Increased Histamine Levels Research Articles

Gastrointestinal symptoms in children with mastocytosis

Introduction. Mastocytosis is a heterogeneous group of diseases characterized by the abnormal accumulation of clonal mast cells (MCs) in various tissues and organs, including skin, bone marrow, liver, spleen and lymph nodes. The clinical picture of cutaneous and indolent systemic mastocytosis is formed by a wide range of symptoms associated with activation of mast cells. Single European studies have demonstrated wide variability in the frequency of gastrointestinal symptoms (GI-symptoms)) in children with mastocytosis (from 15 to 50%).Aim. To analyze the frequency of mediator-related GI-symptoms in children with different subtypes and clinical forms of mastocytosis.Materials and methods. A prospective observational study included data from 289 children aged 3 to 17 years who were under observation at the Moscow Scientific and Practical Center of Dermatovenereology and Cosmetology. Symptoms were assessed using the Pediatric grade scale of symptoms of mastocytosis. Clinical manifestations of reactions caused by mast cell degranulation were compared with data from clinical and laboratory studies. The concentrations of tryptase and histamine in the blood serum of patients were determined. The incidence of organomegaly and mesenteric lymphadenitis in children with mediating symptoms and without symptoms was determined using ultrasound.Results. 67 (23.2%) patients had GI symptoms. More than half of the patients (51.6%) indicated abdominal pain, 32.3% reported diarrhea. The severity of pain symptoms correlated with the level of serum tryptase (ρ = 0.564, p < 0.01). The incidence of hepatomegaly and mesadenitis in children with GI- symptoms was 19.4% and 25.4%, respectively. In a comparative analysis in groups of children with and without GI symptoms, the differences in the number of identified cases of organomegaly and mesadenitis were statistically significant (p < 0.001). An increase in histamine levels in the blood was detected in half of the patients with complaints of heartburn and nausea.Conclusion. Our results demonstrated that a study of the level of serum tryptase, ultrasound of the abdominal organs and lymph nodes should be carried out in all children with mediator-related GI-symptoms regardless of the clinical form of mastocytosis.

Dihydroergotamine Increases Histamine Brain Levels and Improves Memory in a Scopolamine-Induced Amnesia Model.

The beneficial effects of increasing histamine levels on memory have acquired special interest due to their applicability to psychiatric conditions that cause memory impairments. In addition, by employing drug repurposing approaches, it was demonstrated that dihydroergotamine (DHE), an FDA drug approved to treat migraines, inhibits Histamine N Methyl Transferase (HNMT), the enzyme responsible for the inactivation of histamine in the brain. For this reason, in the present work, the effect of DHE on histamine levels in the hippocampus and its effects on memory was evaluated, employing the scopolamine-induced amnesia model, the Novel Object Recognition (NOR) paradigm, and the Morris Water Maze (MWM). Furthermore, the role of histamine 1 receptor (H1R) and histamine 2 receptor (H2R) antagonists in the improvement in memory produced by DHE in the scopolamine-induced amnesia model was evaluated. Results showed that the rats that received DHE (10 mg/kg, i.p.) showed increased histamine levels in the hippocampus after 1 h of administration but not after 5 h. In behavioral assays, it was shown that DHE (1 mg/kg, i.p.) administered 20 min before the training reversed the memory impairment produced by the administration of scopolamine (2 mg/kg, i.p.) immediately after the training in the NOR paradigm and MWM. Additionally, the effects in memory produced by DHE were blocked by pre-treatment with pyrilamine (20 mg/kg, i.p.) administered 30 min before the training in the NOR paradigm and MWM. These findings allow us to demonstrate that DHE improves memory in a scopolamine-induced amnesia model through increasing histamine levels at the hippocampus due to its activity as an HNMT inhibitor.

