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One way to effectively reduce the number of biogenic amines (BAs) in food is through enzymatic reduction using bacteria, such as lactic acid bacteria. This study focuses on the ability of the bacterial strain Lacticaseibacillus casei CCDM 198 to reduce the number of three important BAs (histamine, putrescine and cadaverine) over time, depending on different conditions (temperature and pH) in vitro and for the real dairy product – skimmed milk. The obtained results show that the studied strain significantly (P < 0.05) affects the number of individual amines, and the content of all amines has a decreasing character compared to the initial relative content of BAs at time zero. Furthermore, a statistical dependence (P < 0.05) of the rate of amine degradation on the combination of investigated factors was demonstrated. The presence and the activity of multicopper oxidase enzyme was also detected in this bacterial strain. This is the first known publication demonstrating multicopper oxidase activity in Lacticaseibacillus casei CCDM 198. Moreover, the studied strain is able to reduce the tested BAs in skimmed milk and would be a good candidate for degrading these toxic compounds in other dairy products, such as cheese. These findings could significantly enhance the food safety of dairy products.

Cheese is a food in which toxic concentrations of biogenic amines (BA) may be reached, mainly as a consequence of the decarboxylation of determined amino acids by certain lactic acid bacteria (LAB). To maintain the food safety of cheese, environmentally friendly strategies are needed that specifically prevent the growth of BA-producing LAB and the accumulation of BA. The bacteriocins produced by LAB are natural compounds with great potential as food biopreservatives. This work examines the antimicrobial potential of 7 bacteriocin-containing, cell-free supernatants (CFS: coagulin A-CFS, enterocin A-CFS, enterocin P-CFS, lacticin 481-CFS, nisin A-CFS, nisin Z-CFS and plantaricin A-CFS) produced by LAB against 48 strains of the LAB species largely responsible for the accumulation of the most important BA in cheese, i.e., histamine, tyramine and putrescine. Susceptibility to the different CFS was strain-dependent. The histamine-producing species with the broadest sensitivity spectrum were Lentilactobacillus parabuchneri (the species mainly responsible for the accumulation of histamine in cheese) and Pediococcus parvulus. The tyramine-producing species with the broadest sensitivity spectrum was Enterococcus faecium, while Enterococcus faecalis and Enterococcus hirae were among the most sensitive putrescine producers. Nisin A-CFS was active against 31 of the 48 BA-producing strains (the broadest antimicrobial spectrum recorded). Moreover, commercial nisin A prevented biofilm formation by 67% of the BA-producing, biofilm-forming LAB strains. These findings underscore the potential of bacteriocins in the control of BA-producing LAB, and support the use of nisin A as a food grade biopreservative for keeping BA-producing LAB in check and reducing BA accumulation in cheese.

Background: Histamine intolerance manifests when there is an imbalance between the production of histamine and the body's capacity to metabolise it. Within the gastrointestinal tract, diamine oxidase (DAO) plays a pivotal role in breaking down ingested histamine. Insufficient levels of DAO have been linked to various diseases affecting the respiratory, cardiovascular, nervous, muscular, and digestive systems; some of these symptoms are evidenced in fibromyalgia syndrome. This underscores the crucial role of DAO in maintaining the histamine balance and highlights its association with diverse physiological systems and health conditions. The management of fibromyalgia commonly involves the use of psychotropic medications; however, their potential interactions with DAO remain not fully elucidated. Methods: This study delved into the influence of various psychotropic medications on DAO activity through in vitro experiments. Additionally, we explored their impact on the human intestinal cell line Caco-2, examining alterations in DAO expression at both the mRNA and protein levels along with DAO activity. Results: Notably, the examined drugs-sertraline, pregabalin, paroxetine, alprazolam, and lorazepam-did not exhibit inhibitory effects on DAO activity or lead to reductions in DAO levels. In contrast, citalopram demonstrated a decrease in DAO activity in in vitro assays without influencing DAO levels and activity in human enterocytes. Conclusions: These findings imply that a collaborative approach involving psychotropic medications and DAO enzyme supplementation for individuals with fibromyalgia and a DAO deficiency could offer potential benefits for healthcare professionals in their routine clinical practice.

Although tunas represent a significant part of the global fish economy and a major nutritional resource worldwide, their microbiome still remains poorly documented. Here, we conducted an analysis of the taxonomic composition of the bacterial communities inhabiting the gut, skin, and liver of two most consumed tropical tuna species (skipjack and yellowfin), from individuals caught in the Atlantic and Indian oceans. We hypothesized that each organ harbors a specific microbial assemblage whose composition might vary according to different biotic (sex, species) and/or abiotic (environmental) factors. Our results revealed that the composition of the tuna microbiome was totally independent of fish sex, regardless of the species and ocean considered. Instead, the main determinants of observed diversity were (i) tuna species for the gut and (ii) sampling site for the skin mucus layer and (iii) a combination of both parameters for the liver. Interestingly, 4.5% of all amplicon sequence variants (ASV) were shared by the three organs, highlighting the presence of a core-microbiota whose most abundant representatives belonged to the genera Mycoplasma, Cutibacterium, and Photobacterium. Our study also revealed the presence of a unique and diversified bacterial assemblage within the tuna liver, comprising a substantial proportion of potential histamine-producing bacteria, well known for their pathogenicity and their contribution to fish poisoning cases. These results indicate that this organ is an unexplored microbial niche whose role in the health of both the host and consumers remains to be elucidated.

