Upregulated miR-155 inhibits inflammatory response induced by C. albicans in human monocytes derived dendritic cells via targeting p65 and BCL-10.

BACKGROUND: Candida albicans (C. albicans) is one of the most common fungal pathogens causing superficial and systemic infections. The innate immune system is the first defense line against C. albicans infection. MiR-155, a multifunctional microRNA (miRNA), has been proved to be a crucial regulator in innate immune response against bacterial and virus. However, the biological function of miR-155 in innate immune response against C. albicans infection remains unknown. METHODS: The expression miR-155, as well as inflammatory factors [interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α) and interferon-γ (IFN-γ)], in monocytes derived dendritic cells (DCs) during heat-killed C. albicans infection was detected by quantitative reverse-transcriptase polymerase chain reaction (qRT-PCR). The biological functions of miR-155 were investigated with "gain- and loss-of-function" experiments. Potential targets of miR-155 were identified by bioinformatics analysis, luciferase assay and western blot. Small interfering RNA (siRNA) was used to validate the function of miR-155 target. RESULTS: C. albicans increased the expression of miR-155 and pro-inflammatory factors. MiR-155 induced by C. albicans was depended on Dectin-1-spleen tyrosine kinase (Syk)/Raf-1-MAPK signaling pathway. Furthermore, miR-155 suppressed the secretion of pro-inflammatory cytokines induced by C. albicans by targeting NF-κB p65 and B cell leukemia/lymphoma 10 (BCL-10). CONCLUSIONS: In conclusion, up-regulated miR-155 acts as a negative feedback regulator in the innate immune response against C. albicans infection.

The effects of Salvia przewalskii total phenolic acid extract on immune complex glomerulonephritis.

CONTEXT: Salvia przewalskii Maxim. (Lamiaceae) is a Chinese herbal medicine that has long been used for the treatment of cardiovascular disease. OBJECTIVE: The study investigated the therapeutic efficacy of S. przewalskii total phenolic acid extract (SPE) on immune complex glomerulonephritis (ICG) in rats. MATERIALS AND METHODS: Sixty-two Wistar rats were randomized into six groups. ICG was induced in all groups except normal control group. SPE was administered intragastrically at 24 h intervals for 40 consecutive days. Urine protein (UP), total serum protein (TSP), serum albumin (SA), serum cholesterol (SC) and serum urea nitrogen (SUN) were measured one day before, on day 20 and 40 after SPE administration. On day 40 after SPE administration, the kidneys were removed and prepared into pathologic sections. In addition, kidney wet mass was measured for calculating the kidney wet mass coefficient (KWMC). RESULTS: UP excretion was reduced significantly on day 20 after SPE administration in all three SPE groups as compared with that in medium group, and this effect was observable continuously until 40 days after SPE administration. Compared with medium group, TSP and SA were increased in all three SPE groups after 40 days treatment, while SC and SUN were decreased. KWMC was decreased significantly in 100 mg/kg SPE group after 40 days treatment compared with that in medium group. Histopathologic analyses showed that renal inflammatory infiltration and kidney intumesce were alleviated in all three SPE groups. CONCLUSIONS: SPE may be a potential therapeutic drug for glomerulonephritis.

Gene expression profile of THP-1 cells treated with heat-killed Candida albicans.

