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Mas-related G-protein-coupled receptor X2 (MRGPRX2), expressed on mast cells, is associated with drug-induced pseudo-allergic reactions. Although it is well known that there are differences of sensitivity between species in the pseudo-allergic reactions, no platform for evaluating a human risk of the pseudo-allergic reactions observed in nonclinical studies has been established. Valemetostat tosylate, developed as an anti-cancer drug, induced histamine release in a nonclinical study with dogs. The purpose of the current study was to identify the mechanism and assess the human risk of valemetostat- tosylate-induced histamine release using dog and human MRGPRX2-expressing cells. In an experiment with human or dog MRGPRX2-expressing cells, valemetostat tosylate caused activation of human and dog MRGPRX2. Importantly, the EC50 for dog MRGPRX2 was consistent with the Cmax value at which histamine release was observed in dogs. Furthermore, the EC50 for human MRGPRX2 was ca. 27-fold higher than that for dog MRGPRX2, indicating a species difference in histamine-releasing activity. In a clinical trial, histamine release was not observed in patients receiving valemetostat tosylate. In conclusion, an in vitro assay using human and animal MRGPRX2-expressing cells would be an effective platform to investigate the mechanism and predict the human risk of histamine release observed in nonclinical studies. [ABSTRACT FROM AUTHOR]

• Mechanisms of histamine release from mast cells beyond the activation of the high activity IgE receptor have been reported in chronic spontaneous urticaria patients. These include. • Activation of the coagulation cascade. • The activation of complement system with hyperproduction of C5a. • The activation of the MRGPRX2 receptor. • Hyperexpression of platelet activating factor. There is growing evidence suggesting that in a subset of patients with severe chronic urticaria [CSU] mast cells are activated via mechanisms that bypass the high affinity IgE receptor. This might explain why some patients do not respond at all to anti-IgE therapy [omalizumab]. The present article reviews the pathogenic mechanisms able to lead to histamine release from mast cells described so far in patients with CSU. These include the activation of the coagulation cascade, the activation of the complement system, the activation of the MRGPRX2 receptor, and the platelet activating factor vicious circle. The article suggests some possible interpretations for the clinical events occurring in this specific subset of patients. [ABSTRACT FROM AUTHOR]

Glycopeptide antibiotics are still in demand in clinical practice for treating infections caused by resistant gram-positive pathogens; however, their use is limited due to severe adverse reactions. Their predominant types of side effects are immunoglobulin E-mediated or nonmediated hypersensitivity reactions. Therefore, the development of new glycopeptide antibiotics with improved toxicity profiles remains an important objective in advancing modern antimicrobial agents. We investigated a new eremomycin aminoalkylamide flavancin, its anaphylactogenic properties, influence on histamine levels in blood plasma, pseudoallergic inflammatory reaction on concanavalin A and the change in the amount of flavancin in the blood plasma after administration. It has been shown that flavancin does not demonstrate anaphylactogenic properties. The injection of flavancin resulted in a level of histamine in the blood three times lower than that caused by vancomycin. The therapeutic dose of vancomycin led to a statistically significant increase in the concanavalin A response index compared to flavancin (54% versus 3.7%). Thus, flavancin does not cause a pseudo-allergic reaction. The rapid decrease in flavancin concentration in the blood and the low levels of histamine in the plasma lead us to assume that any pseudoallergic reactions resulting from flavancin application, if they do occur in clinical practice, will be significantly less compared to the use of vancomycin. [ABSTRACT FROM AUTHOR]

Toxicology is an essential part of any drug development plan. Circumnavigating the risk of failure because of a toxicity issue can be a challenge, and failure in late development is extremely costly. To identify potential risks, it requires more than just understanding the biological target. The toxicologist needs to consider a compound's structure, it's physicochemical properties (including the impact of the overall formulation), as well as the biological target (e.g., receptor interactions). Understanding the impact of the physicochemical properties can be used to predict potential toxicities in advance by incorporating key endpoints in early screening strategies and/or used to compare toxicity profiles across lead candidates. This review discussed the risks of off-target and/or non-specific toxicities that may be associated with the physicochemical properties of compounds, especially those carrying dominant positive or negative charges, including amphiphilic small molecules, peptides, oligonucleotides and lipids/liposomes/lipid nanoparticles. The latter of which are being seen more and more in drug development, including the recent Covid pandemic, where mRNA and lipid nanoparticle technology is playing more of a role in vaccine development. The translation between non-clinical and clinical data is also considered, questioning how a physicochemical driven toxicity may be more universal across species, which means that such toxicity may be reassuringly translatable between species and as such, this information may also be considered as a support to the 3 R's, particularly in the early screening stages of a drug development plan. [ABSTRACT FROM AUTHOR]

Glycopeptide antibiotics are still in demand in clinical practice for treating infections caused by resistant gram-positive pathogens; however, their use is limited due to severe adverse reactions. Their predominant types of side effects are immunoglobulin E-mediated or nonmediated hypersensitivity reactions. Therefore, the development of new glycopeptide antibiotics with improved toxicity profiles remains an important objective in advancing modern antimicrobial agents. We investigated a new eremomycin aminoalkylamide flavancin, its anaphylactogenic properties, influence on histamine levels in blood plasma, pseudoallergic inflammatory reaction on concanavalin A and the change in the amount of flavancin in the blood plasma after administration. It has been shown that flavancin does not demonstrate anaphylactogenic properties. The injection of flavancin resulted in a level of histamine in the blood three times lower than that caused by vancomycin. The therapeutic dose of vancomycin led to a statistically significant increase in the concanavalin A response index compared to flavancin (54% versus 3.7%). Thus, flavancin does not cause a pseudo-allergic reaction. The rapid decrease in flavancin concentration in the blood and the low levels of histamine in the plasma lead us to assume that any pseudoallergic reactions resulting from flavancin application, if they do occur in clinical practice, will be significantly less compared to the use of vancomycin.

