bims-supasi Biomed News
on Sulfation pathways and signalling
Issue of 2023‒01‒22
fourteen papers selected by
Jonathan Wolf Mueller
University of Birmingham
  1. HPLC-MS Characterization of Tissue-Derived Heparan Sulfate and Chondroitin Sulfate.
  2. Immunochemical Detection and Glycosaminoglycan Disaccharide-Based Characterization of Chondroitin Sulfate Proteoglycans.
  3. Using heparan sulfate octadecasaccharide (18-mer) as a multi-target agent to protect against sepsis.
  4. Enzymatic Sequencing of Heparin Oligosaccharides Using Exolyase.
  5. A sulfated polysaccharide from Dictyosphaeria cavernosa: Structural characterization and effect on immunosuppressive recovery.
  6. An Enzymatic Activity Assay for Heparanase That Is Useful for Evaluating Clinically Relevant Inhibitors and Studying Kinetics.
  7. Exploring the pathophysiological mechanism of interstitial edema focusing on the role of macrophages and their interaction with the glycocalyx.
  8. Biomimetic chitosan nanoparticles with simultaneous water lubricant and anti-inflammatory.
  9. Glycosyltransferase Extl1 promotes CCR7-mediated dendritic cell migration to restrain infection and autoimmunity.
  10. Endogenous dehydroepiandrosterone and depression in postmenopausal women: a systematic review of observational studies.
  11. Structure-function relationships of pectic polysaccharides from broccoli by-products with in vitro B lymphocyte stimulatory activity.
  12. Marmesin and Marmelosin Interact with the Heparan Sulfatase-2 Active Site: Potential Mechanism for Phytochemicals from Bael Fruit Extract as Antitumor Therapeutics.
  13. Genetic variations in OLR1 gene associated with PCOS and atherosclerotic risk factors.
  14. The development of multifunctional sulfated polyguluronic acid-based polymeric micelles for anticancer drug delivery.
  1. Methods Mol Biol. 2023 ;2619 71-90
    HPLC-MS Characterization of Tissue-Derived Heparan Sulfate and Chondroitin Sulfate.
    Gábor Tóth, Lilla Turiák.
      Glycosaminoglycans (GAGs) are built up of repeating disaccharide units resulting in long, linear polysaccharide chains. In most classes of GAGs, sulfation and epimerization complicate the structure of the chain and influence biochemical functions. The most widespread way of their investigation by instrumental analytical techniques is to degrade them into the constituent disaccharide building blocks, followed by capillary electrophoresis or high-performance liquid chromatography (HPLC) separation. The analysis of GAG disaccharides with varying sulfation degrees poses a real challenge both from chromatographic and mass spectrometric (MS) points of view. This necessitates the constant improvement of their analytical methodology. In this chapter, an optimized workflow will be discussed for the sample preparation and subsequent HPLC-MS characterization of tissue-derived chondroitin sulfate and heparan sulfate.
    Keywords:  Chondroitin sulfate; Digestion; GAG; Glycosaminoglycan; HPLC; HPLC-MS; Heparan sulfate; Purification; Solid-phase extraction; Tissue
    DOI:  https://doi.org/10.1007/978-1-0716-2946-8_6
  2. Methods Mol Biol. 2023 ;2619 25-38
    Immunochemical Detection and Glycosaminoglycan Disaccharide-Based Characterization of Chondroitin Sulfate Proteoglycans.
    Tadahisa Mikami, Hiroshi Kitagawa.
      Chondroitin sulfate proteoglycans (CSPGs) are polyanionic extra/pericellular matrix macromolecules that surround almost all cell types and create microenvironmental niches to support miscellaneous cellular events. In general, the multifunctional properties of CSPGs are attributable to the structural divergence of the CS glycosaminoglycan (GAG) moieties. Because the expression profiles of the GAG chains of CSPGs change with developmental stage, aging, and disease progression, characterization of the GAG chains is essential to understand the functional roles of CSPGs. This chapter describes the basic protocols for GAG moiety-based immunochemical detection of CSPGs in biological samples in conjunction with CS disaccharide composition analysis.
