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Neutrophils are mobilized and recruited to the injured heart after myocardial infarction, and neutrophil count has been clinically implicated to be associated with coronary disease severity. Histidine decarboxylase (HDC) has been implicated in regulating reactive oxidative species (ROS) and the differentiation of myeloid cells. However, the effect of HDC on neutrophils after myocardial infarction remains unclear. Here, we found that neutrophils were disorderly recruited into the ischemic injured area of the myocardium of Hdc deficiency (Hdc−/−) mice. Moreover, Hdc deficiency led to attenuated adhesion but enhanced migration and augmented ROS/neutrophil extracellular traps (NETs) production in neutrophils. Hdc−/− mouse-derived NETs promoted cardiomyocyte death and cardiac fibroblast proliferation/migration. Furthermore, protein arginine methyltransferase 1 (PRMT1) was increased in Hdc−/− mouse-derived neutrophils but decreased with exogenous histamine treatment. Its expression could be rescued by blocking histamine receptor 1 (H1R), inhibiting ATP synthesis or reducing SWItch/sucrose non fermentable (SWI/SNF) chromatin remodeling complex. Accordingly, histamine or MS023 treatment could decrease ROS and NETs ex vivo, and ameliorated cardiac function and fibrosis, along with the reduced NETs in plasma in vivo. Together, our findings unveil the role of HDC in NETosis by histamine–H1R–ATP–SWI/SNF–PRMT1–ROS signaling and provide new biomarkers and targets for identifying and tuning the detrimental immune state in cardiovascular disease.

Myocardial infarction (MI) is a significant contributor to the development of heart failure. Histidine decarboxylase (HDC), the unique enzyme that converts l-histidine to histamine, is highly expressed in CD11b+ immature myeloid cells. However, the relationship between HDC-expressing macrophages and cardiac myofibroblasts remains to be explained. Here, we demonstrate that the GFP (green fluorescent protein)-labeled HDC+CD11b+ myeloid precursors and their descendants could differentiate into fibroblast-like cells in myocardial interstitium. Furthermore, we prove that CD11b+Ly6C+ monocytes/macrophages, but not CD11b+Ly6G+ granulocytes, are identified as the main cellular source for bone marrow-derived myofibroblast transformation, which could be regulated via histamine H1 and H2 receptor-dependent signaling pathways. Using HDC knockout mice, we find that histamine deficiency promotes myofibroblast transformation from Ly6C+ macrophages and cardiac fibrosis partly through upregulating the expression of Kruppel-like factor 5 (KLF5). Taken together, our data uncover a central role of HDC in regulating bone marrow-derived macrophage-to-myofibroblast transformation but also identify a histamine receptor (HR)-KLF5 related signaling pathway that mediates myocardial fibrosis post-MI. CD11b+Ly6C+ monocytes/macrophages are the main cellular source for bone marrow-derived myofibroblast transformation. Histamine inhibits myofibroblasts transformation via H1R and H2R-dependent signaling pathways, and ameliorates cardiac fibrosis partly through upregulating KLF5 expression.

Enzymatic amino acid assays are important in physiological research and clinical diagnostics because abnormal amino acid concentrations in biofluids are associated with various diseases. L-histidine decarboxylase from Photobacterium phosphoreum (PpHDC) is a pyridoxal 5′-phosphate-dependent enzyme and a candidate for use in an L-histidine quantitation assay. Previous cysteine substitution experiments demonstrated that the PpHDC C57S mutant displayed improved long-term storage stability and thermostability when compared with those of the wild-type enzyme. In this study, combinational mutation experiments of single cysteine substitution mutants of PpHDC were performed, revealing that the PpHDC C57S/C101V/C282V mutant possessed the highest thermostability. The stabilizing mechanism of these mutations was elucidated by solving the structures of PpHDC C57S and C57S/C101V/C282V mutants by X-ray crystallography. In the crystal structures, two symmetry-related PpHDC molecules form a domain-swapped homodimer. The side chain of S57 is solvent exposed in the structure, indicating that the C57S mutation eliminates chemical oxidation or disulfide bond formation with a free thiol group, thereby providing greater stability. Residues 101 and 282 form hydrophobic interactions with neighboring hydrophobic residues. Mutations C101V and C282V enhanced thermostability of PpHDC by filling a cavity present in the hydrophobic core (C101V) and increasing hydrophobic interactions.

Histamine is a biogenic amine and a food safety hazard, and it is the only biogenic amine regulated by statute or HACCP Guidance. This paper reviews the regulations for histamine levels in fish in countries around the world, including maximum limits or levels and sampling procedures in different fish preparations. The maximum histamine levels, sampling plans, and fish products are listed. The country-by-country regulations for maximum histamine acceptance levels in some food products vary by a factor of 8, from 50 ppm in some countries to a maximum of 400 ppm in other countries. For similar food products, the maximum histamine levels vary by a factor of 4 (from 50 ppm to 200 ppm) in, for example, fresh tuna. The country-by-country sampling plans vary widely as well and these, too, are covered in detail. Molecules of histamine are formed from L-histidine molecules, an amino acid, by a decarboxylation reaction caused by a bacterial enzyme, histidine decarboxylase. Histamine can form in many different species of saltwater fish that have elevated levels of free L-histidine. Histamine formation is completely preventable, and these methods are described as well. Although there are multiple maximum histamine acceptance levels, rapidly chilling the fish immediately after harvest by any means available is the only method to stop the formation of histamine. Fishermen should rapidly chill the fish using ice, chilled seawater, dense cold brine, or air blast freezers as quickly as possible.

Hakarl is a fermented fish traditionally produced in Iceland. In the present study, no scientific research has so far discussed the implication of histamine in this food. The first quantification o...

Histamine is best known for its role in allergies, but it could also be involved in autoimmune diseases such as multiple sclerosis. However, studies using experimental autoimmune encephalomyelitis (EAE), the most widely used animal model for multiple sclerosis, have reported conflicting observations and suggest the implication of a nonclassical source of histamine. In this study, we demonstrate that neutrophils are the main producers of histamine in the spinal cord of EAE mice. To assess the role of histamine by taking into account its different cellular sources, we used CRISPR–Cas9 to generate conditional knockout mice for the histamine-synthesizing enzyme histidine decarboxylase. We found that ubiquitous and cell-specific deletions do not affect the course of EAE. However, neutrophil-specific deletion attenuates hypothermia caused by IgE-mediated anaphylaxis, whereas neuron-specific deletion reduces circadian activity. In summary, this study refutes the role of histamine in EAE, unveils a role for neutrophil-derived histamine in IgE-mediated anaphylaxis, and establishes a new mouse model to re-explore the inflammatory and neurologic roles of histamine.

