Mechanistic and therapeutic overview of glycosaminoglycans: the unsung heroes of biomolecular signaling

Gulati, Khushboo; Poluri, Krishna Mohan

doi:10.1007/s10719-015-9642-2

Cited by 54 publications

(33 citation statements)

References 233 publications

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“…GAG chains are diverse and are known to play a role in inflammation; however, the complexities underlying how GAGs lead to inflammation in disease settings remains poorly understood. To date, there are four families of GAG typically described; long chain sugars containing repeating disaccharide units of amino sugars and uronic acids (Taylor and Gallo ; Gulati and Poluri ). These four families include HS/heparin, CS/DS, KS and HA.…”

Section: Glycosaminoglycans and Their Role In Mpsmentioning

confidence: 99%

The role of innate immunity in mucopolysaccharide diseases

Parker

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2018

Journal of Neurochemistry

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Mucopolysaccharidoses are lysosomal storage disorders characterised by accumulation of abnormal pathological glycosaminoglycans, cellular dysfunction and widespread inflammation, resulting in progressive cognitive and motor decline. Lysosomes are important mediators of immune cell function, and therefore accumulation of glycosaminoglycans (GAGs) and other abnormal substrates could affect immune function and directly impact on disease pathogenesis. This review summarises current knowledge with regard to inflammation in mucopolysaccharidosis, with an emphasis on the brain and outlines a potential role for GAGs in induction of inflammation. We propose a model by which the accumulation of GAGs and other factors may impact on innate immune signalling with particular focus on the Toll‐like receptor 4 pathway. Innate immunity appears to have a dominating role in mucopolysaccharidosis; however, furthering understanding of innate immune signalling would have significant impact on highlighting novel anti‐inflammatory therapeutics for use in mucopolysaccharide diseases. https://onlinelibrary.wiley.com/page/journal/14714159/homepage/virtual_issues.htm.

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Section: Glycosaminoglycans and Their Role In Mpsmentioning

confidence: 99%

The role of innate immunity in mucopolysaccharide diseases

Parker

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2018

Journal of Neurochemistry

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“…At the pathway level, we have identified a specific association between PsA and the GAG metabolism pathway. GAGs are linear, negatively charged oligosaccharides that include hyaluronic acid (HA), chondroitin sulfate and keratan sulfate (KS) 55. Of relevance, GAGs are crucial components of proteoglycans and the major component of the cartilage, which is the main target tissue of PsA inflammatory destruction 56 57.…”

Section: Discussionmentioning

confidence: 99%

Genetic variation at the glycosaminoglycan metabolism pathway contributes to the risk of psoriatic arthritis but not psoriasis

et al. 2018

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ObjectivePsoriatic arthritis (PsA) is a chronic inflammatory arthritis affecting up to 30% of patients with psoriasis (Ps). To date, most of the known risk loci for PsA are shared with Ps, and identifying disease-specific variation has proven very challenging. The objective of the present study was to identify genetic variation specific for PsA.MethodsWe performed a genome-wide association study in a cohort of 835 patients with PsA and 1558 controls from Spain. Genetic association was tested at the single marker level and at the pathway level. Meta-analysis was performed with a case–control cohort of 2847 individuals from North America. To confirm the specificity of the genetic associations with PsA, we tested the associated variation using a purely cutaneous psoriasis cohort (PsC, n=614) and a rheumatoid arthritis cohort (RA, n=1191). Using network and drug-repurposing analyses, we further investigated the potential of the PsA-specific associations to guide the development of new drugs in PsA.ResultsWe identified a new PsA risk single-nucleotide polymorphism at B3GNT2 locus (p=1.10e-08). At the pathway level, we found 14 genetic pathways significantly associated with PsA (pFDR<0.05). From these, the glycosaminoglycan (GAG) metabolism pathway was confirmed to be disease-specific after comparing the PsA cohort with the cohorts of patients with PsC and RA. Finally, we identified candidate drug targets in the GAG metabolism pathway as well as new PsA indications for approved drugs.ConclusionThese findings provide insights into the biological mechanisms that are specific for PsA and could contribute to develop more effective therapies.

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“…It is synthesized as a single polypeptide chain of about 51 kDa mainly in the liver but also in macrophages and epithelial cells [ 39 ]. Deficiency of this protein is associated with many liver diseases such as neonatal hepatitis [ 40 ], cirrhosis and hepatoma [ 41 ]. Finally, this protein is considered a potential biomarker for hepatitis B virus infection [ 42 ].…”

Section: Discussionmentioning

confidence: 99%

Identification of Candidate Serum Biomarkers for Schistosoma mansoni Infected Mice Using Multiple Proteomic Platforms

2016

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BackgroundSchistosomiasis is an important helminth infection of humans. There are few reliable diagnostic biomarkers for early infection, for recurrent infection or to document successful treatment. In this study, we compared serum protein profiles in uninfected and infected mice to identify disease stage-specific biomarkers.MethodsSerum collected from CD1 mice infected with 50–200 Schistosoma mansoni cercariae were analyzed before infection and at 3, 6 and 12 weeks post-infection using three mass spectrometric (MS) platforms.ResultsUsing SELDI-TOF MS, 66 discriminating m/z peaks were detected between S. mansoni infected mice and healthy controls. Used in various combinations, these peaks could 1) reliably diagnose early-stage disease, 2) distinguish between acute and chronic infection and 3) diagnose S. mansoni infection regardless the parasite burden. The most important contributors to these diagnostic algorithms were peaks at 3.7, 13 and 46 kDa. Employing sample fractionation and differential gel electrophoresis, we analyzed gel slices either by MALDI-TOF MS or Velos Orbitrap MS. The former yielded eight differentially-expressed host proteins in the serum at different disease stages including transferrin and alpha 1- antitrypsin. The latter suggested the presence of a surprising number of parasite-origin proteins in the serum during both the acute (n = 200) and chronic (n = 105) stages. The Orbitrap platform also identified many differentially-expressed host-origin serum proteins during the acute and chronic stages (296 and 220 respectively). The presence of one of the schistosome proteins, glutathione S transferase (GST: 25 KDa), was confirmed by Western Blot. This study provides proof-of-principle for an approach that can yield a large number of novel candidate biomarkers for Schistosoma infection.

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Mechanistic and therapeutic overview of glycosaminoglycans: the unsung heroes of biomolecular signaling

Cited by 54 publications

References 233 publications

The role of innate immunity in mucopolysaccharide diseases

The role of innate immunity in mucopolysaccharide diseases

Genetic variation at the glycosaminoglycan metabolism pathway contributes to the risk of psoriatic arthritis but not psoriasis

Identification of Candidate Serum Biomarkers for Schistosoma mansoni Infected Mice Using Multiple Proteomic Platforms

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