    Keywords:  Chondroitin sulfate; Chondroitinase; Disaccharide composition; Immunocytochemistry; Immunohistochemistry; Proteoglycan; Sulfation pattern; Unsaturated disaccharide neoepitope
    DOI:  https://doi.org/10.1007/978-1-0716-2946-8_2
  3. Proc Natl Acad Sci U S A. 2023 Jan 24. 120(4): e2209528120
    Using heparan sulfate octadecasaccharide (18-mer) as a multi-target agent to protect against sepsis.
    Yi-En Liao, Yongmei Xu, Katelyn Arnold, Fuming Zhang, Jine Li, Rani Sellers, Chaoyin Yin, Vijayakanth Pagadala, Anna Marie Inman, Robert J Linhardt, Ding Xu, Rafal Pawlinski, Jian Liu.
      Sepsis is a lethal syndrome manifested by an unregulated, overwhelming inflammation from the host in response to infection. Here, we exploit the use of a synthetic heparan sulfate octadecasaccharide (18-mer) to protect against sepsis. The 18-mer not only inhibits the pro-inflammatory activity of extracellular histone H3 and high mobility group box 1 (HMGB1), but also elicits the anti-inflammatory effect from apolipoprotein A-I (ApoA-I). We demonstrate that the 18-mer protects against sepsis-related injury and improves survival in cecal ligation and puncture mice and reduces inflammation in an endotoxemia mouse model. The 18-mer neutralizes the cytotoxic histone-3 (H3) through direct interaction with the protein. Furthermore, the 18-mer enlists the actions of ApoA-I to dissociate the complex of HMGB1 and lipopolysaccharide, a toxic complex contributing to cell death and tissue damage in sepsis. Our study provides strong evidence that the 18-mer mitigates inflammatory damage in sepsis by targeting numerous mediators, setting it apart from other potential therapies with a single target.
    Keywords:  HDL; HMGB1; heparin; histone; sepsis
    DOI:  https://doi.org/10.1073/pnas.2209528120
  4. Methods Mol Biol. 2023 ;2619 249-256
    Enzymatic Sequencing of Heparin Oligosaccharides Using Exolyase.
    Qingdong Zhang, Danrong Lu, Fuchuan Li.
      Heparin/heparan sulfate (HP/HS) is a class of acidic polysaccharides with many potential medical applications, especially HP, and its derivatives, low molecular weight heparins (LMWHs), have been widely used as anticoagulants to treat thrombosis for decades. However, the complex structure endows HP/HS a variety of biological functions and hinders the structural and functional studies of HP/HS. Heparinases derived from bacteria are useful tools for the structural studies of HP/HS as well as the preparation of LMWHs. The enzymatic method for the structural analysis of HP/HS chains is easy to operate, requires less samples, and is low cost. Here, we describe an enzymatic approach to investigate the primary sequences of the HP/HS oligosaccharides using a recently discovered exotype heparinase.
    Keywords:  Enzymatic sequencing; Exotype heparinase; Heparan sulfate; Heparin; Oligosaccharides
    DOI:  https://doi.org/10.1007/978-1-0716-2946-8_18
  5. Int J Biol Macromol. 2023 Jan 17. pii: S0141-8130(23)00193-9. [Epub ahead of print] 123311
    A sulfated polysaccharide from Dictyosphaeria cavernosa: Structural characterization and effect on immunosuppressive recovery.
    Yajing Yang, Ling Qin, Yu Wu, Shan Liu, Xiaoxi He, Wenjun Mao.
      A homogeneous sulfated polysaccharide DCS1 was obtained from Dictyosphaeria cavernosa by alkali extraction and chromatography purification. On the basis of chemical and spectroscopic analyses, DCS1 was a novel mannan-type sulfated polysaccharide and had a molecular weight of 15.48 kDa. DCS1 consisted of a main chain of (1 → 4)-α-d-Manp units with partial sulfate substitution at C-2 and branches at C-2/C-6. DCS1 possessed a potent immune-enhancing effect in vitro evaluated by the assays of lymphocytes proliferation and macrophage phagocytosis. The immunomodulatory effect of DCS1 in vivo was further investigated using immunosuppressed mice induced by cyclophosphamide (Cy). The data showed that DCS1 markedly increased the spleen and thymus indexes, and ameliorated the Cy-induced damage to spleen and thymus. Moreover, DCS1 had a significant effect on hematopoietic function recovery, and promoted the secretion of the interleukin-2 and tumor necrosis factor-α. Notably, DCS1 reversed the reduction of CD4+ T cells, improved the disorder of CD4+/CD8+ T cells and enhanced the immune response. The investigation demonstrated that the sulfated polysaccharide DCS1 with novel structure could be a hopeful immunomodulatory agent.
