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Transient receptor potential ankyrin 1 (TRPA1) plays an important role in different cardiovascular diseases. However, the role of TRPA1 in dilated cardiomyopathy (DCM) remains unclear. Here, we aimed to investigate the role of TRPA1 in DCM induced by doxorubicin (DOX) and explore its possible mechanisms. GEO data were used to explore the expression of TRPA1 in DCM patients. DOX (2.5 mg/kg/week, 6 weeks, i.p.) was used to induce DCM. Bone marrow‐derived macrophages (BMDMs) and neonatal rat cardiomyocytes (NRCMs) were isolated to explore the role of TRPA1 in macrophage polarization, cardiomyocyte apoptosis, and pyroptosis. In addition, DCM rats were treated with the TRPA1 activator, cinnamaldehyde to explore the possibility of clinical translation. TRPA1 expression was increased in left ventricular (LV) tissue in DCM patients and rats. TRPA1 deficiency aggravated the cardiac dysfunction, cardiac injury, and LV remodeling in DCM rats. In addition, TRPA1 deficiency promoted the M1 macrophage polarization, oxidative stress, cardiac apoptosis, and pyroptosis induced by DOX. RNA‐seq results showed that TRPA1 knockout promoted the expression of S100A8, an inflammatory molecule that belongs to the family of Ca2+‐binding S100 proteins, in DCM rats. Furthermore, S100A8 inhibition attenuated M1 macrophage polarization in BMDMs isolated from TRPA1 deficiency rats. Recombinant S100A8 promoted the apoptosis, pyroptosis, and oxidative stress in primary cardiomyocytes stimulated with DOX. Finally, TRPA1 activation via cinnamaldehyde alleviated the cardiac dysfunction and reduced S100A8 expression in DCM rats. Taken together, these results suggested that TRPA1 deficiency aggravates DCM by promoting S100A8 expression to induce M1 macrophage polarization and cardiac apoptosis. [ABSTRACT FROM AUTHOR]

Myeloid‐derived suppressor cells (MDSCs) have been known to play a pivotal role in the induction of immune tolerance, which limits the benefits of immune checkpoint inhibitors (ICIs). Recent studies revealed that several chemotherapeutic agents decreased tumor‐infiltrating MDSCs. Therefore, combination therapy with cytotoxic chemotherapeutic agents and ICIs was approved for first‐line treatment for lung cancer. However, the impact of chemotherapeutic agents on MDSCs and an optimal partner of ICIs has not been fully investigated in thoracic tumors, including lung cancer and malignant pleural mesothelioma. In the present study, we found that treatment with 5‐FU and its oral formulation, S‐1, suppressed tumor progression and inhibited the accumulation of MDSCs in thoracic tumor‐bearing mice. Tumor‐infiltrating T cells and dendritic cells were significantly expanded in S‐1‐treated mice. 5‐FU suppressed the ability of tumor cells to recruit MDSCs, while it did not suppress the survival and differentiation of mouse MDSCs in vitro. We also revealed that 5‐FU or S‐1 significantly downregulated the expression of tumor‐derived Bv8 and S100A8. The knockdown of Bv8 or S100A8 in tumor cells suppressed tumor growth and MDSC recruitment in vivo. Furthermore, in comparison with pemetrexed, administration of S‐1 improved the synergistic therapeutic efficacy of anti‐PD‐1 antibodies with or without carboplatin. Our findings revealed a novel mechanism wherein S‐1 primed a favorable tumor microenvironment to provide the rationale for combination therapy with S‐1 and ICIs as the optimal therapy for thoracic cancer. [ABSTRACT FROM AUTHOR]

