Serum S100A12 Levels Research Articles

High Serum S100A12 as a Diagnostic and Prognostic Biomarker for Severity, Multidrug-Resistant Bacteria Superinfection and Herpes Simplex Virus Reactivation in COVID-19.

Neutrophils are critical immune cells in severe coronavirus disease 2019 (COVID-19). S100 calcium-binding protein A12 (S100A12) is highly expressed in neutrophils during acute inflammation. The aim of this study was to evaluate serum S100A12 levels as a diagnostic and prognostic tool in COVID-19. Serum samples of patients with moderate and severe COVID-19 were collected during 2020 to 2024. Enzyme-linked immunosorbent assay was used to measure serum S100A12 levels in 63 patients with moderate COVID-19, 60 patients with severe disease and 33 healthy controls. Serum S100A12 levels were elevated in moderate COVID-19 compared to controls and were even higher in severe cases. In moderate disease, serum S100A12 levels positively correlated with immune cell counts. While C-reactive protein and procalcitonin are established inflammation markers, they did not correlate with serum S100A12 levels in either patient cohort. Patients with severe COVID-19 and vancomycin-resistant enterococcus (VRE) infection had increased S100A12 levels. Elevated S100A12 levels were also observed in patients with herpes simplex reactivation. Fungal superinfections did not alter S100A12 levels. These data show that serum S100A12 increases in moderate and severe COVID-19 and is further elevated by VRE bloodstream infection and herpes simplex reactivation. Therefore, S100A12 may serve as a novel biomarker for severe COVID-19 and an early diagnostic indicator for bacterial and viral infections.

S100 Calcium-Binding Protein A9, a Potential Novel Diagnostic Biomarker for Idiopathic Pulmonary Fibrosis.

Neutrophilic inflammation is a characteristic feature of idiopathic pulmonary fibrosis (IPF). S100 calcium-binding protein A9 (S100A9) is a neutrophil-derived protein involved in the development of neutrophil-related chronic inflammatory disorders. However, the role of S100A9 in IPF remains unclear. We used enzyme-linked immunosorbent assays to measure S100A9 levels in bronchoalveolar lavage fluid (BALF) and serum obtained from healthy controls (HCs) and patients with IPF, non-specific interstitial pneumonia, hypersensitivity pneumonitis, and sarcoidosis. Compared with HCs, BALF S100A9 levels were significantly higher in IPF patients (P < 0.001), patients with hypersensitivity pneumonitis (P = 0.043), and patients with nonspecific interstitial pneumonia (P < 0.001). The S100A9 level in BALF of 0.093 ng/mL could distinguish IPF patients from HCs, with a specificity of 78.8% and a sensitivity of 81.6%. Similarly, the S100A9 level in BALF of 0.239 ng/mL had a specificity of 64.7% and a sensitivity of 66.7% for distinguishing IPF patients from patients with other interstitial lung diseases. Additionally, BALF S100A9 levels were significantly correlated with neutrophil counts (r = 0.356, P < 0.001) in BALF. IPF patients with S100A9 levels in BALF > 0.533 ng/mL had lower survival rates, compared with patients who had levels ≤ 0.553 ng/mL (n = 49; hazard ratio [HR], 3.62; P = 0.021). Combination analysis revealed that IPF patients with S100A9 levels in BALF> 0.553 ng/mL or neutrophil percentages > 49.1% (n = 43) had significantly lower survival rates than patients with S100A9 levels in BALF ≤ 0.553 ng/mL and neutrophil percentages ≤ 49.1% (n = 41) (HR, 3.91; P = 0.014). Additionally, patients with serum S100A9 levels > 0.077 ng/mL (n = 29) had significantly lower survival rates than patients with levels ≤ 0.077 ng/mL (n = 53, HR, 2.52; P = 0.013). S100A9 was expressed on neutrophils and macrophages in BALF from IPF patients as well as α-smooth muscle actin positive cells in the lung tissues. S100A9 is involved in the development and progression of IPF. Moreover, S100A9 levels in BALF and serum may be surrogate markers for IPF diagnosis and survival prediction, particularly when analyzed in combination with neutrophil percentages.