BackgroundPsychological stress and heightened mast cell (MC) activation are linked with important immunologic disorders, including allergy, anaphylaxis, asthma, and functional bowel diseases, but the mechanisms remain poorly defined. We have previously demonstrated that activation of the corticotropin-releasing factor (CRF) system potentiates MC degranulation responses during IgE-mediated anaphylaxis and psychological stress through corticotropin-releasing factor receptor subtype 1 (CRF1) expressed on MCs.ObjectiveIn this study we investigated the role of corticotropin-releasing factor receptor subtype 2 (CRF2) as a modulator of stress-induced MC degranulation and associated disease pathophysiology.MethodsIn vitro MC degranulation assays were performed with bone marrow-derived mast cells (BMMCs) derived from wild-type (WT) and CRF2-deficient (CRF2-/-) mice and RBL-2H3 MCs transfected with CRF2-overexpressing plasmid or CRF2 small interfering RNA. In vivo MC responses and associated pathophysiology in IgE-mediated passive systemic anaphylaxis and acute psychological restraint stress were measured in WT, CRF2-/-, and MC-deficient KitW-sh/W-sh knock-in mice.ResultsCompared with WT mice, CRF2-/- mice exhibited greater serum histamine levels and exacerbated IgE-mediated anaphylaxis and colonic permeability. In addition, CRF2-/- mice exhibited increased serum histamine levels and colonic permeability after acute restraint stress. Experiments with BMMCs and RBL-2H3 MCs demonstrated that CRF2 expressed on MCs suppresses store-operated Ca2+ entry signaling and MC degranulation induced by diverse MC stimuli. Experiments with MC-deficient KitW-sh/W-sh mice systemically engrafted with WT and CRF2-/- BMMCs demonstrated the functional importance of MC CRF2 in modulating stress-induced pathophysiology.ConclusionsMC CRF2 is a negative global modulator of stimuli-induced MC degranulation and limits the severity of IgE-mediated anaphylaxis and stress-related disease pathogenesis.

Background: Sweat aggravates atopic dermatitis (AD). In patients with AD, type-I hypersensitivity to sweat may be shown by histamine release from patients' basophils in response to the semi-purified sweat antigen (QR), and the presence of specific immunoglobulin E (IgE) binding to MGL_1304, the component of QR. However, there has been no information on the immunological changes of type-I hypersensitivity to the sweat antigen in patients with well-controlled AD using topical corticosteroids (TCSs) and/or biologics as treatments. Method: Histamine-releasing tests using patients' basophils and QR and the detection of serum IgE against MGL_1304 and mite allergen Der f 1 were performed in patients with AD who were well controlled by topical TCS with/without dupilumab for 53–96 weeks. Results: In total, 14 patients were enrolled. Seven patients received TCS therapy alone (TCS group), and seven patients received TCS with dupilumab therapy (dupilumab group). In all participants, the level of specific IgE against MGL_1304 decreased after treatments, but histamine release from basophils in response to QR did not show a statistically significant reduction; rather, it increased. In the dupilumab group, all changes in histamine release induced by QR (increase), the IgE level against MGL_1304 (decrease), and that against Der f 1 (decrease) were statistically significant, whereas the TCS group showed no significant change in any of them. Conclusion: The well-controlled condition for 53–96 weeks resulted in no reduction of the hyperreactivity of basophils against in patients with AD, even with the treatment with dupilumab. This study suggests persistent basophil hyperreactivity to sweat antigen over a year or longer. [ABSTRACT FROM AUTHOR]

BackgroundSweat aggravates atopic dermatitis (AD). In patients with AD, type-I hypersensitivity to sweat may be shown by histamine release from patients’ basophils in response to the semi-purified sweat antigen (QR), and the presence of specific immunoglobulin E (IgE) binding to MGL_1304, the component of QR. However, there has been no information on the immunological changes of type-I hypersensitivity to the sweat antigen in patients with well-controlled AD using topical corticosteroids (TCSs) and/or biologics as treatments.MethodHistamine-releasing tests using patients’ basophils and QR and the detection of serum IgE against MGL_1304 and mite allergen Der f 1 were performed in patients with AD who were well controlled by topical TCS with/without dupilumab for 53–96 weeks.ResultsIn total, 14 patients were enrolled. Seven patients received TCS therapy alone (TCS group), and seven patients received TCS with dupilumab therapy (dupilumab group). In all participants, the level of specific IgE against MGL_1304 decreased after treatments, but histamine release from basophils in response to QR did not show a statistically significant reduction; rather, it increased. In the dupilumab group, all changes in histamine release induced by QR (increase), the IgE level against MGL_1304 (decrease), and that against Der f 1 (decrease) were statistically significant, whereas the TCS group showed no significant change in any of them.ConclusionThe well-controlled condition for 53–96 weeks resulted in no reduction of the hyperreactivity of basophils against in patients with AD, even with the treatment with dupilumab. This study suggests persistent basophil hyperreactivity to sweat antigen over a year or longer.

