S100A12 Levels Research Articles

S100A9 Exacerbates the Inflammation in Rosacea through Toll-Like Receptor 4/MyD88/NF-κB Signaling Pathway

Rosacea is a chronic inflammatory skin disorder characterized by immune response-dependent erythema and pustules. S100A9, a proinflammatory alarmin, has been associated with various inflammation-related diseases. However, the specific role of S100A9 in rosacea remains unexplored. Therefore, our objective was to unravel the role of S100A9 in the pathogenesis of rosacea and its underlying molecular mechanisms. In this study, we show that expression levels of S100A9 were elevated in both the lesions and serum of patients with papulopustular rosacea as well as in lesions of the LL37-induced rosacea-like mouse model. Moreover, the upregulation of S100A9 was correlated with clinical severity and levels of inflammatory cytokines. In addition, we demonstrated that S100A9 promoted the production of proinflammatory factors in HaCaT cells by activating toll-like receptor 4/MyD88/NF-κB signaling pathways. Notably, inhibition of S100A9 suppressed the progression of rosacea-like dermatitis and inflammatory responses in the LL37-induced rosacea-like mouse model through toll-like receptor 4/MyD88/NF-κB signaling pathways. In conclusion, this study illustrated that S100A9 participates in the pathogenesis of rosacea by upregulating toll-like receptor 4/MyD88/NF-κB signaling pathways, thereby promoting rosacea-associated skin inflammation. These results not only expand our understanding of the potential role of S100A9 in the development of rosacea but also offer greater insight toward targeted therapies.

S100A12 is involved in the pathology of osteoarthritis by promoting M1 macrophage polarization via the NF-κB pathway

ABSTRACT Background Osteoarthritis (OA) is a degenerative joint disease that affects millions worldwide. Synovitis and macrophage polarization are important factors in the development of OA. However, the specific components of synovial fluid (SF) responsible for promoting macrophage polarization remain unclear. Methods Semi-quantitative antibody arrays were used to outline the proteome of SF. Differential expression analysis and GO/KEGG were performed on the obtained data. Immunohistochemistry and ELISA were used to investigate the relationship between SF S100A12 levels and synovitis levels in clinalclinical samples. In vitro cell experiments were conducted to investigate the effect of S100A12 on macrophage polarization. Public databases were utilized to predict and construct an S100A12-centered lncRNA-miRNA-mRNA competing endogenous RNA network, which was preliminarily validated using GEO datasets. Results The study outlines the protein profile in OA and non-OA SF. The results showed that the S100A12 level was significantly increased in OA SF and inflammatory chondrocytes. The OA synovium had more severe synovitis and higher levels of S100A12 than non-OA synovium. Exogenous S100A12 upregulated the levels of M1 markers and phosphorylated p65 and promoted p65 nuclear translocation, while pretreatment with BAY 11–7082 reversed these changes. It was also discovered that LINC00894 was upregulated in OA and significantly correlated with S100A12, potentially regulating S100A12 expression by acting as a miRNA sponge. Conclusions This study demonstrated that S100A12 promotes M1 macrophage polarization through the NF-κB pathway, and found that LINC00894 has the potential to regulate the expression of S100A12 as a therapeutic approach.

High S100A9 level predicts poor survival, and the S100A9 inhibitor paquinimod is a candidate for treating idiopathic pulmonary fibrosis

BackgroundS100A9 is a damage-associated molecular pattern protein that may play an important role in the inflammatory response and fibrotic processes. Paquinimod is an immunomodulatory compound that prevents S100A9 activity. Its...

Single-cell transcriptome analysis reveals keratinocyte subpopulations contributing to psoriasis in corneum and granular layer.

