Suppression Of Tumorigenicity Research Articles

The Association between Circulating Cytokines and Body Composition in Frail Patients with Cardiovascular Disease.

The burden of cardiovascular disease and the percentage of frail patients in the aging population will increase. This study aims to assess the circulating levels of several cytokines in frail patients. This is an ancillary analysis of the FRAPICA trial. The ratio of men/women changed from robust through frail groups from 3:1 to 1:2. The groups are comparable in terms of age and body measurements analysis (weight, height, and BMI), yet the frail patients have significantly reduced fat-free mass, and more often have been diagnosed with diabetes. Frail patients have higher fibroblast growth factor basic (FGF basic) and follistatin levels (borderline significance). In multiple linear regression modeling of fat-free mass, we identified FGF basic, osteopontin, stem cell factor, soluble suppression of tumorigenicity 2, soluble epidermal growth factor receptor, soluble human epidermal growth factor receptor 2, follistatin, prolactin, soluble interleukin 6 receptor alfa, platelet endothelial cell adhesion molecule 1, soluble vascular endothelial cell growth factor receptor 1, leptin, soluble angiopoietin/tyrosine kinase 2, and granulocyte colony-stimulating factor. We have identified a few cytokines that correlate with fat-free mass, a hallmark of frailty. They comprise the kinins implicated in bone and muscle metabolism, fibrosis, vascular wall function, inflammation, endocrine function, or regulation of bone marrow integrity.

Correlations of sST2 and Gal-3 with Cardiothoracic Ratio in Patients with Chronic Kidney Disease.

Chronic kidney disease (CKD) frequently correlates with cardiovascular complications. Soluble suppression of tumorigenicity 2 (sST2) and Galectin-3 (Gal-3) are emerging as cardiac markers with potential relevance in cardiovascular risk prediction. The cardiothoracic ratio (CTR), a metric easily obtainable from chest radiographs, has traditionally been used to assess cardiac size and the potential for cardiomegaly. Understanding the correlation between these cardiac markers and the cardiothoracic ratio (CTR) could provide valuable insights into the cardiovascular prognosis of CKD patients. This study aimed to explore the relationship between sST2, Gal-3, and the CTR in individuals with CKD. Plasma concentrations of sST2 and Gal-3 were assessed in a cohort of 123 CKD patients by enzyme-linked immunosorbent assay (ELISA). On a posterior-to-anterior chest X-ray view, the CTR was determined by comparing the widths of the heart to that of the thorax. The mean concentration of sST2 in the study participants ranged from 775.4 to 4475.6 pg/mL, and the mean concentration of Gal-3 ranged from 4.7 to 9796.0 ng/mL. Significant positive correlations were observed between sST2 and the CTR (r = 0.291, p < 0.001) and between Gal-3 and the CTR (r = 0.230, p < 0.01). Our findings indicate that elevated levels of sST2 and Gal-3 are associated with an increased CTR in CKD patients. This relationship may enable better cardiovascular risk evaluation for CKD patients. Further studies are warranted to explore the clinical implications of these associations.

Associations of MEFV gene variants, IL-33, and sST2 with the risk of Henoch-Schönlein purpura in children

ObjectiveHenoch-Schönlein purpura (HSP) is the most common systemic vasculitis in children. HSP is a multifactorial inflammatory disease, but its pathogenesis is still unclear. The pathogenicity of familial Mediterranean fever gene (MEFV) variants in HSP remains controversial. The objective of this study was to evaluate relationships between MEFV variants and susceptibility to HSP and their associations with clinical outcomes. We also investigated levels of IL-33 and soluble suppression of tumorigenicity 2 (sST2) in children with HSP and their clinical significance. MethodsWe selected 100 children with HSP as the case group. The control group consisted of 50 children who visited the hospital for physical health examinations. All subjects were screened for MEFV gene exon mutations, and levels of IL-33 and sST2 were measured. ResultsThe frequency of MEFV variants was significantly greater in HSP patients than in healthy controls. The variant with the highest frequency was E148Q. The frequency of the C allele of the MEFV variant E148Q was 32 % in HSP patients and 18 % in controls (P-adjust = 0.04). Patients with the MEFV E148Q variant had more frequent joint involvement and recurrent purpura and higher levels of IL-33 and C-reactive protein (CRP). Levels of IL-33 and sST2 in children with HSP were significantly higher than those in the control group, and the sST2/IL-33 ratio in children with HSP was unbalanced (P-adjust <0.05). Logistic regression analysis revealed the presence of E148Q and an unbalanced sST2/IL-33 ratio to be independent risk factors for HSP. ConclusionThe results of this study suggest that the MEFV variant E148Q is associated with HSP susceptibility in Chinese children and that carriers of the variant may have more severe clinical manifestations and greater inflammatory responses. E148Q and the sST2/IL-33 ratio may play important roles in the pathogenesis of HSP.

