Mast Cells Research Articles

Copper Oxide Nanoparticles Impair Mouse Preimplantation Embryonic Development through Disruption of Mitophagy-Mediated Metabolism.

Copper oxide nanoparticles (CuONPs) have been widely applied, posing potential risks to human health. Although the toxicity of CuONPs on the liver and spleen has been reported, their effects on reproductive health remain unexplored. In this study, we investigate the effects of CuONPs on embryonic development and their potential mechanisms. Our results demonstrate that CuONPs exposure impairs mouse preimplantation embryonic development, particularly affecting the morula-to-blastocyst transition. Additionally, CuONPs were found to reduce the pluripotency of the inner cell mass (ICM) and mouse embryonic stem cells (mESCs). Mechanistically, CuONPs block autophagic flux and impair mitophagy, leading to the accumulation of damaged mitochondria. This mitochondrial dysfunction leads to reduced tricarboxylic acid (TCA) cycle activity and decreased α-ketoglutarate (α-KG) production. Insufficient α-KG induces the failure of DNA demethylation, reducing corresponding chromatin accessibility and consequently inhibiting ICM-specific genes expressions. Similar reduced development and inhibitions of pluripotency gene expression were observed in CuONPs-treated human blastocysts. Moreover, in women undergoing assisted reproductive technology (ART), a negative correlation was found between urinary Cu ion concentrations and clinical outcomes. Collectively, our study elucidates the mitophagy-mediated metabolic mechanisms of CuONPs embryotoxicity, improving our understanding of the potential reproductive toxicity associated with it.

Correlation of intratumoral mast cell quantity with psychosocial distress in patients with pancreatic cancer: the PancStress study

Mast cells are commonly found in pancreatic ductal adenocarcinoma (PDAC), yet their role in the disease remains uncertain. Although mast cells have been associated with depression in several diseases, their connection to PDAC in this context remains unclear. This study explored the correlation between mast cells and psychosocial stress in patients with PDAC. Prior to surgery, 40 patients with PDAC (n = 29 primary resected, n = 11 neoadjuvant treated) completed four questionnaires assessing stress and quality of life. Immunostaining was performed on the resected tumor tissue. Spearman analysis was employed to correlate mast cells with distress and neuropeptides serotonin and beta-endorphin serum and tissue levels. Patients with PDAC exhibited elevated levels of distress and worry. Lower number of mast cells within the tumor correlated with greater psychological burden. Among primary resected patients, mast cell count moderately correlated with joy and inversely with worries. Following neoadjuvant chemotherapy, strong inverse correlation was observed between anxiety, depression, and mast cell quantity. No correlation was found between mast cells and serotonin or beta-endorphin levels. In summary, mast cell presence inversely correlates with psychosocial stress, suggesting a link between immune cells and psychological well-being in pancreatic cancer. Targeting mast cells might offer therapeutic avenues for addressing cancer-induced depression and anxiety.

Neuroplasticity and neuroimmune interactions in fatal asthma.

Alteration of airway neuronal function and density and bidirectional interaction between immune cells and sensory peripheral nerves have been proposed to trigger and perpetuate inflammation that contribute to asthma severity. To date, few studies analysed neuroplasticity and neuroinflammation in tissue of asthmatic individuals. We hypothesized that the presence of these phenomena would be a pathological feature in fatal asthma. We have quantified the expression of the pan-neuronal marker PGP9.5 and the neuronal sensory-derived neuropeptide calcitonin gene-related peptide (CGRP) in the large airways of 12 individuals deceased due to an asthma attack and compared to 10 control lung samples. The proximity between nerve bundles to eosinophils, mast cells and CADM1+ cells was also quantified. We have additionally developed a hPSC-derived sensory neuron/mast cell co-culture model, from where mast cells were purified and differences in gene expression profile assessed. Fatal asthma patients presented a higher PGP9.5 and CGRP positive area in the airways, indicating sensory neuroplasticity. Eosinophils, mast cells and CADM1+ cells were observed in close contact or touching the airway nerve bundles, and this was found to be statistically higher in fatal asthma samples. Invitro co-culture model showed that human mast cells adhere to sensory neurons and develop a distinct gene expression profile characterized by upregulated expression of genes related to heterophilic adhesion, activation and differentiation markers, such as CADM4, PTGS2, C-KIT, GATA2, HDC, CPA3, ATXN1 and VCAM1. Our results support a significant role for neuroplasticity and neuroimmune interactions in fatal asthma, that could be implicated in the severity of the fatal attack. Accordingly, the presence of physical neuron and mast cell interaction leads to differential gene expression profile in the later cell type.

