bims-supasi Biomed News
on Sulfation pathways and signalling
Issue of 2025–08–31
twelve papers selected by
Jonathan Wolf Mueller, University of Birmingham
  1. Dermatan Sulfate: Structure, Biosynthesis, and Biological Roles.
  2. Syndecan-2 positively regulates Wnt/β-catenin signaling in breast cancer cells.
  3. A Cell-Surface-Targeted Fluorogenic Probe for Detection of Sulfatase 2 Activity.
  4. Dehydroepiandrosterone Decline in Aging Males as a Predictor of Erectile Dysfunction and Mood Disorders in Patients With Benign Prostate Hyperplasia Undergoing Dutasteride Treatment.
  5. Chondroitin Sulfate-Mediated Targeted Delivery of Docetaxel and Silibinin-Loaded Nanoparticles for Amelioration of Anticancer Efficacy in Breast Cancer.
  6. In vitroanti-inflammatory effects of alginate sulfate and optimization of alginate sulfate/PVA/CA-based microneedle system.
  7. Davanat-Mimetic Galactomannan and Its Sulfated Derivative: Structure and Antitumor Effects against Melanoma.
  8. Heparanase 2 Modulates Vascular Permeability via Heparan Sulfate-Dependent Growth Factor Signaling.
  9. Keratan Sulfate Is a Multifunctional Brain Glycosaminoglycan With Instructive Capabilities.
  10. Highly Branched Sulfated Glycopolymers as Mucin Mimetics.
  11. Markers in Acute Coronary Syndrome: Distal Coronary Embolism at Percutaneous Coronary Intervention.
  12. Editorial: From pathways to networks: integration of phytohormones and environmental signals.
  1. Biomolecules. 2025 Aug 12. pii: 1158. [Epub ahead of print]15(8):
    Dermatan Sulfate: Structure, Biosynthesis, and Biological Roles.
    Congcong Chen, Xuyang Zhang, Weiting Zhang, Dahai Ding, Ravi Sankar Loka, Kun Zhao, Peixue Ling, Shuaishuai Wang.
      Dermatan sulfate (DS) is a remarkably versatile glycosaminoglycan that plays critical roles across a wide array of biological processes. Its unique structure, characterized by repeating disaccharide units of N-acetyl-D-galactosamine (GalNAc) and Iduronic acid (IdoA) with variable sulfation patterns, enables it to interact with numerous biomolecules. These interactions mediate diverse functions, including the organization of the extracellular matrix, promotion of wound healing, and modulation of cancer progression. Despite its broad biological relevance, deciphering DS function remains challenging due to its pronounced structural complexity and heterogeneity. Variations in chain length, disaccharide composition, and sulfation patterns make it difficult to fully characterize DS's intricate structure-function relationships. In this review, recent developments in biosynthesis, preparation, and applications of DS are summarized.
    Keywords:  biological functions; biosynthesis; dermatan sulfate; preparation
    DOI:  https://doi.org/10.3390/biom15081158
  2. Int J Biochem Cell Biol. 2025 Aug 25. pii: S1357-2725(25)00121-9. [Epub ahead of print]188 106853
    Syndecan-2 positively regulates Wnt/β-catenin signaling in breast cancer cells.
    Leyli Naraghi, Alexey Koval, Vladimir L Katanaev, S Mahmoud A Najafi.
