bims-supasi Biomed News
on Sulfation pathways and signalling
Issue of 2022–05–01
twelve papers selected by
Jonathan Wolf Mueller, University of Birmingham
  1. Chondroitin sulfate E alleviates β-amyloid toxicity in transgenic Caenorhabditis elegans by inhibiting its aggregation.
  2. Roles of Chondroitin Sulfate Proteoglycans as Regulators of Skeletal Development.
  3. Surface Modification of Poly(ether ether ketone) by Simple Chemical Grafting of Strontium Chondroitin Sulfate to Improve its Anti-inflammation, Angiogenesis, Osteogenic Properties.
  4. Disease-Related Protein Variants of the Highly Conserved Enzyme PAPSS2 Show Marginal Stability and Aggregation in Cells.
  5. Catalyst-Free Click Chemistry for Engineering Chondroitin Sulfate-Multiarmed PEG Hydrogels for Skin Tissue Engineering.
  6. Structural characteristics of native and chemically sulfated polysaccharides from seaweed and their antimelanoma effects.
  7. Sulfated galactoglucan impedes xenografted lung cancer cell growth by blocking angiogenesis via binding BMPRs.
  8. Dual-functional hydrogel system for spinal cord regeneration with sustained release of arylsulfatase B alleviates fibrotic microenvironment and promotes axonal regeneration.
  9. Serum Metabolomic Patterns in Patients With Aldosterone-Producing Adenoma.
  10. Sex Steroid Hormones in Urinary Exosomes as Biomarkers for the Prediction of Prostate Cancer.
  11. Cystic Fibrosis Airway Mucus Hyperconcentration Produces a Vicious Cycle of Mucin, Pathogen, and Inflammatory Interactions that Promote Disease Persistence.
  12. From Habitat to Hormones: Year-around territorial behavior in rock-dwelling but not in forest and grassland lagomorphs and the role of DHEA.
  1. Int J Biol Macromol. 2022 Apr 21. pii: S0141-8130(22)00831-5. [Epub ahead of print]
    Chondroitin sulfate E alleviates β-amyloid toxicity in transgenic Caenorhabditis elegans by inhibiting its aggregation.
    Xi Wang, Yong Yang, Jiarui Zou, Yanni Li, Xiao-Gang Zhang.
      Chondroitin sulfate E (CS-E), which is characterized by oversulfated disaccharide units, has been shown to regulate neuronal adhesion, neurite outgrowth and exert neuroprotective effects. In view of these findings, here we investigated the anti-Alzheimer's disease (AD) activities of CSE by using transgenic Caenorhabditis elegans model of Alzheimer's disease. The behavioral experiments demonstrated that CSE at the concentration of 1 mg/ml significantly delayed the worm paralysis caused by Aβ aggregation as compared with control group. Western blot analysis revealed that the level of small oligomers in the transgenic C. elegans was significantly reduced upon treatment with CSE. The number of Aβ plaque deposits in transgenic worm was significantly decreased. In addition, CSE also protected the worms from oxidative stress and rescued chemotaxis dysfunction in transgenic strain CL2355. Taken together, these data suggested that CSE could protect against Aβ-induced toxicity in C. elegans. These results offer valuable evidence for the future use of CSE in the development of agents for the treatment of AD.
    Keywords:  Alzheimer's disease; Amyloid beta-peptide; Caenorhabditis elegans; Chondroitin sulfate E
    DOI:  https://doi.org/10.1016/j.ijbiomac.2022.04.124
  2. Front Cell Dev Biol. 2022 ;10 745372
    Roles of Chondroitin Sulfate Proteoglycans as Regulators of Skeletal Development.
    Nancy B Schwartz, Miriam S Domowicz.