Bakalářská práce podrobně rozebírá téma Histaminové intolerance. První část přibližuje význam histaminu a dalších biogenních aminů pro lidské tělo. Dále vysvětluje metabolismus histaminu a účinky enzymu diaminooxidáza. A v poslední části popisuje jednotlivé příčiny vzniku histaminové intolerance, problematiku diagnostiky a její léčbu., The bachelor thesis discusses in detail the topic of Histamine Intolerance. The first part introduces the importance of histamine and other biogenic amines for the human body. It also explains the metabolism of histamine and the effects of the enzyme diaminooxidase. And in the last part, it describes the various causes of histamine intolerance, diagnostic issues and its treatment., Fakulta chemicko-technologická, 1. Prezentace výsledků bakalářské práce. 2. Diskuze k posudku vedoucího bakalářské práce. 3. Student/ka zodpověděl/a všechny dotazy a připomínky k bakalářské práci., Dokončená práce s úspěšnou obhajobou

Neurotransmiter je látka, která vyvolá specifickou odezvu po jejím uvolnění neuronem. Tato bakalářská práce se věnuje jejich rozdělením, působením na cílové receptory a vlivem nejen na centrální nervovou soustavu., A neurotransmitter is a substance that causes a specific response it's released by a neuron. This bachelor's thesis is devoted to their distribution, effect on target receptors and influence not only the central nervous system., Fakulta chemicko-technologická, 1. Prezentace výsledků bakalářské práce. 2. Diskuze k posudku vedoucího bakalářské práce. 3. Student zodpověděl všechny dotazy a připomínky k bakalářské práci., Dokončená práce s úspěšnou obhajobou

Cheese is a fermented food in which toxic concentrations of biogenic amines (BAs) may accumulate, mainly as a result of the metabolism of certain lactic acid bacteria (LAB); the formation of these compounds needs to be limited. This work reports the antimicrobial potential of bacteriocin AS-48 against the LAB largely responsible for the accumulation of the BA histamine, tyramine and putrescine in cheese. Most of the 50 analysed BA-producing LAB strains were sensitive to AS-48. The bacteriocin also prevented biofilm formation of 92% of the BA-producing strains tested. This result is of great technological importance since, in cheese production, biofilms are an important source of contamination by BA-producing LAB. This study supports the potential use of AS-48 as a biopreservative for controlling BA-producing LAB in fermented food.

Mechanisms of synergistic agonist stimulation and modulation of the electrochemical driving force for anion secretion are still not fully explored in human pancreatic duct epithelial cells. The first objective of this study was therefore to test whether combined agonist stimulation augments anion transport responses in the Capan-1 monolayer model of human pancreatic duct epithelium. The second objective was to test the influence of H+,K+-ATPase inhibition on anion transport in Capan-1 monolayers. The third objective was to analyze the expression and function of K+ channels in Capan-1, which could support anion secretion and cooperate with H+,K+-ATPases in pH and potassium homeostasis. The human pancreatic adenocarcinoma cell line Capan-1 was cultured conventionally or as polarized monolayers that were analyzed by Ussing chamber electrophysiological recordings. Single-cell intracellular calcium was assayed with Fura-2. mRNA isolated from Capan-1 was analyzed by use of the nCounter assay or RT-PCR. Protein expression was assessed by immunofluorescence and western blot analyses. Combined stimulation with different physiological agonists enhanced anion transport responses compared to single agonist stimulation. The responsiveness of Capan-1 cells to histamine was also revealed in these experiments. The H+,K+-ATPase inhibitor omeprazole reduced carbachol- and riluzole-induced anion transport responses. Transcript analyses revealed abundant TASK-2, TWIK-1, TWIK-2, TASK-5, KCa3.1, and KCNQ1 mRNA expression. KCNE1 mRNA and TREK-1, TREK-2, TASK-2, and KCNQ1 protein expression were also shown. This study shows that the Capan-1 model recapitulates key physiological aspects of a bicarbonate-secreting epithelium and constitutes a valuable model for functional studies on human pancreatic duct epithelium.

Lentilactobacillus parabuchneri, a lactic acid bacterium, is largely responsible for the production and accumulation of histamine, a toxic biogenic amine, in cheese. L. parabuchneri strains can form biofilms on the surface of industry equipment. Since they are resistant to cleaning and disinfection, they may act as reservoirs of histamine-producing contaminants in cheese. The aim of this study was to investigate the biofilm-producing capacity of L. parabuchneri strains. Using the crystal violet technique, the strains were first categorized as weak, moderate or strong biofilm producers. Analysis of their biofilm matrices revealed them to be mainly composed of proteins. Two strains of each category were then selected to analyze the influence on the biofilm-forming capacity of temperature, pH, carbon source, NaCl concentration and surface material (i.e., focusing on those used in the dairy industry). In general, low temperature (8 °C), high NaCl concentrations (2–3% w/v) and neutral pH (pH 6) prevented biofilm formation. All strains were found to adhere easily to beech wood. These findings increase knowledge of the biofilm-forming capacity of histamine-producing L. parabuchneri strains and how their formation may be prevented for improving food safety.