Background: The presence of glioma stem cells (GSCs) and the occurrence of mesenchymal phenotype transition contribute to the miserable prognosis of glioblastoma (GBM). Cellular communication network factor 1 (CCN1) is upregulated within various malignancies and associated with cancer development and progression, while the implications of CCN1 in the phenotype transition and tumorigenicity of GSCs remain unclear., Methods: Data for bioinformatic analysis were obtained from The Cancer Genome Atlas (TCGA) and Chinese Glioma Genome Atlas (CGGA) databases. A range of primary GBM and GSC cell models were then used to demonstrate the regulatory role of CCN1 via the phenotype validation, tumor sphere formation assays, extreme limiting dilution assays (ELDA), and transwell assays. To screen out the downstream signaling pathway, we employed high-throughput RNA-seq. Intracranial xenograft GSC mouse models were used to investigate the role of CCN1 in vivo., Results: Among the CCN family members, CCN1 was highly expressed in MES-GBM/GSCs and was correlated with a poor prognosis. Both in vitro and in vivo assays indicated that knockdown of CCN1 in MES-GSCs reduced the tumor stemness, proliferation, invasion, and tumorigenicity, whereas CCN1 overexpression in PN-GSCs exhibited the opposite effects. Mechanistically, CCN1 triggered the FAK/STAT3 signaling in autocrine and paracrine manners to upregulate the expression of S100A8. Knockdown of S100A8 inactivated NF-κB/p65 pathway and significantly suppressed the tumorigenesis of MES-GSCs., Conclusion: Our findings reveal that CCN1 may be an important factor in the enhanced invasiveness and MES phenotype transition of GSCs and highlight the potential to target CCN1 for treating GBM., (© 2024 The Author(s). CNS Neuroscience & Therapeutics published by John Wiley & Sons Ltd.)

As acute pancreatitis progresses to the severe form, a life‐threatening systemic inflammation is triggered. Although the mechanisms involved in this process are not yet well understood, it has been proposed that circulating exosomes may be involved in the progression of inflammation from the pancreas to distant organs. Here, the inflammatory capacity and protein profile of plasma exosomes obtained during the first 24 h of hospitalization of patients diagnosed with acute pancreatitis were characterized and compared with the final severity of the disease. We found that the final severity of the disease strongly correlates with the inflammatory capacity of exosomes in the early stages of acute pancreatitis. Exosomes isolated from patients with mild pancreatitis had no effect on macrophages, while exosomes isolated from patients with severe pancreatitis triggered NFκB activation, TNFα and IL1β expression, and free radical generation. To delve deeper into the mechanism involved, we performed a proteomic analysis of the different exosomes that allowed us to identify different groups of proteins whose concentration was also correlated with the clinical classification of pancreatitis. In particular, an increase in the amount of S100A8 and S100A9 carried by exosomes of severe pancreatitis suggests that the mechanism of action of exosomes is mediated by the effect of these proteins on NADPH oxidase. This enzyme is activated by S100A8/S100A9, thus generating free radicals and promoting an inflammatory response. Along these lines, we observed that inhibition of this enzyme abolished all the pro‐inflammatory effects of exosomes from severe pancreatitis. All this suggests that the systemic effects, and therefore the final severity of acute pancreatitis, are determined by the content of circulating exosomes generated in the early hours of the process. © 2021 The Authors. The Journal of Pathology published by John Wiley & Sons, Ltd. on behalf of The Pathological Society of Great Britain and Ireland. [ABSTRACT FROM AUTHOR]

Immune cells harboring somatic mutations reportedly infiltrate cancer tissues in patients with solid cancers and accompanying clonal hematopoiesis. Loss‐of‐function TET2 mutations are frequently observed in clonal hematopoiesis in solid cancers. Here, using a mouse lung cancer model, we evaluated the activity of Tet2‐deficient immune cells in tumor tissues. Myeloid‐specific Tet2 deficiency enhanced tumor growth in mice relative to that seen in controls. Single‐cell sequencing analysis of immune cells infiltrating tumors showed relatively high expression of S100a8/S100a9 in Tet2‐deficient myeloid subclusters. In turn, treatment with S100a8/S100a9 promoted Vegfa production by cancer cells, leading to a marked increase in the tumor vasculature in Tet2‐deficient mice relative to controls. Finally, treatment of Tet2‐deficient mice with an antibody against Emmprin, a known S100a8/S100a9 receptor, suppressed tumor growth. These data suggest that immune cells derived from TET2‐mutated clonal hematopoiesis exacerbate lung cancer progression by promoting tumor angiogenesis and may provide a novel therapeutic target for lung cancer patients with TET2‐mutated clonal hematopoiesis. [ABSTRACT FROM AUTHOR]

