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1.
Curr Pharm Des ; 29(26): 2036-2049, 2023.
Article in English | MEDLINE | ID: mdl-37670701

ABSTRACT

Sepsis is a syndrome involving complex pathophysiological and biochemical dysregulation. Nanotechnology can improve our understanding of the pathophysiology of sepsis and contribute to the development of novel diagnostic and therapeutic strategies to further reduce the risk of sepsis. Macrophages play a key role in the progression of sepsis, thus, macrophage-associated pathological processes are important targets for both diagnostic and treatment of sepsis. In this paper, we reviewed efforts in the past decade of nanotechnologybased solutions for manipulate macrophages in sepsis diagnosis and management according to the type of nanomaterial. We addressed the latest progress of nanoparticles targeting macrophages for early sepsis detection. Additionally, we summarized the unique advantages of macrophage-targeted nanoparticles in the treatment of sepsis. These nanoparticles can improve the dysregulation of inflammatory response in sepsis by inhibiting the release of inflammatory factors and regulating macrophage apoptosis, activity and polarization. Finally, we present future opportunities as well as challenges of novel diagnostic and therapeutic strategies with the aim of accelerating the clinical translation of nanomedicine for sepsis treatment.

2.
Clin Transl Med ; 13(3): e1209, 2023 03.
Article in English | MEDLINE | ID: mdl-36881611

ABSTRACT

BACKGROUND: P16INK4A is a surrogate signature compensating for the specificity and/or sensitivity deficiencies of the human papillomavirus (HPV) DNA and Papanicolaou smear (Pap) co-test for detecting high-grade cervical squamous intraepithelial lesions or worse (HSIL+). However, traditional p16INK4A immunostaining is labour intensive and skill demanding, and subjective biases cannot be avoided. Herein, we created a high-throughput, quantitative diagnostic device, p16INK4A flow cytometry (FCM) and assessed its performances in cervical cancer screening and prevention. METHODS: P16INK4A FCM was built upon a novel antibody clone and a series of positive and negative (p16INK4A -knockout) standards. Since 2018, 24 100-women (HPV-positive/-negative, Pap-normal/-abnormal) have been enrolled nationwide for two-tier validation work. In cross-sectional studies, age- and viral genotype-dependent expression of p16INK4A was investigated, and optimal diagnostic parameter cut-offs (using colposcopy and biopsy as a gold standard) were obtained. In cohort studies, the 2-year prognostic values of p16INK4A were investigated with other risk factors by multivariate regression analyses in three cervicopathological conditions: HPV-positive Pap-normal, Pap-abnormal biopsy-negative and biopsy-confirmed LSIL. RESULTS: P16INK4A FCM detected a minimal ratio of 0.01% positive cells. The p16INK4A -positive ratio was 13.9 ± 1.8% among HPV-negative NILM women and peaked at the ages of 40-49 years; after HPV infection, the ratio increased to 15.1 ± 1.6%, varying with the carcinogenesis of the viral genotype. Further increments were found in women with neoplastic lesions (HPV-negative: 17.7 ± 5.0-21.4 ± 7.2%; HPV-positive: 18.0 ± 5.2-20.0 ± 9.9%). Extremely low expression of p16INK4A was observed in women with HSILs. As the HPV-combined double-cut-off-ratio criterion was adopted, a Youden's index of 0.78 was obtained, which was significantly higher than that (0.72) of the HPV and Pap co-test. The p16INK4A -abnormal situation was an independent HSIL+ risk factor for 2-year outcomes in all three cervicopathological conditions investigated (hazard ratios: 4.3-7.2). CONCLUSIONS: FCM-based p16INK4A quantification offers a better choice for conveniently and precisely monitoring the occurrence of HSIL+ and directing risk-stratification-based interventions.


Subject(s)
Papillomavirus Infections , Squamous Intraepithelial Lesions , Uterine Cervical Neoplasms , Female , Humans , Adult , Middle Aged , Cyclin-Dependent Kinase Inhibitor p16 , Cross-Sectional Studies , Early Detection of Cancer , Flow Cytometry , Papillomavirus Infections/diagnosis , Uterine Cervical Neoplasms/diagnosis , Cyclin-Dependent Kinase Inhibitor Proteins
3.
J Transl Med ; 21(1): 1, 2023 01 02.
Article in English | MEDLINE | ID: mdl-36593497

ABSTRACT

Myeloid-derived suppressor cells (MDSCs), which are immature heterogeneous bone marrow cells, have been described as potent immune regulators in human and murine cancer models. The distribution of MDSCs varies across organs and is divided into three subpopulations: granulocytic MDSCs or polymorphonuclear MDSCs (G-MDSCs or PMN-MDSCs), monocytic MDSCs (M-MDSCs), as well as a recently identified early precursor MDSC (eMDSCs) in humans. Activated MDSCs induce the inactivation of NK cells, CD4+, and CD8+ T cells through a variety of mechanisms, thus promoting the formation of tumor immunosuppressive microenvironment. ER stress plays an important protecting role in the survival of MDSC, which aggravates the immunosuppression in tumors. In addition, ferroptosis can promote an anti-tumor immune response by reversing the immunosuppressive microenvironment. This review summarizes immune suppression by MDSCs with a focus on the role of endoplasmic reticulum stress-mediated immune suppression in cancer and infectious disease, in particular leprosy and tuberculosis.


