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- The Accumulation of Heparan Sulfate S-Domains in Kidney Transthyretin Deposits Accelerates Fibril Formation and Promotes Cytotoxicity. [Journal Article]
- AJAm J Pathol 2018 Nov 07
- The highly sulfated domains of heparan sulfate (HS), also called HS S-domains, are made up of repeated trisulfated disaccharide units [iduronic acid (2S)-glucosamine (NS, 6S)-] and are selectively re...
The highly sulfated domains of heparan sulfate (HS), also called HS S-domains, are made up of repeated trisulfated disaccharide units [iduronic acid (2S)-glucosamine (NS, 6S)-] and are selectively remodeled by extracellular endoglucosamine 6-sulfatases (Sulfs). Although HS S-domains are critical for signal transduction of several growth factors, their roles in amyloidoses are not yet fully understood. Here, we found HS S-domains in the kidney of a patient with transthyretin amyloidosis (ATTR amyloidosis). In in vitro assays with cells stably expressing human Sulfs, heparin, a structural analog of HS S-domains, promoted aggregation of TTR in an HS S-domain-dependent manner. Interactions of cells with TTR fibrils and cytotoxicity of these fibrils also depended on HS S-domains at the cell surface. Furthermore, glypican-5 (GPC5), encoded by the susceptibility gene for nephrotic syndrome GPC5, was found to be accumulated in the ATTR amyloidosis kidney. Our study thus provides a novel insight into the pathological roles of HS S-domains in amyloidoses, and we propose that enzymatic remodeling of HS chains by Sulfs may offer an effective approach to inhibiting formation and cytotoxicity of amyloid fibrils.
- Characterization of a novel exo-chitosanase, an exo-chitobiohydrolase, from Gongronella butleri. [Journal Article]
- JBJ Biosci Bioeng 2018 Oct 10
- An exo-chitosanase was purified from the culture filtrate of Gongronella butleri NBRC105989 to homogeneity by ammonium sulfate precipitation, followed by column chromatography using CM-Sephadex C-50 ...
An exo-chitosanase was purified from the culture filtrate of Gongronella butleri NBRC105989 to homogeneity by ammonium sulfate precipitation, followed by column chromatography using CM-Sephadex C-50 and Sephadex G-100. The enzyme comprised a monomeric protein with a molecular weight of approximately 47,000 according to sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE). The enzyme exhibited optimum activity at pH 4.0, and was stable between pH 5.0 and 11.0. It was most active at 45°C, but was stable at temperatures below 30°C. The enzyme hydrolyzed soluble chitosan and glucosamine (GlcN) oligomers larger than tetramers, but did not hydrolyze N-acetylglucosamine (GlcNAc) oligomers. To clarify the mode of action of the enzyme, we used thin-layer chromatography (TLC) and high-performance liquid chromatography (HPLC) to investigate the products resulting from the enzyme-catalyzed hydrolysis of chitosan and N1-acetylchitohexaose [(GlcN)5-GlcNAc] with a GlcNAc residue at the reducing end. The results indicated that the enzyme is a novel exo-type chitosanase, exo-chitobiohydrolase, that releases (GlcN)2 from the non-reducing ends of chitosan molecules. Analyses of the hydrolysis products of partially N-acetylated chitooligosaccharides revealed that the enzyme cleaves both GlcN-GlcNAc and GlcNAc-GlcN bonds in addition to GlcN-GlcN bonds in the substrate.
- Osteogenic differentiation enhances the MC3T3-E1 secretion of glycosaminoglycans with an affinity for basic fibroblast growth factor and bone morphogenetic protein-2. [Journal Article]
- RTRegen Ther 2018; 8:58-62
- CONCLUSIONS: It was found that the osteogenic differentiation allowed cells to enhance the secretion of GAG with an affinity for BMP-2 and bFGF.
- Combining a joint health supplement with tibial plateau leveling osteotomy in dogs with cranial cruciate ligament rupture. An exploratory controlled trial. [Journal Article]
- IJInt J Vet Sci Med 2017; 5(2):105-112
- Canine cranial cruciate ligament rupture (CrCLR) is a very common pathology. Surgical stabilization is the first choice treatment, although it does not fully eliminate the increased risk of osteoarth...
Canine cranial cruciate ligament rupture (CrCLR) is a very common pathology. Surgical stabilization is the first choice treatment, although it does not fully eliminate the increased risk of osteoarthritis. This preliminary study was carried out to explore whether a newly formulated joint health supplement would benefit metabolic, clinical and radiographic changes in dogs with CrCLR surgically treated with tibial plateau leveling osteotomy (TPLO). Besides chondroitin sulfate and glucosamine hydrochloride, the studied supplement contained anti-inflammatory and antioxidant ingredients, the main ones being N-palmitoyl-D-glucosamine (Glupamid®) and quercetin. It was thus intended to target not only chondrodegenerative components of osteoarthritis, but also post-injury inflammatory response and oxidative stress of joint tissues. Thirteen dogs underwent TPLO and were randomly allocated to treatment (n = 6) and control groups (n = 7), the former receiving the joint supplement for 90 days. Lameness and radiographic osteoarthritis changes were scored before (i.e., baseline) and at 30 and 90 days post-surgery. Synovial fluid samples were collected from injured stifles at the same time points. Levels of representative metabolites were measured by proton nuclear magnetic resonance spectroscopy in a blinded fashion. In the metabolomic analysis, special attention was paid to lactate, due to its emerging recognition as a key marker of inflammation. In the last time period (from the 30th to the 90th day), lameness improved by a factor of 2.3 compared to control dogs. No significant difference was observed in the radiographic osteoarthritis score between groups. In the first postoperative month, lactate and creatine levels significantly dropped in treated compared to control dogs. Compared to surgery alone, combining the joint supplement with TPLO resulted in a trend to a better clinical outcome in the later time interval but did not influence osteoarthritis radiographic progression. A significantly better rebalance of joint microenvironment in the early time interval (baseline - 30 days) was shown by metabolomic analysis, thus suggesting that the study supplement could limit ongoing inflammatory responses.