Cancer‐associated fibroblasts (CAFs) in the tumor microenvironment have been associated with tumor progression in breast cancer. Although crosstalk between breast cancer cells and CAFs has been studied, the effect of CAFs on non‐neoplastic breast epithelial cells is not fully understood to date. Here, we investigated the effect of CAFs on aggressive phenotypes in non‐neoplastic MCF10A breast epithelial cells. CAFs induced epithelial‐to‐mesenchymal transition (EMT) and invasive phenotype in MCF10A cells. S100A8, a potential prognostic marker in several cancers, was markedly increased in MCF10A cells by CAFs. S100A8 was crucial for CAFs‐induced invasive phenotype of MCF10A cells. Among cytokines increased by CAFs, interleukin (IL)‐8 induced S100A8 through transcription factors p65 NF‐κB and C/EBPβ. In a xenograft mouse model with MCF10A cells and CAFs, tumor was not developed, suggesting that coinjection with CAFs may not be sufficient for in vivo tumorigenicity of MCF10A cells. Xenograft mouse tumor models with MDA‐MB‐231 breast carcinoma cells provided an in vivo evidence for the effect of CAFs on breast cancer progression as well as a crucial role of IL‐8 in tumor growth and S100A8 expression in vivo. Using a tissue microarray of human breast cancer, we showed that S100A8 expression was correlated with poor outcomes. S100A8 expression was more frequently detected in cancer‐adjacent normal human breast tissues than in normal breast tissues. Together, this study elucidated a novel mechanism for the acquisition of invasive phenotype of non‐neoplastic breast cells induced by CAFs, suggesting that targeting IL‐8 and S100A8 may be an effective strategy against breast cancer. [ABSTRACT FROM AUTHOR]

Objectives: Salivary diagnostic using matrix metalloproteinase (MMP) and S100 for periodontitis is a promising issue. However, its prognostic effect is still unclear. This study aimed to evaluate the prognostic ability of salivary MMP‐9 and S100A8 for periodontitis through non‐surgical periodontitis treatment clinical trial. Materials and Methods: Total 149 participants, 99 periodontitis and 50 healthy, were recruited. Among 99 non‐surgical periodontitis treatment participants, 74 participants were revisited after three months. Periodontitis was classified as stage II‐IV of new classification of periodontitis proposed at 2018. Enzyme‐linked immunosorbent assay kit was used to quantify salivary MMP‐9 and S100A8. Receiver operating characteristic curve was applied for diagnostic ability. Paired t test was applied for prognostic ability evaluating changes in salivary markers between pre‐ and post‐treatment. Results: Salivary MMP‐9 and S100A8 were associated with periodontitis (p <.05). The screening ability of algorithm using salivary MMP‐9 and S100A8 for periodontitis was 0.86 (p <.05). After treatment, reduction rate of salivary S100A8 and MMP‐9 was 83.7% and 23.5%, respectively, (p <.05): only salivary S100A8 was superior compared to clinical parameters. Conclusion: Algorithm using salivary MMP‐9 and S100A8 showed high diagnostic power for periodontitis. Both salivary S100A8 and MMP‐9 showed prognostic ability for periodontitis, but S100A8 was better. [ABSTRACT FROM AUTHOR]

Firstly, we measured S100A8 from 78 bone marrow (BM) plasmas, including 50 acute myeloid leukemia (AML) patients, myeloproliferative neoplasms (MPN), myelodysplastic syndrome (MDS), and healthy donors (HD). (D) Correlation of BM [S100A8] with the percentage of leukemic cells in BM, determined through cytology analysis in AML patients. However, no linear correlation was observed between BM [S100A8] and myeloid precursors or granulocytes in BM, ( I P i =.21, I P i =.29, respectively; Figure S1). Interestingly, the percentage of blasts in BM was negatively correlated with BM [S100A8] ( I P i < .05, R = -0.31, Figure D), suggesting that blasts were not the main source of S100A8. [Extracted from the article]

The aim of this study was to research the mechanism of circMAN2B2 in the development of glioma. In our study, we found that circMAN2B2 has a higher expression in glioma tissues and cells, which was negatively related to the overall survival of glioma patients. The cell counting kit‐8 assay, 5‐ethynyl‐2′‐deoxyuridine labeling assay, transwell assay, and the nude mice assay indicated that knockdown of circMAN2B2 inhibited the cell proliferation, invasion, migration and decreased tumor size. In terms of mechanism, knockdown of circMAN2B2 increased the expression of miR‐1205. Moreover, circMAN2B2 regulated S100A8 expression by inhibiting miR‐1205. We also showed that knockdown of S100A8 inhibited cell proliferation, invasion, and migration. Increasing S100A8 expression rescued the effect of si‐circMAN2B2. In conclusion, circMAN2B2 could improve cell proliferation, invasion, and migration of the glioma by inhibiting miR‐1205 and promoting the expression of S100A8. [ABSTRACT FROM AUTHOR]