Subject(s)
Communicable Diseases , Myeloid-Derived Suppressor Cells , Neoplasms , Humans , Animals , Mice , Immunosuppression Therapy , Communicable Diseases/pathology , Endoplasmic Reticulum Stress , Tumor Microenvironment
4.
J Cell Mol Med ; 25(6): 2786-2794, 2021 03.
Article in English | MEDLINE | ID: mdl-33586359

ABSTRACT

Dickkopf-related protein 4 (DKK4) is a member of the dickkopf family and an inhibitor of the Wnt/ß-catenin signalling pathway. This review surveyed the single nucleotide polymorphisms (SNPs), copy number variations (CNVs), hypermethylation, regulation mechanism, correlation with clinicopathological parameters and chemotherapeutic resistance of DKK4. The signal pathways involved in DKK4 mainly include Wnt/ß-catenin pathway and Wnt-JNK pathway independent ß-catenin. DKK4 expression was upregulated in Renal Cell Carcinoma (RCC), Colorectal Cancer, Gastric Cancer (GC), Non-small Cell Lung Cancer (NSCLC) and Epithelial Ovarian Cancer (EOC), while downregulated in Hepatocellular Carcinoma (HCC). DKK4 is not only involved in tumour growth, invasion, migration and chemotherapy resistance, but also in osteoblastogenesis and secondary hair or meibomian gland formation. DKK4 has also been linked to schizophrenia.


Subject(s)
Gene Expression Regulation , Intercellular Signaling Peptides and Proteins/genetics , Intercellular Signaling Peptides and Proteins/metabolism , Signal Transduction , Cell Movement , Cell Proliferation , DNA Copy Number Variations , Drug Resistance, Neoplasm/drug effects , Humans , Multigene Family , Neoplasm Grading , Neoplasm Staging , Neoplasms/drug therapy , Neoplasms/etiology , Neoplasms/metabolism , Neoplasms/pathology , Polymorphism, Single Nucleotide , Wnt Signaling Pathway
5.
J Cancer Res Clin Oncol ; 146(5): 1103-1113, 2020 May.
Article in English | MEDLINE | ID: mdl-32157437

ABSTRACT

BACKGROUND: Microtubule-associated protein 1 light chain 3 (LC3), an autophagic gene, has been reported as a vital marker for many diseases and cancers. However, the role of LC3 in hepatocellular carcinoma (HCC) was not still investigated. Therefore, we conducted a meta-analysis to examine the association of LC3 with its clinicopathological and prognostic in HCC. METHODS: We consulted the PubMed, Cochrane Library, Web of Science, EMBASE, China National Knowledge Infrastructure and Wan Fang databases for published studies on LC3 in HCC. Newcastle-Ottawa scale was used to screen the quality of the literature. The statistical analysis was calculated by STATA 14.2. RESULTS: Of the 1329 titles identified, 10 articles involving 949 patients in HCC were included in this meta-analysis. The results of our study show that increased LC3 expression is related to size of tumor, but not to gender, age, number of tumor, liver cirrhosis, HBsAg, TNM stage, alpha fetoprotein, vascular invasion and histological grade. Positive LC3 expression was associated with overall survival by pooled hazard ratio. CONCLUSIONS: This meta-analysis indicated that positive LC3 expression was related to size of tumor, and could predict prognosis in human hepatocellular carcinoma.


Subject(s)
Carcinoma, Hepatocellular/metabolism , Carcinoma, Hepatocellular/pathology , Liver Neoplasms/metabolism , Liver Neoplasms/pathology , Microtubule-Associated Proteins/biosynthesis , Autophagy/physiology , Humans , Neoplasm Staging , Prognosis
6.
Cell Signal ; 62: 109346, 2019 10.
Article in English | MEDLINE | ID: mdl-31229617

