Heparanase, an endo-β-d-glucuronidase produced by a variety of cells and tissues, cleaves the glycosidic linkage between glucuronic acid (GlcA) and a 3-O- or 6-O-sulfated glucosamine, typified by the disaccharide -[GlcA-GlcNS3S6S]-, which is found within the antithrombin-binding domain of heparan sulfate or heparin. As such, all current forms of heparin are susceptible to degradation by heparanase with neutralization of anticoagulant properties. Here, we have designed a heparanase-resistant, ultralow molecular weight heparin as the structural analogue of fondaparinux that does not contain an internal GlcA residue but otherwise displays potent anticoagulant activity. This heparin oligosaccharide was synthesized following a chemoenzymatic scheme and displays nanomolar anti-FXa activity yet is resistant to heparanase digestion. Inhibition of thrombus formation was further demonstrated after subcutaneous administration of this compound in a murine model of venous thrombosis. Thrombus inhibition was comparable to that observed for enoxaparin with a similar effect on bleeding time.

Background: Most patients with idiopathic pulmonary fibrosis (IPF) have poor prognosis; Effective predictive models for these patients are currently lacking. Epithelial-mesenchymal transition (EMT) often occurs during idiopathic pulmonary fibrosis development, and is closely related to multiple pathways and biological processes. It is thus necessary for clinicians to find prognostic biomarkers with high accuracy and specificity from the perspective of Epithelial-mesenchymal transition. Methods: Data were obtained from the Gene Expression Omnibus database. Using consensus clustering, patients were grouped based on Epithelial-mesenchymal transition-related genes. Next, functional enrichment analysis was performed on the results of consensus clustering using gene set variation analysis. The gene modules associated with Epithelial-mesenchymal transition were obtained through weighted gene co-expression network analysis. Prognosis-related genes were screened via least absolute shrinkage and selection operator (LASSO) regression analysis. The model was then evaluated and validated using survival analysis and time-dependent receiver operating characteristic (ROC) analysis. Results: A total of 239 Epithelial-mesenchymal transition-related genes were obtained from patients with idiopathic pulmonary fibrosis. Six genes with strong prognostic associations (C-X-C chemokine receptor type 7 [CXCR7], heparan sulfate-glucosamine 3-sulfotransferase 1 [HS3ST1], matrix metallopeptidase 25 [MMP25], murine retrovirus integration site 1 [MRVI1], transmembrane four L6 family member 1 [TM4SF1], and tyrosylprotein sulfotransferase 1 [TPST1]) were identified via least absolute shrinkage and selection operator and Cox regression analyses. A prognostic model was then constructed based on the selected genes. Survival analysis showed that patients with high-risk scores had worse prognosis based on the training set [hazard ratio (HR) = 7.31, p < .001] and validation set (HR = 2.85, p = .017). The time-dependent receiver operating characteristic analysis showed that the area under the curve (AUC) values in the training set were .872, .905, and .868 for 1-, 2-, and 3-year overall survival rates, respectively. Moreover, the area under the curve values in the validation set were .814, .814, and .808 for 1-, 2-, and 3-year overall survival rates, respectively. Conclusion: The independent prognostic model constructed from six Epithelial-mesenchymal transition-related genes provides bioinformatics guidance to identify additional prognostic markers for idiopathic pulmonary fibrosis in the future.

