Infectious Diseases and the Lymphoid Extracellular Matrix Remodeling: A Focus on Conduit System

The conduit system was described in lymphoid organs as a tubular and reticular set of structures compounded by collagen, laminin, perlecan, and heparin sulfate proteoglycan wrapped by reticular fibroblasts. This tubular system is capable of rapidly transport small molecules such as viruses, antigens, chemokines, cytokines, and immunoglobulins through lymphoid organs. This structure plays an important role in guiding the cells to their particular niches, therefore participating in cell cooperation, antigen presentation, and cellular activation. The remodeling of conduits has been described in chronic inflammation and infectious diseases to improve the transport of antigens to specific T and B cells in lymphoid tissue. However, malnutrition and infectious agents may induce extracellular matrix remodeling directly or indirectly, leading to the microarchitecture disorganization of secondary lymphoid organs and their conduit system. In this process, the fibers and cells that compound the conduit system may also be altered, which affects the development of a specific immune response. This review aims to discuss the extracellular matrix remodeling during infectious diseases with an emphasis on the alterations of molecules from the conduit system, which damages the cellular and molecular transit in secondary lymphoid organs compromising the immune response.

Positive Association of Metabolic Syndrome with a Single Nucleotide Polymorphism of Syndecan-3 (rs2282440) in the Taiwanese Population

Background/Purpose. Metabolic syndrome (MetS) poses a major public health burden on the general population worldwide. Syndecan-3 (SDC3), a heparin sulfate proteoglycan, had been found by previous studies to be linked with energy balance and obesity, but its association with MetS is not known. The objective of this study is to investigate whether SDC3 polymorphism (rs2282440) is associated with MetS in the Taiwanese population. Methods. Genotypes of SDC3 polymorphism (rs2282440) were analyzed in 545 Taiwanese adult subjects, of which 154 subjects had MetS. Results. Subjects with SDC3 rs2282440 TT homozygote had higher frequency of MetS than those with CC or CT genotype (p=0.0217). SDC3 rs2282440 TT homozygote had a 1.96-fold risk of being obese and 1.8-fold risk of having MetS (with CC genotype as reference). As for the individual components of MetS, subjects with SDC3 rs2282440 TT homozygote were more likely to have large waist circumference and low high-density lipoprotein cholesterol (OR = 1.75 and OR = 1.84, resp.). Conclusion. SDC3 rs2282440 polymorphism is positively associated with MetS in the Taiwanese population. Further investigation is needed to see if this association is mediated by mere adiposity or SDC3 polymorphism is also linked with other components of MetS such as lipid metabolism.

Resveratrol Improves Tube Formation in AGE-Induced Late Endothelial Progenitor Cells by Suppressing Syndecan-4 Shedding

Dysfunction of endothelial progenitor cells (EPCs) contributes to cardiovascular complications in diabetes, and resveratrol has been shown to improve EPC functions. Syndecan-4 (Synd4), a cell surface heparin sulfate proteoglycan, has been shown to promote neovascularization. Thus, the present study was performed to determine whether resveratrol promoted angiogenesis of EPCs by regulating Synd4. Late EPCs were isolated from human peripheral blood and stimulated with AGEs. Western blot showed that AGEs induced Synd4 shedding in a dose- and time-dependent manner. AGE-induced Synd4 shedding was partly reversed by NAC or resveratrol, along with normalized ROS production. Overexpression of Synd4 or pretreatment of resveratrol reversed AGE-impaired tube formation of EPCs and regulated the Akt/eNOS pathway. Furthermore, resveratrol suppressed Synd4 shedding via the inhibition of oxidative stress and improved tube formation of late EPCs via the regulation of the Synd4/Akt/eNOS pathway.

Preliminary study of three tumor markers for hepatocellular carcinoma: AFP, AFP-L3, and Glypican-3

15014 Background: a-Fetoprotein (AFP) is the most widely used biochemical marker for detection of hepatocellular cancer (HCC). AFP is also elevated in acute and chronic liver disease, limiting its utility as an early indicator of HCC. Recently, AFP-L3 and glypican 3 (GPC3) have been reported for early detection of HCC. AFP-L3 is a glycoform of AFP produced by malignant liver cells. Measurement of AFP-L3 as a percentage of total AFP helps distinguish non-malignant hepatic disease from HCC. GPC3 is a heparin sulfate proteoglycan anchored to the plasma membrane. The level of GPC3 in the serum of HCC patients is higher than in the serum of healthy adults or patients with non-malignant hepatopathy. We tested the concordance of AFP, AFP, AFP-L3%, and GPC3and GPC3 to determine if their simultaneous measurement may increase the sensitivity of identifying individuals at risk for HCC. Method: De-identified clinical samples (n = 176) submitted for AFP-L3% measurement were tested. AFP and AFP-L3 levels were measured using the LiBASys automated analyzer (Wako Chemicals USA Inc, Richmond, VA). GPC3 levels were measured with a commercial ELISA kit (BioMosaics, Inc, Burlington, VT). To assess concordance we categorized results according to accepted cut-off values for AFP and AFP-L3, and a clinically established reference range for GPC3. Results: Fourteen of the 176 samples had elevated GPC3 (=180pg/mL), 6 (43%) of which had normal AFP values (<20ng/mL). Forty- seven of the 176 samples had elevated AFP-L3% (L3 =10%), 6 (12.8%) of which had normal AFP levels. Conclusion: These data suggest that GPC3 and AFP-L3% may be used as supplemental markers, and the simultaneous determination of AFP, AFP-L3, and GPC3 may provide a higher sensitivity for identifying individuals with increased risk of HCC. [Table: see text] No significant financial relationships to disclose.

Characterization of a factor that promotes neurite outgrowth: evidence linking activity to a heparan sulfate proteoglycan.

Rat sympathetic neurons, plated onto extracellular matrix produced by cultured bovine corneal endothelial cells, rapidly extended neurites in the absence of nerve growth factor (NGF). The response was unaffected by antiserum to NGF. Rapid outgrowth also occurred when sympathetic neurons were plated onto polylysine-coated surfaces that had been exposed to serum-free medium conditioned by corneal endothelial cells (CMSF). A response was seen even when the neurons were cultured without serum. When plated onto a polylysine-coated dish treated with CMSF over half its surface, only the neurons on the treated half extended neurites. The active factor in CMSF was destroyed by trypsin, acid (pH 1.6), base (pH 12.7), or heating to 80 degrees C; it was stable to heating to 60 degrees C, collagenase, deoxyribonuclease, and neuraminidase. The factor elutes just after the void volume of a Sepharose 6B column. In associative cesium chloride gradients, it sediments as a peak centered at a density of 1.36-1.37, corresponding to a peak of material that can be biosynthetically labeled with [35S]sulfate or [3H]leucine. Material from this fraction was inactivated by heparinase, but not chondroitinase ABC, implying that a heparin sulfate proteoglycan is essential for the factor's activity. Inactivation by contaminants in the heparinase preparation was ruled out. Further purification indicated that the active factor may exist as an aggregate containing a heparin sulfate proteoglycan and other molecules. CMSF also promoted neurite outgrowth by other types of neurons. Furthermore, a variety of cell types were shown to produce factors similar to that in CMSF.