bims-supasi Biomed News
on Sulfation pathways and signalling
Issue of 2025–06–08
twelve papers selected by
Jonathan Wolf Mueller, University of Birmingham
  1. Natural sulfated polysaccharides as biomacromolecules in management of metabolic disorders: A comprehensive review.
  2. Heparan Sulfate-Based Neoproteoglycan for Targeted Lysosomal Degradation of Amyloid-β.
  3. The Biodiversity of KS-Proteoglycans in Cellular Regulation and Tissue Function: Emerging Bioregulatory Roles For Low Sulfation Proteoglycans and Bioconjugates.
  4. Uremic toxin indoxyl sulfate induces the imbalance of cellular iron metabolism and oxidative stress to interfere with myogenesis in myoblasts.
  5. Electroanalysis and electrophysiological recording of bio-doped conducting polymer-modified neural electrodes.
  6. Factor H-related 1 and heparan sulfate architecture contribute to complement dysregulation in C3 glomerulopathy.
  7. Chondroitin sulfate/hyaluronic acid/carboxymethylcellulose macroporous cryogels for controlled delivery of TGF-β1 and IGF-1 to induce chondrogenic differentiation of adipose-derived stem cells in cartilage tissue engineering.
  8. Electrochemical Decarboxylative Sulfation: A Mild and Efficient Method to Access Organosulfates.
  9. Dehydroepiandrosterone sulfate on lifespan in men and women using Mendelian randomization.
  10. Decarboxylative sulfation by persulfates.
  11. Multifunctional applications and research advances of low-molecular-weight heparin.
  12. Preparation, structural identification, and in vitro activity study of polysaccharides and derivatives from Polygonatum hunanense.
  1. Int J Biol Macromol. 2025 Jun 02. pii: S0141-8130(25)05408-X. [Epub ahead of print] 144856
    Natural sulfated polysaccharides as biomacromolecules in management of metabolic disorders: A comprehensive review.
    Pratap Kalita, Manash Pratim Pathak, Pervej Alom Barbhuiya, Freddy Teilang Nongkhlaw.
      Sulfated polysaccharides (SPs), a potential bioactive macromolecule, are involved in exhibiting potential therapeutical responses against several diseases where chronic metabolic disorders such as obesity, cardiovascular disease, diabetes, non-alcoholic fatty liver disease, and dyslipidaemia are the most. Antioxidant, antidiabetic, antihyperlipidemic, anti-inflammatory, cardioprotective, hepatoprotective, chemo-preventive, anti-obesity, anti- metabolic syndrome associated steatotic liver disease (MASLD), and other health benefits of SPs have been recognized. The SPs abundantly available in marine sources characterized with higher molecular weight, molecular geometry, backbone and linkage, enriched amount of sulfate content and sulfate groups in polysaccharide chain, are main precursors that are directly involved in interaction with the different proteins in the matrix and cells resulting in regulation of several pathways and biomarkers to manage different metabolic disorders. The groups of SPs biomacromolecules such as fucoidan, rhamnan sulfate, fucosylated chondroitin sulfate, laminarin sulfate, agar, heteroglycans, fucan sulfate, alginate, ulvan A, ulvan B, xylan, galactan, carrageenan, have been extensively studied for their beneficial role in the management of metabolic disorders through up and down regulation of molecular pathways and mechanisms. This current review focuses on studying sources, characteristics, molecular weight, sulfate content, monosaccharide compositions, structure, backbone and linkage of SPs, up-to-date recent scientific and clinical studies on SPs involved in the management of obesity, cardiovascular disease, diabetes, metabolic syndrome associated steatotic liver disease, dyslipidaemia, and to profile molecular level mechanisms, pathways and mode of actions of SPs.
    Keywords:  Cardioprotective effect; Metabolic diseases; Molecular pathways and mechanisms; Monosaccharide compositions; Sulfated polysaccharides
    DOI:  https://doi.org/10.1016/j.ijbiomac.2025.144856
  2. J Med Chem. 2025 Jun 03.
    Heparan Sulfate-Based Neoproteoglycan for Targeted Lysosomal Degradation of Amyloid-β.
    Sharath S Vishweshwara, Saurabh Anand, Preeti Ravindra Bhoge, Virendrasinh Mahida, Ankita Chandra, Srinivas Vinod Saladi, Raghavendra Kikkeri.