      Syndecans are a family of four-member transmembrane heparan sulfate proteoglycans that bind to various extracellular biomolecules, such as Wnt ligands, via their heparan sulfate chains, thereby controlling a variety of cellular processes. When dysregulated, syndecans can affect tumorigenesis and cancer progression by modulating key signaling pathways involved in the regulation of biological functions. Aberrant activation of Wnt/β-catenin signaling is a hallmark of many human tumors, including breast cancer. Studying the interplay between syndecans and Wnt signaling in human cancers is beneficial for identifying new therapeutic strategies, understanding tumor behavior and improving patient outcomes. Syndecan-2 is predominantly expressed by mesenchymal cells, and its overexpression in tumors of epithelial origin appears to induce aggressive behavior. Here, by measuring β-catenin cytoplasmic stabilization and transcriptional activity, we show that syndecan-2 expression significantly enhances the sensitivity of HEK293T cells and BT-20 triple-negative breast cancer cells to Wnt3a-induced activation of Wnt/β-catenin signaling. In addition, CRISPR/Cas9-mediated deletion of SDC2, the gene encoding syndecan-2, reduced β-catenin transcriptional activity in BT-20 cells in response to Wnt3a stimulation. This reduction was rescued by the re-expression of SDC2. Collectively, our results demonstrate that syndecan-2 is a positive regulator of canonical Wnt signaling. These results also suggest that syndecan-2 is a potential clinical target for inhibiting the progression of some human cancers.
    Keywords:  BT-20; CRISPR-Cas9; Heparan sulfate proteoglycan; Syndecan-2; Triple-negative breast cancer; Wnt/β-catenin signaling
    DOI:  https://doi.org/10.1016/j.biocel.2025.106853
  3. Bioconjug Chem. 2025 Aug 23.
    A Cell-Surface-Targeted Fluorogenic Probe for Detection of Sulfatase 2 Activity.
    Yi Ding, Toshiyuki Kowada, Toshitaka Matsui, Norihiko Sasaki, Shin Mizukami.
      Sulfatase 2 (Sulf-2), an extracellular sulfatase that modulates the sulfation pattern of heparan sulfate proteoglycans (HSPGs), serves as a critical biomarker for various pathological conditions. Monitoring Sulf-2 activity in living cell samples provides valuable insights for diagnostic applications and therapeutic evaluation of Sulf-2-related diseases. In this study, we developed a novel plasma-membrane-targeted fluorogenic probe, MAR-S, to visualize the activity of Sulf-2 secreted by living cells. Upon incubation with Sulf-2-containing culture supernatant from pancreatic cancer cells, MAR-S exhibited a significant increase in fluorescence at approximately 540 nm. Notably, MAR-S allowed for time-lapse monitoring of endogenous Sulf-2 activity in living cancer cells overexpressing Sulf-2, demonstrating its potential as a valuable tool for Sulf-2-related cancer diagnostics and therapeutic research.
    DOI:  https://doi.org/10.1021/acs.bioconjchem.5c00251
  4. Am J Mens Health. 2025 Jul-Aug;19(4):19(4): 15579883251365091
    Dehydroepiandrosterone Decline in Aging Males as a Predictor of Erectile Dysfunction and Mood Disorders in Patients With Benign Prostate Hyperplasia Undergoing Dutasteride Treatment.
    Maja Sofronievska Glavinov, Senol Tahir, Stefan Arsov.
      Age-related decline in dehydroepiandrosterone (DHEA) and its sulfate metabolite, dehydroepiandrosterone-sulfate (DHEAS), affects steroid synthesis in men. DHEA(S) acts as a direct neurosteroid and weak androgen and is the unique steroid unaffected by dutasteride's inhibitory effect on 5α reductases. This study examined the relationship between dutasteride's side effects, specifically erectile dysfunction (ED) and mood disorders, and the age-related decline in DHEAS. The study included 250 patients with benign prostatic hyperplasia (BPH), divided into two age groups (<60 and ≥60 years), and treated with tamsulosin or tamsulosin plus dutasteride. DHEAS levels were measured, and patients were assessed for ED and mood disorders using standardized questionnaires. Some patients experienced worsening ED and mood disorders during the 6-month follow-up period. The study found a correlation between DHEAS levels and erectile function and mood status in both age groups receiving dutasteride combination therapy (p < .05). Regression analyses showed that DHEAS was a positive predictor for ED in older patients treated with tamsulosin (p < .001) and in both age groups receiving dutasteride combination therapy (p < .001). In addition, DHEAS was a significant negative predictor for mood changes in both age groups receiving combination therapy (p < .001). This study suggests that baseline DHEAS levels can predict changes in erectile function and mood status in BPH patients treated with dutasteride therapy. It is, therefore, recommended to perform DHEAS assessment before starting dutasteride treatment in order to reduce the risk of ED and mood disorders.