Analysis of Histamine Level in Lemuru Fish (Sardinella lemuru) in the Canning Industry

The presence of histamine is one of the food safety issues in the canned fish manufacturing industry. Histamine usually appears in canned fish products due the raw material employed is pelagic fish such as lemuru which is rich in histidine amino acid. Histidine can cause histamine production via decarboxylation reaction by bacterial activity during the heat canning process. As a result, the purpose of this study was to investigate the increase in histamine levels that occurred in both canned fish raw materials and final products utilizing the Biofish 300 method. Aside from that, thermocouple and thermometer were used to analyze the fish’s central temperature and surface. SNI 2729:2013 was also utilized to assess the physical quality of raw materials regarding fresh fish. Based on the result, the histamine level increased significantly from raw material to product, accounting for 10.24 ppm and 16.92 ppm respectively (P < 0.05). However, the histamine levels in all samples remained below the company’s threshold (50 ppm) indicating canned fish was still safe to consume. To mitigate the effects of increased histamine, industry must develop a cold chain system by observing the central temperature of raw materials (≤4°C), and the processing room temperature (≤25°C) regularly. Similarly, prior to further processing, the raw material quality should not be less than 7.

Recombinant Human Diamine Oxidase Against Histamine Induced Shock - Implications for Mast Cell Activation Syndrome

Background and Objective:Mastocytosis patients suffer from a clonal increase in mast cells which produce and release excessive amounts of histamine even under stable conditions (Keyzer et al. 1983). Unfortunately, symptom control with new kinase inhibitors is variable and modest at best. Mast cell activation syndrome may further enhance histamine release which can result in recurrent shocks (Böhm et al. 2019), or severe, protracted anaphylaxis refractory to epinephrine (Grafeneder et al. 2022). Previously we demonstrated that recombinant human diamine oxidase (rhDAO) fully degrades 100-fold elevated histamine concentrations in plasma samples from mastocytosis patients. In vivo rhDAO, with a mutated heparin binding motif (mHBM), was able to digest massively increased histamine levels, thereby improving indirect measures of shock such as a temperature drop in mice (Karer et al. 2022). As mice are insensitive to histamine (intravenous LD50 of 385mg/kg in mice compared with 0.18mg/kg in guinea pigs), this unfortunately limits their translational value. To assess the therapeutic potential of rhDAO_mHBM, we tested its efficacy for the prevention and treatment of histamine induced shock in guinea pigs, the only histamine sensitive rodent species. Methods:Guinea pigs received continuous intravenous infusions of 8 µg/kg/min histamine to model its release from activated circulating basophils or subcutaneous injections of 1mg/kg histamine to mimic peripheral histamine release by mast cells. We used intramuscular injections of 5µg/kg adrenaline as a benchmark, because it is recommended in guidelines for the treatment of anaphylaxis, although its efficacy had never been proven. Infusions of rhDAO_mHBM were given either prophylactically before- or therapeutically after - symptom onset. Mean arterial pressure was measured intra-arterially and rhDAO_mHBM levels were quantified by enzyme immunoassay and histamine concentrations by a liquid chromatography -tandem mass spectrometry (LC-MS/MS) method. The primary outcome variable was prevention of shock as defined by a >=30% drop in mean arterial blood pressure. Results:Guinea pigs pretreated with 4 mg/kg rhDAO_mHBM showed lower mean heart rate (p<0.01) and higher body core temperatures at the end of the intravenous histamine infusions compared to controls (p<0.05). Histamine infusions increased median urinary excretion of histamine and N-methyl-histamine 8.6- and 4.0-fold (p<0.05), respectively. Pretreatment with 4 mg/kg rhDAO_mHBM reduced urinary histamine (p<0.01) and N-methyl-histamine (p<0.01) concentrations compared with controls. Subcutaneous injections of 1 mg/kg histamine induced shock within 20 minutes in all control animals, and the experiments had to be terminated prematurely in several animals. Intramuscular injection of 5mcg/kg adrenaline (similar to human adrenaline auto-injector doses) after symptom onset was unable to prevent shock, confirming its lack of efficacy demonstrated previously in an anaphylaxis model in dogs (Mink et al. 2004). In contrast, prophylactic infusions of 4-8mg/kg rhDAO_mHBM prevented hypotensive shock in all treated animals (p<0.01). After an initial histamine induced drop in blood pressure, 8mg/kg rhDAO_mHBM restored blood pressure and prevented shock in all animals when injected at the time of symptom occurrence (p<0.01 Chi2 test). Figure 1 demonstrates the median drop in blood pressure and development of shock (indicated by the dashed line) by subcutaneous injection of 1mg/kg histamine (black squares), and the prevention of shock by rhDAO-mHBM given before (blue up triangles) or after (red circles) histamine injections. Conclusion: This is the first demonstration of the beneficial effects of rhDAO_mHBM in a histamine-sensitive species. rhDAO_mHBM is a novel therapeutic approach targeting histamine excess which effectively prevented shock, in contrast to intramuscular epinephrine. As the mechanism of action is not species specific, these findings can be translated from guinea pigs to humans: it will help to select optimal dosing of rhDAO_mHBM during clinical development for the prophylaxis in - and treatment of - mastocytosis patients suffering from histamine induced symptoms or mast cell activation syndrome, or patients with anaphylaxis induced by asparaginase, plasma products or other medications.

