Histamine Release Research Articles

Immunotherapy with biodegradable nanoparticles encapsulating the oligosaccharide galactose-alpha-1,3-galactose enhance immune tolerance against alpha-gal sensitization in a murine model of alpha-gal syndrome.

IgE antibodies against the mammalian oligosaccharide allergen galactose-α-1,3-galactose (αGal) can result in a severe allergic disease known as alpha-gal syndrome (AGS). This syndrome, acquired by tick bites that cause αGal sensitization, leads to allergic reactions after ingestion of non-primate mammalian meat and mammalian-derived products that contain αGal. Allergen-specific immunotherapies for this tickborne allergic syndrome are understudied, as are the immune mechanisms of allergic desensitization that induce clinical tolerance to αGal. Here, we reveal that prophylactic administration of αGal glycoprotein-containing nanoparticles to mice prior to tick protein-induced αGal IgE sensitization blunts the production of Th2 cytokines IL-4, IL-5, and IL-13 in an αGal-dependent manner. Furthermore, these effects correlated with suppressed production of αGal-specific IgE and hypersensitivity reactions, as measured by reduced basophil activation and histamine release and the systemic release of mast cell protease-1 (MCPT-1). Therapeutic administration of two doses of αGal-containing nanoparticles to mice sensitized to αGal had partial efficacy by reducing the Th2 cytokine production, αGal-specific IgE production, and MCPT-1 release without reducing basophil activation or histamine release. These data identify nanoparticles carrying encapsulated αGal glycoprotein as a potential strategy for augmenting αGal-specific immune tolerance and reveal diverse mechanisms by which αGal nanoparticles modify immune responses for established αGal-specific IgE-mediated allergic reactions.

Acquired and familial cold-induced urticaria: a review

The exposure of skin to cold results in the release of histamine, leukotrienes, and pro-inflammatory mast cell mediators which leads to the appearance of pruritic wheals with or without angioedema and in turn the onset of urticaria. According to the etiology, cold urticaria can be classified into acquired cold urticaria (ACU) and familial cold urticaria (FCU). This study aimed to overview the acquired and FCU. The articles incorporated in writing this review were obtained through searching the scientific databases and using various related keywords. All types of articles were eligible and those written in English language. The current subject was discussed in two main titles, ACU and FCU. Each title overviewed the related condition, diagnosis, and management. There is confusion regarding the classification of urticaria; ACU and FCU are two forms of urticaria based on etiology. However, there is little known about FCU, especially regarding its management. Correct and prompt diagnosis is the key factor to avoid severe consequences of these two conditions.

Antiallergic Effect of the Alpha-Cyclodextrin Moringin Complex in Rat Basophilic Leukaemia (RBL-2H3) Cell Line.

Allergic diseases (ADs) are a major concern when it comes to public well-being. Moringa oleifera Lam is a tropical plant that is used in traditional medicine due to the presence of isothiocyanate. The present study investigated the antiallergic properties of 4-(α-L-rhamnopyranosyloxy)-benzyl isothiocyanate or moringin isolated from Moringa oleifera seeds in the form of alpha-cyclodextrin-moringin (α-CD/MG) complex on rat basophilic leukaemia (RBL-2H3) cell line at both the early and late stages of an allergic reaction. The α-CD/MG complex was initially elucidated using nuclear magnetic resonance (NMR) followed by the 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium inner salt proliferation assay to evaluate the cytotoxicity and cell viability with respect to ketotifen fumarate (KF) and α-CD/MG. The release of beta-hexosaminidase (β-hexosaminidase) and histamine was used to determine the level of inhibition in the early stage while the suppression of the release of prostaglandin (PGD2), tumour necrosis factor-alpha (TNF-α), and interleukin (IL-4) was considered in the late stage. Higher concentrations of α-CD/MG (5 μM, p < 0.001) in mast cell degranulation significantly inhibited the expression of β-hexosaminidase, histamine, TNF-α, PGD2, and IL-4 in both the early and late stages. Thus, α-CD/MG can potentially be developed as an antiallergic drug as it has the ability to inhibit allergic responses in the late and early stages.