Psoriasis is a chronic, inflammatory skin disease that is common and relapses easily. While the importance of keratinocyte proliferation in psoriasis development is well-documented, the specific functional subpopulations of epidermal keratinocytes associated with this disease remain enigmatic. Therefore, in our analysis of single-cell transcriptome data from both normal and psoriatic skin tissues, we observed significant increases in certain keratinocytes in the stratum corneum (KC) and stratum granulosum (KG) within psoriatic skin. Furthermore, we identified upregulated expression of specific secreted factors known to promote inflammatory responses. Additionally, we conducted a KEGG pathway enrichment analysis on these identified subsets. In the stratum corneum, the expression of FTL was upregulated in HIST1H1C+ KC. S100P+ KC displayed a significant increase in the expression of both S100P and S100A10, whereas PRR9+ KC showed upregulated expression of DEFB4B, S100A8, and S100A12. SLURP1+ KC was characterized by elevated expression levels of IL-36G, SLURP1, and S100A12. Meanwhile, in the stratum granulosum, KRT1+ KG highly expressed SLURP1, S100A7, S100A8, and S100A9, while DEFB4B expression was upregulated in PI3+ KG. Our findings indicated that subsets within the stratum corneum primarily participate in pathways related to MAPK, NOD-like receptors, HIF-1, cell senescence, and other crucial processes. In contrast, subsets in the stratum granulosum were predominantly associated with pathways involving MAPK, NOD-like receptors, HIF-1, Hippo, mTOR, and IL-17. These findings not only uncover the keratinocyte subsets linked to psoriasis but also unveil the molecular mechanisms and related signaling pathways that drive psoriasis development. This knowledge opens new horizons for the development of innovative clinical treatment strategies for psoriasis.

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.

Abnormal S100A8 expression associates with postoperative recurrence in chronic rhinosinusitis with nasal polyps

ObjectiveTo investigate the role of S100A8 in chronic rhinosinusitis with nasal polyps (CRSwNP) and assess its value in predicting disease recurrence after surgery. MethodsThirty healthy controls (HC), 30 patients with chronic rhinosinusitis without nasal polyp (CRSsNP), and 60 patients with CRSwNP were enrolled. Serum S100A8 concentration was measured by ELISA. Immunohistochemistry (IHC), western blotting (WB), and reverse transcription-polymerase chain reaction (RT-PCR)were performed to examine tissue expression levels of S100A8. The potential values of S100A8 in predicting postoperative recurrence of CRSwNP were assessed by the receiver operating characteristic (ROC)curve. ResultsSerum S100A8 concentrations in the CRSwNP group were higher than the HC group and the CRSsNP group， especially in the recurrent CRSwNP group (P < 0.05). Serum S100A8 levels were positively correlated with peripheral blood eosinophil numbers (r = 0.263, P = 0.043) and percentages (r = 0.336, P = 0.009), tissue eosinophil percentages (r = 0.273, P = 0.035), VAS score (r = 0.385, P = 0.002) and Lund-Kennedy score (r = 0.283, P = 0.029). IHC, WB, and RT-PCR results showed tissue S100A8 expression was significantly enhanced in the CRSwNP group, especially in the recurrence group (P < 0.05). Binary regression analysis showed that serum S100A8 concentration and tissue eosinophil percentage were correlated with postoperative recurrence of CRSwNP. ROC curve analysis showed that compared with tissue eosinophil percentage, the S100A8 level had a higher value for postoperative recurrence of CRSwNP. ConclusionSerum and tissue S100A8 levels were elevated in patients with CRSwNP， especially in the recurrent CRSwNP patients, and were correlated with the degree of peripheral blood and tissue eosinophilic inflammation. S100A8 seemed to be a potential objective biomarker to predict the postoperative recurrence of CRSwNP.

Suppression of overactivated immunity in the early stage is the key to improve the prognosis in severe burns.