Prognostic significance of peripheral blood S100A12, S100A8, and S100A9 concentrations in idiopathic pulmonary fibrosis

BackgroundS100A12, S100A8, and S100A9 are inflammatory disease biomarkers whose functional significance in idiopathic pulmonary fibrosis (IPF) remains unclear. We evaluated the significance of S100A12, S100A8, and S100A9 levels in IPF development and prognosis. MethodsThe dataset was collected from the Gene Expression Omnibus (GEO) database and differentially expressed genes were screened using GEO2R. We conducted a retrospective study of 106 patients with IPF to explore the relationships between different biomarkers and poor outcomes. Pearson’s correlation coefficient, Kaplan–Meier, Cox regression, and functional enrichment analyses were used to evaluate relationships between these biomarkers’ levels and clinical parameters or prognosis. ResultsSerum levels of S100A12, S100A8, and S100A9 were significantly elevated in patients with IPF. The two most significant co-expression genes of S100A12 were S100A8 and S100A9. Patients with levels of S100A12 (median 231.21 ng/mL), S100A9 (median 57.09 ng/mL) or S100A8 (median 52.20 ng/mL), as well as combined elevated S100A12, S100A9, and S100A8 levels, exhibited shorter progression-free survival and overall survival. Serum S100A12 and S100A8, S100A12 and S100A9, S100A9 and S100A8 concentrations also displayed a strong positive correlation (rs2 = 0.4558, rs2 = 0.4558, rs2 = 0.6373; P < 0.001). S100A12 and S100A8/9 concentrations were independent of FVC%, DLCO%, and other clinical parameters (age, laboratory test data, and smoking habit). Finally, in multivariate analysis, the serum levels of S100A12, S100A8, and S100A9 were significant prognostic factors (hazard ratio 1.002, P = 0.032, hazard ratio 1.039, P = 0.001, and hazard ratio 1.048, P = 0.003). ConclusionsS100A12, S100A8, and S100A9 are promising circulating biomarkers that may aid in determining IPF patient prognosis. Multicenter clinical trials are needed to confirm their clinical value.

The role of S100A12 and Toll-like receptor 4 in assessment of disease activity in familial Mediterranean fever and juvenile idiopathic arthritis.

Our aim was to investigate the possible relationship between the serum S100A12 and Toll-like receptor 4 (TLR4) levels, and the activity of familial Mediterranean fever (FMF) and juvenile idiopathic arthritis (JIA) in accordance with the routine biochemical parameters. Furthermore, the effectiveness of these 2 biomarkers in distinguishing FMF from JIA has been evaluated. Sixty-nine children with FMF, 68 children with JIA, and 35 healthy children were included in this study. S100A12 and TLR4 levels were measured by the sandwich enzyme-linked immunosorbent assay technique. In the FMF patient group, serum S100A12 level was found to be significantly higher than in both the JIA and control groups (P=.000 and P=.000, respectively). Although S100A12 levels were higher in the attack period compared to the attack-free period, this increase was not statistically significant (P > .05). TLR4 levels were statistically significantly higher in the attack period compared to the attack-free period in children with FMF (P < .05). Although there was no relationship between S100A12 levels and disease activity, there is a clear correlation between S100A12 and the Auto-Inflammatory Disease Activity Index in attack-free FMF patients (r=0.612 P=.000). Serum S100A12 levels were not found to be a potentially valuable biomarker for assessing disease activity in either FMF or JIA. However, TLR4 levels were found to be a valuable biomarker for assessing disease activity in children with FMF. Further research which includes serial monitoring of S100A12 and TLR4 levels in a large cohort will provide detailed information about accuracy of these 2 potential biomarkers in both patients group.

Increased serum S100A12 levels are associated with higher risk of acute heart failure in patients with type 2 diabetes.