Efficacy of Cis-Atracurium vs Atracurium in Patients undergoing Abdominal Procedures: A Randomised Clinical Study

Introduction: Cis-atracurium has a neuromuscular blocking capacity approximately three times that of atracurium besylate. The Effective Dose (ED) 95 of cis-atracurium is 0.04 mg/kg, while that of atracurium is 0.2 mg/kg. Cis-atracurium is preferred over atracurium due to the lack of histamine release, providing better cardiovascular stability. This study compares these two drugs in terms of haemodynamic parameters, neuromuscular blocking properties, intubating conditions, and safety profiles. Aim: To assess the efficacy of atracurium and cis-atracurium from various perspectives, including neuromuscular blockade, haemodynamic stability, and safety profiles. Materials and Methods: A double-blinded, randomised clinical study was conducted from January 2019 to October 2019 in Rajkot, Gujarat, India. Sixty patients undergoing abdominal surgeries under general anaesthesia were allocated to two groups. Group A received a loading dose of atracurium 0.5 mg/kg followed by a maintenance dose of 0.1 mg/kg, while Group B received a loading dose of cis-atracurium 0.2 mg/ kg followed by a maintenance dose of 0.03 mg/kg. During the surgical procedure, parameters studied included neuromuscular blockade, hemodynamic changes, intubating conditions, and safety profiles in terms of complications. Student’s t-test was used to analyse normally distributed continuous variables, and the chi-square test was used for qualitative variables. Results: The demographic profiles were comparable in both groups in terms of age (p-value=0.800), sex (p-value=0.393), weight (p-value=0.101), and American Society of Anaesthesiologists (ASA) grading (p-value=0.509). A significant increase in heart rate (99.46±8.06 (/minute) vs. 91.66±9.11 (/ minute)) and mean arterial blood pressure (104.44±10.16 (mm of Hg) vs. 93.4±12.77 (mm of Hg)) was noted post-intubation in Group A compared to Group B. Patients in Group A (3.5±0.62 minutes) had a faster onset of neuromuscular blockade compared to Group B (4.6±0.49 (minutes)), while the duration of action of the first loading dose and the 25% recovery time from the last supplemental dose was longer in Group B (52.86±5.18 minutes and 41.66±3.60 minutes) than in Group A (31.2±4.82 minutes and 20.86±4.37 minutes). Fewer patients experienced complications (hypotension, erythema of the skin) in Group A compared to Group B. Conclusion: Cis-atracurium releases less histamine compared to atracurium and has a longer duration of action. Cis-atracurium can be a better alternative to atracurium as it offers better haemodynamic, neuromuscular, and safety profiles with similar intubating conditions.

Evaluation of the three different doses of cisatracurium during general anaesthesia: A prospective randomized study.

The present study was conducted to determine the optimal dose of cisatracurium for intubating conditions and onset and offset of neuromuscular blockade. Data in Indian population are scarce, and hence, the present study was planned to evaluate different doses of cisatracurium. The prospective randomized double-blind study was conducted on 180 patients of either sex in the age group of 20-60 yrs., having physical status class I to III, scheduled for surgery under general anesthesia. After exclusion 154 patients were randomly divided into three groups comprising 52, 51, and 51, respectively, in Group A, Group B, and group C. They received 0.1 mgkg-1, 0.2 mgkg-1, and 0.3 mgkg-1 of cisatracurium, respectively, to facilitate endotracheal intubation. Time of onset, intubating conditions, hemodynamic parameters, signs of histamine release, and recovery time were noted. Mean time to onset was maximum in group A (4.37 ± 0.48 minutes) and minimum in group C (2.33 ± 0.43 minutes). Intubating conditions were found excellent in 88% patients in group. Change in HR was found to be non-significant at all time periods, but decrease in MAP was found between 2 and 10 minutes in group C. Duration of action was longest in group C. We conclude that cisatracurium in dose of 0.2 mgkg-1 and 0.3 mgkg-1 provides good-to-excellent intubating conditions within less than 3 minutes.