Physicochemical and microbiological attributes of dried anchovies (Stolephorus commersonnii) in the formation of histamine along the supply chain.

Food safety along the supply chain must be safeguarded to protect the public's health from any foodborne disease. Despite the consumption of fish products, scombroid poisoning is not a wellknown occurrence. This study was formulated to evaluate at which stage of the supply chain the increase in the histamine content of dried anchovies (Stolephorus commersonnii) occurs. The study showed that histamine substances and Staphylococcus aureus were detected at all stages of the supply chain. It was also found that the concentration of histamine generally increased from the fisherman to the processors and retailers. Post-hoc analysis using the Fisher test showed no significant difference in the histamine content of dried anchovies from the processing centers (𝑥̅ =5 4.07 mg/kg) and retailers (𝑥̅ = 67.63 mg/kg), but it was significantly higher than in the raw anchovies (𝑥̅ = 8.29 mg/kg). S. aureus remains low at <10 colony-forming units (CFU/g). The aerobic plate count supports this conclusion with a 90.29% increase from the processing centers to the retailers. However, it is still significant as a source of histamine formation influenced by water activity and salt content. A correlation between salt content and water activity with histamine content was identified with a Pearson correlation coefficient of 0.8357. It is recommended to review the processing method to control the salt content and the handling and storage at the retailers, as they showed the highest potential for histamine-forming bacteria growth, leading to an increase in histamine levels in dried anchovies.

0810 Management of Narcolepsy In A Patient With Severe Chronic Iron Deficiency: The Importance of Addressing Nutritional Deficiencies In The Treatment of Narcolepsy and Hypersomnias

Abstract Introduction Since iron is a cofactor used in the synthesis of CNS dopamine, some of which is then converted into norepinephrine, CNS iron deficiency will have an impact on the availability of dopamine and norepinephrine. Medications for narcolepsy and hypersomnia, such as stimulants and wakefulness medications, are dependent on the availability of these neurotransmitters to achieve their clinical response. Unrecognized and untreated nutritional deficiencies may contribute to inadequate responses to treatment of these sleep disorders. Report of Cases: A 26-year-old female with a history of iron deficiency since her pre-kindergarten health evaluation had a history of inadequate responses to stimulants and wakefulness medications. Additional labs were drawn to evaluate for nutritional deficiencies that could be contributing to the combination of fatigue and hypersomnolence. These revealed continued severe iron deficiency along with vitamin B6, B12, and D deficiencies. The treatment plan then expanded to include treatment of the nutritional deficiencies and a trial of pitolisant, which works to increase histamine levels in the brain. Sadly, pitolisant resulted in intolerable headaches, so it was discontinued. Conclusion This author feels that patients with hypersomnia warrant a broader approach that includes evaluating for nutritional deficiencies which may contribute to fatigue and hypersomnolence. In this case, the plan was to address the patient’s nutritional deficiencies and switch to pitolisant which mediates increased CNS histamine levels. This was unsuccessful due to the side effect of increased frequency and intensity of headaches related to pitolisant. Treating her iron deficiency with iron infusions should increase CNS synthesis of dopamine and norepinephrine. She may now have a better response to stimulants or wakefulness medications which depend on the availability of these neurotransmitters. She may also benefit from combination therapy by adding sodium oxybate to one of these medications. Support (If Any)

High-Dose Betahistine Improves Cognitive Function in Patients With Schizophrenia: A Randomized Double-Blind Placebo-Controlled Trial.