IL-33 aggravates extranodal NK/T cell lymphoma aggressiveness and angiogenesis by activating the Wnt/β-catenin signaling pathway.

Extranodal NK/T cell lymphoma (ENKTCL) is an extremely aggressive form of lymphoma and lacks of specific diagnostic markers. The study intended to unearth the role of interleukin-33 (IL-33) in ENKTCL. RT-qPCR was conducted to assess mRNA levels of ENKTCL tissues and cells, while western blot assay was performed for evaluating protein levels. Plate cloning experiment and transwell assay were employed to measure aggressiveness of ENKTCL. Tube formation assay was executed to determine the angiogenesis ability. Mice ENKTCL xenograft model was designed to probe the impacts of IL-33 in vivo. IL-33 and suppression of tumorigenicity 2 receptor (ST2, receptor of IL-33) were enhanced in ENKTCL. IL-33 inhibition suppressed viability, migration, and invasion of ENKTCL cells. Moreover, IL-33 knockdown restricted angiogenesis in human umbilical vein endothelial cells (HUVECs). Furthermore, Wnt/β-catenin pathway associated proteins (β-catenin, c-myc, and cyclin D1) were downregulated by loss of IL-33. However, these impacts were overturned by Wnt/β-catenin signaling agonist lithium chloride (LiCl). Additionally, IL-33 silencing exerted anti-tumor effect via Wnt/β-catenin pathway in vivo. Silencing of IL-33 inhibited ENKTCL tumorigenesis and angiogenesis by inactivating Wnt/β-catenin signaling pathway. As such, IL-33 might be a prospective treatment target for ENKTCL.

Analysis of clinical features of heart failure in children with cardiomyopathy and improved ejection fraction.

The prognosis of children with heart failure varies considerably. After treatment, left ventricular ejection fraction (LVEF) can be improved in some children. The aim of this study was to analyze the clinical features of children with heart failure accompanied by cardiomyopathy and recovered ejection fraction [heart failure with recovered ejection fraction (HFrecEF)] and to identify the predictors of improved LVEF. Children diagnosed with heart failure in Beijing Anzhen Hospital Affiliated to Capital Medical University from 2018 to 2021 were retrospectively enrolled. According to the baseline and change of LVEF, the patients were divided into two groups: a reduced ejection fraction (HFrEF) group and an HFrecEF group. The t-test was used to evaluate the difference between the two groups. The predictive factors of ejection fraction improvement were analyzed with a logistic regression model. A total of 72 children were included in this study, including 31 (43.1%) in the HFrEF group and 41 (56.9%) in the HFrecEF group. Compared with children in the HFrEF group, children in the HFrecEF group were younger and had faster resting heart rates, lower creatinine, lower suppression of tumorigenicity 2 (ST2) expression, a lower platelet-to-lymphocyte (PLT:LYM) ratio, and smaller left atrial diameter. After a mean follow-up of 35.87 months, 26 cases returned to normal ejection fraction. In the HFrEF group, sudden cardiac death occurred in two cases, and four cases received heart transplantation. Logistic analysis showed that virus infection [odds ratio (OR) =1.279; 95% confidence interval (CI): 0.374-4.379; P=0.007], low ST2 expression (cutoff value =1.89 ng/mL: OR =1.042; 95% CI: 1.007-1.082; P=0.032), and treatment with intravenous immunoglobulin (IVIG) (OR =5.077; 95% CI: 1.458-17.684; P=0.011) were predictors of improvement in LVEF in patients with heart failure after treatment. In some patients with HFrecEF, LVEF eventually returned to normal. The combination of viral infection, low ST2 expression, and the application of IVIG therapy were found to be independent predictors of LVEF improvement in patients with heart failure after treatment.