BACKGROUND: Mechanisms under immune response against Candida albicans (C. albicans) remain largely unknown. To better understand the mechanisms of innate immune response against C. albicans, we analyzed the gene expression profile of THP-1 cells stimulated with heat-killed C. albicans. METHODS: THP-1 cells were stimulated with heat-killed C. albicans for 9 hours at a ratio of 1:1, and gene expression profile of the cells was analyzed using Whole Human Genome Oligo Microarray. Differentially expressed genes were defined as change folds more than 2 and with statistical significance. Gene ontology (GO) and pathway analysis were used to systematically identify biological connections of differentially expressed genes, as well as the pathways associated with the immune response against C. albicans. RESULTS: A total of 355 genes were up-regulated and 715 genes were down-regulated significantly. The up-regulated genes were particularly involved in biological process of RNA processing and pathway of the spliceosome. In case of down-regulated genes, the particularly involved immune-related pathways were G-protein coupled receptor signaling pathway, calcium signaling pathway, MAPK signaling pathway and Ras pathway. CONCLUSIONS: We depict the gene expression profile of heat-killed C. albicans stimulated THP-1 cells, and identify the major pathways involved in immune response against C. albicans. These pathways are potential candidate targets for developing anti-C. albicans agent.

Diagnostic Accuracy of Procalcitonin in Bacterial Meningitis Versus Nonbacterial Meningitis: A Systematic Review and Meta-Analysis.

Several studies have investigated the diagnostic accuracy of procalcitonin (PCT) levels in blood or cerebrospinal fluid (CSF) in bacterial meningitis (BM), but the results were heterogeneous. The aim of the present study was to ascertain the diagnostic accuracy of PCT as a marker for BM detection. A systematic search of the EMBASE, Scopus, Web of Science, and PubMed databases was performed to identify studies published before December 7, 2015 investigating the diagnostic accuracy of PCT for BM. The quality of the eligible studies was assessed using the revised Quality Assessment for Studies of Diagnostic Accuracy method. The overall diagnostic accuracy of PCT detection in CSF or blood was pooled using the bivariate model. Twenty-two studies involving 2058 subjects were included in this systematic review and meta-analysis. The overall specificities and sensitivities were 0.86 and 0.80 for CSF PCT, and 0.97 and 0.95 for blood PCT, respectively. Areas under the summary receiver operating characteristic curves were 0.90 and 0.98 for CSF PCT and blood PCT, respectively. The major limitation of this systematic review and meta-analysis was the small number of studies included and the heterogeneous diagnostic thresholds adopted by eligible studies. Our meta-analysis shows that PCT is a useful biomarker for BM diagnosis.

Elevated red blood cell distribution width is associated with liver function tests in patients with primary hepatocellular carcinoma.

BACKGROUND: Red blood cell distribution width (RDW), a routinely tested parameter of the complete blood count (CBC), has been reported to be increased in various cancers and correlated with the patients' clinical characteristics. However, the significance of RDW in primary hepatocellular carcinoma (pHCC) is largely unknown. The aim of this study was to evaluate the associations between RDW and the clinical characteristics of pHCC patients. METHODS: Medical records of 110 treatment-naive pHCC patients were retrospectively reviewed. Their clinical characteristics on admission, including RDW, liver function tests and tumor stage, were extracted, and their relationships were analyzed using Spearman correlation and Kruskal-Wallis test. Sixty-eight healthy individuals were set as controls. RESULTS: RDW was significantly increased in pHCC patients and correlated with the liver function tests. However, no correlation between RDW and tumor stage was found. CONCLUSION: RDW may be used to assess the liver function, but not the tumor stage in pHCC patients.

Diagnostic value of osteopontin in ovarian cancer: a meta-analysis and systematic review.

AIMS: Osteopontin (OPN) plays an important role in many physiological and pathological processes (wound healing, inflammation, immune response, and tumorigenesis). This meta-analysis assessed the diagnostic value of osteopontin in ovarian cancer. METHODS AND RESULTS: Searches in Embase and PubMed were conducted, in order to identify eligible studies on osteopontin expression and its diagnostic value in ovarian cancer. The revised Quality Assessment for Studies of Diagnostic Accuracy (QUADAS-2) tool was applied to examine the quality of these studies and the overall osteopontin diagnostic accuracy in ovarian cancer was pooled using the bivariate model. The publication bias was assessed using funnel plots and Deek's test. This search methodology resulted in 13 studies with a total of 839 ovarian cancer patients and 1439 controls in this meta-analysis. The overall osteopontin diagnostic sensitivity and specificity of ovarian cancer were 0.66 (95% CI, 0.51-0.78) and 0.88 (95% CI, 0.78-0.93), respectively. The area under summary receiver operating characteristic (sROC) curves (AUC) was 0.85 (95%CI, 0.81-0.88). There was no significant publication bias observed across the eligible studies. However, a major design deficiency of the eligible studies is the issue of subject selection bias. CONCLUSIONS: Osteopontin could be a useful biomarker in diagnosis of ovarian cancer. Due to the design deficits of the eligible studies, a future study with a larger sample size and better design is needed to rigorously confirm the diagnostic potential of osteopontin in ovarian cancer.