    Keywords:  Dictyosphaeria cavernosa; Immunomodulatory activity; Structural characterization; Sulfated polysaccharide
    DOI:  https://doi.org/10.1016/j.ijbiomac.2023.123311
  6. Methods Mol Biol. 2023 ;2619 227-238
    An Enzymatic Activity Assay for Heparanase That Is Useful for Evaluating Clinically Relevant Inhibitors and Studying Kinetics.
    Edward Hammond, Vito Ferro.
      The enzyme heparanase cleaves heparan sulfate and is involved in a range of human diseases including cancer, inflammation, diabetes, and viral infection. There is a need for a simple and reliable enzymatic assay to allow for the screening of compounds to find inhibitors of heparanase. We have developed an assay that uses the heparinoid fondaparinux as enzyme substrate and detects one of the products of catalysis, which contains a newly formed reducing terminus, with the tetrazolium salt WST-1. Due to the homogenous substrate and single point of cleavage therein, this assay allows for more systematic kinetic analysis of heparanase inhibitors. Here, we provide a detailed method for conducting this assay and also provide information to assist researchers in evaluating whether the assay is performing properly in their laboratories.
    Keywords:  Cancer; Fondaparinux; Glycosidase; Heparan sulfate; Heparanase; Inflammation; Inhibition; Kinetics
    DOI:  https://doi.org/10.1007/978-1-0716-2946-8_16
  7. J Oral Biosci. 2023 Jan 11. pii: S1349-0079(23)00001-4. [Epub ahead of print]
    Exploring the pathophysiological mechanism of interstitial edema focusing on the role of macrophages and their interaction with the glycocalyx.
    Rie Nishida, Dai Suzuki, Yoshihiro Akimoto, Sachie Matsubara, Junri Hayakawa, Akira Ushiyama, Kiyohito Sasa, Yoichi Miyamoto, Takehiko Iijima, Ryutaro Kamijo.
      OBJECTIVES: Glycocalyx covers the intraluminal space of vascular architects that regulate fluid movement between intra- and extra-vascular space. The depletion of the GCX is associated with leukocyte accumulation, possibly causing the endothelial cells to become hyperpermeable in various organs including oral tissues. Whether neutrophils or macrophages are responsible for the development of interstitial edema remains controversial. We explored the pathophysiological mechanism of interstitial edema by examining the role of responsive neutrophils and macrophages and their interactions with the GCX.METHODS: Anti-MHC class I antibody was administered intravenously to male BALB/c mice to induce pulmonary edema. Pulmonary edema was evaluated by measuring the wet-to-dry weight ratio of the lungs. Changes in the GCX were evaluated by electron microscopy and measurements of the serum level of soluble syndecan-1. Heparin sulphate was administered to examine its protective effect on the GCX. Macrophages were depleted using clodronate to examine their role in the development of the edema.
    RESULTS: The GCX degradation induced by an anti-MHC class I antibody, accompanied by an increase in the serum syndecan-1 and heparan sulfate levels. Macrophage depletion inhibited the development of pulmonary edema, and the administration of supplemental heparin suppressed the edema.
    CONCLUSIONS: We demonstrated that the degradation of GCX induced by anti-MHC class I antibody was suppressed by macrophage depletion. These results suggest that macrophages may play a key role in interstitial edema. Heparin inhibited both the degradation of the GCX and interstial edema. Our study may extrapolate an interventional mechanism for inhibiting interstitial edema in various organs.
    Keywords:  Anti-MHC type I antibody; Glycocalyx; Interstitial edema; Macrophage
    DOI:  https://doi.org/10.1016/j.job.2023.01.001
  8. Carbohydr Polym. 2023 Mar 15. pii: S0144-8617(22)01408-4. [Epub ahead of print]304 120503
    Biomimetic chitosan nanoparticles with simultaneous water lubricant and anti-inflammatory.
