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Adipocyte Dec 2024Obesity is associated with a low-grade chronic inflammatory process characterized by higher circulating TNFα levels, thus contributing to insulin resistance. This study...
Obesity is associated with a low-grade chronic inflammatory process characterized by higher circulating TNFα levels, thus contributing to insulin resistance. This study evaluated the effect of silybin, the main bioactive component of silymarin, which has anti-inflammatory properties, on TNFα levels and its impact on glucose uptake in the adipocyte cell line 3T3-L1 challenged with two different inflammatory stimuli, TNFα or lipopolysaccharide (LPS). Silybin's pre-treatment effect was evaluated in adipocytes pre-incubated with silybin (30 or 80 µM) before challenging with the inflammatory stimuli (TNFα or LPS). For the post-treatment effect, the adipocytes were first challenged with the inflammatory stimuli and then post-treated with silybin. After treatments, TNFα production, glucose uptake, and GLUT4 protein expression were determined. Both inflammatory stimuli increased TNFα secretion, diminished GLUT4 expression, and significantly decreased glucose uptake. Silybin 30 µM only reduced TNFα secretion after the LPS challenge. Silybin 80 µM as post-treatment or pre-treatment decreased TNFα levels, improving glucose uptake. However, glucose uptake enhancement induced by silybin did not depend on GLUT4 protein expression. These results show that silybin importantly reduced TNFα levels and upregulates glucose uptake, independently of GLUT4 protein expression.
Topics: Animals; Silybin; Mice; Tumor Necrosis Factor-alpha; Glucose; 3T3-L1 Cells; Adipocytes; Lipopolysaccharides; Glucose Transporter Type 4; Silymarin
PubMed: 38953241
DOI: 10.1080/21623945.2024.2374062 -
Skin Research and Technology : Official... Jul 2024Observational studies have identified a dual effect of circulating inflammatory proteins and immune cells on cancer progression. However, the specific mechanisms of...
OBJECTIVE
Observational studies have identified a dual effect of circulating inflammatory proteins and immune cells on cancer progression. However, the specific mechanisms of action have not been clarified in the exacerbation of cutaneous-origin tumors. Therefore, this study aims to investigate whether the causal relationship between circulating inflammatory factors and basal cell carcinoma (BCC), cutaneous malignant melanoma (SKCM), and cutaneous squamous cell carcinoma (cSCC) is regulated by immune cells.
METHODS
This study employed the Two-Sample Mendelian Randomization (TSMR) approach to investigate the causal relationships between 91 circulating inflammatory factors and three prevalent types of skin cancer from a genetic perspective. Bayesian Weighted Mendelian Randomization (BWMR) was also used to validate correlation and reverse MR to assess inverse relationships. Subsequent sensitivity analyses were conducted to limit the impact of heterogeneity and pleiotropy. Finally, the two-step Mendelian Randomization (two-step MR) method was utilized to ascertain the mediating effects of specific immune cell traits in the causal pathways linking circulating inflammatory factors with BCC, SKCM, and cSCC.
RESULTS
The Inverse Variance Weighted (IVW) method and the Bayesian Weighted Algorithm collectively identified nine inflammatory factors causally associated with BCC, SKCM, and cSCC. The results from Cochran's Q test, mendelian randomization pleiotropy residual sum and outlier (MR-PRESSO), and MR-Egger intercept were not statistically significant (p < 0.05). Additionally, the proportions mediated by CD4+ CD8dim T cell %leukocyte, CD4-CD8-Natural Killer T %T cell, and CD20 on IgD-CD38-B cell for FIt3L, CCL4, and OSM were 9.26%, 8.96%, and 10.16%, respectively.
CONCLUSION
Immune cell levels potentially play a role in the modulation process between circulating inflammatory proteins and cutaneous-origin exacerbated tumors. This finding offers a new perspective for the in-depth exploration of cutaneous malignancies.