The biological functions of the Eph/ephrin system have been intensively investigated and well documented so far since its discovery in 1987. Although the Eph/ephrin system has been implicated in pathological settings such as Alzheimer's disease and cancer, the molecular mechanism of the Eph/ephrin system in those diseases is not well understood. Especially in cancer, recent studies have demonstrated that most of Eph and ephrin are up‐ or down‐regulated in various types of cancer, and have been implicated in tumor progression, tumor malignancy, and prognosis. However, they lack consistency and are in controversy. The localization patterns of EphA1 and EphA2 in mouse lungs are very similar, and both knockout mice showed similar phenotypes in the lungs. Ephrin‐A1 that is a membrane‐anchored ligand for EphAs was co‐localized with EphA1 and EphA2 in lung vascular endothelial cells. We recently uncovered the molecular mechanism of ephrin‐A1‐induced lung metastasis by understanding the physiological function of ephrin‐A1 in lungs. This review focuses on the function of EphA1, EphA2, and ephrin‐A1 in tumors and an establishment of pre‐metastatic microenvironment in the lungs. ADAM12‐cleaved ephrin‐A1 induces receptor endocytosis and RhoA activation leading to cell retraction. Cleaved ephrin‐A1 competes for pre‐existing Eph/ephrin interactions. Ephrin‐A1‐stimulated vascular endothelial cells are shrunk, and thereby enhances lung vascular permeability. [ABSTRACT FROM AUTHOR]

Aim: This study aims to evaluate the association of salivary S100A8 and A9 proteins with periodontitis and its screening ability for periodontitis cross‐sectionally. Material and Methods: We selected 326 participants from the Yangpyeong Cohort: 218 participants with periodontitis and 108 participants without periodontitis. Stage II‐IV periodontitis according to the modification of new international classification of periodontitis was considered as periodontitis. S100A8 and A9 were assayed using enzyme‐linked immunosorbent assay kit. Age, sex, education, smoking, drinking, exercise, and metabolic syndrome were factored as confounders. Analyses of covariance and logistic regression analysis were applied to evaluate the association of S100A8 and A9 with periodontitis. Receiver operating characteristic curve was applied for screening ability. Results: Those with periodontitis compared to those without periodontitis showed higher adjusted amount of S100A8 (3694 versus 6757 ng/ml, p < 0.001), but less adjusted amount of S100A9 (1341 versus 1030 ng/ml, p = 0.015). The screening ability of S100A8 and A9 on periodontitis was c‐statistics of 0.69 (p < 0.001) for both S100A8 and A9, 0.67 for S100A8 and 0.63 (p < 0.001) for S100A9. Conclusions: Overall, salivary S100A8 and S100A9 could be practical markers for periodontitis. Its screening ability for periodontitis could be beneficial in clinics and at home. [ABSTRACT FROM AUTHOR]

Contents: This study was carried out to examine the changes in plasma concentrations of the Ca‐binding antimicrobial proteins S100A7 and S100A8 during pregnancy in dairy cows. Holstein Friesian cows (n = 19) were inseminated with Holstein Friesian semen. Blood was collected at days 30, 60, 90, 120, 150, 180, 210, 240 and 270 after insemination. Plasma was used for measuring the concentrations of S100A7 and S100A8. Both S100A7 and S100A8 concentrations showed similar patterns during gestation; they increased during the midgestation, between days 90 and 180, and then declined before calving. The findings indicated that plasma concentrations of S100A7 and S100A8 did not change significantly during pregnancy in cows. Further studies are required to determine the roles of S100A7 and S100A8 in physiological function during pregnancy in dairy cows. [ABSTRACT FROM AUTHOR]

The aberrant expression of S100A8 and S100A9 is linked to nonresolving inflammation and ultimately to carcinogenesis, whereas the underlying mechanism that allows inflammation to progress to specific cancer types remains unknown. Here, we report that S100A8 was induced by inflammation and then promoted colorectal tumorigenesis downstream by activating Id3 (inhibitor of differentiation 3). Using gene expression profiling and immunohistochemistry, we found that both S100A8 and S100A9 were upregulated in the chemically-induced colitis-associated cancer mouse model and in human colorectal cancer specimens. Furthermore, we showed that S100A8 and S100A9 acted as chemoattractant proteins by recruiting macrophages, promoting the proliferation and invasion of colon cancer cell, as well as spurring the cycle that culminates in the acceleration of cancer metastasis in a nude mouse model. S100A8 regulated colon cancer cell cycle and proliferation by inducing Id3 expression while inhibiting p21. Id3 expression was regulated by Smad5, which was directly phosphorylated by Akt1. Our study revealed a novel mechanism in which inflammation-induced S100A8 promoted colorectal tumorigenesis by acting upstream to activate the Akt1-Smad5-Id3 axis. [ABSTRACT FROM AUTHOR]