Severe burns can lead to systemic inflammatory response syndrome (SIRS) and multiple organ dysfunction syndrome (MODS) due to inflammation-immunity dysregulation. This study aimed to identify key immune-related molecules and potential drugs for immune regulation in severe burn treatment. Microarray datasets GSE77791 and GSE37069 were analyzed to identify immune-related differentially expressed genes (DEGs), enriched pathways and prognosis-related genes. The DGIdb database was used to identify potentially clinically relevant small molecular drugs for hub DEGs. Hub DEGs were validated by total RNA from clinical blood samples through qPCR. The efficacy of drug candidates was tested in a severe burn mouse model. Pathologic staining was used to observe organ damage. Enzyme Linked Immunosorbent Assay (ELISA) was used to detect the serum IL-1b, IL-6, TNF-a and MCP-1 contents. Activation of the NF-κB inflammatory pathway was detected by western blotting. Transcriptome sequencing was used to observe inflammatory-immune responses in the lung. A total of 113 immune-related DEGs were identified, and the presence of immune overactivation was confirmed in severe burns. S100A8 was not only significantly upregulated and identified to be prognosis-related among the hub DEGs but also exhibited an increasing trend in clinical blood samples. Methotrexate, which targets S100A8, as predicted by the DGIdb, significantly reduces transcription level of S100A8 and inflammatory cytokine content in blood, organ damage (lungs, liver, spleen, and kidneys) and mortality in severely burned mice when combined with fluid resuscitation. The inflammatory-immune response was suppressed in the lungs. S100A8 with high transcription level in blood is a potential biomarker for poor severe burn prognosis. It suggested that methotrexate has a potential application in severe burn immunotherapy. Besides, it should be emphasized that fluid resuscitation is necessary for the function of methotrexate.

Saliva: An Emerging Adjunct Biomarker for Psoriasis –Trends, Scope and Relevance

Psoriasis is a widely prevalent chronic immuno inflammatory dermatological disease resulting from a complex and dynamic interplay of genetic, environmental, and immunological aetiologies. It manifests as characteristic erythematous psoriatic plaques visible to the naked eye, but prognostic biomarkers for disease monitoring and therapeutic effectiveness are still absent. Saliva is a biological fluid that, besides being critical to maintaining oral homeostasis, harbors various salivary microbiota and inflammatory markers. It can be easily collected, stored, and analyzed. Oral fluids offer an excellent advantage for biomarker study as they are non-invasive and fast techniques. Studies showed that the saliva of healthy individuals and those with psoriasis had differences in the levels of inflammatory cytokines, immunoglobulin A, and anti-oxidant biomarkers. In GCF, individuals with psoriasis showed higher levels of S100A8, IL-18, and sE-selectin than healthy individuals, independent of periodontal status. Oxidative stress(OS) is one of the pathogenetic factors of psoriasis. Thus levels of ROS and anti-oxidants can also become important factors in diagnosis.

A novel automated multiplex immunoassay for the ultrasensitive detection of blood‐based biomarkers for neurodegenerative diseases

AbstractBackgroundEfforts to identify accurate blood biomarkers for neurodegenerative disease hallmarks have been hampered by the lack of a proteomic tool that has the required sensitivity to detect very low concentrations of brain‐derived proteins in plasma or serum and the ability to multiplex many analytes in a single assay. Here we evaluated NULISA™, a recently developed novel immunoassay with attomolar level sensitivity and high multiplex capability1, for its ability to detect serum biomarkers associated with Alzheimer’s disease.MethodSerum samples from 31 Alzheimer’s disease (AD) patients and 31 non‐AD controls were analyzed using NULISA with a 200plex inflammation panel targeting a broad spectrum of inflammation‐related cytokines, chemokines and other proteins. Five samples failed quality control and were excluded from further analysis, resulting in 28 AD and 29 control samples in the final dataset. Linear model analysis, including age and sex as covariates, was performed for each target for differential expression between AD patients and controls.ResultTwo significant proteins were identified. The level of glial fibrillary acidic protein (GFAP) was 1.84‐fold higher in AD patients (adjusted p‐value = 0.00014), whereas the level of S100 calcium‐binding protein A12 (S100A12) was 2‐fold higher in non‐AD controls (adjusted p‐value = 0.031). GFAP serum levels correlated strongly with total tau (Spearman rho = 0.69, p = 1.7e‐09), p‐tau181 (rho = 0.69, p = 1.7e‐09) and amyloid beta 42 (rho = ‐0.71, p = 4.7e‐10) levels in cerebrospinal fluid (CSF). S100A12 levels also correlated significantly with total tau (rho = ‐0.39, p = 0.0031), p‐tau181 (rho = ‐0.36, p = 0.0053) and amyloid beta 42 (rho = 0.38, p = 0.0067) CSF levels. Receiver operating characteristic analysis demonstrated that GFAP strongly discriminated AD from controls with an area under the curve (AUC) of 0.93 (95% CI 0.87‐1.0), and S100A12 also exhibited good discrimination with an AUC of 0.72 (95% CI 0.59‐0.86).ConclusionThis exploratory study identified serum GFAP levels as a strong discriminatory biomarker for AD, consistent with previous studies. S100A12 also demonstrated significant associations with AD and CSF biomarkers and thus warrants further study. NULISA holds great promise for the discovery and validation of blood‐based biomarkers for the early detection and monitoring of neurodegenerative diseases.1. Feng, W. et al. bioRxiv 2023.04.09.536130 (2023) https://doi.org/10.1101/2023.04.09.536130.