Topics: Humans; Skin Neoplasms; Melanoma; Carcinoma, Basal Cell; Mendelian Randomization Analysis; Carcinoma, Squamous Cell; Bayes Theorem; Melanoma, Cutaneous Malignant
PubMed: 38953214
DOI: 10.1111/srt.13774 -
ACS Applied Materials & Interfaces Jul 2024Repairing multiphasic defects is cumbersome. This study presents new soft and hard scaffold designs aimed at facilitating the regeneration of multiphasic defects by...
Repairing multiphasic defects is cumbersome. This study presents new soft and hard scaffold designs aimed at facilitating the regeneration of multiphasic defects by enhancing angiogenesis and improving cell attachment. Here, the nonimmunogenic, nontoxic, and cost-effective human serum albumin (HSA) fibril (HSA-F) was used to fabricate thermostable (up to 90 °C) and hard printable polymers. Additionally, using a 10.0 mg/mL HSA-F, an innovative hydrogel was synthesized in a mixture with 2.0% chitosan-conjugated arginine, which can gel in a cell-friendly and pH physiological environment (pH 7.4). The presence of HSA-F in both hard and soft scaffolds led to an increase in significant attachment of the scaffolds to the human periodontal ligament fibroblast (PDLF), human umbilical vein endothelial cell (HUVEC), and human osteoblast. Further studies showed that migration (up to 157%), proliferation (up to 400%), and metabolism (up to 210%) of these cells have also improved in the direction of tissue repair. By examining different in vitro and ex ovo experiments, we observed that the final multiphasic scaffold can increase blood vessel density in the process of per-vascularization as well as angiogenesis. By providing a coculture environment including PDLF and HUVEC, important cross-talk between these two cells prevails in the presence of roxadustat drug, a proangiogenic in this study. In vitro and ex ovo results demonstrated significant enhancements in the angiogenic response and cell attachment, indicating the effectiveness of the proposed design. This approach holds promise for the regeneration of complex tissue defects by providing a conducive environment for vascularization and cellular integration, thus promoting tissue healing.
PubMed: 38953207
DOI: 10.1021/acsami.4c06207 -
Frontiers in Immunology 2024Schistosomiasis (SM) is a parasitic disease caused by . SM causes chronic inflammation induced by parasitic eggs, with collagen/fibrosis deposition in the granuloma...
INTRODUCTION
Schistosomiasis (SM) is a parasitic disease caused by . SM causes chronic inflammation induced by parasitic eggs, with collagen/fibrosis deposition in the granuloma process in the liver, spleen, central nervous system, kidneys, and lungs. Pulmonary arterial hypertension (PAH) is a clinical manifestation characterized by high pressure in the pulmonary circulation and right ventricular overload. This study investigated the production of functional autoantibodies (fAABs) against the second loop of the G-protein-coupled receptor (GPCR) in the presence of hepatic and PAH forms of human SM.
METHODS
Uninfected and infected individuals presenting acute and chronic manifestations (e.g., hepatointestinal, hepato-splenic without PAH, and hepato-splenic with PAH) of SM were clinically evaluated and their blood was collected to identify fAABs/GPCRs capable of recognizing endothelin 1, angiotensin II, and a-1 adrenergic receptor. Human serum was analyzed in rat cardiomyocytes cultured in the presence of the receptor antagonists urapidil, losartan, and BQ123.
RESULTS
The fAABs/GPCRs from chronic hepatic and PAH SM individuals, but not from acute SM individuals, recognized the three receptors. In the presence of the antagonists, there was a reduction in beating rate changes in cultured cardiomyocytes. In addition, binding sites on the extracellular domain functionality of fAABs were identified, and IgG1 and/or IgG3 antibodies were found to be related to fAABs.
CONCLUSION
Our data suggest that fAABs against GPCR play an essential role in vascular activity in chronic SM (hepatic and PAH) and might be involved in the development of hypertensive forms of SM.