ABSTRACT

Chronic hepatitis B (CHB) is associated with the development of hepatocellular carcinoma (HCC). Decoy receptor 3 (DcR3) is a tumor necrosis factor receptor that promotes tumor cell survival by inhibiting apoptosis and interfering with immune surveillance. Previous studies showed that DcR3 was overexpressed in HCC cells and that short hairpin RNA (shDcR3) sensitizes TRAIL-resistant HCC cells. However, the expression of DcR3 during hepatitis B virus (HBV) infection has not been investigated. Here, we demonstrated that DcR3 was overexpressed in CHB patients and that DcR3 upregulation was positively correlated with the HBV DNA load and liver injury (determined by histological activity index, serum alanine aminotransferase level, and aspartate aminotransferase level). We found that hepatitis B virus X protein (HBx) upregulated DcR3 expression in a dose-dependent manner, but this increase was blocked by NF-κB inhibitors. HBx also induced the activation of NF-κB, and the NF-κB subunits p65 and p50 upregulated DcR3 by directly binding to the DcR3 promoters. Inhibition of PI3K significantly downregulated DcR3 and inhibited the binding of NF-κB to the DcR3 promoters. Our results demonstrate that the HBx induced DcR3 expression via the PI3K/NF-κB pathway; this process may contribute to the development of HBV-mediated HCC.


Subject(s)
Carcinoma, Hepatocellular/genetics , Liver Neoplasms/genetics , Receptors, Tumor Necrosis Factor, Member 6b/genetics , Trans-Activators/genetics , Transcription Factor RelA/genetics , Binding Sites/genetics , Carcinoma, Hepatocellular/pathology , Carcinoma, Hepatocellular/virology , Gene Expression Regulation, Neoplastic/genetics , Hep G2 Cells , Hepatitis B, Chronic/genetics , Hepatitis B, Chronic/pathology , Hepatitis B, Chronic/virology , Humans , Liver Neoplasms/pathology , Liver Neoplasms/virology , NF-kappa B p50 Subunit/genetics , Phosphatidylinositol 3-Kinases/genetics , Promoter Regions, Genetic/genetics , Protein Binding/genetics , RNA, Small Interfering/genetics , Signal Transduction/genetics , Viral Regulatory and Accessory Proteins
7.
BMC Biochem ; 19(1): 13, 2018 12 27.
Article in English | MEDLINE | ID: mdl-30587127

ABSTRACT

BACKGROUND: Sepsis is a severe condition characterised by the body's systemic inflammatory response to infection. The specific sepsis-related biomarkers should be used in clinical diagnosis, therapeutic response monitoring, rational use of antibiotics, and prognosis (risk stratification), etc. RESULTS: In this study, we investigated the expression level of Decoy Receptor 3 (DcR3) and the mechanism of high expression in sepsis patients. Septic cell model experiments were performed by treating human umbilical vein endothelial cells (HUVECs) and Jurkat cells with lipopolysaccharide (LPS), lipoteichoic acid (LTA) and zymosan, respectively. SP600125, SB203580 and ammonium pyrrolidinedithiocarbamate (PDTC) were used to inhibit JNK1/2, p38MAPK and NF-κB signalling pathways in septic cell model, respectively. These results showed that DcR3 levels were higher in sepsis group than control. DcR3 mRNA and protein levels in HUVECs were increased following treatment with LPS, LTA and zymosan, and also increased in Jurkat cells treated by LPS, but not by LTA or zymosan. When HUVECs were treated with the NF-κB inhibitor PDTC, DcR3 expression was decreased compared with controls. However, SP600125 and SB203580 had no effect on DcR3 mRNA or protein levels. CONCLUSIONS: The results indicated that DcR3 secretion proceeded through the NF-κB signalling pathway in HUVECs.


Subject(s)
Lipopolysaccharides/pharmacology , Signal Transduction/drug effects , Up-Regulation/drug effects , Anthracenes/pharmacology , Human Umbilical Vein Endothelial Cells , Humans , Imidazoles/pharmacology , Jurkat Cells , NF-kappa B/metabolism , Proline/analogs & derivatives , Proline/pharmacology , Protein Kinase Inhibitors/pharmacology , Pyridines/pharmacology , Receptors, Tumor Necrosis Factor, Member 6b/metabolism , Teichoic Acids/pharmacology , Thiocarbamates/pharmacology , Zymosan/pharmacology
8.
Oncol Lett ; 16(1): 1147-1154, 2018 Jul.
Article in English | MEDLINE | ID: mdl-30061940

ABSTRACT

Decoy receptor 3 (DcR3) is a tumor necrosis factor receptor, which may inhibit apoptosis. The aim of the present study was to investigate the clinical significance of DcR3 upregulation in patients with chronic hepatitis B (CHB) and hepatic fibrosis. A total of 128 patients with a clinical diagnosis of CHB who underwent liver biopsy were included in the present study. The expression levels of DcR3, hyaluronic acid (HA), type III procollagen, type IV collagen (IV-C) and laminin protein were assessed. The diagnostic value of DcR3 in patients with CHB with hepatic fibrosis was determined using receiver operating characteristic (ROC) curve analysis. DcR3 was significantly upregulated in patients with CHB, particularly in patients with active CHB. The expression of DcR3 was significantly increased in patients with CHB with liver fibrosis and liver cirrhosis, compared with patients with CHB without liver fibrosis. The area under the ROC curve for the diagnosis of CHB liver fibrosis based on DcR3 or DcR3 combined with IV-C/HA was 0.807 or 0.869, with a sensitivity and specificity of 76.9 and 77.8% or 84.6 and 81.2%, respectively. DcR3 is a marker for liver fibrosis in patients with hepatitis B infection. The use of DcR3 in combination with IV-C and HA may further increase its diagnostic value for liver fibrosis.