Targeting of the IL-5 pathway in severe asthma reduces mast cell progenitors

BackgroundTherapies targeting interleukin-5 (IL-5) or its receptor (IL-5Rα) are currently used to treat patients with severe eosinophilic asthma. ObjectiveTo investigate the impact of anti-IL-5 and anti-IL-5Rα biological therapies on mast cells (MCs) and their progenitors. MethodsSurface IL-5Rα expression was investigated on MCs and their progenitors in mouse lungs and bone marrow, and in human lungs and blood. Isolated human MC progenitors cultured in the presence or absence of IL-5 were analyzed in vitro. Circulating MC progenitors were quantified in patients with severe asthma, before and after anti-IL-5 (mepolizumab) or anti-IL-5Rα (benralizumab) therapy. Gene expression analysis of MC progenitors was performed before and after anti-IL-5Rα therapy. ResultsApproximately 50% of the human primary lung MCs, and 30% of the human MC progenitors from individuals with allergic asthma expressed IL-5Rα. In patients with mild-to-moderate allergic asthma and mice with acute allergic airway inflammation, the fraction of IL-5Rα + MC progenitors was elevated. Additionally, IL-5 promoted the proliferation and/or survival of isolated human MC progenitors. Further, patients with severe asthma from two independent cohorts demonstrated a reduction of blood MC progenitors after anti-IL-5 or anti-IL-5Rα treatment. This was associated with improved asthma control, as well as a decline in both blood eosinophils and Th2 cells. Finally, the blood MC progenitors remaining after anti-IL-5Rα (benralizumab) treatment exhibited a downregulated expression of genes involved in growth and proliferation. ConclusionThis study introduces the possibility that the clinical effects of targeting IL-5/IL-5Rα in severe asthma also may involve reduction of MC 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.

Subcellular expression of CD30 in cutaneous mastocytosis-An important factor for targeted treatment.

The subcellular distribution of CD30 on mast cells and the presence of eosinophils in cutaneous mastocytosis require further investigation, especially as the cell surface expression of CD30 is critical for the therapeutic response of systemic mastocytosis to brentuximab vedotin. Investigation of 147 biopsy specimens from 143 patients with cutaneous mastocytosis for mast cell density and distribution, frequency of CD30 expression, CD30 staining patterns, and presence and distribution of eosinophils. Correlation with clinical patterns. Retrospective multicenter immunohistochemical study of CD30 expression, eosinophils and basic clinical data in cutaneous mastocytosis. CD30 expression was found in all samples (cut-off: ≥1%), whereby the staining was predominantly cytoplasmic in 99% of the samples. Additional membrane staining was detected in 62% of the samples. Surface expression of CD30 was more common in biopsy specimens with a high mast cell burden and in biopsy specimens with a higher CD30 expression rate. Eosinophils were admixed in 58% of the samples. Females and older patients showed a trend of a lower mast cell burden. Retrospective study on formalin-fixed and paraffin-embedded tissue without functional analysis. Most cases of cutaneous mastocytosis show cell surface expression of CD30 expression and is, therefore, in principle, accessible for therapy with antibodies against CD30, provided the overall situation of the patient warrants.

C1QTNF Related protein 8 (CTRP8) is a marker of myeloid derived innate immune cell populations in the human breast cancer microenvironment.

Innate immune cells in the tumor microenvironment (TME) play an important role in breast cancer (BC) metastatic spread and influence patient survival. Macrophages differentiate along a proinflammatory M1 to protumorigenic M2 phenotype spectrum which affects distinct functions, like angiogenesis and cytokine production, and modulates BC aggressiveness and affects patient survival. Mast cells (MCs) are myeloid derived cells that serve as the first line of innate immune defense but their role in the TME of BC is not well understood. In this study, we have identified a subpopulation of innate immune cells that shows strong immunopositivity for the least studied adipokine CTRP8. Using a new and highly specific polyclonal antiserum on patient BC tissues, we identify a subset of tryptase + MCs and CD68 + macrophages co-expressing immunoreactive CTRP8. In M1 polarized THP-1 myeloid cells, this adipokine stimulated increased secretion of pro-inflammatory cytokines and elevated expression of the relaxin/ CTRP8 receptor RXFP1. Comparative analysis of secreted cytokine profiles in THP-1 M1 macrophages exposed to either CTRP8, relaxin-2 (RLN2), or the small molecule RXFP1 agonist ML-290 revealed ligand-specific cytokine signatures. Our study identified novel subsets of CTRP8 + myeloid derived innate immune cells and links this adipokine to pro-inflammatory events in the TME of BC.