Background: There is currently no effective treatment for cognitive impairment associated with schizophrenia (CIAS). Recent studies have shown that increased histamine levels in the brain may help to improve CIAS symptoms. Betahistine is an H1-receptor agonist and H3-receptor antagonist. This study evaluated the effect of high-dose betahistine on cognitive function as well as its safety in Chinese Han patients with schizophrenia.Methods: This randomized double-blind, placebo-controlled trial enrolled 89 patients with schizophrenia who were randomly administered betahistine (72 mg/d) or placebo for 12 weeks. At baseline and at 4, 8, and 12 weeks after commencing the intervention, we measured changes in cognitive function and clinical symptoms using the MATRICS Consensus Cognitive Battery (MCCB) and Positive and Negative Syndrome Scale (PANSS), respectively. Furthermore, we used the Treatment Emergent Symptom Scale (TESS) to assess the adverse effects of the patients' medications.Results: Compared to the placebo group, the betahistine group showed significant improvements in the MCCB composite score after 12 weeks of treatment (p = 0.003) as well as improvements in MCCB verbal learning (p = 0.02) and visual learning (p = 0.001) domain scores. However, there were no significant improvements in the PANSS total scores or subscores (p > 0.05). Generally, high-dose betahistine treatment was considered safe in patients with schizophrenia.Conclusions: Additional use of high-dose betahistine can effectively improve cognitive function but not psychiatric symptoms in patients with schizophrenia. Betahistine (72 mg/d) is well tolerated by Chinese Han patients with schizophrenia.Trial Registration: chictr.org.cn, identifier: ChiCTR1900021078. http://www.chictr.org.cn/edit.aspx?pid=35484&htm=4

Identification of biomarkers of brown adipose tissue aging highlights the role of dysfunctional energy and nucleotide metabolism pathways

Brown adipose tissue function declines during aging and may contribute to the onset of metabolic disorders such as diabetes and obesity. Only limited understanding of the mechanisms leading to the metabolic impairment of brown adipocytes during aging exists. To this end, interscapular brown adipose tissue samples were collected from young and aged mice for quantification of differential gene expression and metabolite levels. To identify potential processes involved in brown adipocyte dysfunction, metabolite concentrations were correlated to aging and significantly changed candidates were subsequently integrated with a non-targeted proteomic dataset and gene expression analyses. Our results include novel age-dependent correlations of polar intermediates in brown adipose tissue. Identified metabolites clustered around three biochemical processes, specifically energy metabolism, nucleotide metabolism and vitamin metabolism. One mechanism of brown adipose tissue dysfunction may be linked to mast cell activity, and we identify increased histamine levels in aged brown fat as a potential biomarker. In addition, alterations of genes involved in synthesis and degradation of many metabolites were mainly observed in the mature brown adipocyte fraction as opposed to the stromal vascular fraction. These findings may provide novel insights on the molecular mechanisms contributing to the impaired thermogenesis of brown adipocytes during aging.

Inhibition of Astrocytic Histamine N-Methyltransferase as a Possible Target for the Treatment of Alzheimer's Disease.

Alzheimer’s disease (AD) represents the principal cause of dementia among the elderly. Great efforts have been established to understand the physiopathology of AD. Changes in neurotransmitter systems in patients with AD, including cholinergic, GABAergic, serotoninergic, noradrenergic, and histaminergic changes have been reported. Interestingly, changes in the histaminergic system have been related to cognitive impairment in AD patients. The principal pathological changes in the brains of AD patients, related to the histaminergic system, are neurofibrillary degeneration of the tuberomammillary nucleus, the main source of histamine in the brain, low histamine levels, and altered signaling of its receptors. The increase of histamine levels can be achieved by inhibiting its degrading enzyme, histamine N-methyltransferase (HNMT), a cytoplasmatic enzyme located in astrocytes. Thus, increasing histamine levels could be employed in AD patients as co-therapy due to their effects on cognitive functions, neuroplasticity, neuronal survival, neurogenesis, and the degradation of amyloid beta (Aβ) peptides. In this sense, the evaluation of the impact of HNMT inhibitors on animal models of AD would be interesting, consequently highlighting its relevance.

Increased level of Histamine in keloid Tissue

Background: Keloid and hypertrophic scars (HTS) caused by an imbalance between the production and destruction of collagen during wound healing with an unknown underlying pathophysiological mechanism. This study was designed to evaluate the histamine level in the Keloid and HTS and comparison of results with normal skin. Materials and Methods: This pilot study included 36 participants, aged from 18 to 70 years with keloid (n=11), HTS (n=13) and normal (n=12) skin. The level of histamine in the skin samples was measured using enzyme-linked immunosorbent assay (ELISA). Results: Histamine level in keloid samples was significantly higher than in the normal (p=0.0012) or HTS (p=0.0028) groups. However, there was no significant difference between the normal and HTS samples (p=0.92). Conclusion: The increased histamine level in the keloid tissue may contribute to its pathogenesis and the application of anti-histamines could be of benefit for the prevention and treatment of keloids.

