bims-supasi Biomed News
on Sulfation pathways and signalling
Issue of 2024–03–10
seven papers selected by
Jonathan Wolf Mueller, University of Birmingham
  1. Specific GAG ratios in the diagnosis of mucopolysaccharidoses.
  2. Metabolism mechanism of glycosaminoglycans by the gut microbiota: Bacteroides and lactic acid bacteria: A review.
  3. 6-O-endosulfatases in tumor metastasis: heparan sulfate proteoglycans modification and potential therapeutic targets.
  4. Job demands and DHEA-S levels: a study on healthcare workers.
  5. Enzymatic construction of a library of even- and odd-numbered heparosan oligosaccharides and their N-sulfonated derivatives.
  6. Cellular response of advanced triple cultures of human osteocytes, osteoblasts and osteoclasts to high sulfated hyaluronan (sHA3).
  7. Early-life matters: The role of fetal adrenal steroids in the relationship between cytokines within the placental circulation and cognitive development among infants in the Philippines.
  1. JIMD Rep. 2024 Mar;65(2): 116-123
    Specific GAG ratios in the diagnosis of mucopolysaccharidoses.
    Déborah Mathis, Jean-Christophe Prost, Gabriela Maeder, Liya Arackal, Haoyue Zhang, Sandra Kurth, Katrin Freiburghaus, Jean-Marc Nuoffer.
      Mucopolysaccharidoses (MPS) screening is tedious and still performed by analysis of total glycosaminoglycans (GAG) using 1,9-dimethylmethylene blue (DMB) photometric assay, although false positive and negative tests have been reported. Analysis of differentiated GAGs have been pursued classically by gel electrophoresis or more recently by quantitative LC-MS assays. Secondary elevations of GAGs have been reported in urinary tract infections (UTI). In this manuscript, we describe the diagnostic accuracy of urinary GAG measurements by LC-MS for MPS typing in 68 untreated MPS and mucolipidosis (ML) patients, 183 controls and 153 UTI samples. We report age-dependent reference values and cut-offs for chondroitin sulfate (CS), dermatan sulfate (DS), heparan sulfate (HS) and keratan sulfate (KS) and specific GAG ratios. The use of HS/DS ratio in combination to GAG concentrations normalized to creatinine improves the diagnostic accuracy in MPS type I, II, VI and VII. In total 15 samples classified to the wrong MPS type could be correctly assigned using HS/DS ratio. Increased KS/HS ratio in addition to increased KS improves discrimination of MPS type IV by excluding false positives. Some samples of UTI patients showed elevation of specific GAGs, mainly CS, KS and KS/HS ratio and could be misclassified as MPS type IV. Finally, DMB photometric assay performed in MPS and ML samples reveal four false negative tests (sensitivity of 94%). In conclusion, specific GAG ratios in complement to quantitative GAG values obtained by LC-MS enhance discrimination of MPS types. Exclusion of patients with UTI improve diagnostic accuracy in MPS IV but not in other types.
    Keywords:  GAG; LC–MS; MPS; chondroitin sulfate; dermatan sulfate; diagnosis; dimethylmethylene blue dye‐binding (DMB) assay; glycosaminoglycans; heparan sulfate; keratan sulfate; mucopolysaccharidosis; ratios; reference values; urinary tract infection
    DOI:  https://doi.org/10.1002/jmd2.12412
  2. Carbohydr Polym. 2024 May 15. pii: S0144-8617(24)00131-0. [Epub ahead of print]332 121905
    Metabolism mechanism of glycosaminoglycans by the gut microbiota: Bacteroides and lactic acid bacteria: A review.
    Jiahuan Dong, Yanhua Cui, Xiaojun Qu.
      Glycosaminoglycans (GAGs), as a class of biopolymers, play pivotal roles in various biological metabolisms such as cell signaling, tissue development, cell apoptosis, immune modulation, and growth factor activity. They are mainly present in the colon in free forms, which are essential for maintaining the host's health by regulating the colonization and proliferation of gut microbiota. Therefore, it is important to explain the specific members of the gut microbiota for GAGs' degradation and their enzymatic machinery in vivo. This review provides an outline of GAGs-utilizing entities in the Bacteroides, highlighting their polysaccharide utilization loci (PULs) and the enzymatic machinery involved in chondroitin sulfate (CS) and heparin (Hep)/heparan sulfate (HS). While there are some variations in GAGs' degradation among different genera, we analyze the reputed GAGs' utilization clusters in lactic acid bacteria (LAB), based on recent studies on GAGs' degradation. The enzymatic machinery involved in Hep/HS and CS metabolism within LAB is also discussed. Thus, to elucidate the precise mechanisms utilizing GAGs by diverse gut microbiota will augment our understanding of their effects on human health and contribute to potential therapeutic strategies for diseases.