      The extracellular matrix (ECM) is critically important for most cellular processes including differentiation, morphogenesis, growth, survival and regeneration. The interplay between cells and the ECM often involves bidirectional signaling between ECM components and small molecules, i.e., growth factors, morphogens, hormones, etc., that regulate critical life processes. The ECM provides biochemical and contextual information by binding, storing, and releasing the bioactive signaling molecules, and/or mechanical information that signals from the cell membrane integrins through the cytoskeleton to the nucleus, thereby influencing cell phenotypes. Using these dynamic, reciprocal processes, cells can also remodel and reshape the ECM by degrading and re-assembling it, thereby sculpting their environments. In this review, we summarize the role of chondroitin sulfate proteoglycans as regulators of cell and tissue development using the skeletal growth plate model, with an emphasis on use of naturally occurring, or created mutants to decipher the role of proteoglycan components in signaling paradigms.
    Keywords:  chondrogenesis; degradation; growth plate; proteoglycans; regeneration; signaling factors
    DOI:  https://doi.org/10.3389/fcell.2022.745372
  3. Adv Healthc Mater. 2022 Apr 28. e2200398
    Surface Modification of Poly(ether ether ketone) by Simple Chemical Grafting of Strontium Chondroitin Sulfate to Improve its Anti-inflammation, Angiogenesis, Osteogenic Properties.
    Zhe Zheng, Liqiu Hu, Yongmei Ge, Jianchao Qi, Qili Sun, Zhenjian Li, Lijun Lin, Bin Tang.
      Besides inducing osteogenic differentiation, the surface modification of Poly(ether ether ketone) (PEEK) is highly expected to improve its angiogenic activity and reduce the inflammatory response in the surrounding tissue. Herein, strontium chondroitin sulfate is first attempted to be introduced into the surface of sulfonated PEEK (SPEEK-CS@Sr) based on the schiff base reaction between PEEK and ethylenediamine (EDA) and the amidation reaction between EDA and CS. The surface characteristics of SPEEK-CS@Sr implant are systematically investigated, and its biological properties in vitro and in vivo are also evaluated. The results show that the surface of SPEEK-CS@Sr implant exhibits 3D microporous structure and good hydrophilicity, and can steadily release Sr ions. Importantly, the SPEEK-CS@Sr not only displays excellent biocompatibility, but also can remarkably promote cell adhesion and spread, improve osteogenic activity and angiogenic activity, and reduce the inflammatory response compared to the original PEEK. Therefore, this study presents the surface modification of PEEK material by simple chemical grafting of strontium chondroitin sulfate to improve its angiogenesis, anti-inflammation, and osteogenic properties, and the as-fabricated SPEEK-CS@Sr has the potential to serve as a promising orthopedic implant in bone tissue engineering. This article is protected by copyright. All rights reserved.
    Keywords:  angiogenesis; anti-inflammation; chondroitin sulfate; osteogenic fixation; poly(ether ether ketone) (PEEK); strontium
    DOI:  https://doi.org/10.1002/adhm.202200398
  4. Front Mol Biosci. 2022 ;9 860387
    Disease-Related Protein Variants of the Highly Conserved Enzyme PAPSS2 Show Marginal Stability and Aggregation in Cells.
    Oliver Brylski, Puja Shrestha, Philip J House, Patricia Gnutt, Jonathan Wolf Mueller, Simon Ebbinghaus.
      Cellular sulfation pathways rely on the activated sulfate 3'-phosphoadenosine-5'-phosphosulfate (PAPS). In humans, PAPS is exclusively provided by the two PAPS synthases PAPSS1 and PAPSS2. Mutations found in the PAPSS2 gene result in severe disease states such as bone dysplasia, androgen excess and polycystic ovary syndrome. The APS kinase domain of PAPSS2 catalyzes the rate-limiting step in PAPS biosynthesis. In this study, we show that clinically described disease mutations located in the naturally fragile APS kinase domain are associated either with its destabilization and aggregation or its deactivation. Our findings provide novel insights into possible molecular mechanisms that could give rise to disease phenotypes associated with sulfation pathway genes.