The hyperglycaemic stress induces the release of inflammatory proteins such as S100A12, one of the endogenous ligands of the receptors for advanced glycation end products (RAGE). Chronic activation of RAGE has multiple deleterious effects in target tissues such as the heart and the vessels by promoting oxidative stress, inflammation by the release of cytokines, macrophages infiltration, and vascular cell migration and proliferation, causing ultimately endothelial cell and cardiomyocyte dysfunction. The aim of our study was to investigate the prognostic value of circulating S100A12 beyond established cardiovascular risk factors (CVRF) for heart failure (HF) and major adverse cardiovascular events (MACE) in a cohort of patients with type 2 diabetes. Serum S100A12 concentrations were measured at baseline in 1345 type 2 diabetes patients (58% men, 64±11years) recruited in the SURDIAGENE prospective cohort. Endpoints were the occurrence of acute HF requiring hospitalization (HHF) and MACE. We used a proportional hazard model adjusted for established CVRF (age, sex, duration of diabetes, estimated glomerular filtration rate, albumin/creatinine ratio, history of coronary artery disease) and serum S100A12. During the median follow-up of 84months, 210 (16%) and 505 (38%) patients developed HHF and MACE, respectively. Baseline serum S100A12 concentrations were associated with an increased risk of HHF [hazard ratio (HR) (95% confidence interval) 1.28 (1.01-1.62)], but not MACE [1.04 (0.90-1.20)]. After adjustment for CVRF, S100A12 concentrations remained significantly associated with an increased risk of HHF [1.29 (1.01-1.65)]. In a sub-analysis, patients with high probability of pre-existing HF [N terminal pro brain natriuretic peptide (NT-proBNP) >1000pg/mL, n=87] were excluded. In the remaining 1258 patients, the association of serum S100A12 with the risk of HHF tended to be more pronounced [1.39 (1.06-1.83)]. When including the gold standard HF marker NT-proBNP in the model, the prognostic value of S100A12 for HHF did not reach significance. Youden method performed at 7years for HHF prediction yielded an optimal cut-off for S100A12 concentration of 49ng/mL (sensitivity 53.3, specificity 52.2). Compared with those with S100A12≤49ng/mL, patients with S100A12>49ng/mL had a significantly increased risk of HHF in the univariate model [HR=1.58 (1.19-2.09), P=0.0015] but also in the multivariate model [HR=1.63 (1.23-2.16), P=0.0008]. After addition of NT-proBNP to the multivariate model, S100A12>49ng/mL remained associated with an increased risk of HHF [HR=1.42 (1.07-1.90), P=0.0160]. However, the addition of S100A12 categories on top of multivariate model enriched by NT-pro BNP did not improve the ability of the model to predict HHF (relative integrated discrimination improvement=1.9%, P=0.1500). In patients with type 2 diabetes, increased serum S100A12 concentration is independently associated with risk of HHF, but not with risk of MACE. Compared with NT-proBNP, the potential clinical interest of S100A12 for the prediction of HF events remains limited. However, S100A12 could be a candidate for a multimarker approach for HF risk assessment in diabetic patients.

Elevated serum S100A12 levels are associated with increased risk of heart failure in patients with type 2 diabetes: the SURDIAGENE prospective study

The hyperglycemic stress induces the release of inflammatory proteins such as S100A12, one of the endogenous ligands of the receptors for advanced glycation end products (RAGE). Chronic activation of RAGE favors vascular disease and cardiac dysfunction. The aim of our study was to investigate the prognostic value of circulating S100A12 for predicting major adverse cardiovascular events (MACE) and acute heart failure (AHF) in patients with type 2 diabetes (T2D) beyond established cardiovascular (CV) risk factors. Serum S100A12 levels were measured at baseline in T2D patients recruited in the SURDIAGENE prospective cohort. Outcomes were defined as occurrence of AHF requiring hospitalization, MACE and all-cause death. We used a proportional hazard model, and adjustments were performed for established CV risk factors. Among 1345 patients, 210 developed AHF, 505 MACE, and 446 died during a median follow-up of 84 months. Baseline serum S100A12 levels were associated with an increased risk of AHF (HR [95%CI] 1.28 [1.01-1.62], P = 0.0436), but neither death ( P = 0.1658) nor MACE ( P = 0.600). After adjustment for CV risk factors, S100A12 levels remained significantly associated with an increased risk of AHF (HR = 1.29 [1.01-1.65], P = 0.0422). After exclusion of 217 patients with basal NT-proBNP levels > 450 pg/ml suggesting pre-existing chronic HF, the predictive value of baseline serum S100A for future AHF events tended to be more significant (HR = 1.45 [1.06-1.97], P = 0.0202). In patients with T2D, increased serum S100A12 levels are independently associated with risk of future AHF events, but neither with risk of MACE nor death.

Serum S100A12 levels in children with childhood-onset systemic lupus erythematosus, systemic juvenile arthritis, and systemic undefined recurrent fevers.