9.
Cell Mol Biol Lett ; 23: 22, 2018.
Article in English | MEDLINE | ID: mdl-29760745

ABSTRACT

The levels of decoy receptor 3 (DcR3), soluble urokinase type plasminogen activator receptor (suPAR) and procalcitonin (PCT) are significantly increased in sepsis. We investigated the diagnostic value of DcR3 combined with suPAR and PCT in sepsis. Patients with sepsis, non-infectious systemic inflammatory response comprehensive syndrome (SIRS) and healthy controls were recruited according to the diagnostic standard. We measured DcR3, suPAR, PCT, interleukin-6 (IL-6) and C-reactive protein (CRP), and the diagnostic value was evaluated by receiver operating characteristics (ROC) curves. In our analysis, serum DcR3, suPAR and PCT levels of the sepsis group were significantly higher than those of the SIRS and control groups. However, IL-6, CRP and WBC showed no significant difference between the SIRS group and the sepsis group. The serum DcR3 level was positively correlated with the serum suPAR level (r = 0.37, p = 0.0022) and PCT level (r = 0.37, p = 0.0021). Using DcR3, suPAR and PCT to distinguish SIRS from sepsis, the area under the curve (AUC) values were 0.892, 0.778 and 0.692. When DcR3, suPAR and PCT combined were used for diagnosis of sepsis, the AUC was 0.933, at a cut-off point of 0.342. This combination improved the sensitivity and specificity of diagnosis of sepsis, suggesting that use of the combination of three indexes enhanced the efficiency of sepsis diagnosis.


Subject(s)
Calcitonin/blood , Mannose-Binding Lectins/blood , Membrane Glycoproteins/blood , Receptors, Cell Surface/blood , Receptors, Tumor Necrosis Factor, Member 6b/blood , Sepsis/diagnosis , Systemic Inflammatory Response Syndrome/diagnosis , Adult , Aged , Area Under Curve , Biomarkers/blood , C-Reactive Protein/analysis , Female , Humans , Interleukin-6/blood , Male , Middle Aged , ROC Curve , Sensitivity and Specificity
10.
PLoS One ; 13(2): e0191545, 2018.
Article in English | MEDLINE | ID: mdl-29444104

ABSTRACT

Evidence has shown that most hepatocellular carcinoma (HCC) cells are resistant to tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL)-mediated apoptosis. However, the molecular mechanisms underlying TRAIL-mediated apoptosis resistance are not well understood. In this study, we reported that downregulation of Decoy receptor 3 (DcR3) expression by lentiviral vectors carrying shRNA against DcR3 (LV-ShDcR3, shDcR3) in Huh7 both greatly enhanced TRAIL-mediated apoptosis and reduced cell proliferation capability. In addition, silencing DcR3 resulted in upregulation of the cell apoptotic regulators including Bid, caspase-3, and caspase-8. Caspase inhibitors inhibited shDcR3-mediated cell death, which indicated that downregulation of DcR3 expression in Huh7 cells increased TRAIL-induced caspase-dependent apoptotic cell death. Furthermore, although the knockdown of DcR3 altered the expression of some Bcl-2- and IAP-family proteins, this change was inhibited by pretreatment with a pancaspase inhibitor, which indicated the cytotoxic effect of shDcR3 was not due to the expression of these proteins. In contrast, shDcR3 significantly inhibited TRAIL-induced transcription factor nuclear κB (NF-κB) activation through the IκB kinase (IKK) pathway, as well as inhibited TRAIL-induced increases in FLICE-inhibitory protein long form (cFLIPL) expression at the transcriptional level. Silencing cFLIPL expression mimicked the cytotoxic effect of shDcR3 on TRAIL-mediated cell apoptosis. Moreover, overexpression of cFLIPL effectively prevented the increase in cell apoptosis in Huh7 cells co-treated with TRAIL and shDcR3. Taken together, our findings indicated that silencing DcR3 sensitizes TRAIL-mediated apoptosis in HCC cells by inhibiting NF-κB.