Tyramine oxidase (TAO), peroxidase (HRP), and Amplex Red (AR) have been immobilized on cellulose to obtain disposable biosensors for the determination of histamine. During the enzymatic reaction, AR is oxidized and a pink spot is obtained. Using a smartphone and measuring the G (green) color coordinate, histamine can be determined in the presence of other biogenic amines (putrescine and cadaverine) in concentrations ranging from 2·10−5 M to 5·10−4 M with a 7.5·10−6 M limit of detection (LoD). Despite tyramine interference, experimental conditions are provided which allow rapid and simple histamine and simultaneous histamine/tyramine (semi)quantitative determination in mixtures. Finally, tyramine and histamine were determined in a tuna extract with good results (compared to the reference HPLC–MS method). The methodology can also be applied in solution allowing histamine (and simultaneous histamine/tyramine) determination with a lower LoD (1.8·10−7 M) and a similar selectivity.

Lysosomes and the endoplasmic reticulum (ER) are Ca2+ stores mobilized by the second messengers NAADP and IP3, respectively. Here, we establish Ca2+ signals between the two sources as fundamental building blocks that couple local release to global changes in Ca2+. Cell-wide Ca2+ signals evoked by activation of endogenous NAADP-sensitive channels on lysosomes comprise both local and global components and exhibit a major dependence on ER Ca2+ despite their lysosomal origin. Knockout of ER IP3 receptor channels delays these signals, whereas expression of lysosomal TPC2 channels accelerates them. High-resolution Ca2+ imaging reveals elementary events upon TPC2 opening and signals coupled to IP3 receptors. Biasing TPC2 activation to a Ca2+-permeable state sensitizes local Ca2+ signals to IP3. This increases the potency of a physiological agonist to evoke global Ca2+ signals and activate a downstream target. Our data provide a conceptual framework to understand how Ca2+ release from physically separated stores is coordinated.

Histamine (HA) is a key biogenic monoamine involved in a wide range of physiological and pathological processes in both the central and peripheral nervous systems. Because the ability to directly measure extracellular HA in real time will provide important insights into the functional role of HA in complex circuits under a variety of conditions, we developed a series of genetically encoded G-protein-coupled receptor-activation-based (GRAB) HA (GRABHA) sensors with good photostability, sub-second kinetics, nanomolar affinity, and high specificity. Using these GRABHA sensors, we measured electrical-stimulation-evoked HA release in acute brain slices with high spatiotemporal resolution. Moreover, we recorded HA release in the preoptic area of the hypothalamus and prefrontal cortex during the sleep-wake cycle in freely moving mice, finding distinct patterns of HA dynamics between these specific brain regions. Thus, GRABHA sensors are robust tools for measuring extracellular HA transmission in both physiological and pathological processes.

Blood levels of histamine and serotonin (5-HT) are altered in human malaria, and, at these levels, we have shown they have broad, independent effects on Anopheles stephensi following ingestion by this invasive mosquito. Given that histamine and 5-HT are ingested together under natural conditions and that histaminergic and serotonergic signaling are networked in other organisms, we examined effects of combinations of these biogenic amines provisioned to A. stephensi at healthy human levels (high 5-HT, low histamine) or levels associated with severe malaria (low 5-HT, high histamine). Treatments were delivered in water (priming) before feeding A. stephensi on Plasmodium yoelii-infected mice or via artificial blood meal. Relative to effects of histamine and 5-HT alone, effects of biogenic amine combinations were complex. Biogenic amine treatments had the greatest impact on the first oviposition cycle, with high histamine moderating low 5-HT effects in combination. In contrast, clutch sizes were similar across combination and individual treatments. While high histamine alone increased uninfected A. stephensi weekly lifetime blood feeding, neither combination altered this tendency relative to controls. The tendency to re-feed 2 weeks after the first blood meal was altered by combination treatments, but this depended on mode of delivery. For blood delivery, malaria-associated treatments yielded higher percentages of fed females relative to healthy-associated treatments, but the converse was true for priming. Female mosquitoes treated with the malaria-associated combination exhibited enhanced flight behavior and object inspection relative to controls and healthy combination treatment. Mosquitoes primed with the malaria-associated combination exhibited higher mean oocysts and sporozoite infection prevalence relative to the healthy combination, with high histamine having a dominant effect on these patterns. Compared with uninfected A. stephensi, the tendency of infected mosq

L’angioedème (AO) qu'il soit lié à la libération d'histamine ou à la présence excessive de bradykinine représente un motif fréquent d’admission en salle d’urgence. Il s’agit aussi d’une affection potentiellement grave voire fatale. Sa prise en charge diagnostique et thérapeutique peut se révéler difficile. Cet article détaille la gestion pratique de l’AO en salle d’urgence, en particulier sa forme bradykinique, ainsi que les modalités et objectifs du bilan allergologique spécialisé fréquemment indiqué. Finalement, cet article accorde une place toute particulière à l’AO héréditaire, une maladie rare justifiant une prise en charge thérapeutique spécialisée et récemment révolutionnée par de nouvelles molécules très prometteuses.

Terahertz waves have gained increasingly more attention because of their unique characteristics and great potential in a variety of fields. In this study, we introduced the recent progress of our versatile terahertz chemical microscope (TCM) in the detection of small biomolecules, ions, cancer cells, and antibody-antigen immunoassaying. We highlight the advantages of our TCM for chemical sensing and biosensing, such as label-free, high-sensitivity, rapid response, non-pretreatment, and minute amount sample consumption, compared with conventional methods. Furthermore, we demonstrated its new application in detection of allergic-related histamine at low concentration in buffer solutions.