Objective Advanced glycation end products ( AGE) are involved in the progression of diabetic complications. Although our previous reports show that AGE increased dental pulp calcification, AGE accumulation is also associated with inflammation. This study examined AGE effect on the expression of inflammation factors using rat dental pulp tissues and cell cultures. Materials and Methods Receptor for AGE ( RAGE), S100A8, S100A9, and interleukin ( IL)-1 β were selected as inflammation parameters. Rat dental pulp cells were cultured and treated with AGE, and the effects were determined by real-time PCR. An anti- RAGE antibody or MAPK pathway inhibitors ( PD98059, SB203580, and SP60012) were used to investigate AGE signaling pathway. Results The mRNA levels of RAGE, S100A8, S100A9, and IL-1 β were higher in diabetic pulp tissues. AGE increased mRNA expressions of S100A8, S100A9, and IL-1 β in cultured dental pulp cells. In the presence of anti-RAGE antibody, AGE did not increase in S100A8 or S100A9 expressions. The AGE-induced increases in S100A8 and S100A9 were inhibited by PD98059 and SB203580, respectively. Conclusions Advanced glycation end products increased mRNA expression of S100A8, S100A9, and IL-1 β under diabetic pulp conditions, and AGE-induced increases in S100A8 and S100A9 expressions may be associated with the RAGE-MAPK signaling pathway. [ABSTRACT FROM AUTHOR]

Problem The contribution of systemic S100A8 protein in menstrual cycle, pregnancy, and early pregnancy loss ( EPL) is not known. Altered expression of S100A8 in maternal decidua is associated with recurrent early pregnancy loss. The objective of this study was to investigate the systemic level of S100A8 in different phases of menstrual cycle, different trimester of pregnancy, and in EPL. Method of Study Level of S100A8 was investigated in serum samples of the subjects through enzyme-linked immunosorbent assay ( ELISA). Result and Conclusion S100A8 levels were elevated during proliferative phase of menstural cycle. We found no statistical difference in S100A8 level in different trimester of pregnancy. S100A8 level was found to be significantly elevated in patients with EPL. This is the first study evaluating the systemic level of S100A8 predicting its role during menstural cycle and pregnancy. It opens a new perspective in which S100A8 can be used as a prognostic marker for EPL. [ABSTRACT FROM AUTHOR]

Airway mucus hyperproduction is a common feature of chronic airway diseases such as severe asthma, chronic obstructive pulmonary disease and cystic fibrosis, which are closely associated with neutrophilic airway inflammation. S100A8, S100A9 and S100A12 are highly abundant proteins released by neutrophils and have been identified as important biomarkers in many inflammatory diseases. Herein, we report a new role for S100A8, S100A9 and S100A12 for producing MUC5AC, a major mucin protein in the respiratory tract. All three S100 proteins induced MUC5AC mRNA and the protein in normal human bronchial epithelial cells as well as NCI-H292 lung carcinoma cells in a dose-dependent manner. A Toll-like receptor 4 (TLR4) inhibitor almost completely abolished MUC5AC expression by all three S100 proteins, while neutralization of the receptor for advanced glycation end-products (RAGE) inhibited only S100A12-mediated production of MUC5AC. The S100 protein-mediated production of MUC5AC was inhibited by the pharmacological agents that block prominent signalling molecules for MUC5AC expression, such as mitogen-activated protein kinases, nuclear factor- κB (NF- κB) and epidermal growth factor receptor. S100A8, S100A9 and S100A12 equally elicited both phosphorylation of extracellular signal-regulated kinase (ERK) and nuclear translocation of NF- κB/degradation of cytosolic I κB with similar kinetics through TLR4. In contrast, S100A12 preferentially activated the ERK pathway rather than the NF- κB pathway through RAGE. Collectively, these data reveal the capacity of these three S100 proteins to induce MUC5AC production in airway epithelial cells, suggesting that they all serve as key mediators linking neutrophil-dominant airway inflammation to mucin hyperproduction. [ABSTRACT FROM AUTHOR]