Lysophosphatidylcholine Acyltransferase 2 Contributes to Increased Allergic and Irritant Inflammation in Mice.

Platelet-activating factor (PAF) is an important chemical mediator in the field of inflammation, but its function in the skin is unclear. To unravel the role of PAF, we focused on lysophosphatidylcholine acyltransferase 2 (LPCAT2 also called LPLAT9), a biosynthetic enzyme involved in PAF production, and investigated the role of PAF in allergic contact dermatitis (ACD) and irritant contact dermatitis (ICD). We measured the amount of PAF in the skin and investigated the ear swelling responses and leukocyte infiltration into the skin following the application of 2,4,6-trinitro-1-chlorobenzene (TNCB) or croton oil in wild-type (WT) and LPCAT2 knockout (LPCAT2-KO) mice. The amount of PAF was increased in the skin of WT mice after TNCB or croton oil application but not detected in LPCAT2-KO mice. The ear swelling response was decreased in LPCAT2-KO mice compared with that in WT mice. In the ACD model, the numbers of lymphocytes, eosinophils, macrophages, mast cells and neutrophils were smaller in LPCAT2-KO mice than in WT mice. In the ICD model, the ear swelling response was also decreased in LPCAT2-KO mice compared with that in WT mice. When double staining of each inflammatory cell type and LPCAT2 was performed in ACD tissue, marked co-staining of the eosinophil marker and LPCAT2 was observed. In addition, LPCAT2 expression was observed in the epidermis. These results indicate that PAF is involved in the infiltration of several cell types into the sites of allergic and non-allergic skin inflammation. Furthermore, eosinophils and keratinocytes are primarily responsible for PAF production in skin inflammation.

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.

Lysate of bovine adipose-derived stem cells accelerates in-vitro development and increases cryotolerance through reduced content of lipid in the in vitro fertilized embryos

Mesenchymal stem cells such as adipose-derived stem cells (ADSCs) are known to secrete factors that stimulate cell division and promote regeneration in neighboring cells. While conditioned medium from stem cells has been used in blastocyst production, no studies have examined the use of cell lysates. In this study we investigated the effects of adding ADSC lysate to in vitro culture (IVC) medium. ADSCs and fibroblasts were isolated from bovine adipose tissue and auricular tissue, respectively, and their lysates were prepared by freeze-thaw disruption. ADSC lysate was added to synthetic oviductal fluid medium. The effects on cleavage, blastocyst development rates, cell numbers, cryotolerance, gene expression (POU5F1, BAX, IGF1R, IGF2R, SOD2), lipid content, and membrane integrity were evaluated according to the experimental design. In Expt. 1, the comparison involved adding ADSC or fibroblast lysate alongside the control group. The total blastocyst rate increased when ADSC lysate was introduced (ADSCs: 40.1%, fibroblasts: 33.1%, control: 27.3%). However, there were no significant differences in the number of trophoblast cells or in the inner cell mass. Experiment 2 confirmed that this increase in blastocyst development was not due to the solvent, PBS(-). In Expt. 3, addition of 10% fetal calf serum (FCS) or ADSC lysate increased the total blastocyst rate compared to the control (control, 26.2%; 10% FCS, 43.4%; 1% ADSC lysate, 34.2%; 10% ADSC lysate, 48.1%). After freezing and thawing, the survival and hatching rates of embryos with FCS were significantly lower than those of the control as well as those with added ADSC lysate. In Expt. 4, the addition of ADSC lysate or FCS had no significant effect on gene expression in blastocysts compared to control. However, the addition of FCS significantly increased the gray intensity, indicating higher lipid content compared to the control, with a significant increase in the number of dead cells in the blastocyst. These results indicate that the addition of ADSC lysate to the IVC medium accelerates bovine blastocyst development and that its 10% addition, corresponding to 1 x 105 cells/mL, is as effective as 10% FCS without a decrease in cryotolerance due to the increased lipid content.