5-HT containing enteroendocrine cells (EEC), the most abundant type of EEC in the gut, regulate many functions including motility, secretion and inflammatory responses. We examined the morphologies of 5-HT cells from stomach to rectum, patterns of hormone co-expression in the stomach and colon, and the relationship of 5-HT cells with nerve fibres. We also reviewed some of the relevant literature. The morphologies of 5-HT cells were distinct, depending on their location in the gut. A noticeable feature of some 5-HT cells in the antrum and colon was their long basal processes, which resembled processes of neurons, whereas 5-HT cells in the small intestinal mucosa lacked basal processes. In the stomach, numerous 5-HT cells, including cells with basal processes, were identified as enterochromaffin-like cells by their expression of histidine decarboxylase. In the colon, we observed a small number of 5-HT cells that were in close contact with, but distinct from, oxyntomodulin (OXM) and PYY immunoreactive EEC. We did not find specific relationships between nerve fibres and the processes of colonic 5-HT cells. We conclude that five major features, i.e., gut region, morphology, hormone content, receptor repertoire and cell lineage, can be used to define 5-HT cells.

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.

Background & Aims Histidine decarboxylase (HDC), the histamine-synthesizing enzyme, is expressed in a subset of myeloid cells but also marks quiescent myeloid-biased hematopoietic stem cells (MB-HSCs) that are activated upon myeloid demand injury. However, the role of MB-HSCs in dextran sulfate sodium (DSS)-induced acute colitis has not been addressed. Methods We investigated HDC+ MB-HSCs and myeloid cells by flow cytometry in acute intestinal inflammation by treating HDC–green fluorescent protein (GFP) male mice with 5% DSS at various time points. HDC+ myeloid cells in the colon also were analyzed by flow cytometry and immunofluorescence staining. Knockout of the HDC gene by using HDC-/-; HDC-GFP and ablation of HDC+ myeloid cells by using HDC-GFP; HDC–tamoxifen-inducible recombinase Cre system; diphtheria toxin receptor (DTR) mice was performed. The role of H2-receptor signaling in acute colitis was addressed by treatment of DSS-treated mice with the H2 agonist dimaprit dihydrochloride. Kaplan–Meier survival analysis was performed to assess the effect on survival. Results In acute colitis, rapid activation and expansion of MB-HSC from bone marrow was evident early on, followed by a gradual depletion, resulting in profound HSC exhaustion, accompanied by infiltration of the colon by increased HDC+ myeloid cells. Knockout of the HDC gene and ablation of HDC+ myeloid cells enhance the early depletion of HDC+ MB-HSC, and treatment with H2-receptor agonist ameliorates the depletion of MB-HSCs and resulted in significantly increased survival of HDC-GFP mice with acute colitis. Conclusions Exhaustion of bone marrow MB-HSCs contributes to the progression of DSS-induced acute colitis, and preservation of quiescence of MB-HSCs by the H2-receptor agonist significantly enhances survival, suggesting the potential for therapeutic utility.

There has been little information about the role of histamine on the central nervous system (CNS), different from dopamine and serotonin. In the present study, therefore, the effects of histamine and related compounds on the CNS were studied using rats. Intracerebroventricular (i.c.v.) injection of histamine and 2-methylhistamine ameliorated memory deficit after long interrution of learning in active avoidance response. First generation H1-antagonists inhibited active avoidance response, whereas newly develpoed H1-antagonists showed little effect. α-Fluoromethylhistidine, an histidine decarboxylase inhibitor, also inhibited active avoidance response. In radial maze performance, almost the same findings were obtained. I.c.v. injection of histamine and H1-agonists inhibited amygdaloid kindled seizures. First generation H1-antagonists attenuated histamine-induced inhibition of amygdaloid kindled seizures. Both i.c.v. and intraperitoneal injections of H3-antagonist, thioperamide, resulted in a dose-related inhibition of amygdaloid kindled seizures. The effect of thioperamide was inhibited by an H3-agonists and H1-antagonists. Similar to nitrazepam, diphenhydramine and chlorpheniramine caused a shortening of sleep latency. On the other hand, no significant effects were observed with second generation H1-antagonists. These findings suggest that histamine plays an important role in learning and memory via H1-receptors, an inhibition of amygdaloid kindled seizures induced by histamine occurred through not only H1-receptors but also H3-receptors, and that classic H1-antagonists can be useful as a effective hypnotic for difficulty in falling asleep.

Histamine-producing bacteria to predict histamine level production can be identified by a molecular approach. The purpose of this study was to identify the types of histamine-producing bacteria on tuna, little tuna, and skipjack (TTC) meat, to analyze its bioinformatics through phylogenetic tree construction also to determine the levels of its histamine. The identification of histamine-producing bacteria was conducted using a molecular technique based on the hdc and 16S rRNA genes. Histamine levels were measured by a spectrofluorometer. The results showed types of histamine-producing bacteria had been successfully identified, both using specific hdc and 16S rRNA universal primers, including Morganella morganii, Enterobacter hormaechei, Klebsiella aerogenes, and Enterobacter bugandensis. The phylogenetic tree showed that the bacteria M. morganii and E. hormaechei were closely related to one cluster. Meanwhile, the other close relative cluster were Klebsiella aerogenes, Enterobacter bugandensis, and Escherichia fergusonii. In addition, histamine levels of frozen tuna, little tuna, and skipjack were 2.96±0.22 ppm, 2.14±0.23 ppm, and 1.02±0.97 ppm, respectively.

Histamine release is involved in developing wakefulness and activation of cortex. The purpose of the study was to find an alternative to these antihistamines by inhibiting the enzyme histidine decarboxylase which is responsible for the production of histamine. Histamine brings about the allergic response due to mast cell degranulation. It is also necessary that the enzyme is not completely inhibited as it plays a role as a neurotransmitter and also regulates gastric acid secretion. In the present study, the methanolic extract of commercially available fennel seeds were examined for its inhibitory activity on the purified extract of bacterial histidine decarboxylase. The methanolic extract of fennel was analyzed to check the presence of various phytochemical constituents. The spice extract was quantified to estimate the presence of flavonoids. The extract was subjected to purification by thin layer chromatography and HPLC in order to isolate and identify the flavonoids present in spice extract. The HPLC results with reference to the standard indicated the presence of ellagic acid and quercetin. The spice extracts were subjected to inhibitory studies at increasing concentrations. The fennel extract at concentration of 0.625 moles was found to be inhibiting histidine decarboxylase which was determined using the Dixon plot. The identified flavonoids were then subjected to software’s like Molinspiration and Swiss ADME in order to study the molecular properties, drug likeliness and pharmacokinetics.

