Mast Cell Activation Research Articles

Biotinylated Heptapeptides with D-amino Acids Suppress Allergic Reactions by Inhibiting Mast Cell Activation and Antagonizing the Histamine Receptor

Biotinylated Heptapeptides with D-amino Acids Suppress Allergic Reactions by Inhibiting Mast Cell Activation and Antagonizing the Histamine Receptor

The importance of mast cell histamine secretion in IgG-mediated systemic anaphylaxis.

IgG can mediate murine and human systemic anaphylaxis (SA). The roles of mast cells (MCs) and histamine in IgG-mediated anaphylaxis are controversial for mice and have not been studied in vivo for humans. We now investigate these issues. Actively or passively sensitized wild-type and immune-deficient mice were induced to develop anaphylaxis by i.v. antigen challenge. Anaphylaxis was characterized by evaluating hypothermia, hypomobility, histamine, and mast cell protease responses. In contrast to our previous results with protein-immunized mice from a conventional colony, IgG-mediated passive SA in our SPF colony mice depended considerably on histamine produced by connective tissue MCs (CTMCs) in response to FcγRIII crosslinking. This was found for C57BL/6 and young male and female BALB/c mice, including BALB/c mice freshly arrived from 3 vendors. IgG-mediated anaphylaxis was less histamine-dependent in old than young mice. Although both mucosal MC (MMC) and CTMC responses were severely depleted in c-kit-deficient mice, MMC responses depended considerably more than CTMC responses on c-kit for maintenance. In immunologically naïve mice, FcγRIII crosslinking strongly activated a subset of CTMCs, but had little ability to activate MMCs. In vivo LPS + poly I.C treatment decreased histamine-dependence of IgG-mediated anaphylaxis while a strong Th2 immune response increased FcγRIII crosslinking-induced MMC activation. IgG-mediated activation of human MCs in reconstituted immunodeficient mice induced histamine-dependent anaphylaxis. IgG-dependent SA can be mediated largely by histamine released by mouse CTMCs and human MCs; histamine dependence is influenced by mouse age, sex, immune and infectious history, and the anaphylaxis model studied.

Biomarkers in the diagnosis of mast cell activation

Purpose of review Mast cell activation is defined by activation of mast cells by varying stimuli with release of chemical mediators either through degranulation or release of de novo synthesized proteins or lipid mediators. Currently, tryptase measurement increase during symptomatic episodes is the most accepted biomarker measurement for mast cell activation. However, newer diagnostic tools including clinically available urinary mast cell mediators are noninvasive and can be more readily obtained compared to serum tryptase levels. This review will highlight biomarker measurement in the diagnosis of mast cell activation. Recent findings This review will highlight biomarker measurement in mast cell activation including serum tryptase and urinary mast cell mediators including N-methylhistamine, leukotriene E4, and 2,3-dinor-11beta-prostaglandin F2 alpha. Summary Urine mast cell mediators obtained at baseline and during symptom exacerbation are emerging biomarkers in the diagnosis of mast cell activation. Tryptase measurement and urinary mast cell mediator measurement are currently the most accepted biomarkers for mast cell activation. Further research is needed to establish new biomarkers for mast cell activation.

Association between immune cells and urticaria: a bidirectional Mendelian randomization study

Urticaria is characterized by transient itchy symptoms on the skin, usually accompanied by swelling, which is caused by mast cell activation leading to increased vascular permeability and dilation of the dermis. Urticaria involves recurrent activation of mast cells, T cells, eosinophils, and other immune cells around lesioned venules, with complex regulatory systems affecting mast cell functions, potentially contributing to urticaria pathogenesis. The direct causal relationship between immune cells and urticaria is currently unclear. To address this, our study utilized a bidirectional Mendelian randomization analysis, employing instrumental variables (IVs) associated with immune cells and urticaria, to investigate this causal relationship. First, by utilizing Genome-wide Association Study (GWAS) data, we identified 31 immunophenotypes associated with urticaria risk, with 18 increasing and 13 decreasing the risk. Through rigorous criteria, we identified 4 immunophenotypes that have a strong causal relationship with urticaria. Notably, HLA DR+ CD4+AC, CD45 on CD8br, and HLA DR on plasmacytoid dendritic cells were associated with an increased risk, while CD8dim NKT %lymphocyte was identified as a protective factor. Sensitivity analyses, including the MR-Egger intercept test, scatter plots, funnel plots, and leave-one-out analysis, supported the robustness of the findings. Reverse MR analysis suggested an inverse causal effect of urticaria on CD8dim NKT %lymphocyte, reinforcing the potential bidirectional nature of the relationship between urticaria and immune cell phenotypes. Our research substantiates the bidirectional causal relationship between immune cells and urticaria, thus benefiting for urticaria-targeted therapy development.

