bims-supasi 2024-12-15 papers

bims-supasi

Biomed News

on Sulfation pathways and signalling

Issue of 2024–12–15
thirteen papers selected by
Jonathan Wolf Mueller, University of Birmingham

Chondroitin sulfate in invertebrate development.
Docking heparan sulfate-based ligands as a promising inhibitor for SARS-CoV-2.
Versican controlled by Lmx1b regulates hyaluronate density and hydration for semicircular canal morphogenesis.
State-of-the-art chromatographic and mass spectrometric techniques in heparin structural analysis.
Fine-tuning of Fgf8 morphogen gradient by heparan sulfate proteoglycans in the extracellular matrix.
Indoxyl Sulfate and Altered Gut Microbiome Heightened the Risk of Chronic Kidney Disease in Obstructive Sleep Apnea.
Ternary complex of soluble undenatured type II collagen-hydrophobic phytochemical-chondroitin sulfate facilitates high stability and targeted intestinal release properties to active substance.
Performance of dehydroepiandrosterone sulfate and baseline cortisol in assessing adrenal insufficiency.
The uremic toxin indoxyl sulfate decreases osteocyte RANKL/OPG and increases Wnt inhibitor RNA expression that is reversed by PTH.
A potential bimodal interplay between heme and complement factor H 402H in the deregulation of the complement alternative pathway by SARS-CoV-2.
Phytosulfokine downregulates defense-related WRKY transcription factors and attenuates pathogen-associated molecular pattern-triggered immunity.
Sulfur isotope anomalies in coal combustion: Applications to the present and early Earth environments.
Green synthesis of self-assembly, self-healing, and injectable polyelectrolyte complex hydrogels using chitosan, sulphated polysaccharides, hydrolyzed collagen and nanocellulose.

Proteoglycan Res. 2024 Oct-Dec;2(4):pii: e70009. [Epub ahead of print]2(4):

Chondroitin sulfate in invertebrate development.

Ayano Moriya, Eriko Nakato, Jin-Ping Li, Hiroshi Nakato.

  Chondroitin sulfate (CS) is one of the most evolutionarily conserved glycosaminoglycans (GAGs). Although CS's function in skeletal development is well established in vertebrates, CS exists in more primitive animal species with no cartilage or bone, such as C. elegans and Drosophila, indicating that the original role of CS was not in the skeletal system. In this review, we focus on the roles of CS and the mechanisms of action during development of two genetically trackable model organisms, C. elegans and Drosophila.

Keywords:  Caenorhabditis elegans; Chondroitin sulfate; Drosophila; basement membrane; development

DOI:  https://doi.org/10.1002/pgr2.70009
J Mol Model. 2024 Dec 12. 31(1): 19

Docking heparan sulfate-based ligands as a promising inhibitor for SARS-CoV-2.

Luiz F M A Benício, Érica C M Nascimento, João B L Martins.

   CONTEXT: Heparan sulfate (HS) linear polysaccharide glycosaminoglycan compound is linked to components from the cell surface and the extracellular matrix. HS mediates SARS-CoV-2 infection through spike protein binding to cell surface receptors and is required to bind ACE2, prompting the need for electronic structure and molecular docking evaluation of this core system to exploit this attachment in developing new derivatives. Therefore, we have studied five molecules based on HS using molecular docking and electronic structure analysis. Non-covalent interaction analysis shows hydrogen bonding and van der Waals interactions in the binding to RBD-ACE2 interface and 3CLpro. SDM3 and SDM1 molecules present the lowest gap, including solvent effect under 154.6 kcal/mol, and exhibit the most reactivity behavior in this group, potentially leading to enhanced interaction in docking studies.
METHODS: Heparan sulfate and four derivatives were optimized using B3LYP functional with two basis sets 6-31 + G(d,p) and def2SVP. Electronic structure was used to explore the main interactions and the reactivity of these molecules, and these optimized structures were used in the molecular docking study against 3CLpro, RBD, and ACE2.

Keywords:  B3LYP; Heparan sulfate; Molecular docking; SARS-CoV-2

DOI:  https://doi.org/10.1007/s00894-024-06236-0
Development. 2024 Dec 09. pii: dev.203003. [Epub ahead of print]

Versican controlled by Lmx1b regulates hyaluronate density and hydration for semicircular canal morphogenesis.