Histidine is a dietary essential amino acid because it cannot be synthesized in humans. The WHO/FAO requirement for adults for histidine is 10 mg · kg body weight(−1) · d(−1). Histidine is required for synthesis of proteins. It plays particularly important roles in the active site of enzymes, such as serine proteases (e.g., trypsin) where it is a member of the catalytic triad. Excess histidine may be converted to trans-urocanate by histidine ammonia lyase (histidase) in liver and skin. UV light in skin converts the trans form to cis-urocanate which plays an important protective role in skin. Liver is capable of complete catabolism of histidine by a pathway which requires folic acid for the last step, in which glutamate formiminotransferase converts the intermediate N-formiminoglutamate to glutamate, 5,10 methenyl-tetrahydrofolate, and ammonia. Inborn errors have been recognized in all of the catabolic enzymes of histidine. Histidine is required as a precursor of carnosine in human muscle and parts of the brain where carnosine appears to play an important role as a buffer and antioxidant. It is synthesized in the tissue by carnosine synthase from histidine and β-alanine, at the expense of ATP hydrolysis. Histidine can be decarboxylated to histamine by histidine decarboxylase. This reaction occurs in the enterochromaffin-like cells of the stomach, in the mast cells of the immune system, and in various regions of the brain where histamine may serve as a neurotransmitter.

Histamine is a degradation product of the bacterial decarboxylation of the amino acid histidine; such activity is determined by histidine decarboxylase encoded by a gene cluster, carried by some Gram-positive bacteria, that includes the hdcA gene. In this study, the presence of the hdcA gene in ready-to-eat surstromming samples collected from three producers based in Sweden was directly assessed via qPCR analysis for the very first time. Samples from producer A showed hdcA average gene abundance of 6.67 ± 0.13 Log cells/gene copies g−1; in samples from producer B the average value attested at 5.56 ± 0.06 Log cells/gene copies g−1, whereas for samples of producer C hdcA average gene abundance attested at 5.30 ± 0.08 Log cells/gene copies g−1. ANOVA showed a significantly higher average hdcA gene copy number in samples from producer A, whereas no significant differences were seen between average values of hdcA gene copy numbers detected in samples from producer B and C. The hdcA gene copies detected in the present study could give an estimation of the load of potential histamine-producing bacteria in surstromming.

The hypoglossal nucleus (HN) controls the movement of the genioglossus (GG) muscle whose dysfunction leads to airway occlusion and occurrence of obstructive sleep apnea (OSA). Histamine produced by the tuberomammillary nucleus (TMN) has a potent excitatory action on GG muscle activity. The aim of the study was to investigate the role histaminergic neurons play in the regulation of the genioglossus. C57BL/6 mice were exposed to chronic intermittent hypoxia (CIH) for 3 weeks to resemble OSA. The histamine H3 receptor (H3R) antagonist ciproxifan was applied to increase histamine in the brain. Histamine levels and GG activity were measured by liquid chromatography–tandem mass spectrometry (LC-MS/MS) and electromyogram (EMG) separately. Neuronal activity and repair ability of the HN and TMN and key proteins of histamine were analyzed by immunohistochemistry and western blots. Significant decline of histamine level and GG activity of the HN and TMN induced by CIH exposure could be ameliorated by ciproxifan. Application of ciproxifan could also partly reverse the decline of the histidine decarboxylase (HDC) by CIH. This investigation studied the impacts of ciproxifan on the HN and TMN in CIH conditions and revealed that the negative effects on the HN and TMN caused by CIH could be partly ameliorated by ciproxifan, which might open new perspectives for the development of pharmacological treatment for OSA.

Histamine is a bioactive monoamine that is synthesized by the enzymatic activity of histidine decarboxylase (HDC) in basophils, mast cells, gastric enterochromaffin‐like (ECL) cells and histaminergic neuronal cells. Upon a series of cellular stimuli, these cells release stored histamine, which elicits allergies, inflammation, and gastric acid secretion and regulates neuronal activity. Recent studies have shown that certain other types of myeloid lineage cells also produce histamine with HDC induction under various pathogenic stimuli. Histamine has been shown to play a series of pathophysiological roles by modulating immune and inflammatory responses in a number of disease conditions, whereas the mechanistic aspects underlying induced HDC expression remain elusive. In the present review, we summarize the current understanding of the regulatory mechanism of Hdc gene expression and the roles played by histamine in physiological contexts as well as pathogenic processes. We also introduce a newly developed histaminergic cell‐monitoring transgenic mouse line (Hdc‐BAC‐GFP) that serves as a valuable experimental tool to identify the source of histamine and dissect upstream regulatory signals., Histamine is a bioactive monoamine that is synthesized by the enzymatic activity of histidine decarboxylase (HDC) in various cells. We summarize the current understanding of the regulatory mechanism of Hdc gene expression and the roles played by histamine in physiological contexts and pathogenic processes. We also introduce a newly developed histaminergic cell‐monitoring transgenic mouse line (Hdc‐BAC‐GFP) that serves as a valuable experimental tool to identify the source of histamine and dissect upstream regulatory signals.

One of an important quality parameter in tuna is the level of histamine content. The contamination of histamine in tuna is mainly due to the activity of histidine decarboxylase produced by the bacteria. A rapid growth of histamine producing bacteria is correlated with the practice of temperature abuse during handling. This study aimed to develop predictive growth modeling of two histamine-producing bacteria in the function of temperature. The growth and histamine production of Klebsiella sp. CK02 and Morganella morganii ATCC 25830 at various temperatures were measured in tryptic soy broth histidine (TSBH) and tuna fish infusion broth (TFIB) growth media. Broths were incubated at 4°C and 15°C for 7 days, and at 30°C and 40°C for 24 hours. The Baranyi and Roberts model was used with DMFit to determine primary growth kinectics, and the Ratkowsky square root model to describe bacterial growth rate as a function of temperature. Histamine production was enumerated by the apparent yield factor (pYhis/CFU) value. Growth rate increased with temperature, with a maximum rate at 40°C for Klebsiella sp. CK02 (0.740 log CFU/h) and M. morganii (0.578 log CFU/h). The Tmin for Klebsiella sp. CK02 in TFIB was -8.9°C, indicating better survival in low storage temperature, compare to M. morganii ATCC 25830. In addition, Klebsiella sp. CK02 produced a lower pYhis/CFU at 15 and 30°C compared to M. morganii ATCC 25830.