The neural bases of itchy eye transmission remain unclear compared with those involved in body itch. Here, we show in rodents that the gastrin-releasing peptide receptor (GRPR) of the trigeminal sensory system is involved in the transmission of itchy eyes. Interestingly, we further demonstrate a difference in scratching behaviour between the left and right hindfeet in rodents; histamine instillation into the conjunctival sac of both eyes revealed right-foot biased laterality in the scratching movements. Unilateral histamine instillation specifically induced neural activation in the ipsilateral sensory pathway, with no significant difference between the activations following left- and right-eye instillations. Thus, the behavioural laterality is presumably due to right-foot preference in rodents. Genetically modified rats with specific depletion of Grpr-expressing neurons in the trigeminal sensory nucleus caudalis of the medulla oblongata exhibited fewer and shorter histamine-induced scratching movements than controls and eliminated the footedness. These results taken together indicate that the Grp-expressing neurons are required for the transmission of itch sensation from the eyes, but that foot preference is generated centrally. These findings could open up a new field of research on the mechanisms of the laterality in vertebrates and also offer new potential therapeutic approaches to refractory pruritic eye disorders.

BackgroundSystemic allergic reaction is characterized by vasodilation and vascular leakage, which causes a rapid, precipitous and sustained decrease in arterial blood pressure with a concomitant decrease of cardiac output. Histamine is a major mediator released by mast cells in allergic inflammation and response. It causes a cascade of inflammation and strongly increases vascular permeability within minutes through its four G-protein-coupled receptors (GPCRs) on endothelial cells. High mobility group box-1 (HMGB1), a nonhistone chromatin-binding nuclear protein, can be actively secreted into the extracellular space by endothelial cells. HMGB1 has been reported to exert pro-inflammatory effects on endothelial cells and to increase vascular endothelial permeability. However, the relationship between histamine and HMGB1-mediated signaling in vascular endothelial cells and the role of HMGB1 in anaphylactic-induced hypotension have never been studied. Methods and resultsEA.hy 926 cells were treated with different concentrations of histamine for the indicated periods. The results showed that histamine induced HMGB1 translocation and release from the endothelial cells in a concentration- and time-dependent manner. These effects of histamine were concentration-dependently inhibited by d-chlorpheniramine, a specific H-1 receptor antagonist, but not by H-2 or H-3/4 receptor antagonists. Moreover, an H-1-specific agonist, 2-pyridylethylamine, mimicked the effects of histamine, whereas an H-2-receptor agonist, 4-methylhistamine, did not. Adrenaline and noradrenaline, which are commonly used in the clinical treatment of anaphylactic shock, also inhibited the histamine-induced HMGB1 translocation in endothelial cells. We therefore established a rat model of allergic shock by i.v. injection of compound 48/80, a potent histamine-releasing agent. The plasma HMGB1 levels in compound 48/80-injected rats were higher than those in controls. Moreover, the treatment with anti-HMGB1 antibo

Like other seafood products, tuna is highly perishable and sensitive to microbial spoilage. Its consumption, whether fresh or canned, can lead to severe food poisoning due to the activity of specific microorganisms, including histamine-producing bacteria. Yet many grey areas persist regarding their ecology, conditions of emergence and proliferation in fish. In this study, we used 16S rDNA barcoding to investigate post-mortem changes in the bacteriome of fresh and brine-frozen yellowfin tuna (Thunnus albacares), until late stages of decomposition (i.e. 120 h). The results revealed that despite standard refrigeration storage conditions (i.e. 4°C), a diverse and complex spoilage bacteriome developed in the gut and liver. The relative abundance of spoilage bacterial taxa increased rapidly in both organs, representing 82% of the bacterial communities in fresh yellowfin tuna, and less than 30% in brine-frozen tuna. Photobacterium was identified as one of the dominant bacterial genera, and its temporal dynamics were positively correlated with histamine concentration in both gut and liver samples, which ultimately exceeded the recommended sanitary threshold of 50 ppm in edible parts of tuna. The results from this study show that the sanitary risks associated with the consumption of this widely eaten fish are strongly influenced by post-capture storage conditions.

Background Prior studies suggested lower risk of heart failure (HF) in individuals taking H2 receptor antagonists (H2RA) compared with H2RA nonusers in relatively small studies. We evaluated the association of H2RA use and incident HF in postmenopausal women in the large-scale WHI (Women's Health Initiative) study. Methods and Results This study included postmenopausal women from the WHI without a history of HF at baseline. HF was defined as first incident hospitalization for HF and physician adjudicated. Multivariable Cox proportional hazards regression models evaluated the association of H2RA use as a time-varying exposure with HF risk, after adjustment for demographic, lifestyle, and medical history variables. Sensitivity analyses examined (1) risk of HF stratified by the ARIC (Atherosclerosis Risk in Communities) score, (2) propensity score matching on H2RA use, (3) use of proton pump inhibitors rather than H2RA nonuse as the referent, and (4) exclusion of those taking diuretics at baseline. The primary analysis included 158 854 women after exclusion criteria, of whom 9757 (6.1%) were H2RA users. During median 8.2 years of follow-up, 376 H2RA users (4.9 events/1000 person-years) and 3206 nonusers (2.7 events/1000 person-years) developed incident HF. After multivariable adjustment, there was no association between H2RA use and HF in the primary analysis (hazard ratio, 1.07; 95% CI, 0.94-1.22; P=0.31) or in any of the sensitivity analyses. Conclusions Clinical H2RA use was not associated with incident HF among postmenopausal women. Future studies are needed to evaluate potential effect modification by sex, HF severity, or patterns of use on H2RA exposure and HF risk. Registration URL: https://www.clinicaltrials.gov; Unique identifier: NCT00000611.