Highly-efficient co-production of microbial lipid and magnesium ammonium phosphate from N-acetyl-D-glucosamine

The valorization of chitin-rich wastes into chemicals and biofuels holds immense economic and environmental benefits. Here, N-acetyl-D-glucosamine (GlcNAc), the basic structural unit of chitin, was firstly described for co-producing microbial lipid and magnesium ammonium phosphate (MAP). Due to the strong substrate inhibition of GlcNAc, a fed-batch culture mode was successfully adopted to achieve high cell density by Cutaneotrichosporon oleaginosum. When a phosphate limitation strategy was applied, cell mass, lipid titer, content, yield, and productivity were 102.7 g/L, 74.2 g/L, 72.2 %, 21.4 g/100 g, and 0.69 g/L/h, respectively. The ammonium ion was efficiently precipitated by forming MAP with a removal rate around 95.4 %. The lipid samples showed high similarity to vegetable oil, which emerged as high-quality precursor for biodiesel production. This study offers a promising strategy for full conversion of GlcNAc into lipid and slow-release fertilizer, which provides an attractive technical route for turning the chitin-rich materials into valuable products.

Treatment Approaches for Diffuse Cutaneous Mastocytosis in Children: Literature Review and Actual Clinical Experience

Background. Mastocytosis is a very rare disease with various manifestations, based on abnormal clonal proliferation of mast cells in organs and tissues, such as: skin, bone marrow, lymph nodes, liver, spleen, and gastrointestinal tract. The diagnosis can be established according to clinical manifestations, laboratory, and instrumental data. Darier’s sign and histological examination are crucial for mastocytosis diagnosis. The presented clinical case describes very rare cutaneous form of mastocytosis. Clinical case description. The girl, 2.5 years old, was hospitalized with multiple erythematous papules on her body, face, and limbs. Comprehensive examination, including bone marrow biopsy and positron-emission tomography, allowed us to exclude mastocytosis systemic manifestations. Conclusion. Despite the fact that mastocytosis in children is mostly represented by skin form, it is necessary to perform complex patient examination on any systemic damage. Antihistamines in combination with topical and/or systemic glucocorticoids are often effective, but complete response does not always occur. Implementation of other therapeutic options, such as targeted drugs (tyrosine kinase inhibitors), is suggested In case of no or insufficient therapeutic effect.

The oncogenic functions of SPARCL1 in bladder cancer.

Secreted protein, acidic and rich in cysteine-like 1 (SPARCL1) belongs to the SPARC family of matricellular proteins. However, underlying functions of SPARCL1 in bladder cancer (BCa) remain understudied. We performed an integrated search for the expression patterns of SPARCL1 in relation to various clinicopathological features of BCa. We then carried out Gene Ontology (GO) enrichment analysis, Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis, and gene set enrichment analysis (GSEA). Furthermore, we investigated the correlations between SPARCL1 and immunological features, such as tumour mutation burden (TMB), immune activation processes, immune checkpoint expression, tumour immune dysfunction and exclusion (TIDE) scores, and chemotherapeutic sensitivity in BCa. Our analysis revealed that SPARCL1 was downregulated across multiple cancers. In BCa, elevated SPARCL1 was linked with advanced histopathologic stage, higher T and N stage, and poorer prognosis in the clinical cohort. Invitro experiments demonstrated that increased SPARCL1 expression inhibited cell proliferation, migration, and invasion. Additionally, highly expressed SPARCL1 was linked to elevated immune, stromal and ESTIMATE scores, as well as an increase in naive B cells, M2 macrophages, and resting mast cells. We observed a moderate correlation between SPARCL1 expression and CD163, VSIG4 and MS4A4A, which are markers of M2 macrophages. Furthermore, SPARCL1 expression was positively related to TMB, immune activation processes, TIDE scores, immune checkpoint expression, and chemotherapeutic sensitivity in BCa. Our study highlights the potential involvement of SPARCL1 in macrophage recruitment and polarization and suggests its utility as a biomarker for prognosis in BCa.

