Intestinal barrier biomarkers in clinical evaluation of patients with inflammatory bowel disease.

BACKGROUND: Inflammatory bowel disease (IBD) is associated with chronic intestinal barrier dysfunction, though its non-invasive assessment remains challenging. This study aimed to determine how four putative circulating markers vary across differing states of intestinal inflammation and with therapy in patients with IBD. METHODS: Plasma samples from one prospective cross-sectional and four longitudinal studies, including healthy controls, were analysed for markers of lipopolysaccharide translocation, lipopolysaccharide-binding protein (LBP) and soluble-CD14 (sCD14), and markers of epithelial injury, syndecan-1 and intestinal-type fatty acid-binding protein (IFABP). Inflammatory activity was determined using objective measures. RESULTS: Compared with healthy subjects, concentrations of LBP and sCD14 were higher in patients with active (P < 0.001) and severe ulcerative colitis (UC) (P < 0.0001) and active Crohn's disease (CD) (P < 0.001). In UC in remission, LBP was less than in active disease (P = 0.011) LBP levels decreased longitudinally before and after induction of medical therapy in patients with IBD (P = 0.030) and as severe UC was brought into remission at weeks 2 and 12 (P ≤ 0.022). Response to treatment was associated with higher baseline levels of LBP (P = 0.019) and soluble-CD14 (P = 0.014). Concentrations of syndecan-1 and IFABP were or tended to be lower in UC and CD in active disease and did not change with successful therapy. CONCLUSION: While markers of epithelial injury were subnormal with active disease and did not change with therapy, markers of lipopolysaccharide translocation directly reflected intestinal inflammation, reduced with successful therapy and predicted treatment response.

SDC1-TGM2-FLOT1-BHMT complex determines radiosensitivity of glioblastoma by influencing the fusion of autophagosomes with lysosomes.

Rationale: Glioblastoma (GBM) is the most common and malignant primary brain tumor in adults. Radiotherapy has long been an important treatment for GBM. Despite recent advances in tumor radiotherapy, the prognosis of GBM remains poor due to radioresistance. Autophagy has been reported as a basic factor to prolong the survival of tumor under radiation stress, but the molecular mechanism of how autophagy contributes to GBM radioresistance was still lacking. Methods: We established radioresistant GBM cells and identified their protein profiles by Tandem mass tag (TMT) quantitative proteomic analysis, then chose the radioresistant genes based on the TMT analysis of GBM cells and differentially expressed genes (DEGs) analysis of GEO database. Colony formation, flow cytometry, qPCR, western blotting, mRFP-GFP-LC3, transmission electron microscopy, immunofluorescence, and co-IP assays were conducted to investigate the regulation mechanisms among these new-found molecules. Results: Syndecan 1 (SDC1) and Transglutaminase 2 (TGM2) were both overexpressed in the radioresistant GBM cells and tissues, contributing to the dismal prognosis of radiotherapy. Mechanically, after irradiation, SDC1 carried TGM2 from cell membrane into cytoplasm, and transported to lysosomes by binding to flotillin 1 (FLOT1), then TGM2 recognized the betaine homocysteine methyltransferase (BHMT) on autophagosomes to coordinate the encounter between autophagosomes and lysosomes. Conclusions: The SDC1-TGM2-FLOT1-BHMT copolymer, a novel member of the protein complexes involved in the fusion of lysosomes and autophagosomes, maintained the autophagic flux in the irradiated tumor cells and ultimately enhanced radioresistance of GBM, which provides new insights of the molecular mechanism and therapeutic targets of radioresistant GBM.

Endothelial biomarkers as predictors for haemodialysis need in severe leptospirosis patients (Weil's disease).