Role of Platelet-Activating Factor in the Pathogenesis of Chronic Spontaneous Urticaria

Chronic spontaneous urticaria (CSU) is a debilitating condition characterized by mast cell activation. Platelet-activating factor (PAF) is produced by various immune cells, including mast cells, basophils, lymphocytes, and eosinophils, which play crucial roles in CSU pathogenesis. It induces mast cell degranulation, increases vascular permeability, and promotes the chemotaxis of inflammatory cells. These effects result in the release of inflammatory mediators, the development of edema, and the persistence of inflammation, which are key features of CSU. Notably, elevated PAF levels have been linked to heightened disease activity and resistance to antihistamine treatment in CSU patients. Despite these findings, the precise role of PAF in CSU pathogenesis remains unclear. Rupatadine, an antihistamine, and heat shock protein 10, a natural anti-inflammatory peptide that selectively inhibits PAF-induced mast cell degranulation, have demonstrated anti-PAF activity. Furthermore, with the molecular structure of the PAF receptor now identified, several experimental PAF receptor antagonists have been synthesized. However, there remains a significant need for the development of therapeutic options targeting PAF in CSU management.

Prevalence of Autoantibodies in patients with Hereditary Alpha Tryptasemia.

Hereditary alpha-tryptasemia (HT) is associated with postural orthostatic tachycardic syndrome (POTS), hypermobile Ehlers Danlos Syndrome (hEDS), and mast cell activation syndrome (MCAS). While POTS, hEDS and MCAS have all demonstrated increased prevalence of autoimmunity, this has not been investigated in HT populations. Our objective was to describe the prevalence of autoantibodies in individuals with HT. We retrospectively studied a cohort of patients with positive genotyping for HT at a tertiary care allergy clinic. Demographic data including previous autoimmune history and autoantibody serologies were extracted on chart review. A literature search was conducted to determine the prevalence of specific autoimmune and autoantibody prevalences in the general population. We compared the proportions of autoantibody positivity and established autoimmune diseases in our cohort of HT individuals against those in general populations. We identified 101 patients with HT. Median age was 43 years (range 15-75) and most were female (87/101; 86.1%). Prevalence of self-reported drug hypersensitivity was 52/101 (52.5%) patients. The proportion of individuals with HT with positive tTG antibody (3/61, 4.9%) was significantly higher than that reported in the general population (133/16667, 0.8%) (p<0.001). The prevalence of SLE (1/101, 1%) and celiac disease (5/101, 5%) in our cohort were found to be significantly higher than the prevalence in the general population [194/96996, 0.2% (p=0.035) and 26/2845, 0.9% (p<0.001), respectively]. Patients with HT have increased prevalence of celiac disease, SLE and positive anti-tTG serology as well as self-reported drug hypersensitivity, relative to general populations.

Berberine ameliorates inflammation by inhibiting MrgprB2 receptor-mediated activation of mast cell in mice