A Rare Case of Angioedema Face due to Fish Allergy - A Case Report

Angioedema is defined by World Allergy Organization as a transient swelling of the skin or submucosal surface due to increased vascular permeability of small venules. Most common etiologies include IgE-mediated allergic reactions (to food, drug, or environmental triggers), nonsteroidal anti-inflammatory drug (NSAID), and chemically induced histamine release (most commonly opiates, highly cationic antibiotics, and muscle relaxants). Recent publications show a global incidence of anaphylaxis between 50 and 112 episodes per 100 000 person-years while the estimated lifetime prevalence is 0.3-5.1%. Timely intubation and administration of steroids/ antihistaminic agents will prevent a catastrophic cannot intubate cannot ventilate situation. In small, resource limited environment of a field hospital which may be compared to a rural setting in India managing such emergencies is challenging. If available in a case of anticipated difficult airway like this difficult airway cart must contain a whole armamentarium of airway adjuncts and gadgets. History of consumption of fish (Nile Perch) a rare form of allergen causing airway and breathing issues leading to timely intubation saved the life of patient.

Modulation of the Immune Response to Allergies Using Alternative Functional Foods.

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.

A Methodical Review on Allergens and Allergic Reactions

Allergic reactions can lead to a variety of symptoms, like rhinorrhoea, nasal congestion, and sneezing; eye and ear irritation, too few apparent symptoms include throat problems, cough, asthma and breathlessness and eczema. The major side effect of older antihistamines is drowsiness. Recent antihistamines normally do not cause drowsiness. Human develops hypersensitivity as a result of their immune system being overactive. Gamma globulins are created in excess during an allergic reaction. Normally, the purpose of these gamma globulins is to combat microbial infections. IgE gamma globulin functions abnormally in case of allergic onset. Various allergens (pollens, animal dander) are considered as a foreign material. IgE try to “destroy” the allergens. A series of chemical reactions take place when IgE attaches to the allergens which involves the release of histamine into the body from mast cells and results in various allergic symptoms. In this review, various allergic causes, symptoms, allergens, and treatments for allergic reactions are summarized.

Inhibitory effects of catalpol on DNCB-induced atopic dermatitis and IgE-mediated mast cells reaction

Atopic dermatitis (AD) is a chronic, inflammatory cutaneous disease driven by immune dysregulation. Catalpol is an iridoids, possessing anti-inflammatory, antioxidant, and neuroprotective activities. It can be added to food as a dietary supplement. To evaluate the effects and mechanisms of catalpol on AD, both in vitro and in vivo studies were conducted. It was found that catalpol downregulated the phosphorylation of Lyn and Syk to inhibit various downstream pathways, including intracellular Ca2+ elevation, cytokines generation, and histamine release, which ultimately controlled mast cell (MCs) degranulation. The results showed that catalpol alleviated AD-like skin lesions and MC infiltration via regulation of pro-Th2 and Th2 cytokines in vivo. Furthermore, this compound reduced the levels of IgE in AD mice and improved allergic reactions in PCA mice. The results provided that catalpol was potentially developed as a dietary supplement to improve AD and other atopic diseases.

Mathematical-based morphological classification of skin eruptions corresponding to the pathophysiological state of chronic spontaneous urticaria

BackgroundChronic spontaneous urticaria (CSU) is one of the most intractable human-specific skin diseases. However, as no experimental animal model exists, the mechanism underlying disease pathogenesis in vivo remains unclear, making the establishment of a curative treatment challenging.MethodsA novel approach combining mathematical modelling, in vitro experiments and clinical data analysis was used to infer the pathological state of CSU patients from geometric features of the skin eruptions.ResultsBased on our hierarchical mathematical modelling, the eruptions of CSU were classified into five categories, each with distinct histamine, basophils, mast cells and coagulation factors network signatures. The analysis of 105 real CSU patients with this classification by six individual dermatologists achieved 87.6% agreement. Furthermore, our network analysis revealed that the coagulation status likely determines boundary/area pattern of wheals, while the state of spontaneous histamine release from mast cells may contribute to the divergence of size and outline of the eruptions.ConclusionsOur multi-faceted approach was accurate in defining pathophysiological states of disease based on geometric features offering the potential to improve the accuracy of CSU diagnosis and better management of the disease in the clinic.