OBJECTIVE: To investigate the prediction ability of vascular injury biomarkers for haemodialysis requirement in patients with severe leptospirosis. METHODS: Prospective study with severe leptospirosis patients hospitalised in Fortaleza, Brazil. Blood samples were collected hospital admission to quantify vascular injury biomarkers: syndecan-1, ICAM-1, VCAM-1, angiopoietin-2 and FGF-23. Two groups were evaluated according to haemodialysis requirement during hospital stay. RESULTS: Twenty-seven patients were included, with a mean age of 39 ± 18 years. 88.9% were males. 53.8% needed haemodialysis and presented higher levels on hospital admission of syndecan-1 (572 [300-811] vs. 263 [106-421] ng/ml; p = 0.03), angiopoietin-2 (1.52 [0.72-2.72] vs. 0.63 [0.4-1.38] ng/ml; p = 0.01), and FGF-23 (291 [56-2031] vs. 10 [10-806] pg/ml; p = 0.021). Syndecan-1 showed significant correlation with creatinine (r = 0.546; p = 0.05) and total bilirubin levels (r = 0.534; p = 0.013) on hospital admission. Angiopoietin-2 showed significant correlation with creatinine levels (r = 0.513; p = 0.009) on hospital admission and with number of haemodialysis sessions (r = 0.406; p = 0.049). No significant correlation was found with FGF-23. Regarding prognostic performance, combined syndecan-1 and angiopoietin-2 levels had a better ability to predict haemodialysis need in patients with severe leptospirosis (AUC-ROC = 0.744 [95% CI: 0.545-0.943] p = 0.035). CONCLUSION: Syndecan-1 and angiopoietin-2 were associated with haemodialysis need in patients with severe leptospirosis and may be useful to improve therapeutic approach and reduce mortality.

Vitamin C Improves the Outcomes of Cardiopulmonary Resuscitation and Alters Shedding of Syndecan-1 and p38/MAPK Phosphorylation in a Rat Model.

Background Post-resuscitation syndrome, involves a severe inflammatory response following successful cardiopulmonary resuscitation. The potential mechanism of Vitamin C (VitC) after cardiopulmonary resuscitation on myocardial and cerebral function, duration of survival is undefined. Methods and Results A first set of experiments were done in 18 male Sprague-Dawley rats for the investigation of short-term follow-up, randomized into 3 groups: (1) sham; (2) controls; (3) VitC. Ventricular fibrillation was electrically induced and untreated for 6 minutes. Cardiopulmonary resuscitation including chest compression and mechanical ventilation were then initiated and continued for 8 minutes followed by defibrillation. At 5 minutes after return of spontaneous circulation, either VitC (200 mg/kg) or placebo was administered by intravenous infusion with a syringe pump for half an hour. There were significant improvements in myocardial function and buccal microcirculation in rats treated with VitC after return of spontaneous circulation 4 hours compared with controls. VitC inhibited proinflammatory cytokines (interleukin-6 and tumor necrosis factor-α), SDC-1 (Syndecan-1), and hyaluronic acid in plasma compared with controls (P<0.01). VitC decreased reactive oxygen species production and inhibited p38/MAPK (mitogen-activated protein kinase) pathway phosphorylation. A second set with 20 animals was used for assessing the neurological deficit score after return of spontaneous circulation 72 hours, randomized into 2 groups: 1) controls; 2) VitC. The survival rate and neurological deficit score after return of spontaneous circulation 72 hours were improved in VitC-treated animals compared with those of the control group. Conclusions VitC reduces the severity of post-resuscitation myocardial and cerebral dysfunction and improves the survival. The mechanisms may involve inhibiting transcription of inflammatory cytokines and oxidative stress, thus protecting the integrity of the vascular endothelium. Meanwhile VitC reduces shedding of SDC-1 and alters p38/MAPK phosphorylation and microcirculation.

Growth Differentiation Factor-15 and Syndecan-1 Are Potential Biomarkers of Cardiac and Renal Involvement in Classical Fabry Disease under Enzyme Replacement Therapy.

BACKGROUND AND AIMS: Inflammation and endothelial damage play a pivotal role in Fabry disease (FD) manifestations. In daily clinical practice, FD is mainly monitored by traditional biomarkers of target organ injury, such as serum creatinine and proteinuria, which provide no information about inflammation and endothelial damage. MATERIALS AND METHODS: We investigated the serum levels of 3-nitrotyrosine (3-NT), an oxidative stress biomarker, and of growth differentiation factor-15 (GDF-15) and syndecan-1 in classical FD patients on enzyme replacement therapy (ERT) for at least 6 months and their relationship with Fabry-related cardiac and renal manifestations. RESULTS: Fifty-two classical FD patients (37 females) on ERT for 62.0 ± 27.5 months were included in the study. The main clinical manifestations included nephropathy (67.3%) and cardiomyopathy (21.1%). Serum levels of 3-NT, syndecan-1, and GDF-15 were 33.3 (4.8-111.1) nmol/mL, 55.7 (38.8-74.9) ng/mL, and 541.8 (392.2-784.4) pg/mL, respectively. There was a direct correlation between interventricular septal thickness and serum GDF-15 (r = 0.59; p < 0.001) and syndecan-1 (r = 0.30, p = 0.04). Among kidney parameters, there was a significant correlation between estimated glomerular filtration rate and GDF-15 (r = -0.61; p < 0.001), as well as between 24 h proteinuria and syndecan-1 (r = 0.28; p = 0.04). Serum GDF-15 levels were significantly higher in patients with cardiomyopathy (p = 0.03) as well in those with both nephropathy and cardiomyopathy (p = 0.02) than in patients without these comorbidities. Serum GDF-15 levels were also significantly higher in patients who started ERT at an older age (≥40 years). In multivariate analysis, syndecan-1, 3-NT, GDF-15, time on ERT, and arterial pressure differentiated Fabry patients with both cardiac and renal involvement from those without these manifestations. CONCLUSIONS: GDF-15 and syndecan-1 were associated with parameters of cardiac and renal involvement in classic FD patients on ERT. Their potential association with residual risk and disease outcomes should be investigated.