BackgroundBerberine, an isoquinoline alkaloid, is known for anti-inflammatory activities. However, the research on the anti-inflammatory mechanism of berberine is not comprehensive. Recently, studies have shown that MrgprB2 (Mas-related G-protein-coupled receptor B2) in mice and MrgprX2 (Mas-related G-protein-coupled receptor X2) in humans play vital roles in inflammation. Therefore, this study aims to investigate whether the anti-inflammatory activity of berberine is related to MrgprB2 receptor. MethodsThe anti-inflammatory activity of BH (berberine hydrochloride) was evaluated by hindpaw edema analysis, pathological analysis and RT-qPCR. Transgenic mice (MrgprB2−/− mice), HEK293T cell transfection, calcium imaging, electrophysiology, molecular docking and other methods were employed to investigate the potential relationship between the anti-inflammatory activity of BH and the MrgprB2 receptor. ResultsThe results demonstrated that BH significantly alleviated C48/80 (compound 48/80)-induced local inflammation in vivo. This was evidenced by a decrease in paw edema, reduced infiltration of inflammatory cells, inhibition of mast cell activation, and down-regulation of inflammatory factors such as CXCL13 (CXC subfamily 13) and TNF-α (tumor necrosis factor-α). It was also found that knockout of MrgprB2 receptor could block the anti-inflammatory activity of BH in mice. Furthermore, calcium imaging revealed that BH effectively inhibited the activity of MrgprB2 receptor in overexpressed HEK293T cells in vitro. Additionally, it was observed that BH also inhibited MrgprB2-mediated voltage-dependent current changes in mouse peritoneal mast cells. Molecular docking results further indicated that BH had affinity with MrgprX2 protein. ConclusionsThe anti-inflammatory mechanism of BH may be partially attributed to the inhibition of MrgprB2 receptor-mediated mast cell activation.

Proposed receptor-mediated mechanisms of melatonin in nitroglycerin-induced migraine-like hyperalgesic conditions in rats

Melatonin has a therapeutic effect on migraine, but the mechanisms underlying its antimigraine effect have not been elucidated. This study therefore investigated for the first time the receptor-mediated mechanisms of action of melatonin in nitroglycerin (NTG)- induced migraine-like hyperalgesic conditions in rats. Melatonin, nonselective MT1/MT2 antagonist luzindole, selective MT2 antagonist DH97 or potent MT3 antagonist prazosin, alone or in various combinations, were administered to NTG-induced migraine rats and ex-vivo meningeal preparations. Basal and drug-treated pain behaviors were assessed with the von-Frey test. CGRP levels in the trigeminal ganglia, trigeminal nucleus caudalis (TNC) and ex-vivo superfusate medium, as well as c-fos level in the TNC, were measured by ELISA. Meningeal mast cells were stained with toluidine-blue and examined histologically for their activation and count. Melatonin mitigated mechanical hyperalgesia, and c-fos and CGRP expression in the TNC, CGRP expression in trigeminal ganglia, CGRP release from meningeal afferents, all of which were induced by NTG, and also suppressed NTG-stimulated meningeal mast cell activation. The effects of melatonin were abolished in the presence of luzindole and DH97, respectively. However, prazosin did not reverse the effects of melatonin except for mechanical hyperalgesia. Luzindole and DH97 in combinations with prazosin also canceled the effects of melatonin, respectively, other than CGRP expression in the TNC. Melatonin exerts its anti-hyperalgesic effects through modulation of trigeminal expression and meningeal release of CGRP, and meningeal mast cell activation in experimental migraine-like conditions. The effects of melatonin are mainly mediated by MT2 receptors, without excluding a possible role for MT1.

Water-avoidance stress aggravates prostatic inflammation in a murine model of chronic prostatitis.

To date, few studies have considered the influence of psychological factors on chronic prostatitis (PRO) models. Here, we aimed to refine a murine PRO model combining chemically induced prostatitis with psychological stress. A total of 40 mice were randomly divided into four groups: normal control (NC) group, PRO group, water avoidance stress (WAS) group, and PRO + WAS group. Ten mice were assigned to each group: five for cystometrograms (CMGs) and five for von Frey testing and histological analysis. PRO was induced through a prostatic injection of 10% paraformaldehyde. The WAS mice were placed on the middle platform for 1 h per day for 10 consecutive days. The results of the von Frey test demonstrated that both WAS and PRO induced bladder hyperalgesia in mice, and the WAS + PRO group showed significant pelvic pain symptoms either. The CMG results suggested that the PRO group, the WAS group, and the PRO + WAS group all exhibited bladder overactivity, presented as a shortened micturition interval and decreased threshold pressure evoking bladder contraction. The symptoms of the PRO group and the PRO + WAS group were more severe than those of the WAS group. The tissue staining results indicated that WAS itself caused only mild prostatic inflammation but could significantly aggravate chemical-induced prostatic inflammation, as well as the total number of mast cells and proportion of activated mast cells. Our refined murine PRO model could manifest persistent bladder overactivity, pelvic hyperalgesia and prostatic inflammation. WAS could induce mild prostatic inflammation and aggravate primary prostatic inflammation.