We compared serum levels of S100A12, aproinflammatory protein predominantly secreted by neutrophils, in children with newly diagnosed childhood-onset systemic lupus erythematosus (cSLE), systemic juvenile arthritis (sJIA), and systemic undefined recurrent fevers (SURFS) to examine its role as adiagnostic and discriminative marker of inflammation and to indirectly point out the importance of neutrophils and innate immunity in the pathogenesis of these diseases. In across-sectional study, the serum levels of S100A12 protein of 68children (19with cSLE, 18with sJIA, 7with SURFS, and 24controls) were determined by enzyme-linked immunosorbent assay and compared between groups and with clinical and laboratory findings. The median serum S100A12 levels were 469 ng/mL in the cSLE group, 6103 ng/mL in the sJIA group, 480 ng/mL in the SURFS group, and 44 ng/mL in the control group. Children with cSLE, sJIA, and SURFS had significantly higher serum S100A12 levels compared to the control group (p < 0.0001). sJIA patients had the highest levels of S100A12 in comparison to other patients (p < 0.0001), while there was no significant difference between children with cSLE and SURFS. Elevated serum SA100A12 levels in children with cSLE, sJIA, and SURFS may indicate intense neutrophil activation, which may play an important role in innate immunity in chronic inflammation in these diseases. Serum S100A12 levels could be used as adiagnostic marker of inflammation and be suitable for distinguishing sJIA and other disorders.

Serum S100A8 and S100A9 as prognostic biomarkers in acute exacerbation of idiopathic pulmonary fibrosis.

Acute exacerbation of idiopathic pulmonary fibrosis (AE-IPF) is a devastating and life-threatening condition during its clinical course. Biomarkers for precisely anticipating the prognosis of AE-IPF remain to be fully established. The objective of this study was to clarify whether S100A8 and S100A9, which are calcium-binding proteins mainly produced by activated neutrophils, are significant prognostic biomarkers in AE-IPF. Thirty-seven patients with AE-IPF who were diagnosed and treated at our hospital were retrospectively evaluated. The serum levels of S100A8 and S100A9 were measured using enzyme-linked immunosorbent assay, and the relationships between these levels and clinical parameters or prognosis were evaluated. The serum levels of S100A8 (median 386.5ng/mL) and S100A9 (median 60.2ng/mL) in patients with AE-IPF were significantly higher than those in age-matched healthy controls and in patients at IPF diagnosis (p<0.001 for all combinations). The serum levels of S100A8 negatively correlated with percent forced vital capacity (r=-0.356, p=0.049) and positively correlated with peripheral white blood cell number (r=0.509, p=0.002). Immunohistochemical staining of autopsy lung specimens showed that neutrophils, present mainly in the alveolar septum, were positive for S100A8 and S100A9. Patients with AE-IPF with higher levels of S100A8 or S100A9 showed significantly worse 3-month survival than those with lower levels (log-rank test, both p=0.028). Finally, in multivariate analysis, the serum levels of both S100A8 and S100A9 were significant prognostic factors (hazard ratio 4.032, p=0.023 and hazard ratio 4.327, p=0.012). The serum levels of S100A8 and S100A9 at AE were significant prognostic biomarkers in patients with AE-IPF.

High Serum S100A12 Levels Predict Poor Outcome After Acute Primary Intracerebral Hemorrhage.

ObjectiveIntracerebral hemorrhage (ICH) triggers an inflammatory cascade that damages brain tissues and worsens functional outcome. S100A12 functions to promote brain inflammation. We aimed to investigate the relationship between serum S100A12 levels and functional outcome in ICH patients.MethodsSerum S100A12 levels were measured in 101 ICH patients hospitalized within 24 h after symptom onset. Poor functional outcome was defined as a modified Rankin scale of 3 or greater at 3 months after stroke. Early neurologic deterioration was defined as an increase of ≥4 points in the National Institutes of Health Stroke Scale (NIHSS) score or death at 24 hours from symptoms onset.ResultsHigh serum S100A12 levels were independently correlated with NIHSS score (t = 5.384, P < 0.001), hematoma volume (t = 4.221, P < 0.001) and serum C-reactive protein levels (t = 5.068, P < 0.001). Serum S100A12 levels were substantially higher in patients with a poor outcome (median, 66.5 versus 37.7 ng/mL; P < 0.001) or early neurological deterioration (median, 76.5 versus 40.1 ng/mL; P < 0.001) than in the other remainders, independently predicted a poor outcome (odds ratio, 1.035; 95% confidence interval, 1.007–1.064; P = 0.015) and early neurologic deterioration (odds ratio,1.032; 95% confidence interval, 1.003–1.060; P = 0.027), and significantly discriminated a poor outcome (area under curve, 0.794; 95% confidence interval, 0.702–0.868) and early neurologic deterioration (area under curve, 0.760; 95% confidence interval, 0.664–0.839) under receiver operating characteristic curve.ConclusionHigh serum S100A12 levels at admission are highly associated with the extent of inflammatory response, severity, a poor functional outcome and early neurologic deterioration in ICH patients, substantializing serum S100A12 as a promising prognostic biomarker for ICH.