Role of Cardiac Biomarkers in Hepatic Disorders: A Literature Review.

Various studies have reported the association between cardiac markers and hepatic disorders. The main objective of this review article was to elucidate the significance of important cardiac indicators such as ischemia-modified albumin, cardiac troponin, cardiac natriuretic peptides, creatine kinase, creatine kinase-MB, lactate dehydrogenase, heart-type fatty acid-binding protein, osteopontin, soluble suppression of tumorigenicity 2, C-reactive protein, and lipoprotein(a) in the development of hepatic disorders. In addition, it highlighted recent notable discoveries and accomplishments in this field and identified areas requiring further investigation, ongoing discussions, and potential avenues for future research. Early identification and control of these cardiac markers might be helpful to control the prevalence of hepatic disorders associated with cardiovascular diseases.

Novel oncogenic transcriptional targets of mutant p53 in esophageal squamous cell carcinoma.

Missense mutations in the DNA binding domain of p53 are observed frequently in esophageal squamous cell carcinoma (ESCC). Recent studies have revealed the potentially oncogenic transcriptional networks regulated by mutant p53 proteins. However, majority of these studies have focused on common "hotspot" p53 mutations while rarer mutations are poorly characterized. In this study, we report the characterization of rare, "non-hotspot" p53 mutations from ESCC. In vitro tumorigenic assays performed following ectopic-expression of certain "non-hotspot" mutant p53 proteins caused enhancement of oncogenic properties in squamous carcinoma cell lines. Genome-wide transcript profiling of ESCC tumor samples stratified for p53 status, revealed several genes exhibiting elevated transcript levels in tumors harboring mutant p53. Of these, ARF6, C1QBP, and TRIM23 were studied further. Reverse transcription-quantitative PCR (RT-qPCR) performed on RNA isolated from ESCC tumors revealed significant correlation of TP53 transcript levels with those of the three target genes. Ectopic expression of wild-type and several mutant p53 forms followed by RT-qPCR, chromatin affinity-purification (ChAP), and promoter-luciferase assays indicated the exclusive recruitment of p53 mutants-P190T and P278L, to the target genes leading to the activation of expression. Several functional assays following knockdown of the target genes revealed a significant suppression of tumorigenicity in squamous carcinoma cell lines. Rescue experiments confirmed the specificity of the knockdown. The tumorigenic effects of the genes were confirmed in nude mice xenograft assays. This study has therefore identified novel oncogenic targets of "non-hotspot" mutant p53 proteins relevant for ESCC besides validating the functional heterogeneity of the spectrum of tumor-specific p53 mutations.

Prognostic value of morphological, biochemical, molecular markers of fibrosis in patients with hypertrophic cardiomyopathy

Hypertrophic cardiomyopathy (HCM) at the cellular level is characterized by hypertrophy, cardiomyocyte disorganization and myocardial fibrosis areas. The leading death cause in HCM remains sudden cardiac death (SCD). Despite the existing risk scores for SCD in HCM, there are still patients with uncertain SCD risk. In addition, SCD cases are also recorded among low-risk patients. From the above, search for novel markers for a more accurate risk assessment should be continued. Fibrosis is currently suspected to be a substrate of potentially life-threatening ventricular arrhythmias. Despite the increasingly widespread use of cardiac magnetic resonance imaging in the diagnosis of myocardial fibrosis and stratification of patients at high SCD risk, the determination of myocardial fibrosis biomarkers remains a relevant and promising area. The article presents the results of studies proving the diagnostic significance and relationship with the risk of life-threatening cardiac arrhythmias of the following markers: C-propeptide of type I procollagen, matrix metalloproteinase proteins, tissue inhibitor of metalloproteinases 1, microRNA family, soluble suppression of tumorigenicity 2, galectin-3, apelin. Evaluation of these biomarkers can be used to improve risk stratification of patients with HCM.