Analysis of the diagnostic value of CD138 for chronic endometritis, the risk factors for the pathogenesis of chronic endometritis and the effect of chronic endometritis on pregnancy: a cohort study.

BACKGROUND: To investigate the role of CD138 immunohistochemistry in the diagnosis of chronic endometritis (CE) and the risk factors for assisted conception patients having CE complications. METHODS: Ninety-three patients, with normal uterine shape confirmed by examination and who were planning to undergo assisted conception treatments, were selected as research subjects. Endometrial tissue was isolated for routine hematoxylin and eosin (HE) and CD138 immunohistochemical staining. Additionally, the disease histories of patients were collected, and the reproductive prognosis was followed up. RESULTS: ① CE detection rate: The rate of CD138 immunohistochemical staining was greater than that of HE staining (27.96 % vs. 26.89 %, P <0.05); ② Pregnancy rate: the pregnancy rate of CD138-positive patients (7.7 %) was lower than the pregnancy rate of CD138-negative patients (31.3 %) (p = 0.017 < 0.05); ③ The results from univariate analysis showed that a previous history of prolonged menstrual bleeding episodes, an abortion history, and complications of fallopian tube obstruction were associated with CE (P <0.05). The results of logistic regression analysis confirmed that prolonged menstrual bleeding episodes (P = 0.014, OR = 5.394, 95 % CI 1.405-20.699), a previous abortion history (P = 0.029, OR = 3.194, 95 % CI 1.125-9.073), and fallopian tube obstruction (P = 0.028, OR = 3.274, 95 % CI 1.139-9.415) were independent risk factors for positive CD138 results. CONCLUSIONS: CD138 immunohistochemistry can improve the CE diagnosis rate. A previous history of prolonged menstrual bleeding episodes, an abortion history, and a history of fallopian tube obstruction are risk factors for chronic endometritis, and a CD138 immunohistochemical examination should be advised among them.

Syndecan-Fc hybrid molecule as a potent in vitro microbicidal anti-HIV-1 agent.

In the absence of a vaccine, there is an urgent need for the development of safe and effective topical microbicides to prevent the sexual transmission of human immunodeficiency virus type 1 (HIV-1). In this study, we proposed to develop a novel class of microbicides using syndecan as the antiviral agent. Specifically, we generated a soluble syndecan-Fc hybrid molecule by fusing the ectodomain of syndecan-1 to the Fc domain of a human IgG. We then tested the syndecan-Fc hybrid molecule for various in vitro microbicidal anti-HIV-1 properties. Remarkably, the syndecan-Fc hybrid molecule possesses multiple attractive microbicidal properties: (i) it blocks HIV-1 infection of primary targets including T cells, macrophages, and dendritic cells (DC); (ii) it exhibits a broad range of antiviral activity against primary HIV-1 isolates, multidrug resistant HIV-1 isolates, HIV-2, and simian immunodeficiency virus (SIV); (iii) it prevents transmigration of HIV-1 through human primary genital epithelial cells; (iv) it prevents HIV-1 transfer from dendritic cells to CD4(+) T cells; (v) it is potent when added 2 h prior to addition of HIV-1 to target cells; (vi) it is potent at a low pH; (vii) it blocks HIV-1 infectivity when diluted in genital fluids; and (viii) it prevents herpes simplex virus infection. The heparan sulfate chains of the syndecan-Fc hybrid molecule are absolutely required for HIV-1 neutralization. Several lines of evidence suggest that the highly conserved Arg298 in the V3 region of gp120 serves as the locus for the syndecan-Fc hybrid molecule neutralization. In conclusion, this study suggests that the syndecan-Fc hybrid molecule represents the prototype of a new generation of microbicidal agents that may have promise for HIV-1 prevention.