Long-Term Elevated Inflammatory Protein Levels in Asymptomatic SARS-CoV-2 Infected Individuals.

The clinical features of SARS-CoV-2 infection range from asymptomatic to severe disease with life-threatening complications. Understanding the persistence of immune responses in asymptomatic individuals merit special attention because of their importance in controlling the spread of the infections. We here studied the antibody and T cell responses, and a wide range of inflammation markers, in 56 SARS-CoV-2 antibody-positive individuals, identified by a population screen after the first wave of SARS-CoV-2 infection. These, mostly asymptomatic individuals, were reanalyzed 7-8 months after their infection together with 115 age-matched seronegative controls. We found that 7-8 months after the infection their antibodies to SARS-CoV-2 Nucleocapsid (N) protein declined whereas we found no decrease in the antibodies to Spike receptor-binding domain (S-RBD) when compared to the findings at seropositivity identification. In contrast to antibodies to N protein, the antibodies to S-RBD correlated with the viral neutralization capacity and with CD4+ T cell responses as measured by antigen-specific upregulation of CD137 and CD69 markers. Unexpectedly we found the asymptomatic antibody-positive individuals to have increased serum levels of S100A12, TGF-alpha, IL18, and OSM, the markers of activated macrophages-monocytes, suggesting long-term persistent inflammatory effect associated with the viral infection in asymptomatic individuals. Our results support the evidence for the long-term persistence of the inflammation process and the need for post-infection clinical monitoring of SARS-CoV-2 infected asymptomatic individuals.

S100A9 in adult asthmatic patients: a biomarker for neutrophilic asthma

The biomarkers and therapeutic targets of neutrophilic asthma (NA) are poorly understood. Although S100 calcium-binding protein A9 (S100A9) has been shown to correlate with neutrophil activation, its role in asthma pathogenesis has not been clarified. This study investigated the mechanism by which S100A9 is involved in neutrophil activation, neutrophil extracellular trap (NET)-induced airway inflammation, and macrophage polarization in NA. The S100A9 levels (by ELISA) in sera/culture supernatant of peripheral blood neutrophils (PBNs) and M0 macrophages from asthmatic patients were measured and compared to those of healthy controls (HCs). The function of S100A9 was evaluated using airway epithelial cells (AECs) and PBNs/M0 macrophages from asthmatic patients, as well as a mouse asthma model. The serum levels of S100A9 were higher in NA patients than in non-NA patients, and there was a positive correlation between serum S100A9 levels and sputum neutrophil counts (r = 0.340, P = 0.005). Asthmatic patients with higher S100A9 levels had lower PC20 methacholine values and a higher prevalence of severe asthma (SA) (P < .050). PBNs/M0 macrophages from SA released more S100A9 than those from non-SA patients. PBNs from asthmatic patients induced S100A9 production by AECs, which further activated AECs via the extracellular signal-regulated kinase (ERK) pathway, stimulated NET formation, and induced M1 macrophage polarization. Higher S100A9 levels in sera, bronchoalveolar lavage fluid, and lung tissues were observed in the mouse model of NA but not in the other mouse models. These results suggest that S100A9 is a potential serum biomarker and therapeutic target for NA.

Association Between Serum Alarmin Levels and Disease-specific Indices in Patients With Anti-neutrophil Cytoplasmic Antibody-associated Vasculitis.

We evaluated the relationship between serum alarmin levels and disease-specific indices in patients with anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV). Sera and data from 79 patients were utilized. For AAV-specific indices, Birmingham vasculitis activity score (BVAS), five-factor score (FFS), and vasculitis damage index (VDI) were collected and serum levels of four alarmins (hepatoma-derived growth factor, high mobility group box protein 1, S100A9, and S100A12) were measured using enzyme-linked immunosorbent assay. Associations between alarmin levels, AAV-specific indices, and inflammatory laboratory markers were assessed. S100A9 levels were significantly correlated with C-reactive protein levels (r=0.316, p=0.005) and S100A12 levels correlated with VDI (r=0.232, p=0.040), which was consistent in a subgroup of patients with myeloperoxidase (perinuclear)-ANCA positivity. No other associations were found between alarmin levels and BVAS, FFS, and VDI. The serum S100A12 level was associated with organ damage in AAV, especially in myeloperoxidase (perinuclear)-ANCA-positive patients.