Heparan sulfate is a ubiquitous, variably sulfated interactive glycosaminoglycan that consists of repeating disaccharides of glucuronic acid and glucosamine that are subject to a number of modifications (acetylation, de-acetylation, epimerization, sulfation). Variable heparan sulfate chain lengths and sequences within the heparan sulfate chains provide structural diversity generating interactive oligosaccharide binding motifs with a diverse range of extracellular ligands and cellular receptors providing instructional cues over cellular behaviour and tissue homeostasis through the regulation of essential physiological processes in development, health, and disease. heparan sulfate and heparan sulfate-PGs are integral components of the specialized glycocalyx surrounding cells. Heparan sulfate is the most heterogeneous glycosaminoglycan, in terms of its sequence and biosynthetic modifications making it a difficult molecule to fully characterize, multiple ligands also make an elucidation of heparan sulfate functional properties complicated. Spatio-temporal presentation of heparan sulfate sulfate groups is an important functional determinant in tissue development and in cellular control of wound healing and extracellular remodelling in pathological tissues. The regulatory properties of heparan sulfate are mediated via interactions with chemokines, chemokine receptors, growth factors and morphogens in cell proliferation, differentiation, development, tissue remodelling, wound healing, immune regulation, inflammation, and tumour development. A greater understanding of these HS interactive processes will improve therapeutic procedures and prognoses. Advances in glycosaminoglycan synthesis and sequencing, computational analytical carbohydrate algorithms and advanced software for the evaluation of molecular docking of heparan sulfate with its molecular partners are now available. These advanced analytic techniques and artificial intelligence offer predictive capability in the elucidation of heparan sulfate conformational effects on heparan sulfate-ligand interactions significantly aiding heparan sulfate therapeutics development.

Hereditary angioedema (HAE) is an autosomal dominant disorder caused by a mutation in the C1 esterase inhibitor gene. HAE affects 1/50,000 people worldwide. Three main types of HAE exist: type I, type II, and type III. Type I is characterized by a deficiency in C1-INH. C1-INH is important in the coagulation complement, contact systems, and fibrinolysis. Most HAE cases are type I. Type I and II HAE result from a mutation in the SERPING1 gene, which encodes C1-INH. Formally known as type III HAE is typically an estrogen-dependent or hereditary angioedema with normal C1-INH activity. Current guidelines now recommend subdividing hereditary angioedema with normal C1 esterase inhibitor gene (HAE-nl-C1-INH formerly known as HAE type III) based on underlying mutations such as in kininogen-1 (HAE-KNG1), plasminogen gene (PLG-HAE), myoferlin gene mutation (MYOF-HAE), heparan sulfate-glucosamine 3-sulfotransferase 6 (HS3ST6), mutation in Hageman factor (factor XII), and in angiopoietin-1 (HAE-ANGPT-1). The clinical presentation of HAE varies between patients, but it usually presents with nonpitting angioedema and occasionally abdominal pain. Young children are typically asymptomatic. Those affected by HAE usually present with symptoms in their early 20s. Symptoms can arise as a result of stress, infection, or trauma. Laboratory testing shows abnormal levels of C1-INH and high levels of bradykinin. C4 and D-dimer levels can also be monitored if an acute HAE attack is suspected. Acute treatment of HAE can include IV infusions of C1-INH, receptor antagonists, and kallikrein inhibitors. Short- and long-term prophylaxis can also be administered to patients with HAE. First-line therapies for long-term prophylaxis also include IV infusion of C1-INH. This review aims to thoroughly understand HAE, its clinical presentation, and how to treat it.

Osteoarthritis (OA) is one of the most common joint degenerative diseases in the world. At present, the management of OA depends on the lifestyle modification and joint replacement surgery, with the lifespan of prosthesis quite limited yet. Effective drug treatment of OA is essential. However, the current drugs, such as the non-steroidal anti-inflammatory drugs and acetaminophen, as well as glucosamine, chondroitin sulfate, hyaluronic acid, are accompanied by obvious side effects, with the therapeutic efficacy to be enhanced. Recently, novel reagents such as IL-1 antagonists and nerve growth factor inhibitors have entered clinical trials. Moreover, increasing evidence demonstrated that active ingredients of natural plants have great potential for treating OA. Meanwhile, the use of novel drug delivery strategies may overcome the shortcomings of conventional preparations and enhance the bioavailability of drugs, as well as decrease the side effects significantly. This review therefore summarizes the pathological mechanisms, management strategies, and research progress in the drug molecules including the newly identified active ingredient derived from medicinal plants for OA therapy, with the drug delivery technologies also summarized, with the expectation to provide the summary and outlook for developing the next generation of drugs and preparations for OA therapy.