    Keywords:  Bacteroides; Enzymatic machinery; Glycosaminoglycans; Lactic acid bacteria; Polysaccharide utilization loci
    DOI:  https://doi.org/10.1016/j.carbpol.2024.121905
  3. Am J Cancer Res. 2024 ;14(2): 897-916
    6-O-endosulfatases in tumor metastasis: heparan sulfate proteoglycans modification and potential therapeutic targets.
    Mengzhen Han, He Zhu, Xiaoping Chen, Xin Luo.
      Metastasis is the leading cause of cancer-associated mortality. Although advances in the targeted treatment and immunotherapy have improved the management of some cancers, the prognosis of metastatic cancers remains unsatisfied. Therefore, the specific mechanisms in tumor metastasis need further investigation. 6-O-endosulfatases (SULFs), comprising sulfatase1 (SULF1) and sulfatase 2 (SULF2), play pivotal roles in the post-synthetic modifications of heparan sulfate proteoglycans (HSPGs). Consequently, these extracellular enzymes can regulate a variety of downstream pathways by modulating HSPGs function. During the past decades, researchers have detected the expression of SULF1 and SULF2 in most cancers and revealed their roles in tumor progression and metastasis. Herein we reviewed the metastasis steps which SULFs participated in, elucidated the specific roles and mechanisms of SULFs in metastasis process, and discussed the effects of SULFs in different types of cancers. Moreover, we summarized the role of targeting SULFs in combination therapy to treat metastatic cancers, which provided some novel strategies for cancer therapy.
    Keywords:  HSPG; SULF1; SULF2; metastasis; therapeutic target
  4. Occup Med (Lond). 2024 Mar 08. pii: kqae017. [Epub ahead of print]
    Job demands and DHEA-S levels: a study on healthcare workers.
    F Marcatto, E Patriarca, D Bramuzzo, E Lucci, F Larese Filon.
       BACKGROUND: The intricate interplay between work-related stress and its physiological impact has drawn extensive research attention. Dehydroepiandrosterone sulphate (DHEA-S) emerges as a potential biomarker reflecting stress-related endocrine changes.
    AIMS: This cross-sectional study aimed to examine the association between job demands and DHEA-S levels among healthcare workers. The study also explored potential correlations between DHEA-S levels and psychophysical symptoms commonly linked to work-related stress.
    METHODS: A sample of 488 healthcare workers from a local health authority participated. Job demands were measured using the Demands scale of the Health and Safety Management Standards Indicator Tool. DHEA-S levels and symptom prevalence were assessed through serum analysis and questionnaires, respectively.
    RESULTS: Workers exposed to high job demands exhibited significantly lower DHEA-S levels compared to those with low job demands. Psychophysical symptoms, including sleep disorders, depression, and headache, were more prevalent in the high-demands group. DHEA-S levels showed significant negative correlations with the prevalence of all considered symptoms.
    CONCLUSIONS: The study shows the inverse relationship between job demands and DHEA-S levels among healthcare workers, indicating that high job demands correlate with reduced DHEA-S secretion and increased symptom prevalence. The findings suggest DHEA-S as a potential biomarker for assessing the physiological consequences of work-related stress. Proactive interventions in managing job demands are crucial for promoting employee well-being and productivity in demanding work environments. By recognizing DHEA-S as a stress biomarker, organizations can effectively address stress-related health risks and implement targeted interventions for enhancing employees' overall health and work performance.
    DOI:  https://doi.org/10.1093/occmed/kqae017
  5. Int J Biol Macromol. 2024 Mar 03. pii: S0141-8130(24)01304-7. [Epub ahead of print]264(Pt 1): 130501
    Enzymatic construction of a library of even- and odd-numbered heparosan oligosaccharides and their N-sulfonated derivatives.
    Xintong Xi, Weijiao Zhang, Litao Hu, Ruirui Xu, Yang Wang, Guocheng Du, Jian Chen, Zhen Kang.
      Low-molecular-weight heparins (LMWHs), especially the specific-sized heparin oligosaccharides, are attractive for the therapeutic applications, while their synthesis remains challenging. In the present study, unsaturated even-numbered heparosan oligosaccharides were firstly prepared by cleaving high-molecular-weight heparosan using recombinant heparinase III (HepIII). The conversion rates of the unsaturated disaccharides, tetrasaccharides, hexasaccharides, octasaccharides, and decasaccharides were 33.9 %, 47.9 %, 78.7 %, 71.8 %, and 53.4 %, respectively. After processing the aforementioned heparosan oligosaccharides with the Δ4,5 unsaturated glycuronidase, saturated odd-numbered heparosan trisaccharides, pentasaccharides, heptasaccharides, and nonasaccharides were produced. It was observed that among them, the pentasaccharides were the smallest units of saturated odd-numbered oligosaccharides recognized by HepIII. These oligosaccharides were further catalyzed with bifunctional heparan sulfate N-deacetylase/N-sulfotransferase (NDST) under optimized reaction conditions. It was found that the tetrasaccharide was defined as the smallest recognition unit for NDST, obtaining the N-sulfonated heparosan tetrasaccharides, pentasaccharides, and hexasaccharides with a single sulfonate group, as well as N-sulfonated heparosan heptasaccharides, octasaccharides, and nonasaccharides with multiple sulfonate groups. These results provide an easy pathway for constructing a library of specific-sized N-sulfonated heparosan oligosaccharides that can be used as the substrates for the enzymatic synthesis of LMWHs and heparin oligosaccharides, shedding new light on the substrate preference of NDST.