Clinical severity of serum S100A12 levels in patients with osteoarthritis and S100A12 open inflammation of osteoarthritis model by NLRP3

Osteoarthritis is a common chronic bone and joint disease, which is characterized by degenerative changes and destruction of articular cartilage, secondary hyperostosis. This study aimed to investigate the clinical severity and mechanism of S100A12 in patients with osteoarthritis. Serum samples were obtained from patients with osteoarthritis or normal volunteer in Minhang Branch of Yueyang Hospital of Integrated Traditional Chinese and Western Medicine affiliated to Shanghai University of Traditional Chinese Medicine (Shanghai, China). C57BL/6J mice performed Resection of the medial collateral ligament and medial meniscus as mice model. MC3T3-E1 cells were induced with 100 ng of LPS as vitro model. The serum level of S100A12 was increased in patients with osteoarthritis. Similarly, S100A12 levels of serum and bone tissue from mice model of osteoarthritis were also higher than those of sham group. Over-expression of S100A12 promoted inflammation levels while down-regulation of S100A12 decreased inflammation levels in in vitro model of osteoarthritis. NLRP3 is an important target of S100A12 in pro-inflammation effects of osteoarthritis. NLRP3 was involved in the effects of S100A12 on inflammation in in vitro model of osteoarthritis. S100A12 also accelerated inflammation by NLRP3 in mice model of osteoarthritis. We conclude that serum S100A12 levels was a possible clinical severity, open inflammation of osteoarthritis model by NLRP3 and its receptors may be effective in preventing the development of osteoarthritis.

Clinical Implications of S100A12 and Resolvin D1 Serum Levels, and Related Genes in Children with Familial Mediterranean Fever

AbstractThe aim of this article was to study the role of S100A12 and resolvin D1-related genes and serum levels in the diagnosis and detection of subclinical inflammation in children with familial Mediterranean fever (FMF) during the quiescent stage of the disease. Seventy-eight children with FMF during the silent state and 60 healthy control were studied. Serum S100A12 and resolvin D1 were quantitatively measured using enzyme-linked immunosorbent assay. In addition, the levels of C-reactive protein, erythrocyte sedimentation rate, and hemoglobin were determined. The clinical severity was evaluated. The link between the Mediterranean fever (MEFV) gene and the genes related to the two studied biomarkers was also assessed. Correlation between S100A12 and resolvin D1 and the clinical severity was assessed. The mean serum levels of S100A12 and resolvin D1 were 847.4 and 793.3, respectively, which were highly significantly increased (p = 0.001) compared with the controls (324.3 and 235.1, respectively). The receiver operating characteristic curve test showed that S100A12 had a sensitivity of 97.4% and specificity of 80% with cutoff value of 529.5, while resolvin D1 showed a sensitivity of 100% and specificity of 50% with cutoff value of 231.2. A correlation was detected between the clinical severity and S100A12 and resolvin D1. This study delineated that S100A12 and resolvin D1 are sensitive biomarkers to detect the degree of inflammation in children with FMF during the silent period. Consequently, we recommend adjusting the colchicine dose to ameliorate the disease's symptoms and to improve the quality of life in these patients.

Serum S100A12 levels: Possible association with skin sclerosis and interstitial lung disease in systemic sclerosis.

Damage-associated molecular patterns (DAMPs) have drawn much attention as a member of disease-associated molecules in systemic sclerosis (SSc). In this study, we investigated the potential contribution of S100A12, a member of DAMPs, to the development of SSc by evaluating S100A12 expression in the lesional skin and the clinical correlation of serum S100A12 levels. S100A12 expression was markedly elevated in the epidermis of SSc-involved skin at protein levels and in the bulk skin at mRNA levels. The deficiency of transcription factor Fli1, a predisposing factor of SSc, enhanced S100A12 expression and Fli1 occupied the S100A12 promoter in normal human keratinocytes. Serum S100A12 levels were higher in SSc patients, especially in those with diffuse cutaneous involvement, than in healthy controls and positively correlated with skin score. Furthermore, the presence of interstitial lung disease significantly augmented serum levels of S100A12. Importantly, serum S100A12 levels correlated inversely with both per cent forced vital capacity and per cent diffusing capacity for carbon monoxide and positively with serum levels of KL-6 and surfactant protein-D. Collectively, these results indicate a possible contribution of S100A12 to skin sclerosis and interstitial lung disease associated with SSc, further supporting the critical roles of DAMPs in the pathogenesis of this disease.