    Keywords:  PAPS synthase; in-cell spectroscopy; protein folding; stability and aggregation; sulfation pathways
    DOI:  https://doi.org/10.3389/fmolb.2022.860387
  5. J Funct Biomater. 2022 Apr 18. pii: 45. [Epub ahead of print]13(2):
    Catalyst-Free Click Chemistry for Engineering Chondroitin Sulfate-Multiarmed PEG Hydrogels for Skin Tissue Engineering.
    Gustavo F Sousa, Samson Afewerki, Dalton Dittz, Francisco E P Santos, Daniele O Gontijo, Sérgio R A Scalzo, Ana L C Santos, Lays C Guimaraes, Ester M Pereira, Luciola S Barcelos, Semiramis J H Do Monte, Pedro P G Guimaraes, Fernanda R Marciano, Anderson O Lobo.
      The quest for an ideal biomaterial perfectly matching the microenvironment of the surrounding tissues and cells is an endless challenge within biomedical research, in addition to integrating this with a facile and sustainable technology for its preparation. Engineering hydrogels through click chemistry would promote the sustainable invention of tailor-made hydrogels. Herein, we disclose a versatile and facile catalyst-free click chemistry for the generation of an innovative hydrogel by combining chondroitin sulfate (CS) and polyethylene glycol (PEG). Various multi-armed PEG-Norbornene (A-PEG-N) with different molecular sizes were investigated to generate crosslinked copolymers with tunable rheological and mechanical properties. The crosslinked and mechanically stable porous hydrogels could be generated by simply mixing the two clickable Tetrazine-CS (TCS) and A-PEG-N components, generating a self-standing hydrogel within minutes. The leading candidate (TCS-8A-PEG-N (40 kD)), based on the mechanical and biocompatibility results, was further employed as a scaffold to improve wound closure and blood flow in vivo. The hydrogel demonstrated not only enhanced blood perfusion and an increased number of blood vessels, but also desirable fibrous matrix orientation and normal collagen deposition. Taken together, these results demonstrate the potential of the hydrogel to improve wound repair and hold promise for in situ skin tissue engineering applications.
    Keywords:  biomaterial; bioorthogonal chemistry; chondroitin sulfate; polyethylene glycol; skin tissue engineering
    DOI:  https://doi.org/10.3390/jfb13020045
  6. Carbohydr Polym. 2022 Aug 01. pii: S0144-8617(22)00341-1. [Epub ahead of print]289 119436
    Structural characteristics of native and chemically sulfated polysaccharides from seaweed and their antimelanoma effects.
    Ester Mazepa, Stellee M P Biscaia, Daniel de L Bellan, Edvaldo da S Trindade, Fernanda F Simas.
      Polysaccharides from seaweed have been shown to present a variety of antitumor effects, however the understanding of which structural patterns are responsible for these biological effects are still unclear. This review aimed to gather and critically evaluate published data of seaweed polysaccharide's chemical structure elucidation and their relation with antimelanoma effects. Data were collected at the electronic article databases Science Direct, NCBI/Pubmed and Google Scholar, selecting papers with polysaccharide structural information and biological effects on melanoma models. Most of the papers referred to sulfated polysaccharides as fucans and fucoidans, and to a lesser extent galactans, rhamnans, alginates, and neutral one's glucans. Fine chemical features as presence and position of sulfate groups, monosaccharide composition, linear or branched backbones, and glycosidic linkage type are crucial to antimelanoma effects, as well as molecular weight and macromolecular conformation.
    Keywords:  Antitumoral; Melanoma; Seaweed; Structure-activity relationship; Sulfated polysaccharides
    DOI:  https://doi.org/10.1016/j.carbpol.2022.119436
  7. Carbohydr Polym. 2022 Aug 01. pii: S0144-8617(22)00316-2. [Epub ahead of print]289 119412
    Sulfated galactoglucan impedes xenografted lung cancer cell growth by blocking angiogenesis via binding BMPRs.
    Lulin Huang, Hui Zeng, Can Jin, Xiaonan Ma, Yiwen Zhang, Chunfan Huang, Zhenyun Du, Kan Ding.