Yusuke Mori, Sierra Smith, Jiacheng Wang, Nadia Eliora, Kira L Heikes, Akankshi Munjal.

  During inner ear semicircular canal morphogenesis in zebrafish, patterned canal-genesis zones express genes for extracellular matrix component synthesis. These include hyaluronan and the hyaluronan-binding chondroitin sulfate proteoglycan Versican, which are abundant in the matrices of many developing organs. Charged hyaluronate polymers play a key role in canal morphogenesis through osmotic swelling. However, the developmental factor(s) that pattern the synthesis of the matrix components and regulation of hyaluronate density and swelling are unknown. Here, we identify the transcription factor, Lmx1b, as a positive transcriptional regulator of hyaluronan, Versican, and chondroitin synthesis genes crucial for canal morphogenesis. We show that Versican regulates hyaluronan density through its protein core, whereas the charged chondroitin side chains contribute to the hydration of hyaluronate-ECM. Versican-tuned properties of hyaluronate matrices may be a broadly used mechanism in morphogenesis with important implications for understanding diseases where these matrices are impaired, and for hydrogel engineering for tissue regeneration.

Keywords:  ECM; Inner ear semicircular canals; Lmx1b; Tissue morphogenesis; Versican-hyaluronan; Zebrafish development

DOI:  https://doi.org/10.1242/dev.203003
J Pharm Biomed Anal. 2024 Dec 06. pii: S0731-7085(24)00667-8. [Epub ahead of print]255 116625

State-of-the-art chromatographic and mass spectrometric techniques in heparin structural analysis.

Yilan Ouyang, Siqi Yang, Wei Wang, Jianzhou Cui, Zhenqing Zhang.

  Heparin is the most extensively used anticoagulant in clinical practice. It is a highly sulfated, linear polysaccharide composed of repeating disaccharide units. As a member of the glycosaminoglycan (GAG) family, heparin's complex structure features significant molecular weight variability, diverse sugar residues, and variable sulfation patterns. Low molecular weight heparins (LMWHs), produced through chemical or enzymatic depolymerization, are distinguished by their reduced molecular weight and offer therapeutic advantages, including lower bleeding risks, reduced immunogenicity, and higher bioavailability following subcutaneous administration. The structural intricacy of heparin-based drugs presents major challenges for quality control, clinical safety, process optimization, and therapeutic expansion. Advanced analytical methods, particularly LC and MS, remain at the forefront of efforts to elucidate the detailed structures of these drugs. This review highlights recent progress in chromatographic and MS-based analysis techniques for heparin and its derivatives, including the application of computational algorithms for structural elucidation. The focus is on the analytical methodologies, their innovations, and limitations, while also exploring how machine learning and bioinformatics tools are shaping the future of heparin quality control and therapeutic application. This comprehensive review provides a reference point for researchers engaged in the structural analysis of heparin-based drugs and offers insights into the future development of novel analytical strategies for improving the safety and efficacy of these critical anticoagulants.

Keywords:  Chromatography; Heparin; Mass spectrometry; Structure analysis

DOI:  https://doi.org/10.1016/j.jpba.2024.116625
Biophys J. 2024 Dec 11. pii: S0006-3495(24)04070-0. [Epub ahead of print]

Fine-tuning of Fgf8 morphogen gradient by heparan sulfate proteoglycans in the extracellular matrix.

Mansi Gupta, Thomas Kurth, Fabian Heinemann, Petra Schwille, Sebastian Keil, Franziska Knopf, Michael Brand.

Embryonic development is orchestrated by the action of morphogens, which spread out from a local source and activate, in a field of target cells, different cellular programs based on their concentration gradient. Fibroblast growth factor 8 (Fgf8) is a morphogen with important functions in embryonic organizing centers. It forms a gradient in the extracellular space by free diffusion, interaction with the extracellular matrix (ECM) and receptor-mediated endocytosis. However, morphogen gradient regulation by ECM is still poorly understood. Here we show that specific Heparan Sulfate Proteoglycans (HSPGs) bind Fgf8 with different affinities directly in the ECM of living zebrafish embryos, thus affecting its diffusion and signaling. Using single-molecule Fluorescence Correlation Spectroscopy, we quantify this binding in vivo, and find two different modes of interaction. First, reducing or increasing the concentration of specific HSPGs in the extracellular space alters Fgf8 diffusion, and thus, its gradient shape. Second, ternary complex formation of Fgf8 ligand with Fgf-receptors and HSPGs at the cell surface requires HSPG attachment to the cell membrane. Together, our results show that graded Fgf8 morphogen distribution is achieved by constraining free Fgf8 diffusion through successive interactions with HSPGs at the cell surface and in ECM space.