A Day 14 Endpoint for Acute GVHD Clinical Trials

The overall response rate (ORR) 28 days after treatment has been adopted as the primary endpoint for clinical trials of acute graft versus host disease (GVHD). However, physicians often need to modify immunosuppression earlier than day (D) 28, and non-relapse mortality (NRM) does not always correlate with ORR at D28. We studied 1144 patients that received systemic treatment for GVHD in the Mount Sinai Acute GVHD International Consortium (MAGIC) and divided them into a training set (n=764) and a validation set (n=380). We used a recursive partitioning algorithm to create a Mount Sinai model that classifies patients into favorable or unfavorable groups that predicted 12 month NRM according to overall GVHD grade at both onset and D14. In the Mount Sinai model grade II GVHD at D14 was unfavorable for grade III/IV GVHD at onset and predicted NRM as well as the D28 standard response model. The MAGIC algorithm probability (MAP) is a validated score that combines the serum concentrations of suppression of tumorigenicity 2 (ST2) and regenerating islet-derived 3-alpha (REG3α) to predict NRM. Inclusion of the D14 MAP biomarker score with the D14 Mount Sinai model created three distinct groups (good, intermediate, poor) with strikingly different NRM (8%, 35%, 76% respectively). This D14 MAGIC model displayed better AUC, sensitivity, positive and negative predictive value, and net benefit in decision curve analysis compared to the D28 standard response model. We conclude that this D14 MAGIC model could be useful in therapeutic decisions and may offer an improved endpoint for clinical trials of acute GVHD treatment.

Novel Biomarkers in Early Detection of Heart Failure: A Narrative Review.

Heart failure (HF) represents a significant global health challenge, characterized by a variety of symptoms resulting from cardiac dysfunction. This dysfunction often leads to systemic and pulmonary congestion. The pathophysiology of HF is complex, involving stimulation of the sympathetic nervous system, which is insufficiently balanced by the release of natriuretic peptide. This imbalance leads to progressive hypertrophy and dilatation of the heart's chambers, impairing its pumping efficiency and increasing the risk of arrhythmias and conduction disorders. The prevalence of HF is exceptionally high in industrialized nations and is expected to increase owing to an aging population and advancements in diagnostic methods. This study emphasizes the critical role of early diagnosis in reducing morbidity and mortality associated with HF, focusing specifically on the evolving importance of biomarkers in managing this condition. Biomarkers have played a key role in transforming the diagnosis and treatment of HF. Traditional biomarkers such as b-type natriuretic peptide and N-terminal pro-b-type natriuretic peptide have been widely adopted for their cost-effectiveness and ease of access. However, the rise of novel biomarkers such as growth differentiation factor 15 and adrenomedullin has shown promising results, offering superior sensitivity and specificity. These new biomarkers enhance diagnostic accuracy, risk stratification, and prognostic evaluation in HF patients. Despite these advancements, challenges remain, such as limited availability, high costs, and the need for further validation in diverse patient populations. Through a comprehensive literature review across databases such as PubMed, Google Scholar, and the Cochrane Library, this study compiles and analyzes data from 18 relevant studies, offering a detailed understanding of the current state of HF biomarkers.The study examines both traditional and emerging biomarkers such as galectin-3 and soluble suppression of tumorigenicity 2 in HF, exploring their clinical roles and impact on patient outcomes.

In vitro evolution of diagnostic antibodies targeting native antigens in plasma by sandwich flow cytometry.

