Search Results (183)

This narrative review explains the history of anaphylactic or hypersensitivity reactions, their connection to the cardiovascular system, and Kounis syndrome, which is linked to hypersensitivity. Additional subjects discussed include immunoglobulin E and serum tryptase, common pathways of allergic and nonallergic cardiovascular events, current perspectives on Kounis syndrome, allergic myocardial infarction, allergic angina, and the impact of COVID-19 and its vaccination on Kounis syndrome. Kounis syndrome is a distinct kind of acute vascular disease that affects the coronary, cerebral, mesenteric, peripheral, and venous systems. Kounis syndrome is currently used to describe coronary symptoms linked to disorders involving mast cell activation and inflammatory cell interactions, such as those involving T-lymphocytes and macrophages, which further induce allergic, hypersensitive, anaphylactic, or anaphylactic insults. Platelet activating factor, histamine, neutral proteases like tryptase and chymase, arachidonic acid products, and a range of cytokines and chemokines released during the activation process are among the inflammatory mediators that cause it. Proinflammatory cytokines are primarily produced by mast cells in COVID-19 infections. Mast cell-derived proteases and eosinophil-associated mediators are also more prevalent in the lung tissues and sera of COVID-19 patients. As a modern global threat to civilization, COVID-19 is linked to chemical patterns that can activate mast cells; therefore, allergic stimuli are usually the reason. Virus-associated molecular patterns can activate mast cells, but allergic triggers are typically the cause. By activating SARS-CoV-2 and other toll-like receptors, a variety of proinflammatory mediators, including IL-6 and IL-1β, are released, potentially contributing to the pathology of COVID-19. Full article

Microglia, the brain’s resident innate immune cells, play a fundamental role in maintaining neural homeostasis and mediating responses to injury or infection. Upon activation, microglia undergo morphological and functional changes, including phenotypic switching between pro- and anti-inflammatory types and the release of different inflammatory mediators. These processes contribute to neuroprotection and the pathogenesis of various central nervous system (CNS) disorders. Mast cells, although sparsely located in the brain, exert a significant influence on neuroinflammation through their interactions with microglia. Through degranulation and secretion of different mediators, mast cells disrupt the blood–brain barrier and modulate microglial responses, including alteration of microglial phenotypes. Notably, mast cell-derived factors, such as histamine, interleukins, and tryptase, activate microglia through various pathways including protease-activated receptor 2 and purinergic receptors. These interactions amplify inflammatory cascades via various signaling pathways. Previous studies have revealed an exceedingly complex crosstalk between mast cells and microglia suggesting a bidirectional regulation of CNS immunity, implicating their cooperation in both neurodegenerative progression and repair mechanisms. Here, we review some of the diverse communication pathways involved in this complex interplay. Understanding this crosstalk may offer novel insights into the cellular dynamics of neuroinflammation and highlight potential therapeutic targets for a variety of CNS disorders. Full article

Specific venom immunotherapy (VIT) in patients with hymenoptera venom allergy (HVA) represents a well-studied approach to reduce the severity of a possible anaphylactic reaction. Currently, data on mechanisms of tolerance induction at the cellular level within the first hours of therapy are lacking. To address this, total and unoccupied high-affinity IgE receptor (FcεRI) numbers per basophil, soluble FcεRI (sFcεRI) and serum tryptase levels were measured before and after the first day of VIT induction in HVA patients. Additionally, basophil activation tests (BATs) were performed at those time points. In the early phase of VIT induction, no significant change in total FcεRI receptor density on basophils was observed, but a significant increase in unoccupied FcεRI was noticeable, predominantly in patients with high total IgE and low baseline unoccupied FcεRI density. No meaningful difference in serum tryptase levels or sFcεRI levels was observed after VIT induction. BATs showed heterogeneous results, often unchanged before and after VIT (in 47% of the cases), sometimes increased (in 40%) and only rarely decreased EC₅₀ sensitivity (in 13%). Changes in the BAT EC₅₀ correlated with FcεRI receptor density changes in basophils. In summary, VIT induction led to an increased ratio of unoccupied-to-total FcεRI without notable tryptase or sFcεRI serum elevation, pointing towards subthreshold cell activation with receptor internalization and recycling. However, the mostly unchanged or even increased basophil sensitivity in EC₅₀ calls for further research to clarify the clinical relevance of these rapid receptor modulations. Full article