DOI: https://doi.org/10.1016/j.bpj.2024.12.009
Sleep. 2024 Dec 07. pii: zsae286. [Epub ahead of print]

Indoxyl Sulfate and Altered Gut Microbiome Heightened the Risk of Chronic Kidney Disease in Obstructive Sleep Apnea.

Mohit, Pooran Chand, Sheetal Verma.

DOI: https://doi.org/10.1093/sleep/zsae286
Int J Biol Macromol. 2024 Dec 09. pii: S0141-8130(24)09412-1. [Epub ahead of print] 138601

Ternary complex of soluble undenatured type II collagen-hydrophobic phytochemical-chondroitin sulfate facilitates high stability and targeted intestinal release properties to active substance.

Rong Xu, Yue Gu, David Julian McClements, Lin Zheng, Mingtao Huang, Mouming Zhao.

  Researchers have reported that soluble undenatured type II collagen (SC II) and hydrophobic phytochemicals (HPs) can ameliorate osteoarthritis (OA) through several mechanisms. However, the solubility of HPs, the stability of SC II, and the bio-accessibility of both need to be greatly improved before they can be successfully used for this purpose. In this study, two common HPs, curcumin (CUR, a hydrophobic polyphenol) and astaxanthin (AST, a carotenoid), were first loaded into SC II, which was then complexed with chondroitin sulfate (CS) to form ternary complexes: SC II-HP-CS. The results showed that SC II had the highest loading capacity for CUR (19.00 ± 0.76 μg/mg) and AST (21.15 ± 1.67 μg/mg) at pH 2.0. The CUR and AST bound to the SC II through non-covalent interactions (mainly hydrophobic interaction) and they both existed in an amorphous form within the complexes. In addition, the binding affinity and hydrophobic interaction between SC II and CUR was higher than those of AST. The thermal stability of the SC II-CUR-CS (Td = 118.0 ± 2.1 °C) and SC II-AST-CS (Td = 118.8 ± 3.5 °C) complexes were significantly higher than that of the SC II-CUR (Td = 104.27 ± 0.28 °C) and SC II-AST (Td = 103.8 ± 1.6 °C) complexes. SC II-HP complexes dissolved in gastric fluids, resulting in serious degradation of the SC II, while SC II-HP-CS complexes existed in an insoluble form to protect the triple helix structure of SC II (24-46 % retained). The CUR release (94.2 ± 5.8 %) and the free radical scavenging activity (84.6 ± 5.3 %) of SC II-CUR-CS was relatively high after 6 h of intestinal digestion, while AST in SC II-AST and SC II-AST-CS had low solubility and antioxidant activity. Therefore, the ternary complex of SC II-HP-CS was more advantageous as multifunctional delivery systems for the encapsulation, protection, and controlled release of hydrophobic polyphenols, which may provide guidance for the synergistic use of hydrophobic polyphenols and SC II to improve OA.

Keywords:  Chondroitin sulfate; Hydrophobic phytochemicals; Soluble undenatured type II collagen; Stability; Targeted intestinal release; Ternary complexes

DOI:  https://doi.org/10.1016/j.ijbiomac.2024.138601
J Clin Endocrinol Metab. 2024 Dec 09. pii: dgae855. [Epub ahead of print]

Performance of dehydroepiandrosterone sulfate and baseline cortisol in assessing adrenal insufficiency.

Ashley J Han, Malavika Suresh, Lucinda Gruber, Alicia Algeciras-Schimnich, Sara J Achenbach, Elizabeth J Atkinson, Irina Bancos.