Safety profile and disease stabilization in late stage, heavily pretreated, solid tumor patients in a first-in-human (FIH) study of ATX-101, a drug targeting proliferating cell nuclear antigen (PCNA).

3067 Background: PCNA is a conserved scaffold protein orchestrating DNA replication, repair or bypass pathways as well as cellular signaling and apoptosis. More than 500 protein-PCNA interactions have been identified which are mediated via two binding motifs, the PIP-box and APIM. Cellular stress, to which cancer cells and cells of tumor microenvironment are exposed, increases the affinity of the APIM motif. APIM-containing proteins bind to PCNA and mediate processes of escape mechanisms and survival of cancer cells. ATX-101 is a cell penetrating peptide containing APIM. It inhibits protein binding via APIM, resulting in cancer cell death and altered cellular signaling. Anticancer effects of ATX-101 have been demonstrated in vitro and in vivo. Methods: A FIH study using a 3+3 dose escalation design was conducted. Patients with late-stage solid tumors received weekly infusions of 20, 30, 45 and 60 mg/m² over 6 weeks. Primary objective was safety, secondary objectives were PK and efficacy. Patients with stable disease (SD) after 6 weeks could continue treatment in a long-term follow-up (LTFU) study. Results: As of January 2021, 22 patients have been treated. All patients received in average 3.8 [1-9] prior treatment lines, all but one had progressive disease at study entry and 80% were refractory to the last therapy. No dose limiting toxicity or death and no treatment related Grade 3/4 or serious adverse events were reported. The maximum tolerated dose was not reached. Mild to moderate infusion related reactions (IRR) were observed in 73% of patients. They were not dose dependent and resolved completely after treatment interruption and/or symptomatic treatment. IRRs occurred despite premedication and could cause infusion interruptions with extended infusion duration. Experiments in dogs indicate that transiently increased histamine levels may cause IRRs. However, elevated histamine and tryptase levels could not be measured in patients so far. ATX-101 exposure was dose-dependent. Cmax was reached either at the middle or at the end of infusion. ATX-101 disappeared quickly from plasma and was not detectable 5 - 60 minutes post infusion. 13 patients finished the FIH study, 10 had SD after 6 weeks. 9 of 10 patients moved into the LTFU study. The treatment duration in the LTFU study varied from 2.1 to 15.6 months (median 4.2 months). Conclusions: ATX-101 is well tolerated at all dose levels with IRRs being the most frequent AEs. Drug exposure is dose dependent with rapid plasma clearance, which confirms in vivo data demonstrating the quick uptake by cells of all organs. The observed duration of SD may be attributed to ATX-101 activity. Proof of concept combination studies are being initiated. Clinical trial information: 375262.

Histamine-forming ability of Lentilactobacillus parabuchneri in reduced salt Cheddar cheese

Lentilactobacillus parabuchneri, a member of the non-starter microbiota in cheese, was recently associated with fast and effective histamine-formation ability, a safety issue. The present study was performed to investigate Lentilactobacillus parabuchneri KUH8, a histamine-producer (HP) in reduced-salt Cheddar cheese. Four cheeses were manufactured: 1) normal-salt (NS); 2) reduced-salt (RS); 3) normal-salt with HP (NS+HP); 4) reduced-salt with HP (RS+HP). Two replicates were produced with milk from the same batch, and the cheeses ripened at 10 and 15 °C. Cheeses were sampled immediately after manufacture and after 1, 3 and 6 months of ripening. Ultra-high-performance-liquid chromatography indicated that with the HP, histamine reached higher levels in reduced-salt cheeses (3.5–3.7% S/M) at 15 °C (86, 1112, 2149 and 3149 mg kg−1), compared to normal-salt cheeses (5.4–6.3% S/M) at 10 °C (78, 584, 593 and 1389 mg kg−1), at each respective cheese-sampling point. Higher salt-content reduced the growth rate of non-starter microbiota, but after six months the levels in all cheeses were similar, according to the ripening temperature: at 10 °C (8.05–8.30 log10 cfu g−1), and at 15 °C (6.00–6.94 log10 cfu g−1). A correlation between increased histamine levels, non-starter-cell development and pH was found. This study highlights the importance of normal-salt content and low-ripening temperature as measures to control histamine-formation and to improve safety in cheese.