    Lumin Yang, Haofei Huang, Huajing Zeng, Xiaoduo Zhao, Rui Wang, Zhengfeng Ma, Zengjie Fan, Yong-Min Liang, Shuanhong Ma, Feng Zhou.
      Rheumatoid arthritis (RA) is a chronic inflammatory immune and lubrication dysfunction disease that causes great damage to the joints. Herein, inspired by the unique biochemistry structure and excellent hydration of chondroitin sulfate (CHI) existing in joint system, one kind of novel polysaccharide nanoparticle lubricant, that is chitosan nanoparticles (CS NPs) grafting CHI (CS-CHI), is synthesized by one-step surface chemistry reaction. CHI with negative charges can form hydration layers on the surface of CS NPs, thus improving the lubricity of nanoparticles. Simultaneously, CS-CHI NPs have effective loading and sustained drug release ability for anti-inflammatory drug diclofenac sodium (DS), along with good biocompatibility. Finally, based on a collagen-induced rat RA model, in vitro animals experimental results indicate that the as-synthesized CS-CHI@DS NPs has obvious inhibitory effects on inflammatory factors and can effectively prevent the damaged cartilage from further destruction.
    Keywords:  Arthritis treatment; Chitosan/chondroitin sulfate; Nanoparticles; Polysaccharide; Water lubrication
    DOI:  https://doi.org/10.1016/j.carbpol.2022.120503
  9. Cell Rep. 2023 Jan 18. pii: S2211-1247(23)00002-5. [Epub ahead of print]42(1): 111991
    Glycosyltransferase Extl1 promotes CCR7-mediated dendritic cell migration to restrain infection and autoimmunity.
    Juan Liu, Yujie Cheng, Xiaomin Zhang, Yali Chen, Ha Zhu, Kun Chen, Shuxun Liu, Zhiqing Li, Xuetao Cao.
      CCR7-triggered DC migration toward draining lymph nodes is critical for the initiation of protective immunity and maintenance of immune tolerance. How to promote CCR7-mediated DC migration to determine T cell responses under inflammatory and homeostatic conditions remains poorly understood. Here we demonstrate that the Extl1 (Exostosin like glycosyltransferase 1) promotes CCR7-triggered DC migration in a heparan sulfate proteoglycans (HSPG)-dependent manner. Mechanistically, Extl1 mediates HSPG production via its glycosyltransferase domain to inhibit C1q expression. Extl1/HSPG axis relieves C1q-mediated restriction of CCR7 surface expression and internalization, and thus enhances CCR7-dependent migratory signaling activation. Consequently, Extl1 is required for DC-mediated Th1 and Th17 responses in immune defense against bacterial infection and for Treg cell development in the prevention of autoimmunity. Our study adds mechanistic insights to the regulation of CCR7-triggered DC migration in immunity and tolerance and provides a potential target for the treatment of infectious and autoimmune diseases.
    Keywords:  CCR7; CP: Immunology; Exostosin like glycosyltransferase 1; autoimmunity; bacterial infection; complement C1q; dendritic cell migration; heparan sulfate proteoglycans; immune defense; immune tolerance; inflammation
    DOI:  https://doi.org/10.1016/j.celrep.2023.111991
  10. Menopause. 2023 Jan 17.
    Endogenous dehydroepiandrosterone and depression in postmenopausal women: a systematic review of observational studies.
    Chandima Hemachandra, Susan R Davis, Robin J Bell, Farhana Sultana, Rakibul M Islam.
      IMPORTANCE: The associations between endogenous dehydroepiandrosterone (DHEA) and DHEA sulfate (DHEAS), and depression in older women are uncertain. However, DHEA supplements are widely available over the counter in some countries, and some people may be taking DHEA with the hope of positive mood effects.OBJECTIVE: This systematic review aimed to investigate the association between endogenous DHEA/DHEAS blood concentrations and depression/depressive symptoms in community-dwelling postmenopausal women.
