the presence of neuroinflammation. In this complicated situation, the mathematical model will be useful for interpreting data and conducting in silico experiments to understand causal mechanisms. And, better understanding can suggest new therapeutic drug targets.

Microbiome-mediated suppression of carcinogenesis may open new avenues for identification of therapeutic targets and prevention strategies in oncology. Histidine decarboxylase (HDC) deficiency has been shown to promote inflammation-associated colorectal cancer by accumulation of CD11b + Gr-1 + immature myeloid cells, indicating a potential antitumorigenic effect of histamine. Here, we demonstrate that administration of hdc + Lactobacillus reuteri in the gut resulted in luminal hdc gene expression and histamine production in the intestines of Hdc -/- mice. This histamine-producing probiotic decreased the number and size of colon tumors and colonic uptake of [ 18 F]-fluorodeoxyglucose by positron emission tomography in Hdc -/- mice. Administration of L. reuteri suppressed keratinocyte chemoattractant (KC), Il22, Il6, Tnf, and IL1α gene expression in the colonic mucosa and reduced the amounts of proinflammatory, cancer-associated cytokines, keratinocyte chemoattractant, IL-22, and IL-6, in plasma. Histamine-generating L. reuteri also decreased the relative numbers of splenic CD11b + Gr-1 + immature myeloid cells. Furthermore, an isogenic HDC-deficient L. reuteri mutant that was unable to generate histamine did not suppress carcinogenesis, indicating a significant role of the cometabolite, histamine, in suppression of chronic intestinal inflammation and colorectal tumorigenesis. These findings link luminal conversion of amino acids to biogenic amines by gut microbes and probiotic-mediated suppression of colorectal neoplasia., (Copyright © 2017 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.)

The loss of specific neuronal phenotypes, as determined by immunohistochemistry, has become a powerful tool for identifying the nature and cause of neurological diseases. Here we show that the number of neurons identified and quantified using this method misses a substantial percentage of extant neurons in a phenotype specific manner. In mice, 24% more hypocretin/orexin (Hcrt) neurons are seen in the night compared to the day, and an additional 17% are seen after inhibiting microtubule polymerization with colchicine. We see no such difference between the number of MCH (melanin concentrating hormone) neurons in dark, light or colchicine conditions, despite MCH and Hcrt both being hypothalamic peptide transmitters. Although the size of Hcrt neurons did not differ between light and dark, the size of MCH neurons was increased by 15% in the light phase. The number of neurons containing histidine decarboxylase (HDC), the histamine synthesizing enzyme, was 34% greater in the dark than in the light, but, like Hcrt, cell size did not differ. We did not find a significant difference in the number or the size of neurons expressing choline acetyltransferase (ChAT), the acetylcholine synthesizing enzyme, in the horizontal diagonal band (HBD) during the dark and light conditions. As expected, colchicine treatment did not increase the number of these neurons. Understanding the function and dynamics of transmitter production within "non-visible" phenotypically defined cells has fundamental implications for our understanding of brain plasticity.

Background: The efficacy of epinastine 0.05% ophthalmic solution for pollen allergic conjunctivitis has already been shown in a conjunctival allergen challenge (CAC) test using cedar pollen as a challenge. The present study investigated the efficacy of this solution against birch pollen conjunctivitis in a CAC test., Methods: Ten adult subjects (eight males and two females) with asymptomatic birch pollen conjunctivitis were enrolled in this study. The average age of the subjects was 41.1 years. This study was conducted during a period without birch pollen dispersion. In each subject, the epinastine 0.05% ophthalmic solution was instilled in one eye, and an artificial tear fluid was instilled in the fellow eye in a double-blind manner. Five minutes or 4 h after the drug instillation, both eyes were challenged with an optimal concentration of birch pollen, and ocular itching and conjunctival hyperemia were then graded. Tears were collected before the drug instillation and 20 min after the pollen challenge, and the histamine level was measured., Results: The ocular itching scores and palpebral conjunctival hyperemia scores of the epinastine-treated eyes were significantly lower than those of the contralateral control eyes when the eyes were pretreated with the drug 4 h before the CAC. There was a significant correlation between the tear histamine level and mean ocular itching score of three time points (3, 5 and 10 min) following the CAC in the control eyes but not the epinastine-treated eyes., Conclusions: Epinastine is effective in suppressing ocular itching and conjunctival hyperemia in birch pollen conjunctivitis., (Copyright © 2017 Japanese Society of Allergology. Production and hosting by Elsevier B.V. All rights reserved.)