Subject(s)
Apoptosis/drug effects , CASP8 and FADD-Like Apoptosis Regulating Protein/metabolism , Carcinoma, Hepatocellular/pathology , Caspases/metabolism , Liver Neoplasms/pathology , NF-kappa B/metabolism , Receptors, Tumor Necrosis Factor, Member 6b/physiology , TNF-Related Apoptosis-Inducing Ligand/pharmacology , Cell Line, Tumor , Down-Regulation , Humans , Transcription, Genetic
11.
J Diabetes Res ; 2017: 8293207, 2017.
Article in English | MEDLINE | ID: mdl-29082263

ABSTRACT

The objectives of the study were to investigate serum ANGPTL8 concentrations in different glucose metabolic statuses and to explore the correlations between serum ANGPTL8 levels and various metabolic parameters. Serum ANGPTL8 levels were determined using ELISA in 22 subjects with NGT (normal glucose tolerance), 74 subjects with IGR (impaired glucose regulation), and 33 subjects with T2DM (type 2 diabetes mellitus). Subjects with IFG, IGT, CGI, and T2DM had higher levels of serum ANGPTL8 than subjects with NGT. Serum ANGPTL8 was positively correlated with FPG, fasting C-peptide, and postprandial C-peptide and negatively correlated with BETA/IR when adjusted for age and BMI. Multivariate analysis suggested FPG and fasting C-peptide as independent factors associated with serum ANGPTL8 levels. Serum ANGPTL8 concentrations were significantly increased in IGR and T2DM. Serum ANGPTL8 might play a role in the pathological mechanism of glucose intolerance.


Subject(s)
Angiopoietin-like Proteins/blood , Diabetes Mellitus, Type 2/blood , Glucose Intolerance/blood , Peptide Hormones/blood , Prediabetic State/blood , Angiopoietin-Like Protein 8 , Biomarkers/blood , Blood Glucose/metabolism , C-Peptide/blood , Case-Control Studies , Chi-Square Distribution , Cross-Sectional Studies , Diabetes Mellitus, Type 2/diagnosis , Female , Glucose Intolerance/diagnosis , Humans , Male , Middle Aged , Multivariate Analysis , Prediabetic State/diagnosis , Up-Regulation
12.
Int J Clin Exp Pathol ; 10(9): 9644-9648, 2017.
Article in English | MEDLINE | ID: mdl-31966844

ABSTRACT

OBJECTIVE: This study aimed to observe the inhibitory effects of mitogen activated protein kinase (MAPK/ERK) specific inhibitor PD98059 on Mtb-Ag activated Î³Î´Τ cells and to investigate the role of MAPK in MAPK/ERK pathway of Î³Î´Τ cells activated by Mtb-Ag. METHODS: Healthy human peripheral blood mononuclear cell (PBMC) was isolated from the peripheral blood, and then stimulated by phorbol esters (PMA), ionomycin (IM) and Mtb-Ag. PBMC of the experimental group was pretreated by PD98059 of 0, 1, 10 or 100 µmol/L while the control group was given no pretreatment. Flow cytometry was applied to detect the expression of CD69 in Î³Î´Τ cells at 0 h, 6 h, 12 h, 24 h, 48 h and 72 h after treatment respectively. The influence of PD98059 on the amplification of Î³Î´Τ cells was also detected. RESULTS: After stimulated by PMA and IM for 6 hours, the expression of CD69 in Î³Î´Τ reached the peak of (99.3±1.09)%, while in the Mtb-Ag stimulation group, it reached the highest level of 75.2% at 24 hours. The level of CD69 in two group was significant difference between the two groups at each time respectively (p<0.05). Pretreated with PD98059 of 0, 1, 10, 100 µmol/L, the level of CD 69 expression in Mtb-Ag stimulated Î³Î´Τ was 79±0.8%, 75±0.7%, 54±0.5% and 17±0.2% respectively; In PMA+IM stimulated group, CD69 expression were all more than 98% in different concentration of PD98059. After treated with PD98059 of 0, 1, 10, 100 µmol/L, total cell number increased from 1.5×106 to (10.3±2.5)×106, (9.5±2.1)×106, (5.8±1.8)×106 and (2.1±0.5)×106 respectively. Number of Î³Î´Τ cells reached to (6.2±0.9)×106, (5.02±0.8)×106, (2.05±0.5)×106 and (0.41±0.1)×106 respectively. CONCLUSION: Î³Î´Τ cells were specifically activated by Mtb-Ag, and the activation was depended on MAPK/ERK pathway. The activation effects of Mtb-Ag on Î³Î´Τ cells can be obviously inhibited by PD98059.