    Keywords:  benign prostate hyperplasia; dehydroepiandrosterone; dutasteride; erectile dysfunction; mood disorders
    DOI:  https://doi.org/10.1177/15579883251365091
  5. ACS Appl Bio Mater. 2025 Aug 25.
    Chondroitin Sulfate-Mediated Targeted Delivery of Docetaxel and Silibinin-Loaded Nanoparticles for Amelioration of Anticancer Efficacy in Breast Cancer.
    Mayur Aalhate, Srushti Mahajan, Rahul Kumar, Arun Kumar, Barkha Jangir, Sharon Munagalasetty, Umarani Brahma, Ujala Gupta, Indrani Maji, Durga P Mishra, Vasundhra Bhandari, Pankaj Kumar Singh.
      Breast cancer is the second leading cause of mortality in women worldwide. Chemotherapeutic drugs like docetaxel (DTX) remain key molecules in cancer management. Silibinin (SLB) is an effective agent causing apoptosis and autophagy resulting in cancer cell death. Recently, ligand-anchored targeted nanocarrier-based drug delivery has achieved substantial improvement in cancer therapy. In the present study, chondroitin sulfate (CS) was used as a ligand to target CD44 receptors overexpressed in breast cancer cells. Herein, CS-coated chitosan-lecithin nanoparticles (CS-DTX-SLB-LCNPs) were developed for co-delivery of DTX and SLB. The CS-DTX-SLB-LCNP resulted in a particle size of 208.33 ± 2.20 nm with an entrapment efficiency of 83.81% for DTX and 92.96% for SLB. Further, the dialysis release study showed sustained release behavior, and a hemocompatible nature which was proved by the hemolysis study. The cell cytotoxicity in MDA-MB-231 cells revealed considerably higher cell killing with CS-DTX-SLB-LCNP compared to free drugs. The cell uptake studies showed a 1.97-fold and 2.45-fold rise in fluorescence intensity from C6-LCNP and CS-C6-LCNP, respectively, as compared to free C6. CS-DTX-SLB-LCNP caused a sharp rise in the ROS level and resulted in mitochondrial membrane depolarization, which induced apoptosis and cell death. An in vivo efficacy study in Balb/c mice demonstrated 2.24-fold and 2-fold reduction in tumor volume after CS-DTX-SLB-LCNP treatment as compared to free DTX and free SLB groups. In conclusion, CS-DTX-SLB-LCNPs showed encouraging prospects in increasing cellular uptake and targeting specificity to treat breast cancer.
    Keywords:  Breast cancer; Chitosan; Chondroitin Sulfate; Docetaxel; Silibinin
    DOI:  https://doi.org/10.1021/acsabm.5c01098
  6. Colloids Surf B Biointerfaces. 2025 Aug 20. pii: S0927-7765(25)00571-5. [Epub ahead of print]256(Pt 2): 115064
    In vitroanti-inflammatory effects of alginate sulfate and optimization of alginate sulfate/PVA/CA-based microneedle system.
    Akshad Balde, Rasool Abdul Nazeer.