      Targeted lysosomal degradation of proteins (LDP) represents a promising strategy for clearing unwanted toxic extracellular and secreted proteins. Yet, significant challenges persist, including identifying potential ligands for these proteins and lysosome-driving probes capable of facilitating their internalization and degradation through receptor-mediated endocytosis. Herein, we show that synthetic neoproteoglycan probes stably anchor to the cell membrane, facilitate the internalization of amyloid-β (Aβ) peptide into the lysosomal compartment, and mediate the programmed death of Aβ. We have identified sulfated oligo l-idose tetrasaccharide (ID49) and heparan sulfate hexasaccharides (HH26S) as potential ligands for Aβ1-42 peptide. When these molecules are expressed on the peptide-based fluorescent neoproteoglycan backbone, PG@HH26S persists on the cell membrane and facilitates Aβ1-42 endocytosis to the lysosomal compartment and subsequent targeted degradation of Aβ1-42. Overall, neoproteoglycans open a new avenue to generate LDP for degrading HS-binding proteins, including growth factors, morphogens, and toxic secreted proteins.
    DOI:  https://doi.org/10.1021/acs.jmedchem.5c00845
  3. Am J Physiol Cell Physiol. 2025 Jun 03.
    The Biodiversity of KS-Proteoglycans in Cellular Regulation and Tissue Function: Emerging Bioregulatory Roles For Low Sulfation Proteoglycans and Bioconjugates.
    James Melrose.
      The aim of this study was to illustrate the biodiverse properties of keratan sulfate (KS) Proteoglycans (PGs), their varied functions in tissues and emerging roles for low sulfation isoforms of KS PGs now detectable due to the development of some novel KS antibodies. KS is a glycosaminoglycan (GAG), of diverse structure and functional properties and decorates a large range of PGs and equips these with cell regulatory properties. KSPGs also have biophysical roles in tissue stabilization and specific roles in electroconductive bioregulation of neural processes controlling tissue functions. Compared to the multitude of studies on other GAGs, KS has been rather neglected. In the past the major focus was on the biology of high charge density isoforms of KS. In the present day the development of antibodies that can now detect low sulfation isoforms of KS have demonstrated their potential roles in novel cell regulatory processes adding to the diverse bioregulatory properties of KSPGs. KS and KSPGs are now entering new areas in bioregulation adding to the functional roles of PGs in the regulation of connective tissue form and function in health and disease.
    Keywords:  Cellular regulation; Electroconduction; Electrolocation; KS sulfation; Keratan sulfate; Neuron signal transduction; Proton detection
    DOI:  https://doi.org/10.1152/ajpcell.00268.2025
  4. Chem Biol Interact. 2025 May 29. pii: S0009-2797(25)00217-0. [Epub ahead of print]418 111587
    Uremic toxin indoxyl sulfate induces the imbalance of cellular iron metabolism and oxidative stress to interfere with myogenesis in myoblasts.
    Jia-Hua Jhuang, Ching-Chia Wang, Chih-Kang Chiang, Shing-Hwa Liu, Kuo-Cheng Lan.
      Chronic kidney disease (CKD) leads to the accumulation of uremic toxins such as indoxyl sulfate (IS), which has been linked to myopathy. Iron is essential for muscle growth and differentiation, with ferrous iron (Fe2+) contributing to intracellular oxidative stress. Although IS known to affect muscle differentiation and regeneration, the underlying mechanisms remain poorly understood. Both iron overload and deficiency can negatively impact muscle growth. We hypothesized that IS impairs myoblast differentiation by disrupting the balance between intracellular oxidative stress and iron metabolism. To test this, we exposed C2C12 myoblasts and primary human skeletal muscle myoblasts to IS during the proliferation phase and maintained IS exposure throughout the differentiation process. IS treatment reduced both intracellular reactive oxygen species (ROS) and free Fe2+ levels during differentiation. It also altered intracellular iron metabolism and upregulated the gene expression and activity of antioxidant-related enzymes, maintaining the cells in a high-antioxidant state and establishing a new oxidative balance. Unexpectedly, Fe2+ (FeSO4) supplementation, with or without IS, significantly increased ROS levels and further exacerbated the inhibition of myoblast differentiation induced by IS, suggesting that cellular redox homeostasis was disrupted. These findings reveal that IS induces an imbalance in cellular iron metabolism and oxidative stress, providing new insights into an alternative mechanism by which IS inhibits muscle differentiation and regeneration.
    Keywords:  Ferrous iron; Indoxyl sulfate; Myoblast differentiation; Oxidative stress
    DOI:  https://doi.org/10.1016/j.cbi.2025.111587
  5. Ann N Y Acad Sci. 2025 Jun 05.
    Electroanalysis and electrophysiological recording of bio-doped conducting polymer-modified neural electrodes.
    Alexander R Harris, Ben J Allitt, Antonio G Paolini.