Osteoarthritis is a very disabling disease that can be treated with both non-pharmacological and pharmacological approaches. In the last years, pharmaceutical-grade chondroitin sulfate (CS) and glucosamine emerged as symptomatic slow-acting molecules, effective in pain reduction and improved function in patients affected by osteoarthritis. CS is a sulfated glycosaminoglycan that is currently produced mainly by extraction from animal tissues, and it is commercialized as a pharmaceutical-grade ingredient and/or food supplement. However, public concern on animal product derivatives has prompted the search for alternative non-extractive production routes. Thus, different approaches were established to obtain animal-free natural identical CS. On the other hand, the unsulfated chondroitin, which can be obtained via biotechnological processes, demonstrated promising anti-inflammatory properties in vitro, in chondrocytes isolated from osteoarthritic patients. Therefore, the aim of this study was to explore the potential of chondroitin, with respect to the better-known CS, in an in vivo mouse model of knee osteoarthritis. Results indicate that the treatment with biotechnological chondroitin (BC), similarly to CS, significantly reduced the severity of mechanical allodynia in an MIA-induced osteoarthritic mouse model. Decreased cartilage damage and a reduction of inflammation- and pain-related biochemical markers were also observed. Overall, our data support a beneficial activity of biotechnological unsulfated chondroitin in the osteoarthritis model tested, thus suggesting BC as a potential functional ingredient in pharmaceuticals and nutraceuticals with the advantage of avoiding animal tissue extraction.

Mountain Zizania latifolia is produced at scale in China, and the edible swollen culm is exported to many countries, but little attention has been paid to its functional components. In this work, microwave-assisted enzymatic extraction (MAEE) is used for the first time to extract polysaccharides from mountain Z. latifolia swollen culm (PMZL). MAEE conditions optimized by Box-Behnken design-response surface methodology were as follows: 2.4% cellulase, microwaving for 6.0 min at 607 W, with a liquid-to-solid ratio of 63:1 ml g-1 . Under these conditions, a notably high yield of 60.43% ± 1.12% for PMZL was achieved, which was significantly higher (p < 0.01) than from plain-grown varieties. PMZL are naturally occurring sulfated polysaccharide-protein complexes containing 8.46% ± 0.18% proteins and 7.86% ± 0.73% sulfates. PMZL comprises mannose, glucosamine, rhamnose, glucose, galactose, and arabinose at molar ratios of 3.80:2.68:1.00:17.41:5.12:2.91, with a weight-average molecular weight of 1569,219 Da and a number-average molecular weight of 364,088 Da. The surface morphology of PMZL is composed of tightly packed oval particles, and this kind of promising polysaccharides preferentially scavenges reactive nitrogen species. PRACTICAL APPLICATION: Due to global warming, the land available for planting vegetables is likely to expand to higher areas, so greater attention should now be paid to mountain-grown vegetables. This study provides an efficient way to obtain novel polysaccharides from mountain Zizania latifolia using microwave-assisted enzymatic extraction with a remarkably high yield of 60.4%. This promising source of natural carbohydrates has potential uses in pharmaceutical, nutraceutical, functional foods, cosmetics, and functional materials industries.

The dominant collagen of the cartilaginous matrix in adults is type II collagen. The amount of type II collagen in the intercellular matrix of cartilage is significantly reduced against the background of musculoskeletal system diseases. The basis of articular cartilage is hyaline cartilage tissue consisting of chondrocytes with tissue-specific antigens that induce the production of antibodies in patients with osteoarthritis (OA). Today, new approaches are being considered in the treatment of OA with the use of udenatured type II collagen (UC-II). Such molecular mechanisms of action of UC-II as the formation of a systemic response through oral tolerance are discussed, since the induction of tolerance is the immune pathway, by default, in the intestine. A number of experimental, preclinical (on volunteers) and clinical studies have shown the effectiveness and safety of the use of UC-II in OA. Standardized extracts of UC-II exhibit anti-inflammatory, immunoregulatory, chondroprotective effects, contributing to the reduction of pain symptoms of OA. Against the background of taking UC-II with induced OA, there is a statistically significant decrease in the level of proinflammatory cytokines, such as interleukin (IL-1β, IL-6), tumor necrosis factor alpha (TNF), C-reactive protein (CRP) in serum and the level of max proteinases (MMP-3), nucleated factor «kappa-bi» (NF-κB) in the knee joint. UC-II significantly inhibits the production of prostaglandin E2 (by 20%) and the expression of genes encoding proinflammatory proteins. In experimental models and in OA patients, a decrease in the severity of pain syndrome, an increase in endurance, mobility and an improvement in the functional state of the joints were noted. Clinically, no changes in the structure of the muscle fiber were detected with increased physical exertion. With OA on the background of UC-II (10-40 mg/s), there was a statistically significant decrease in joint pain according to WOMAC. A promising direction of OA therapy is the combination of UC-II with chondroitin sulfate and glucosamine sulfate.