Potential for Scombroid Poisoning from Ingestion of Selar crumenophthalmus Due to Increased Histamine Levels in Grenada, West Indies

In scombroid poisoning, a seafood-associated disease, consumption of fish that contains high levels of histamine results in allergy-like symptoms that range from mild to occasionally severe. To date, there is no published information on scombroid poisoning from Selar crumenophthalmus on the Caribbean island of Grenada, West Indies. S. crumenophthalmus is of particular interest because it is a common and heavily consumed fish that has been implicated in scombroid poisoning in Hawaii. Preliminary data on S. crumenophthalmus in Grenada have demonstrated the presence of Photobacterium damselae, a bacterium associated with scombroid poisoning. The present study further tested S. crumenophthalmus purchased in Grenada for factors that would indicate the potential for scombroid poisoning, including increased histamine levels in fish muscle and DNA evidence of bacteria associated with scombroid poisoning. Histamine levels between 7,160 and 66,688 ppm were found after temperature abuse at 37°C for 19 h; this far exceeds the acceptable limit for the United States (50 ppm) and the European Union (100 to 200 ppm). Even after 4 h of incubation at ambient temperature (28.9°C) during a time-point study, histamine levels exceeded U.S. acceptable limits (>50 ppm), and five samples used for temperature-abuse studies had elevated histamine levels (ranging from 141 to 2,510 ppm) at 0 h. PCR and sequence analysis of bacteria in temperature-abused fish identified P. damselae and Morganella morganii, which are histamine-producing bacteria known to be implicated in scombroid poisoning. These results suggest the potential for scombroid poisoning in Grenada and the need for promoting awareness about this disease.

Immune-Mediated Mechanisms in Cofactor-Dependent Food Allergy and Anaphylaxis: Effect of Cofactors in Basophils and Mast Cells.

Cofactors may explain why in some cases food ingestion leads to anaphylaxis while in others elicits a milder reaction or tolerance. With cofactors, reactions become more severe and/or have a lower allergen threshold. Cofactors are present in up to 58% of food anaphylaxis (FAn). Exercise, NSAIDs, and alcohol are the most frequently described, although the underlying mechanisms are poorly known. Several hypotheses have suggested the influence of these cofactors on basophils and mast cells (MCs). Exercise has been suggested to enhance MC activation by increasing plasma osmolarity, redistributing blood flow, and activating adenosine and eicosanoid metabolism. NSAIDs’ cofactor effect has been related with cyclooxygenase inhibition and therefore, prostaglandin E2 (PGE2) production. Indeed, overexpression of adenosine receptor 3 (A3) gene has been described in NSAID-dependent FAn; A3 activation potentiates FcϵRI-induced MC degranulation. Finally, alcohol has been related with an increase of histamine levels by inhibition of diamino oxidase (DAO) and also with and increase of extracellular adenosine by inhibition of its uptake. However, most of these mechanisms have limited evidence, and further studies are urgently needed. In conclusion, the study of the immune-related mechanisms involved in food allergic reactions enhanced by cofactors is of the utmost interest. This knowledge will help to design both tailored treatments and prophylactic strategies that, nowadays, are non-existent.

Beneficial effects of polyherbal formulation (Bronco-T) on formaldehyde-induced lung toxicity in male Wistar rats.

Polyherbal compound (Bronco-T) has been extensively used as a traditional medicine for various therapies. However, very few report studies on anti-inflammatory and lung regeneration properties are evidenced. In the present study, we evaluated the beneficial actions and anti-inflammatory properties of polyherbal medicine, Bronco-T, exhibited by treating the lungs of rats exposed to formaldehyde to evaluate the beneficial properties. For this study, we divided into five groups': i.e. Group-I served as a control and the other four groups such as II, III, IV, and V are experimental. All animals maintained by regular feed and water ad libitum during the study. Formaldehyde vapors exposure at a single period of time (1hour) daily (40%formaldehyde at room temperature) for 21days period exposed all groups. The Bronco-T extracts about 50mg/kg BW administered to experimental groups and group IV rats treated with 500μ grams/Kg BW salbutamol. To understand the impact of formaldehyde exposure on the beneficial effects of Bronco-T, we evaluated hematological parameters, bronchoalveolar lavage (BAL), histamine levels, and histological alterations of lung architecture. Formaldehyde-induced adverse effects in lung and increased histamine levels in BAL compared to Bronco-T-treated rats act as a preventive immunological role in blood toxicity and recovery of lung architecture in Bronco-T-treated rats. This study showed the evaluation of antihistamine levels through HPLC analysis. Bronco-T has antioxidant and anti-histamine properties as the widest therapeutic window, and we continue to evaluate the pharmacological evaluations needed in our further studies.