Histamine Receptors: Ex Vivo Functional Studies Enabling the Discovery of Hits and Pathways.

Histamine receptors (HRs) are G-protein-coupled receptors involved in diverse responses triggered by histamine release during inflammation or by encounters with venomous creatures. Four histamine receptors (H1R-H4R) have been cloned and extensively characterized. These receptors are distributed throughout the body and their activation is associated with clinical manifestations such as urticaria (H1R), gastric acid stimulation (H2R), regulation of neurotransmitters in neuronal diseases (H3R), and immune responses (H4R). Despite significant homologous overlap between H3R and H4R, much remains unknown about their precise roles. Even though some drugs have been developed for H1R, H2R, and H3R, not a single H4R antagonist has been approved for clinical use. To enhance our understanding and advance innovative therapeutic targeting of H1R, H2R, H3R, and H4R, we established a robust ex vivo functional platform. This platform features the successful heterologous expression of H1R-H4R in Xenopus laevis oocytes, utilizing an electrophysiological readout. Our findings contribute to a deeper understanding of the function and pharmacological properties of the histamine receptors. Researchers can benefit from the utility of this platform when investigating the effects of histamine receptors and exploring potential therapeutic targets. In doing so, it broadens the horizon of drug discovery, offering new perspectives for therapeutic interventions.

Biomarkers of Autoimmune Chronic Spontaneous Urticaria.

Chronic spontaneous urticaria and chronic inducible urticaria (CSU/CindU) are caused by mast cell and basophil activation leading to degranulation and the release of histamine and several other mediators. Three kinds of factors can trigger mast cells in CSU: (1) activation of stimulating receptor(s) on the mast cell membrane, (2) upregulation of certain receptor(s), and (3) intracellular dysregulation in signaling with overexpression of the spleen tyrosine kinase (SYK) or reduced activation of the inhibitory Src homology 2 (SH2)-containing inositol phosphatases (SHIP)-related pathways. In CSU, two major endotypes exist based on the primary receptor activating mechanism: type I hypersensitivity (IgE-mediated, directed against auto-allergens) and type IIb (autoimmune, via IgG autoantibodies directed against IgE or the IgE-receptor). Their treatment responses vary. We discuss in vitro and in vivo biomarkers. Patients with auto-allergic CSU have clinical characteristics that can distinguish them partly from those with autoimmune CSU. Most importantly, their disease generally presents a less aggressive course, a better response to second generation (up-dosed) antihistamines and a good response to omalizumab, if necessary. Meanwhile, autoimmune CSU/CindU patients fare less well and often need immunosuppressive drugs. Biomarkers that might help endotype CSU/CindU patients and select the most appropriate treatment, dose, and duration, e.g., for autoallergic CSU, high total IgE and IgE against auto-allergens; for autoimmune CSU, low IgE, basopenia, and IgG against autoantigens like thyroid peroxidase and a positive autologous serum skin test (but sometimes also positive in autoallergy). Some biomarkers are easily accessible but of low specificity; others are highly specific but more futuristic.

Ligand-directed biased agonism at human histamine H3 receptor isoforms across Gαi/o- and β-arrestin2-mediated pathways

