Histidine Decarboxylase Research Articles

Dynamics of bacterial composition and association with quality formation and histamine accumulation during Antarctic krill fish sauce fermentation.

In this study, we first verified the feasibility of using Antarctic krill as a raw material for quick-brewed fish sauce, and the results showed that the amino acid nitrogen (AAN)and total soluble nitrogen(TSN) in the fermented 30days fish sauce met the national level fish sauce standards, but the histamine content exceeded the maximum limit value of histamine in fish sauce (400mg/kg) set by the International Codex Alimentarius Commission (CAC) and the European Union (EU). On this basis, the correlation between physicochemical indexes and bacterial communities during the fermentation of fish sauce was investigated using high-throughput sequencing, culture method. The correlation analyses revealed the relationship between bacterial communities and the quality and safety of fish sauce, and these studies will be helpful for the development of Antarctic krill fish sauce. The results showed that Staphylococcus were positively correlated with the accumulation of histamine and TVB-N during fermentation. This may be due to the presence of genes encoding histidine decarboxylase in Staphylococcus. Virgibacillus was positively correlated with the accumulation of AAN during fermentation. It was also found that Virgibacillus dokdonensis had a high protease activity (153.22U/mL) and Staphylococcus epidermidis was the most capable of producing histamine at 31.59mg/kg. Therefore histamine can be reduced by adding bacteria that inhibit the growth of Staphylococcus or degrade histamine as a fermenter.

Review of the potential of bioactive compounds in seaweed to reduce histamine formation in fish and fish products.

The formation of histamine in food is influenced by temperature, and histamine growth can be inhibited by maintaining a cold chain. However, simply relying on temperature control is insufficient, as certain bacteria can produce the enzyme histidine decarboxylase even at temperatures below 5°C. To address this issue, various methods, such as modified atmosphere packaging, high hydrostatic pressure, and irradiation, have been developed to control histamine in fishery products. However, these methods often require significant investments. Therefore, there is a need for a cost-effective solution to overcome this problem. This review explores a cost-effective solution through the utilization of bioactive compounds derived from underexplored seaweeds. Seaweed bioactive compounds, either in their pure form or as extracts, offer a promising alternative method to regulate histamine generation in fishery products due to their antibacterial activity, and this review provides comprehensive insights into the potential of different seaweed-derived bioactive compounds as inhibitors of histamine production, detailing their diverse applications in fishery products. It also explores the mechanism by which bioactive compounds prevent histamine formation by bacteria, focusing on the potential of seaweed bioactive compounds to inhibit bacterial histidine decarboxylase. Future trends in the inhibition of histidine decarboxylation are also discussed. The bioactive compounds considered, such as flavonoids, alkaloids, terpenes, and phenolic acids, exhibit their antibacterial effects through various mechanisms, including the inhibition of DNA and RNA synthesis, disruption of cytoplasmic and cell membranes, and inhibition of enzymes by reacting with sulfhydryl groups on proteins. In conclusion, the integration of underexplored seaweeds in fishery product preservation represents a promising and innovative approach for future food safety and sustainability.

Genetic background and microbiome drive susceptibility to epicutaneous sensitization and food allergy in adjuvant-free mouse model

BackgroundThe dual allergen exposure hypothesis states that sensitization to food antigens occurs through a damaged skin barrier in individuals with no previous oral tolerance to certain foods. However, the resulting allergic reaction could depend on factors such as the host’s genetic predisposition as well as the skin and gut microbiota.MethodsSpecific-pathogen-free BALB/c and C57BL/6 and germ-free (GF) BALB/c mice were epicutaneously sensitized with ovalbumin (OVA) via dorsal tape-stripped skin and challenged with OVA by intragastric gavage. The development of food allergy (FA) symptoms, the Th2 and mast cell immune response and differences in the skin and gut microbiota were investigated.ResultsBALB/c mice, but not C57BL/6 mice, showed severe clinical signs of FA (hypothermia, diarrhea) as well as a stronger serum antibody response and Th2 cytokine secretion in the spleen and jejunum after OVA-treatment. The increased mast cell count correlated with higher MCPT-1 production and histidine decarboxylase mRNA expression in the jejunum of these mice. The 16S rRNA sequencing analysis revealed lower abundance of short-chain fatty acids producing bacteria in the gut microbiome of OVA-treated BALB/c mice. Changes in the β-diversity of the gut microbiome reflect both the genetic background as well as the OVA treatment of experimental mice. Compared to SPF mice, GF mice developed more severe anaphylactic hypothermia but no diarrhea, although they had a higher mast cell count, increased MCPT-1 production in the jejunum and serum, and increased arachidonate 5-lipoxygenase mRNA expression.ConclusionsWe show that the BALB/c mice are a mouse strain of choice for model of adjuvant-free epicutaneous sensitization through the disrupted skin barrier and following food allergy development. Our results highlight the significant influence of genetic background and microbiota on food allergy susceptibility, emphasizing the complex interplay between these factors in the allergic response.