The role of transforming growth factor-β in lung damage in COVID-19: clinical and diagnostic parallels

BACKGROUND: Coronavirus 2 (SARS-CoV-2), which causes severe acute respiratory syndrome in COVID-19, leads to complex immune reactions, hyperactivation of immunocompetent cells, including increased degranulation activity of mast cells and the release of their secretome products. The SARS-CoV-2 virus and the subsequent strong immune and inflammatory response, as well as a violation of the regulation of coagulation and fibrinolytic pathways, cause massive activation of latent TGF-β in the lungs, as well as the latent pool of TGF-β in the blood of patients with COVID-19. AIMS: To assume the participation of transforming growth factor-β (TGF-β) in lung damage in patients with COVID-19 by determining its quantitative level in autopsy lung samples in patients with COVID-19 and to conduct a correlation analysis with clinical and laboratory parameters. MATERIALS AND METHODS: The study included samples of lung autopsy material obtained from patients who died from severe COVID-19. A correlation analysis of TGF-β-positive cells and clinical and laboratory parameters was also performed. RESULTS: Extensive representation of TGF-β-positive cells was found in lung tissues of patients who died from COVID-19.A negative correlation was revealed: between TGF-β and the content of nucleated neutrophils in the blood (r = - 0,617; p = 0,033); between TGF-β and the level of C-reactive protein (CRP) according to the results of blood biochemistry (r = - 0,491; p = 0,013). A positive correlation was revealed between TGF-β and the content of blood platelets (r = 0,384; p =0,012);TGF-β with the level of erythrocyte sedimentation rate (ESR) (r = 0,409; p = 0,025). A positive correlation was also found between TGF-β and the presence of cough in the patient at the beginning of hospitalization (r = 0,367; p = 0,046). CONCLUSIONS: Activation of TGF-β in the lungs of patients who died from severe COVID-19 correlates with the level of neutrophils, platelets, ESR, CRP and the presence of cough in the patient. Further research is needed on the activation, release of TGF-β and its interactions in larger cohorts of patients. These correlations suggest the negative involvement of the transforming growth factor and consider the therapeutic possibilities of regulatory influence on its activation.

Antidepressant-like Effects of Cannabis sativa L. Extract in an Lipopolysaccharide Model: Modulation of Mast Cell Activation in Deep Cervical Lymph Nodes and Dura Mater.

Lipopolysaccharide (LPS)-induced neuroinflammation is a well-established model for studying depression-like behavior, driven by pro-inflammatory cytokines such as TNF-α and IL-1β. Mast cells (MCs) contribute to neuroinflammation by releasing mediators that exacerbate depressive-like symptoms. This study evaluates the antidepressant-like and anti-inflammatory effects of Cannabis sativa L. inflorescence extract (CSL) in an LPS-induced neuroinflammation model. Male C57BL/6 mice were intraperitoneally injected with CSL at doses of 10, 20, and 30 mg/kg, 30 min prior to LPS (0.83 mg/kg) administration. Depressive behaviors were assessed using the sucrose preference test (SPT), tail suspension test (TST), and forced swimming test (FST). The neutrophil-to-lymphocyte ratio (NLR) was measured to assess systemic inflammation. Cytokine levels in the prefrontal cortex (PFC) were measured, and mast cell degranulation in the lymph nodes and dura mater was analyzed histologically (approval number: WKU24-64). CSL significantly improved depressive-like behaviors and decreased the NLR, indicating reduced systemic inflammation. CSL also significantly reduced TNF-α and IL-1β levels in the PFC. Furthermore, CSL inhibited MC degranulation in the deep cervical lymph nodes and dura mater, with the strongest effects observed at 30 mg/kg. CSL demonstrated antidepressant-like and anti-inflammatory effects in an LPS-induced neuroinflammation model, likely through the modulation of cytokine expression and mast cell activity. These results suggest the potential of CSL as a therapeutic option for treating inflammation-related depression.