S100A9 and S100A8 are called damage-associated molecular pattern (DAMP) molecules because of their pro-inflammatory properties. Few studies have evaluated S100A9 and S100A8 function as DAMP molecules in atopic dermatitis (AD). We investigated how house-dust mites affect S100A9 and S100A8 expression in Th2 cytokine- and Th17 cytokine-treated keratinocytes, and how secretion of these molecules affects keratinocyte-derived cytokines. Finally, we evaluated expression of these DAMP molecules in AD patients. S100A9 expression and S100A8 expression were strongly induced in IL-17A- and Dermatophagoides ( D.) farinae-treated keratinocytes, respectively. Furthermore, co-treatment with D. farinae and IL-17A strongly increased expression of S100A9 and S100A8 compared with D. farinae-Th2 cytokine co-treatment. The IL-33 mRNA level increased in a dose-dependent manner in S100A9-treated keratinocytes, but TSLP expression did not change. S100A8/A9 levels were also higher in the lesional skin and serum of AD patients, and correlated with disease severity. Taken together, S100A9 and S100A8 may be involved in inducing DAMP-mediated inflammation in AD triggered by IL-17A and house-dust mites. [ABSTRACT FROM AUTHOR]

The antimicrobial peptide S100A8 is known to be upregulated in lesional psoriatic skin compared with non-lesional psoriatic skin and is believed to play a role in the pathogenesis of psoriasis. However, little is known about the signalling pathways involved in the regulation of S100A8 expression. Using quantitative real-time RT- PCR analysis, we demonstrated that stimulation with TNFα and IL-17A in combination resulted in a significant and synergistic induction of S100A8 mRNA in human keratinocytes. TNFα and IL-17A also induced the S100A8 promoter activity synergistically. This was demonstrated by a gene reporter assay in cells transfected with a luciferase plasmid construct, consisting of 3502 base pairs of the human S100A8 promoter. The TNFα- and IL-17A-mediated induction of S100A8 mRNA and protein was mediated by a p38 MAPK-dependent mechanism, as demonstrated by the use of a p38 MAPK inhibitor. Finally, adalimumab treatment for patients with psoriasis significantly decreased S100A8 mRNA at day fourteen after start of treatment, but not at day four. Taken together, this study demonstrates that the p38 MAPK signalling pathway plays a key role in the TNFα- and IL-17A-induced expression of S100A8 in cultured human keratinocytes. [ABSTRACT FROM AUTHOR]

Objective and Background Gingival epithelium protects against bacterial infection by producing antimicrobial peptides such as calprotectin. Calprotectin consists of proteins S100 A8 and S100 A9. Although in vitro assay has shown that neutrophils and gingival epithelial cells express calprotectin, the expression of S100 A8 and S100 A9 and colocalization of both S100 proteins in gingival tissue in vivo are not fully understood. The aim of this study was to investigate the distribution of S100 A8 and S100 A9 expression in gingival epithelium of mice in the presence and absence of infection. Materials and Methods A quantitative analysis of S100 A8 and S100 A9 m RNA in junctional epithelium ( JE) and oral gingival epithelium ( OGE) of both germ-free mice and conventional mice was performed using laser microdissection and real-time polymerase chain reaction ( PCR). Confirmation of S100 A8 and S100 A9 m RNA expression in the JE was conducted by fluorescent immunohistochemistry. Results Real-time PCR analysis indicated that S100 A8 and S100 A9 expressions were mainly detected in JE and only slightly or not detected in OGE. Levels of both S100 A8 and S100 A9 m RNA expression in JE of conventional mice were significantly higher than those in JE of germ-free mice. Additionally, fluorescent immunohistochemistry showed that S100 A8 expression was observed in the JE of both conventional and germ-free mice, whereas S100 A9 was expressed in the JE of conventional but not germ-free mice. Conclusion S100 A8 protein is expressed in JE cells of mice in the presence and in the absence of infection with oral bacteria. S100 A9 expression in JE cells in the presence of microflora is significantly increased compared with the absence of microflora, which suggests that S100 A9 expression may be induced by infection of microflora. The production of calprotectin in gingival epithelial cells may be mediated through S100 A9 induction by bacterial infection. [ABSTRACT FROM AUTHOR]