Background: Patients with mastocytosis may present with exacerbated respiratory symptoms and lung diseases resulting from mast cell mediator release. However, their prevalence and severity level remain under debate. The study aims to analyze the prevalence of respiratory symptoms and the usefulness of lung function tests like spirometry, diffusing capacity of the lung for carbon monoxide (DLCO), and high-resolution computed tomography (HRCT) of the chest in mastocytosis patients presenting with dyspnea, cough, and exercise intolerance. Methods: We included 104 patients with mastocytosis and 71 healthy controls. Data collection encompassed patient interview, clinical examination, spirometry, DLCO, and chest HRCT. Diagnosis of mastocytosis included bone marrow biopsies and serum tryptase measurements. Results: Compared to controls, patients with mastocytosis exhibited significantly lower values in FEV1/VC ratio, absolute DLCO/VA, predicted DLCO/VA, absolute DLCOcSB, and predicted DLCOcSB (p < 0.001). Commonly reported respiratory symptoms included dyspnea (36.5%), chest tightness (22.1%), and wheezing (9.6%). Airway obstruction was identified in 7.7% of patients; however, it appeared to be independent of the mastocytosis subtype. A decreased DLCO/VA ratio was observed in 4.8% of patients, but HRCT did not reveal any evidence of underlying lung disease. Conclusions: Mastocytosis appears to be a risk factor for the occurrence and exacerbation of respiratory symptoms. However, airway obstruction and impairment of the alveolar–capillary membrane seem to occur independently of the clinical subtype of mastocytosis. Additionally, the causal relationship between pulmonary involvement, mast cell infiltration of the alveolar–capillary membrane, and the systemic circulation of mast cell mediators remains unclear and requires further research. Full article

Metabolic dysfunction-associated steatotic liver disease (MASLD) has recently become the leading cause of chronic liver disease and can progress to hepatocellular carcinoma (HCC) through multiple pathogenic mechanisms. Protease-activated receptor 2 (PAR2) is a G-protein-coupled receptor activated by proteases such as trypsin, tryptase or coagulation factors VII and Xa. Recent studies have shown that PAR2 expression is increased in the liver of patients with MASLD or liver fibrosis. Its activation is linked to metabolic dysfunction through several pathways, including SREBP1c activation, AMPK inhibition and Akt-induced insulin resistance. Inhibition of PAR2 has been effective in reducing MASLD progression in different animal models. Notably, PAR2 blockade has also been effective in more advanced stages of the disease by dampening chronic inflammation and fibrogenesis through the inhibition of hepatic stellate cell activation and of TGF-β and SerpinB3 production. PAR2 also plays a role in cancer development, promoting tumour proliferation, angiogenesis and expression of immune checkpoint inhibitors (like PD-L1, CD47 and CD24). Due to its multifaceted involvement in liver disease, PAR2 is emerging as a key therapeutic target in this clinical context. This review aims to summarise current knowledge on PAR2′s role in MASLD and its potential as a therapeutic target. Full article