Prognostic value of neutrophil to lymphocyte ratio for gastric cancer.

BACKGROUND: Although the prognostic value of the neutrophil to lymphocyte ratio (NLR) in gastric cancer (GC) patients has been investigated by many studies, the results are heterogeneous. The objective of this systematic review is to ascertain the prognostic value of NLR in GC patients. METHODS: PubMed and Embase were retrieved to identify potential studies published before 8 June, 2014. Newcastle-Ottawa Scale (NOS) for cohort study was used to assess the quality of all eligible studies. RESULTS: Of the 20 studies included in this systematic review, 17 studies investigated the effect of NLR on overall survival (OS), 11 studies reported that NLR negatively affected OS in their multivariante analysis, and 16 studies reported that NLR negatively affected OS in univariate analysis. Three studies investigated the effect of NLR on progression-free survival (PFS), reporting that increased NLR was associated with worse PFS. Four studies investigated the effect of NLR on disease-free survival (DFS), two of which reported that increased NLR was associated with worse DFS. Two studies investigated the effect of NLR on disease special survival (DSS), but neither observed any significant association between NLR and DSS. The major design deficiencies of the studies available were retrospective data collection, inadequacy of follow-up cohorts, and unavailability of the method used for outcome assessment. CONCLUSIONS: Based on the above findings, we conclude that NLR may be a useful prognostic index (PI) for GC. In addition, future studies with prospective design, long-term follow-up and fully adjusted confounding factors are needed to rigorously assess the prognostic value of NLR for GC.

Red blood cell distribution width and neutrophil/lymphocyte ratio are positively correlated with disease activity in primary Sjögren's syndrome.

OBJECTIVE: The red blood cell distribution width (RDW) and neutrophil/lymphocyte ratio (NLR) are increased in various inflammation related diseases, but their clinical significance in primary Sjögren's syndrome (pSS) has not been reported. The aim of the present study was to investigate the clinical significance of RDW and NLR in pSS patients. METHODS: The medical records of pSS patients who were admitted to Changhai Hospital of the Second Military Medical University between April 2012 and December 2013 were retrospectively reviewed. Correlations between RDW, NLR and the patient clinical characteristics were analyzed using the Spearman approach and the multiple linear regression model. RESULTS: Fifty-two pSS patients and 58 healthy controls were enrolled. RDW and NLR were increased in pSS patients and positively correlated with the Sjögren's syndrome disease activity index (SSDAI). CONCLUSION: RDW and NLR may prove to be useful indices to estimate pSS disease activity.

Prognostic value of red blood cell distribution width for patients with heart failure: a systematic review and meta-analysis of cohort studies.