    EVIDENCE REVIEW: Searches were conducted in Ovid MEDLINE, EMBASE, PsycINFO, and Web of Science databases for observational studies with at least 100 community-dwelling participants until March 9, 2022. The bibliographies of retrieved articles were manually searched. The studies published in English and meeting the inclusion criteria were included in the review. The risk of bias was assessed with the modified Hoy tool for cross-sectional designs and the Joanna Briggs Institute modified critical appraisal checklist for cohort studies.
    FINDINGS: Of the 30 articles retrieved for full-text review, 14 met the criteria for inclusion. Seven studies were cross-sectional, six were longitudinal, and one had both cross-sectional and longitudinal data. Five of eight cross-sectional studies found no association between DHEAS and depression, whereas three studies reported an inverse association. Similarly, most of the studies (n = 4) with longitudinal data reported no association, whereas two studies reported either an inverse association or mixed results for DHEAS and depression severity. No association between DHEA and depression was found irrespective of the study design. Heterogeneity of design was a barrier to meta-analysis and between study comparison. The majority of studies were limited by high risk of bias in at least one assessed domain.
    CONCLUSION AND RELEVANCE: This systematic review does not support an association between endogenous DHEA/DHEAS and depression in postmenopausal women.
    DOI:  https://doi.org/10.1097/GME.0000000000002142
  11. Carbohydr Polym. 2023 Mar 01. pii: S0144-8617(22)01337-6. [Epub ahead of print]303 120432
    Structure-function relationships of pectic polysaccharides from broccoli by-products with in vitro B lymphocyte stimulatory activity.
    Sónia S Ferreira, Alexandra Correia, Artur M S Silva, Dulcineia Ferreira Wessel, Susana M Cardoso, Manuel Vilanova, Manuel A Coimbra.
      To study structure-function relationships of pectic polysaccharides with their immunostimulatory activity, broccoli by-products were used. Pectic polysaccharides composed by 64 mol% uronic acids, 18 mol% Ara, and 10 mol% Gal, obtained by hot water extraction, activated B lymphocytes in vitro (25-250 μg/mL). To disclose active structural features, combinations of ethanol and chromatographic fractionation and modification of the polysaccharides were performed. Polysaccharides insoluble in 80 % ethanol (Et80) showed higher immunostimulatory activity than the pristine mixture, which was independent of molecular weight range (12-400 kDa) and removal of terminal or short Ara side chains. Chemical sulfation did not promote B lymphocyte activation. However, the action of pectin methylesterase and endo-polygalacturonase on hot water extracted polysaccharides produced an acidic fraction with a high immunostimulatory activity. The de-esterified homogalacturonan region seem to be an important core to confer pectic polysaccharides immunostimulatory activity. Therefore, agri-food by-products are a source of pectic polysaccharide functional food ingredients.
    Keywords:  Arabinogalactans; Brassica by-products; Enzyme modified pectin; Methylation analysis; NMR; Structure-function relationships; Sulfated pectic polysaccharides
    DOI:  https://doi.org/10.1016/j.carbpol.2022.120432
  12. Oxid Med Cell Longev. 2023 ;2023 9982194
    Marmesin and Marmelosin Interact with the Heparan Sulfatase-2 Active Site: Potential Mechanism for Phytochemicals from Bael Fruit Extract as Antitumor Therapeutics.
    C Hemakumar, B S Ravindranath, G A Ravishankar, D C Ramirez, S V Kiran.
      Human heparan sulfatase-2 (HSULF-2) is an oncoprotein overexpressed in the surface of all types of tumor cells and its activity plays a critical role in cancer survival and progression. Our previous studies have shown that bael fruit extract, containing marmesin and marmelosin, inhibits the HSULF-2 activity and kills breast tumor cells, but the mechanism of these processes remains fairly known mainly because the HSULF-2's 3D structure is partially known. Herein, we aimed at providing an in silico molecular mechanism of the inhibition of human HSULF-2 by phytochemicals from bael fruit extract. Pharmacokinetic parameters of the main phytochemicals contained in the bael fruit extract, sequence-based 3D structure of human HSULF-2, and the interaction of bael fruit's phytochemicals with the enzyme active site was modeled, evaluated, and verified. Docking studies revealed marmesin and marmelosin as potential inhibitors with binding score -8.5 and -7.7 Kcal/mol; these results were validated using molecular dynamics simulations, which exhibited higher stability of the protein-ligand complexes. Taking together, with our earlier in vitro data, our computational analyses suggest that marmesin and marmelosin interact at the active site of HSULF-2 providing a potential mechanism for its inhibition and consequent antitumor activity by phytochemicals contained in the bael fruit extract.