Histamine, a monoamine implicated in stress-related arousal states, is synthesized in neurons exclusively located in the hypothalamic tuberomammillary nucleus (TMN) from where they diffusely innervate striatal and mesolimbic networks including the nucleus accumbens (NAc), a vital node in the limbic loop. Since histaminecontaining TMN neuron output increases during stress, we hypothesized that exposure of mice to acute restrain stress (ARS) recruits endogenous histamine type 2 receptor (H2R) signaling in the NAc, whose activation increases medium spiny neurons (MSNs) intrinsic excitability via downregulation of A-type K+ currents. We employed an ARS paradigm in which mice were restrained for 120 min, followed by a 20-min recovery period, after which brain slices were prepared for ex vivo electrophysiology. Using whole-cell patch-clamp recordings, we found that pharmacological activation of H2R failed to affect MSN excitability and A-type K+ currents in mice that underwent ARS. Interestingly, in mice treated with H2R-antagonist prior to ARS paradigm, H2R activation increased evoked firing and decreased A-type K+ currents similarly to what observed in control mice. Furthermore, H2R-antagonist treatment ameliorated anxiety-like behavior in ARS mice. Together, our findings indicate that ARS paradigm recruits endogenous H2R signaling in MSNs and suggest the involvement of H2R signaling in stress-related motivational states.

Some bacteria decarboxylate amino acids as a means of resisting acid stress. It is a mechanism commonly used by bacteria in fermented dairy products. The decarboxylation of histidine to histamine occurs frequently in some types of cheese, but high concentrations of histamine can be harmful to consumers. Not all amino acid decarboxylation products are, however, undesirable. GABA, the decarboxylation product of glutamate, has positive effects on human health. Although histamine and GABA accumulate in large quantities in many types of cheese, there is little information regarding their relationship, and that which is available is restricted to a few cheese varieties. The present work examines whether cheeses exist with high concentrations of GABA but safe concentrations of histamine. The GABA and histamine contents of 250 cheeses representing 143 European varieties were examined, and the technological, environmental and metabolic (TEM) traits governing their accumulation identified. Two TEM profiles were associated with high GABA contents and safe histamine concentrations. These findings could help the dairy industry select the best technological conditions for making GABA-rich, histamine-safe cheeses.

There is an urgent need to identify therapies that prevent SARS-CoV-2 infection and improve the outcome of COVID-19 patients. Although repurposed drugs with favorable safety profiles could have significant benefit, widely available prevention or treatment options for COVID-19 have yet to be identified. Efforts to identify approved drugs with in vitro activity against SARS-CoV-2 resulted in identification of antiviral sigma-1 receptor ligands, including antihistamines in the histamine-1 receptor binding class. We identified antihistamine candidates for repurposing by mining electronic health records of usage in population of more than 219,000 subjects tested for SARS-CoV-2. Usage of diphenhydramine, hydroxyzine and azelastine was associated with reduced incidence of SARS-CoV-2 positivity in subjects greater than age 61. We found diphenhydramine, hydroxyzine and azelastine to exhibit direct antiviral activity against SARS-CoV-2 in vitro. Although mechanisms by which specific antihistamines exert antiviral effects is not clear, hydroxyzine, and possibly azelastine, bind Angiotensin Converting Enzyme-2 (ACE2) and the sigma-1 receptor as off-targets. Clinical studies are needed to measure the effectiveness of diphenhydramine, hydroxyzine and azelastine for disease prevention, for early intervention, or as adjuvant therapy for severe COVID-19.

Sleep is critical for the survival of all animals and serves many vital functions throughout the body, including brain development, cognition, immune function, and metabolic control. Indeed, sleep disorders such as insomnia can have devastating consequences on human health. Additionally, emerging evidence suggests a complex, bi-causal relationship between sleep disturbances and neuropsychiatric disorders. Despite the importance of proper sleep-wake regulation, it remains unclear how exactly the brain controls sleep-wake transitions. Historically, the focus on sleep regulation has focused exclusively on neurons, but astrocytes, the largest class of non-neuronal cells in the brain, are also positioned to play a critical role. The primary focus of this dissertation is to explore the complex role of cortical astrocytes in sleep regulation. First, we present a novel tool that allows for the accurate quantification of astrocyte calcium dynamics (Chapter 2), an essential step in studying astrocyte physiology in the context of sleep. Next, we demonstrate, for the first time, that astrocytes play a causal role in regulating distinct features of sleep through different GPCR pathways (Chapter 3). Lastly, we begin to explore the mechanistic pathways by which astrocytes regulate sleep. We explore the neuromodulator histamine as a candidate endogenous ligand for astrocytic control of sleep (Chapter 4) and we investigate astrocytic regulation of extracellular glutamate and GABA, putative functional astrocyte outputs of Gi-GPCR signaling (Chapter 5). Together, we present evidence that cortical astrocytes are a vital part of the sleep regulatory system, bringing us closer to understanding this critical behavior.