    Keywords:  Heparin; Heparosan oligosaccharides; N-sulfonated heparosan
    DOI:  https://doi.org/10.1016/j.ijbiomac.2024.130501
  6. Mater Today Bio. 2024 Apr;25 101006
    Cellular response of advanced triple cultures of human osteocytes, osteoblasts and osteoclasts to high sulfated hyaluronan (sHA3).
    Katharina Wirsig, Jana Bacova, Richard F Richter, Vera Hintze, Anne Bernhardt.
      Bone remodelling, important for homeostasis and regeneration involves the controlled action of osteoblasts, osteocytes and osteoclasts. The present study established a three-dimensional human in vitro bone model as triple culture with simultaneously differentiating osteocytes and osteoclasts, in the presence of osteoblasts. Since high sulfated hyaluronan (sHA3) was reported as a biomaterial to enhance osteogenesis as well as to dampen osteoclastogenesis, the triple culture was exposed to sHA3 to investigate cellular responses compared to the respective bone cell monocultures. Osteoclast formation and marker expression was stimulated by sHA3 only in triple culture. Osteoprotegerin (OPG) gene expression and protein secretion, but not receptor activator of NF-κB ligand (RANKL) or sclerostin (SOST), were strongly enhanced, suggesting an important role of sHA3 itself in osteoclastogenesis with other targets than indirect modulation of the RANKL/OPG ratio. Furthermore, sHA3 upregulated osteocalcin (BGLAP) in osteocytes and osteoblasts in triple culture, while alkaline phosphatase (ALP) was downregulated.
    Keywords:  BMP-2; Osteoblast; Osteoclast; Osteocyte; Triple culture; sHA3
    DOI:  https://doi.org/10.1016/j.mtbio.2024.101006
  7. Brain Behav Immun. 2024 Feb 29. pii: S0889-1591(24)00280-0. [Epub ahead of print]
    Early-life matters: The role of fetal adrenal steroids in the relationship between cytokines within the placental circulation and cognitive development among infants in the Philippines.
    Yeonjin Lee, Emily McDonald, Fusun Gundogan, Christopher V Barry, Veronica Tallo, Susannah Colt, Jennifer F Friedman.
      Prenatal exposure to inflammation is related to the risk for cognitive impairment in offspring. However, mechanisms underlying the link between inflammatory cytokines at the maternal-fetal interface and human cognitive development are largely unknown. This study addressed this research gap by examining whether i) cytokines within the placenta are associated with different domains of neurocognitive development during infancy, and ii) if DHEA-S in cord blood mediates these associations. We also explored the role of early-life socioeconomic status (SES) in moderating the effect of fetal adrenal steroids on cognitive development in low- and middle-income country contexts. A cohort of 242 mother-infant dyads in Leyte, the Philippines participated in the study and all of them were followed from early pregnancy until 12-months. Concentrations of pro- and anti-inflammatory cytokines in the placenta, and DHEA-S in cord blood collected at delivery were evaluated. The multifactorial aspects of the infant's cognitive functioning were assessed based on the Bayley Scales of Infant Development, third edition (BSID-III). We used Structural Equation Modelling (SEM) with an orthogonal rotation to examine associated paths among latent variables of pro- and anti-inflammatory cytokines in the placenta, fetal neuroendocrine factors, and cognitive development. Pathway analyses showed that both pro- and anti-inflammatory cytokines in the placenta were indirectly related to cognitive (p < 0.05) and language developmental outcomes (p < 0.1) via DHEA-S in cord blood among the low SES group. Yet, we found no statistically significant indirect effect of pro- or anti-inflammatory cytokines on neurocognitive development among the high SES sub-sample. This study extends our understanding of how early-life socioeconomic conditions modify biological pathways underlying the relationship between prenatal factors and postpartum cognitive development.
    Keywords:  DHEA-S; Neurocognitive development; Offspring; Placental cytokines; Socioeconomic status; Structural Equation Model
    DOI:  https://doi.org/10.1016/j.bbi.2024.02.036
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