Histamine is synthesized via histidine decarboxylase (HDC) in wide types of immune cells and is involved in abundant physiologic and pathologic processes. Histamine is a mediator released during inflammatory reactions, such as food allergy. Food allergy is immunological reactions to 'fight off' specific allergens within food in susceptible individuals. The aim of this study is investigation of the histamine hemostasis and food allergy to discover the relationship between them. Analysis of data from multiple electronic databases such as Scopus, PubMed, Google Scholar and Science Direct were performed. Various criteria were applied to select the articles for inclusion.Food allergy reaction is divided to 4 types of the immune response. These reactions with different mechanisms cause increased concentrations of histamine. Histamine does various action in different tissue. The correct and timely diagnosis of food allergy can lead to reduction of the chemicals release and inhibit of abnormal reaction of the body. According to some studies, Measurement of N-methylhistamine (NMH) as the major metabolite of histamine may help to diagnose patients with food-allergen induced clinical symptoms.

Significance Histamine has been known to play important roles in inflammation, and its inhibition has been expected to ameliorate the pathological statement of heart failure and chronic kidney disease. In this paper, we found that histamine is elevated in the plasma of a preclinical mouse model with severe cardiac dysfunction and showed that it acts protectively rather than harmfully on heart and kidney damages in this model. In addition, we showed that a histamine H3 agonist, Imm, prevents the cardiorenal damages in this model. Accordingly, this paper will be helpful for developing new therapeutic strategies for cardiorenal syndrome, and it will serve as a basis for repositioning the application of H3 agonists to the inflammatory heart and kidney damages., Heart failure and chronic kidney disease are major causes of morbidity and mortality internationally. Although these dysfunctions are common and frequently coexist, the factors involved in their relationship in cardiorenal regulation are still largely unknown, mainly due to a lack of detailed molecular targets. Here, we found the increased plasma histamine in a preclinical mouse model of severe cardiac dysfunction, that had been cotreated with angiotensin II (Ang II), nephrectomy, and salt (ANS). The ANS mice exhibited impaired renal function accompanied with heart failure, and histamine depletion, by the genetic inactivation of histidine decarboxylase in mice, exacerbated the ANS-induced cardiac and renal abnormalities, including the reduction of left ventricular fractional shortening and renal glomerular and tubular injuries. Interestingly, while the pharmacological inhibition of the histamine receptor H3 facilitated heart failure and kidney injury in ANS mice, administration of the H3 agonist immethridine (Imm) was protective against cardiorenal damages. Transcriptome analysis of the kidney and biochemical examinations using blood samples illustrated that the increased inflammation in ANS mice was alleviated by Imm. Our results extend the pharmacological use of H3 agonists beyond the initial purposes of its drug development for neurogenerative diseases and have implications for therapeutic potential of H3 agonists that invoke the anti-inflammatory gene expression programming against cardiorenal damages.

Primary sclerosing cholangitis (PSC) is characterized by biliary damage and fibrosis. Multidrug resistance-2 gene knockout (Mdr2-/-) mice and PSC patients have increased histamine (HA) levels (synthesized by l-histidine decarboxylase, HDC) and HA receptor (HR) expression. Cholestatic HDC-/- mice display ameliorated biliary damage and hepatic fibrosis. The current study evaluated the effects of knockout of HDC-/- in Mdr2-/- mice (DKO) on biliary damage and hepatic fibrosis. WT, Mdr2-/- mice, and homozygous DKO mice were used. Selected DKO mice were treated with HA. We evaluated liver damage along with HDC expression and HA serum levels. Changes in ductular reaction were evaluated along with liver fibrosis, inflammation and bile acid signaling pathways. The expression of H1HR/PKC-α/TGF-β1 and H2HR/pERK/VEGF-C was determined. In vitro, cholangiocyte lines were treated with HA with/without H1/H2 inhibitors before measuring: H1/H2HR, TGF-β1, and VEGF-C expression. Knockout of HDC ameliorates hepatic damage, ductular reaction, fibrosis, inflammation, bile acid signaling and H1HR/PKC-α/TGF-β1 and H2HR/pERK/VEGF-C signaling. Reactivation of the HDC/HA axis increased these parameters. In vitro, stimulation with HA increased HR expression and PKC-α, TGF-β1, and VEGF-C expression, which was reduced with HR inhibitors. Our data demonstrate the key role for the HDC/HA axis in the management of PSC progression.

Neutrophil‐platelet interactions are responsible for thrombosis as well as inflammatory responses following acute myocardial infarction (AMI). While histamine has been shown to play a crucial role in many physiological and pathological processes, its effects on neutrophil‐platelet interactions in thromboinflammatory complications of AMI remain elusive. In this study, we show a previously unknown mechanism by which neutrophil‐derived histamine protects the infarcted heart from excessive neutrophil‐platelet interactions and redundant arterial thrombosis. Using histamine‐deficient (histidine decarboxylase knockout, HDC−/−) and wild‐type murine AMI models, we demonstrate that histamine deficiency increases the number of microthrombosis after AMI, in accordance with depressed cardiac function. Histamine‐producing myeloid cells, mainly Ly6G+ neutrophils, directly participate in arteriole thrombosis. Histamine deficiency elevates platelet activation and aggregation by enhancing Akt phosphorylation and leads to dysfunctional characteristics in neutrophils which was confirmed by high levels of reactive oxygen species production and CD11b expression. Furthermore, HDC−/− platelets were shown to elicit neutrophil extracellular nucleosomes release, provoke neutrophil‐platelet interactions and promote HDC‐expressing neutrophils recruitment in arteriole thrombosis in vivo. In conclusion, we provide evidence that histamine deficiency promotes coronary microthrombosis and deteriorates cardiac function post‐AMI, which is associated with the enhanced platelets/neutrophils function and neutrophil‐platelet interactions.