      Polymeric modification and transdermal delivery are rapidly growing fields. In this study, alginate sulfate (AlgS) was synthesized with varying degrees of sulfation using chlorosulfonic acid. The results indicated a greater level of sulfation for the reaction with increased chlorosulfonic content. Moreover, spectroscopic investigation revealed characteristic functional peaks indicating the successful integration of the sulfate group. The results of anti-inflammatory tests showed that AlgS-3 (prepared with 5 % chlorosulfonic acid v/v) exhibited greater anti-inflammatory properties within the concentration range of 0.5-2 % w/v. In addition, both murine and human fibroblast cells demonstrated that the formulated AlgS-3 exhibited no toxicity and effectively inhibited elevated nitrite levels at greater concentrations. Furthermore, when the AlgS-3 concentration was increased to 2 % w/v, the levels of inflammatory mediators were decreased in fibroblast cells. To further explore advanced delivery systems, microneedle patches were prepared with AlgS-3 and poly-vinyl alcohol crosslinked with citric acid and optimized using response surface methodology. The optimized microneedle formulations (7.83 % w/v PVA; 1.84 % w/v AlgS-3; 3.46 % w/v citric acid; 500 μm microneedle length) demonstrated high encapsulation efficiency of the model protein BSA. Protein release studies revealed a sustained release profile, with approximately 80 % of BSA released within one hr. Cytotoxicity assays on murine and human fibroblast cells confirmed the biocompatibility of the microneedle patches, with cell viability exceeding 90 %. These AlgS/PVA microneedles are designed for localized transdermal delivery in inflammatory skin and joint disorders. Compared to conventional anti-inflammatory materials, they can offer enhanced biocompatibility, reduced systemic toxicity, and sustained protein release for improved therapeutic outcomes.
    Keywords:  Alginate sulfate; Inflammation; Microneedle patch; Oxidative stress; Protein delivery
    DOI:  https://doi.org/10.1016/j.colsurfb.2025.115064
  7. Biomacromolecules. 2025 Aug 21.
    Davanat-Mimetic Galactomannan and Its Sulfated Derivative: Structure and Antitumor Effects against Melanoma.
    Odair Braz Júnior, Aline Miranda Cristal, Daniel de Lima Bellan, Gustavo Rodrigues Rossi, Stellee Marcela Petris Biscaia, Camila Laís Gonçalves Ribeiro, Jacqueline Gonçalves Dos Santos, Anderson Fraga da Cruz, João Luiz Aldinucci Buzzo, Helyn Barddal, Thales R Cipriani, Marcelo Dias-Baruffi, Edvaldo da Silva Trindade, Fernanda Fogagnoli Simas, Carolina Camargo de Oliveira.
      Melanoma is the most aggressive skin cancer, with a high metastatic potential and limited treatment options in advanced stages. Polysaccharides are promising antitumor agents, and therefore, this study investigated a galactomannan from guar gum hydrolysis (GGH) and its sulfated derivative (GGHS) for their antimelanoma and immunostimulatory effects. GGH shares structural similarity with DAVANAT, a galectin-1 ligand with anticolorectal cancer activity, while GGHS has anticoagulant properties, like heparin used in cancer patients. In vitro, 100 μg/mL GGH or GGHS inhibited melanoma cell invasion, increased adhesion, and reduced colony size, while GGHS also reduced proliferation. Both compounds bind galectin-3 and -1, but only GGH suppressed tumor progression in mice. Both treatments stimulated macrophage proinflammatory responses, including reactive oxygen species production and cytokine secretion. Although in vitro lymphocyte proliferation was not observed, CD3+ cells increased in the metastatic lungs. These results suggest GGH and GGHS as immunostimulatory agents, with GGH as potential melanoma adjuvant therapy.
    DOI:  https://doi.org/10.1021/acs.biomac.5c00290
  8. Arterioscler Thromb Vasc Biol. 2025 Aug 21.
    Heparanase 2 Modulates Vascular Permeability via Heparan Sulfate-Dependent Growth Factor Signaling.
    Yannic Becker, Sergey Tkachuk, Anne Jörns, Nelli Shushakova, Song Rong, Ahmad Alwakaa, Jan Hegermann, Heiko Schenk, Yulia Kiyan, Hermann Haller.
       BACKGROUND: Vessel-lining endothelial cells (ECs) rely on heparan sulfate (HS) proteoglycans to regulate vascular permeability and to maintain vascular homeostasis. Hpa2 (heparanase 2) is a little-known, nonenzymatic, HS-binding protein. We hypothesized major functions and thus characterized the role of endogenous Hpa2 in the vertebrate vascular system.