      Electroanalytical methods are used to understand, modify, and control bionic devices. Bionic devices can record or stimulate cells to understand and/or control normal or abnormal biological processes. These devices contain electrodes that transduce electrical current within the electrical circuit into ionic current within a tissue. Despite the similarity between electroanalysis and electrophysiology, there remains a poor understanding of the relationship between the two techniques, including their methodology and theory. This paper investigates the electrochemical and acute electrophysiological recording performance of neural electrodes. A range of behaviors is achieved by modifying electrodes with the conducting polymer poly(3,4-ethylenedioxythiophene) (PEDOT) doped with chondroitin sulfate, dextran sulfate, or para-toluene sulfonate. The results support previous studies showing that increased electrode area reduced total impedance below the Maxwell-Wagner relaxation frequency and thermal noise while increasing the signal-to-noise ratio and neural spike count. The results allowed novel investigation of relative contributions of biological and electrode properties to electrophysiological performance, with increased electrode area having a larger impact on neural population within recording range rather than reducing thermal noise. The utility of measuring electrode impedance for predicting electrophysiological performance is mainly for an indirect measure of electrode area. The results provide insight into noise sources from electrophysiological recordings and limitations in cable theory in neuroscience.
    Keywords:  conducting polymer; electroanalysis; electrophysiology; neural implant; neural recording
    DOI:  https://doi.org/10.1111/nyas.15371
  6. Front Immunol. 2025 ;16 1589674
    Factor H-related 1 and heparan sulfate architecture contribute to complement dysregulation in C3 glomerulopathy.
    Amanda K Slagle, Nicolo Ghiringhelli Borsa, Kai Wang, Amanda O Taylor, Nicole C Meyer, Michael B Jones, William D Walls, Angela F M Nelson, Sarah M Roberts, Mingyao Sun, Elena Goicoechea de Jorge, Santiago Rodriguez de Cordoba, Diana I Jalal, Carla M Nester, Yuzhou Zhang, Richard J H Smith.
       Introduction: Dysregulation of the alternative pathway of complement underlies the pathogenesis of C3 glomerulopathy (C3G). Because Factor H (FH) prevents excessive alternative pathway activity while Factor H-related protein 1 (FHR-1) is believed to enhance this response, we investigated the balance between FH and FHR-1 in C3G.
    Methods: To assess the role of FHR-1 in C3G pathogenicity, we used a multiplex ligation-dependent probe amplification to detect copy number variants in CFHR3-CFHR1 and enzyme linked immunosorbent assays to measure circulating protein levels in C3G patients compared to controls. Additionally, an in vitro C3b deposition assay was used to characterize the functional impact of FHR-1 on local complement activity.
    Results: In this study, we confirm that CFHR3-CFHR1 copy number impacts C3G risk. In C3G patients with two copies of CFHR3-CFHR1, the FHR-1:FH protein ratios are increased compared to controls; however, this increase is not disease specific. Rather, it is reflective of deteriorating renal function and was also observed in a second cohort of patients with chronic kidney disease from a variety of other causes. Functional studies showed that FHR-1 competes with FH to increase C3b deposition on mouse mesangial cell surfaces, an effect enhanced by heparan sulfate cleavage.
    Discussion: Altogether, we show that as renal function declines, a change in the FHR-1:FH ratio combined with changes in heparan sulfate architecture increase complement activity. These findings suggest that complement activity may contribute to the chronic inflammation and progression of renal damage associated with chronic kidney disease.
    Keywords:  C3 glomerulopathy; FHR-1; Factor H; chronic kidney disease; complement regulation
    DOI:  https://doi.org/10.3389/fimmu.2025.1589674
  7. Int J Biol Macromol. 2025 May 29. pii: S0141-8130(25)05308-5. [Epub ahead of print]317(Pt 2): 144756
    Chondroitin sulfate/hyaluronic acid/carboxymethylcellulose macroporous cryogels for controlled delivery of TGF-β1 and IGF-1 to induce chondrogenic differentiation of adipose-derived stem cells in cartilage tissue engineering.
    Chih-Hao Chen, Chia-Jui Chang, Chang-Yi Kuo, Guan-Jie Luo, Banendu Sunder Dash, Darshan Tagadur Govindaraju, Jyh-Ping Chen.