Introduction: Cisatracurium is a new non depolarising, Neuromuscular Blocking Drug (NMBD) with fast onset and short duration of action. It is a stereoisomer of atracurium with a potency of approximately 3 to 4 times greater than that of atracurium. As it is devoid of histamine release, it reduces the chances of adverse effects during operative procedures. However, the optimum intubating dosage needs to be established in patients. This warrants the need for studies focusing on the efficacy of different doses of cisatracurium and their outcomes. Aim: To study the efficacy of three different doses of cisatracurium {2x Effective dose (ED) 95, 4x ED95, and 6x ED95} for the time of onset of action, duration and haemodynamic stability offered for intubation. Materials and Methods: A double-blind, randomised clinical study was conducted from December 2017 to July 2019 at a tertiary care hospital and research center, Kolhapur, Maharashtra, India. Total 90 patients, undergoing surgeries under general anaesthesia were allocated into three groups, group A received 0.1 mg/kg, group B received 0.2 mg/kg and group C received 0.3 mg/kg of cisatracurium. Time taken for Train Of Four (TOF) to reach 0 was taken as the onset of action, and appearance of TOF 2/3 or patient's attempt to breathe was taken as duration of action. Haemodynamic changes were also assessed preoperatively and postintubation immediately after confirmation of placement of ETT. Results: Mean age 33.23±6.26 years in group A, 37.70±10.80 years in group B, 38.23±8.764 years in group C (p-value=0.06). Least time was required for the TOF to become zero by group C (5.10±1.01 minutes) as compared to groups A and B (9.91±1.39 and 7.48±1.45 minutes) which was statistically significant (p-value <0.001). The duration of action was also more in group C (49.83±5.33) compared to group A (27.23±6.97) and group B (36.17±7.62) (p-value=0.00001). Group C had better haemodynamic stability as the heart rate remained more stable than group A and group B. Conclusion: Higher dose of cisatracurium provides faster onset, longer duration of action with better cardiovascular stability. This predictable recovery from non depolarising muscle relaxation makes it a good choice of muscle relaxant agent for intubation. [ABSTRACT FROM AUTHOR]

Introduction: Cisatracurium is a new non depolarising, Neuromuscular Blocking Drug (NMBD) with fast onset and short duration of action. It is a stereoisomer of atracurium with a potency of approximately three to four times greater than that of atracurium. As it is devoid of histamine release, it reduces the chances of adverse effects during operative procedures. However, the optimum intubating dosage needs to be established in patients. This warrants the need for studies focusing on the efficacy of different doses of cisatracurium and their outcomes. Aim: To study the efficacy of three different doses of cisatracurium {2x Effective dose (ED) 95, 4x ED95, and 6x ED95} for the time of onset of action, duration and haemodynamic stability offered for intubation. Materials and Methods: A double-blind, randomised clinical study was conducted from December 2017 to July 2019 at a tertiary care hospital and research centre, Kolhapur, Maharashtra, India. Total 90 patients, undergoing surgeries under general anaesthesia were allocated into three groups, group A received 0.1 mg/kg, group B received 0.2 mg/kg and group C received 0.3 mg/kg of cisatracurium. Time taken for Train Of Four (TOF) to reach 0 was taken as the onset of action, and appearance of TOF two, three or patient’s attempt to breathe was taken as duration of action. Haemodynamic changes were also assessed preoperatively and postintubation immediately after confirmation of placement of ETT. Results: Mean age 33.23±6.26 years in group A, 37.70±10.80 years in group B, 38.23±8.764 years in group C (p-value=0.06). Least time was required for the TOF to become zero by group C (5.10±1.01 minutes) as compared to groups A and B (9.91±1.39 and 7.48±1.45 minutes) which was statistically significant (p-value

Chronic urticaria (CU) is characterised by intense recurrent itch, wheals, and/or angioedema, persisting for >6 weeks. CU can be subdivided into chronic spontaneous urticaria and chronic inducible urticaria; the latter usually appears with physical stimuli, such as heat, cold, pressure, and sunlight. The recommended treatment for CU is non-sedating oral antihistamines, administered up to four times a day. The monoclonal antibody omalizumab (anti-IgE) is recommended as an add-on therapy for patients with antihistamine-refractory CU. The fluctuating nature of urticaria symptoms and varying response to omalizumab often makes it difficult to predict the response to omalizumab; this often leads to individualised dosage regimens for CU patients. However, being able to predict the response to omalizumab treatment would lead to an improvement in dosage regimens and treatment plans in the clinical setting. Several studies have investigated potential CU biomarkers; however, no reliable biomarkers have been discovered that can be used to assess the treatment response to omalizumab in the clinic. Some potential biomarkers, such as plasma D-dimer, serum total IgE levels, the basophil histamine release assay, the autologous serum skin test, and the basophil activation test, have been suggested for predicting disease activity and response to omalizumab but are not implemented routinely in clinical practice. This paper presents an overview of the various biomarkers associated with response to omalizumab in CU.

Canine mastocytomas (MCTs) are characterized by rapid proliferation of neoplastic mast cells (MCs) and clinical signs caused by MC‐derived mediators. In dogs suffering from MCT, histamine receptor 1 (HR1) antagonists are frequently used to control mediator‐related clinical symptoms. Previous studies have shown that the HR1 antagonists loratadine and terfenadine exert some growth‐inhibitory effects on neoplastic MCs. We examined whether other HR1 antagonists used in clinical practice (desloratadine, rupatadine, cyproheptadine, dimetindene, diphenhydramine) affect proliferation and survival of neoplastic MCs. Furthermore, we analysed whether these HR1 antagonists counteract IgE‐dependent histamine release from a MC line harbouring a functional IgE‐receptor. HR1 antagonists were applied on two canine MC lines, C2 and NI‐1, and on primary MCs obtained from three MCT samples. The HR1 antagonists desloratadine, rupatadine and cyproheptadine were found to be more potent in decreasing proliferation of C2 and NI‐1 cells when compared with dimetindene and diphenhydramine. Similar effects were seen in primary neoplastic MCs, except for diphenhydramine, which exerted more potent growth‐inhibitory effects than the other HR1 antagonists. Drug‐induced growth‐inhibition in C2 and NI‐1 cells was accompanied by apoptosis. Loratadine, desloratadine and rupatadine also suppressed IgE‐dependent histamine release in NI‐1 cells. However, drug concentrations required to elicit substantial effects on growth or histamine release were relatively high (>10 µM). Therefore, it remains unknown whether these drugs or similar, more potent, HR1‐targeting drugs can suppress growth or activation of canine neoplastic MCs in vivo. [ABSTRACT FROM AUTHOR]