AIMS: Multiple studies have investigated the prognostic role of red blood cell distribution width (RDW) for patients with heart failure (HF), but the results have been inconsistent. The aim of the present study was to estimate the impact of RDW on the prognosis of HF by performing a systematic review and meta-analysis. METHODS AND RESULTS: The Embase, PubMed, and Web of Science databases were searched up to November 16, 2013 to identify eligible cohort studies. The quality of each study was assessed using the Newcastle-Ottawa Scale (NOS). The association between RDW, either on admission or at discharge, and HF outcomes (all-cause mortality [ACM], heart transplantation, cardiovascular mortality, and rehospitalization, etc.) were reviewed. The overall hazard ratio (HR) for the effect of RDW on ACM was pooled using a random-effects model, and the publication bias was evaluated using funnel plots and Eggers' tests. Seventeen studies, with a total of 18288 HF patients, were included for systematic review. All eligible studies indicated that RDW on admission and RDW at discharge, as well as its change during treatment, were of prognostic significance for HF patients. The HR for the effect of a 1% increase in baseline RDW on ACM was 1.10 (95% confidence interval: 1.07-1.13), based on pooling of nine studies that provided related data. However, publication bias was observed among these studies. CONCLUSIONS: HF patients with higher RDW may have poorer prognosis than those with lower RDW. Further studies are needed to explore the potential mechanisms underlying this association.

Increased expression of Siglec-1 on peripheral blood monocytes and its role in mononuclear cell reactivity to autoantigen in rheumatoid arthritis.

OBJECTIVES: Elevated expression of Siglec-1 on circulating monocytes has been reported in some inflammatory and autoimmune diseases, but its expression and role in RA has not been elucidated. The aims of this study were to determine the expression of Siglec-1 in peripheral blood and to explore its role in mononuclear cell reactivity to autoantigen in RA. METHODS: Siglec-1 protein and mRNA levels in 42 RA patients, 39 OA patients, 28 SLE patients and 42 normal controls were determined by flow cytometry and quantitative RT-PCR, respectively. In addition, 10 patients with active RA received DMARDs for 12 weeks and the frequencies of Siglec-1-positive cells and the 28-joint DAS (DAS28) were assessed before and after therapy. Furthermore, TNF-α, IFN-γ and type II collagen were used to up-regulate Siglec-1. Peripheral blood mononuclear cells (PBMCs) from different groups were stimulated with mitogens or antigens and cell proliferation and cytokine production were determined. RESULTS: The protein and mRNA levels of Siglec-1 on PBMCs and monocytes in RA patients were significantly higher than those in OA patients and healthy controls. Moreover, the expression of Siglec-1 protein on PBMCs was positively correlated with DAS28, ESR, high-sensitivity CRP and IgM-RF, but not with anti-CCP antibody. Interestingly, Siglec-1 expression was decreased in parallel with the decrease in the DAS28 after 12 weeks of anti-rheumatic treatment. Furthermore, TNF-α, IFN-γ and type II collagen can up-regulate Siglec-1 in PBMCs. Elevated PBMC proliferation and proinflammatory cytokine production to collagen stimulation in RA patients decreased when Siglec-1 was inhibited by anti-Siglec-1 antibodies. CONCLUSION: Elevated Siglec-1 expression in PBMCs and monocytes can potentially serve as a biomarker for monitoring disease activity in RA. Siglec-1 may also play a proinflammatory role in stimulating lymphocyte proliferation and activation in RA.

[Abnormal expression of miR-let-7b in primary biliary cirrhosis and its clinical significance].

OBJECTIVE: To evaluate the expression of microRNA (miR)-let-7b in peripheral blood cells of patients with primary biliary cirrhosis (PBC) and investigate its relationship to clinical disease parameters. METHODS: Peripheral blood and serum samples were obtained for study from 60 PBC patients and 60 healthy controls. Peripheral blood cells were extracted and subjected to real-time PCR to measure miR-let-7b expression. Serum levels of interleukin (IL)-18, total bilirubin (TBIL), alkaline phosphatase (ALP), and gamma-glutamyl transferase (GGT) were measured by standard biochemical assays. The relationship between miR-let-7b expression and disease parameters was assessed by Spearman's rank correlation test. RESULTS: PBC patients showed significantly lower expression of miR-let-7b in peripheral blood cells than healthy controls (P less than 0.001); moreover, the miR-let-7b expression level decreased in parallel to increases in disease severity (stage I > II / III > IV). In PBC patients, the miR-let-7b expression was significantly correlated with Mayo risk scores (r = -0.4930, P less than 0.001), IL-18 (r = -0.4643, P less than 0.001) and ALP (r = -4119, P less than 0.001), but not with TBIL or GGT. CONCLUSION: Decreased expression of miR-let-7b may be associated with development and progression of PBC, and this miRNA may represent a novel target of improved diagnostic and preventive strategies for PBC.