13.
Int J Mol Med ; 38(1): 131-8, 2016 Jul.
Article in English | MEDLINE | ID: mdl-27246196

ABSTRACT

MicroRNAs (miRNAs or miRs) are small, non-coding RNA molecules that play significant roles in numerous diseases. However, there is limited information regarding the plasma expression of miRNAs in patients with primary biliary cirrhosis (PBC) as well as the potential role of miRNAs in the development of PBC. miRNA microarray analysis was performed using plasma obtaind from three patients with PBC and three healthy controls. Reverse transcription-quantitative polymerase chain reaction (RT-qPCR) was performed to confirm the differential expression of miRNAs in the plasma and peripheral blood mononuclear cells (PBMCs) isolated from 20 patients with PBC, 20 patients with chronic hepatitis B (CHB) and 20 healthy controls. These miRNAs in PBMCs and plasma were validated by linear regression analyses. The T cell subset frequency was analyzed by flow cytometry. Correlations between altered miRNA expression and the frequency of the T cell subsets were determined by linear regression analyses. The co-expression of miRNAs and IL-17A was examined using fluorescence in situ hybridization (FISH) and immunohistochemistry. The microarray analysis identified sixteen miRNAs that were differentially expressed. Four miRNAs were validated by RT-qPCR. The expression pattern of miR-572 and miR-92a in the PBMCs correlated with the expression pattern in plasma. We also found that miR-92a expression closely correlated with the frequency of a subset of IL-17-producing T helper cells (Th17), and that miR-92a was co-expressed with IL-17A in patients with PBC. Taken together, these findings revealed that plasma from patients with PBC has a unique miRNA expression profile. Moreover, miR-92a may play an important role in the pathogenesis of PBC by regulating Th17 cell differentiation.


Subject(s)
Gene Expression Regulation , Liver Cirrhosis, Biliary/genetics , Liver Cirrhosis, Biliary/immunology , MicroRNAs/genetics , Th17 Cells/metabolism , Adult , Female , Flow Cytometry , Gene Expression Profiling , Humans , Interleukin-17/metabolism , Liver Cirrhosis, Biliary/blood , Lymphocyte Count , Lymphocyte Subsets/immunology , Male , MicroRNAs/metabolism , Oligonucleotide Array Sequence Analysis , Real-Time Polymerase Chain Reaction , Reproducibility of Results
14.
J Crit Care ; 31(1): 90-5, 2016 Feb.
Article in English | MEDLINE | ID: mdl-26589770

ABSTRACT

Cell-free circulating DNA (cf-DNA) can be detected by various of laboratory techniques. We described a branched DNA-based Alu assay for measuring cf-DNA in septic patients. Compared to healthy controls and systemic inflammatory response syndrome (SIRS) patients, serum cf-DNA levels were significantly higher in septic patients (1426.54 ± 863.79 vs 692.02 ± 703.06 and 69.66 ± 24.66 ng/mL). The areas under the receiver operating characteristic curve of cf-DNA for normal vs sepsis and SIRS vs sepsis were 0.955 (0.884-1.025), and 0.856 (0.749-0.929), respectively. There was a positive correlation between cf-DNA and interleukin 6 or procalcitonin or Acute Physiology and Chronic Health Evaluation II. The cf-DNA concentration was higher in intensive care unit nonsurviving patients compared to surviving patients (2183.33 ± 615.26 vs 972.46 ± 648.36 ng/mL; P < .05). Branched DNA-based Alu assays are feasible and useful to quantify serum cf-DNA levels. Increased cf-DNA levels in septic patients might complement C-reactive protein and procalcitonin in a multiple marker format. Cell-free circulating DNA might be a new marker in discrimination of sepsis and SIRS.


Subject(s)
DNA/blood , Sepsis/diagnosis , Systemic Inflammatory Response Syndrome/diagnosis , Adult , Aged , Biomarkers/blood , Calcitonin/blood , Calcitonin Gene-Related Peptide , Case-Control Studies , Cell-Free System , Female , Humans , Interleukin-6/blood , Male , Mass Screening/methods , Middle Aged , Predictive Value of Tests , Protein Precursors/blood , ROC Curve , Sensitivity and Specificity , Sepsis/blood , Systemic Inflammatory Response Syndrome/blood
15.
Autoimmunity ; 49(1): 21-30, 2016.
Article in English | MEDLINE | ID: mdl-26334951

ABSTRACT

Type 1 diabetes mellitus (T1DM) is an autoimmune disease characterized by an autoimmune-mediated loss of insulin secreting ß-cells. Each B lymphocyte clone that escapes immune tolerance produces a specific antibody. No specific treatment against autoantibodies is available for autoimmune diseases. We have developed a strategy to produce an antiserum against autoantibodies for the treatment of T1DM. Non-obese diabetic (NOD) but not Balb/c mouse serum contains autoantibodies. Antisera were produced by immunizing Balb/c mice with affinity-purified IgG from NOD or BALB/c mice along with the immune adjuvant (hereafter, NIgG or BIgG, respectively). A bolus administration of NIgG significantly reduced serum autoantibodies, autoantibody-positive B lymphocytes in the spleens of NOD mice, mortality and morbidity of diabetes, blood glucose and islet immune infiltration, whereas it increased islet mass in NOD mice for at least 26 weeks. NIgG antiserum treatment has no significant effect on CD3(+), CD4(+) or CD8(+) T cells and B220(+) or CD19(+) B cells. BIgG also imparted a moderate therapeutic effect, although it was considerably lower than that of NIgG. NIgG did not cross-react with allogeneic serum. NIgG showed no effect on Balb/c mice. The results show the feasibility of producing antiserum against autoantibodies to prevent and treat autoimmune-induced T1DM with a single bolus administration.