HDC downregulation induced by chronic stress promotes ovarian cancer progression via the IL-6/STAT3/S100A9 pathway

ObjectiveThis study aimed to investigate the underlying mechanism of chronic stress promoting ovarian cancer growth comorbid with depression and evaluate the potential role of histamine (HIS) in treating this comorbidity.MethodsChronic unpredictable mild stress (CUMS) was used to establish a comorbid mouse model of ovarian cancer and depression. The behavioral phenotypes were assessed using the sucrose preference test (SPT), tail suspension test (TST), forced swimming test (FST), and open field test (OFT). Ovarian cancer growth was monitored by tracking the tumor volume and weight. Histidine decarboxylase (HDC) expression in the tumor tissue was analyzed using Western blot and qRT-PCR techniques. The serum levels of inflammatory factors (IL-6 and IL-17A), stress hormones (norepinephrine, NE and cortisol, and COR), histamine, and 5-hydroxytryptamine (5-HT) were detected by enzyme-linked immunosorbent assay (ELISA). In vitro experiments were conducted to explore the direct impacts of stress hormones on A2780 and ES-2 ovarian cancer cell lines, as well as the modulation of these effects by histamine. HDC knockdown and overexpression approaches were used to study its regulatory role in the IL-6/STAT3/S100A9 signaling pathway.ResultsChronic stress not only induced depressive behaviors but also accelerated ovarian cancer growth in mice by downregulating HDC expression in tumors, whereas exogenous HIS treatment alleviated depressive symptoms, suppressed cancer growth, and countered the decreased levels of HIS and increased levels of IL-6, IL-17A, NE, COR, and 5-HT induced by CUMS. Furthermore, HIS positively modulated the immune response by increasing the populations of CD3+T and CD8+ T cells and reducing IL-17A secretion. In vitro experiments revealed that stress hormones downregulated HDC expression, consequently promoting cancer cell proliferation, migration, and invasion via the IL-6/STAT3/S100A9 pathway. Knockdown of HDC activated this pathway, whereas HDC overexpression inhibited its activation.ConclusionChronic stress leads to the downregulation of HDC expression, thereby facilitating the progression of ovarian cancer through the IL-6/STAT3/S100A9 pathway. HIS might serve as a potential molecule for treating the comorbidities of ovarian cancer and depression.

Novel insights on the biology and immunologic effects of histamine: Aroad map for allergists and mast cell biologists.

Histamine (C5H9N3, molecular weight 111.15 g/mol) is a well-studied endogenous biogenic amine composed of an imidazole ring attached to an ethylamine side chain. It has a limited half-life of a few minutes within tissues and in circulation. Several cell types including mast cells (MCs), basophils, platelets, histaminergic neurons, and enterochromaffin cells produce varying amounts of histamine using histidine decarboxylase. However, only MCs and basophils have complex mechanisms to pack and store histamine in granules along with other mediators using serglycin and its carried glycosaminoglycan side chains. Relatively low granule pH (∼5.5) supports the binding of stored histamine to heparin, whereas exposure to neutral pH after degranulation weakens the binding and histamine becomes liberated. Histamine exerts multifaceted regulatory biofunctions by engaging its 4 types of heptahelical G protein-coupled receptors (H1R-H4R), which have different expression profiles and functions. MCs express H1R, H2R, and H4R, which gives them a dual role in histamine biology as producers and responsive target cells. Histamine plays a role in a variety of physiologic and pathologic processes such as cell proliferation, differentiation, hematopoiesis, vascular permeability, embryogenesis, tissue regeneration, and wound healing. The emergence of histamine receptor-deficient mouse models and the development of multiple histamine receptor agonists and antagonists have helped researchers better understand these physiologic and pathogenic functions of histamine. We review the biology of histamine with a focus on immunologic aspects and the role of histamine in allergy and MC biology.