Abstract Background Diagnostic workup of penicillin allergy comprises skin testing with penicillins, and patients are deemed allergic if skin test is positive. However, the literature suggests that skin test-positive patients may be challenge-negative, indicating that the skin test may be falsely positive. Objective To investigate real-time histamine release from a positive intracutaneous test induced by penicillin in patients with positive and negative challenges to penicillin. Methods Skin microdialysis was performed in 21 penicillin-allergic patients with positive skin test, 13 non-allergic volunteers serving as negative controls, and 7 grass pollen-allergic patients serving as positive controls. Histamine was measured by microdialysis after skin test with penicillin/grass/NaCl. Penicillin challenge was subsequently performed in 12 of the patients. Results Only 10/21 patients (47.6%) were skin test positive at microdialysis. During microdialysis 13 single intracutaneous tests were positive and histamine was detected in 4/13 occurring in four challenge positive patients. Thirteen/21 patients (61.9%) were deemed allergic to penicillin; eight had positive skin test. Two patients with positive skin test were challenge negative. In grass pollen allergic patients, 7/7 had a positive intracutaneous test to grass and all released histamine in the wheals. All 13 negative controls had negative intracutaneous test to penicillin and no histamine release. Conclusion Histamine was only detected in the minority of positive intracutaneous tests with penicillin in penicillin-allergic patients. Other mediators may be involved.

The increasing number of patients suffering from allergic diseases is a global health problem. Grifola frondosa is an edible mushroom consumed as a health food in Asia, and has recently been reported to have anti-allergic effects. We previously reported that G. frondosa extract (GFE) and its active components, ergosterol and its derivatives, inhibited the antigen-induced activation of RBL-2H3 cells. Here, we demonstrated that GFE and ergosterol also had an inhibitory effect on the degranulation of bone marrow–derived mast cells (BMMCs) and alleviated anaphylactic cutaneous responses in mice. Using an air pouch-type allergic inflammation mouse model, we confirmed that oral administration of GFE and ergosterol suppressed the degranulation of mast cells in vivo. Our findings suggest that G. frondosa, including ergosterol as its active component, reduces type I allergic reactions by suppressing mast cell degranulation in mice, and might be a novel functional food that prevents allergic diseases. Grifola frondosa, including ergosterol as its active component, reduces type I allergic reactions by suppressing degranulation of mast cells in mice. [ABSTRACT FROM AUTHOR]

The Bruton's tyrosine kinase (BTK) inhibitor ibrutinib is effective in the treatment of human chronic lymphocytic leukaemia and mantle cell lymphoma. Recent data have shown that ibrutinib also blocks IgE‐dependent activation and histamine release in human basophils (BAs) and mast cells (MCs). The aim of this study was to investigate whether BTK serves as a novel therapeutic target in canine mast cell tumours (MCTs). We evaluated the effects of ibrutinib on two canine MC lines, C2 and NI‐1 and on primary MCs obtained from canine MCTs (n = 3). Using flow cytometry, we found that ibrutinib suppresses phosphorylation of BTK and of downstream STAT5 in both MC lines. In addition, ibrutinib decreased proliferation of neoplastic MCs, with IC50 values ranging between 0.1 and 1 μM in primary MCT cells and between 1 and 3 μM in C2 and NI‐1 cells. In C2 cells, the combination "ibrutinib + midostaurin" produced synergistic growth‐inhibitory effects. At higher concentrations, ibrutinib also induced apoptosis in both MC lines. Finally, ibrutinib was found to suppress IgE‐dependent histamine release in primary MCT cells, with IC50 values ranging from 0.05 to 0.1 μM in NI‐1 cells, and from 0.05 to 1 μM in primary MCT cells. In summary, ibrutinib exerts anti‐proliferative effects in canine neoplastic MCs and counteracts IgE‐dependent histamine release in these cells. Based on our data, ibrutinib may be considered as a novel therapeutic agent for the treatment of canine MCT. The value of BTK inhibition in canine MCT patients remains to be elucidated in clinical trials. [ABSTRACT FROM AUTHOR]

The effects of thermal stimuli on rat basophilic leukemia mast cells were studied. The cells in calcium-contained or calcium-free buffers were thermally stimulated in the temperature range of 25-60 °C. The corresponding calcium ion concentration in cells [Ca2+]i as well as the released histamine from cells was measured with fluorescence staining methods. The ruthenium red (RR), a block of membrane calcium channels (transient receptor potential family V (TRPV)), was used in experiments. Under the stimulus of 25-50 °C, no significant difference on [Ca2+]i was found between these three groups of the cells in calcium-contained buffer without or with RR and cells in calcium-free saline, indicating that the increased calcium in cytosol did not result from the extracellular buffer but came from the intracellular calcium stores. The [Ca2+]i continuously increased under the temperature of 50-60 °C, but the RR and calcium-free saline can obviously diminish the [Ca2+]i increase at these high temperatures, reflecting that the opening of the TRPV2 channels leads to a calcium influx resulting in the [Ca2+]i increment. The histamine release also became significant in these cases. Since the released histamine is a well-known mediator for the microcirculation promotion, the histamine release from mast cells could be one of the mechanisms of thermal therapy. [ABSTRACT FROM AUTHOR]