Topics: Autoantibodies; Humans; Animals; Receptors, G-Protein-Coupled; Rats; Male; Female; Adult; Hypertension, Pulmonary; Middle Aged; Myocytes, Cardiac; Schistosomiasis mansoni; Schistosoma mansoni; Schistosomiasis
PubMed: 38953035
DOI: 10.3389/fimmu.2024.1404384 -
Frontiers in Immunology 2024Icanbelimod (formerly CBP-307) is a next-generation S1PR modulator, targeting S1PR. In this first-in-human study, icanbelimod was investigated in healthy men in... (Randomized Controlled Trial)
Randomized Controlled Trial
Icanbelimod (CBP-307), a next-generation Sphingosine-1-phosphate receptor modulator, in healthy men: pharmacokinetics, pharmacodynamics, safety, and tolerability in a randomized trial in Australia.
BACKGROUND
Icanbelimod (formerly CBP-307) is a next-generation S1PR modulator, targeting S1PR. In this first-in-human study, icanbelimod was investigated in healthy men in Australia.
METHODS
Participants were randomized 3:1, double-blind, to icanbelimod or placebo in four single-dose cohorts (0.1 mg, 0.25 mg, 0.5 mg [n=8 per cohort], 2.5 mg [n=4]) or for 28-days once-daily treatment in two cohorts (0.15 mg, 0.25 mg [n=8 per cohort]). Participants in the 0.25-mg cohort received 0.1 mg on Day 1. Treatments were administered orally after fasting; following one-week washout, icanbelimod was administered after breakfast in the 0.5-mg cohort.
RESULTS
Icanbelimod exposure increased rapidly and dose-dependently with single and multiple dosing (T 4-7 hours). Lymphocyte counts decreased rapidly after single (-11%, 0.1 mg; -40%, 0.25 mg; -71%, 0.5 mg; -77%, 2.5 mg) and multiple doses (-49%, 0.15 mg; -75%, 0.25 mg), and recovered quickly, 7 days after dosing. After single-dose 0.5 mg, although a high-fat breakfast versus fasting did not affect maximal decrease, lymphocyte counts tended to be lower after breakfast across most timepoints up to 72 hours. Twenty-eight participants (63.6%) experienced mainly mild treatment-emergent adverse events (TEAEs). After single-dose icanbelimod, the most common TEAEs were headache (28.6%, n=6) and dizziness (19.0%, n=4). Three participants experienced transient bradycardia, with one serious, following single-dose 2.5 mg icanbelimod. After multiple-dose icanbelimod, the most common TEAEs were headache (50.0%, n=6) and lymphopenia (41.7%, n=5), and two participants withdrew due to non-serious TEAEs. Up-titration attenuated heart rate reductions.
CONCLUSION
Icanbelimod was well-tolerated up to 0.5 mg and effectively reduced lymphocyte counts.
CLINICAL TRIAL REGISTRATION
ClinicalTrials.gov, identifier NCT02280434.b.
Topics: Humans; Male; Adult; Australia; Double-Blind Method; Young Adult; Healthy Volunteers; Sphingosine 1 Phosphate Receptor Modulators; Middle Aged; Sphingosine-1-Phosphate Receptors; Lymphocyte Count; Adolescent
PubMed: 38953034
DOI: 10.3389/fimmu.2024.1380975 -
Frontiers in Immunology 2024Our study aimed to elucidate the role of Galectin-1 (Gal-1) role in the immunosuppressive tumor microenvironment (TME) of prostate cancer (PCa). Our previous findings...