[ES] En el presente estudio se llevó a cabo una evaluación del riesgo de histamina asociado al consumo de tres tipos de productos de la pesca: atún fresco, atún en conserva y semiconservas de anchoas en salazón. Para ello se empleó la herramienta Risk Ranger, que permite generar una clasificación de riesgos aplicando un enfoque semicuantitativo. De acuerdo con las estimaciones obtenidas, la población española presenta un riesgo bajo de intoxicación por histamina como consecuencia de la ingesta de los productos de la pesca mencionados. El atún fresco se identificó como el producto con un mayor riesgo relativo, seguido de las conservas de atún y de las semiconservas de anchoa. Así mismo, se plantearon dos posibles escenarios con el objetivo de evaluar el efecto de la ruptura de la cadena de frío sobre el riesgo de intoxicación en el atún fresco. En este sentido, el riesgo relativo pasó de un 32 a un 52 % como resultado de un abuso en la temperatura de almacenamiento. En base a estos resultados, la temperatura y tiempo de almacenamiento son los factores que más influyen en la formación de histamina en el pescado fresco. En productos de la pesca procesados, la histamina se puede controlar fácilmente mediante la aplicación de buenas prácticas higiénicas, el empleo de materias primas con una buena calidad microbiológica y la aplicación combinada de tecnologías de conservación (refrigeración, disminución de la actividad de agua, maduración enzimática, etc.), [EN] In the present study, an evaluation of the histamine risk associated with the consumption of three types of fishery products (fresh tuna, canned tuna and semi-preserved salted anchovies) was carried out. For this, the Risk Ranger tool was used, which allows to generate a risk classification applying a semi-quantitative approach. According to the estimates obtained, the Spanish population has a low risk of histamine poisoning as a consequence of the intake of the aforementioned fishery products. Fresh tuna was identified as the product with the highest relative risk, followed by canned tuna and semi-preserved anchovy. Likewise, two possible scenarios were proposed in order to evaluate the effect of breaking the cold chain on the risk of poisoning in fresh tuna. In this sense, the relative risk went from 32 to 52 % as result of an abuse in the storage temperature. Histamine can be easily controlled through the application of good hygienic practices, the use of raw materials with good microbiological quality and the combined application of preservation technologies (refrigeration, decreased water activity, enzymatic maturation, etc.)

Degradation of undesirable biogenic amines (BAs) in foodstuffs by microorganisms is considered one of the most effective ways of eliminating their toxicity. In this study, we design two sets of primers for the detection and quantification of the amine oxidase gene (yobN) and endogenous (housekeeping) gene (gyrB) in Bacillus subtilis. Moreover, these sets can be used for relative quantification of yobN by real-time PCR (qPCR). We also tested the degradation of BAs by three bacterial strains (B. subtilis strains: IB1a, CCM 2216, CCM 2267) in a mineral medium over a two-day period. Their degradation abilities were verified by high performance liquid chromatography with UV detection (HPLC/UV). According to the results, two strains significantly (P < 0.05) reduced histamine, tyramine, putrescine, and cadaverine. Moreover, our results indicate that the degradation ability of B. subtilis strains could be limited by sporulation because the gene encoding amine oxidase (yobN) is no longer expressed in the spores. © 2021, Association of Food Scientists & Technologists (India).

Military personnel deployed in combat operations are highly prone to develop Parkinson's disease (PD) in later lives. PD largely involves dopaminergic pathways with hallmarks of increased alpha synuclein (ASNC), and phosphorylated tau (p-tau) in the cerebrospinal fluid (CSF) precipitating brain pathology. However, increased histaminergic nerve fibers in substantia nigra pars Compacta (SNpc), striatum (STr) and caudate putamen (CP) associated with upregulation of Histamine H3 receptors and downregulation of H4 receptors in human cases of PD is observed in postmortem cases. These findings indicate that modulation of histamine H3 and H4 receptors and/or histaminergic transmission may induce neuroprotection in PD induced brain pathology. In this review effects of a potent histaminergic H3 receptor inverse agonist BF-2549 or clobenpropit (CLBPT) partial histamine H4 agonist with H3 receptor antagonist, in association with monoclonal anti-histamine antibodies (AHmAb) in PD brain pathology is discussed based on our own observations. Our investigation shows that chronic administration of conventional or TiO2 nanowired BF 2649 (1 mg/kg, i.p.) or CLBPT (1 mg/kg, i.p.) once daily for 1 week together with nanowired delivery of HAmAb (25 mu L) significantly thwarted ASNC and p-tau levels in the SNpC and STr and reduced PD induced brain pathology. These observations are the first to show the involvement of histamine receptors in PD and opens new avenues for the development of novel drug strategies in clinical strategies for PD, not reported earlier.

Background/Aims: Microglia are the dynamic motile phagocytes of the brain considered the first line of defense against threats or disturbances to the Central Nervous System (CNS). Microglia help orchestrate the immunological response by interacting with others immune cells. Mast cells (MCs) are effector cells of the innate immune system distributed in all organs and vascularized tissues, brain included. Several molecular mechanisms for potential interactions between MCs and microglia have been determined. However, the effect of MCs on regulated exocytosis and phagocytic clearance in microglia has not been explored. Methods: Cocktails of MCs mediators (MCM) obtained at 37°C and 53°C were used to induce microglia activation. Changes in intracellular calcium [Ca2+]i and ATP release were studied by calcium and quinacrine fluorescence imaging. Fluorescent latex beads were used to assay phagocytosis in microglia after MCM treatment and compared to that measured in the presence of histamine, ATP and lipopolysaccharide (LPS). Iba-1 expression and area were quantified by immunofluorescence and histamine levels evaluated by ELISA techniques. Results: Local application onto microglia of the MC mediator cocktail elicited Ca2+ transients and exocytotic release associated with quinacrine dye de-staining. Ca2+ signals were mimicked by histamine and blocked by the H1 receptor (H1R) antagonist, cetirizine. Hydrolysis of ATP by apyrase also affected Ca2+ transients to a lesser extent. Iba-1 fluorescence, cell area and phagocytosis were enhanced by histamine through H1R. However, ATP prevented iba-1 expression and microglial phagocytosis. MCM showed combined effects of histamine and ATP, increasing the number of internalized microbeads per cell and area without raising iba1 expression. Conclusion: Our results highlight the relevance of MC-derived histamine and ATP in the modulation of secretory and phagocytic activities that would explain the heterogeneity of microglial responses in d