      To repair articular cartilage defects using adipose-derived stem cells (ASCs), we aim to fabricate macroporous cryogel scaffolds from chondroitin sulfate (CS) and hyaluronic acid (HA), two of the most abundant glycosaminoglycans in cartilage extracellular matrix. Carboxymethylcellulose was blended with HA and CS and crosslinked with 1,4-butanediol diglycidyl ether to prepare a supramacroporous chondroitin sulfate/hyaluronic acid/carboxymethylcellulose (CHC) cryogel. The cryogel is biodegradable and has unique mechanical properties for use as a scaffold for cartilage tissue engineering. The transforming growth factor-β1 (TGF-β1) and insulin-like growth factor-1 (IGF-1) were bound to CS for prolonged presentation of these growth factors in the scaffolds, with controlled release extended to >21 days. The TGF-β1 and IGF-1 can act in combination to regulate chondrogenic differentiation of seeded ASCs. The CHC/TGF-β1/IGF-1 cryogel scaffold promotes the chondrogenesis over CHC/TGF-β1 from cell morphology, matrix and type II collagen production. From qRT-PCR analysis, it also upregulated the gene expression of SRY-box transcription factor 9 (SOX9), type II collagen (COL2A1), aggrecan (ACAN), and proteoglycan 4 (PRG4) while downregulated the gene expression of type X collagen (COL10A1) After in vitro culture ASCs in CHC/TGF-β1/IGF-1 cryogel for 14 days, the cell/scaffold constructs were implanted in rabbit knees to repair full-thickness articular cartilage defects. The regenerated neocartilage tissue on the surface of defect in the cellular group demonstrates similar morphological and histological features and comparable mechanical properties as the native cartilage. The CHC/TGF-β1/IGF-1 cryogel is an excellent scaffold for preparing tissue-engineered cartilage from ASCs in treating articular cartilage defects.
    Keywords:  Carboxymethylcellulose; Cartilage tissue engineering; Chondroitin sulfate; Cryogel; Glycoaminoglycans; Growth factors; Hyaluronic acid
    DOI:  https://doi.org/10.1016/j.ijbiomac.2025.144756
  8. J Org Chem. 2025 Jun 04.
    Electrochemical Decarboxylative Sulfation: A Mild and Efficient Method to Access Organosulfates.
    Wei Sheng, Huanhuan Peng, Chunlan Song, Jiakun Li.
      Sulfation is a crucial transformation in both pathological and physiological processes. However, the conventional synthesis of organosulfates primarily relies on O-sulfonation, which is limited to hydroxyl-containing substrates. Here, we developed a practical and cost-efficient method for electrochemical decarboxylative sulfation. This approach opens new avenues to access organosulfates from readily available carboxylic acids with a broad substrate scope and good functional group compatibility.
    DOI:  https://doi.org/10.1021/acs.joc.5c00504
  9. Nutr Metab Cardiovasc Dis. 2025 May 13. pii: S0939-4753(25)00282-0. [Epub ahead of print] 104128
    Dehydroepiandrosterone sulfate on lifespan in men and women using Mendelian randomization.
    C Mary Schooling, Jie V Zhao.
       BACKGROUND AND AIM: Dehydroepiandrosterone (DHEA) and DHEA-sulfate (-s) fall with age and are implicated in aging. Observational studies suggest DHEA/DHEA-s could lengthen life in specifically older men. No trial has established the role of DHEA/DHEA-s in aging or lifespan. We assessed the role of DHEA-s in lifespan and key biological determinants, (blood pressure, Apolipoprotein B (ApoB), and haemoglobin A1C (HbA1c)), for men and women in a two-sample mendelian randomization (MR) study using naturally occurring genetic randomization to obviate confounding.
    METHODS AND RESULTS: We assessed associations of sex-specific DHEA-s from Life-Adult/Life-Heart (men = 4327, women = 3501) with lifespan, based on paternal (n = 415311) and maternal (n = 412937) attained age, and with blood pressure, ApoB and Hba1c (men = 167020, women = 194,174) from the UK Biobank. We used inverse variance weighted (IVW) estimates with sensitivity analysis. DHEA-s was unrelated to lifespan in women using IVW, 0.04 years per logged μmol/L DHEA-s, 95 % confidence interval (CI) -0.50 to 0.58, DHEA-s was associated with shorter lifespan in men (-1.15 years, 95 % CI -1.72 to -0.58) with a difference by sex (p = 0.0017), sensitivity analysis gave similar estimates. DHEA-s was unrelated to blood pressure in women and positively associated with systolic and diastolic blood pressure in men with a difference by sex for diastolic blood pressure. DHEA-s was possibly associated with lower ApoB in men.
    CONCLUSIONS: DHEA-s has different associations with lifespan and blood pressure in men and women. In settings where DHEA is an unregulated supplement, such as the United States, whether public health benefits might accrue from more regulation could be considered.