Our study aimed to elucidate the role of Galectin-1 (Gal-1) role in the immunosuppressive tumor microenvironment (TME) of prostate cancer (PCa). Our previous findings demonstrated a correlation between elevated Gal-1 expression and advanced PCa stages. In this study, we also observed that Gal-1 is expressed around the tumor stroma and its expression level is associated with PCa progression. We identified that Gal-1 could be secreted by PCa cells, and secreted Gal-1 has the potential to induce T cell apoptosis. Gal-1 knockdown or inhibition of Gal-1 function by LLS30 suppresses T cell apoptosis resulting in increased intratumoral T cell infiltration. Importantly, LLS30 treatment significantly improved the antitumor efficacy of anti-PD-1 . Mechanistically, LLS30 binds to the carbohydrate recognition domain (CRD) of Gal-1, disrupting its binding to CD45 leading to the suppression of T cell apoptosis. In addition, RNA-seq analysis revealed a novel mechanism of action for LLS30, linking its tumor-intrinsic oncogenic effects to anti-tumor immunity. These findings suggested that tumor-derived Gal-1 contributes to the immunosuppressive TME in PCa by inducing apoptosis in effector T cells. Targeting Gal-1 with LLS30 may offer a strategy to enhance anti-tumor immunity and improve immunotherapy.
Topics: Male; Galectin 1; Prostatic Neoplasms; Humans; Animals; Tumor Microenvironment; T-Lymphocytes; Mice; Apoptosis; Immunotherapy; Cell Line, Tumor; Lymphocytes, Tumor-Infiltrating
PubMed: 38953033
DOI: 10.3389/fimmu.2024.1372956 -
Frontiers in Immunology 2024Hereditary angioedema (HAE) is a rare disease characterized by localized and self-limited angioedema (AE) attacks. A local increase of bradykinin (BK) mediates AE...
BACKGROUND
Hereditary angioedema (HAE) is a rare disease characterized by localized and self-limited angioedema (AE) attacks. A local increase of bradykinin (BK) mediates AE attacks in HAE, however the role of inflammation in HAE has been poorly explored We aim to analyze the role of inflammatory mediators in HAE patients during AE attacks.
METHODS
Patients with a confirmed HAE diagnosis due to C1 inhibitor deficiency (HAE-C1INH) or patients gene mutations (HAE-FXII) attending to our outpatient clinic between November-2019 and May-2022 were included. Demographic and clinical characteristics were analyzed. Blood samples were collected both during symptom-free periods (baseline) and during HAE attacks, and acute phase reactants (APR), such as serum amyloid A (SAA), erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), D-Dimer and white blood cells were measured.
RESULTS
Seventy-eight patients were enrolled in the study, with a predominant representation of women (76%, n=59), and a mean age of 47.8 years (range 6-88). Among them, 67% (n=52) of patients had HAE-C1INH (46 classified as type 1 and 6 as type 2) while 33% (n=26) had HAE-FXII. During attack-free periods, the majority of patients exhibited normal levels of SAA, ESR, D-dimer, ACE and WCC. However, in a subset of patients (16% for SAA, 18% for ESR, and 14.5% for D-dimer), elevations were noted at baseline. Importantly, during HAE attacks, significant increases were observed in SAA in 88% of patients (p< 0.0001 vs. baseline), in ESR in 65% (p= 0.003 baseline) and D-dimer in 71% (p=0.001 . baseline) of the patients. A comparison between baseline and acute attack levels in 17 patients revealed significant differences in SAA AA (p<0. 0001), ESR (p<0.0001) and D-dimer (p= 0.004). No significant differences were observed in CRP (p=0.7), ACE (p=0.67) and WCC (p=0.54). These findings remained consistent regardless of HAE type, disease activity or location of angioedema.
CONCLUSION
The systemic increase in APR observed during HAE attacks suggests that inflammation extends beyond the localized edematous area. This finding underscores the potential involvement of inflammatory pathways in HAE and highlights the need for further investigation into their role in the pathophysiology of HAE.