Studies of Structure–Activity Relationship of 2-(Pyrrolidin-1ylmethyl)-1H-pyrrole-Based ST2 Inhibitors and Their Inhibition of Mast Cells Activation

Studies of Structure–Activity Relationship of 2-(Pyrrolidin-1ylmethyl)-1<i>H</i>-pyrrole-Based ST2 Inhibitors and Their Inhibition of Mast Cells Activation

Gastrointestinal symptoms in children with mastocytosis

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

Decoding the Genetic Basis of Mast Cell Hypersensitivity and Infection Risk in Hypermobile Ehlers-Danlos Syndrome.

Hypermobile Ehlers-Danlos syndrome (hEDS) is a connective tissue disorder marked by joint hypermobility, skin hyperextensibility, and tissue fragility. Recent studies have linked hEDS with mast cell activation syndrome (MCAS), suggesting a genetic interplay affecting immune regulation and infection susceptibility. This study aims to decode the genetic basis of mast cell hypersensitivity and increased infection risk in hEDS by identifying specific genetic variants associated with these conditions. We conducted whole-genome sequencing (WGS) on 18 hEDS participants and 7 first-degree relatives as controls, focusing on identifying genetic variants associated with mast cell dysregulation. Participants underwent clinical assessments to document hEDS symptoms and mast cell hypersensitivity, with particular attention to past infections and antihistamine response. Our analysis identified specific genetic variants in MT-CYB, HTT, MUC3A, HLA-B and HLA-DRB1, which are implicated in hEDS and MCAS. Protein-protein interaction (PPI) network analysis revealed significant interactions among identified variants, highlighting their involvement in pathways related to antigen processing, mucosal protection, and collagen synthesis. Notably, 61.1% of the hEDS cohort reported recurrent infections compared to 28.5% in controls, and 72.2% had documented mast cell hypersensitivity versus 14.2% in controls. These findings provide a plausible explanation for the complex interplay between connective tissue abnormalities and immune dysregulation in hEDS. The identified genetic variants offer insights into potential therapeutic targets for modulating mast cell activity and improving patient outcomes. Future research should validate these findings in larger cohorts and explore the functional implications of these variants to develop effective treatment strategies for hEDS and related mast cell disorders.

In vitro diagnostics of drug allergies.

In vitro diagnostics for drug hypersensitivity reactions distinguish between serological and cellular-based tests. A serological test used for the diagnosis of immediate type reactions is the detection of specific IgE antibodies. The cellular tests include the basophil activation test for immediate type reactions and the lymphocyte transformation test, which is mainly used to detect delayed type hypersensitivity reactions. Further cellular-based tests are the CAST-ELISA and the mast cell activation test. None of the above-mentioned tests can definitively exclude an allergy if the result is negative. In addition, it is important to note that even a positive test result is not necessarily associated with an allergy but has to be interpreted in the clinical context.