Value of S100A12 in predicting in‑stent restenosis in patients with coronary drug‑eluting stent implantation

In-stent restenosis (ISR) after drug-eluting stent (DES) placement has recently emerged as a major concern for cardiologists. Identification of biomarkers to predict ISR may be invaluable for tailored management strategies. The present study aimed to evaluate the prognostic utility of circulating S100 calcium-binding protein A12 (S100A12) for ISR. Out of 2,443 patients with DES-based percutaneous coronary intervention (PCI) and follow-up angiography at ~1 year after DES-based PCI, 258 patients were diagnosed with ISR and 258 patients without ISR were randomly selected as controls. Serum S100A12 levels were determined in the two subsets on admission. The association between ISR and the circulating levels of S100A12 was determined by constructing two multivariate stepwise logistic regression models. In addition, S100A12 was assessed for its ability to predict ISR using receiver operating characteristic (ROC) curve analysis. The serum levels of S100A12 at baseline were significantly elevated in patients in the ISR group compared with those in the non-ISR group (P<0.001). In the multivariate logistic regression analysis, after adjusting for conventional cardiovascular risk factors, laboratory parameters and medication after the procedure, the S100A12 level was revealed to be independently associated with ISR. When a cut-off for serum S100A12 levels of 34.75 ng/ml was used, the ROC curve was able to predict ISR with 72.8% sensitivity and 79.1% specificity, and the area under the ROC curve was 0.796 (95% CI: 0.757 to 0.834, P<0.001). Furthermore, addition of S100A12 to established risk factors significantly improved the predictive power of reference models for ISR. S100A12 may serve as an independent marker to predict ISR in patients undergoing coronary DES implantation.

Unraveling the Role of Receptor for Advanced Glycation End Products (RAGE) and Its Ligands in Myasthenia Gravis.

Myasthenia gravis (MG) is an autoimmune T cell-dependent B cell-mediated disorder of the neuromuscular junction (NMJ) characterized by fluctuating skeletal muscle weakness, most commonly attributed to pathogenic autoantibodies against postsynaptic nicotinic acetylcholine receptors (AChRs). Although MG pathogenesis is well-documented, there are no objective biomarkers that could effectively correlate with disease severity or MG clinical subtypes, and current treatment approaches are often ineffective. The receptor for advanced glycation end products (RAGE) is a multiligand cell-bound receptor highly implicated in proinflammatory responses and autoimmunity. Preclinical evidence demonstrates that RAGE and its ligand S100B are upregulated in rat models of experimental autoimmune myasthenia gravis (EAMG). S100B-mediated RAGE activation has been shown to exacerbate EAMG, by enhancing T cell proinflammatory responses, aggravating T helper (Th) subset imbalance, increasing AChR-specific T cell proliferative capacity, and promoting the production of antibodies against AChRs from the spleen. Soluble sRAGE and esRAGE, acting as decoys of RAGE ligands, are found to be significantly reduced in MG patients. Moreover, MG has been associated with increased serum levels of S100A12, S100B and HMGB1. Several studies have shown that the presence of thymic abnormalities, the onset age of MG, and the duration of the disease may affect the levels of these proteins in MG patients. Herein, we discuss the emerging role of RAGE and its ligands in MG immunopathogenesis, their clinical significance as promising biomarkers, as well as the potential therapeutic implications of targeting RAGE signaling in MG treatment.

Serum S100A12 levels are correlated with clinical severity in patients with dermatomyositis-associated interstitial lung disease.

ObjectiveS100A12 is an emerging inflammatory disease biomarker. Interstitial lung disease (ILD) is a common, severe complication of dermatomyositis (DM). This study was performed to investigate the association between S100A12 and disease activity and prognosis in patients with DM-associated ILD (i.e., DM-ILD).MethodsSerum S100A12 levels were measured using enzyme-linked immunosorbent assays in patients with stable DM-ILD, patients with acute exacerbation of DM-ILD (AE DM-ILD), and healthy controls (HCs). The relationships of serum S100A12 levels with C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), ferritin, high-resolution computed tomography (HRCT) scores, and pulmonary functions were evaluated by multiple unpaired t-tests and Pearson correlation.ResultsSerum S100A12 levels were higher in patients with stable DM-ILD and those with AE DM-ILD than in HCs. Serum S100A12 levels in patients with stable DM-ILD and those with AE DM-ILD were positively correlated with CRP, ESR, and ferritin. S100A12 levels were positively correlated with HRCT scores in patients with stable DM-ILD and those with AE DM-ILD, while they were negatively correlated with predicted percentages of forced vital capacity and predicted percentages of carbon monoxide diffusing capacity in those patients.ConclusionOur findings demonstrate the usefulness of serum S100A12 levels for assessing clinical severity and prognosis of DM-ILD.