Topics: Humans; Female; Male; Adult; Angioedemas, Hereditary; Middle Aged; Biomarkers; Aged; Inflammation; Adolescent; Child; Young Adult; Aged, 80 and over; Complement C1 Inhibitor Protein; Serum Amyloid A Protein; Factor XII; Blood Sedimentation; Inflammation Mediators; Fibrin Fibrinogen Degradation Products
PubMed: 38953032
DOI: 10.3389/fimmu.2024.1400526 -
Frontiers in Immunology 2024Unbalanced inflammatory response is a critical feature of sepsis, a life-threatening condition with significant global health burdens. Immune dysfunction, particularly... (Observational Study)
Observational Study
BACKGROUND
Unbalanced inflammatory response is a critical feature of sepsis, a life-threatening condition with significant global health burdens. Immune dysfunction, particularly that involving different immune cells in peripheral blood, plays a crucial pathophysiological role and shows early warning signs in sepsis. The objective is to explore the relationship between sepsis and immune subpopulations in peripheral blood, and to identify patients with a higher risk of 28-day mortality based on immunological subtypes with machine-learning (ML) model.
METHODS
Patients were enrolled according to the sepsis-3 criteria in this retrospective observational study, along with age- and sex-matched healthy controls (HCs). Data on clinical characteristics, laboratory tests, and lymphocyte immunophenotyping were collected. XGBoost and k-means clustering as ML approaches, were employed to analyze the immune profiles and stratify septic patients based on their immunological subtypes. Cox regression survival analysis was used to identify potential biomarkers and to assess their association with 28-day mortality. The accuracy of biomarkers for mortality was determined by the area under the receiver operating characteristic (ROC) curve (AUC) analysis.
RESULTS
The study enrolled 100 septic patients and 89 HCs, revealing distinct lymphocyte profiles between the two groups. The XGBoost model discriminated sepsis from HCs with an area under the receiver operating characteristic curve of 1.0 and 0.99 in the training and testing set, respectively. Within the model, the top three highest important contributions were the percentage of CD38CD8T cells, PD-1NK cells, HLA-DRCD8T cells. Two clusters of peripheral immunophenotyping of septic patients by k-means clustering were conducted. Cluster 1 featured higher proportions of PD1 NK cells, while cluster 2 featured higher proportions of naïve CD4T cells. Furthermore, the level of PD-1NK cells was significantly higher in the non-survivors than the survivors (15.1% vs 8.6%, <0.01). Moreover, the levels of PD1 NK cells combined with SOFA score showed good performance in predicting the 28-day mortality in sepsis (AUC=0.91,95%CI 0.82-0.99), which is superior to PD1 NK cells only(AUC=0.69, sensitivity 0.74, specificity 0.64, cut-off value of 11.25%). In the multivariate Cox regression, high expression of PD1 NK cells proportion was related to 28-day mortality (aHR=1.34, 95%CI 1.19 to 1.50; <0.001).
CONCLUSION
The study provides novel insights into the association between PD1NK cell profiles and prognosis of sepsis. Peripheral immunophenotyping could potentially stratify the septic patients and identify those with a high risk of 28-day mortality.
Topics: Humans; Sepsis; Male; Female; Programmed Cell Death 1 Receptor; Middle Aged; Aged; Killer Cells, Natural; Retrospective Studies; Biomarkers; Prognosis; Immunophenotyping; ROC Curve; Machine Learning
PubMed: 38953031
DOI: 10.3389/fimmu.2024.1426064 -
Frontiers in Immunology 2024Equine asthma (EA) is a common lower airway disease in horses, but whether its pathogenesis is allergic is ambiguous. Extrinsic stimuli like hay dust induce acute...
INTRODUCTION
Equine asthma (EA) is a common lower airway disease in horses, but whether its pathogenesis is allergic is ambiguous. Extrinsic stimuli like hay dust induce acute exacerbation of clinical signs and sustained local neutrophilic inflammation in susceptible horses. is an EA stimulus, but it is unclear if it merely acts as an IgE-provoking allergen. We aimed to comprehensively analyze immunoglobulin (Ig) isotypes in EA, elucidating their binding to different antigens, and their quantities systemically in serum and locally in bronchoalveolar lavage fluid (BALF).