Modulation of the allergic immune response through alternative therapies is a field of study that aims to address allergic reactions differently from traditional approaches. These therapies encompass the utilization of natural functional foods, which have been observed to exert an influence on the immune response, thus mitigating the severity of allergies. Indeed, some studies suggest that the incorporation of these nutraceuticals can regulate immune function, leading to a reduction in histamine release and subsequent alleviation of allergic symptoms. Moreover, certain herbs and dietary supplements, such as curcumin, are believed to possess anti-inflammatory properties, which may serve to moderate allergic responses. Although the results remain somewhat mixed and require further research, these alternative therapies exhibit the potential to impact the allergic immune response, thereby providing complementary options to conventional treatments. Therefore, in this review, we aim to provide an updated account of functional foods capable of modulating the immune response to allergies. In that sense, the review delves into functional foods sourced from plants (phytochemicals), animals, and marine algae. Emphasis is placed on their potential application in the treatment of allergic disorders. It also provides an overview of how these foods can be effectively utilized as functional foods. Additionally, it explores the molecular mechanisms and scientific validity of various bioactive natural compounds in the management of allergies.

Stroke is the most common cause of long-term disability and places a high economic burden on the global healthcare system. Functional outcomes from stroke are largely determined by the extent of ischemic injury, however, there is growing recognition that systemic inflammatory responses also contribute to outcomes. Mast cells (MCs) rapidly respond to injury and release histamine (HA), a pro-inflammatory neurotransmitter that enhances inflammation. The gut serves as a major reservoir of HA. We hypothesized that cromolyn, a mast cell stabilizer that prevents the release of inflammatory mediators, would decrease peripheral and central inflammation, reduce MC trafficking to the brain, and improve stroke outcomes. We used the transient middle cerebral artery occlusion (MCAO) model of ischemic stroke in aged (18 mo) male mice to investigate the role of MC in neuroinflammation post-stroke. After MCAO we treated mice with 25 mg/kg body weight of cromolyn (MC stabilizer) by oral gavage. Cromolyn was administered at 3 h, 10 h, 24 h and every 24 h for 3 days post-stroke. Three control groups were used. One group underwent a sham surgery and was treated with cromolyn, one received sham surgery with PBS vehicle and the third underwent MCAO with PBS vehicle. Mice were euthanized at 24 h and 3 days post-stroke. Cromolyn administration significantly reduced MC numbers in the brain at both 24 h and 3 days post-stroke. Infarct volume was not significantly different between groups, however improved functional outcomes were seen at 3 days post-stroke in mice that received cromolyn. Treatment with cromolyn reduced plasma histamine and IL-6 levels in both the 24-h and 3-day cohorts. Gut MCs numbers were significantly reduced after cromolyn treatment at 24 h and 3 days after stroke. To determine if MC trafficking from the gut to the brain occurred after injury, GFP + MCs were adoptively transferred to c-kit -/- MC knock-out animals prior to MCAO. 24 h after stroke, elevated MC recruitment was seen in the ischemic brain. Preventing MC histamine release by cromolyn improved gut barrier integrity and an improvement in stroke-induced dysbiosis was seen with treatment. Our results show that preventing MC histamine release possesses prevents post-stroke neuroinflammation and improves neurological and functional outcomes., (© 2023. BioMed Central Ltd., part of Springer Nature.)

Background: Hepoxilins are biologically active metabolites of arachidonic acid that are formed through the 12-lipoxygenase pathway. Hepoxilin A3 is now known to be an important regulator of mucosal inflammation in response to infection by bacterial pathogens and was recently identified as a potent neutrophil chemoattractant in the intestinal mucosa. Our goal in this study was to determine if airway infection with Chlamydia in a murine model of allergic airway disease (AAD) induces hepoxilin secretion along with airway neutrophilia.Methods: We utilized an AAD adult Balb/c mouse model to evaluate airway pathology and immune response by assaying bronchoalveolar lavage (BAL) fluid cytokine, cellularity, histidine decarboxylase (HDC) as well as histamine released in response to in-vivo chlamydial antigen stimulation of purified airway neutrophils. Hepoxilin A3 production was determined by Western blot identification of 12-lipoxygenase precursor (12-LO).Results: Chlamydial infection induced increased production of IL-2, IL-12, TNF-α, and IFN-γ in BAL fluid compared to uninfected animals. Chlamydia-infected mice responded with robust airway neutrophil infiltration and upon induction of AAD increased their production of IL-4, IL-5, and IL-13 by >3 fold compared to unsensitized groups. In addition, 12-LO mRNA was upregulated in infected, but not in uninfected AAD mice, suggesting the production of hepoxilin A3. mRNA expression of HDC was induced only in neutrophils from the airways of Chlamydia-infected mice, but was not seen in AAD only or uninfected controls. When purified neutrophils from infected animals were challenged with chlamydial antigen in vitro there was significant histamine release.Conclusions: Our data confirms the production and release of hepoxilin A3 in the murine airways concomitant with airway neutrophilia in response to chlamydial infection. We further confirmed that Chlamydia provokes the production and release of histamine by these neutrophils. These findings suggest that neutrophils, provoked by Chlamydia infection can synthesize and release histamine, thereby contributing directly to airway inflammation.