This study demonstrates for the first time that a non-commercial selected autochthonous O. oeni strain has been used to conduct malolactic fermentation (MLF) while lowering histamine formation in the same winery. Lactic acid bacteria (LAB) were isolated from 13 vats before and after spontaneous MLF at the Pago de Carraovejas winery from the Ribera del Duero region (Spain). Only O. oeni were present, typed and characterized, and both histamine producer and non-producers existed. From the non-producers, one strain was selected to become a starter according to its genetic profile, prevalence in the different wines in the winery, resistance to alcoholic degree, resistance to high polyphenolic content, inability to synthesise histamine, growth kinetics and malolactic activity. This starter was produced at semi-industrial levels to inoculate 20,000L of Tempranillo red wine. The inoculated vat showed 5-fold less histamine than the non-inoculated control vat. After 1year, the barrel-ageing histamine concentrations were 3-fold lower in the inoculated vat than in the non-inoculated vat., (Copyright © 2016 Elsevier B.V. All rights reserved.)

Landlocked shad is a freshwater clupeid fish ( Alosa fallax lacustris ) whose consumption is associated with the risk of scombrotoxin poisoning. Traditionally, fresh shad are subjected to an artisanal processing procedure, consisting of dry salting and maturation under pressure, to give a fish product named missoltino , which is stored in large metallic barrels and is sold to local consumers and restaurants. In recent years, the introduction of modern food packaging technologies has enabled this product to also be distributed in shops and supermarkets. Consequently, the determination of the safety of this product is an urgent issue. The aims of the present research were to measure histamine levels and histamine-forming bacteria in shad products collected at different phases of preparation and ripening, in order to minimize poison hazards, to provide technical information about risk, and to standardize the production process. One hundred twenty-six samples of shad (21 fresh fish and 105 dried) at different phases of preparation and ripening were collected from seven producers and were analyzed for chemical composition, histamine content, and microbiological properties. After 130 days of ripening, samples from three producers presented unacceptable amounts of histamine (>200 mg/kg), according to European Union legislation. A moderate negative correlation was found between histamine levels and salt content (r =-0.504, P < 0.01) and between histamine levels and water phase salt content (r =-0.415, P < 0.01). Several bacterial strains that were positive on Niven's medium were isolated during the early phases of production, whereas the extreme environment of salted shad at the end of ripening led to a drastic decrease of bacteria, but not of histamine. The most effective preventive measures for histamine formation and accumulation in salted shad were strictly related to fish handling and storage conditions during processing.

Antizymes and antizyme inhibitors are key regulatory proteins of polyamine levels by affecting ornithine decarboxylase and polyamine uptake. Our previous studies indicated a metabolic interplay among polyamines, histamine and serotonin in mast cells, and demonstrated that polyamines are present in mast cell secretory granules, being important for histamine storage and serotonin levels. Recently, the novel antizyme inhibitor-2 (AZIN2) was proposed as a local regulator of polyamine biosynthesis in association with mast cell serotonin-containing granules. To gain insight into the role of AZIN2 in the biosynthesis and storage of serotonin and histamine, we have generated bone marrow derived mast cells (BMMCs) from both wild-type and transgenic Azin2 hypomorphic mice, and have analyzed polyamines, serotonin and histamine contents, and some elements of their metabolisms. Azin2 hypomorphic BMMCs did not show major mast cell phenotypic alterations as judged by morphology and specific mast cell proteases. However, compared to wild-type controls, these cells showed reduced spermidine and spermine levels, and diminished growth rate. Serotonin levels were also reduced, whereas histamine levels tended to increase. Accordingly, tryptophan hydroxylase-1 (TPH1; the key enzyme for serotonin biosynthesis) mRNA expression and protein levels were reduced, whereas histidine decarboxylase (the enzyme responsible for histamine biosynthesis) enzymatic activity was increased. Furthermore, microphtalmia-associated transcription factor, an element involved in the regulation of Tph1 expression, was reduced. Taken together, our results show, for the first time, an element of polyamine metabolism -AZIN2-, so far described as exclusively devoted to the control of polyamine concentrations, involved in regulating the biosynthesis and content of other amines like serotonin and histamine.