Colon-targeted S100A8/A9-specific peptide systems ameliorate colitis and colitis-associated colorectal cancer in mouse models.

The link between chronic inflammation and cancer development is well acknowledged. Inflammatory bowel disease including ulcerative colitis and Crohn's disease frequently promotes colon cancer development. Thus, control of intestinal inflammation is a therapeutic strategy to prevent and manage colitis-associated colorectal cancer (CRC). Recently, gut mucosal damage-associated molecular patterns S100A8 and S100A9, acting via interactions with their pattern recognition receptors (PRRs), especially TLR4 and RAGE, have emerged as key players in the pathogenesis of colonic inflammation. We found elevated serum levels of S100A8 and S100A9 in both colitis and colitis-associated CRC mouse models along with significant increases in their binding with PRR, TLR4, and RAGE. In this study we developed a dual PRR-inhibiting peptide system (rCT-S100A8/A9) that consisted of TLR4- and RAGE-inhibiting motifs derived from S100A8 and S100A9, and conjugated with a CT peptide (TWYKIAFQRNRK) for colon-specific delivery. In human monocyte THP-1 and mouse BMDMs, S100A8/A9-derived peptide comprising TLR4- and RAGE-interacting motif (0.01, 0.1, 1 μM) dose-dependently inhibited the binding of S100 to TLR4 or RAGE, and effectively inhibited NLRP3 inflammasome activation. We demonstrated that rCT-S100A8/A9 had appropriate drug-like properties including in vitro stabilities and PK properties as well as pharmacological activities. In mouse models of DSS-induced acute and chronic colitis, injection of rCT-S100A8/A9 (50 μg·kg-1·d-1, i.p. for certain consecutive days) significantly increased the survival rates and alleviated the pathological injuries of the colon. In AOM/DSS-induced colitis-associated colorectal cancer (CAC) mouse model, injection of rCT-S100A8/A9 (50 μg·kg-1·d-1, i.p.) increased the body weight, decreased tumor burden in the distal colon, and significantly alleviated histological colonic damage. In mice bearing oxaliplatin-resistant CRC xenografts, injection of rCT-S100A8/A9 (20 μg/kg, i.p., every 3 days for 24-30 days) significantly inhibited the tumor growth with reduced EMT-associated markers in tumor tissues. Our results demonstrate that targeting the S100-PRR axis improves colonic inflammation and thus highlight this axis as a potential therapeutic target for colitis and CRC.

Aortic valve calcification is promoted by clonal hematopoiesis associated with DNMT3A and TET2 gene driver mutations