The role of Siglec-1 and SR-BI interaction in the phagocytosis of oxidized low density lipoprotein by macrophages.

BACKGROUND: Macrophages play a proatherosclerotic role in atherosclerosis via oxLDL uptake. As an adhesion molecular of I-type lectins, Siglec-1 is highly expressed on circulating monocytes and plaque macrophages of atherosclerotic patients, but the exact role of Siglec-1 has not been elucidated. METHODS: In this study, oxLDL was used to stimulate Siglec-1 and some oxLDL receptors (SR-BI, CD64, CD32B, LOX-1 and TLR-4) expression on bone marrow-derived macrophages, whereas small interfering RNA was used to down-regulate Siglec-1. Meanwhile, an ELISA-based assay for Siglec-1-oxLDL interaction was performed, and co-immunoprecipitation (co-IP) and laser scanning confocal microscopy (LSCM) were used to determine the role of Siglec-1 in oxLDL uptake by macrophages. RESULTS: We found that oxLDL could up-regulate the expression of various potential oxLDL receptors, including Siglec-1, in a dose-dependent manner. Moreover, down-regulation of Siglec-1 could attenuate oxLDL uptake by Oil red O staining. LSCM revealed that Siglec-1 and CD64/SR-BI may colocalize on oxLDL-stimulated macrophage surface, whereas co-IP showed that Siglec-1 and SR-BI can be immunoprecipitated by each other. However, no direct interaction between Siglec-1 and oxLDL was found in the in vitro protein interaction system. CONCLUSIONS: Thus, Siglec-1 can interact with SR-BI in the phagocytosis of oxLDL by macrophages, rather than act as an independent receptor for oxLDL.

Value of baseline platelet count for prediction of complications in primary biliary cirrhosis patients treated with ursodeoxycholic acid.

BACKGROUND: Decreased platelet count has been observed in various liver diseases, but its significance in primary biliary cirrhosis (PBC) remains unknown. The present study aimed to evaluate the predictive value of the platelet count at diagnosis for PBC-related complications in patients newly diagnosed with PBC and treated with ursodeoxycholic acid (UDCA). METHODS: Ninety-six PBC patients without complications treated with UDCA immediately after diagnosis were retrospectively reviewed. All hematologic and chemical parameters, Mayo risk score and PBC-related complications including upper gastrointestinal hemorrhage, presence of ascites, serum bilirubin concentration > 102.6 µmol/L and onset of hepatic encephalopathy were extracted. The associations between these parameters at diagnosis and complications were determined and the prognostic value of the platelet count was evaluated by receiver operating characteristics (ROC) analysis, Kaplan-Meier method and Cox proportional hazard model with the hazard ratio (HR) and 95% confidence interval (CI) calculated. RESULTS: Patients with PBC-related complications had significantly decreased platelet count and serum bilirubin concentration, prolonged prothrombin time, and increased Mayo risk score compared to those without complications. A platelet count of ≤ 132.5 × 10(9)/L was associated with the occurrence of complications, with an area under the ROC curve of 0.74 (95% CI: 0.64-0.85). The association remained even after adjustment for Mayo risk score (HR: 2.85; 95% CI: 1.46-5.54; p < 0.01), as shown in the Cox proportional hazard model. CONCLUSIONS: Decreased platelet count is a predictive factor for PBC-related complications. A cut-off value of ≤ 132.5 × 10(9)/L is recommended for the baseline platelet count to predict complications in patients newly diagnosed with PBC and treated with UDCA.