Region-specific regulation of central histaminergic H3 receptor expression in a mouse model of cow’s milk allergy

Central histaminergic H3 receptor (H3R) has been extensively investigated as a potential therapeutic target for various neurological and neurodegenerative disorders. Despite promising results in preclinical rodent models, clinical trials have not provided conclusive evidence for the benefit of H3R antagonists to alleviate cognitive and behavioral symptoms of these disorders. Inconsistent pharmacological efficacies may arise from aberrant changes in H3R over time during disease development. Because H3R is involved in feedback inhibition of histamine synthesis and secretion, the expression of the autoreceptor may also be reciprocally regulated by altered histamine levels in a pathological condition. Thus, we investigated H3R expression in a mouse model of cow’s milk allergy, a condition associated with increased histamine levels. Mice were sensitized to bovine whey proteins (WP) over 5 weeks and H3R protein and transcript levels were examined in the brain. Substantially increased H3R immunoreactivity was observed in various brain regions of WP-sensitized mice compared to sham mice. Elevated H3R expression was also found in the thalamic/hypothalamic region. The expression of histaminergic H1, but not H2, receptor subtype was also increased in this and the midbrain regions. Unlike the brain, all three histaminergic receptors were increased in the small intestine. These results indicated that the central histaminergic receptors were altered in WP-sensitized mice in a subtype- and region-specific manner, which likely contributed to behavioral changes we observed in these mice. Our study also suggests that altered levels of H3R could be considered during a pharmacological intervention of a neurological disease.

Effect of omalizumab use on glucose homeostasis in non-diabetic patients with chronic urticaria

Purpose In some diabetic patients receiving omalizumab therapy, blood glucose regulation is impaired. However, the effect of omalizumab on glucose homeostasis in non-diabetic patients remains unknown. Methods The patients were given subcutaneous omalizumab at a dose of 300 mg every four weeks for the treatment of chronic urticaria in this study. Fasting blood glucose, fasting plasma insulin, total cholesterol, triglyceride, and high-density (HDL) and low-density lipoprotein (LDL) were studied before and at the 12th week of treatment. The homeostatic model assessment for insulin resistance (HOMA-IR) was used to determine insulin resistance. Results Forty of the 45 patients included in the study completed 12 weeks of treatment. While fasting blood glucoses (p = 0.011) and HOMA-IR values (p = 0.027) were significantly increased in the 12th week, the increase in fasting insulin level was not significant (p = 0.07). After treatment, 10 patients developed impaired fasting glucose and 13 developed insulin resistance. Conclusion The increase in blood glucose levels may be associated with the paradoxically increase of histamine levels in the blood by omalizumab. If this increase cannot be balanced with insulin, patients may develop impaired glucose tolerance and insulin resistance. Therefore, we suggest that patients using omalizumab should be followed up for glucose homeostasis and insulin resistance.

Mast cell degranulation and histamine release during A/H5N1 influenza infection in influenza-sensitized mice

Here we evaluate the role of mast cells in infection with influenza A/H5N1 virus in immunized mice. CBA mice were immunized intramuscularly with formalin-inactivated A/Vietnam/1194/2004 (H5N1)NIBRG-14 (H5N1). Serum samples were obtained on days 7, 12, 14, 21 after immunization. At day 14, the mice were infected intranasally with the A/Indonesia/5/2005 (H5N1)IDCDC-RG2 (H5N1) influenza virus with half of the animals receiving a mixture of the antihistamines. 67% of the vaccinated mice were protected from the lethality compared to 43% in the PBS-immunized group. Administration of antihistamines increased survival up to 85%–95%. Immunohistochemical examination using CD117 staining of the lungs demonstrated a larger quantity of activated mast cells after infection of immunized mice compared to mock-immunized mice. This was correlated to increased histamine level in the lungs and blood. Our experimental results suggest the involvement of mast cells and the histamine they produce in the pathogenesis of influenza infection in case of incomplete formation of the immune response to vaccination and mismatch of the vaccine and infection influenza viruses.