Abstract Background Clonal hematopoiesis (CH) due to DNMT3A or TET2-driver mutations is associated with coronary heart disease and worse prognosis among patients with aortic valve stenosis (AVS) and inflammation. However, it is unknown what role CH plays in the pathogenesis of AVS. AVS is the most common age-related heart valve disease, with no medical therapy to halt progression. Methods and Results Single-cell RNA-sequencing of immune cells of CAVD patients (n=13) with and without the most prevalent CH-mutations (DNMT3A and TET2), with mean CH-driver gene variant allele frequency was 6.5% for DNMT3A and 17.9% for TET2. Monocytes of patients harboring DNMT3A and TET2 mutations shared 836 upregulated genes, many associated with glycolytic, pro-inflammatory activation (CXCL10, IL38) and paracrine pro-calcific factors (oncostatin M (OSM), S100A9), suggesting that CH might be causally involved in AVS. Indeed, silencing of TET2 or DNMT3A in macrophages promotes M1-like polarization and increases release of pro-calcific mediators, particularly S100A9 and OSM. To assess whether CH-gene silenced macrophages may stimulate mesenchymal cells to secrete calcium, secreted factors from TET2 or DNMT3A-silenced macrophages were applied mesenchymal cells. Indeed, CH-gene silenced secretomes induced osteoblastic differentiation of mesenchymal cells, evidenced by increased Alizarin red calcium staining and elevated levels of ALP and RUNX2. This CH-mediated enhancement in osteoblastic conversion could be ablated by silencing of OSM. Finally, valves from atheroprone Ldlr-/- mice receiving TET2-/- bone marrow transplants demonstrated increased total calcified area (1.49-fold) along with increased numbers of calcification deposits (2.33-fold) as evidenced by von Kossa staining, along with enhanced OSM and S100A9 levels. Conclusion This is the first study to demonstrate that somatic CH-driver mutations in monocytes may accelerate AVS. Moreover, calcification was ablated via silencing of OSM in CH-gene silenced macrophages. These data suggest Oncostatin M may be a therapeutically promising target in halting the progression of AVS in patients harboring CH mutations.

Topical anti-TNF-a ssDNA aptamer decreased the imiquimod induced psoriatic inflammation in BALB/c mice

BackgroundTumor Necrosis Factor-α (TNF-α) is a pro-inflammatory factor that plays a pivotal role in psoriasis. Due to limitations of monoclonal antibody-based therapies, it is needed to discover new anti-TNF-α factors instead of usual anti-TNF-α monoclonal antibodies. Compared to antibodies, single-stranded DNA or RNA molecules named aptamers, have advantages such as time-saving, less risk for immunogenicity and cost-effectiveness. Therefore, the aim of the present study was to assess the therapeutic effects of T1-T4 dimer anti-TNF-ɑ ssDNA aptamer topical treatment in the imiquimod (IMQ)-induced psoriasis animal model. Methods5% IMQ cream was prescribed on the right ear of BALB/c to induce psoriasis model. The hydrogel-containing anti-TNF-ɑ aptamer or treatment control aptamer (anti- Interleukin (IL)17A) was topically prescribed to the mice's ears 10 min before IMQ cream treatment. The psoriasis area severity index (PASI) score was used to evaluate psoriasis intensity. Histopathology analysis was done for mice ears sections. Mass, size, and cell number of mice spleens were measured. The IL-17 level was determined in culture supernatants of axillary lymph node cells using ELISA. The mRNA expression levels of IL-17A, IL-1β, STAT3, and S100a9, were evaluated in mice treated ear with quantitative Real Time-PCR. ResultsThe anti-TNF-ɑ ssDNA aptamer lower doses had significant decrease in IMQ-induced PASI score (p < 0.05). In addition, in these groups, the IL-17A, STAT3, and S100a9 mRNA levels were significantly lower than the IMQ group (p < 0.05). ConclusionAccording to our findings, this aptamer seems to be a prospective candidate for treating psoriatic inflammation especially in lower concentrations.

Differential expression of antimicrobial peptides in human fungal keratitis.