Chitin and chitosan are abundant unique sources of biologically-fixed nitrogen mainly derived from residues of the fishery productive chain. Their high potential as nitrogen-based highly added-value platform molecules is still largely unexploited and a catalytic way for their valorization would be strongly desirable within a biorefinery concept. Here we report our results obtained with a series of heterogeneous catalysts in the depolymerization of chitosan and chitin to acetylglucosamine. Copper catalysts supported on SiO2, SiO2-Al2O3, SiO2-ZrO2, ZrO2 and the corresponding bare oxides/mixed oxides were tested, together with a sulfated zirconia system (ZrO2-SO3H) that revealed to be extremely selective towards glucosamine, both for chitosan and chitin, thus giving pretty high yields with respect to the values reported so far (44% and 21%, respectively). The use of a heterogeneous catalyst alone, without the need of any additives or the combination with a mineral acid, makes these results remarkable.

Glycosaminoglycans (GAGs) are long, linear polysaccharides that are ubiquitously expressed on the cell surface and in the extracellular matrix of all animal cells. These complex carbohydrates are composed of alternating glucosamine and uronic acids that can be heterogeneously N- and O-sulfated. The arrangement and orientation of the sulfated sugar residues specify the location of distinct ligand binding sites on the cell surface, and their capacity to bind ligands impacts cell growth and development, the ability to form tissues and organs, and normal physiology. The heterogeneous nature of GAGs and their inherent structural diversity across different tissues, cell types, and disease states creates challenges to characterizing their structure and function. Here, we describe detailed methods to investigate GAG-protein interactions in vitro and evaluate the structural composition of two classes of sulfated GAGs, heparan sulfate and chondroitin/dermatan sulfate, using liquid chromatography, mass spectrometry, and radiolabeling techniques. Overall, these methods facilitate the evaluation of GAG structure and function to uncover the unique roles these molecules play in cell biology and human disease.

Of undoubted interest is the search for new drugs comparable in effectiveness to nonsteroidal anti-inflammatory drugs (NSAIDs), but with a safer application profile. NSAIDs are characterized by a good analgesic effect due to the modulation of prostaglandin metabolism by inhibition of cyclooxygenase-2. One of the promising directions of pharmacotherapy of degenerative-dystrophic joint lesions is the use of symptom-modifying drugs of delayed action, which include chondroitin sulfate (CS). CS has antiresorptive activity, anti-inflammatory and anti-inflamaging effects. In addition to the direct effect on pain syndrome severity, he also have a modulating level effect of systemic inflammation of cartilage tissue. According to experts of international and Russian societies, pharmaceutical prescription-quality CS is a basic part of the treatment of osteoarthritis. One of the advantages of CS over NSAIDs is the preservation of the effect for 24 months after the treatment. Against the background of the use of CS, it is possible to reduce the dose or completely cancel NSAIDs, which helps to reduce the frequency of adverse events associated with their intake. CS has a favorable safety profile, which is important for elderly patients and those with comorbid diseases (cardioprotective effects). CS drugs can be administered per orally, intramuscularly, intra-articularly and in combination with different administration methods. Several clinical trials of CS (Chondrogard), including randomized, were conducted in Russia. The Russia Health Ministry approved the appointment of parenteral CS in clinical guidelines: Chronic pain in elderly and senile patients (2020), Falls in elderly and senile patients(2020), "Knee osteoarthritis" (2021), "Hip osteoarthritis" (2021).