Abstract 4133170: Insulin resistance triggers histamine release from endothelial cells, which disrupts endothelial barrier function and causes vasoconstriction.

Diabetic vascular dysfunction is a serious health concern, affecting ~38 million people in the USA, according to the 2020 CDC-National Diabetes Statistics Reports. Type 2 diabetes (T2D) causes several vascular changes leading to major clinical consequences such as stroke and ~3-fold elevated risk of cardiovascular diseases (CVD) and the underlying causes of vascular dysfunction in T2D are complex. The anatomical position of endothelial cells (ECs) between the circulating blood and vessel walls makes them the first to encounter and respond to cellular stressors in the bloodstream. Here, we investigated the role of long-term increases in plasma histamine levels as observed in T2D and its effects on ECs and vascular contractility. The high-fat diet-low-dose streptozotocin protocol induced T2D in C57BL/6J mice. Endothelial cell function was analyzed using Western blotting, in vitro blood-brain barrier assays, histamine measurements, immunofluorescence, and pressurized artery myography. In our T2D model, EC-mediated histamine synthesis occurred after the onset of IR. A spike in plasma histamine levels was observed immediately following the onset of insulin resistance, followed by a brief plateau. A second spike in plasma histamine levels was noted four weeks later. In isolated control ECs, the addition of external histamine showed a concentration-dependent increase in histidine decarboxylase expression, and cellular histamine levels were observed, which was inhibited by the H2R blocker, famotidine. The tight junction marker, JAM-A (CD321), expression in diabetic cerebral arteries was ~42% less compared to the non-diabetic controls. Transendothelial Electrical Resistance testing showed a ~2-fold higher permeability with diabetic ECs than controls. Pressure myography on isolated cerebral arteries indicated that external histamine passed through the lumen of arteries from T2D mice 4 weeks after onset of IR constricted whereas control arteries dilated. Additionally, T2D mice cerebral artery myogenic tone at 60 mmHg was 70% greater compared to control arteries. These data indicate that the onset of IR triggers an increase in circulating histamine levels, which in turn stimulates histamine synthesis and release from endothelial cells leading to the loss of endothelial barrier function, blood-brain barrier leakage, and vasoconstriction. We are currently investigating the molecular pathways that precede the increase in circulating histamine levels during T2D.

Clinicopathologic and Genomic Features of Invasive Stratified Mucin-producing Carcinoma of the Uterine Cervix Coexisting With High-grade Squamous Intraepithelial Lesion.

Invasive stratified mucin-producing carcinoma (ISMC) is a specific type of adenocarcinoma of the cervix, which is associated with human papillomavirus infection and often coexists with other types of carcinomas. However, given its rarity, understanding of this disease remains insufficient. We present a unique case of ISMC of the cervix coexisting with a high-grade squamous intraepithelial lesion (HSIL). In addition to histologic and immunohistochemical feature observation, genomic profiling of the 2 lesions was performed. Histologically, the ISMC and HSIL lesions were independent of each other. Aside from the typical morphology, various architectural features of ISMC were observed. Immunohistochemically, the ISMC and HSIL lesions were strongly and diffusely positive for p16 and exhibited high Ki-67 expression. The ISMC lesion was also positive for CK7, MUC5AC, and MUC6, while it was negative for PAX-8. The HSIL lesion was positive for CK5/6 and p40. The combined positive score of PD-L1 was 55. The other markers were all negative in both lesions, and the p53 was wild-type. Next-generation sequencing analysis revealed multiple gene mutations in the ISMC and HSIL lesions. A total of 88 gene mutations were identified in the ISMC lesion, while 20 gene mutations were identified in the HSIL lesion. Three mutations (ERBB2, histidine decarboxylase gene [HDC], and BSN) were detected in the ISMC and HSIL lesions. Both lesions had a low tumor mutation burden and microsatellite-stable status. No copy number-associated variants or structural variations were identified in either lesion. These results suggest that patients with ISMC may benefit from PD-L1 immunotherapy and targeted therapy.