The consumption of food containing large amounts of histamine can lead to histamine poisoning. Cheese is one of the most frequently involved foods. Histamine, one of the biogenic amines (BAs) exhibiting the highest safety risk, accumulates in food contaminated by microorganisms with histidine decarboxylase activity. The origin of these microorganisms may be very diverse with contamination likely occurring during post-ripening processing, but the microorganisms involved during this manufacturing step have never been identified. The present work reports the isolation of 21 histamine-producing Lactobacillus parabuchneri strains from a histamine-containing grated cheese. PCR revealed that every isolate carried the histidine decarboxylase gene (hdcA). Eight lineages were identified based on the results of genome PFGE restriction analysis plus endonuclease restriction profile analysis of the carried plasmids. Members of all lineages were able to form biofilms on polystyrene and stainless steel surfaces. L. parabuchneri is therefore an undesirable species in the dairy industry; the biofilms it can produce on food processing equipment represent a reservoir of histamine-producing bacteria and thus a source of contamination of post-ripening-processed cheeses., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Scombroid poisoning is a common cause of food poisoning worldwide. It is caused by ingestion of oily fish contaminated with bacteria that trigger the formation of high concentrations of histamine. Scombroid poisoning manifests mainly as a skin complaint (flushing that spreads downward and/or an erythematous urticarial rash affecting the face and upper trunk). Although the clinical course is usually self-limiting and benign, vascular compromise, bronchospasm, and arrhythmias have been described. It is important to establish a differential diagnosis that includes conditions such as fish allergy. Oral antihistamines are the mainstay of treatment. Scombroid poisoning is best prevented by refrigerating fish properly. The practical review of scombroid poisoning provided here is intended for dermatologists., (Copyright © 2016 AEDV. Publicado por Elsevier España, S.L.U. All rights reserved.)

Histamine and its release can be studied by multicolor flow cytometry on a single cell level by an enzyme affinity method (HistaFlow®). However, for the time-being, the clinical and scientific application of the HistaFlow® technique remains limited. This study aims at verifying the reliability of the HistaFlow® as an instrument to quantify IgE-mediated basophil responses to drugs, i.e., rocuronium, which are believed to be less potent basophil activators than large proteinaceous allergens. Ten patients and three exposed control individuals were included in this study. Each subject underwent in vitro basophil activation tests (HistaFlow®) with 0.16 and 1.6 mmol/L rocuronium. Patients showed an activation of basophils ranging from 11 to 86% of CD63 positive basophils and a median histamine release per cell from 68 to 100% after stimulation with an optimal concentration of 1.6 mmol/L rocuronium. For the control individuals no activation was demonstrable. This study confirms that the HistaFlow® technique is a reliable tool to study histamine release by individual cells in response to drugs. Although the HistaFlow® technique will probably not add to the diagnostic management of rocuronium allergy, our findings suggest that the technique could constitute an important asset for future studies on the pathomechanism(s) of immediate drug hypersensitivity reactions. © 2015 International Clinical Cytometry Society., (© 2015 International Clinical Cytometry Society.)

The validation of a HPLC-PDA-MS/MS chromatographic method for the quali/quantitative characterization of histaminol, hydroxytyrosol, tyrosol, and tryptophol in wine has been described and discussed. Four standards showed a good linearity with high correlation coefficient values (over 0.9989) and LOD and LOQ were 0.001-0.015 mg/L and 0.004-0.045 mg/L, respectively. Furthermore, this study reported how factors such as temperature, alcoholic degree, and amino acids concentration are able to influence the formation of these four alcohols in Monastrell wines. The quantification values of these alcohols has been detected both at the half and end of alcoholic fermentation, and at the end of malolactic fermentation. In relation to interactions between factors, several significant variations emerged (p ⩽ 0.001). The impact of amino acids supplementation in Monastrell must it has been demonstrated, mainly in regards to histaminol and tryptophol., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Scombrotoxin fish poisoning (SFP) remains the main contributor of fish poisoning incidents in the United States, despite efforts to control its spread. Psychrotrophic histamine-producing bacteria (HPB) indigenous to scombrotoxin-forming fish may contribute to the incidence of SFP. We examined the gills, skin, and anal vents of yellowfin (n = 3), skipjack (n = 1), and albacore (n = 6) tuna for the presence of indigenous HPB. Thirteen HPB strains were isolated from the anal vent samples from albacore (n = 3) and yellowfin (n = 2) tuna. Four of these isolates were identified as Photobacterium kishitanii and nine isolates as Photobacterium angustum; these isolates produced 560 to 603 and 1,582 to 2,338 ppm histamine in marine broth containing 1% histidine (25°C for 48 h), respectively. The optimum growth temperatures and salt concentrations were 26 to 27°C and 1% salt for P. kishitanii and 30 to 32°C and 2% salt for P. angustum in Luria 70% seawater (LSW-70). The optimum activity of the HDC enzyme was at 15 to 30°C for both species. At 5°C, P. kishitanii and P. angustum had growth rates of 0.1 and 0.2 h(-1), respectively, and the activities of histidine decarboxylase (HDC) enzymes were 71% and 63%, respectively. These results show that indigenous HPB in tuna are capable of growing at elevated and refrigeration temperatures. These findings demonstrate the need to examine the relationships between the rate of histamine production at refrigeration temperatures, seafood shelf life, and regulatory limits., (Copyright © 2016, American Society for Microbiology. All Rights Reserved.)