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

Oral squamous cell carcinoma (OSCC), the most common oral malignancy, shows an increasing rate of incidence worldwide. In spite of the recent advances in cancer research, OSCC therapy continues to have unfavourable outcomes, and thus, patient’s prognosis remains relatively poor. Current research has been devoted to identifying novel therapeutic targets also in the tumour microenvironment (TME). Histamine and its G‐protein‐coupled receptors (H1R‐H4R) play vital roles in multiple cancer‐associated processes in TME, where histamine is mainly produced by mast cells. However, oral epithelial cells were recently shown to produce low concentrations of histamine in autocrine and paracrine modes. These findings, together with the discovery of the high‐affinity histamine H4 receptor, have led to a massive increase in our understanding of histamine functions. In this review, we aim to summarize the most recent findings regarding histamine and its receptors and their involvement in oral carcinogenesis—from oral potentially malignant disorders (OPMDs) to invasive OSCC. Importantly, histamine receptors are differentially expressed in OPMDs and OSCC. Furthermore, H1R and H4R are associated with clinicopathological characteristics of OSCC patients, suggesting a role in prognosis. Due to the enormous success of histamine‐based medications, histamine receptors may also represent promising and viable drug targets in oral cancer.

Transcranial focal stimulation (TFS) is a non-invasive neuromodulation strategy with neuroprotective effects. On the other hand, 6-hidroxidopamine (6-OHDA) induces neurodegeneration of the nigrostriatal system producing modifications in the dopaminergic, serotoninergic, and histaminergic systems. The present study was conducted to test whether repetitive application of TFS avoids the biogenic amines changes induced by the intrastriatal injection of 6-OHDA. Experiments were designed to determine the tissue content of dopamine, serotonin, and histamine in the brain of animals injected with 6-OHDA and then receiving daily TFS for 21 days. Tissue content of biogenic amines was evaluated in the cerebral cortex, hippocampus, amygdala, and striatum, ipsi- and contralateral to the side of 6-OHDA injection. Results obtained were compared to animals with 6-OHDA, TFS alone, and a Sham group. The present study revealed that TFS did not avoid the changes in the tissue content of dopamine in striatum. However, TFS was able to avoid several of the changes induced by 6-OHDA in the tissue content of dopamine, serotonin, and histamine in the different brain areas evaluated. Interestingly, TFS alone did not induce significant changes in the different brain areas evaluated. The present study showed that repetitive TFS avoids the biogenic amines changes induced by 6-OHDA. TFS can represent a new therapeutic strategy to avoid the neurotoxicity induced by 6-OHDA.

Inhibition of mTOR is the standard of care for lymphangioleiomyomatosis (LAM). However, this therapy has variable tolerability and some patients show progressive decline of lung function despite treatment. LAM diagnosis and monitoring can also be challenging due to the heterogeneity of symptoms and insufficiency of non-invasive tests. Here, we propose monoamine-derived biomarkers that provide preclinical evidence for novel therapeutic approaches. The major histamine-derived metabolite methylimidazoleacetic acid (MIAA) is relatively more abundant in LAM plasma, and MIAA values are independent of VEGF-D. Higher levels of histamine are associated with poorer lung function and greater disease burden. Molecular and cellular analyses, and metabolic profiling confirmed active histamine signaling and metabolism. LAM tumorigenesis is reduced using approved drugs targeting monoamine oxidases A/B (clorgyline and rasagiline) or histamine H1 receptor (loratadine), and loratadine synergizes with rapamycin. Depletion of Maoa or Hrh1 expression, and administration of an L-histidine analog, or a low L-histidine diet, also reduce LAM tumorigenesis. These findings extend our knowledge of LAM biology and suggest possible ways of improving disease management.

The ABC transporter, Scarlet, and its binding partner, White are involved in pigment synthesis in the insect eye and mutations in these genes are used as genetic markers. Recent studies have suggested that these transporters also have additional functions in the neuronal system. In our previous study, we generated scarlet mutant in the small crustacean, Daphnia magna and showed that the mutant lacked the eye pigment in the mutant. Here, we show that the scarlet mutant exhibits spinning behavior. This phenotype is partly associated with the presence of light. Metabolomic analysis of a juvenile mutant revealed that the scarlet mutant has approximately one-tenth of the histamine content of the wild type. Application of histamine to the scarlet mutant rescued the spinning behavior in juveniles, suggesting that the spinning behavior of the mutant is caused by the reduction of histamine. However, the altered behavior was not rescued in the adult mutant by the addition of histamine, suggesting that Scarlet plays an irreversible role in the development of histaminergic neurons. These results suggest that Scarlet plays an important role in histaminergic signaling, which might be related to control the spinning behavior, in addition to its role in eye pigmentation.