Progression of Mast Cell Activation Syndrome to Systemic Mastocytosis

Abstract Introduction/Objective Mast cell activation syndrome (MCAS) is characterized by the abnormal release of mast cell mediators, leading to symptoms such as flushing, abdominal pain, and allergic reactions. In some cases, MCAS progresses to systemic mastocytosis (SM), a mast cell disorder marked by organ infiltration and dysfunction. However, predictors of MCAS progression to SM remain poorly understood, and long-term prognosis data are limited. Methods/Case Report We conducted a retrospective study of patients diagnosed with MCAS at Penn Medicine from January 1, 2019, through December 30, 2021. The primary endpoint was progression to SM, defined by World Health Organization criteria, with a secondary endpoint set for September 24, 2023. Results (if a Case Study enter NA) We identified 47 patients with MCAS (Table 1). Of these, 11 patients (23.4%) progressed to SM. Notably, all five patients with c-KIT mutations progressed to SM (100%, 5/5), while six out of 22 patients without c-KIT mutations also progressed (27.2%). Additionally, baseline serum tryptase levels were identified as a significant predictor of progression at two years. Conclusion The relative risk of progression varied depending on the subtype of MCAS, with higher rates observed in those with KIT D816V presence. Compared to the incidence of SM in the general population, our findings suggest a higher risk of progression from MCAS to SM, even without a c-KIT mutation. Identification of prognostic factors, such as specific genetic mutations and baseline serum tryptase levels, may aid in risk stratification and early intervention strategies for individuals with MCAS. HaT mutation testing should be considered in future studies on this topic. Our findings have important implications for the clinical management and understanding of MCAS progression to SM. Additionally, our data imply the importance of recognizing MCAS in the early phase and proper monitoring, considering the low rate of MCAS diagnosis. Patients with MCAS may need annual monitoring, including serum tryptase levels, to detect progression to SM and related complications. Early detection and intervention may improve outcomes and quality of life for individuals with MCAS.

Identification of novel biomarkers for atherosclerosis using single-cell RNA sequencing and machine learning.

Atherosclerosis (AS) is a predominant etiological factor in numerous cardiovascular diseases, with its associated complications such as myocardial infarction and stroke serving as major contributors to worldwide mortality rates. Here, we devised dependable AS-related biomarkers through the utilization of single-cell RNA sequencing, weighted co-expression network (WGCNA), and differential expression analysis. Furthermore, we employed various machine learning techniques (LASSO and SVM-RFE) to enhance the identification of AS biomarkers, subsequently validating them using the GEO dataset. Following this, CIBERSORT was employed to investigate the correlation between biomarkers and infiltrating immune cells. Consequently, 256 differentially expressed genes (DEGs) were selected in samples of AS and normal. GO and KEGG analyses indicated that these DEGs may be related to the negative regulation of leukocyte-mediated immunity, leukocyte cell-cell adhesion, and immune system processes. Notably, C1QC and COL1A1 were pinpointed as potential diagnostic markers for AS, a finding that was further validated in the GSE21545 dataset. Moreover, the area under the curve (AUC) values for these markers exceeded 0.8, underscoring their diagnostic utility. Analysis of immune cell infiltration revealed that the expression of C1QC was correlated with M0 macrophages, gamma delta T cells, activated mast cells and memory B cells. Similarly, COL1A1 expression was linked to M0 macrophages, memory B cells, activated mast cells, gamma delta T cells, and CD4 native T cells. Finally, these results were validated using mice and human samples through immunofluorescence, immunohistochemistry, and ELISA analysis. Overall, C1QC and COL1A1 would be potential biomarkers for AS diagnosis, and that would provides novel perspectives on the diagnosis and treatment of AS.

Short-term influence of Immufen™ on mild allergic rhinitis: a randomized, double-blind, placebo-controlled study.

Allergic rhinitis (AR) is an IgE-mediated reaction to inhaled allergens, and is a prominent health concern affecting approximately 400 million people worldwide. A comprehensive understanding of AR's pathophysiology is imperative for developing novel therapies, especially considering its frequent co-morbidity with asthma and conjunctivitis. The escalating prevalence of AR is correlated with increased urbanization and environmental pollutants, recognized as prominent contributing factors. Dysregulation in immune networks, Th1/Th2 cytokine imbalance, activation of mast cells and eosinophils are implicated in AR progression. Classic AR symptoms include nasal congestion, nasal itching, rhinorrhea, and sneezing which significantly impact the quality of life, social interactions, and workplace productivity. This randomized, double-blind, placebo-controlled, three-arm, three-sequence study was aimed to assess the efficacy of supplementation of a co-delivery form of turmeric extract with ashwagandha extract (CQAB) in comparison with a bioavailable curcumin (CGM) and placebo in alleviating AR symptoms and enhancing the quality of life in individuals with mild AR. Participants received either placebo, CGM, or CQAB twice/day for 28 days, and subjective measures were recorded at the baseline and at the end of study. CQAB supplementation demonstrated a significant (P < 0.05) improvement in Total Nasal Symptom Score (TNSS) compared to placebo and CGM. Furthermore, CQAB administration resulted in enhanced sleep quality (P < 0.05) as evaluated by the BIS questionnaire, heightened energy levels, and decreased fatigue and overall mood disturbance (POMS-SF) compared to both placebo and CGM. The results suggests that CQAB has the potential to be used as a dietary supplement in alleviating AR discomforts. https://ctri.nic.in/Clinicaltrials/login.php; Identifier CTRI/2021/01/030355.