      Evidences propound tumor growth may be impeded by blocking angiogenesis. Before we showed that sulfated glucan or arabinogalactan might bind to BMP2 or its receptors to inhibit angiogenesis. Whether sulfated galactoglucan can target both BMPRIA and BMPRII to impede angiogenesis and tumor cells growth is still vague. Here, we prepare galactoglucan and its sulfated derivatives Sul-CDA-0.05. The sulfate groups substituted are at the C-6 of 1, 4-linked α-Glcp and 1, 4-linked α-Galp backbone and at the C-6 of branch chain T-linked α-Glcp. Sul-CDA-0.05 can inhibit angiogenesis in vitro and in vivo. Indeed, Sul-CDA-0.05 impedes xenografted A549 lung tumor cells growth. Mechanism study demonstrates that this polysaccharide may target both BMPRIA and BMPRII to block BMP/Smad/Id1 signaling and attenuate VEGF and its transcription factor. Our evidences suggest that Sul-CDA-0.05 may be a new drug candidate for anti-lung cancer therapy by targeting both BMPRIA and BMPRII.
    Keywords:  BMPR; Galactoglucan; Lung cancer; Smad; Sulfated polysaccharide; VEGF
    DOI:  https://doi.org/10.1016/j.carbpol.2022.119412
  8. Biomaterials. 2022 Apr 14. pii: S0142-9612(22)00166-1. [Epub ahead of print]284 121526
    Dual-functional hydrogel system for spinal cord regeneration with sustained release of arylsulfatase B alleviates fibrotic microenvironment and promotes axonal regeneration.
    Hee Hwan Park, Young-Min Kim, Le Thi Anh Hong, Hyung Soon Kim, Sung Hoon Kim, Xuelian Jin, Dong Hoon Hwang, Min Jung Kwon, Soo-Chang Song, Byung Gon Kim.
      Traumatic damage to the spinal cord does not spontaneously heal, often leading to permanent tissue defects. We have shown that injection of imidazole-poly(organophosphazene) hydrogel (I-5) bridges cystic cavities with the newly assembled fibronectin-rich extracellular matrix (ECM). The hydrogel-created ECM contains chondroitin sulfate proteoglycans (CSPGs), collagenous fibrils together with perivascular fibroblasts, and various fibrotic proteins, all of which could hinder axonal growth in the matrix. In an in vitro fibrotic scar model, fibroblasts exhibited enhanced sensitivity to TGF-β1 when grown on CSPGs. To alleviate the fibrotic microenvironment, the I-5 hydrogel was equipped with an additional function by making a complex with ARSB, a human enzyme degrading CSPGs, via hydrophobic interaction. Delivery of the I-5/ARSB complex significantly diminished the fibrotic ECM components. The complex promoted serotonergic axonal growth into the hydrogel-induced matrix and enhanced serotonergic innervation of the lumbar motor neurons. Regeneration of the propriospinal axons deep into the matrix and to the lumbar spinal cord was robustly increased accompanied by improved locomotor recovery. Therefore, our dual-functional system upgraded the functionality of the hydrogel for spinal cord regeneration by creating ECM to bridge tissue defects and concurrently facilitating axonal connections through the newly assembled ECM.
    Keywords:  Arylsulfatase B; Axon regeneration; Chondroitin sulfate proteoglycan; Fibrotic microenvironment; Injectable hydrogel; Spinal cord injury
    DOI:  https://doi.org/10.1016/j.biomaterials.2022.121526
  9. Front Mol Biosci. 2022 ;9 816469
    Serum Metabolomic Patterns in Patients With Aldosterone-Producing Adenoma.
    Yule Chen, Hanjiang Wang, Ke Wang, Guodong Zhu, Zhishang Yang, Min Wang, Wenbin Song.