Background: To the authors’ knowledge, there are no reports describing the use of cis-atracurium in the horse. Objective: To describe the onset time and the duration of the neuromuscular blockade (NMB) of three different doses of cis-atracurium in horses and to determine the appropriate dose needed maintain a NMB. Study design: Retrospective study. Methods: Horses which received cis-atracurium as part of a balanced anaesthetic protocol at the Equine Teaching Hospital of the University of Liège between March 2014 and June 2017 were included in this study. A train-of-four (TOF) stimulation pattern was used to assess the NMB. The cis-atracurium induction dose, the onset and duration of action (when TOF count was under three twitches) of the first bolus, the number of supplementary boluses of cis-atracurium and the total dose of cis-atracurium administered per horse, the total duration of the NMB and the recovery time were recorded and analysed. Also the use of an antidote and any side effects produced by cis-atracurium were recorded. Results: From 37 horses that received cis-atracurium during this period, only 23 had a complete records and were included in the study. Three different doses of cis-atracurium were used to induce NMB: 100 μg/kg (n = 8) 75 μg/kg (n = 3) and 50 μg/kg (n = 12). Cis-atracurium 50 μg/kg failed to induce NMB in 3 horses. The onset of action was not significantly different between the three doses (5 minutes). The duration of the NMB was dose-dependent. The calculated dose of cis-atracurium necessary to maintain a NMB was 2.3 μg/kg/minute based on the sum of the induction dose and the supplementary boluses divided by the duration of the NMB. Main limitations: A further prospective study is needed to confirm the results. Conclusions: Cis-atracurium can be an alternative to other NMBA in horses. [ABSTRACT FROM AUTHOR]

Allergic diseases afflict many people worldwide. Allergic inflammation encompassing acute allergic reaction and chronic inflammatory response is the major pathogenesis. To discovery novel therapeutic approach for allergic diseases, we have evaluated the anti-allergic inflammatory effects of irisflorentin using RBL-2H3 cells. The results showed certain concentrations of irisflorentin could suppress histamine release and secretion of TNF-α, IL-1β and IL-6. Further investigations indicated that the effects of irisflorentin were associated with a reduction of intracellular calcium, suppression of NF-κB signaling pathway and inhibition of caspase-1 activity. Therefore, the results of the current study demonstrated that irisflorentin can ameliorate mast cell-mediated allergic inflammation. These results can provide evidence for the discovery of novel therapy for allergic diseases and application of irisflorentin in practice. [ABSTRACT FROM AUTHOR]

Apelin is an endogenous ligand of seven‐transmembrane G‐protein‐coupled receptor APJ. Apelin and APJ are distributed in various tissues, including the heart, lung, liver, kidney, and gastrointestinal tract and even in tumor tissues. Studies show that apelin messenger RNA is widely expressed in gastrointestinal (GI) tissues, including stomach and small intestine, which is closely correlated with GI function. Thus, the apelin/APJ system may exert a broad range of activities in the digestive system. In this paper, we review the role of the apelin/APJ system in the digestive system in physiological conditions, such as gastric acid secretion, control of appetite and food intake, cell proliferation, cholecystokinin secretion and histamine release, gut–brain axis, GI motility, and others. In pathological conditions, the apelin/APJ system plays an important role in the healing process of stress gastric injury, the clinical features and prognosis of patients with gastric cancers, the reduction of inflammatory response to enteritis and pancreatitis, the mediation of liver fibrogenesis, the promotion of liver damage, the inhibition of liver regeneration, the contribution of splanchnic neovascularization in portal hypertension, the treatment of colon cancer, and GI oxidative damage. Overall, the apelin/APJ system plays diversified functions and regulatory roles in digestive physiology and pathology. Further exploration of the relationship between the apelin/APJ system and the digestive system will help to find new and effective drugs for treating and alleviating the pain of digestive diseases. The role of the apelin/APJ system in the digestive system. [ABSTRACT FROM AUTHOR]

Abstract The resources of released histamine from activated mast cells, as initial effectors of allergic disease, include not only endogenous prepackaged histamine and newly synthesized histamine, but also histamine that is obtained through the de novo reuptake pathway. To investigate the de novo histamine production pathway, a mast cell line, RBL-2H3 Sc98 in which endogenous histamine production is lacking and only the de novo histamine release pathway via transporters is maintained, was used to dissect histamine reuptake in the present study. Histamine content measurements indicated that RBL-2H3 Sc98 cells took up extracellular histamine for storage in granules and subsequent release after stimulation by an antigen. Profiling and inhibition analysis of possible transporters suggested that the plasma membrane monoamine transporter and organic cation transporter 1 may be candidate transporters for histamine uptake from extracellular spaces, and that vesicular monoamine transporter 2 was responsible for intracellular vesicle uptake. These results may provide the foundation to understand the contribution of exogenous histamine to outward histamine release that is mediated by mechanisms other than conventional exocytosis. [ABSTRACT FROM AUTHOR]

Protein transduction domains (PTDs) have been shown to promote the delivery of therapeutic proteins or peptides into the living cells. In a previous study, we showed that the double mutant of TCTP-PTD 13, TCTP-PTD 13M2, was more effective in the delivery of insulin than the wild-type TCTP-PTD 13. In this study, we applied this approach to the nasal delivery of a different peptide, exendin-4, using as carriers, several modified TCTP-PTDs, such as TCTP-PTD 13M1, 13M2, and 13M3. Nasal co-administration of TCTP-PTD 13M2 with exendin-4 showed the highest exendin-4 uptake among the three analogs in normal rats, and also decreased blood glucose levels by 43.3% compared with that of exendin-4 alone and by 18.6% compared with that of exendin-4 plus TCTP-PTD 13 in diabetic mice. We also designed an additional covalently linked conjugate of TCTP-PTD 13M2 and exendin-4 and evaluated its hypoglycemic effect after subcutaneous or intranasal delivery. Subcutaneous administration of exendin-4 that its C-terminus is covalently linked to TCTP-PTD 13M2 showed hypoglycemic effect of 42.2% compared to that in untreated group, whereas intranasal delivery was not successful in diabetic mice. We conclude that a simple mixing TCTP-PTD 13M2 with peptide/protein drugs can be potentially a generally applicable approach for intranasal delivery into animals. [ABSTRACT FROM AUTHOR]