    Keywords:  Blood pressure; DHEA-S; Lifespan; Mendelian randomization; Sex
    DOI:  https://doi.org/10.1016/j.numecd.2025.104128
  10. Chem Sci. 2025 May 29.
    Decarboxylative sulfation by persulfates.
    Zhen Xia, Ting Deng, Chunlan Song, Jiakun Li.
      Direct decarboxylative sulfation via C-O bond formation is an unexplored disconnection strategy for the synthesis of organosulfates, with the potential to overcome the significant limitations of O-sulfonation, which is restricted to hydroxyl-containing compounds. Reported here is a radical process for direct decarboxylative sulfation by persulfates. In this reaction, persulfates serve a dual role: acting as a versatile oxidant to generate carbon-centered radicals in decarboxylation, and providing an O-O source to facilitate the synthesis of organosulfates via C-OSO3 - bond formation. This method enables the replacement of diverse carboxylic acids with ionizable organosulfate groups, which could be potential isosteres to improve molecules' metabolic profiles.
    DOI:  https://doi.org/10.1039/d5sc03129j
  11. Front Pharmacol. 2025 ;16 1585762
    Multifunctional applications and research advances of low-molecular-weight heparin.
    Yanru Zhang, Shuixian Guo, Jingchao Xu.
      Low-molecular-weight heparin (LMWH) is a class of anticoagulant drugs derived from the controlled depolymerization of heparin. LMWH possesses a lower molecular weight and a shorter glycan chain length than unfractionated heparin (UFH), resulting in higher bioavailability, a more predictable pharmacokinetic profile, and consequently, a more convenient administration route. These characteristics make LMWH a primary choice for thromboprophylaxis of deep vein thrombosis. LMWH is clinically indicated for the prevention and treatment of venous thromboembolic diseases. Its role in obstetric complications, inflammation modulation, and antitumor therapy is also increasingly being recognized. The objective of this review was to systematically summarize the progress of LMWH research and to thoroughly explore its mechanisms of action and clinical indications. By analyzing the advantages and disadvantages of LMWH, evaluating its safety and adverse reactions, discussing the challenges in its clinical application, and proposing future research directions, in this review, we aim to promote the application and development of LMWH in a broader range of fields.
    Keywords:  anticoagulant effect; clinical application; low-molecular-weight heparin; mechanism of action; personalized treatment; pharmacokinetics
    DOI:  https://doi.org/10.3389/fphar.2025.1585762
  12. Carbohydr Res. 2025 May 31. pii: S0008-6215(25)00176-4. [Epub ahead of print]555 109550
    Preparation, structural identification, and in vitro activity study of polysaccharides and derivatives from Polygonatum hunanense.
    Runcheng Zhang, Jun Zhou, Ruiding Wen, Xia Qin, Chensi Tan, Xudong Zhou, Jing Liu, Yu Ge, Zhifeng Zhang, Wei Wang, Limin Gong.
      Polysaccharides are one of the main active components of Polygonatum hunanense (PHP). This study extracted polysaccharides from the roots of PHP using water extraction and ethanol precipitation methods. Additionally, PHP was isolated and purified through various techniques, particularly through Diethylaminoethyl-52 (DEAE-52) cellulose and Sephadex G-100 chromatography columns. Structural analysis revealed that PHP is composed of 94.9 % fructose and 5.1 % glucose, with a molecular weight of 6.01 kDa. Moreover, the main chain of PHP residues linkage was found to be β-D-Fruf-(2 → 6)-D-Glcp-(1 → 2)-β-D-Fruf-(6,1 → 2)-β-D-Fruf-(1 → 2)-β-D-Fruf. Branch chain analysis revealed the presence of →2)-β-D-Fruf-(1, 6 → 2)-β-D-Fruf-(1 → 2)-β-D-Fruf. Subsequently, PHP was chemically modified, yielding acetylated polysaccharides (Ac-PHP) and sulfated polysaccharides (Su-PHP). The identification results from Fourier-transform infrared spectroscopy and 13C nuclear magnetic resonance spectra indicated the successful derivatization of the polysaccharides. In vitro bioactivity experiments demonstrated that PHP, Ac-PHP, and Su-PHP can induce cell apoptosis and affect the cell cycle, leading to cytotoxicity toward tumor cells. Compared to PHP, Ac-PHP and Su-PHP exhibited enhanced effects in all groups. These results suggest that PHP might be a promising candidate and supplement for cancer treatment, while the acetylated and sulfated PHP polysaccharides may enhance their antitumor activity by altering their structures.
    Keywords:  Acetylation; Antitumor activity; Polygonatum hunanense; Polysaccharide; Structure characterization; Sulfation
    DOI:  https://doi.org/10.1016/j.carres.2025.109550
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