   CONTEXT: Diagnosing adrenal insufficiency (AI) often requires complex testing which can be time consuming and expensive. Dehydroepiandrosterone sulfate (DHEAS) is a promising marker of hypothalamic-pituitary-adrenal (HPA) axis function, however its diagnostic performance has not yet been evaluated in a large-scale study.
OBJECTIVE: Evaluate the performance of DHEAS and baseline cortisol in assessing AI.
DESIGN: Single-center retrospective cohort study.
SETTING: Referral center.
PATIENTS: Adults who underwent Cosyntropin stimulation testing (CST) between 2005-2023 and had DHEAS measured within 3 months prior to CST.
MAIN OUTCOME MEASURES: Area under receiver operating characteristic curve (AUROC) for DHEAS and baseline cortisol. Prevalence of AI based on various DHEAS and baseline cortisol concentrations.
RESULTS: Among 1135 patients, 195 (17.2%) had AI. Both baseline cortisol and DHEAS independently had good diagnostic performance with AUROC 0.81 (95% CI 0.77-0.84) and 0.81 (95% CI 0.78-0.85), respectively. Time of CST performance had no significant effect on diagnostic accuracy of baseline cortisol while recent glucocorticoid use decreased diagnostic performance of DHEAS (AUROC 0.72 vs 0.83). Only 1.2% of patients with baseline cortisol ≥10 mcg/dL had AI based on CST. Among patients with baseline cortisol between 5-9.9 mcg/dL, only 1.3% had AI if DHEAS was ≥60 mcg/dL. Conversely, the majority (72.2%) of patients with both baseline cortisol <5 mcg/dL and DHEAS <25 mcg/dL were found to have AI.
CONCLUSION: DHEAS has good diagnostic performance in assessing AI. Measuring both baseline cortisol and DHEAS concentrations may eliminate the need for further dynamic testing in many patients.

Keywords:  CST; DHEAS; Synacthen; cortisol; cosyntropin; diagnosis; stimulation test

DOI:  https://doi.org/10.1210/clinem/dgae855
JBMR Plus. 2025 Jan;9(1): ziae136

The uremic toxin indoxyl sulfate decreases osteocyte RANKL/OPG and increases Wnt inhibitor RNA expression that is reversed by PTH.

Neal X Chen, Kalisha D O'Neill, Hannah E Wilson, Shruthi Srinivasan, Lynda Bonewald, Sharon M Moe.

  Renal osteodystrophy (ROD) leads to increased fractures, potentially due to underlying low bone turnover in chronic kidney disease (CKD). We hypothesized that indoxyl sulfate (IS), a circulating toxin elevated in CKD and a ligand for the aryl hydrocarbon receptor (AhR), may target the osteocytes leading to bone cell uncoupling in ROD. The IDG-SW3 osteocytes were cultured for 14 days (early) and 35 days (mature osteocytes) and incubated with 500 μM of IS after dose finding studies to confirm AhR activation. Long-term incubation of IS for 14 days led to decreased expression of Tnfsf11/Tnfrsf11b ratio (RANKL/OPG), which would increase osteoclast activity, and increased expression of Wnt inhibitors Sost and Dkk1, which would decrease bone formation in addition to decreased mineralization and alkaline phosphatase (ALP) activity. When osteocytes were incubated with IS and the AhR translocation inhibitor CH223191, mineralization and ALP activity were restored. However, the Tnfsf11/Tnfrsf11b ratio and Sost, Dkk1 expression were not altered compared with IS alone, suggesting more complex signaling. In both early and mature osteocytes, co-culture with parathyroid hormone (PTH) and IS reversed the IS-induced upregulation of Sost and Dkk1, and IS enhanced the PTH-induced increase of the Tnfsf11/Tnfrsf11b ratio. Co-culture of IS with PTH additively enhanced the AhR activity assessed by Cyp1a1 and Cyp1b1 expression. In summary, IS in the absence of PTH increased osteocyte messenger RNA (mRNA) Wnt inhibitor expression in both early and mature osteocytes, decreased mRNA expression ofTnfsf11/Tnfrsf11b ratio and decreased mineralization in early osteocytes. These changes would lead to decreased resorption and formation resulting in low bone remodeling. These data suggest IS may be important in the underlying low turnover bone disease observed in CKD when PTH is not elevated. In addition, when PTH is elevated, IS interacts to further increase Tnfsf11/Tnfrsf11b ratio for osteoclast activity in both early and mature osteocytes, which would worsen bone resorption.