The incidence of fatal anaphylaxis is increasing, but there is still no recognized “golden standard” for forensic diagnosis. Due to its non-specific symptoms, especially cardiovascular symptoms without cutaneous changes, it can easily be misdiagnosed as acute myocardial infarction. Here, we established rat models (n = 12) of fatal anaphylaxis (FA), acute myocardial infarction (AMI), and coronary atherosclerosis with anaphylaxis (CAA). The untargeted metabolomics of plasma and 16S rRNA sequencing of fecal matter was performed, and a random forest was used to identify potential biomarkers. Three metabolites (tryptophan, trans-3-indole acrylic acid, and imidazole acetic acid) and three microbial genera (g_Prevotellaceae_Ga6A1_group, g_UCG_008, and g_Eubacterium_hallii_group) were identified as potential biomarkers for distinguishing anaphylaxis and non-anaphylaxis. The classification model of plasma metabolites showed a much better discriminatory performance than that of microbial genus, serum IgE, and tryptase. The performance of the microbial genera was superior to the serum IgE but inferior to the serum tryptase. Forensic samples of fatal anaphylaxis and non-anaphylaxis deaths (n = 12) were collected for untargeted metabolomics detection. The results showed that among the three identified metabolic biomarkers, tryptophan has better stability in cadaveric blood samples. Its diagnostic performance (AUC = 87.1528) was superior to serum IgE and tryptase, making it more suitable as a postmortem biomarker of fatal anaphylaxis. Full article

Hereditary α-tryptasemia (HαT)—a genetic trait caused by increased α-tryptase-encoding typtase alpha/beta-1 (TPSAB1) copy number—is associated with adult mastocytosis. The primary objective was to assess the association between α-tryptase and pediatric mastocytosis. We also want to evaluate whether the KIT p.D816V mutation in peripheral blood leukocytes (PBLs) reliably predicts systemic mastocytosis (SM) in children. A prospective cohort of 68 children from a referral center in Slovenia with cutaneous mastocytosis (CM) underwent tryptase genotyping by droplet digital PCR and examination for KIT p.D816V in PBL using a sensitive PCR test. A significant majority of patients (57 of 68; [83.8%]) had at least one α-tryptase-encoding gene; none had HαT. 7 of the 68 (10.3%) who were positive for KIT p.D816V in PBL, one fulfilled diagnostic criteria for indolent SM, and another was diagnosed with monoclonal mast cell activation syndrome. One of those individuals had an increased basal serum tryptase (BST) level (14.5 ng/mL). We found a high presence of germline α-tryptase in children with CM, but not HαT. By employing sensitive examination for KIT p.D816V in PBL, in combination with clinical data and other examinations, our study suggests that KIT p.D816V in PBL may indicate systemic disease in children with CM. Full article

Background: Irritable bowel syndrome (IBS) significantly impairs the lifestyle and quality of life of the global population. However, the underlying pathophysiological mechanisms remain largely elusive. While conventional pharmacological approaches show limited therapeutic efficacy, emerging microbiota-targeted dietary interventions present promising alternatives. Objectives: The present study aimed to elucidate the molecular mechanisms by which a synbiotic mitigates IBS and associated colonic dysfunctions in C57BL/6 mice. Methods: The mouse model was induced by a Citrobacter rodentium (C. rodentium) infection combined with water avoidance stress (WAS). Galacto-oligosaccharides (GOS) were identified as the optimal carbon source for the growth of Lactobacillus plantarum ZYC501 (L. plantarum ZYC501), leading to the establishment of the synbiotic formulation. Results: The 32-day synbiotic intervention, consisting of L. plantarum ZYC501 (1 × 10⁹ CFU/day) and GOS (10 g/L, w/w), significantly alleviated colonic transit dysfunction, visceral hypersensitivity, and anxiety-like behaviors in IBS mice. The synbiotic treatment significantly inhibited the expression levels of histamine, mast cell tryptase, and prostaglandin E2 (PGE2) (p < 0.05). The synbiotic also suppressed colonic inflammation by reducing the levels of lipopolysaccharide (LPS), TNF-α, and IL-6 (p < 0.05). Moreover, the synbiotic increased the expression of MUC2 and the production of short-chain fatty acids (SCFAs), including acetate, propionate, and butyrate (p < 0.05). In terms of gut microbiota modulation, the synbiotic reshaped the gut microbiota composition, increasing the abundance of Lactobacillus and Akkermansia while decreasing the levels of Helicobacter and Saccharibacteria. Correlation analysis further revealed a strong association among SCFAs, colonic inflammation, and the gut microbiota. Conclusions: In conclusion, the synbiotic composed of L. plantarum ZYC501 and GOS effectively alleviates IBS and associated colonic dysfunctions by modulating the gut microbiota, reducing mast cell hyperactivity, and enhancing colonic barrier integrity. These findings provide a theoretical basis for developing gut microbiota-targeted dietary interventions for the management of IBS and improvement in gut health. Full article