To analyze a series of antimicrobial peptides (AMPs) in corneal tissue from individuals with fungal keratitis (FK) during the active phase of the fungus infection and after healing. Patients undergone lamellar keratoplasty for the treatment of severe FK or corneal scar had their corneal buttons sampled. Quantitative real-time polymerase chain reaction (PCR) was used to ascertain the gene expression of human beta-defensin (HBD)-1, -2, -3, -9, S100A7, 8, 9, and LL-37. All AMPs' messenger ribonucleic acid (mRNA) expression was considerably elevated in all samples (n=12). In contrast to controls, where HBD-2, -3, and S100A7 mRNAs were expressed at very low levels, it was discovered that HBD-1, -9, S100A8, S100A9, and LL-37 were constitutively expressed in all healed samples (n=4). HBD-1, -2 -3, S100A7, and LL-37 mRNAs were significantly increased in all active FK samples (n=8). The levels of HBD-9, S100A8, and S100A9 mRNAs were moderately upregulated in all active FK samples. Subgroup comparison showed that HBD-2 was significantly increased in Fusarium keratitis samples (n=5), and LL-37 mRNAs were significantly enhanced in Aspergillus keratitis samples (n=3). Whereas there was not significantly increased of HBD-1, -3, -9, S100A7, 8, 9 mRNA in Aspergillus keratitis samples compared with Fusarium keratitis samples. AMPs expression is increased in active FK, but not all AMPs are equally expressed. HBD-2 and LL-37 expression levels are the highest, showing some specificity of AMP expression related to FK. Human AMPs, particularly HBD-2 may play a significant role in Fusarium keratitis and LL-37 might be the key player in Aspergillus keratitis.

Viral nanoparticle vaccines against S100A9 reduce lung tumor seeding and metastasis

Metastatic cancer accounts for 90% of all cancer-related deaths and continues to be one of the toughest challenges in cancer treatment. A growing body of data indicates that S100A9, a major regulator of inflammation, plays a central role in cancer progression and metastasis, particularly in the lungs, where S100A9 forms a premetastatic niche. Thus, we developed a vaccine against S100A9 derived from plant viruses and virus-like particles. Using multiple tumor mouse models, we demonstrate the effectiveness of the S100A9 vaccine candidates in preventing tumor seeding within the lungs and outgrowth of metastatic disease. The elicited antibodies showed high specificity toward S100A9 without cross-reactivity toward S100A8, another member of the S100A family. When tested in metastatic mouse models of breast cancer and melanoma, the vaccines significantly reduced lung tumor nodules after intravenous challenge or postsurgical removal of the primary tumor. Mechanistically, the vaccines reduce the levels of S100A9 within the lungs and sera, thereby increasing the expression of immunostimulatory cytokines with antitumor function [(interleukin) IL-12 and interferonγ] while reducing levels of immunosuppressive cytokines (IL-10 and transforming growth factorβ). This also correlated with decreased myeloid-derived suppressor cell populations within the lungs. This work has wide-ranging impact, as S100A9 is overexpressed in multiple cancers and linked with poor prognosis in cancer patients. The data presented lay the foundation for the development of therapies and vaccines targeting S100A9 to prevent metastasis.

Extracellular proteins as potential biomarkers in Sepsis-related cerebral injury.

Sepsis can cause brain damage known as septic encephalopathy (SAE), which is linked to higher mortality and poorer outcomes. Objective clinical markers for SAE diagnosis and prognosis are lacking. This study aimed to identify biomarkers of SAE by investigating genes and extracellular proteins involved in sepsis-induced brain injury. Extracellular protein differentially expressed genes (EP-DEGs) from sepsis patients' brain tissue (GSE135838) were obtained from Gene Expression Omnibus (GEO) and evaluated by protein annotation database. The function and pathways of EP-DEGs were examined using GO and KEGG. Protein-protein interaction (PPI) networks were built and crucial EP-DEGs were screened using STRING, Cytoscape, MCODE, and Cytohubba. The diagnostic and prognostic accuracy of key EP-DEGs was assessed in 31 sepsis patients' blood samples and a rat cecal ligation and puncture (CLP)-induced sepsis model. Cognitive and spatial memory impairment was evaluated 7-11 days post-CLP using behavioral tests. Blood and cerebrospinal fluid from 26 rats (SHAM n=14, CLP n=12) were collected 6 days after CLP to analyze key EP-DEGs. Thirty-one EP-DEGs from DEGs were examined. Bone marrow leukocytes, neutrophil movement, leukocyte migration, and reactions to molecules with bacterial origin were all enhanced in EP-DEGs. In comparison to the sham-operated group, sepsis rats had higher levels of MMP8 and S100A8 proteins in their venous blood (both p<0.05) and cerebrospinal fluid (p=0.0506, p<0.0001, respectively). Four important extracellular proteins, MMP8, CSF3, IL-6, and S100A8, were identified in clinical peripheral blood samples. MMP8 and S100A8 levels in the peripheral blood of sepsis patients were higher in SAE than in non-SAE. In comparison to MMP8, S100A8 had a higher area under the curve (AUC: 0.962, p<0.05) and a higher sensitivity and specificity (80% and 100%, respectively) than MMP8 (AUC: 0.790, p<0.05). High levels of S100A8 strongly correlated with 28-day mortality and the Glasgow Coma Scale (GCS) scores. The extracellular proteins MMP8, CSF3, IL-6, and S100A8 may be crucial in the pathophysiology of SAE. S100A8 and MMP8 are possible biomarkers for SAE's onset and progression. This research may help to clarify the pathogenesis of SAE and improve the diagnosis and prognosis of the disease.