Monoclonal antibodies (mAbs) that recognize and bind to specific antigens (Ags) have a wide range of applications in research, therapy, and diagnostics. However, many of these antibodies cannot bind well to the native Ags. In this study, based on the Chinese hamster ovary (CHO) cell display platform developed previously in our lab, we reported a novel artificial evolution procedure to improve the affinity of mAb against the native Ag directly using the plasma samples without purification of the native Ag. In this procedure, a pair of antibodies able to bind the Ag in sandwich manner are first confirmed (Ab1/Ab2) and the antibody (Ab) to be affinity-improved (Ab1) is displayed on CHO cells for Ab mutation. Then the cells were detected and sorted with flow cytometry in the form of Ab1-Ag-fluorescence labeled Ab2, which we named sandwich flow cytometry. Here, we used soluble isoform of suppression of tumorigenicity 2 (sST2) protein as model Ag, carried out "sandwich" maturation directly using the plasma samples containing the native sST2 protein and optimized a pair of antibodies with significantly improved sensitivity in the detection of the native sST2 in plasma. This method could be very useful in optimization of the diagnostic Ab pairs working in a "sandwich" manner if more antibodies were also successfully affinity-matured with this method.

Evaluation of soluble suppression of tumorigenicity 2 (sST2) as serum marker for liver fibrosis

Background & aimsWith the increase in patients at risk of advanced liver disease due to the obesity epidemic, there will be a need for simple screening tools for advanced liver fibrosis. Soluble suppression of tumorigenicity 2 (sST2) is a serum biomarker for fibrotic processes. The aim of this study was to evaluate sST2 as marker for liver fibrosis in patients successfully treated for chronic hepatitis C.Methods424 patients from the Swiss Hepatitis C Cohort Study were screened for inclusion in this post-hoc cohort study. Inclusion criteria were sustained virological response (SVR), available elastography (VCTE) and serum samples for biomarker analysis before and after treatment. For the validation of sST2, values were compared to VCTE, FIB-4 and APRI using Spearman’s correlation and AUROC analyses.ResultsData of 164 subjects were finally analyzed. Median sST2 values slightly increased with VCTE-derived fibrosis stages and remained stable after reaching SVR within the respective fibrosis stage, suggesting that sST2 is not influenced by liver inflammation. However, correlation of sST2 pre- and post-treatment with VCTE was fair (Spearman’s rho = 0.39 and rho = 0.36). The area under the curve (AUROC) for sST2 in detecting VCTE-defined F4 fibrosis (vs. F0-F3) before therapy was 0.74 (95%CI 0.65–0.83), and 0.67(95%CI 0.56–0.78) for the discrimination of F3/F4 fibrosis vs. F0-F2. Adding sST2 to either APRI or FIB-4, respectively, increased diagnostic performance of both tests.ConclusionssST2 can potentially identify patients with advanced fibrosis as a single serum marker and in combination with APRI and FIB-4.

Activation of interleukin 33-NFκB axis in granulosa cells during atresia and its role in disposal of atretic follicles†.

It has been previously shown that the cytokine interleukin 33 is required for two processes, i.e., autophagic digestion of granulosa cells and recruitment of macrophages into atretic follicles, for full disposal of atretic follicles. Now, this study shows that activation of interleukin 33-suppression of tumorigenicity 2-Nuclear Factor ĸB (NFκB) axis in granulosa in early atretic follicles may regulate those two events. Injection of human chorionic gonadotropin has been shown to induce a transient peak of interleukin 33 expression with synchronized atresia. In this model, interleukin 33-independent expression of suppression of tumorigenicity 2 in granulosa cells was detected in early atretic follicles before macrophage invasion. The activation of NFκB pathway in ovaries was further demonstrated in vivo in Tg mice with luciferase-reporter for NFκB activation; the activation was microscopically localized to granulosa cells in early atretic follicles. Importantly, antibody blockage of interleukin 33 or interleukin 33 Knock-out (KO) (Il33-/-) not only inhibited NFκB activity in ovaries, but it also altered expression of two key genes, i.e., reduction in proinflammatory interleukin6 (IL6) expression, and a surge of potential autophagy-inhibitory mammalian target of rapamycin (mTOR) expression in atretic follicles. By contrast, apoptosis and other genes, such as interleukin1β (IL1β) were not affected. In conclusion, in parallel to apoptosis, atresia signals also trigger activation of the interleukin 33-suppression of tumorigenicity 2-NFκB pathway in granulosa, which leads to (1) down-regulated expression of mTOR that is a negative regulator of autophagy and (2) up-regulated expression of proinflammatory IL6.