Carrier peptides, termed protein transduction domains (PTDs), serve as provide promising vehicles for intranasal delivery of macromolecular drugs. A mutant PTD derived from human translationally controlled tumor protein (TCTP-PTD 13, MIIFRALISHKK) was reported to provide enhanced intranasal delivery of insulin. In this study, we tested whether its efficiency could be further improved by replacing amino acids in TCTP-PTD 13 or changing the amino acids in the carrier peptides from the L- to the D-form. We assessed the pharmacokinetics of PTD-mediated transmucosal delivery of insulin in normal rats and the activity of insulin in alloxan-induced diabetic rats. The safety/toxicity profile of the carrier peptides was evaluated based on the release of lactate dehydrogenase (LDH) in nasal wash fluid, body weight changes, and several biochemical parameters. Pharmacokinetic and pharmacodynamic studies showed that the L-form of a double substitution A6L, I8A (MIIFRLLASHKK), designated as L-TCTP-PTD 13M2 was the most effective carrier for intranasal insulin delivery. The relative bioavailability of insulin co-administered intranasally with L-TCTP-PTD 13M2 was 37.1% of the value obtained by the subcutaneous route, which was 1.68-fold higher than for insulin co-administered with L-TCTP-PTD 13. Moreover, co-administration of insulin plus L-TCTP-PTD 13M2 reduced blood glucose levels compared to levels in diabetic rats treated with insulin plus L-TCTP-PTD 13. There was no evidence of toxicity. These results suggest that the newly designed PTD is a useful carrier peptide for the intranasal delivery of drugs or biomolecules. [ABSTRACT FROM AUTHOR]

Background: Hepoxilins are biologically active metabolites of arachidonic acid that are formed through the 12-lipoxygenase pathway. Hepoxilin A3 is now known to be an important regulator of mucosal inflammation in response to infection by bacterial pathogens and was recently identified as a potent neutrophil chemoattractant in the intestinal mucosa. Our goal in this study was to determine if airway infection with Chlamydia in a murine model of allergic airway disease (AAD) induces hepoxilin secretion along with airway neutrophilia. Methods: We utilized an AAD adult Balb/c mouse model to evaluate airway pathology and immune response by assaying bronchoalveolar lavage (BAL) fluid cytokine, cellularity, histidine decarboxylase (HDC) as well as histamine released in response to in-vivo chlamydial antigen stimulation of purified airway neutrophils. Hepoxilin A3 production was determined by Western blot identification of 12-lipoxygenase precursor (12-LO). Results: Chlamydial infection induced increased production of IL-2, IL-12, TNF-α, and IFN-γ in BAL fluid compared to uninfected animals. Chlamydia -infected mice responded with robust airway neutrophil infiltration and upon induction of AAD increased their production of IL-4, IL-5, and IL-13 by >3 fold compared to unsensitized groups. In addition, 12-LO mRNA was upregulated in infected, but not in uninfected AAD mice, suggesting the production of hepoxilin A3. mRNA expression of HDC was induced only in neutrophils from the airways of Chlamydia -infected mice, but was not seen in AAD only or uninfected controls. When purified neutrophils from infected animals were challenged with chlamydial antigen in vitro there was significant histamine release. Conclusions: Our data confirms the production and release of hepoxilin A3 in the murine airways concomitant with airway neutrophilia in response to chlamydial infection. We further confirmed that Chlamydia provokes the production and release of histamine by these neutrophils. These findings suggest that neutrophils, provoked by Chlamydia infection can synthesize and release histamine, thereby contributing directly to airway inflammation. [ABSTRACT FROM AUTHOR]

Background: The characteristics of the aggregation reaction that follows allergen binding to cell surface IgE on basophils and mast cells depend on a variety of factors that include the density of IgE and the affinity of the allergen for IgE. For simple bivalent stimuli, one prediction is that the location of the optimum for aggregation is not dependent on IgE density, only the affinity for IgE. However, this behavior does not occur for stimulation with an anti-IgE antibody (Ab) during the treatment of patients with omalizumab. Methods: This study re-examined the stability of the optimum for histamine release, relative to cell surface IgE density, using the simple bivalent penicillin hapten (BPO2) or a bivalent monoclonal anti-IgE Ab. Results: The results validated one prediction for one bivalent hapten, BPO2. Across a range of BPO-specific IgE density of 270–23,500/cell, optimal histamine release remained constant (10 nM BPO2). In contrast, across a range of approximately 6,000–110,000/cell, optimal histamine release shifted 8- to 30-fold for anti-IgE Ab. The distinguishing characteristic between the 2 bivalent stimuli was the difference in their crosslink re-equilibration. Recent modeling of histamine release suggested that the SYK-to-receptor ratio could determine the position of histamine release optimum. The study showed that there were significant shifts in the SYK-to-receptor ratio (from 1: 6 to 5: 1) but the basophil's ability to sense this ratio was restricted to transient crosslinks, as occurred with anti-IgE Ab. Conclusions: The results suggest that ligand crosslinking dynamics couple with SYK and receptor expression levels to determine qualitative characteristics of the dose response curve for secretion. [ABSTRACT FROM AUTHOR]