Lentilactobacillus parabuchneri is a heterofermentative lactic acid bacteria usually present in fermented dairy products that was identified as the main responsible for the production and accumulation of elevated concentrations of histamine in cheese. The consumption of cheeses with high concentration of this biogenic amine has toxicological effects in consumers and is a safe concern. Our group has found that some L. parabuchneri strains produce biofilms on the surface of dairy industry equipment. These biofilms are very resistant against cleaning and disinfection procedures, and act as reservoirs of histamine-producing bacteria. Therefore, the cheeses become contaminated during the elaboration processes and when consumed, they may have undesirable concentrations of histamine. The present work was aimed to investigate the biofilm production of 25 dairy L. parabuchneri strains. The strains were categorized as strong, moderate and weak biofilms formers and two of them were selected from each category. The influence of temperature, surface materials, and pH on their ability to form biofilms was studied. In addition, the nature of extracellular matrix was also investigated. This study highlights the importance of the industrial environment control to decrease undesired bacterial biofilms and improve cheese safety.

Bacteria have evolved sophisticated signaling mechanisms to coordinate interactions with organisms of other domains, such as plants, animals and human hosts. Several important signal molecules have been identified that are synthesized by members of different domains and that play important roles in inter-domain communication. In this article, we review recent data supporting that histamine is a signal molecule that may play an important role in inter-domain and inter-species communication. Histamine is a key signal molecule in humans, with multiple functions, such as being a neurotransmitter or modulator of immune responses. More recent studies have shown that bacteria have evolved different mechanisms to sense histamine or histamine metabolites. Histamine sensing in the human pathogen Pseudomonas aeruginosa was found to trigger chemoattraction to histamine and to regulate the expression of many virulence-related genes. Further studies have shown that many bacteria are able to synthesize and secrete histamine. The release of histamine by bacteria in the human gut was found to modulate the host immune responses and, at higher doses, to result in host pathologies. The elucidation of the role of histamine as an inter-domain signaling molecule is an emerging field of research and future investigation is required to assess its potential general nature.

Background: Microdialysis can be used to measure amino acids in the extracellular space in vivo, based on the principle of diffusion. Variations in experimental set-up result in variations in baseline levels of the compounds measured. Variations may also be due to circadian rhythms. Method: We systematically searched and mapped the literature on all studies reporting baseline microdialysis measurements of histamine and the amino acids asparagine, aspartate, GABA, glutamate, glutamine, glycine, proline and taurine. We fully reviewed the studies describing circadian rhythms for histamine and the selected amino acids. Results: We retrieved 2331 papers describing baseline measurements of one or more of the compounds of interest. We provide a numerical summary and lists of the publications by compound. We retrieved 11 references describing studies on the circadian rhythms of the compounds of interest. Aspartate, glutamate and histamine are generally higher during the dark than during the light phase in nocturnal rodents. For glutamine, no rhythmicity was observed. For GABA, the results were too inconsistent to generalise. For asparagine, glycine, proline and taurine, insufficient data are available. Conclusion: The literature on intracerebral microdialysis measurements of the amino acids is vast, but certain primary studies are still warranted. Future systematic reviews on the individual compounds can shed light on the effects of experimental variations on baseline concentrations.

Inhibition of mTOR is the standard of care for lymphangioleiomyomatosis (LAM). However, this therapy has variable tolerability and some patients show progressive decline of lung function despite treatment. LAM diagnosis and monitoring can also be challenging due to the heterogeneity of symptoms and insufficiency of non-invasive tests. Here, we propose monoamine-derived biomarkers that provide preclinical evidence for novel therapeutic approaches. The major histamine-derived metabolite methylimidazoleacetic acid (MIAA) is relatively more abundant in LAM plasma, and MIAA values are independent of VEGF-D. Higher levels of histamine are associated with poorer lung function and greater disease burden. Molecular and cellular analyses, and metabolic profiling confirmed active histamine signaling and metabolism. LAM tumorigenesis is reduced using approved drugs targeting monoamine oxidases A/B (clorgyline and rasagiline) or histamine H1 receptor (loratadine), and loratadine synergizes with rapamycin. Depletion of Maoa or Hrh1 expression, and administration of an L-histidine analog, or a low L-histidine diet, also reduce LAM tumorigenesis. These findings extend our knowledge of LAM biology and suggest possible ways of improving disease management.

In order to ensure high food quality, one of the prime importance is the detection and quantification of histamine, well known marine food poison. In this work, we constructed novel electrochemical biosensor for the detection of histamine based on gold nanoparticles decorated on manganese dioxide (Au/MnO2) and used for modification of screen-printed carbon electrode (Au/MnO2@SPCE). The constructed sensor was then used for the estimation of histamine content in a single drop. Materials used in this study were synthesized and characterized using HR-TEM, XRPD and electrochemical methods. The amperometric detection method was optimized and, under selected operating parameters (supporting electrolyte pH 6, working potential of 1 V), the proposed sensor possesses linear working range from 0.3 µM to 5.1 µM, with a detection limit of 0.08 µM. The effect of selected interferences was investigated and it was found that the developed approach offers accurate, precise, selective, fast and reproducible quantification of histamine using only one drop of the sample. In the end, this work stands as a proof-of-concept of the modified electrodes and electrochemical detection as a promising and prospective approach for the applications in real-time monitoring of the food quality.