bims-supasi Biomed News
on Sulfation pathways and signalling
Issue of 2022‒04‒03
six papers selected by
Jonathan Wolf Mueller
University of Birmingham

  1. Anal Bioanal Chem. 2022 Mar 28.
      Chronic liver diseases have both high incidence and mortality rates; therefore, a deeper understanding of the underlying molecular mechanisms is essential. We have determined the content and sulfation pattern of chondroitin sulfate (CS) and heparan sulfate (HS) in human hepatocellular carcinoma and cirrhotic liver tissues, considering the etiology of the diseases. A variety of pathological conditions such as alcoholic liver disease, hepatitis B and C virus infections, and primary sclerosing cholangitis were studied. Major differences were observed in the total abundance and sulfation pattern of CS and HS chains. For example, the 6-O-sulfation of CS is fundamentally different regarding etiologies of cirrhosis, and a 2-threefold increase in HS N-sulfation/O-sulfation ratio was observed in hepatocellular carcinoma compared to cirrhotic tissues.
    Keywords:  Chondroitin sulfate; Cirrhosis; Glycosaminoglycan; Heparan sulfate; Hepatocellular carcinoma; Liver cancer
  2. Org Biomol Chem. 2022 Mar 30.
      Steroid bis(sulfate) metabolites derived from the two-fold sulfation of unconjugated precursors represent an important yet understudied portion of the steroid profile. The investigation of these compounds in fields such as medicine or anti-doping science relies on mass spectrometry (MS) as the principal tool to identify and quantify biomarkers of interest and depends in turn on access to steroid reference materials and their stable isotope labelled (SIL) derivatives. A new [18O] stable isotope label for sulfate metabolites is reported, which allows for the selective, late-stage and 'one-pot' synthesis of a variety of SIL-steroid conjugates suitable as MS probes and internal standards. The method is applied to more comprehensively study the MS behaviour of steroid bis(sulfate) compounds through collision-induced dissociation (CID) experiments.
  3. Sci Rep. 2022 Mar 30. 12(1): 5382
      Survival from influenza A virus (IAV) infection largely depends on an intricate balance between pathogen clearance and immunomodulation in the lung. We demonstrate that genetic alteration of the glycan heparan sulfate (HS) in CD11c + cells via Ndst1f/f CD11cCre + mutation, which inhibits HS sulfation in a major antigen presenting cell population, reduces lung inflammation by A/Puerto Rico/8/1934(H1N1) influenza in mice. Mutation was also characterized by a reduction in lung infiltration by CD4+ regulatory T (Treg) cells in the late infection/effector phase, 9 days post inoculation (p.i.), without significant differences in lung CD8 + T cells, or Treg cells at an earlier point (day 5) following infection. Induction of under-sulfated HS via Ndst1 silencing in a model dendritic cell line (DC2.4) resulted in up-regulated basal expression of the antiviral cytokine interferon β (IFN-β) relative to control. Stimulating cells with the TLR9 ligand CpG resulted in greater nuclear factor-κB (NFκB) phosphorylation in Ndst1 silenced DC2.4 cells. While stimulating cells with CpG also modestly increased IFN-β expression, this did not lead to significant increases in IFN-β protein production. In further IFN-β protein response studies using primary bone marrow DCs from Ndst1f/f CD11cCre + mutant and Cre- control mice, while trace IFN-β protein was detected in response to CpG, stimulation with the TLR7 ligand R848 resulted in robust IFN-β production, with significantly higher levels associated with DC Ndst1 mutation. In vivo, improved pathogen clearance in Ndst1f/f CD11cCre + mutant mice was suggested by reduced IAV AA5H nucleoprotein in lung examined in the late/effector phase. Earlier in the course of infection (day 5 p.i.), mean viral load, as measured by viral RNA, was not significantly different among genotypes. These findings point to novel regulatory roles for DC HS in innate and adaptive immunity during viral infection. This may have therapeutic potential and guide DC targeted HS engineering platforms in the setting of IAV or other respiratory viruses.