The histamine H3 receptor (H3R) is a neurotransmitter receptor that is primarily found in the brain, where it controls the release and synthesis of histamine, as well as the release of other neurotransmitters (e.g. dopamine, serotonin). Notably, 20 H3R isoforms are differentially expressed in the human brain as a consequence of alternative gene splicing. The hH3R-445, -415, -365 and -329 isoforms contain the prototypical GPCR (7TM) structure, yet exhibit deletions in the third intracellular loop, a structural domain that is pivotal for G protein-coupling, signaling and regulation. To date, the physiological relevance underlying the individual and combinatorial function of hH3R isoforms remains poorly understood. Nevertheless, given their significant implication in physiological processes (e.g. cognition, homeostasis) and neurological disorders (e.g. Alzheimer’s and Parkinson’s disease, schizophrenia), widespread targeting of hH3R isoforms by drugs may lead to on-target side effects in brain regions that are unaffected by disease. To this end, isoform- and/or pathway-selective targeting of hH3R isoforms by biased agonists could be of therapeutic relevance for the development of region- and disease-specific drugs. Hence, we have evaluated ligand biased signaling at the hH3R-445, -415, -365 and -329 isoforms across various Gαi/o-mediated (i.e. [35S]GTPγS accumulation, cAMP inhibition, pERK1/2 activation, pAKT T308/S473 activation) and non Gαi/o-mediated (i.e. β-arrestin2 recruitment) endpoints that are relevant to neurological diseases. Our findings indicate that H3R agonists display significantly altered patterns in their degree of ligand bias, in a pathway- and isoform-dependent manner, underlining the significance to investigate GPCRs with multiple isoforms to improve development of selective drugs. Subject categoryNeuropharmacology.

Leaves and pseudostems extract of Curcuma longa attenuates immunoglobulin E/bovine serum albumin-stimulated bone marrow-derived cultured mast cell activation and passive cutaneous anaphylaxis in BALB/c mice

Ethnopharmacological relevanceCurcuma longa, known as turmeric, is an herbaceous perennial plant belonging to the genus Curcuma. It is dispersed throughout tropical and subtropical regions worldwide. Since ancient times, turmeric has been used as an ethnomedicinal plant in the Ayurvedic system, particularly in Asian countries. Rhizomes of turmeric possess several pharmacological properties that give high value as a medicinal remedy for treating a range of conditions, including inflammation, pain, allergies, and digestive issues. Moreover, turmeric leaves and pseudostems also contain a variety of health-enhancing secondary metabolites, such as curcumin, flavonoids, and other phenolic compounds, which exhibit anti-inflammatory, antitumor, antibacterial, and antioxidant properties. Aim of the studyAllergic diseases are a group of immune-mediated disorders mainly caused by an immunoglobulin E (IgE)-dependent immunological response to an innocuous allergen. Therefore, this study aimed to investigate the effect of leaves and pseudostems extract of turmeric (TLSWE-8510) on IgE/bovine serum albumin (BSA)-stimulated allergic responses in mouse bone marrow-derived cultured mast cells (BMCMCs) and passive cutaneous anaphylaxis (PCA) in BALB/c mice. Materials and methodsThe effect of TLSWE-8510 on mast cell degranulation has been evaluated by investigating the release of β-hexosaminidase and histamine in IgE/BSA-stimulated BMCMCs. Additionally, anti-allergic properties of TLSWE-8510 on IgE/BSA-stimulated BMCMCs were investigated using suppression of nuclear factor-kappa B (NF-κB), and spleen tyrosine kinase (Syk)-linker for T-cell activation (LAT)-extracellular-signal-regulated kinase (ERK)-GRB2 associated binding protein 2 (Gab2) signaling pathway and downregulation of allergy-related cytokines and chemokines expression. Furthermore, in vivo, studies were conducted using IgE-mediated PCA in BALB/c mice. ResultsTLSWE-8510 treatment significantly inhibited the degranulation of IgE/BSA-stimulated BMCMCs by inhibiting the release of β-hexosaminidase and histamine dose-dependently. Additionally, TLSWE-8510 reduced the expression of high-affinity IgE receptors (Fc epsilon receptor I-FcεRI) on the surface of BMCMCs and the binding of IgE to FcεRI. Besides, the expression of cytokines and chemokines is triggered by IgE/BSA stimulation via activating the allergy-related signaling pathways. TLSWE-8510 dose-dependently downregulated the mRNA expression and the production of allergy-related cytokines (interleukin (IL)-1β, IL-3, IL-4, IL-5, IL-6, IL-13, tumor necrosis factor (TNF)-α, and interferon (IFN)-γ), and chemokines (thymus and activation-regulated chemokine (TARC), and regulated upon activation, normal T cell expressed and secreted (RANTES)) by regulating the phosphorylation of downstream signaling molecules, NF-κB, and Syk, LAT, ERK and Gab2 in IgE/BSA-stimulated BMCMCs. Moreover, PCA reaction in IgE/BSA-stimulated BALB/c mice ears was effectively decreased by TLSWE-8510 treatment in a dose-dependent manner. ConclusionsThese results collectively demonstrated that TLSWE-8510 suppressed mast cell degranulation by inhibiting the release of chemical mediators related to allergies. TLSWE-8510 downregulated the allergy-related cytokines and chemokines expression and phosphorylation of downstream signaling molecules in IgE/BSA-stimulated BMCMCs. Furthermore, in vivo studies with IgE-mediated PCA reaction in the BALB/c mice ears were attenuated by TLSWE-8510 treatment. These findings revealed that TLSWE-8510 has the potential as a therapeutic agent for the treatment of allergic diseases.