METHODS
Serum and BALF from healthy horses (HE, = 18) and horses with mild-moderate asthma (MEA, = 20) or severe asthma (SEA, = 24) were compared. Ig isotype (IgG1, IgG3/5, IgG4/7, IgG6, IgA, and IgE) binding to nine antigens ( lysate, and recombinant Asp f 1, Asp f 7, Asp f 8, dipeptidyl-peptidase 5, class II aldolase/adducin domain protein, glucoamylase, beta-hexosaminidase, and peptide hydrolase) was compared by enzyme-linked immunosorbent assays. Total Ig isotype contents were determined by bead-based assays.
RESULTS
MEA and SEA differed from HE but hardly from each other. Compared to HE, asthmatic horses showed increased anti- binding of IgG (BALF and serum) and IgA (BALF). Serum and BALF IgE binding and total IgE contents were similar between HE and EA. Single antigens, as well as lysate, yielded similar Ig binding patterns. Serum and BALF IgG1 binding to all antigens was increased in SEA and to several antigens in MEA. Serum IgG4/7 binding to two antigens was increased in SEA. BALF IgA binding to all antigens was increased in SEA and MEA. Total BALF IgG1 and IgG4/7 contents were increased in SEA, and serum IgG4/7 content was increased in MEA compared to HE. Yet, total isotype contents differentiated EA and HE less clearly than antigen-binding Ig.
DISCUSSION
immunogenicity was confirmed without identification of single dominant antigens here. provoked elevated BALF IgG1 and IgA binding, and these isotypes appear relevant for neutrophilic EA, which does not support allergy. BALF Ig isotype differentiation beyond IgE is crucial for a comprehensive analysis of immune responses to fungi in EA pathogenesis.
Topics: Animals; Horses; Aspergillus fumigatus; Bronchoalveolar Lavage Fluid; Asthma; Immunoglobulin G; Immunoglobulin A; Horse Diseases; Antigens, Fungal; Male; Neutrophils; Female; Immunoglobulin E; Antibodies, Fungal
PubMed: 38953030
DOI: 10.3389/fimmu.2024.1406794 -
Frontiers in Immunology 2024Human Herpesvirus 6B (HHV-6B) impedes host immune responses by downregulating class I MHC molecules (MHC-I), hindering antigen presentation to CD8+ T cells....
INTRODUCTION
Human Herpesvirus 6B (HHV-6B) impedes host immune responses by downregulating class I MHC molecules (MHC-I), hindering antigen presentation to CD8+ T cells. Downregulation of MHC-I disengages inhibitory receptors on natural killer (NK) cells, resulting in activation and killing of the target cell if NK cell activating receptors such as NKG2D have engaged stress ligands upregulated on the target cells. Previous work has shown that HHV-6B downregulates three MHC-like stress ligands MICB, ULBP1, and ULBP3, which are recognized by NKG2D. The U20 glycoprotein of the related virus HHV-6A has been implicated in the downregulation of ULBP1, but the precise mechanism remains undetermined.
METHODS
We set out to investigate the role of HHV-6B U20 in modulating NK cell activity. We used HHV-6B U20 expressed as a recombinant protein or transduced into target cells, as well as HHV-6B infection, to investigate binding interactions with NK cell ligands and receptors and to assess effects on NK cell activation. Small-angle X-ray scattering was used to align molecular models derived from machine-learning approaches.
RESULTS
We demonstrate that U20 binds directly to ULBP1 with sub-micromolar affinity. Transduction of U20 decreases NKG2D binding to ULBP1 at the cell surface but does not decrease ULBP1 protein levels, either at the cell surface or in toto. HHV-6B infection and soluble U20 have the same effect. Transduction of U20 blocks NK cell activation in response to cell-surface ULBP1. Structural modeling of the U20 - ULBP1 complex indicates some similarities to the m152-RAE1γ complex.
Topics: Humans; Killer Cells, Natural; Herpesvirus 6, Human; GPI-Linked Proteins; NK Cell Lectin-Like Receptor Subfamily K; Lymphocyte Activation; Protein Binding; Viral Proteins; Glycoproteins; Intracellular Signaling Peptides and Proteins
PubMed: 38953028
DOI: 10.3389/fimmu.2024.1363156