Glycoproteins carrying O-linked N-acetylgalactosamine, N-acetylglucosamine, mannose, fucose, glucose, and xylose are found in the nervous system. Lipids are glycosylated by distinct glycosylation enzymes as well. Membrane lipid, ceramide, is modified by the addition of either glucose or galactose to form glycosphingolipid, galactosylceramide, or glucosylceramide. Recent careful analyses by MS have identified glucosylated lipids of cholesterol and phosphatidic acid. These O-linked carbohydrate residues are found primarily on the outer surface of the plasma membrane or in the extracellular space. Their expression is cell or tissue specific and developmentally regulated. Due to their structural diversity, they play important roles in a variety of biological processes such as membrane transport, metabolic stress responses, cell-cell interactions and so on. Discoveries of human diseases associated with glycosylation enzyme deficits have proved modification of lipids and proteins with carbohydrates play critical roles in human health and disease in the nervous systems.

Jellyfishes are considered a new potential resource in food, pharmaceutical and biomedical industries. In these latter cases, they are studied as source of active principles but are also exploited to produce marine collagen. In the present work, jellyfish skin polysaccharides (JSP) with glycosaminoglycan (GAG) features were extracted from Rhizostoma pulmo, a main blooming species of Mediterranean Sea, massively augmented by climate leaded "jellyfishication" of the sea. Two main fractions of R. pulmo JSP (RP-JSPs) were isolated and characterized, namely a neutral fraction (RP-JSP1) and a sulphate rich, negatively charged fraction (RP-JSP2). The two fractions have average molecular weights of 121 kDa and 590 kDa, respectively. Their sugar composition was evaluated through LC-MS analysis and the result confirmed the presence of typical GAG saccharides, such as glucose, galactose, glucosamine and galactosamine. Their use as promoters of wound healing was evaluated through in vitro scratch assay on murine fibroblast cell line (BALB/3T3 clone A31) and human keratinocytes (HaCaT). Both RP-JSPs demonstrated an effective confluency rate activity leading to 80% of scratch repair in two days, promoting both cell migration and proliferation. Additionally, RP-JSPs exerted a substantial protection from oxidative stress, resulting in improved viability of treated fibroblasts exposed to H2O2. The isolated GAG-like polysaccharides appear promising as functional component for biomedical skin treatments, as well as for future exploitation as pharmaceutical excipients.

Objective: The objective of this study is to evaluate the cost-effectiveness of different knee OA care sequences compared to standard treatment reimbursed by the major health insurance payer in Thailand. Method: We used decision analytical modeling to evaluate the effect of either adding etoricoxib or crystalline glucosamine sulfate compared to standard treatment from a societal perspective over patients' lifetimes. Data were analyzed based on efficacy, whereas adverse events were considered as a substate. Model input data were retrieved from relevant published literature and the Standard Cost Lists for Health Technology Assessment, Thailand. All health outcomes were measured in a unit of quality-adjusted life-year (QALY). An incremental cost-effectiveness ratio (ICER) was applied to examine the costs and QALYs. Sensitivity analysis was performed to investigate the robustness of the model. Result: The results demonstrated that adding crystalline glucosamine sulfate (before diclofenac plus proton pump inhibitors, PPI) into the standard care sequence was a dominant strategy compared to the standard care sequence. Adding etoricoxib alone or including crystalline glucosamine sulfate (after diclofenac plus PPI) was dominated by adding crystalline glucosamine sulfate (before diclofenac plus PPI), whereas in a willingness-to-pay (WTP) threshold in Thailand, adding of both crystalline glucosamine sulfate (before diclofenac plus PPI) and etoricoxib were cost-effective when compared to adding crystalline glucosamine sulfate alone with ICER of 125,547 Thai baht/QALY (3,472 US dollars/QALY). Conclusion: The addition of crystalline glucosamine sulfate and etoricoxib into standard knee OA treatment were cost-effective at the WTP threshold in Thailand. In addition, early initiation of crystalline glucosamine sulfate would be less costly and more effective than delayed treatment or the use of standard treatment alone.