In food, the biogenic amine (BA) histamine is mainly produced by histidine decarboxylation catalysed by microbial histidine decarboxylase. The consumption of foods containing high concentrations of histamine can trigger adverse neurological, gastrointestinal and respiratory reactions. Indeed, histamine is one of the most toxic of all BAs, and is often detected in high concentration in cheese. However, little is known about the microorganisms responsible for its accumulation in this food. In the present work, 25 histamine-producing Lactobacillus vaginalis strains were isolated from a blue-veined cheese (the first time that histamine-producing strains of this species have been isolated from any food). The restriction profiles of their genomes were analysed by PFGE, and seven lineages identified. The presence of the histidine decarboxylase gene (hdcA) was confirmed by PCR. The nucleotide sequence and genetic organisation of the histamine biosynthesis gene cluster (HDC) and its flanking regions are described for a representative strain (L. vaginalis IPLA11050)., (Copyright © 2015 Elsevier B.V. All rights reserved.)

Aims: Photobacterium damselae subsp. damselae is a potent histamine-producing micro-organism. The aim of this study was to isolate and characterize a bacteriophage Phda1 that infected P. damselae subsp. damselae to inhibit its growth and histamine accumulation., Methods and Results: Phda1 was isolated from a raw oyster, and the host range, morphology and the bacteriophage genome size were analysed. Phda1 formed a clear plaque only against P. damselae subsp. damselae JCM8969 among five Gram-positive and 32 Gram-negative bacterial strains tested. Phda1 belongs to the family Myoviridae, and its genome size was estimated as 35·2-39·5 kb. According to the one-step growth curve analysis, the latent period, rise period and burst size of Phda1 were 60 min, 50 min and 19 plaque-forming units per infected cell, respectively. Divalent cations, especially Ca(2+) and Mg(2+) , strongly improved Phda1 adsorption to the host cells and its propagation. Phda1 treatment delayed the growth and histamine production of P. damselae subsp. damselae in an in vitro challenge test., Conclusions: The bacteriophage Phda1 might serve as a potential antimicrobial agent to inhibit the histamine poisoning caused by P. damselae subsp. damselae., Significance and Impact of the Study: This is the first description of a bacteriophage specifically infecting P. damselae subsp. damselae and its potential applications. Bacteriophage therapy could prove useful in the prevention of histamine poisoning., (© 2015 The Society for Applied Microbiology.)

Transcription factor GATA binding protein 2 (GATA2) plays critical roles in hematopoietic stem cell survival and proliferation, granulocyte-monocyte progenitor differentiation, and basophil and mast cell differentiation. However, precise roles of GATA2 in basophil and mast cell differentiation and maintenance have not been delineated. We have identified GATA2 as an essential transcription factor in differentiation of newly identified common basophil and mast cell progenitors into basophils and mast cells. We observed Gata2 haploinsufficiency for mast cell differentiation, but not for basophil differentiation. We examined the precise role of GATA2 in maintaining the expression of a wide range of genes that are important for performing basophil or mast cell functions. The effects of GATA2 on gene expression were broadly based. We demonstrated that GATA2 was required for maintaining Fcer1a mRNA and FcεRIα protein expression on both basophils and mast cells, as well as for maintaining Kit mRNA and c-Kit protein expression on mast cells. GATA2 was required for histamine synthesis and was also critical for Il4 mRNA expression in basophils and Il13 mRNA expression in mast cells. We demonstrate a STAT5-GATA2 connection, showing that the STAT5 transcription factor directly bound to the promoter and an intronic region of the Gata2 gene. Overexpression of the Gata2 gene was sufficient to direct basophil and mast cell differentiation in the absence of the Stat5 gene. Our study reveals that the STAT5-GATA2 pathway is critical for basophil and mast cell differentiation and maintenance., (Copyright © 2015 by The American Association of Immunologists, Inc.)