Serum S100A6, S100A8, S100A9 and S100A11 proteins in colorectal neoplasia: results of a single centre prospective study

S100 proteins are involved in biological events related to colorectal carcinogenesis. Aim of this prospective study was to assess serum concentration of S100A6, A8, A9 and A11 proteins in patients with colorectal neoplasia. Eighty-four subjects were enrolled: 20 controls (average risk population with normal findings on colonoscopy; 7 men, 13 women, age 23–74, mean 55 ± 14), 20 patients with non-advanced colorectal adenoma (non-AA, 10 men, 10 women, age 41–82, mean 62 ± 11), 22 with advanced colorectal adenoma (AA, 15 men, 7 women, age 49–80, mean 64 ± 8) and 22 with colorectal cancer (CRC, 12 men, 10 women, age 49-86, mean 69 ± 10). Peripheral venous blood was obtained. Serum S100 proteins were investigated by enzyme immunoassay technique. Serum S100A6 was significantly lower in CRC (mean 8530 ± 4743 ng/L), p = .035 compared to controls (mean 11308 ± 2968 ng/L). Serum S100A8 was significantly higher in AA (median 11955 ng/L, IQR 2681-34756 ng/L), p = .009 and in CRC (median 27532 ng/L, IQR 6794–35092 ng/L), p < .001 compared to controls (median 2513 ng/L, IQR 2111-4881 ng/L). Serum S100A9 concentrations did not differ between any tested group and controls, p > .05. Serum concentration of S100A11 was significantly lower in non-AA (mean 3.5 ± 2.4 μg/L), p = .004 and in CRC (mean 3.4 ± 2.4 μg/L), p = .002 compared to controls (mean 5.9 ± 2.5 μg/L). Sensitivity and specificity for S100A8 protein in patients with CRC were 94% and 73%; positive predictive value 68% and negative predictive value 95%. Patients with colorectal neoplasia have significantly lower serum S100A6 and S100A11 levels, significantly higher S100A8 and unaltered serum S100A9 levels.

S100 Calcium Binding Protein A9 Represses Angiogenic Activity and Aggravates Osteonecrosis of the Femoral Head.

Ischemic damage aggravation of femoral head collapse is a prominent pathologic feature of osteonecrosis of the femoral head (ONFH). In this regard, S100 calcium binding protein A9 (S100A9) is known to deteriorate joint integrity, however, little is understood about which role S100A9 may play in ONFH. In this study, a proteomics analysis has revealed a decrease in the serum S100A9 level in patients with ONFH upon hyperbaric oxygen therapy. Serum S100A9 levels, along with serum vascular endothelial growth factor (VEGF), soluble vascular cell adhesion molecule-1 (sVCAM-1), interleukin-6 (IL-6), and tartrate-resistant acid phosphatase 5b levels were increased in patients with ONFH, whereas serum osteocalcin levels were decreased as compared to healthy controls. Serum S100A9 levels were increased with the Ficat and Arlet stages of ONFH and correlated with the patients with a history of being on glucocorticoid medication and alcohol consumption. Osteonecrotic tissue showed hypovasculature histopathology together with weak immunostaining for vessel marker CD31 and von Willrbrand factor (vWF) as compared to femoral head fracture specimens. Thrombosed vessels, fibrotic tissue, osteocytes, and inflammatory cells displayed strong S100A9 immunoreactivity in osteonecrotic lesion. In vitro, ONFH serum and S100A9 inhibited the tube formation of vessel endothelial cells and vessel outgrowth of rat aortic rings, whereas the antibody blockade of S100A9 improved angiogenic activities. Taken together, increased S100A9 levels are relevant to the development of ONFH. S100A9 appears to provoke avascular damage, ultimately accelerating femoral head deterioration through reducing angiogenesis. This study provides insight into the molecular mechanism underlying the development of ONFH. Here, analysis also highlights that serum S100A9 is a sensitive biochemical indicator of ONFH.