Keywords:  bone remodeling; indoxyl sulfate; mineralization; osteocytes; parathyroid hormone; uremic toxins

DOI:  https://doi.org/10.1093/jbmrpl/ziae136
Infect Genet Evol. 2024 Dec 04. pii: S1567-1348(24)00150-3. [Epub ahead of print]126 105698

A potential bimodal interplay between heme and complement factor H 402H in the deregulation of the complement alternative pathway by SARS-CoV-2.

Stefanos A Tsiftsoglou, Eleni Gavriilaki.

  The recent discovery that the trimeric SARS-CoV-2 spike S glycoprotein carries heme within an NTD domain pocket of the S1 subunits, suggested that this virus may be cleverly utilizing heme, in addition to the S1 RBD domains, for invading target cells carrying a specific entry receptor like ACE2, TMEM106B and others. Studies during the COVID-19 pandemic revealed that the infectivity of this virus depends on cell surface heparan sulfate and that the infection induces non-canonical activation of the Complement Alternative pathway (AP) on the surface of infected cells. In our recent COVID-19 genomic studies, among the coding SNPs of interest we also detected the presence of the CFH rs1061170, rs800292 and rs1065489 within all the infected patient subgroups examined. The minor C allele of rs1061170 encodes CFH 402H that over the years has been associated with diseases characterized by complement dysregulation namely the age-related macular degeneration (AMD) and the atypical haemolytic uremic syndrome (aHUS). Also, more recently with the diminishment of CD4+ T cell responses with ageing. The rs800292 minor allele A encodes CFH 62I that supports enhanced cofactor activity for Complement factor I (CFI). Also, the rs1065489 minor allele T encodes CFH 936D and is located within the CCP16 domain that influences the affinity of CFH with extracellular laminins. A subsequent computational analysis revealed that the CFH residue 402 is located centrally within a heme-binding motif (HBM) in domain CCP7 (398YNQNYGRKF406). Heme on the viral spike glycoprotein S1 subunit could recruit CFH 402H for masking free viral particles from opsonisation, and when in proximity to cell surface, act as a bait disrupting CFH 402H from the heparan sulphate coat of the target cells. Publicly available genetic data for European populations indicate that the minor C allele of rs1061170 is present only in haplotypes that carry the major alleles of rs800292 and rs1065489. This combination encodes for CFH 402H that exhibits increased biochemical affinity for heme in proximity, without enhanced cofactor activity for CFI and weaker association with the extracellular matrix. In the theatre of infection, this combination can promote heme-mediated viral infection with weaker complement opsonisation and potential AP deregulation. This strategy may be evolutionary conserved among various classes of infectious agents.

Keywords:  CFH 402H; COVID-19; Cell surface engagement; Complement alternative pathway; HBMs; Heme; Heparan sulfate; Infection; SARS-CoV-2; rs1061170

DOI:  https://doi.org/10.1016/j.meegid.2024.105698
Plant J. 2024 Dec 11.

Phytosulfokine downregulates defense-related WRKY transcription factors and attenuates pathogen-associated molecular pattern-triggered immunity.

Dian Liu, Joanna Jelenska, Jessica M Morgan, Jean T Greenberg.

  Phytosulfokine (PSK) is a plant growth-promoting peptide hormone that is perceived by its cell surface receptors PSKR1 and PSKR2 in Arabidopsis. Plants lacking the PSK receptors show phenotypes consistent with PSK signaling repressing some plant defenses. To gain further insight into the PSK signaling mechanism, comprehensive transcriptional profiling of Arabidopsis treated with PSK was performed, and the effects of PSK treatment on plant defense readouts were monitored. Our study indicates that PSK's major effect is to downregulate defense-related genes; it has a more modest effect on the induction of growth-related genes. WRKY transcription factors (TFs) emerged as key regulators of PSK-responsive genes, sharing commonality with a pathogen-associated molecular pattern (PAMP) responses, flagellin 22 (flg22), but exhibiting opposite regulatory directions. These PSK-induced transcriptional changes were accompanied by biochemical and physiological changes that reduced PAMP responses, notably mitogen-activated protein kinase (MPK) phosphorylation (previously implicated in WRKY activation) and the cell wall modification of callose deposition. Comparison with previous studies using other growth stimuli (the sulfated plant peptide containing sulfated tyrosine [PSY] and Pseudomonas simiae strain WCS417) also reveals WRKY TFs' overrepresentations in these pathways, suggesting a possible shared mechanism involving WRKY TFs for plant growth-defense trade-off.