Integrated machine learning and Mendelian randomization reveal PALMD as a prognostic biomarker for nonspecific orbital inflammation

Background: Nonspecific Orbital Inflammation (NSOI) remains a perplexing enigma among proliferative inflammatory disorders. Its etiology is idiopathic, characterized by distinctive and polymorphous lymphoid infiltration within the orbital region. Preliminary investigations suggest that PALMD localizes within the cytosol, potentially playing a crucial role in cellular processes, including plasma membrane dynamics and myogenic differentiation. The potential of PALMD as a biomarker for NSOI warrants meticulous exploration. Methods: PALMD was identified through the intersection analysis of common DEGs from datasets GSE58331 and GSE105149 from the GEO database, alongside immune-related gene lists from the ImmPort database, using Lasso regression and SVM-RFE analysis. GSEA and GSVA were conducted with gene sets co-expressed with PALMD. To further investigate the correlation between PALMD and immune-related biological processes, the CIBERSORT algorithm and ESTIMATE method were employed to evaluate immune microenvironment characteristics of each sample. The expression levels of PALMD were subsequently validated using GSE105149. Results: Among the 314 DEGs identified, several showed significant differences. Lasso and SVM-RFE algorithms pinpointed 15 hub genes. Functional analysis of PALMD emphasized its involvement in cell-cell adhesion, leukocyte migration, and leukocyte-mediated immunity. Enrichment analysis revealed that gene sets positively correlated with PALMD were enriched in immune-related pathways. Immune infiltration analysis indicated that resting dendritic cells, resting mast cells, activated NK cells, and plasma cells positively associate with PALMD expression. Conversely, naive B cells, activated dendritic cells, M0 and M1 macrophages, activated mast cells, activated CD4 memory T cells, and naive CD4 T cells showed a negative correlation with PALMD expression. PALMD demonstrated significant diagnostic potential in differentiating NSOI. Conclusions: This study identifies PALMD as a potential biomarker linked to NSOI, providing insights into its pathogenesis and offering new avenues for tracking disease progression.

On the pathogenesis of COVID-19: the role of transforming growth factor beta

Proteins of the transforming growth factor beta (TGF-β) family regulate numerous cellular processes that are essential in the pathogenesis of acute respiratory distress syndrome (ARDS), contributing to increased alveolar epithelial permeability, activation of fibroblasts, and extracellular matrix remodeling. TGF-β is involved in the pathogenesis of inflammatory respiratory diseases during the development of COVID-19. SARS-CoV-2 leads to complex immune responses that include the release of inflammatory cytokines, increased activity of mast cells, and the release of mast cell secretome, in particular profibrotic enzymes and cytokines, including TGF-β.Tryptaseand chymase-positive mast cells play a major role in pulmonary fibrosis and embolism in COVID-19. Mast cell chymase is angiotensin-converting enzyme 2-independent due to extracellular formation of angiotensin II in the interstitium; it also activates TGF-β and other molecules, thereby playing a role in tissue remodeling. Mast cell β-tryptase increases the secretion of TGF-β1 by airway smooth muscle tissue and the expression of α-smooth muscle actin (α-SMA). TGF-β also induces the generation of mitochondrial reactive oxygen species (ROS), which enhances the production of ROS in lung fibroblasts. TGF-β is crucial for induing the synthesis of extracellular matrix components by fibroblasts.The review is devoted to the structure of TGF-β, the sources of its secretion and functions, the mechanism of its involvement in the pathogenesis of COVID-19, and the possibility of its use as a prognostic marker of COVID-19 severity.