      Aldosterone-producing adenoma (APA), the main cause of endocrine hypertension, has recently been reported to be associated with other diseases, such as metabolic syndrome, but the detailed mechanism underlying this association remains unclear. Here, we used untargeted metabolomics and compared the abundance of serum metabolites between essential hypertension (EHT) and APA patients, as well as the serum metabolites of APA patients before and after adrenalectomy. Our results revealed 44 differential metabolites between APA and EHT patients and 39 differential metabolites between pre- and postoperative APA patients. Several metabolites involved in cardiovascular disease, obesity, and diabetes were dysregulated in APA patients compared to EHT patients, including arachidonic acid metabolites [e.g., 5(S)-HpETE and 12-HETE], amino acids (e.g., L-carnitine, taurine, and L-arginine), nucleotide metabolites (e.g., hypoxanthine) and cholesterol 3-sulfate. Importantly, the levels of hypoxanthine and cholesterol 3-sulfate, two metabolites that promote the development of atherosclerotic lesions and obesity, were originally increased in APA patients, but those elevated levels were reversed by adrenalectomy. Conversely, levels of L-carnitine and (3-carboxypropyl) trimethylammonium cation, two metabolites participating in lipid metabolism, were decreased in APA patients but increased postoperatively. We conclude that APA might participate in cardiovascular and metabolic diseases by regulating serum metabolites.
    Keywords:  adrenalectomy; aldosterone-producing adenoma; hypertension; metabolomics; serum
    DOI:  https://doi.org/10.3389/fmolb.2022.816469
  10. Clin Chim Acta. 2022 Apr 26. pii: S0009-8981(22)01124-X. [Epub ahead of print]
    Sex Steroid Hormones in Urinary Exosomes as Biomarkers for the Prediction of Prostate Cancer.
    Liuxi Chu, Xin Shu, Yao Huang, Tong Chu, Meina Ge, Qin Lu.
       BACKGROUND: Although they are involved in the progression of PCa, the use of sex steroid hormones in urinary exosomes as biomarkers for PCa remains obscure. Here, the potential use of sex steroid hormones in urinary exosomes as biomarkers was investigated for the prediction of early-stage PCa to assist in clinical diagnosis.
    METHODS: Two hundred and eighty-six participants were randomly recruited, 231 patients with PCa and 55 healthy controls. According to their Gleason scores (GSs), the patients with PCa were divided into two groups, mild PCa (GS6) (n=116) and severe (≥ GS7) group (n=115),. The concentrations of 8 sex steroid hormones in urinary exosomes were quantitated using liquid chromatography tandem mass spectrometry with atmospheric pressure chemical ionization (LC-APCI-MS/MS).
    RESULTS: The results showed that the levels of 7 out of 8 sex steroids including dehydroepiandrosterone (DHEA), dehydroepiandrosteronesulfate (DHEAS), androstenedione (A4), testosterone (T), progesterone (P), dihydrotestosterone (DHT), and estrone (E1), but not estradiol (E2) in urinary exosomes, were not only distinguished the PCa patients from healthy controls, can also differentiate between patients with mild and severe PCa. Of the 8 selected urinary exosomal biomarkers, DHEA, DHEAS, T, and DHT were finally screened further to build the regression model, and the detection method of the 4 biomarkers-combined achieved an area under the ROC curve (AUC) of 0.854 and predictive accuracy of 78.2%.
    CONCLUSION: Our data showed the use of exosomal sex steroids in urine could be as biomarkers for predicting PCa for the first time. This finding would supply a novel insight for PCa diagnosis.
    Keywords:  LC–MS/MS; Prediction; Prostate cancer; Sex steroids; Urinary exosomes
    DOI:  https://doi.org/10.1016/j.cca.2022.04.995
  11. Am J Respir Cell Mol Biol. 2022 Apr 29.
    Cystic Fibrosis Airway Mucus Hyperconcentration Produces a Vicious Cycle of Mucin, Pathogen, and Inflammatory Interactions that Promote Disease Persistence.
    Bethany Batson, Bryan Zorn, Giorgia Radicioni, Stephanie Livengood, Tadahiro Kumagai, Hong Dang, Agathe Ceppe, Phillip Clapp, Michael Tunney, Stuart Elborn, Gerry McElvaney, Marianne Muhlebach, Richard C Boucher, Michael Tiemeyer, Matthew Wolfgang, Mehmet Kesimer.