Aim We aimed at identifying potential roles of vesicular monoamine transporter 2, also known as Solute Carrier protein 18 A2 (SLC18A2) (hereafter, Vmat2), in brain monoamine regulation, their turnover, behaviour and brain development using a novel zebrafish model. Methods A zebrafish strain lacking functional Vmat2 was generated with the CRISPR/Cas9 system. Larval behaviour and heart rate were monitored. Monoamines and their metabolites were analysed with high-pressure liquid chromatography. Amine synthesising and degrading enzymes, and genes essential for brain development, were analysed with quantitative PCR, in situ hybridisation and immunocytochemistry. Results The 5-bp deletion in exon 3 caused an early frameshift and was lethal within 2 weeks post-fertilisation. Homozygous mutants (hereafter, mutants) displayed normal low locomotor activity during night-time but aberrant response to illumination changes. In mutants dopamine, noradrenaline, 5-hydroxytryptamine and histamine levels were reduced, whereas levels of dopamine and 5-hydroxytryptamine metabolites were increased, implying elevated monoamine turnover. Consistently, there were fewer histamine, 5-hydroxytryptamine and dopamine immunoreactive cells. Cellular dopamine immunostaining, in wild-type larvae more prominent in tyrosine hydroxylase 1 (Th1)-expressing than in Th2-expressing neurons, was absent in mutants. Despite reduced dopamine levels, mutants presented upregulated dopamine-synthesising enzymes. Further, in mutants the number of histidine decarboxylase-expressing neurons was increased, notch1a and pax2a were downregulated in brain proliferative zones. Conclusion Lack of Vmat2 increases monoamine turnover and upregulates genes encoding amine-synthesising enzymes, including histidine decarboxylase. Notch1a and pax2a, genes implicated in stem cell development, are downregulated in mutants. The zebrafish vmat2 mutant strain may be a useful model to study how monoamine transport affects brain development and function, and for use in drug screening.

Histamine intoxication is an important food safety and public health concern. Ripened cheeses are the most common dairy products in which histamine can accumulate. Histamine is formed by the microbiota present in cheese by decarboxylation of histidine, due to the action of the histidine decarboxylase. This study's objective was to identify the responsible for the formation of histamine accumulated in commercial cheeses. The content of histamine of 39 different types of cheeses marketed in Spain, of varying milk origin, was assessed. About one third of the cheeses analysed contained more than 200 mg/kg histamine; two cheeses exceeded 500 mg/kg histamine, the consumption of such cheeses can be harmful or even toxic for consumers. The five cheeses with the highest histamine concentrations were selected for in-depth molecular analysis. Firstly, bacterial and yeast isolates were obtained, and then the total genetic material from the cheeses was analysed, in order to verify the putative presence of the hdc histidine decarboxylase gene. In order to identify the histamine producing microorganisms, the nucleotide sequences of the histidine decarboxylase genes from the cheeses were amplified, and subjected them to Sanger sequencing. In four of the five selected cheeses, the main histamine producer was identified as Lentilactobacillus parabuchneri, whereas in the remaining cheese it was Tetragenococcus halophilus. The hdc gene was located in an unstable plasmid, only present in that cheese sample. Since all histamine producing microorganisms identified in this study are not part of the species used in cheese starter cultures, an improvement of hygienic manufacturing practices and/or thermal treatments for microbial inactivation in milk may be considered to prevent histamine accumulation in cheeses during ripening.

Background Histamine is a key mediator of the anti-inflammatory activity conferred by the probiotic organism Lactobacillus reuteri ATCC PTA 6475 in animal models of colitis and colorectal cancer. In L. reuteri, histamine synthesis and secretion requires l-histidine decarboxylase and a l-histidine/histamine exchanger. Chloride channel (ClC)-family proton/chloride antiporters have been proposed to act as electrochemical shunts in conjunction with amino acid decarboxylase systems, correcting ion imbalances generated by decarboxylation through fixed ratio exchange of two chloride ions for one proton. This family is unique among transporters by facilitating ion flux in either direction. Here we examine the histidine decarboxylase system in relation to ClC antiporters in the probiotic organism Lactobacillus reuteri. Results In silico analyses reveal that L. reuteri possesses two ClC transporters, EriC and EriC2, as well as a complete histidine decarboxylase gene cluster (HDC) for the synthesis and export of histamine. When the transport activity of either proton/chloride antiporter is disrupted by genetic manipulation, bacterial histamine output is reduced. Using fluorescent reporter assays, we further show that ClC transporters affect histamine output by altering intracellular pH and membrane potential. ClC transport also alters the expression and activity of two key HDC genes: the histidine decarboxylase (hdcA) and the histidine/histamine exchanger (hdcP). Conclusions Histamine production is a potentially beneficial feature for intestinal microbes by promoting long-term colonization and suppression of inflammation and host immune responses. ClC transporters may serve as tunable modulators for histamine production by L. reuteri and other gut microbes.

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

International audience; An increased number of histaminergic neurons, identified by labeling histidine-decarboxylase (HDC) its synthesis enzyme, was unexpectedly found in patients with narcolepsy type 1 (NT1). In quest for enlightenment, we evaluate whether an increase in HDC cell number and expression level would be detected in mouse models of the disease, in order to provide proof of concepts reveling possible mechanisms of compensation for the loss of orexin neurons, and/or of induced expression as a consequence of local neuroinflammation, a state that likely accompanies NT1. To further explore the compensatory hypothesis, we also study the noradrenergic wake-promoting system. Immunohistochemistry for HDC, orexin, and melanin-concentrating hormone (MCH) was used to count neurons. Quantitative-PCR of HDC, orexin, MCH, and tyrosine-hydroxylase was performed to evaluate levels of mRNA expression in the hypothalamus or the dorsal pons. Both quantifications were achieved in genetic and neuroinflammatory models of narcolepsy with major orexin impairment, namely the orexin-deficient (Orex-KO) and orexin-hemagglutinin (Orex-HA) mice respectively. The number of HDC neurons and mRNA expression level were unchanged in Orex-KO mice compared to controls. Similarly, we found no change in tyrosine-hydroxylase mRNA expression in the dorsal pons between groups. Further, despite the presence of protracted local neuroinflammation as witnessed by the presence of reactive microglia, we found no change in the number of neurons nor the expression of HDC in Orex-HA mice compared to controls. Importantly, no correlation was found in all conditions between HDC and orexin. Our findings indicate that, in mice, the expression of histamine and noradrenalin, two wake-promoting systems, are not modulated by orexin level whether the lack of orexin is constitutive or induced at adult age, showing thus no compensation. They also show no recruitment of histamine by local neuroinflammation. Further studies will be needed to further define the role of histamine in the pathophysiology of NT1.

Here, we explored the influences of thyme microcapsules on the growth, gene expression, and histamine accumulation by Proteus bacillus isolated from smoked horsemeat sausage. RT-qPCR was employed to evaluate the gene expression level of histidine decarboxylase (HDC) cascade-associated genes. We used HPLC to monitor histamine concentration both in pure culture as well as in the processing of smoked horsemeat sausage. Results showed that histamine accumulation was suppressed by thyme microcapsule inhibitory effect on the histamine-producing bacteria and the reduction in the transcription of hdcA and hdcP genes. Besides, compared with thyme essential oil (EO), thyme microcapsules exhibited higher antibacterial activity and had a higher score for overall acceptance. Therefore, the addition of thyme microcapsules in Xinjiang smoked horsemeat sausage inhibits histamine accumulation.