    DOI:  https://doi.org/10.1155/2023/9982194
  13. J Investig Med. 2023 Jan 16. 10815589221141831
    Genetic variations in OLR1 gene associated with PCOS and atherosclerotic risk factors.
    Serap Baydur Sahin, Ihsan Nalkiran, Teslime Ayaz, Ali Irfan Guzel, Tugba Eldes, Tugba Calapoglu, Hatice Sevim Nalkiran.
      Polycystic ovary syndrome (PCOS) is the most common endocrinopathy in women of reproductive age. The aim of this study was to investigate the association of oxidized low-density lipoprotein receptor 1 (OLR1) gene variations with the susceptibility of PCOS and to examine the relationship between the frequencies of OLR1 gene variations and atherosclerotic risk factors. Genomic DNA was extracted from blood samples collected from 49 patients with PCOS and 43 healthy controls. The variants in the OLR1 gene were identified using next-generation sequencing (NGS). Heterozygous rs11053646 (K167N), rs11611438, rs11611453, and rs35688880 genotype frequencies were significantly higher in the PCOS group than that of control group. Single nucleotide polymorphism (SNP) rs34163097 minor A allele increased the PCOS risk by ∼10-fold (p = 0.03). SNPs rs11053646, rs11611438, rs11611453, rs34163097, and rs35688880 were positively correlated with body mass index (BMI). The logistic regression model (area under the curve: 0.770, p = 0.000) further revealed a combination of 2-h plasma glucose (PG-2 h), dehydroepiandrosterone sulfate (DHEAS), and rs11053646 as predictors of PCOS phenotype. This is the first study reporting the NGS data of OLR1 gene variants which might be associated with the pathogenesis of PCOS and several atherosclerotic risk factors, particularly higher BMI and DHEAS. To fully understand the genetic basis of PCOS and the contribution of OLR1 gene variants to PCOS pathogenesis, additional large-scale studies are warranted.
    Keywords:  OLR1 gene; PCOS; atherosclerotic risk factors; next-generation sequencing; single nucleotide polymorphism; single nucleotide variation
    DOI:  https://doi.org/10.1177/10815589221141831
  14. Carbohydr Polym. 2023 Mar 01. pii: S0144-8617(22)01356-X. [Epub ahead of print]303 120451
    The development of multifunctional sulfated polyguluronic acid-based polymeric micelles for anticancer drug delivery.
    Xiaolei Qiu, Shengzhou Ma, Dingfu Wang, Zirui Fan, Peiju Qiu, Shixin Wang, Chunxia Li.
      Numerous disseminated tumor cells specifically overexpress P-selectin. Therefore, it was thought to be a potential target for tumor therapy. Herein, we described a novel P-selectin-targeted glycosyl ligand-sulfated polyguluronic acid (PGS), as an oriented carrier of P-selectin-targeted drug delivery system. Specifically, the PGS-SS-DOX polymeric micelles were constructed to confirm the practicability of the PGS carrier as a new P-selectin-targeted ligand. PGS-SS-DOX micelles comprised P-selectin-targeted PGS, doxorubicin (DOX) as an anticarcinogen, and pH/redox dual-sensitive bio-linker facilitating drug release in tumor tissues. In vitro and in vivo data showed that PGS-SS-DOX micelles significantly increased tumor cell killing capacity and exhibited a favorable biocompatibility comparison with Free-DOX. This work proved that PGS was an ideal low immunogenic, biodegradable drug carrier for the delivery of anti-cancer drugs. The facile PGS-SS-drug micelle system provided enormous opportunities for treating disseminated tumors utilizing many irreplaceable anticarcinogens.
    Keywords:  Doxorubicin; P-selectin; Polymeric micelle; Sulfated polyguluronic acid; Targeted drug delivery system; pH/redox dual-sensitive
    DOI:  https://doi.org/10.1016/j.carbpol.2022.120451
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