Leukemia Inhibitory Factor Receptor inhibition by EC359 reduces atherosclerotic stenosis grade in Ldlr-/- mice

Cytokines are involved in all stages of atherosclerosis, generally contributing to disease progression. Previously, members of the IL-6 cytokine family, such as Interleukin-6, oncostatin M, and cardiotrophin-1, have been extensively studied in atherosclerosis. However, the role of leukemia inhibitory factor (LIF), member of the IL-6 family, and its receptor (LIFR), remains to be further elucidated. Therefore, the aim of this study is to provide insight in LIF receptor signalling in atherosclerosis development.Single-cell RNA sequencing analysis of human carotid artery plaques revealed that mast cells highly express LIF, whereas LIFR was specifically expressed on activated endothelial cells. A similar expression pattern of Lifr was observed in mouse atherosclerotic plaques. Next, female Western-type diet fed Ldlr-/- mice were treated with LIF receptor inhibitor EC359 (5 mg/kg s.c., n=15) or control solvent (n=15) three times per week for eight weeks. Stenosis grade was reduced in the aortic root of EC359 treated mice compared to control mice, but treatment did not affect plaque composition. Serum cholesterol levels were significantly reduced in EC359 treated mice, likely attributed to a reduction in VLDL cholesterol levels. Furthermore, LIF receptor inhibition reduced Pecam1 and Vcam1 expression in the aorta. Consequently, immune cell infiltration was reduced in aortic plaques of EC359 treated mice compared to control mice.Conclusively, we demonstrated that LIF receptor is a potential therapeutic target in atherosclerosis by reducing plaque size, attributed to lower serum cholesterol levels, reduced endothelial activation and less immune cell infiltration in the plaque.

Difficult Cases in Mast Cell Disorders

Difficult Cases in Mast Cell Disorders

A Novel Gene Signature Based on Immune Cell Infiltration Landscape Predicts Prognosis in Lung Adenocarcinoma Patients.

The tumor microenvironment (TME) is created by the tumor and dominated by tumor-induced interactions. Long-term survival of lung adenocarcinoma (LUAD) patients is strongly influenced by immune cell infiltration in TME. The current article intends to construct a gene signature from LUAD ICI for predicting patient outcomes. For the initial phase of the study, the TCGA-LUAD dataset was chosen as the training group for dataset selection. We found two datasets named GSE72094 and GSE68465 in the Gene Expression Omnibus (GEO) database for model validation. Unsupervised clustering was performed on the training cohort patients using the ICI profiles. We employed Kaplan-Meier estimators and univariate Cox proportional-hazard models to identify prognostic differentially expressed genes in immune cell infiltration (ICI) clusters. These prognostic genes are then used to develop a LASSO Cox model that generates a prognostic gene signature. Validation was performed using Kaplan-Meier estimation, Cox, and ROC analysis. Our signature and vital immune-relevant signatures were analyzed. Finally, we performed gene set enrichment analysis (GSEA) and immune infiltration analysis on our finding gene signature to further examine the functional mechanisms and immune cellular interactions. Our study found a sixteen-gene signature (EREG, HPGDS, TSPAN32, ACSM5, SFTPD, SCN7A, CCR2, S100P, KLK12, MS4A1, INHA, HOXB9, CYP4B1, SPOCK1, STAP1, and ACAP1) to be prognostic based on data from the training cohort. This prognostic signature was certified by Kaplan-Meier, Cox proportional-hazards, and ROC curves. 11/15 immune-relevant signatures were related to our signature. The GSEA results indicated our gene signature strongly correlates with immune-related pathways. Based on the immune infiltration analysis findings, it can be deduced that a significant portion of the prognostic significance of the signature can be attributed to resting mast cells. We used bioinformatics to determine a new, robust sixteen-gene signature. We also found that this signature's prognostic ability was closely related to the resting mast cell infiltration of LUAD patients.

Arctiin Alleviates Atopic Dermatitis Against Inflammation and Pyroptosis Through Suppressing TLR4/MyD88/NF-κB and NLRP3/Caspase-1/GSDMD Signaling Pathways.