Subject(s)
Autoantibodies/pharmacology , B-Lymphocytes/immunology , Diabetes Mellitus, Type 1/therapy , Immunoglobulin G/pharmacology , Islets of Langerhans/immunology , Adjuvants, Immunologic/administration & dosage , Animals , B-Lymphocytes/pathology , Blood Glucose/immunology , Diabetes Mellitus, Type 1/immunology , Diabetes Mellitus, Type 1/mortality , Diabetes Mellitus, Type 1/pathology , Disease Models, Animal , Female , Humans , Immunization , Islets of Langerhans/pathology , Mice , Mice, Inbred BALB C , Mice, Inbred NOD , Spleen/immunology , Spleen/pathology , Survival Analysis , T-Lymphocytes/immunology , T-Lymphocytes/pathology
16.
Dig Dis Sci ; 60(11): 3264-70, 2015 Nov.
Article in English | MEDLINE | ID: mdl-26138652

ABSTRACT

BACKGROUND AND AIMS: PepT1 can transport bacterial oligopeptide products and induce intestinal inflammation. Our aim was to investigate the mechanism of the small intestine injury induced by bacterial oligopeptide product muramyl dipeptide (MDP) which is transported by PepT1. METHODS: We perfused the jejunum with a solution with or without MDP, or with a solution of MDP + Gly-Gly and explored the degree of inflammation to determine the role of PepT1-Nod2 signaling pathway in small intestine mucosa. RESULTS: MDP perfusion induced inflammatory cell accumulation and intestinal damage, accompanied by an increase in mucosal Nod2 and Rip2 transcript expression. NFκB activity and inflammatory cytokine expression, including serum levels of TNF-α, IL-1ß, and IL-6, increased in the MDP group compared to the controls; these effects were reversed by perfusion of the nutritional dipeptide Gly-Gly. CONCLUSION: MDP can be transported through PepT1, causing inflammatory damage in the rat small intestine. Nod2-Rip2-NFκB signaling involved in the small intestinal inflammatory injury caused by MDP which is transported through PepT1.


Subject(s)
Acetylmuramyl-Alanyl-Isoglutamine/toxicity , Enteritis/chemically induced , Intestinal Mucosa/drug effects , Jejunum/drug effects , Nod2 Signaling Adaptor Protein/metabolism , Receptor-Interacting Protein Serine-Threonine Kinase 2/metabolism , Symporters/metabolism , Acetylmuramyl-Alanyl-Isoglutamine/metabolism , Animals , Cytokines/metabolism , Enteritis/enzymology , Enteritis/pathology , Glycylglycine/pharmacology , Inflammation Mediators/metabolism , Intestinal Mucosa/enzymology , Intestinal Mucosa/pathology , Jejunum/enzymology , Jejunum/pathology , Male , NF-kappa B/metabolism , Peptide Transporter 1 , Rats, Sprague-Dawley , Signal Transduction/drug effects
17.
PLoS One ; 10(6): e0131680, 2015.
Article in English | MEDLINE | ID: mdl-26121476

ABSTRACT

PURPOSE: Unbalanced inflammatory response and lymphocyte apoptosis is associated with high mortality in septic patients. Decoy receptor 3 (DcR3), a member of the tumor necrosis factor receptor superfamily, is an anti-inflammatory and anti-apoptotic factor. Recently, DcR3 expression was found to be increased in septic patients. This study evaluated the therapeutic effect and mechanisms of DcR3 on cecal ligation and puncture (CLP)-induced sepsis in mice. METHODS: C57BL/6 mice were subjected to CLP-induced polymicrobial sepsis. DcR3 Fc was intravenously injected 30 min before and 6 h after CLP. Bacterial clearance, cytokine production, histology, lymphocyte apoptosis and survival were evaluated. Furthermore, we investigated the systemic effects of DcR3 in in vitro lymphocyte apoptosis regulation. RESULTS: Our results demonstrated that DcR3 protein treatments significantly improved survival in septic mice (p <0.05). Treatment with DcR3 protein significantly reduced the inflammatory response and decreased lymphocyte apoptosis in the thymus and spleen. Histopathological findings of the lung and liver showed milder impairment after DcR3 administration. In vitro experiments showed that DcR3 Fc inhibited Fas-FasL mediated lymphocyte apoptosis. CONCLUSIONS: Treatment with the DcR3 protein protects mice from sepsis by suppressing the inflammatory response and lymphocyte apoptosis. DcR3 protein may be useful in treatment of sepsis.