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.

Enteric health of children in coastal Bangladesh: A cross-sectional study

Objective: To investigate the environmental factors associated with enteric diseases among children in coastal Bangladesh. Methods: A cross-sectional descriptive study was conducted between July 2018 and November 2018, enrolling 59 preschool children from Nabipur village in Bhola district and Paikgacha village in Khulna district. Keraniganj in Dhaka district was selected as a control village for comparison. A self-administered semi-structured questionnaire was used to collect data, including health information (height, weight, food habits, and hygiene practices), age and history of medication. Food, water and stool samples were also collected from the participants. Results: Children in coastal zones experience an average of 6 episodes per year as compared to 3 diarrhea episodes in Dhaka. The salinity of drinking water varied significantly across the study sites (480±30 ppm in Bhola, 450±36 ppm Khulna, 180±17 ppm in Dhaka). The coastal children had higher fecal calprotectin levels (67±2.7 ng/mg and 77±12 ng/mg in Khulna and Bhola, respectively) compared to those living in Dhaka (25±1.5 ng/mg). The levels of fecal calprotectin and fecal s100A12 were both positively correlated with the salinity of drinking water in Bhola (r=0.66 for calprotectin; r=0.51 for s100A12) and Khulna (r=0.77 for calprotectin; r=0.54 for s100A12). Conclusions: The study revealed a positive correlation between the salinity levels in drinking water and the elevated levels of fecal calprotectin and fecal s100A12 in children living in coastal villages of Khulna and Bhola in Bangladesh, whereas no such association was found among children living in central Bangladeshi locality of Keraniganj, Dhaka.

Transcriptomics and metabolomics study in mouse kidney of the molecular mechanism underlying energy metabolism response to hypoxic stress in highland areas.

Exposure to hypoxia disrupts energy metabolism and induces inflammation. However, the pathways and mechanisms underlying energy metabolism disorders caused by hypoxic conditions remain unclear. In the present study, a hypoxic animal model was created and transcriptomic and non-targeted metabolomics techniques were applied to further investigate the pathways and mechanisms of hypoxia exposure that disrupt energy metabolism. Transcriptome results showed that 3,007 genes were significantly differentially expressed under hypoxic exposure, and Gene Ontology annotation analysis and Kyoto Encyclopaedia of Genes and Genomes (KEGG) enrichment analysis showed that the differentially expressed genes (DEGs) were mainly involved in energy metabolism and were significantly enriched in the tricarboxylic acid (TCA) cycle and oxidative phosphorylation (OXPHOS) pathway. The DEGs IDH3A, SUCLA2, and MDH2 in the TCA cycle and the DEGs NDUFA3, NDUFS7, UQCRC1, CYC1 and UQCRFS1 in the OXPHOS pathway were validated using mRNA and protein expression, and the results showed downregulation. The results of non-targeted metabolomics showed that 365 significant differential metabolites were identified under plateau hypoxia stress. KEGG enrichment analysis showed that the differential metabolites were mainly enriched in metabolic processes, such as energy, nucleotide and amino acid metabolism. Hypoxia exposure disrupted the TCA cycle and reduced the synthesis of amino acids and nucleotides by decreasing the concentration of cis-aconitate, α-ketoglutarate, NADH, NADPH and that of most amino acids, purines, and pyrimidines. Bioinformatics analysis was used to identify inflammatory genes related to hypoxia exposure and some of them were selected for verification. It was shown that the mRNA and protein expression levels of IL1B, IL12B, S100A8 and S100A9 in kidney tissues were upregulated under hypoxic exposure. The results suggest that hypoxia exposure inhibits the TCA cycle and the OXPHOS signalling pathway by inhibiting IDH3A, SUCLA2, MDH2, NDUFFA3, NDUFS7, UQCRC1, CYC1 and UQCRFS1, thereby suppressing energy metabolism, inducing amino acid and nucleotide deficiency and promoting inflammation, ultimately leading to kidney damage.