La amina biógena más importante en pescado es la histamina, ya que es el peligro más frecuentemente implicado en los brotes relacionados con estos alimentos. Causa una intoxicación de tipo alérgico asociada con el consumo de pescado, sobre todo de escómbridos como el atún y la caballa. La histamina resulta de la descarboxilación del aminoácido histidina por la enzima histidina descarboxilasa, que se produce por un grupo de bacterias. La mayoría de éstas son mesófilas, sin embargo, investigaciones recientes indican que algunas bacterias producen cantidades significativas de histamina a temperaturas de 0 a 5 grados centígrados. Además, la enzima histidina descarboxilasa, generada durante el almacenamiento del pescado a altas temperaturas, continúa activa a temperaturas inferiores y es responsable de la producción de histamina a 5 grados centígrados o por debajo. Los modelos matemáticos predictivos aplicados en este estudio, muestran cómo la formación de histamina en pescados frescos ricos en histidina, es marcadamente más rápida cuando éstos se conservan a temperaturas de refrigeración más elevadas.

Rugosin G, an ellagitannin trimer, was isolated from the water-soluble fraction of red rose petals, and its inhibitory activity against recombinant human histidine decarboxylase was investigated. Rugosin G showed potent inhibition compared to ellagitannin monomers and a dimer with macrocyclic structure (oenothein B), suggesting the potent inhibition of rugosin G was attributed to its linear oligomeric conformation. Abbreviations: HDC, histidine decarboxylase; Me2CO, acetone; EtOAc, ethyl acetate

We have reported that moderate prenatal alcohol exposure (PAE) elevates histamine H3 receptor-mediated inhibition of glutamatergic neurotransmission in dentate gyrus (DG), and that the H3 receptor antagonist ABT-239 ameliorates PAE-induced deficits in DG long-term potentiation. Here, we investigated whether PAE alters other markers of histaminergic neurotransmission. Long-Evans rat dams voluntarily consumed either a 0% or a 5% ethanol solution 4 h each day throughout gestation. Young adult female offspring from each prenatal treatment group were used in histidine decarboxylase (HDC) immunohistochemical studies of histamine neuron number in ventral hypothalamus, quantitative Western blotting studies of HDC expression in multiple brain regions, radiohistochemical studies of H2 receptor density in multiple brain regions, and in biochemical studies of H2 receptor-effector coupling in dentate gyrus. Rat dams consumed a mean of 1.90 g of ethanol/kg/day during pregnancy. This level of consumption did not affect maternal weight gain, offspring birth weight, or litter size. PAE did not affect the number of HDC-positive neurons in ventral hypothalamus. However, HDC expression was reduced in frontal cortex, dentate gyrus, and cerebellum of PAE rats compared to controls. Specific [125I]-iodoaminopotentidine binding to H2 receptors was not altered in any of the brain regions measured, nor was basal or H2 receptor agonist-stimulated cAMP accumulation in DG altered in PAE rats compared to controls. These results suggest that not all markers of histaminergic neurotransmission are altered by PAE. However, the observation that HDC levels were reduced in the same brain regions where elevated H3 receptor-effector coupling was observed previously raises the question of whether a cause-effect relationship exists between HDC expression and H3 receptor function in affected brain regions of PAE rats. This relationship, along with the question of why these effects occur in some, but not all brain regions, requires more-detailed investigation.

Histamine dysregulation was implicated as a rare cause of Tourette syndrome and other tic disorders a decade ago by a landmark genetic study in a high density family pedigree, which implicated a hypomorphic mutation in the histidine decarboxylase (Hdc) gene as a rare but high penetrance genetic cause. Studies in Hdc knockout (KO) mice have confirmed that this mutation causes tic-relevant behavioural and neurochemical abnormalities that parallel what is seen in patients and thus validate the KO as a potentially informative model of tic pathophysiology. Recent studies have focused on the potential role of the histamine H3 receptor in this model, and by association in tic disorders and related neuropsychiatric conditions. The H3 receptor is up-regulated in the striatum in Hdc KO mice. As the H3 receptor has constitutive activity in the absence of ligand, this receptor up-regulation may have significant cellular effects despite the absence of neurotransmitter histamine in these mice. Activation in vivo of H3 receptors in wild type mice regulates signalling in striatal medium spiny neurons (MSNs) that interacts non-linearly with dopamine receptor signalling. Baseline signalling alterations in MSNs in Hdc KO mice resemble those seen after H3 receptor agonist treatment in wild type animals. H3 receptor agonist treatment in the KOs further accentuates most of these signalling abnormalities and produces behavioural stereotypy. Together, these data suggest the intriguing hypothesis that constitutive signalling by up-regulated H3 receptors explains many of the molecular and behavioural abnormalities seen in these animals. LINKED ARTICLES: This article is part of a themed section on New Uses for 21st Century. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v177.3/issuetoc.

Purpose Polyphenols possess anti-allergic activities. Catechin is one of the polyphenols that are abundantly present in the Acacia catechu. In this study, the authors investigated the effect of catechin isolated from A. catechu in an experimental mouse model of ovalbumin (OVA)-induced allergic asthma. Design/methodology/approach Catechin was isolated from A. catechu, and phytochemical analysis was carried out by ultraviolet visible and thin-layer chromatography (TLC), high pressure thin-layer chromatography was used for the determination of an amount of catechin present. In a first set of an experiment, the authors have carried out dose-dependent evaluation of catechin on histamine synthesis in normal rats. In another study, allergic asthma was induced in BALB/c mice by intraperitoneal injection of 50 mg OVA dissolved in 4 mg aluminum hydroxide dissolved in 0.2 ml saline on Days 0 and 14. Catechin was given orally at the dose of 100 mg/kg, once a day from Day 1 to Day 35 and after which various respiratory parameters such as tidal volume, respiratory rate and airflow rate, biochemical parameters such as histamine release from mast cells, bronchoalveolar (BAL) lavage fluid analysis and histopathology of lungs were carried out. Findings Catechin showed significant (p < 0.05) improvement in respiratory parameters such as tidal volume, respiratory rate and airflow rate, as well as biochemical and hematological parameters such as blood histamine, serum bicarbonate and nitric oxide levels as compared to the disease control group. The treatment also showed inhibitory effects on histamine synthesis in rat peritoneal as well as BAL mast cells. Also, a significant (p < 0.05) improvement in lung histopathology was observed with catechin. Originality/value From the present study, the authors can conclude that catechin exhibited potent anti-allergic activity by inhibition of histamine synthesis by inhibition of histidine decarboxylase enzyme. The study suggests that catechin has therapeutic potential for the treatment of allergic inflammatory disease in humans.