The Effect of Levagen+ (Palmitoylethanolamide) Supplementation on Symptoms of Allergic Rhinitis—A Double-Blind Placebo-Controlled Trial

Background: Allergic rhinitis (AR) is an inflammatory, symptomatic disorder stimulated by antigen-specific immunoglobulin E inflammation in response to allergens. Current treatments include the use of corticosteroids and antihistamines to reduce inflammation by preventing histamine release. Palmitoylethanolamide (PEA) is reported to be an alternative treatment, shown to downregulate mast cell activation and increase the synthesis of endocannabinoid 2-Arachidonoylglycerol to reduce histamine and the symptoms of AR. Method: A double-blind, randomised, placebo-controlled clinical trial in which 108 participants presenting with seasonal AR were supplemented with either 350 mg of PEA (Levagen+) or a placebo daily for two weeks. Symptom scores were recorded using the reflective total nasal symptom score (rTNSS) twice a day (morning and evening) for the two weeks, and blood was taken at baseline and week 2. Results: 101 participants completed the study with no baseline group differences. No significant difference was seen between groups for allergy symptoms scores (rTNSS) throughout the 14 days of treatment. A sub-group analysis of participants scoring over four (mild-to-moderate) on the total rTNSS at baseline showed that Levagen+ significantly reduced scores compared to the placebo group. Only 36 participants had full sets of blood taken due to COVID-19. The pathology results showed a significant difference in change from baseline between groups. The Levagen+ group had a significant decrease from baseline in histamine, IL-4, IL-8, IL-10, and TNF-α. The placebo group only had a reduction in IL-4. Conclusion: The results of this study show that Levagen+ can alleviate AR symptoms, resulting in a reduction in histamine and inflammatory markers.

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 &amp;gt;=30% drop in mean arterial blood pressure. Results:Guinea pigs pretreated with 4 mg/kg rhDAO_mHBM showed lower mean heart rate (p&amp;lt;0.01) and higher body core temperatures at the end of the intravenous histamine infusions compared to controls (p&amp;lt;0.05). Histamine infusions increased median urinary excretion of histamine and N-methyl-histamine 8.6- and 4.0-fold (p&amp;lt;0.05), respectively. Pretreatment with 4 mg/kg rhDAO_mHBM reduced urinary histamine (p&amp;lt;0.01) and N-methyl-histamine (p&amp;lt;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&amp;lt;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&amp;lt;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.

Eucalyptus torquata L. flowers: a comprehensive study reporting their metabolites profiling and anti-gouty arthritis potential