    METHODS: We use zebrafish larvae as our primary animal model. Hpa2 loss-of-function (LOF) was induced by CRISPR-Cas9 (clustered regularly interspaced short palindromic repeats/clustered regularly interspaced short palindromic repeat-associated 9) and morpholino antisense strategies. We assessed vascular permeability, blood vessel architecture, and EC morphology using transgenic zebrafish and transmission electron microscopy. rHpa2 (recombinant heparanase 2) was generated to study the functionality of Hpa2 in endothelial tissue cultures, zebrafish, and mice.
    RESULTS: We detected Hpa2 expression in hepatic tissue and localized Hpa2 protein in the vasculature of zebrafish and mammals. Hpa2 LOF increased zebrafish vascular permeability and altered EC and extracellular matrix morphology. rHpa2 rescued the Hpa2 LOF phenotype. Hpa2 LOF reduced HS levels and caused EC gene expression changes involved in signal transduction. rHpa2 competed with growth factors FGF2 (fibroblast growth factor-2) and VEGFA165 (vascular endothelial growth factor A165) for binding on the EC surface and consequently reduced the signal response these factors elicit. rHpa2 prevented VEGFA165-induced vascular permeability in murine ex vivo kidneys. Pharmacological inhibition of FGF2/VEGFR (VEGF receptor) signaling alleviated the Hpa2 LOF phenotype in zebrafish.
    CONCLUSIONS: We suggest that Hpa2 is a circulating molecule that maintains vascular integrity by regulating vascular HS-dependent growth factor signaling. Our model outlines Hpa2-related vascular function and could indicate therapeutic utilities.
    Keywords:  endothelial cells; heparan sulfate proteoglycans; heparanase; homeostasis; zebrafish
    DOI:  https://doi.org/10.1161/ATVBAHA.125.323060
  9. J Neurochem. 2025 Aug;169(8): e70208
    Keratan Sulfate Is a Multifunctional Brain Glycosaminoglycan With Instructive Capabilities.
    James Melrose.
      Keratan sulfate (KS) is a glycosaminoglycan (GAG) with unique functions including electroconductive properties that support neurotransmission. KS-proteoglycans contribute to tissue stabilization and functional organization, and have diverse interactive properties with cytokines, growth factors, morphogens, neuregulatory proteins, and neuron receptors that control the formation and function of neural networks. As side chain components of a diverse range of brain proteoglycans, KS assists neural development and axonal guidance, storage and transport of neurotransmitters in synaptic vesicles, neurotransduction, synaptic plasticity, cognition, and memory in perineuronal nets, neuronal proliferation, and differentiation. KS is thus a multifunctional instructive brain GAG with essential roles to play in brain function and homeostasis, with instructive roles in the assembly and repair of functional network structures from secreted molecules produced by glial cells and neurons in the assembly of transmitter and effector receptors and ion channels which affect brain function and neuronal control. KS is a component of neuropils in white matter; however, its specific roles in the function of this tissue have yet to be determined. Dysfunctional KS-mediated cell signaling, however, may predispose to the development of a number of neurological disorders.
    Keywords:  KS; KS‐proteoglycans; axonal guidance; neuronal cell regulation; perineuronal nets
    DOI:  https://doi.org/10.1111/jnc.70208
  10. J Am Chem Soc. 2025 Aug 27.
    Highly Branched Sulfated Glycopolymers as Mucin Mimetics.
    Melina I Feldhof, Rebecca Schlatterer, Friederike Strahl, Jonathan Garthe, Sylvain Prévost, Stephan Schmidt, Matthias Karg, Bizan N Balzer, Laura Hartmann.