ENZYMES AND METABOLITES OF ENDOGENOUS CARBON MONOXIDE IN THE FETOPLACENTAL SYSTEM DURING PHYSIOLOGICAL GESTATION AND PLACENTAL DYSFUNCTION

Introduction. Prenatal ontogenesis largely depends on the functional and metabolic viability of the placenta and the entire fetoplacental complex. That is why the dysfunction of the placenta due to the changes in cellular regulation processes will lead to pregnancy complications and impaired fetal develop-ment. An important component of the system of intra- and intercellular regulators is the gas transmitter – carbon monoxide. Its role in cellular signaling and communication reactions, and at the same time, insufficient data of its metabolism, justifies the need to conduct research on this gas transmitter during complicated pregnancy. The aim of the work. To study the features of the metabolism of the active cellular mediator - the gas transmitter carbon monoxide in different objects of the fetoplacental system during physiological pregnancy and placental dysfunction. Material and methods. The research materials included placental tissue, amnion and amniotic fluid. The work uses spectrophotometric methods, enzyme immunoassay, and ion exchange chromatography. Results. Multidirectional changes in the activity of the studied enzymes (heme oxygenase and histidine decarboxylase), the content of the substrate of His-tidine reaction and the product of reaction of Histamine are established in case of placental disfunction. There is a certain correlation between the discov-ered studied components. Indicators of carbon monoxide metabolism can be markers for predicting postnatal damage – cerebral disorders in newborns. Conclusions. The identified injuries are obviously important links in the chain of disorders accompanied by the development of placental dysfunction.

Association Between Elevated Serum Histidine Decarboxylase and Tumor Necrosis Factor-Alpha Levels and High Risk in tic Disorder Children

Background: Children with tic disorder (TD) have been reported to exhibit abnormal levels of certain peripheral proteins, but none of these abnormalities have been established as biomarkers for diagnosis. Objectives: The purpose of this study is to evaluate serum histidine decarboxylase (HDC) and tumor necrosis factor-alpha (TNF-α) levels in children with TD, assess their relationship with TD development, and provide reliable biomarkers for prediction and risk management in clinical settings. Methods: In the present study, serum HDC and TNF-α levels from 118 no-comorbid and medication-naive TD patients and 111 age-matched healthy controls were measured using enzyme-linked immunosorbent assay (ELISA) kits. Tic severity was assessed using the Yale Global Tic Severity Scale (YGTSS). Binary logistic regression analysis was used to evaluate the relationship between serum HDC and TNF-α levels and TD development. Results: An increase in serum HDC and TNF-α levels was observed in TD patients compared with controls. Further analysis revealed a significant association between elevated HDC and TNF-α levels and TD development, with a significant ROC curve for HDC and TNF-α as potential risk factors. Conclusions: This study identified a high prevalence of elevated serum HDC and TNF-α levels in children with TDs and provides evidence that elevated blood HDC and TNF-α may be potential risk factors for TD development.

A CXCR4 partial agonist improves immunotherapy by targeting polymorphonuclear myeloid-derived suppressor cells and cancer-driven granulopoiesis.

Polymorphonuclear myeloid-derived suppressor cells (PMN-MDSCs) are pathologically activated neutrophils that potently impair immunotherapy responses. The chemokine receptor CXCR4, a central regulator of hematopoiesis, represents an attractive PMN-MDSC target1. Here, we fused a secreted CXCR4 partial agonist TFF2 to mouse serum albumin (MSA) and demonstrated that TFF2-MSA peptide synergized with anti-PD-1 to induce tumor regression or eradication, inhibited distant metastases, and prolonged survival in multiple gastric cancer (GC) models. Using histidine decarboxylase (Hdc)-GFP transgenic mice to track PMN-MDSC in vivo , we found TFF2-MSA selectively reduced the immunosuppressive Hdc-GFP + CXCR4 hi tumor PMN-MDSCs while preserving proinflammatory neutrophils, thereby boosting CD8 + T cell-mediated anti-tumor response together with anti-PD-1. Furthermore, TFF2-MSA systemically reduced PMN-MDSCs and bone marrow granulopoiesis. In contrast, CXCR4 antagonism plus anti-PD-1 failed to provide a similar therapeutic benefit. In GC patients, expanded PMN-MDSCs containing a prominent CXCR4 + LOX-1 + subset are inversely correlated with the TFF2 level and CD8 + T cells in circulation. Collectively, our studies introduce a strategy of using CXCR4 partial agonism to restore anti-PD-1 sensitivity in GC by targeting PMN-MDSCs and granulopoiesis.