Gouty arthritis is one of the most common metabolic disorders affecting people. Plant based drugs can lower the risk of this health disorder. The anti-gouty potential of Eucalyptus torquata flowers methanol extract (ETME) was evaluated in vitro via measuring the inhibitory effects of five pro-inflammatory enzymes; xanthine oxidase (XO), hyaluronidase, lipoxygenase (5-LOX), cyclooxygenases COX-1, and COX-2, in addition to evaluating the inhibition of histamine release, albumin denaturation, membrane stabilization, tyrosinase, and protease inhibitory activities. Also, its antioxidant potential was determined using 2,2-diphenyl-1-picrylhydrazyl (DPPH), 2,2′-Azino-bis(3-ethylbenzothiazoline-6-sulfonic acid (ABTS) radical scavenging assays and ferric reducing power assay (FRAP). HPLC–PDA-MS/MS was used to identify the metabolites in the tested extract. The latter exhibited substantial anti-arthritic properties in all assays with comparable potential to the corresponding reference drugs. HPLC–MS/MS analysis of this bioactive extract tentatively annotated 46 metabolites including phloroglucinols, gallic and ellagic acids derivatives, terpenes, flavonoids, fatty acids, and miscellaneous metabolites. Our study highlights the medicinal importance of E. torquata as an anti-gouty candidate and opens new avenues of gouty management.

Adiponectin in the mammalian host influences ticks' acquisition of the Lyme disease pathogen Borrelia.

Arthropod-borne pathogens cause some of the most important human and animal infectious diseases. Many vectors acquire or transmit pathogens through the process of blood feeding. Here, we report adiponectin, the most abundant adipocyte-derived hormone circulating in human blood, directly or indirectly inhibits acquisition of the Lyme disease agent, Borrelia burgdorferi, by Ixodes scapularis ticks. Rather than altering tick feeding or spirochete viability, adiponectin or its associated factors induces host histamine release when the tick feeds, which leads to vascular leakage, infiltration of neutrophils and macrophages, and inflammation at the bite site. Consistent with this, adiponectin-deficient mice have diminished pro-inflammatory responses, including interleukin (IL)-12 and IL-1β, following a tick bite, compared with wild-type animals. All these factors mediated by adiponectin or associated factors influence B. burgdorferi survival at the tick bite site. These results suggest a host adipocyte-derived hormone modulates pathogen acquisition by a blood-feeding arthropod.

A shift of paradigm: From avoiding nanoparticular complement activation in the field of nanomedicines to its exploitation in the context of vaccine development

The complement system plays a central role in our innate immunity to fight pathogenic microorganisms, foreign and altered cells, or any modified molecule. Consequences of complement activation include cell lysis, release of histamines, and opsonization of foreign structures in preparation for phagocytosis. Because nanoparticles interact with the immune system in various ways and can massively activate the complement system due to their virus-mimetic size and foreign texture, detrimental side effects have been described after administration like pro-inflammatory responses, inflammation, mild to severe anaphylactic crisis and potentially complement activated-related pseudoallergy (CARPA). Therefore, application of nanotherapeutics has sometimes been observed with restraint, and avoiding or even suppressing complement activation has been of utmost priority. In contrast, in the field of vaccine development, particularly protein-based immunogens that are attached to the surface of nanoparticles, may profit from complement activation regarding breadth and potency of immune response. Improved transport to the regional lymph nodes, enhanced antigen uptake and presentation, as well as beneficial effects on immune cells like B-, T- and follicular dendritic cells may be exploited by strategic nanoparticle design aimed to activate the complement system. However, a shift of paradigm regarding complement activation by nanoparticular vaccines can only be achieved if these beneficial effects are accurately elicited and overshooting effects avoided.

Enzyme-linked immunosorbent assay and immunohistochemical analysis of mast cell related biochemicals in oral submucous fibrosis

Oral submucous fibrosis (OSMF), a potentially malignant disorder, is developed by progressive fibrous tissue deposition in connective tissue along with atrophy of oral mucosa. Histological sections also show the mast cell infiltration in submucosa which may indicate their possible role in this entity. Abundant availability of biochemicals in mast cells like histamine and serine proteases like chymase may be released and play specific pathways in the disease pathophysiology. Possibly, if the histamine release has some part to play, diamine oxidase may also be found to have a relationship as it metabolizes histamine. The present study is proposed to identify the presence of chymase, histamine, and diamine oxidase in both, serum as well as tissue by enzyme-linked immunosorbent assay (ELISA) and immunohistochemistry (IHC) respectively. This study may provide probable insight into the mast cell-related chemicals and their association with OSMF.