      The dynamics describing the vicious cycle characteristic of CF lung disease, initiated by stagnant mucus and perpetuated by infection and inflammation, remain unclear. Here we determine the effect of the CF airway milieu, with persistent muco-obstruction, resident pathogens, and inflammation, on the mucin quantity/quality that govern lung disease pathogenesis/progression. The concentrations of MUC5AC and MUC5B, were measured and characterized in sputum samples from CF (N=44) and healthy (N=29) subjects with respect to their macromolecular properties, degree of proteolysis, and glycomics diversity. These parameters were related to quantitative microbiome and clinical data. MUC5AC, and MUC5B concentrations were elevated, 30- and 8-fold respectively, in CF as compared to control sputum. Mucin parameters did not correlate with hypertonic saline, inhaled corticosteroids or antibiotics use. No differences in mucin parameters were detected at baseline vs during exacerbations. Mucin concentrations significantly correlated with the age and sputum human neutrophil elastase (HNE) activity. Although significantly more proteolytic cleavages were detected in CF mucins, their macromolecular properties, e.g., size and molecular weight, were not significantly different than controls likely reflecting the role of S-S bonds in maintaining multimeric structures. No evidence of giant mucin macromolecule reflecting oxidative stress-induced cross-linking was found. Mucin glycomic analysis revealed significantly more sialylated glycans in CF and the total abundance of non-sulfated O-glycans was correlated with the relative abundance of pathogens. Collectively, the interaction of mucins, pathogens, epithelium, and inflammatory cells promotes proteomic and glycomic changes that reflects a persistent muco-obstructive, infectious, and inflammatory state.
    Keywords:  bronchiectasis; cystic fibrosis; glycomics; microbiome; mucin
    DOI:  https://doi.org/10.1165/rcmb.2021-0359OC
  12. Horm Behav. 2022 Apr 23. pii: S0018-506X(22)00073-3. [Epub ahead of print]142 105179
    From Habitat to Hormones: Year-around territorial behavior in rock-dwelling but not in forest and grassland lagomorphs and the role of DHEA.
    Rudy Boonstra, Nisha Gandhi, Alec Kraushaar, Kurt Galbreath.
      Year-around defense of extremely patchy habitat may require hormones that drive territorial behavior, but have no other costly physiological effects. The American pika (Ochotona princeps), but not the snowshoe hare (Lepus americanus) nor the eastern cottontail rabbit (Sylvilagus floridanus), exhibits this behavior. The former engages in contest competition against all individuals independent of sex to protect its territory in highly fragmented patches on mountain talus slopes; the latter in scramble competition in more continuous forests, grasslands, and shrublands. The hormonal basis for this difference in lagomorphs is unknown. Dehydroepiandrosterone is a prohormone produced by the zona reticularis of the adrenal cortex. It has no effect on aggressive behavior until converted in the brain to estrogen. We assessed levels (DHEA-S plus DHEA) in all species collected in the wild. In nonbreeding pikas, levels were 256 times higher than in hares and 22 times higher than in rabbits. Within species, females and males had similar levels. The proportion of the adrenal cortex devoted to the zona reticularis was significantly larger in pikas than in hares or rabbits. Our evidence is consistent with the hypothesis that dehydroepiandrosterone drives this individual-based, year-around territoriality in pikas. We propose a definitive experiment to determine this and recommend comparative studies in central Asia where there is high diversity of pika species whose behavior ranges from individual-based territoriality to colonial. Thus, we speculate that the wild American pika has the adrenal-brain nexus for all seasons and is an excellent model to understand how habitat drives the hormonal control of spacing behavior.
    Keywords:  Adrenal cortex and zona reticularis; Aggression; Contest and scramble competition; Prohormone; Spacing behavior
    DOI:  https://doi.org/10.1016/j.yhbeh.2022.105179
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