Atopic dermatitis (AD) is a prevalent skin condition worldwide. The immune response plays a crucial role in the pathogenesis of AD. Arctiin (ARC), a natural lignan, has been extensively investigated because of its anti-inflammatory, antioxidant, and anticancer properties. However, the impact of ARC on AD remains uncertain. Therefore, this study investigated the therapeutic effects of ARC in AD. AD-like lesions were induced in mice by applying 2,4-dinitrochlorobenzene (DNCB). The efficacy of ARC in AD was assessed by measuring skin lesion scores and thickness, pathological observation, and serum IgE concentrations. The expression of relevant proteins and genes in the back skin of the mice was assessed. Moreover, the TLR4/MyD88/NF-κB and NLRP3/Caspase-1/GSDMD signaling pathways were assessed in HaCaT cells stimulated with TNF-α and IFN-γ. ARC effectively alleviated AD-like dermatitis induced by DNCB in mice, reducing the skin thickness, mast cell infiltration in skin tissue, and serum total IgE levels. In addition, the expression of IL-1β and the mRNA transcription of TSLP and IFN-γ were downregulated. ARC also suppressed the TLR4/MyD88/NF-κB pathway, and molecular docking confirmed that ARC had exceptional binding properties with TLR4. Moreover, ARC ameliorated pyroptosis by inhibiting the activation of the nod-like receptor protein-3/Caspase-1/GSDMD cascade. ARC has remarkable anti-AD effects by inhibiting inflammation and pyroptosis through the TLR4/MyD88/NF-κB and NLRP3/Caspase-1/GSDMD signaling pathways. This suggests that ARC has potential as a new drug candidate for treating AD, which provides a novel approach to the clinical management of AD.

Severe chronic spontaneous urticaria responding and not responding to omalizumab: analysis of the prognostic value of known and novel in-vitro variables.

Background. Chronic spontaneous urticaria (CSU) response to anti-IgE treatment can be rapid, late or absent. Recently, potential mechanisms of activation of mast cells alternative to FceRI, including mas-related G protein-coupled receptor X2 (MRGPRX2), activation of coagulation cascade, and activation of eosinophils have been described. We measured several potential in-vitro markers, including well-known MRGPRX2 activators, in sera of patients CSU both responding and not responding to omalizumab. Methods. D-dimer, substance P (SP), eosinophil cationic protein (ECP), soluble MRGPRX2, IgE anti-FceRI, IgE anti-FceRII, IgG anti-FceRI and IgG anti-FceRII were measured in 32 patients with severe CSU at baseline and one week after the start of omalizumab therapy, and in 20 healthy controls. Results. At baseline CSU patients showed significantly higher levels of D-dimer, IgE anti-FceRI, IgG anti-FceRI, and ECP (p < 0.001 in all cases), and significantly lower levels of soluble MRGPRX2 (p = 0.009) than controls. The two groups showed similar levels of IgG and IgE to FceRII and SP. One week after the first omalizumab administration there was a significant drop of IgE anti-FceRI (p < 0.001) and D-dimer (p = 0.028), in early responders. SP increased in all CSU patients (p < 0.001) irrespective of the final response to omalizumab. IgE anti-FceRI response at one week was associated with the final response to omalizumab (OR:0.12 [95%CI 0.01-1.06]). Conclusions. Severe CSU is associated with high plasma levels of several biomarkers including D-dimer, IgE anti-FceRI, IgG anti-FceRI and ECP and low levels of soluble MRGPRX2. IgE anti-FceRI response at one week may predict the final response to omalizumab.

An Overview of Pathological Pathway of Asthma and Molecular Mechanisms of Anti-Asthmatic Phytoconstituents

: Asthma presents with chronic inflammation and airway constriction triggered by allergens or pollution. Inflammatory mediators such as histamine and leukotrienes, released in response to inflammation, prompt bronchoconstriction, contracting the smooth muscles around the airways. This constriction obstructs airflow and worsens symptoms such as coughing, wheezing, and breathlessness. Additionally, airways become hyperresponsive, reacting excessively even to harmless stimuli. Persistent inflammation leads to the production of thick mucus, further blocking airflow and worsening symptoms. Mast cell-released histamine triggers bronchoconstriction, leukotrienes, and prostaglandins (eg, Interleukin-4, Interleukin-13) and promotes airway inflammation while cytokines drive Th2-mediated immune responses. Current therapies in asthma include long-acting beta agonists, leukotriene modifiers, inhaled corticosteroids, and immunomodulators. Natural products, due to their anti-inflammatory, antioxidant and immunomodulatory properties, have emerged as promising anti-asthmatic candidates. Polyphenols (quercetin, resveratrol, curcumin, etc.) and Omega-3 fatty acids offer anti-inflammatory benefits by suppressing cytokines and oxidative stress. Natural products intervene at various levels of these pathways. Quercetin inhibits the release of mast cell histamines, alleviating bronchoconstriction. Curcumin suppresses Th2 cytokines, mitigating the allergic response. Omega-3 fatty acids modulate leukotriene and prostaglandin production, reducing airway inflammation. This review concludes that natural phytobioactives have potential in asthma management due to their complex mechanisms that target various immuno-inflammatory mediators.

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.