Arylalkylamine N-acetyltransferase like 7 (AANATL7) catalyzes the formation of N-acetylarylalkylamides and N-acetylhistamine from acetyl-CoA and the corresponding amine substrate. AANATL7 is a member of the GNAT superfamily of >10000 GCN5-related N-acetyltransferases, many members being linked to important roles in both human metabolism and disease. Drosophila melanogaster utilizes the N-acetylation of biogenic amines for the inactivation of neurotransmitters, the biosynthesis of melatonin, and the sclerotization of the cuticle. We have expressed and purified D. melanogaster AANATL7 in Escherichia coli and used the purified enzyme to define the substrate specificity for acyl-CoA and amine substrates. Information about the substrate specificity provides insight into the potential contribution made by AANATL7 to fatty acid amide biosynthesis because D. melanogaster has emerged as an important model system contributing to our understanding of fatty acid amide metabolism. Characterization of the kinetic mechanism of AANATL7 identified an ordered sequential mechanism, with acetyl-CoA binding first followed by histamine to generate an AANATL7·acetyl-CoA·histamine ternary complex prior to catalysis. Successive pH-activity profiling and site-directed mutagenesis experiments identified two ionizable groups: one with a pKa of 7.1 that is assigned to Glu-26 as a general base and a second pKa of 9.5 that is assigned to the protonation of the thiolate of the coenzyme A product. Using the data generated herein, we propose a chemical mechanism for AANATL7 and define functions for other important amino acid residues involved in substrate binding and regulation of catalysis.

Asthma, a common disorder that affects >250 million people worldwide, is defined by exaggerated bronchoconstriction to inflammatory mediators including acetylcholine (ACh), bradykinin and histamine-also termed airway hyper-responsiveness. Nearly 10% of people with asthma have severe, treatment-resistant disease, which is frequently associated with immunoglobulin-E sensitization to ubiquitous fungi, typically Aspergillus fumigatus (Af). Here we show that a major Af allergen, Asp f13, which is a serine protease, alkaline protease 1 (Alp 1), promotes airway hyper-responsiveness by infiltrating the bronchial submucosa and disrupting airway smooth muscle (ASM) cell-extracellular matrix (ECM) interactions. Alp 1-mediated ECM degradation evokes pathophysiological RhoA-dependent Ca(2+) sensitivity and bronchoconstriction. These findings support a pathogenic mechanism in asthma and other lung diseases associated with epithelial barrier impairment, whereby ASM cells respond directly to inhaled environmental allergens to generate airway hyper-responsiveness.

In this study, we investigated the differences in histamine accumulation between blue scad and chub mackerel and methods of inhibiting histamine-forming bacteria and controlling histamine accumulation in fish. The free histidine contents in blue scad and chub mackerel were 1.45 and 2.75 mg/g, respectively. The histamine-forming bacteria isolated from them were identified as Citrobacter freundii, Citrobacter braakii, and Enterobacter aerogenes using 16S rDNA sequence analysis, the VITEK 2 Compact system, and MALDI-TOF MS. The histamine-producing capacities of C. freundii, C. braakii, and E. aerogenes were 470, 1,057, and 4,213 mg/liter, respectively, after culture at 37°C for 48 h. Among the different antimicrobials and preservatives tested, potassium sorbate and sodium diacetate effectively inhibited the histamine-forming bacteria and their histamine production. After chub mackerel was dipped into 0.5% potassium sorbate or sodium diacetate, its histamine content increased more slowly at room temperature. Therefore, a potassium sorbate or sodium diacetate dipping treatment could effectively control histamine accumulation in fish.

Mast cells (MCs) are selectively found at the host environment interface and are capable of secreting a wide array of pharmacologically active mediators, many of which are prepackaged in granules. Over the past two decades, it has become clear that these cells have the capacity to recognize a range of infectious agents allowing them to play a key role in initiating and modulating early immune responses to infectious agents. However, a number of pathogenic and commensal microbes appear to have evolved distinct mechanisms to suppress MC mediator release to avoid elimination in the host. Understanding how these microbes suppress MC functions may have significant therapeutic value to relieve inflammatory disorders mediated by MCs., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

In the past decades an increasing prevalence of allergic disorders was observed in industrialized countries. Thus, it is necessary to develop adequate therapeutic and preventive strategies. Many of the conservative strategies possess diverse harmful side effects. Therefore agents with fewer side effects and a better compliance among afflicted patients would be of interest. Especially substances with natural origin acting immunomodulatory on mast cells - the key effector cells of allergic diseases - could be used. Among them there are components of the daily diet such as distinct fatty acids and amino acids as well as a range of secondary plant substances such as carotenoids, flavonoids and spices. These nutritional substances could be applied as nutraceuticals in the therapy of mast cell associated diseases. Many of these substances show inhibitory influences on the release of prestored mast cell mediators such as histamine or de novo expression of mast cell mediators such as cytokines and eicosanoids which are involved in the pathogenesis of mast cell associated inflammatory conditions like allergic reactions., (Copyright © 2014 Elsevier Ltd. All rights reserved.)