Safety assessment of enterocin-producing Enterococcus strains isolated from sheep and goat colostrum

BackgroundThis study investigates the safety evaluation of enterocin-producing 11 E. mundtii and two E. faecium strains previously isolated from small livestock colostrums. Enterococcus species do not possess Generally Recognized as Safe (GRAS) status. Hence, it is critical to scrutinize enterococci’s antibiotic resistance, virulence characteristics, and biogenic amine production capabilities in order to assess their safety before using them as starter or adjunct cultures.ResultsEnterococcus strains showed susceptibility to medically significant antibiotics. Multiple-drug resistance (MDR) was found in only E. faecium HC121.4, and its multiple antibiotic resistance (MAR) index was detected to be 0.22. The tetL and aph(3')-IIIa were the most commonly found antibiotic resistance genes in the strains. However, E. mundtii strains HC56.3, HC73.1, HC147.1, and E. faecium strain HC121.4 were detected to lack any of the antibiotic resistance genes examined in this study. Only E. mundtii HC166.3 showed hemolytic activity, while none of the strains engage in gelatinase activity. The strains were identified to have virulence factor genes with a low rate. None of the virulence factor genes could be detected in E. mundtii HC26.1, HC56.3, HC73.1, HC165.3, HC166.8, and E. faecium HC121.4. The E. mundtii HC73.2 strain displayed the highest presence of virulence factor genes, namely gelE, efaAfs, cpd, and ccf. Similarly, the E. mundtii HC112.1 strain showed a significant presence of genes efaAfm, ccf, and acm. There was no decarboxylation of histidine, ornithine, or lysine seen in any of the strains. Nevertheless, E. faecium HC121.4 and HC161.1 strains could decarboxylate tyrosine, but E. mundtii HC26.1, HC56.3, HC73.1, HC73.2, HC112.1, HC147.1, HC155.2, HC165.3, HC166.3, HC166.5, and HC166.8 strains only showed a limited capacity for tyrosine decarboxylation. None of the strains possessed the hdc, odc, or ldc genes, but all of them had the tdc gene.ConclusionThe E. mundtii HC56.3 and HC73.1 strains were deemed appropriate for utilization in food production. Using the remaining 11 strains as live cultures in food production activities could pose a possible risk to consumer health.

Structural Basis for Histaminergic Regulation of Neural Circuits in the Mouse Olfactory Bulb.

Odor information is modulated by centrifugal inputs from other brain regions to the olfactory bulb (OB). Neurons containing monoamines, such as serotonin, acetylcholine, and noradrenaline, are well known as centrifugal inputs; however, the role of histamine, which is also present in the OB, is not well understood. In this study, we examined the histaminergic neurons projecting from the hypothalamus to the OB. We used an antibody against histidine decarboxylase (HDC), a synthesizing enzyme of histamine, to identify histaminergic neurons and assess their localization within the OB and the ultrastructure of their fibers and synapses using multiple immunostaining laser microscopy, ultra-high voltage electron microscopy (EM), and EM to confirm their relationships with other neurons. To further identify the origin nucleus of the histaminergic neurons projecting to the OB, we injected the retrograde tracer FluoroGold and analyzed the pathway to the OB anterogradely. HDC-immunoreactive (-ir) fibers were abundant in the olfactory nerve (ON) layer compared to other monoamines. HDC-ir neurons received asymmetrical synapses from ONs and formed synapses containing pleomorphic vesicles with variable postsynaptic densities to non-ON elements, thus forming serial synapses. We also confirmed that histaminergic neurons project from the rostral ventral tuberomammillary nucleus to the granule cell layer of the OB and, for the first time, successfully visualized their axons from the hypothalamus to the OB. These findings indicate that histamine may regulate odor discrimination in the OB, suggesting a regulatory relationship between hypothalamic function and olfaction. We thus elucidate morphological mechanisms with tuberomammillary nucleus-derived histaminergic neurons involved in olfactory information.

Immunohistochemical analysis and distribution of epithelial mast cells in the rat larynx and trachea.