S100A8 and S100A9, two heterodimer-forming members of the cytosolic S100 Ca2+ signaling protein family, are overexpressed in various cancer types, including prostate cancer. They act as proinflammatory danger signals when secreted to the extracellular space and are thought to play an important role during tumorigenesis, affecting inflammatory processes, proliferation, invasion and metastasis of tumor cells. Despite this fact, little is known about tumor environmental factors influencing S100A8/A9 expression. The aim of this study was to test the effect of hypoxia and its master transcriptional regulator hypoxia-inducible factor 1 (HIF-1) on S100A8/A9 expression. Hypoxia treatment resulted in induction of S100A8/A9 protein and mRNA expression in prostate epithelial BPH-1 cells, the latter was also confirmed in the prostate cancer cell lines PC-3 and DU-145. Furthermore, overexpression of HIF-1α caused increase in S100A8/A9 protein and mRNA expression as well as secretion. Functional hypoxia response elements mediating promoter activation on HIF-1α overexpression were identified within the S100A8 and S100A9 promoters using promoter luciferase reporter constructs. Binding of HIF-1α to S100A8 and S100A9 promoters was confirmed by chromatin immunoprecipitation. Immunohistochemical analysis of a prostate cancer tissue array showed clear correlation of S100A8 and S100A9 with HIF-1α expression. Multivariate proportional hazard analysis revealed association of high S100A9 level with time to prostate cancer recurrence. In conclusion, we identified hypoxia and HIF-1 as novel regulators of S100A8/A9 expression in prostate cancer. S100A9 might be useful as prognostic marker for prostate cancer recurrence after radical prostatectomy. [ABSTRACT FROM AUTHOR]

Sun X, Meng H, Shi D, Xu L, Zhang L, Chen Z, Feng X, Lu R. Analysis of plasma calprotectin and polymorphisms of S100A8 in patients with aggressive periodontitis. J Periodont Res 2011; 46: 354-360. © 2011 John Wiley & Sons A/S Calprotectin is an important proinflammatory mediator in various inflammatory diseases and is composed of two subunits (S100A8 and S100A9). However, the level of calprotectin in plasma of patients with aggressive periodontitis and its relationship with gene polymorphisms of S100A8 are unclear. The plasma concentrations of calprotectin were measured, using an enzyme immunoassay, in 139 patients with aggressive periodontitis and in 88 periodontally healthy control subjects. These patients were genotyped for the rs3795391 and rs3806232 polymorphisms of S100A8. The plasma concentration of calprotectin in patients with aggressive periodontitis was significantly higher than in controls (2.17 mg/L vs. 1.72 mg/L, respectively, p = 0.001). The percentage of the AA genotype of S100A8 rs3795391 was significantly higher in patients than in controls (82% vs. 69.3%, respectively, p = 0.027), while the frequency of the allele G was decreased among patients compared with controls (9.6% vs. 16.1%, respectively, p = 0.036), which was especially apparent in men (rs3795391 genotype, p = 0.005; rs3795391 allele, p = 0.015). The mean probing depth in patients carrying the AA genotype was significantly higher than that of patients carrying the GA + GG genotype of two polymorphisms of S100A8 (rs3795391, p = 0.035; rs3806232, p = 0.040), whereas the levels of calprotectin between different genotypes were not significantly different (rs3795391, p = 0.11; rs3806232, p = 0.15). These findings indicate that aggressive periodontitis is associated with elevated levels of plasma calprotectin and that gene polymorphisms of S100A8 may influence the susceptibility and severity of aggressive periodontitis. [ABSTRACT FROM AUTHOR]

Calgranulins comprise three proteins, S100A8 (Calgranulin A), S100A9 (Calgranulin B) and S100A12 (Calgranulin C) that are predominantly expressed by neutrophils, monocytes and activated macrophages. These S100 calcium-binding proteins are important molecular mediators in a range of diseases, including inflammatory arthritis, atherosclerosis and microbial infections. Much of the literature has focused on the pro-inflammatory functions of calgranulins, and this has tended to underplay important regulatory, anti-oxidant and protective properties. S100A8 and S100A9 are particularly complex in their actions because they exert intracellular and extracellular functions, they form a heterocomplex, S100A8–A9 (calprotectin), and have actions that are independent of or dependent on heterocomplex formation. In some circumstances S100A9 appears to regulate, rather than synergize with the actions of S100A8 and vice versa. Moreover, these calgranulins also bind zinc and other divalent cations and are sensitive to post-translational oxidative modifications, properties that also affect some functions. It is important to note that S100A8 has potent anti-oxidant activity, which could be important in host protection. Furthermore, although the genes for S100A8 and S100A9 are induced by activation of the toll-like receptor/interleukin-1 pathway, their expression is enhanced by interleukin-10 and glucocorticoids, thus suggesting a regulatory role in inflammation. On the other hand, S100A12 appears to be predominantly pro-inflammatory, particularly by its ability to activate mast cells. Measurement of S100A12 levels may be a highly sensitive biomarker for inflammatory disease activity. This review summarizes the current understanding of the biology of calgranulins, with a focus on their pleiotropic roles in inflammatory arthritis. [ABSTRACT FROM AUTHOR]