      Mucins are highly complex glycoproteins that form protective and lubricating barriers around epithelial surfaces, e.g., in the respiratory tract, to protect against pathogens. The isolation and purification of natural mucins without compromising their structure and thus their properties remain challenging. Glycopolymers as mucin mimetics have shown great potential in biomedical research, for example, in mucosal barrier enhancement and respiratory disease treatment, or in improving surface lubrication and adhesion properties. Here, we introduce double-brushed mucin mimetic glycopolymers, replicating for the first time a structural design that more closely imitates key architectural features of natural mucins. By combining solid-phase synthesis of sequence-defined glycooligomers and their attachment onto polyactive ester scaffolds, we enable access to a library of linear, brushed, and double-brushed glycopolymers with controlled variations of structural parameters, such as overall chain length, number, and length of branches, as well as number of carbohydrates and degree of sulfation. By using light and neutron scattering as well as atomic force microscopy-based single-molecule force spectroscopy and imaging, we can demonstrate that the double-brushed architecture is responsible for successfully mimicking critical mucin properties, such as their adhesion to hydrophilic surfaces and an extended conformation, properties that are not achieved with single-brushed or linear analogues. Thus, our findings show that double-brushed sulfated glycopolymers effectively replicate key characteristics of natural mucins, advancing their potential as mucin models, as well as for use in biomedical applications.
    DOI:  https://doi.org/10.1021/jacs.5c08232
  11. J Cardiovasc Dev Dis. 2025 Aug 19. pii: 315. [Epub ahead of print]12(8):
    Markers in Acute Coronary Syndrome: Distal Coronary Embolism at Percutaneous Coronary Intervention.
    Niya Emilova Semerdzhieva, Simeon Dimitrov, Adelina Tsakova, Mariana Gospodinova, Petar Atanasov, Vesela Lozanova.
      (1) Introduction: Distal coronary emboli occur in up to 15-30.5% of patients undergoing percutaneous coronary intervention (PCI) for acute myocardial infarction (AMI) and are associated with poor myocardial reperfusion in the territory of the infarct-related artery. The objective of this study was to analyze the possible laboratory, clinical and imaging indicators of distal coronary embolism detected with an angiography at the time of PCI with stent implantation for acute coronary syndrome (ACS). (2) Methods: This analysis included 137 patients with ACS. The levels of cardiac enzymes (creatine kinase [CK], muscle-brain fraction of CK, high-sensitivity troponin T [hsTnT]), inflammatory markers (high-sensitivity C-reactive protein, white blood cell counts), sex steroids (total 17β-estradiol, total testosterone, dehydroepiandrosterone sulfate [DHEA-S]), serum lipids and oxidized low-density lipoproteins (oxLDL) were measured and analyzed for their relationship with the incidence of distal coronary embolism at PCI. (3) Results: Slow coronary blood flow was detected in the coronary artery subject to intervention in 9.4% (n = 13) of patients. Triglyceride (TG), high-density lipoprotein (HDL), glucose and serum DHEA-S levels were found to be associated with distal coronary embolization and slow coronary flow at PCI with stenting (DHEA-S: 1.316, OR 1.044-1.659, p = 0.020; TG: 1.130, OR 0.990-1.300, p = 0.072; HDL: 2.326, OR 0.918-5.8977, p = 0.075; glucose: 1.130, OR 0.990-1.300, p = 0.072). In the multivariable model, only DHEA-S after PCI tended to indicate a risk of distal coronary embolism (DHEA-S: p = 0.071; TG: p = 0.339; glucose: p = 0.582; HDL: p = 0.502). (4) Conclusions: Patients with ACS with higher triglyceride levels are at risk of developing slow blood flow after percutaneous intervention with stent implantation. Elevated DHEA-S possibly reflects sympathoadrenal and hypothalamus-pituitary-adrenal hyperactivity associated with ACS and coronary intervention.
    Keywords:  TIMI flow grade; acute coronary syndrome; dehydroepiandrosterone sulfate; distal coronary embolism; myocardial blush grade; percutaneous coronary intervention; triglycerides
    DOI:  https://doi.org/10.3390/jcdd12080315
  12. Front Plant Sci. 2025 ;16 1667710
    Editorial: From pathways to networks: integration of phytohormones and environmental signals.
    Takuya Yoshida.
      
    Keywords:  HPLC-MS/MS; abscisic acid (ABA); auxin; brassinosteroid (BR); cytokinin (CK); phosphatidic acid (PA); phytohormone signaling; sulfated peptide
    DOI:  https://doi.org/10.3389/fpls.2025.1667710
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