Mast cells (MCs) in rat airways have been classified into two subtypes: epithelial MCs and connective tissue MCs (CTMCs). However, the immunohistochemical characteristics, cellular morphology, and distribution of epithelial MCs in the upper airways remain unclear. The present study investigated the morphological characteristics and distribution of epithelial MCs using 5-hydroxytryptamine (5-HT) and other immunohistochemical markers in sectioned or whole-mount preparations of the rat larynx and trachea. A double immunofluorescence analysis revealed the colocalization of 5-HT immunoreactivity with c-kit, a stem cell factor receptor commonly used as a MC marker, in both epithelial MCs and CTMCs. Dopa decarboxylase, an enzyme involved in 5-HT synthesis, was detected in both subtypes, suggesting their ability to synthesize and release 5-HT. Tryptase and histidine decarboxylase (a biosynthetic enzyme of histamine), which are well-known mediators of MCs, were exclusive to CTMCs. Epithelial MCs were pleomorphic with long cytoplasmic processes, whereas CTMCs were round and lacked cytoplasmic processes. The density of epithelial MCs was significantly higher in the glottis and cranial part of the trachea than in the epiglottis and other parts of the trachea. The present results showed that the morphology and immunohistochemical characteristics of epithelial MCs were different from those of CTMCs in the rat larynx and trachea, and variform epithelial MCs were predominantly located at the entrance of the upper airways. Epithelial MCs may release 5-HT to regulate innate immune responses by modulating epithelial cell functions at the entrance gate of the upper airways.

Microbiological profile and prevalence of histamine-producing bacteria in fresh sardines stored at different temperatures.

The European pilchard (Sardina pilchardus) is an important fish species for the Moroccan economy in terms of production and export. Biogenic amine histamine is a metabolite produced in the flesh of some fish species after death due to the decarboxylation of free histidine by histaminogenic bacteria. Failure to control the histamine risk in European pilchard may lead to public health and socioeconomic issues. This study aimed to estimate the prevalence of histaminogenic bacteria in association with histamine levels and the growth of microflora in Moroccan sardines (European pilchard). We conducted the study by monitoring Moroccan sardines of histamine content and microbiological profile (aerobic plate count [APC], coliforms, and thermo-tolerant coliforms [TTC]) during 6 days of storage at three different temperatures (0°C, 10°C, and ambient temperature [22°C]). The histamine assay was performed using a spectrofluorometric method, and the microbiological identification of histamine-producing bacteria was performed using a combination of biochemical and molecular tests. The histamine content in European pilchard stored at 0°C was negligible. However, high concentrations were observed at 10°C and 22°C. The microbiological profile showed a positive association between microflora counts and histamine content according to storage time. At 0°C, a moderate increase in the APC, a decrease in coliforms, and an absence of TTC were observed. The rapid proliferation of all microflora was observed at 10°C, whereas at 22°C, the proliferation was almost exponential. Bacterial identification revealed the exclusive presence of species belonging to the Enterobacteriaceae family at varying frequencies depending on storage temperature. Morganella morganii and Proteus mirabilis had the highest histamine induction rates in L-histidine-supplemented broth, with 1600 and 255 parts per million (ppm), respectively, after 48-h incubation at 35°C. Klebsiella ozaenae could produce 136 ppm and Serratia plymuthica 115 ppm. Reverse transcription polymerase chain reaction showed positive results for the presence of genes associated with histidine decarboxylase. The hdc genes of M. morganii, P. mirabilis, and K. ozaenae were successfully amplified and exhibited strong similarity with the reference gene of M. morganii. This study describes for the first time the hdc gene in bacteria that form histamine in Moroccan sardines. The results also confirm that respect for the cold chain integrity is a crucial factor in histamine management. This information should help stakeholders in the implementation of sound strategies for managing the hazards associated with seafood and their products.

Histamine synthesis and transport are coupled in axon terminals via a dual quality control system

Monoamine neurotransmitters generated by de novo synthesis are rapidly transported and stored into synaptic vesicles at axon terminals. This transport is essential both for sustaining synaptic transmission and for limiting the toxic effects of monoamines. Here, synthesis of the monoamine histamine by histidine decarboxylase (HDC) and subsequent loading of histamine into synaptic vesicles are shown to be physically and functionally coupled within Drosophila photoreceptor terminals. This process requires HDC anchoring to synaptic vesicles via interactions with N-ethylmaleimide-sensitive fusion protein 1 (NSF1). Disassociating HDC from synaptic vesicles disrupts visual synaptic transmission and causes somatic accumulation of histamine, which leads to retinal degeneration. We further identified a proteasome degradation system mediated by the E3 ubiquitin ligase, purity of essence (POE), which clears mislocalized HDC from the soma, thus eliminating the cytotoxic effects of histamine. Taken together, our results reveal a dual mechanism for translocation and degradation of HDC that ensures restriction of histamine synthesis to axonal terminals and at the same time rapid loading into synaptic vesicles. This is crucial for sustaining neurotransmission and protecting against cytotoxic monoamines.