Heart transplantation and biomarkers: a review about their usefulness in clinical practice.

Advanced heart failure (AdvHF) can only be treated definitively by heart transplantation (HTx), yet problems such right ventricle dysfunction (RVD), rejection, cardiac allograft vasculopathy (CAV), and primary graft dysfunction (PGD) are linked to a poor prognosis. As a result, numerous biomarkers have been investigated in an effort to identify and prevent certain diseases sooner. We looked at both established biomarkers, such as NT-proBNP, hs-troponins, and pro-inflammatory cytokines, and newer ones, such as extracellular vesicles (EVs), donor specific antibodies (DSA), gene expression profile (GEP), donor-derived cell free DNA (dd-cfDNA), microRNA (miRNA), and soluble suppression of tumorigenicity 2 (sST2). These biomarkers are typically linked to complications from HTX. We also highlight the relationships between each biomarker and one or more problems, as well as their applicability in routine clinical practice.

Interleukin-33/ST2 axis involvement in atrial remodeling and arrhythmogenesis

Interleukin (IL)-33, a cytokine involved in immune responses, can activate its receptor, suppression of tumorigenicity 2 (ST2), is elevated during atrial fibrillation (AF). However, the role of IL-33/ST2 signaling in atrial arrhythmia is unclear. This study explored the pathological effects of the IL-33/ST2 axis on atrial remodeling and arrhythmogenesis. Patch clamping, confocal microscopy, and Western blotting were used to analyze the electrical characteristics of and protein activity in atrial myocytes (HL-1) treated with recombinant IL-33 protein and/or ST2-neutralizing antibodies for 48 hrs. Telemetric electrocardiographic recordings, Masson's trichrome staining, and immunohistochemistry staining of the atrium were performed in mice receiving tail vein injections with nonspecific immunoglobulin (control), IL-33, and IL-33 combined with anti-ST2 antibody for 2 weeks. IL-33-treated HL-1 cells had a reduced action potential duration, lower L-type Ca2+ current, greater sarcoplasmic reticulum (SR) Ca2+ content, increased Na+/Ca2+ exchanger (NCX) current, elevation of K+ currents, and increased intracellular calcium transient. IL-33-treated HL-1 myocytes had greater activation of the calcium–calmodulin-dependent protein kinase II (CaMKII)/ryanodine receptor 2 (RyR2) axis and nuclear factor kappa B (NF-κB) / NLR family pyrin domain containing 3 (NLRP3) signaling than did control cells. IL-33 treated cells also had greater expression of Nav1.5, Kv1.5, NCX, and NLRP3 than did control cells. Pretreatment with neutralizing anti-ST2 antibody attenuated IL-33-mediated activation of CaMKII/RyR2 and NF-κB/NLRP3 signaling. IL-33-injected mice had more atrial ectopic beats and increased AF episodes, greater atrial fibrosis, and elevation of NF-κB/NLRP3 signaling than did controls or mice treated with IL-33 combined with anti-ST2 antibody. Thus, IL-33 recombinant protein treatment promotes atrial remodeling through ST2 signaling. Blocking the IL-33/ST2 axis might be an innovative therapeutic approach for patients with atrial arrhythmia and elevated serum IL-33.

Relationship between serum soluble suppression of tumorigenicity (ST) 2 and global longitudinal strain in early onset preeclampsia