Hypertension-induced cardiac remodeling is a complex process driven by interconnected molecular and cellular mechanisms that culminate in hypertensive myocardium, characterized by ventricular hypertrophy, fibrosis, impaired angiogenesis, and myocardial dysfunction. This review discusses the histomorphometric changes in capillary density, fibrosis, and mast cells in the hypertensive myocardium and delves into the roles of key regulatory systems, including the apelinergic system, vascular endothelial growth factor (VEGF)/VEGF receptor (VEGFR) pathways, and nitric oxide (NO)/nitric oxide synthase (NOS) signaling in the pathogenesis of hypertensive heart disease (HHD). Capillary rarefaction, a hallmark of HHD, contributes to myocardial ischemia and fibrosis, underscoring the importance of maintaining vascular integrity. Targeting capillary density (CD) through antihypertensive therapy or angiogenic interventions could significantly improve cardiac outcomes. Myocardial fibrosis, mediated by excessive collagen deposition and influenced by fibroblast growth factor-2 (FGF-2) and transforming growth factor-beta (TGF-β), plays a pivotal role in the structural remodeling of hypertensive myocardium. While renin–angiotensin–aldosterone system (RAAS) inhibitors show anti-fibrotic effects, more targeted therapies are needed to address fibrosis directly. Mast cells, though less studied in humans, emerge as critical regulators of cardiac remodeling through their release of pro-fibrotic mediators such as histamine, tryptase, and FGF-2. The apelinergic system emerges as a promising therapeutic target due to its vasodilatory, anti-fibrotic, and cardioprotective properties. The system counteracts the deleterious effects of the RAAS and has demonstrated efficacy in preclinical models of hypertension-induced cardiac damage. Despite its potential, human studies on apelin analogs remain limited, warranting further exploration to evaluate their clinical utility. VEGF signaling plays a dual role, facilitating angiogenesis and compensatory remodeling during the early stages of arterial hypertension (AH) but contributing to maladaptive changes when dysregulated. Modulating VEGF signaling through exercise or pharmacological interventions has shown promise in improving CD and mitigating hypertensive cardiac damage. However, VEGF inhibitors, commonly used in oncology, can exacerbate AH and endothelial dysfunction, highlighting the need for therapeutic caution. The NO/NOS pathway is essential for vascular homeostasis and the prevention of oxidative stress. Dysregulation of this pathway, particularly endothelial NOS (eNOS) uncoupling and inducible NOS (iNOS) overexpression, leads to endothelial dysfunction and nitrosative stress in hypertensive myocardium. Strategies to restore NO bioavailability, such as tetrahydrobiopterin (BH₄) supplementation and antioxidants, hold potential for therapeutic application but require further validation. Future studies should adopt a multidisciplinary approach to integrate molecular insights with clinical applications, paving the way for more personalized and effective treatments for HHD. Addressing these challenges will not only enhance the understanding of hypertensive myocardium but also improve patient outcomes and quality of life. Full article

Tryptase, which is abundant in human mast cells and is involved in allergic inflammations such as asthma, is a serine protease. We isolated a tryptase inhibitor, procyanidin B8 3,3′-di-O-gallate (PB8GG’), a tannin, from the methanol extract of rhubarb (RHEI RHIDOMA), which is a traditional Chinese medicine (Kampo medicine in Japan). Since it did not inhibit another serine protease trypsin, PB8GG’ specifically inhibited tryptase. A standard kinetic analysis of the inhibitory fashion of PB8GG’ against tryptase suggested that PB8GG’ inhibited tryptase in an allosteric manner. We searched for other tannins like PB8GG’ expected to bind tryptase using AutoDock vina. Two ellagitannins, carpinins B and E, isolated from young leaves of Carpinus japonica were selected as candidates of tryptase inhibitors. Carpinins B and E themselves had almost no inhibitory activity against tryptase but enhanced the inhibitory activity of PB8GG’ against tryptase. This is an example that shows that a combination of an allosteric inhibitor with other compounds that bind but have no inhibitory activity can be used to develop a clinically useful combinatorial enzyme inhibitor. Full article