Heparan sulfate (HS) has multifaceted biological activities. To date, no libraries of HS oligosaccharides bearing systematically varied sulfation structures are available owing to the challenges in synthesizing a large number of HS oligosaccharides. To overcome the obstacles and expedite the synthesis, a divergent approach was designed, where 64 HS tetrasaccharides covering all possible structures of 2-O-, 6-O- and N-sulfation with the glucosamine-glucuronic acid-glucosamine-iduronic acid backbone were successfully produced from a single strategically protected tetrasaccharide intermediate. This extensive library helped identify the structural requirements for HS sequences to have strong fibroblast growth factor-2 binding but a weak affinity for platelet factor-4. Such a strategy to separate out these two interactions could lead to new HS-based potential therapeutics without the dangerous adverse effect of heparin-induced thrombocytopenia.

The glycocalyx attached to the apical surface of vascular endothelial cells is a rich network of proteoglycans, glycosaminoglycans, and glycoproteins with instrumental roles in vascular homeostasis. Given their molecular complexity and ability to interact with the intra- and extracellular environment, heparan sulfate proteoglycans uniquely contribute to the glycocalyx's role in regulating endothelial permeability, mechanosignaling, and ligand recognition by cognate cell surface receptors. Much attention has recently been devoted to the enzymatic shedding of heparan sulfate proteoglycans from the endothelial glycocalyx and its impact on vascular function. However, other molecular modifications to heparan sulfate proteoglycans are possible and may have equal or complementary clinical significance. In this narrative review, we focus on putative mechanisms driving non-proteolytic changes in heparan sulfate proteoglycan expression and alterations in the sulfation of heparan sulfate side chains within the endothelial glycocalyx. We then discuss how these specific changes to the endothelial glycocalyx impact endothelial cell function and highlight therapeutic strategies to target or potentially reverse these pathologic changes.

Myelodysplastic syndromes (MDS) comprise a heterogeneous group of hematologic malignancies characterized by clonal hematopoiesis, one or more cytopenias such as anemia, neutropenia, or thrombocytopenia, abnormal cellular maturation, and a high risk of progression to acute myeloid leukemia. The bone marrow microenvironment (BMME) in general and mesenchymal stromal cells (MSCs) in particular contribute to both the initiation and progression of MDS. However, little is known about the role of MSC-derived extracellular matrix (ECM) in this context. Therefore, we performed a comparative analysis of in vitro deposited MSC-derived ECM of different MDS subtypes and healthy controls. Atomic force microscopy analyses demonstrated that MDS ECM was significantly thicker and more compliant than those from healthy MSCs. Scanning electron microscopy showed a dense meshwork of fibrillar bundles connected by numerous smaller structures that span the distance between fibers in MDS ECM. Glycosaminoglycan (GAG) structures were detectable at high abundance in MDS ECM as white, sponge-like arrays on top of the fibrillar network. Quantification by Blyscan assay confirmed these observations, with higher concentrations of sulfated GAGs in MDS ECM. Fluorescent lectin staining with wheat germ agglutinin and peanut agglutinin demonstrated increased deposition of N-acetyl-glucosamine GAGs (hyaluronan (HA) and heparan sulfate) in low risk (LR) MDS ECM. Differential expression of N-acetyl-galactosamine GAGs (chondroitin sulfate, dermatan sulfate) was observed between LR- and high risk (HR)-MDS. Moreover, increased amounts of HA in the matrix of MSCs from LR-MDS patients were found to correlate with enhanced HA synthase 1 mRNA expression in these cells. Stimulation of mononuclear cells from healthy donors with low molecular weight HA resulted in an increased expression of various pro-inflammatory cytokines suggesting a contribution of the ECM to the inflammatory BMME typical of LR-MDS. CD34+ hematopoietic stem and progenitor cells (HSPCs) displayed an impaired differentiation potential after cultivation on MDS ECM and modified morphology accompanied by decreased integrin expression which mediate cell-matrix interaction. In summary, we provide evidence for structural alterations of the MSC-derived ECM in both LR- and HR-MDS. GAGs may play an important role in this remodeling processes during the malignant transformation which leads to the observed disturbance in the support of normal hematopoiesis.