Effort Displayed During Appetitive Phase of Feeding Behavior Requires Infralimbic Cortex Activity and Histamine H1 Receptor Signaling.

The chances to succeed in goal-directed behaviors, such as food or water-seeking, improve when the subject is in an increased arousal state. The appetitive phase of these motivated behaviors is characterized by high levels of behavioral and vegetative excitation. The key decision of engaging in those particular behaviors depends primarily on prefrontal cortical areas, such as the ventromedial prefrontal cortex. We propose that the infralimbic cortex (ILC) located in the medial prefrontal cortex induces an increase in arousal during the appetitive phase of motivated behavior, and that this increase in arousal is, in turn, mediated by the activation of the brain histaminergic system, resulting in higher motivation for getting food rewards. To test this hypothesis, we conduct a progressive ratio operant conditioning to test the degree of motivation for food, while simultaneously manipulating the histaminergic system through pharmacologic interventions. We found that the behavioral responses to obtain food in hungry rats were disrupted when the ILC was inhibited through muscimol infusion, blocking brain H1 histamine receptors by intracerebroventricular infusion of pyrilamine or by satiety. In contrast, the consummatory behavior was not affected by ILC inhibition. The extracellular histamine levels in the ILC were increased in direct correlation with the degree of motivation measured in the progressive ratio test. ILC inhibition also prevented this increase in histamine levels. The rise in extracellular histamine levels during the progressive ratio test was similar (ca. 200%) during the active or the resting period of the day. However, different basal levels are observed for these two periods. Our findings suggest that increased histamine levels during this behavior are not simply explained by the awaked state, but instead, there is a motivation-related release of histamine, suggestive of a specific form of brain activation. Serotonin (another critical component of the ascending arousal system) was also tested. Interestingly, changes in levels of this neuromodulator were not detected during the progressive ratio test. In conclusion, our results suggest that ILC activation and subsequent increase in brain histamine release are both necessary for the normal performance of a motivated behavior such as feeding.

Neutrophilia, gelatinase release and microvascular leakage induced by human mast cell tryptase in a mouse model: Lack of a role of protease-activated receptor 2 (PAR2).

SummaryBackgroundTryptase, the most abundant protease of the human mast cell, has been implicated as a key mediator of allergic inflammation that acts through activation of PAR2.ObjectivesTo investigate the contribution of PAR2 in the pro‐inflammatory actions mediated by tryptase in a mice model.MethodsWe have injected recombinant human βII‐tryptase into the peritoneum of PAR2‐deficient and wild‐type C57BL/6 mice. After 6, 12 and 24 hours, mice were killed, peritoneal lavage performed and inflammatory changes investigated.ResultsTryptase stimulated an increase in neutrophil numbers in the peritoneum, but responses did not differ between PAR2‐deficient and wild‐type mice. Heat inactivation of tryptase or pre‐incubation with a selective tryptase inhibitor reduced neutrophilia, but neutrophil accumulation was not elicited with a peptide agonist of PAR2 (SLIGRL‐NH 2). Zymography indicated that tryptase stimulated the release of matrix metalloproteinases (MMP) 2 and 9 in the peritoneum of both mouse strains. Studies involving immunomagnetic isolation of neutrophils suggested that neutrophils represent the major cellular source of tryptase‐induced MMP2 and MMP9. At 24 hours after tryptase injection, there was increased microvascular leakage as indicated by high levels of albumin in peritoneal lavage fluid, and this appeared to be partially abolished by heat‐inactivating tryptase or addition of a protease inhibitor. There was no corresponding increase in levels of histamine or total protein. The extent of tryptase‐induced microvascular leakage or gelatinase release into the peritoneum did not differ between PAR2‐deficient and wild‐type mice.ConclusionsOur findings indicate that tryptase is a potent stimulus for neutrophil accumulation, MMP release and microvascular leakage. Although these actions required an intact catalytic site, the primary mechanism of tryptase in vivo would appear to involve processes independent of PAR2.