Tryptase is a tetrameric serine protease and a key component of mast cell granules. Here, we explored an integrated approach to characterize tryptase ligands, combining novel experimental binding studies using Surface Plasmon Resonance, with in silico analysis through the Exscalate platform. For this, we focused on three inhibitors previously reported in the literature, including a bivalent inhibitor and its corresponding monovalent compound. All three ligands showed concentration-dependent binding to immobilized human tryptase with the bivalent inhibitor showing the highest affinity. Furthermore, Rmax values were similar, indicating that the compounds occupy all four binding pockets of the tryptase tetramer. This hypothesis was supported by in silico computational analysis that revealed the binding mode of the monovalent ligand, one in each monomer pocket, compared with crystal structure of the bivalent one, which simultaneously occupies two binding pockets. Additionally, we solved the 2.06 Å X-ray crystal structures of human Tryptase beta-2 (hTPSB2), in both its apo form and in complex with compound #1, experimentally confirming the binding mode and the key molecular interactions predicted by docking studies for this compound. This integrated approach offers a robust framework for elucidating both the strength and mode of interaction of potential tryptase inhibitors. Full article

Background/Objectives: Kinase inhibition is a hot therapeutic strategy for several human diseases, including neurodegeneration. Tyrosine kinase c-KIT activates peripheral mast cells, while other kinases including Abelson (c-Abl) promotes autophagy and FYN mediates Tau phosphorylation. We synthesized a novel broad kinase inhibitor (BK40196) and investigated its effects on tau hyper-phosphorylation, cell loss, inflammation and behavior in transgenic rTg4510 and TgAPP (TgSwDI) mice. Methods: Drug synthesis and investigation of the pharmacokinetics and pharmacodynamics effects of BK40196 on behavior, protein levels, mast cells and microglial activity in vivo. Results: We synthesized a novel kinase inhibitor (BK40196) that exhibited high brain penetration and a potentially wide therapeutic dose. BK40196 is a dual c-KIT/c-Abl (Abelson) inhibitor but also displays binding affinity to other kinases, including fused in sarcoma (SRC) and FYN. BK40196 induces autophagy in vitro and limits the maturation of mast cells in vitro and in vivo. BK40196 significantly reduces the levels of hyper-phosphorylated tau and attenuates cell loss, while improving motor, cognitive and behavioral (anxiety) functions in models of neurodegeneration. BK40196 reduces microglial activity and the levels of brain tryptase in parallel with mast cell activation. Conclusions: BK40196 inhibits c-Kit and may play an important role in peripheral and central immunity via mast cells and microglia, respectively, and induces synergistic mechanisms through anti-inflammation and protein clearance that are mutually beneficial to alleviate neurodegenerative pathology. BK40196 is a potential candidate for the treatment of human tauopathies. Full article