We investigated the role of Bruton's tyrosine kinase (Btk) in FcepsilonRI-dependent activation of mouse mast cells, using xid and btk null mutant mice. Unlike B cell development, mast cell development is apparently normal in these btk mutant mice. However, mast cells derived from these mice exhibited significant abnormalities in FcepsilonRI-dependent function. xid mice primed with anti-dinitrophenyl monoclonal IgE antibody exhibited mildly diminished early-phase and severely blunted late-phase anaphylactic reactions in response to antigen challenge in vivo. Consistent with this finding, cultured mast cells derived from the bone marrow cells of xid or btk null mice exhibited mild impairments in degranulation, and more profound defects in the production of several cytokines, upon FcepsilonRI cross-linking. Moreover, the transcriptional activities of these cytokine genes were severely reduced in FcepsilonRI-stimulated btk mutant mast cells. The specificity of these effects of btk mutations was confirmed by the improvement in the ability of btk mutant mast cells to degranulate and to secrete cytokines after the retroviral transfer of wild-type btk cDNA, but not of vector or kinase-dead btk cDNA. Retroviral transfer of Emt (= Itk/Tsk), Btk's closest relative, also partially improved the ability of btk mutant mast cells to secrete mediators. Taken together, these results demonstrate an important role for Btk in the full expression of FcepsilonRI signal transduction in mast cells.

Objectives: This study was conducted to clarify the effects of agarwood on histamine release from mast cells in rats and on the scratching behaviors in mice. Methods: Histamine release from rat mast cells induced by compound 48/80 or concanavalin A (Con A) and compound 48/80-induced scratching behavior in mice were examined to investigate

A high incidence of hypersensitivity reactions (HSRs) largely limits the use of paclitaxel injection. Currently, these reactions are considered to be mediated by histamine release and complement activation. However, the evidence is insufficient and the molecular mechanism involved in paclitaxel injection-induced HSRs is still incompletely understood. In this study, a mice model mimicking vascular hyperpermeability was applied. The vascular leakage induced merely by excipients (polyoxyl 35 castor oil) was equivalent to the reactions evoked by paclitaxel injection under the same conditions. Treatment with paclitaxel injection could cause rapid histamine release. The vascular exudation was dramatically inhibited by pretreatment with a histamine antagonist. No significant change in paclitaxel injection-induced HSRs was observed in complement-deficient and complement-depleted mice. The RhoA/ROCK signaling pathway was activated by paclitaxel injection. Moreover, the ROCK inhibitor showed a protective effect on vascular leakage in the ears and on inflammation in the lungs. In conclusion, this study provided a suitable mice model for investigating the HSRs characterized by vascular hyperpermeability and confirmed the main sensitization of excipients in paclitaxel injection. Histamine release and RhoA/ROCK pathway activation, rather than complement activation, played an important role in paclitaxel injection-induced HSRs. Furthermore, the ROCK inhibitor may provide a potential preventive approach for paclitaxel injection side effects.

Introduction: Atracurium and cisatracurium are promising drugs offering a predictable recovery due to non-organ dependent elimination. However, due to the variability in metabolism and narrow therapeutic window, monitoring of neuromuscular functions has significant importance. Aim: To compare the onset time, duration of block and recovery indices of atracurium and cisatracurium in equipotent doses. The secondary aim included comparing haemodynamic profile and signs of histamine release. Materials and Methods: The present study was a prospective randomised observational study conducted in the Department of Anaesthesia, Government Medical College, Amritsar, Punjab, India (December 2016 to March 2017). It comprised of 60 ASA Grade I patients in the age group of 18-65 years posted for elective laparoscopic cholecystectomies. Patients were divided into two groups of 30 each. Group C (Cisatracurium) patients received cisatracurium 0.1 mg/kg as loading dose while Group A (Atracurium), patients were administered atracurium 0.5 mg/ kg. The onset time, duration of block and recovery index were recorded using Train of Four (TOF) response along with the haemodynamic profile and signs of histamine release, using SPSS 22.0 software considering a p-value

Mast cells are multifunctional immune cells with complex roles in tissue homeostasis and disease. Cardiac mast cells (HCMCs) are strategically located within the human myocardium, in atherosclerotic plaques, in proximity to nerves, and in the aortic valve. HCMCs express the high-affinity receptor (FcεRI) for IgE and can be activated by anti-IgE and anti-FcεRI. Autoantibodies to IgE and/or FcεRI have been found in the serum of patients with a variety of immune disorders. We have compared the effects of different preparations of IgG anti-IgE obtained from patients with atopic dermatitis (AD) with rabbit IgG anti-IgE on the release of preformed (histamine and tryptase) and lipid mediators [prostaglandin D 2 (PGD 2 ) and cysteinyl leukotriene C 4 (LTC 4 )] from HCMCs. Functional human IgG anti-IgE from one out of six AD donors and rabbit IgG anti-IgE induced the release of preformed (histamine, tryptase) and de novo synthesized mediators (PGD 2 and LTC 4 ) from HCMCs. Human IgG anti-IgE was more potent than rabbit IgG anti-IgE in inducing proinflammatory mediators from HCMCs. Human monoclonal IgE was a competitive antagonist of both human and rabbit IgG anti-IgE. Although functional anti-IgE autoantibodies rarely occur in patients with AD, when present, they can powerfully activate the release of proinflammatory and vasoactive mediators from HCMCs., (© 2022. The Author(s).)