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. CONCLUSIONS 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. This article is protected by copyright. All rights reserved.

Although histamine inhibitors have been used in the motility-associated vertigo, the link between histamine and sleep deprivation (SD)-induced vertigo has not been clearly demonstrated. The histamine plasma levels were assayed in the SD volunteers before SD and 24 h after SD. Pinnacle's automated sleep deprivation system was used to establish the female C57BL/6 mice SD model. Histidine decarboxylase inhibitor 4-bromo-3-hydroxybenzoic acid (BHOA), and antihistamine diphenhydramine (DPHM) were injected intraperitoneally to test their effects on SD-induced vertigo. Rotarod tests and vestibular scores 24 and 48 h post SD were utilized to assay the vestibular function. Western blot was used to determine the expression of histidine decarboxylase (HDC) in the vestibular, and PowerChrom was utilized to quantify the concentrations of cerebrospinal fluid (CSF) histamine. SD increased plasma concentration of histamine in humans. Upregulated HDC in the vestibular and increased CSF concentration of histamine can be detected in the SD mice, indicating vestibular dysfunction which can be ameliorated by both BHOA and DPHM. Histamine signaling inhibition may ameliorate SD-induced vertigo, and histamine can be considered as a potential treatment target.

Histamine-producing bacteria (HPB) produce histamine from histidine contained in food through the action of histidine decarboxylase. To identify HPB isolated from food, it is necessary to detect histamine produced by the bacteria. In this study, we concurrently identified HPB and detected histamine by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry. After 24 h of incubation, 30 of 34 bacterial strains were correctly identified. Histamine was detected in all HPB cultured on Niven’s medium, and 94% of HPB cultured in histidine broth, except for two strains with low histamine production. This method may greatly simplify the procedure and reduce the time required to identify HPB.

The ability of recognizing familiar conspecifics is essential for many forms of social interaction including reproduction, establishment of dominance hierarchies, and pair bond formation in monogamous species. Many hormones and neurotransmitters have been suggested to play key roles in social discrimination. Here we demonstrate that disruption or potentiation of histaminergic neurotransmission differentially affects short (STM) and long-term (LTM) social recognition memory. Impairments of LTM, but not STM, were observed in histamine-deprived animals, either chronically (Hdc−/− mice lacking the histamine-synthesizing enzyme histidine decarboxylase) or acutely (mice treated with the HDC irreversible inhibitor α-fluoromethylhistidine). On the contrary, restriction of histamine release induced by stimulation of the H3R agonist (VUF16839) impaired both STM and LTM. H3R agonism-induced amnesic effect was prevented by pre-treatment with donepezil, an acetylcholinesterase inhibitor. The blockade of the H3R with ciproxifan, which in turn augmented histamine release, resulted in a procognitive effect. In keeping with this hypothesis, the procognitive effect of ciproxifan was absent in both Hdc−/− and αFMH-treated mice. Our results suggest that brain histamine is essential for the consolidation of LTM but not STM in the social recognition test. STM impairments observed after H3R stimulation are probably related to their function as heteroreceptors on cholinergic neurons.

Histamine is a critical inflammatory mediator in allergic diseases. We showed in a previous work that neutrophils from allergic patients produce histamine in response to allergens to which the patients were sensitized. Here, we investigate the molecular mechanisms involved in this process using peripheral blood neutrophils. We challenged these cells in vitro with allergens and analyzed histamine release in the culture supernatants. We also explored the effect of common therapeutic drugs that ameliorate allergic symptoms, as well as allergen-specific immunotherapy. Additionally, we examined the expression of histidine decarboxylase and diamine oxidase, critical enzymes in the metabolism of histamine, under allergen challenge. We show that allergen-induced histamine release is dependent on the activation of the phosphoinositide 3-kinase, mitogen-activated protein kinase p38, and extracellular signal-regulated kinase 1/2 signaling pathways. We also found a contribution of the phosphatase calcineurin to lesser extent. Anti-histamines, glucocorticoids, anti-M3-muscarinic receptor antagonists, and mainly β2 -receptor agonists abolished the allergen-dependent histamine release. Interestingly, allergen-specific immunotherapy canceled the histamine release through the downregulation of histidine decarboxylase expression. Our observations describe novel molecular mechanisms involved in the allergen-dependent histamine release by human neutrophils and provide new targets to inhibit histamine production.

The diverse bacteria encoding histidine decarboxylase gene during the fermentation of Sichuan-style sausages were investigated by culture-dependent techniques, polymerase chain reaction-denaturing gradient gel electrophoresis (PCR-DGGE), and high-throughput sequencing. All microbial indicators exhibited the advantages of mixed starter culture and the stability of microecosystem was more in the inoculation group than in the control group. DGGE and selected band sequencing were used to investigate the bacterial diversity of these sausages. Weissella were the main lactic acid bacteria (LAB) in the initial fermentation stage, whereas Weissella and Lactobacillus were the dominant bacteria in the later fermentation stage. After sequence alignment analysis, Enterobacter aerogenes and Citrobacter freundi were the two main bacteria encoding histidine decarboxylase gene and could produce histamine. These findings facilitate the better understanding of bacteria producing histidine decarboxylase during sausage fermentation and provide a theoretical basis for the control of histamine-producing bacteria in the process of fermented sausage processing.

Three of the four histamine receptors have been identified in zebrafish. Whereas only one histamine receptor 1 gene (hrh1) is known, two copies of histamine receptor 2 (hrh2a and hrh2b) have been identified. Although initially only one gene encoding for histamine receptor 3 (hrh3) was recognized in zebrafish, the genome database contains information for two more hrh3-like genes, whereas no genes corresponding for histamine receptor 4 with expression mainly in the immune system have been identified. Hrh1 and hrh3 show prominent uneven expression in the zebrafish brain, with the strongest expression in the dorsal telencephalon. Quantitatively significant expression of hrh1, hrh2, and hrh3 can also be found in several peripheral organs. Whereas antagonists of hrh1, hrh2, and hrh3 all affect the locomotor activity of zebrafish larvae, interpretation of the data is hampered by a lack of information on receptor binding and signaling characteristics. Zebrafish mutants lacking any of the three histamine receptors have shown modest behavioral phenotypes, possibly due to genetic compensation. None of the receptor mutant fish have shown significant sleep phenotypes. Adult zebrafish lacking hrh3 display decreased locomotor activity. The zebrafish histamine system shows significant life-long plasticity: presenilin 1 mutant zebrafish develop an abnormally large number of histamine neurons and increased thigmotaxis and anxiety-related phenotype. Overexpression of histidine decarboxylase (hdc) in larval zebrafish is associated with an increased number of hypocretin neurons, whereas translation inhibition of hdc or exposure to α-fluoromethylhistidine leads to decreased numbers of hypocretin neurons. Current pharmacological evidence suggests that this may be mediated by hrh1. Further studies using acute, e.g., pharmacogenetic or optogenetic manipulation of selected components of brain circuits, are required to understand the full range of physiological functions of zebrafish histamine receptors.