Mastocytosis is a rare neoplastic disease of the bone marrow. Common symptoms like urticaria, diarrhea, bronchspasm and flushing are caused by mast cell degranulation and are mostly based on mast cell mediator release and Th2 type inflammation that occurs frequently in these patients. Psychological disorders are more prevalent in patients with systemic mastocytosis, though little is known about the mechanism behind this. The aim of the study was to investigate the Th2 cytokine (IL-4, TSLP, IL-31 and IL-33) profile in patients with mastocytosis in relation to classic degranulation symptoms and the psychometric measures of cognition and distress symptoms.In total, 115 patients diagnosed with mastocytosis were enrolled. Mini-Mental State Examination (MMSE) was performed for all subjects. Other variables: Quality of life in mastocytosis, a mood assessment commonly used in systemic mastocytosis by a certified rater—the Hamilton-17 Depression Scale, Pruritus Visual Analog Score, serum tryptase concentration and bone marrow biopsy results (archival) were also analyzed/included. Serum concentrations of IL-4, TSLP, IL-33 and IL-31 were analyzed as primary outcomes. For comparison with continuous variables linear regression was used. The mean MMSE result was 27.9. Regression analysis did not reveal significant correlation between the IL-4 (p = 0.82), IL-31 (p = 0.24) and TSLP (p = 0.37) serum concentrations and MMSE. The IL-33 concentration analysis resulted in 0 for all patients (was not detected). No significant effect was observed with other endpoints as well. One in four patients with mastocytosis presents cognitive decline. This impairment does not correlate with Il-4, TSLP, nor IL-31 serum protein concentrations. Full article

Bilio-biliary anastomosis (BBA) is a critical surgical procedure that is performed with the objective of restoring bile duct continuity. This procedure is often required in cases where there has been an injury to the extrahepatic bile ducts or during liver transplantation. Despite advances in surgical techniques, the healing of BBA remains a significant challenge, with complications such as stricture formation and leakage affecting patient outcomes. The stromal vascular fraction (SVF), a heterogeneous cell population derived from adipose tissue, has demonstrated promise in regenerative medicine due to its rich content of stem cells, endothelial progenitor cells, and growth factors. The objective of this study was to evaluate the potential of locally administered autologous SVF to enhance the healing of BBAs. Bilio-biliary anastomosis was performed on a swine model (female Landrace pigs). Six swine were divided into two groups: the treatment group (n = 3) received a local application of autologous SVF around the anastomosis site immediately following BBA formation, while the control group (n = 3) received saline. The primary outcomes were assessed over an eight-week period post-surgery, and included anastomosis healing, stricture formation, and bile leakage. Histological analysis was performed to evaluate fibrosis, angiogenesis, and inflammation. Immunohistochemistry was conducted to assess healing-related markers (CD34, α-SMA) and the immunological microenvironment (CD3, CD10, tryptase). The SVF-treated group exhibited significantly enhanced healing of the BBA. Histological examination revealed increased angiogenesis and reduced fibrosis in the SVF group. Immunohistochemical staining demonstrated higher vascular density in the anastomosed area of the SVF-treated group (390 vs. 210 vessels per 1 mm², p = 0.0027), as well as a decrease in wall thickness (1.9 vs. 1.0 mm, p = 0.0014). There were no statistically significant differences in mast cell presence (p = 0.40). Immunohistochemical staining confirmed the overexpression of markers associated with tissue repair. Local injections of autologous SVF at the site of BBA have been demonstrated to significantly enhance healing and promote tissue regeneration. These findings suggest that SVF could be a valuable adjunctive therapy in BBA surgery, potentially improving surgical outcomes. However, further investigation is needed to explore the clinical applicability and long-term benefits of this novel approach in clinical practice as a minimally manipulated cell application. Full article

This study explored the anti-pruritic and immunomodulatory effects of Coix sprouts extract, focusing on histamine release and IL-31 cytokine production in HMC-1 cells. The extract significantly inhibited both factors, indicating its potential for pruritus relief. In a pruritus induction mouse model, Coix sprouts extract outperformed prednisolone in anti-pruritus effectiveness, also improving skin lesions and inhibiting mast cell infiltration. The extract suppressed tryptase expression, reduced release, inhibited mast cell proliferation, and lowered nitric oxide production, suggesting anti-inflammatory properties. Coix sprouts extract shows promise in suppressing inflammation and pruritus, making it a valuable candidate for clinical use. Additionally, the analysis of coixol content in Coix sprouts revealed variations in growth time, indicating their potential as functional materials with anti-pruritus and immune-enhancing applications. Full article