Phylogenetically diverse bacterial species produce histamine

Histamine is an important biogenic amine known to impact a variety of patho-physiological processes ranging from allergic reactions, gut-mediated anti-inflammatory responses, and neurotransmitter activity. Histamine is found both endogenously within specialized host cells and exogenously in microbes. Exogenous histamine is produced through the decarboxylation of the amino acid L-histidine by bacterial-derived histidine decarboxylase enzymes. To investigate how widespread histamine production is across bacterial species, we examined 102,018 annotated genomes in the Integrated Microbial Genomes Database and identified 3,679 bacterial genomes (3.6 %) which possess the enzymatic machinery to generate histamine. These bacteria belonged to 10 phyla: Bacillota, Bacteroidota, Actinomycetota, Pseudomonadota, Lentisphaerota, Fusobacteriota, Armatimonadota, Cyanobacteriota, Thermodesulfobacteriota, and Verrucomicrobiota. The majority of the identified bacteria were terrestrial or aquatic in origin, although several bacteria originated in the human gut microbiota. We used liquid chromatography-tandem mass spectrometry (LC-MS/MS)-based targeted metabolomics to confirm our genome discoveries correlated with L-histidine-to-histamine conversion in a chemically defined bacterial growth medium by a cohort of select environmental and human gut bacteria. We found that environmental microbes Vibrio harveyi, Pseudomonas fluorescens and Streptomyces griseus generated considerable levels of histamine (788 – 8,730 ng/mL). Interestingly, we found higher concentrations of histamine produced by gut-associated Fusobacterium varium, Clostridium perfringens, Limosilactobacillus reuteri and Morganella morganii (8,510––82,400 ng/mL). This work expands our knowledge of histamine production by diverse microbes.

Histamine promotes mouse decidualization through stimulating epithelial amphiregulin release.

Accumulating evidence shows that inflammation is essential for embryo implantation and decidualization. Histamine, a proinflammatory factor that is present in almost all mammalian tissues, is synthesized through decarboxylating histidine by histidine decarboxylase (HDC). Although histamine is known to be essential for decidualization, the underlying mechanism remains undefined. In the present study, histamine had no obvious direct effects on in vitro decidualization in mice. However, the obvious differences in HDC protein levels between day 4 of pregnancy and day 4 of pseudopregnancy, as well as between delayed and activated implantation, suggested that the blastocyst may be involved in regulating HDC expression. Furthermore, blastocyst-derived tumor necrosis factor α (TNFα) significantly increased HDC levels in the luminal epithelium. Histamine increased the levels of amphiregulin (AREG) and disintegrin and metalloproteinase domain-containing protein 17 (ADAM17) proteins, which was abrogated by treatment with famotidine, a specific histamine type 2 receptor (H2R) inhibitor, or by TPAI-1 (a specific inhibitor of ADAM17). Intraluminal injection of urocanic acid (HDC inhibitor) on day 4 of pregnancy significantly reduced the number of implantation sites on day 5 of pregnancy. TNFα-stimulated increases in HDC, AREG and ADAM17 protein levels was abrogated by urocanic acid, a specific inhibitor of HDC. Additionally, AREG treatment significantly promoted in vitro decidualization. Collectively, our data suggests that blastocyst-derived TNFα induces luminal epithelial histamine secretion, and histamine increases mouse decidualization through ADAM17-mediated AREG release.

Histamine deficiency exacerbates cisplatin-induced ferroptosis in cochlea hair cells of HDC knockout mice

Cisplatin (CDDP) is extensively utilized in the management of diverse types of cancers, but its ototoxicity cannot be ignored, and clinical interventions are not ideal. Histidine decarboxylase (HDC) is the exclusive enzyme for histamine synthesis. Anti-histamine receptor drugs are ubiquitously employed in the therapeutics of allergies and gastrointestinal diseases. Yet, the specific role of histamine and its signaling in the inner ear is not fully understood. This study utilized cisplatin treated mice and HEI-OC1 auditory hair cell line to establish a cisplatin-induced ototoxicity (CIO) model. Histidine decarboxylase knockout (HDC−/−) mice and histamine receptor 1 (H1R) antagonist were utilized to investigate the influence of HDC/histamine/H1R signaling on ototoxicity. The results identified HDC and H1R expression in mouse hair cells. Transcriptomics indicated that the expression levels of oxidative stress-related genes in the cochlea of HDC−/− mice increased. Furthermore, histamine deficiency or suppression of H1R signaling accelerated HC ferroptosis, a pivotal factor underlying the aggravation of CIO in vivo and in vitro, conversely, the supplementation of exogenous histamine reversed these deleterious effects. Mechanistically, this study revealed that the malfunction of HDC/histamine/H1R signaling induced upregulation of NRF2 expression, accompanied by the upregulation of ACSL4 and downregulation of GPX4 expression, which are major regulatory factors of ferroptosis. In summary, histamine deficiency may induce hair cell death by regulating the H1R pathway and exacerbate CIO. Our findings have indicated a potential therapeutic target for CIO.