Sulodexide (SDX), a purified glycosaminoglycan mixture used to treat vascular diseases, has been reported to exert endothelial protective effects against ischemic injury. However, the mechanisms underlying these effects remain to be fully elucidated. The emerging evidence indicated that a relatively high intracellular concentration of reduced glutathione (GSH) and a maintenance of the redox environment participate in the endothelial cell survival during ischemia. Therefore, the aim of the present study was to examine the hypothesis that SDX alleviates oxygen-glucose deprivation (OGD)-induced human umbilical endothelial cells' (HUVECs) injury, which serves as the in vitro model of ischemia, by affecting the redox state of the GSH: glutathione disulfide (GSSG) pool. The cellular GSH, GSSG and total glutathione (tGSH) concentrations were measured by colorimetric method and the redox potential (ΔEh) of the GSSG/2GSH couple was calculated, using the Nernst equation. Furthermore, the levels of the glutamate-cysteine ligase catalytic subunit (GCLc) and the glutathione synthetase (GSS) proteins, a key enzyme for de novo GSH synthesis, were determined using enzyme-linked immunoassay (ELISA). We demonstrated that the SDX treatment in OGD conditions significantly elevated the intracellular GSH, enhanced the GSH:GSSG ratio, shifting the redox potential to a more pro-reducing status. Furthermore, SDX increased the levels of both GCLc and GSS. The results show that SDX protects the human endothelial cells against ischemic stress by affecting the GSH levels and cellular redox state. These changes suggest that the reduction in the ischemia-induced vascular endothelial cell injury through repressing apoptosis and oxidative stress associated with SDX treatment may be due to an increase in GSH synthesis and modulation of the GSH redox system.

Glucosamine sulfate is an oral supplement used in the management and treatment of osteoarthritis. This activity outlines the indications, hypothesized action, and contraindications for glucosamine sulfate as a valuable agent in managing osteoarthritis. This activity will highlight the hypothesized mechanism of action, adverse event profile, suggested dosing, monitoring for relevant interactions, and other key elements of glucosamine sulfate supplementation in the clinical setting pertinent for members of an interprofessional team managing the care of patients with osteoarthritis.

Glucosamine and chondroitin sulfate have been used as nutritional supplementation for joint tissues and osteoarthritis (OA). Biofermented glucosamine is of great interest in the supplement industry as an alternative source of glucosamine. The purpose of this study is to compare the pharmacokinetics of chitosan-derived glucosamine and biofermentation-derived glucosamine as nutritional supplementation. In a randomized, double-blind and cross-over study design, we recruited subjects of healthy men and women. The pharmacokinetics of glucosamine were examined after a single dose of glucosamine sulfate 2KCl (1500 mg) with two different sources of glucosamine (chitosan-derived glucosamine and biofermentation-derived glucosamine) to male and female subjects fitted with intravenous (iv) catheters for repeated blood sampling up to 8 h. According to plasma concentration-time curve of glucosamine after an oral administration of 1500 mg of glucosamine sulfate 2KCl, AUC0-8h and AUC0-∞ values of glucosamine following oral administration of chitosan-derived and biofermentation-derived glucosamine formulations were within the bioequivalence criteria (90% CI of ratios are within 0.8-1.25). The mean Cmax ratios for these two formulations (90% CI of 0.892-1.342) did not meet bioequivalence criteria due to high within-subject variability. There were no statistically significant effects of sequence, period, origin of glucosamine on pharmacokinetic parameters of glucosamine such as AUC0-8h, AUC0-∞, Cmax. Our findings suggest that biofermentation-derived glucosamine could be a sustainable source of raw materials for glucosamine supplement.

The extracellular human endo-6-O-sulfatases (Sulf-1 and Sulf-2) are responsible for the endolytic cleavage of the 6-sulfate groups from the internal D-glucosamine residues in the highly sulfated subdomains of heparan sulfate proteoglycans. A trisaccharide sulfate, IdoA2OS-GlcNS6S-IdoA2OS, was identified as the minimal size of substrate for Sulf-1. In order to study the complex structure with Sulf-1 for developing potential drugs, two trisaccharide analogs, IdoA2OS-GlcNS6OSO2NH2-IdoA2OS-OMe and IdoA2OS-GlcNS6NS-IdoA2OS-OMe, were rationally designed and synthesized as the Sulf-1 inhibitors with IC50 values at 0.27 and 4.6 μM, respectively.