Non-thermal atmospheric plasma (NTAP) has gained attention as a decontamination and shelf-life extension technology. In this study its effect on psychrotrophic histamine-producing bacteria (HPB) and histamine formation in fish stored at 0–5°C was evaluated. Mackerel filets were artificially inoculated with Morganella psychrotolerans and Photobacterium phosphoreum and exposed to NTAP to evaluate its effect on their viability and the histidine decarboxylase (HDC) activity in broth cultures and the accumulation of histamine in fish samples, stored on melting ice or at fridge temperature (5°C). NTAP treatment was made under wet conditions for 30 min, using a dielectric barrier discharge (DBD) reactor. The voltage output was characterized by a peak-to-peak value of 13.8 kV (fundamental frequency around 12.7 KHz). This treatment resulted in a significant reduction of the number of M. psychrotolerans and P. phosphoreum (≈3 log cfu/cm2) on skin samples that have been prewashed with surfactant (SDS) or SDS and lactic acid. A marked reduction of their histamine-producing potential was also observed in HDC broth incubated at either 20 or 5°C. Lower accumulation of histamine was observed in NTAP-treated mackerel filets that have been inoculated with M. psychrotolerans or P. phosphoreum and pre-washed with either normal saline or SDS solution (0.05% w/v) and stored at 5°C for 10 days. Mean histamine level in treated and control groups for the samples inoculated with either M. psychrotolerans or P. phosphoreum (≈5 log cfu/g) varied from 7 to 32 and from 49 to 66 μg/g, respectively. No synergistic effect of SDS was observed in the challenge test on meat samples. Any detectable amount of histamine was produced in the meat samples held at melting ice temperature (0–2°C) for 7 days. The effects of NTAP on the quality properties of mackerel’s filets were negligible, whereas its effect on the psychrotrophic HPB might be useful when time and environmental conditions are challenging for the cool-keeping capacity throughout the transport/storage period.

By comprehensively measuring changes in metabolites in the hippocampus of stress-loaded mice, we investigated the reasons for stress vulnerability and the effect of theanine, i.e., an abundant amino acid in tea leaves, on the metabolism. Stress sensitivity was higher in senescence-accelerated mouse prone 10 (SAMP10) mice than in normal ddY mice when these mice were loaded with stress on the basis of territorial consciousness in males. Group housing was used as the low-stress condition reference. Among the statistically altered metabolites, depression-related kynurenine and excitability-related histamine were significantly higher in SAMP10 mice than in ddY mice. In contrast, carnosine, which has antidepressant-like activity, and ornithine, which has antistress effects, were significantly lower in SAMP10 mice than in ddY mice. The ingestion of theanine, an excellent antistress amino acid, modulated the levels of kynurenine, histamine, and carnosine only in the stress-loaded SAMP10 mice and not in the group-housing mice. Depression-like behavior was suppressed in mice that had ingested theanine only under stress loading. Taken together, changes in these metabolites, such as kynurenine, histamine, carnosine, and ornithine, were suggested to be associated with the stress vulnerability and depression-like behavior of stressed SAMP10 mice. It was also shown that theanine action appears in the metabolism of mice only under stress loading.

Histamine-producing cells include storage-type cells (e.g., mast cells and basophils), which store histamine intracellularly, and inducible-type cells (e.g., keratinocytes and macrophages), which induce histidine decarboxylase (HDC, a key enzyme for histamine biosynthesis) activity but do not have a storage pool of histamine. Most of the studies focused on identifying HDC-expressing cells by using cultured cells, and few on investigating the localization of HDC by using skin tissues. Hence, this study conducted immunohistochemical studies using human healthy skin samples. HDC-positive and cytokeratin 14 (a marker of basal keratinocytes)-negative cells were present around the basal layer of the epidermis. These cells did not immunohistochemically react with mast cell tryptase but expressed tyrosinase (a key enzyme for melanin biosynthesis) and microphthalmia-associated transcription factor (MITF, a transcription factor controlling the expression of tyrosinase genes). Melanin granules were clearly observed around HDC-positive and MITF-positive cells. Moreover, HDC mRNA and protein were both detected in cultured normal human epidermal melanocytes. In conclusion, HDC-positive and cytokeratin 14-negative cells around the basal layer of the epidermis are melanocytes.

IntroductionSystemic histaminergic activity is elevated in patients with diabetes mellitus. There are a few studies suggesting that histamine is implicated in the pathogenesis of diabetes, but the exact role of histamine in the development of diabetic retinopathy is unclear. The aim of this study was to investigate the role of histamine receptor H4 (HRH4) in the regulation of retinal pigment epithelium (RPE)-derived pro-angiogenic and anti-angiogenic factors under diabetic conditions.Research design and methodsThe levels of vascular endothelial growth factor (VEGF), interleukin-6 (IL-6), histamine and histidine decarboxylase (HDC) in the serum and vitreous samples of patients with diabetes were compared with those of patients without diabetes. The effect of hyperglycemia on expression levels of HRH4, VEGF, IL-6 and pigment epithelium-derived factor (PEDF) in the RPE was determined. The role of HRH4 in high glucose-induced regulation of VEGF, IL-6 and PEDF in ARPE-19 cells and the underlying regulatory mechanism were verified using an RNA interference-mediated knockdown study.ResultsThe serum and vitreous levels of VEGF, IL-6, histamine and HDC were more increased in patients with diabetic retinopathy than in patients without diabetes. HRH4 was overexpressed in RPE both in vitro and in vivo. Histamine treatment upregulated VEGF and IL-6 and downregulated PEDF expression in ARPE-19 cells cultivated under hyperglycemic conditions. Hyperglycemia-induced phosphorylation of p38 and subsequent upregulation of VEGF and IL-6 and downregulation of PEDF were dampened by small interfering RNA-mediated knockdown of HRH4 in ARPE-19 cells.ConclusionsTaken together, HRH4 was a critical regulator of VEGF, IL-6 and PEDF in the RPE under hyperglycemic conditions and the p38 mitogen-activated protein kinase pathway mediated this regulatory mechanism.