- Topical therapies for knee osteoarthritis. [Review]
- PMPostgrad Med 2018; 130(7):607-612
- CONCLUSIONS: Although some controversy exists on the role of topical NSAIDs, current management guidelines advise topical NSAIDs as an option and even first-line therapy for knee OA treatment, particularly among elderly patients. Topical NSAIDs may be contemplated as similar options to oral NSAIDs and are associated with fewer gastrointestinal complications when compared with oral NSAIDs. Caution should be taken with the use of both topical and oral NSAIDs, including close adherence to dosing regimens and monitoring, especially for patients with previous complications of NSAIDs. The role of other topical therapies needs further research.
- The case report of capillary leakage syndrome secondary to malignant hypertension. [Case Reports]
- MMedicine (Baltimore) 2018; 97(34):e11913
- CONCLUSIONS: Up to now, there has been no case report of CLS caused by MHT. We should pay more attention to CLS induced by MHT, try to diagnose it as soon as possible, and give prompt treatment to CLS and primary disease.
- Isolation and Characterization of a Chinese Hamster Ovary Heparan Sulfate Cell Mutant Defective in Both Met Receptor Binding and Hepatocyte Growth Factor NK1/Met Signaling. [Journal Article]
- CPCell Physiol Biochem 2018; 48(4):1480-1491
- CONCLUSIONS: This study demonstrated that soluble Met recombinant protein bound to cell surface HS at physiological conditions and a Met /HGF or NK1/HS ternary signaling complex might be involved in Met signaling. Shorter HS chains and reduced 6-O-sulfation might be responsible for reduced Met binding and the diminished NK1-initiated signaling in the CHO-Negative cells. The unique CHO-Positive and CHO-Negative cell clones established in current study should be effective tools for studying the role of specific glycosaminoglycan structures in regulating Met signaling. Such knowledge should be useful in developing glycosaminoglycan-based compounds that target HGF/Met signaling.
- Downstream Products are Potent Inhibitors of the Heparan Sulfate 2-O-Sulfotransferase. [Journal Article]
- SRSci Rep 2018 Aug 07; 8(1):11832
- Heparan Sulfate (HS) is a cell signaling molecule linked to pathological processes ranging from cancer to viral entry, yet fundamental aspects of its biosynthesis remain incompletely understood. Here...
Heparan Sulfate (HS) is a cell signaling molecule linked to pathological processes ranging from cancer to viral entry, yet fundamental aspects of its biosynthesis remain incompletely understood. Here, the binding preferences of the uronyl 2-O-sulfotransferase (HS2ST) are examined with variably-sulfated hexasaccharides. Surprisingly, heavily sulfated oligosaccharides formed by later-acting sulfotransferases bind more tightly to HS2ST than those corresponding to its natural substrate or product. Inhibition assays also indicate that the IC50 values correlate simply with degree of oligosaccharide sulfation. Structural analysis predicts a mode of inhibition in which 6-O-sulfate groups located on glucosamine residues present in highly-sulfated oligosaccharides occupy the canonical binding site of the nucleotide cofactor. The unexpected finding that oligosaccharides associated with later stages in HS biosynthesis inhibit HS2ST indicates that the enzyme must be separated temporally and/or spatially from downstream products during biosynthesis in vivo, and highlights a challenge for the enzymatic synthesis of lengthy HS chains in vitro.
- Impact of oral osteoarthritis therapy usage among other risk factors on knee replacement: a nested case-control study using the Osteoarthritis Initiative cohort. [Journal Article]
- ARArthritis Res Ther 2018 Aug 07; 20(1):172
- CONCLUSIONS: This study provides evidence that the main risk factors leading to KR are disease severity, symptoms and high BMI. Importantly, exposure to oral OA therapies was not associated with the occurrence of KR.
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- Heparan sulfate S-domains and extracellular sulfatases (Sulfs): their possible roles in protein aggregation diseases. [Review]
- GJGlycoconj J 2018 Jul 12
- Highly sulfated domains of heparan sulfate (HS), also known as HS S-domains, consist of repeated trisulfated disaccharide units [iduronic acid (2S)-glucosamine (NS, 6S)-]. The expression of HS S-doma...
Highly sulfated domains of heparan sulfate (HS), also known as HS S-domains, consist of repeated trisulfated disaccharide units [iduronic acid (2S)-glucosamine (NS, 6S)-]. The expression of HS S-domains at the cell surface is determined by two mechanisms: tightly regulated biosynthetic machinery and enzymatic remodeling by extracellular endoglucosamine 6-sulfatases, Sulf-1 and Sulf-2. Intracellular or extracellular deposits of misfolded and aggregated proteins are characteristic of protein aggregation diseases. Although proteins can aggregate alone, deposits of protein aggregates in vivo contain a number of proteinaceous and non-protein components. HS S-domains are one non-protein component of these aggregated deposits. HS S-domains are considered to be critical for signal transduction of several growth factors and several disease conditions, such as tumor progression, but their roles in protein aggregation diseases are not yet fully understood. This review summarizes the current understanding of the possible roles of HS S-domains and Sulfs in the formation and cytotoxicity of protein aggregates.