  4. J Mol Med (Berl). 2022 Mar 26.
      Multisystem inflammatory syndrome in children (MIS-C) represents a rare but severe complication of severe acute respiratory syndrome coronavirus 2 infection affecting children that can lead to myocardial injury and shock. Vascular endothelial dysfunction has been suggested to be a common complicating factor in patients with coronavirus disease 2019 (COVID-19). This study aims to characterize endothelial glycocalyx degradation in children admitted with MIS-C. We collected blood and urine samples and measured proinflammatory cytokines, myocardial injury markers, and endothelial glycocalyx markers in 17 children admitted with MIS-C, ten of which presented with inflammatory shock requiring intensive care admission and hemodynamic support with vasopressors. All MIS-C patients presented signs of glycocalyx deterioration with elevated levels of syndecan-1 in blood and both heparan sulfate and chondroitin sulfate in the urine. The degree of glycocalyx shedding correlated with tumor necrosis factor-α concentration. Five healthy age-matched children served as controls. Patients with MIS-C presented severe alteration of the endothelial glycocalyx that was associated with disease severity. Future studies should clarify if glycocalyx biomarkers could effectively be predictive indicators for the development of complications in adult patients with severe COVID-19 and children with MIS-C. KEY MESSAGES : Children admitted with MIS-C presented signs of endothelial glycocalyx injury with elevated syndecan-1 and heparan sulfate level. Syndecan-1 levels were associated with MIS-C severity and correlated TNF-α concentration. Syndecan-1 and heparan sulfate may represent potential biomarkers for patients with severe COVID-19 or MIS-C.
    Keywords:  COVID-19; Endothelium; Glycocalyx; Heparan sulfate; Inflammation; MIS-C
  5. J Biomol Struct Dyn. 2022 Mar 28. 1-11
      Thromboembolic diseases are a major cause of mortality in human and the currently available anticoagulants are associated with various drawbacks, therefore the search for anticoagulants that have better safety profile is highly desirable. Compounds that are part of the dietary routine can be modified to possibly increase their anticoagulant potential. We show mannose 2,3,4,5,6-O-pentasulfate (MPS) as a synthetically modified form of mannose that has appreciable anticoagulation properties. An in silico study identified that mannose in sulfated form can bind effectively to the heparin-binding site of antithrombin (ATIII) and heparin cofactor II (HCII). Mannose was sulfated using a simple sulfation strategy-involving triethylamine-sulfur trioxide adduct. HCII and ATIII were purified from human plasma and the binding analysis using fluorometer and isothermal calorimetry showed that MPS binds at a unique site. A thrombin inhibition analysis using the chromogenic substrate showed that MPS partially enhances the activity of HCII. Further an assessment of in vitro blood coagulation assays using human plasma showed that the activated partial thromboplastin time (APTT) and prothrombin time (PT) were prolonged in the presence of MPS. A molecular dynamics simulation analysis of the HCII-MPS complex showed fluctuations in a N-terminal loop and the cofactor binding site of HCII. The results indicate that MPS is a promising lead due to its effect on the in vitro coagulation rate.Communicated by Ramaswamy H. Sarma.
    Keywords:  Anticoagulant; antithrombin; heparin cofactor II; serpin; sulfated mannose; thrombosis
  6. Front Plant Sci. 2022 ;13 837517
      The use of sulfur (S) stable isotopes to study S metabolism in plants is still limited by the relatively small number of studies. It is generally accepted that less S stable isotope discrimination occurs during sulfate (SO4 2-) uptake. However, S metabolism and allocation are expected to produce separations of S stable isotopes among the different plant S pools and organs. In this study, we measured the S isotope composition of the main S pools of rice plants grown under different SO4 2- availabilities in appropriate closed and open hydroponic-plant systems. The main results indicate that fractionation against 34S occurred during SO4 2- uptake. Fractionation was dependent on the amount of residual SO4 2- in the solution, showing a biphasic behavior related to the relative expression of two SO4 2- transporter genes (OsSULTR1;1 and OsSULTR1;2) in the roots. S isotope separations among S pools and organs were also observed as the result of substantial S isotope fractionations and mixing effects occurring during SO4 2- assimilation and plant S partitioning. Since the S stable isotope separations conserve the memory of the physiological and metabolic activities that determined them, we here underline the potential of the 32S/34S analysis for the detailed characterization of the metabolic and molecular processes involved in plant S nutrition and homeostasis.
    Keywords:  Oryza sativa L.; fractionation; sulfate uptake; sulfur assimilation; sulfur stable isotopes