Keywords:  Arabidopsis thaliana (L.) Heynh.; PAMP; RNA‐seq; WRKY; flg22; phytosulfokine; plant defense

DOI:  https://doi.org/10.1111/tpj.17115
Proc Natl Acad Sci U S A. 2024 Dec 17. 121(51): e2408199121

Sulfur isotope anomalies in coal combustion: Applications to the present and early Earth environments.

Yanan Shen, Qixin Zhang, Yilun Xu, Menghan Li, Mark H Thiemens.

  The observation of mass-independent sulfur isotope fractionations (S-MIF) in Archean-Paleoproterozoic rocks has been instrumental in constraining oxygen levels on early Earth. The S-MIF effect, experimentally demonstrated to result from photochemical reactions, has now been observed in coal combustion, expanding our understanding of this phenomenon. Our study reveals that the negative Δ33S anomalies produced by coal combustion are consistent with similar anomalies observed in present-day sulfate aerosols in Beijing, China, and the black crust sulfates formed on building stones, monument walls, and sculptures in Europe that contribute to carbonate stone deterioration and cultural heritage damage. This finding provides independent evidence for a critical role of atmospheric sulfate from coal combustion in maintaining isotopic balance and offers an effective method for tracing sulfate aerosol sources. These insights are vital for developing more effective regulatory policies to control air pollution and protect public health. Given that coal energy production remains a significant issue in climate science, accurately mapping the global distribution of its by-products is imperative.

Keywords:  coal combustion; mass-independent isotope effects; sulfate aerosols; sulfur isotopes

DOI:  https://doi.org/10.1073/pnas.2408199121
Int J Biol Macromol. 2024 Dec 08. pii: S0141-8130(24)09377-2. [Epub ahead of print] 138566

Green synthesis of self-assembly, self-healing, and injectable polyelectrolyte complex hydrogels using chitosan, sulphated polysaccharides, hydrolyzed collagen and nanocellulose.

Jianan Lin, Guangling Jiao, Alison J Scott, Chunbao C Xu, Graham Gagnon, Azadeh Kermanshahi-Pour.

  This study introduces a green method for preparing self-assembly hydrogels via polyelectrolyte complex (PEC) coacervation using chitosan, sulphated polysaccharides (chondroitin sulphate or fucoidan), and hydrolyzed collagen, followed by treatments, such as centrifugation, nanocellulose incorporation, algal fucoidan substitution, freezing-thawing, saline solution addition, and dialysis. Chitosan alters the non-gelling characteristics of chondroitin sulphate, fucoidan, and hydrolyzed collagen, initiating quick gelling. This study compared the effects of biopolymer concentrations, pHs, and treatments on hydrogel properties. Hydrogels fabricated using sulphated polysaccharides from different sources demonstrated distinct properties. Nanocellulose incorporation significantly modified the hydrogel performance, with hydrogel containing 4 % nanocellulose showing the lowest E-factor (~1 kg waste/kg product), the highest swelling capacity (up to 766 %), robust rheological strength (storage modulus >20 kPa), interconnected fibrous, highly porous structures, and outstanding thermal stabilities (no significant degradation below 200 °C). The hydrogels also exhibited self-healing and injectable potentials. Centrifugation further improved solid-like behaviours through compacting structures and enhancing interactions. Biopolymer concentrations and pHs had minimal impacts on hydrogel properties. The tailored properties resulting from the biopolymer components and treatments indicated the potential for customizing biomaterial functionality for biomedical applications. The eco-friendly synthesis of PEC hydrogels from marine by-products leverages underutilized renewable resources, contributing to a sustainable bioeconomy.

Keywords:  Hydrogels; Marine biopolymers; Physical crosslinking; Polyelectrolyte complex; Polysaccharides

DOI:  https://doi.org/10.1016/j.ijbiomac.2024.138566