BackgroundPreeclampsia is one of the leading causes of death in childbearing women worldwide. Hemodynamic changes in preeclampsia can trigger cardiac remodeling as indicated by increase of soluble-ST2 (sST2). Global longitudinal strain were able to detect systolic dysfunction better than the ejection fraction. This study aims to evaluate the correlation between serum levels of sST2 towards GLS in patients with early-onset preeclampsia.MethodsThis is a cross-sectional observational study with correlation analysis. Subjects were patients with severe preeclampsia with gestational age before 34 weeks at Dr. Hasan Sadikin Central General Hospital Bandung and Bandung Kiwari Regional General Hospital from June to August 2022. Examination of sST2 was carried out through blood samples using the ELISA method. sST2 was measured using Presage ST2 Assay reagent. GLS examination was carried out using speckle tracking technique with EchoPAC. Correlation analysis was conducted using the Pearson test if normally distributed, otherwise Spearman’s correlation was conducted. Correlation analysis was followed by linear regression.ResultsA total of 30 patients met the inclusion criteria. The mean age was 30.83 ± 7.09, with 17 (56.7%) multiparous patients. The median sST2 was 145.75 ng/mL, and the median GLS was − 17.4%. Spearman correlation analysis showed that there was a significant positive correlation with moderate strength between sST2 and GLS (r = 0.583; p < 0.002). Linear regression showed that every 1 ng/ml increase in sST2 would give an increase in GLS of 0.014%.ConclusionThere is a significant correlation between sST2 and GLS in patients with early onset severe preeclampsia.

Predictive value of soluble suppression of tumorigenicity 2 in atrial fibrillation: a systematic review and meta-analysis.

Atrial fibrosis is the main pathological basis for the pathogenesis and progression of atrial fibrillation (AF). Soluble suppression of tumorigenicity 2 (sST2) is involved in fibrosis. Recent studies have explored its predictive value in AF outcomes. We performed this study to assess whether sST2 is an independent biomarker of AF outcomes and explore the potential mechanism. PubMed, Web of Science, EMBASE, and Cochrane Library databases were searched systematically from inception through July 1, 2023, to identify relevant studies. Outcomes of interest included occurrence, recurrence, and major adverse cardiac events (MACEs) of AF. This meta-analysis was reported following the criteria outlined in PRISMA 2020, and the protocol was registered in PROSPERO (number: CRD42023459789). All statistical analyses were performed using the STATA version 16. Twenty four studies with 14,755 patients were included in the meta-analysis. The meta-analyses found that sST2 was significantly associated with the risk of occurrence [HR:1.04, 95% CI: 1.02-1.07, P < 0.01; I2 = 67.8%], recurrence [HR:1.09, 95% CI: 1.02-1.16, P < 0.01; I2 = 89.5%], and MACEs (HR:1.60, 95% CI: 1.13-2.27, P < 0.01; I2 = 82.0%) of AF. Furthermore, patients with AF showed higher sST2 than controls without AF (SMD: 0.41, 95% CI: 0.27-0.54, P < 0.01; I2 = 0%), and AF patients with recurrence after catheter ablation (CA) showed significantly higher sST2 than those without recurrence (SMD: 0.81, 95% CI: 0.33-1.28, P < 0.01; I2 = 83.9%). Sensitivity analyses showed that the outcomes were stable. Higher sST2 was association with an increased risk of occurrence, recurrence, and MACEs of AF. Assessing sST2 can be used as a potential screening method to predict AF outcomes. PROSPERO (CRD42023459789).

ST2-Mediated Neutrophilic Airway Inflammation: A Therapeutic Target for Patients With Uncontrolled Asthma.

Suppression of tumorigenicity 2 (ST2) has been proposed as the receptor contributing to neutrophilic inflammation in patients with type 2-low asthma. However, the exact role of ST2 in neutrophil activation remains poorly understood. A total of 105 asthmatic patients (classified into 3 groups according to control status: the controlled asthma [CA], partly-controlled asthma [PA], and uncontrolled asthma [UA] groups), and 104 healthy controls were enrolled to compare serum levels of soluble ST2 (sST2) and interleukin (IL)-33. Moreover, the functions of ST2 in neutrophils and macrophages (Mϕ) were evaluated ex vivo and in vivo. Serum sST2 levels were significantly higher in the UA group than in the CA or PA groups (P < 0.05 for all) with a negative correlation between serum sST2 and forced expiratory volume in 1 second % (r = -0.203, P = 0.038). Significantly higher expression of ST2 receptors on peripheral neutrophils was noted in the UA group than in the PA or CA groups. IL-33 exerted its effects on the production of reactive oxygen species, the formation of extracellular traps from neutrophils, and Mϕ polarization/activation. In neutrophilic asthmatic mice, treatment with anti-ST2 antibody significantly suppressed proinflammatory cytokines (tumor necrosis factor-alpha and IL-17A) as well as the numbers of immune cells (neutrophils, Mϕ, and group 3 innate lymphoid cells) in the lungs. These results suggest that IL-33 induces the activation of neutrophils and Mϕ via ST2 receptors, leading to neutrophilic airway inflammation and poor control status of asthma. ST2 could be a therapeutic target for neutrophilic airway inflammation in patients with UA.