Subject(s)
Apoptosis/genetics , Apoptosis/immunology , Lymphocytes/immunology , Lymphocytes/metabolism , Receptors, Tumor Necrosis Factor, Member 6b/genetics , Sepsis/genetics , Sepsis/immunology , Animals , Cytokines/metabolism , Disease Models, Animal , Fas Ligand Protein/metabolism , Liver/pathology , Lung/pathology , Mice , Sepsis/mortality , Spleen/immunology , Spleen/metabolism , Spleen/pathology , Thymus Gland/immunology , Thymus Gland/metabolism , Thymus Gland/pathology
18.
Int J Mol Med ; 35(1): 72-80, 2015 Jan.
Article in English | MEDLINE | ID: mdl-25374065

ABSTRACT

In the present study, we aimed to develop and validate a rapid and sensitive, Alu-based real-time PCR method for the detection of circulating cell-free DNA (cfDNA). This method targeted repetitive elements of the Alu reduplicative elements in the human genome, followed by signal amplification using fluorescence quantification. Standard Alu-puc57 vectors were constructed and 5 pairs of specific primers were designed. Valuation was conducted concerning linearity, variation and recovery. We found 5 linear responses (R1-5=0.998-0.999). The average intra- and inter-assay coefficients of variance were 12.98 and 10.75%, respectively. The recovery was 82.33-114.01%, with a mean recovery index of 101.26%. This Alu-based assay was reliable, accurate and sensitive for the quantitative detection of cfDNA. Plasma from normal controls and patients with myocardial infarction (MI) were analyzed, and the baseline levels of cfDNA were higher in the MI group. The area under the receiver operating characteristic (ROC) curve for Alu1, Alu2, Alu3, Alu4, Alu5 and Alu (Alu1 + Alu2 + Alu3 + Alu4 + Alu5) was 0.887, 0.758, 0.857, 0.940, 0.968 and 0.933, respectively. The optimal cut-off value for Alu1, Alu2, Alu3, Alu4, Alu5 and Alu to predict MI was 3.71, 1.93, 0.22, 3.73, 6.13 and 6.40 log copies/ml. We demonstrate that this new method is a reliable, accurate and sensitive method for the quantitative detection of cfDNA and that it is useful for studying the regulation of cfDNA in certain pathological conditions. Alu4, Alu5 and Alu showed better sensitivity and specificity for the diagnosis of MI compared with cardiac troponin I (cTnI), creatine kinase MB (CK-MB) isoenzyme and lactate dehydrogenase (LDH). Alu5 had the best prognostic ability.


Subject(s)
Alu Elements/genetics , DNA/blood , Myocardial Infarction/blood , Myocardial Infarction/genetics , Adult , Aged , Aged, 80 and over , Case-Control Studies , Female , Humans , Male , Middle Aged , Myocardial Infarction/diagnosis , ROC Curve , Real-Time Polymerase Chain Reaction/methods , Reproducibility of Results , Sensitivity and Specificity
20.
PLoS One ; 9(2): e88299, 2014.
Article in English | MEDLINE | ID: mdl-24516630

ABSTRACT

Obesity is associated with increased production of inflammatory mediators in adipose tissue, which contributes to chronic inflammation and insulin resistance. Midkine (MK) is a heparin-binding growth factor with potent proinflammatory activities. We aimed to test whether MK is associated with obesity and has a role in insulin resistance. It was found that MK was expressed in adipocytes and regulated by inflammatory modulators (TNF-α and rosiglitazone). In addition, a significant increase in MK levels was observed in adipose tissue of obese ob/ob mice as well as in serum of overweight/obese subjects when compared with their respective controls. In vitro studies further revealed that MK impaired insulin signaling in 3T3-L1 adipocytes, as indicated by reduced phosphorylation of Akt and IRS-1 and decreased translocation of glucose transporter 4 (GLUT4) to the plasma membrane in response to insulin stimulation. Moreover, MK activated the STAT3-suppressor of cytokine signaling 3 (SOCS3) pathway in adipocytes. Thus, MK is a novel adipocyte-secreted factor associated with obesity and inhibition of insulin signaling in adipocytes. It may provide a potential link between obesity and insulin resistance.


Subject(s)
Adipocytes/metabolism , Cytokines/metabolism , Insulin Resistance/physiology , Insulin/metabolism , Obesity/metabolism , 3T3-L1 Cells , Adipocytes/drug effects , Animals , Cell Differentiation , Female , Glucose Transporter Type 4/metabolism , Humans , Insulin Receptor Substrate Proteins/metabolism , Male , Mice , Middle Aged , Midkine , Phosphorylation/drug effects , Rosiglitazone , Signal Transduction/drug effects , Suppressor of Cytokine Signaling Proteins/metabolism , Thiazolidinediones/pharmacology , Tumor Necrosis Factor-alpha/pharmacology
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