Cross S S, Hamdy F C, Deloulme J C&Rehman I(2005)Histopathology46,256–269Expression of S100 proteins in normal human tissues and common cancers using tissue microarrays: S100A6, S100A8, S100A9 and S100A11 are all overexpressed in common cancers: To survey the expression of members of the S100 family of calcium-binding proteins in normal human tissues and common cancers using tissue microarrays. S100A6, S100A8, S100A9 and S100A11 have all been suggested to have potential roles in carcinogenesis and tumour progression but their expression has not been described in a wide range of human tissues and tumours.: A custom-made tissue array, containing 291 tissue cores representing 28 tissue types and 21 tumour types, was used to produce sections that were immunostained for S100A2, S100A6, S100A8, S100A9, S100A11, calbindin 1, calbindin 2, S100B and parvalbumin. S100A6, S100A8 and S100A9 were expressed in 32%, 12% and 28% of breast cancers, respectively. There was a translocation of S100A11 expression from exclusively nuclear in normal tissues to cytoplasmic and nuclear in all common cancers.: S100A6, S100A8, S100A9 and S100A11 are all expressed in common cancers, especially breast cancer. In addition, S100A11 undergoes a nucleocytoplasmic translocation which may have a direct influence on the proliferation of the cancer cells. [ABSTRACT FROM AUTHOR]

In a previous study, the S100A8/A9 protein, a Ca2+ - and arachidonic acid-binding protein, abundant in neutrophil cytosol, was found to potentiate the activation of the redox component of the O2 – generating oxidase in neutrophils, namely the membrane-bound flavocytochrome b , by the cytosolic phox proteins p67phox, p47phox and Rac (Doussière J., Bouzidi F. and Vignais P.V. (2001) Biochem. Biophys. Res. Commun. 285 , 1317–1320). This led us to check by immunoprecipitation and protein fractionation whether the cytosolic phox proteins could bind to S100A8/A9. Following incubation of a cytosolic extract from nonactivated bovine neutrophil with protein A–Sepharose bound to anti-p67phox antibodies, the recovered immunoprecipitate contained the S100 protein, p47phox and p67phox. Cytosolic protein fractionation comprised two successive chromatographic steps on hydroxyapatite and DEAE cellulose, followed by isoelectric focusing. The S100A8/A9 heterodimeric protein comigrated with the cytosolic phox proteins, and more particularly with p67phox and Rac2, whereas the isolated S100A8 protein displayed a tendancy to bind to p47phox. Using a semirecombinant cell-free system of oxidase activation consisting of recombinant p67phox, p47phox and Rac2, neutrophil membranes and arachidonic acid, we found that the S100A8/A9-dependent increase in the elicited oxidase activity corresponded to an increase in the turnover of the membrane-bound flavocytochrome b , but not to a change of affinity for NADPH or O2 . In the absence of S100A8/A9, oxidase activation departed from michaelian kinetics above a critical threshold concentration of cytosolic phox proteins. Addition of S100A8/A9 to the cell-free system rendered the kinetics fully michaelian. The propensity of S100A8/A9 to bind the cytosolic phox proteins, and the effects of S100A8/A9 on the kinetics of oxidase activation, suggest that S100A8/A9 might be a scaffold... [ABSTRACT FROM AUTHOR]

We report on a 5-year-old boy with hyperzincemia and hypercalprotectinemia. Treatment began with Tacrolimus at the age of 4 years and 6 months. Despite an initial correction of clinical and biological symptoms, zincemia and calprotectinemia progressively worsened with secondary reappearance of symptoms. Conclusion: Tacrolimus seems to have a transient effect in the treatment of Hyperzincemia and hyperprolactinemia. [ABSTRACT FROM AUTHOR]