Иммунные механизмы нейтрофильного воспаления при бронхиальной астме

This review presents an analysis of scientific publications in recent years devoted to the study of cellular and molecular mechanisms of neutrophilic airway inflammation as potential therapeutic targets in the treatment of severe, poorly controlled asthma of the neutrophil phenotype, the presence of which is still debated and there is no generally accepted definition. The conditional term "neutrophilic asthma" implies the existence of a certain asthma endotype, in which neutrophils are the main type of cells mediating the pathophysiology and disease symptoms. The involvement of the inverted protein response associated with endoplasmic reticulum (ER) stress and the sensory signal transduction protein in the endoplasmic reticulum membrane in the deregulation of the T helper 17 (Th17) cells function and neutrophilic airway inflammation is considered. Polarization and activation of M1 macrophages play an important role in the neutrophilic inflammation immunopathogenesis, in particular, in asthma associated with obesity. Soluble suppression of tumorigenicity 2 protein is considered as a receptor that promotes neutrophil activation and neutrophilic inflammation. The involvement of neutrophil extracellular traps and the respiratory tract microbiome in the neutrophilic inflammation progression, in particular, the role of bacterial outer membrane vesicles, is discussed. KEYWORDS: neutrophils, neutrophilic inflammation, asthma, Th17 cells, M1 macrophages, suppression of tumorigenicity 2 protein, neutrophil extracellular traps, respiratory tract microbiome. FOR CITATION: Kuzubova N.A., Lebedeva E.S. Immune mechanisms of neutrophilic inflammation in asthma. Russian Medical Inquiry. 2024;8(8):453–458 (in Russ.). DOI: 10.32364/2587-6821-2024-8-8-2.

HucMSC-Ex alleviates DSS-induced colitis in mice by decreasing mast cell activation via the IL-33/ST2 axis.

Inflammatory bowel disease (IBD) is a chronic inflammatory disease that poses challenges in terms of treatment. The precise mechanism underlying the role of human umbilical cord mesenchymal stem cell-derived exosome (HucMSC-Ex) in the inflammatory repair process of IBD remains elusive. Mucosal mast cells accumulate within the intestinal tract and exert regulatory functions in IBD, thus presenting a novel target for addressing this intestinal disease. A mouse model of Dextran Sulfate Sodium (DSS)-induced colitis was established and hucMSC-Ex were administered to investigate their impact on the regulation of intestinal mast cells. An in vitro co-culture model using the human clonal colorectal adenocarcinoma cell line (Caco-2) and human mast cell line (LAD2) was also established for further exploration of the effect of hucMSC-Ex. We observed the accumulation of mast cells in the intestines of patients with IBD as well as mice. In colitis mice, there was an upregulation of mast cell-related tryptase, interleukin-33 (IL-33), and suppression of tumorigenicity 2 receptor (ST2 or IL1RL1), and the function of the intestinal mucosal barrier related to intestinal tight junction protein was weakened. HucMSC-Ex treatment significantly reduced mast cell infiltration and intestinal damage. In the co-culture model, a substantial number of mast cells interact with the epithelial barrier, triggering activation of the IL-33/IL1RL1 (ST2) pathway and subsequent release of inflammatory factors and trypsin. This disruption leads to aberrant expression of tight junction proteins, which can be alleviated by supplementation with hucMSC-Ex. Our results suggest that hucMSC-Ex may reduce the release of mast cell mediators via the IL-33/IL1RL1 (ST2) axis, thereby mitigating its detrimental effects on intestinal barrier function.