[MicroRNA profiling in T cells of peripheral blood mononuclear cell from patients with primary biliary cirrhosis].

OBJECTIVE: To explore the expression pattern of microRNA (miRNA) in T cells of peripheral blood mononuclear cell (PBMC) from patients with primary biliary cirrhosis (PBC). METHODS: The expression profile of miRNA in T cells of PBMC was determined by microarray assay and validated by real-time quantitative reverse transcription-polymerase chain reaction (qRT-PCR). RESULTS: In comparison with the healthy controls, 23 miRNA were down-regulated and 2 miRNA had a higher expression (all P < 0.05). As revealed by qRT-PCR, the expressions of miR-346, miR-17-5p, miR-20a and miR-let-7b decreased obviously while miR-451 and miR-129 became up-regulated. The results were in agreement with those of microarray. CONCLUSIONS: The PBC patients and healthy controls have significantly different expression profiles of microRNA in T cells of PBMC. The differential expression of microRNA may be involved in the pathogenesis of PBC.

Contribution of monocytes Siglec-1 in stimulating T cells proliferation and activation in atherosclerosis.

OBJECTIVE: Atherosclerosis (AS) is widely accepted as an inflammatory disease and monocytes are particularly important in inflammatory immune responses. As an important biomarker of monocytes activation, Siglec-1 is highly expressed on circulating monocytes and atherosclerotic plaques of coronary artery disease (CAD) patients, but the exact role of Siglec-1 has not been elucidated. METHODS: M-CSF, INF-α, IFN-γ, TNF-α and ox-LDL alone or in combination were used to stimulate Siglec-1 expression on monocytes, whereas small interfering RNA (si-RNA) or blocking antibody was used to down-regulate Siglec-1. Meanwhile, the role of Siglec-1 in chemokines secretion was determined. Then monocytes from CAD patients or healthy controls were cocultured with CD4+ or CD8+ T cells from a third healthy individual, and lymphocyte proliferation and activation were determined. RESULTS: All the stimuluses could enhance Siglec-1 expression on monocytes in a dose-dependent manner, and M-CSF could synergistically stimulate Siglec-1 expression with ox-LDL. Moreover, the secretion of MCP-1, MIP-1α and MIP-2 were enhanced when Siglec-1 was up-regulated and down to normal level when Siglec-1 was blocked. More importantly, increased Siglec-1 expression on monocytes was related to the increased T cell proliferation and pro-inflammatory cytokines secretion in CAD patients. However, down-regulation of Siglec-1 could attenuate proliferation and activation of cocultured CD4+ and CD8+ T cells. CONCLUSION: Siglec-1 can promote chemokines and pro-inflammatory cytokines secretion and influence the inflammatory process of AS.

Circulating microRNA expression is associated with genetic subtype and survival of multiple myeloma.

Circulating microRNAs (miRNAs) have shown potential as non-invasive prognostic biomarkers in cancer. Here, we investigated whether miRNAs present in the plasma of multiple myeloma (MM) patients have prognostic utility. We evaluated global miRNA expression profiles in the plasma of 12 multiple myeloma patients and 8 healthy controls using TaqMan Low-Density Arrays. Six miRNAs (miR-148a, miR-181a, miR-20a, miR-221, miR-625, and miR-99b) that were significantly upregulated in MM were selected and further quantified independently by quantitative reverse transcription PCR in plasma from 28 MM patients and 12 healthy controls. Moreover, within the patient group, the expression levels of miR-99b and miR-221 were associated with chromosomal abnormalities t(4; 14) and del(13q), respectively. High levels of miR-20a and miR-148a were related to shorter relapse-free survival. In summary, we have identified aberrant expression of particular circulating miRNAs that are associated with the genetic subtype and survival of MM. These plasma miRNAs have potential as clinical biomarkers in MM.