Usefulness of Proguanylin, Pentraxin 3 and S100A12 Serum Concentrations in Diagnosis and Monitoring the Disease Activity in Crohn's Disease.

The aim of our case-control study was to identify novel biomarkers of Crohn's disease (CD) that hold the potential to be employed in both disease diagnosis and monitoring activity. In the context of the contribution of intestinal barrier integrity and immune response to the pathogenesis of CD, we assessed the serum concentrations of proguanylin (pro-GN), pentraxin 3 (PTX3) and S100A12 in 20 patients before and after anti-inflammatory treatment, as well as in 20 healthy individuals. Statistical analyses revealed a significant difference in the levels of pro-GN (5.5 vs. 11.35, p < 0.001), PTX3 (2117.9 vs. 1608.37, p < 0.05) and S100A12 (79.4 vs. 19.74, p < 0.001) between pretreatment patients with CD and healthy individuals. Moreover, we noted a significant relationship between the serum profile of PTX3 and disease activity, expressed as CDAI, both before (p < 0.005, r = 0.63) and after (p < 0.05, r = 0.60) treatment. A similar correlation was noted in the case of S100A12 (p < 0.005, r = 0.81), albeit exclusively within the post-treatment group of patients. Anti-inflammatory treatment resulted in an elevation of pro-GN concentration (5.5 vs. 8.04, p < 0.001) and a reduction in PTX3 level (2117.9 vs. 1609.5, p < 0.05) in the serum of patients with CD. In comparison to our previous research conducted on a group of patients with ulcerative colitis (UC), those with CD exhibited reduced levels of PTX3 (2117.9 vs. 3197.05, p < 0.005) and elevated concentrations of S100A12 (79.4 vs. 39.36, p < 0.05). The results obtained from this investigation suggest that measurements of pro-GN, PTX3 and S100A12 could prove beneficial in the diagnosis of Crohn's disease. Assessment of changes in the serum profile of PTX3 appears to be a good marker of response to treatment but also, along with analysis of S100A12 protein serum levels, a useful marker in differentiating CD from UC.

IL18R1-Related Molecules as Biomarkers for Asthma Severity and Prognostic Markers for Idiopathic Pulmonary Fibrosis.

To determine the role of inflammation-related proteins in predicting asthma severity and outcome, 92 inflammation-related proteins were measured in the asthmatic serum using Olink analysis. Different bioinformatics algorithms were developed to cross analyze with the single-cell or transcriptome data sets from the Gene Expression Omnibus database to explore the role of IL18R1 and related genes in asthma and idiopathic pulmonary fibrosis (IPF). Olink identified 52 differentially expressed proteins in asthma. They were strongly linked to the cytokine-cytokine receptor interaction, TNF, and NF-κB signaling pathway. Seven proteins were found in both single-cell RNA and Olink analyses. Among them, IL18R1 was predominantly expressed in mast cells, and the results suggested enhanced communication between mast cells and CD 8+ T cells. IL18R1 was upregulated in serum and induced sputum and bronchoalveolar lavage fluid of patients with uncontrolled or severe asthma. IL18R1 was positively correlated with TNFSF1 and OSM and S100A12. The diagnostic efficacy of these serum IL18R1-related molecules for asthma ranged from 0.839 to 0.921. Moreover, high levels of IL18R1, TNFSF1, OSM, and S100A12 were significantly associated with shorter survival times and worse lung function. IL18R1-related molecules may serve as biomarkers for monitoring uncontrolled or severe asthma and as prognostic markers for IPF.