Suppression of excitatory synaptic transmission in the centrolateral amygdala via presynaptic histamine H3 heteroreceptors.

The central histaminergic system has a pivotal role in emotional regulation and psychiatric disorders, including anxiety, depression and schizophrenia. However, the effect of histamine on neuronal activity of the centrolateral amygdala (CeL), an essential node for fear and anxiety processing, remains unknown. Here, using immunostaining and whole-cell patch clamp recording combined with optogenetic manipulation of histaminergic terminals in CeL slices prepared from histidine decarboxylase (HDC)-Cre rats, we show that histamine selectively suppresses excitatory synaptic transmissions, including glutamatergic transmission from the basolateral amygdala, on both PKC-δ- and SOM-positive CeL neurons. The histamine-induced effect is mediated by H3 receptors expressed on VGLUT1-/VGLUT2-positive presynaptic terminals in CeL. Furthermore, optoactivation of histaminergic afferent terminals from the hypothalamic tuberomammillary nucleus (TMN) also significantly suppresses glutamatergic transmissions in CeL via H3 receptors. Histamine neither modulates inhibitory synaptic transmission by presynaptic H3 receptors nor directly excites CeL neurons by postsynaptic H1, H2 or H4 receptors. These results suggest that histaminergic afferent inputs and presynaptic H3 heteroreceptors may hold a critical position in balancing excitatory and inhibitory synaptic transmissions in CeL by selective modulation of glutamatergic drive, which may not only account for the pathophysiology of psychiatric disorders but also provide potential psychotherapeutic targets. KEY POINTS: Histamine selectively suppresses the excitatory, rather than inhibitory, synaptic transmissions on both PKC-δ- and SOM-positive neurons in the centrolateral amygdala (CeL). H3 receptors expressed on VGLUT1- or VGLUT2-positive afferent terminals mediate the suppression of histamine on glutamatergic synaptic transmission in CeL. Optogenetic activation of hypothalamic tuberomammillary nucleus (TMN)-CeL histaminergic projections inhibits glutamatergic transmission in CeL via H3 receptors.

The effectiveness of garlic extracts on biogenic amine formation by foodborne pathogens and fish spoilage bacteria

SummaryImpacts of aqueous and ethanolic extracts of garlic were investigated in suppressing bacterial growth and biogenic amine (BA) formation by selected foodborne pathogens (Candida albicans, Salmonella paratyphi A, Escherichia coli and Staphylococcus aureus) and fish spoilage bacteria (Enterococcus faecalis, Photobacterium damselae and Pseudomonas luteola). The spread‐plate method was used to monitor bacterial growth in histidine decarboxylase broth (HDB), whereas the rapid high‐performance liquid chromatographic (HPLC) method was used for BA analysis. Bacterial growth and their ammonia and BA production were monitored using HDB. The results showed that bacterial growth on HDB was in the range from 9.13, for P. luteola, to 9.54 log CFU (colony‐forming units) mL−1, for S. aureus and C. albicans. The presence of garlic extracts in HDB resulted considerably in lowering bacterial growth and BA formation (P < 0.05). The highest inhibitory activities of ethanolic and water garlic extracts were obtained for Gram‐positive S. aureus with 1.4 and 1.5 logarithmic reduction on bacterial growth, followed by Gram‐negative Salmonella Paratyphi A and E. coli. Application of garlic extracts, mainly ethanolic ones, showed a significant inhibitory effect on bacterial ammonia production, with 4‐100‐fold lower ammonia accumulation (P < 0.05). Bacteria produced all tested BAs, mainly dopamine, agmatine and tryptamine. The highest levels of histamine and tyramine (61.99 and 36.45 mg L−1) were produced by S. aureus. In the presence of aqueous or ethanolic garlic extracts, putrescine production by E. faecalis was around 110‐fold lower than that of the control group. Results revealed that both garlic extracts are potent antimicrobials that can control the growth of foodborne pathogens and their harmful BA formation.