bims-supasi 2025-12-28 papers

bims-supasi

Biomed News

on Sulfation pathways and signalling

Issue of 2025–12–28
twelve papers selected by
Jonathan Wolf Mueller, University of Birmingham

Merging Enzymatic Catalysis with Iron Catalysis for Highly Stereoselective Heparan Sulfate Oligosaccharide Assembly.
High molecular weight fucosylated glycosaminoglycan promotes the binding of antithrombin and thrombin: a template mechanism and structure-activity relationship study.
Dehydroepiandrosterone sulfate as a potential biomarker for assessing the etiology of canine naturally occurring Cushing's syndrome.
Synthesis of Heparan Sulfate Hexadecasaccharides and Their Molecular Interaction with Mycobacterial Heparin-Binding Hemagglutinin for the Detection of Mycobacterium tuberculosis.
Enzymatic and chemical depolymerization of Fucus evanescens fucoidan: Impact on structure and hemostatic activity.
Structure-activity relationships of acid-hydrolyzed Carrageenans: Molecular modifications and anticancer activity in colorectal Cancer cells.
Heparan sulphate and neural development: dissecting the roles of astrocyte-expressed heparan sulphate.
Enhancing the efficiency of bone tissue regeneration by using a 3D printed scaffold optimized with heparan sulfate proteoglycan 2.
Cervical Glycosaminoglycans and Extracellular Matrix Remodeling: New Insights and the Therapeutic Promise of Tafoxiparin.
Use of Andexanet Alfa to Reverse Heparin After Cardiopulmonary Bypass.
Precision-Engineered Dermatan Sulfate-Mimetic Glycopolymers for Multi-Targeted SARS-CoV-2 Inhibition.
Postmortem correlation of ethanol and minor metabolites ethylglucuronide and ethylsulfate in blood, vitreous humor and bile.

J Am Chem Soc. 2025 Dec 21.

Merging Enzymatic Catalysis with Iron Catalysis for Highly Stereoselective Heparan Sulfate Oligosaccharide Assembly.

Dakang Zhang, Zixiang Jiang, Le Yin, Xiao-Wen Zhang, Haoyu Yang, Pinzhi Wang, Changmin Xie, Eduardo Stancanelli, Yongmei Xu, Haoran Wang, Junjiang Sun, Jian Liu, Hao Xu.

Heparan sulfate (HS) regulates numerous biological processes, but it occurs naturally as a heterogeneous mixture of sulfated complex glycans. Therefore, pursuing a broadly effective approach for homogeneous HS synthesis to advance biological studies has been an outstanding challenge in glycoscience. By merging the catalytic power of sulfotransferases (SULTs) with two distinct iron-catalyzed glycosylation reactions, we report herein a highly stereoselective and generally applicable HS assembly strategy. Every glycosidic linkage in HS was assembled by one of these iron-catalyzed, entirely stereoselective glycosylation reactions. An array of sulfate groups that are essential to HS's function were installed at their desired locations via the SULT-controlled sulfation of HS precursors. This general approach is showcased in the synthesis of an anticoagulant HS hexasaccharide and other full-length precursors of HS octasaccharides.

DOI: https://doi.org/10.1021/jacs.5c19067
Glycoconj J. 2025 Dec 23. 43(1): 2

High molecular weight fucosylated glycosaminoglycan promotes the binding of antithrombin and thrombin: a template mechanism and structure-activity relationship study.

Chuang Xiao, Li Xu, Ying Cai, Zhenhua Liu, Yingnian Li, Na Gao, Jinhua Zhao.

  Native fucosylated glycosaminoglycan (FG), a structurally unique polysaccharide with chondroitin sulfate like backbone and sulfated fucose side chains, has multiple anticoagulant mechanisms. Analyzing the interaction between FG and coagulation proteins will help to further understand its pharmacological mechanisms. Previously, we have reported that high molecular weight depolymerized FG (dFG) and unfractionated heparin (UFH) exhibit different binding models for antithrombin (AT), which is a primary natural anticoagulant in plasma by inhibiting coagulation proteases including thrombin (FIIa). In this study, the effect of dFG or UFH on the interaction between AT and FIIa was detected by biolayer interferometry. The relative AT binding affinity and AT-dependent anti-FIIa activity of dFG derivatives were measured to elucidate the structure-activity relationship. The results demonstrate that high molecular weight dFG significantly promotes the irreversible binding of FIIa and AT by a template mechanism. As the molecular weight decreases, the relative AT binding affinity of dFG decreases and molecular weight above 8.55 kDa is required for their interaction in this study. Both the fucose side chains and carboxyl groups are indispensable for dFG to bind with AT and inhibit FIIa activity. This study clarifies the mechanism and structure-activity relationship of dFG inhibiting FIIa by AT, providing references for the development of novel anticoagulant drugs based on FG and its derivatives.

Keywords:  Antithrombin; Biolayer interferometry; Fucosylated glycosaminoglycan; Structure-activity relationship; Template mechanism; Thrombin

DOI:  https://doi.org/10.1007/s10719-025-10200-2
Domest Anim Endocrinol. 2025 Dec 20. pii: S0739-7240(25)00082-7. [Epub ahead of print]95 106993

Dehydroepiandrosterone sulfate as a potential biomarker for assessing the etiology of canine naturally occurring Cushing's syndrome.

Inês Oliveira, Patrícia Marques, Francesca Del Baldo, Mariachiara Re, Luísa Mateus, Rodolfo Oliveira Leal.

  Canine naturally occurring Cushing's syndrome (CS) is usually caused by a pituitary tumor (pituitary-dependent hypercortisolism; PDH) or a functional adrenocortical tumor (adrenal-dependent hypercortisolism; ADH). Although endogenous adrenocorticotropic hormone (eACTH) measurement combined with imaging tests is one of the most reliable methods for differentiating PDH from ADH, it has some limitations. In humans, dehydroepiandrosterone sulfate (DHEAS) levels may help determine CS etiology. This study aimed to assess the role of DHEAS concentrations in differentiating PDH from ADH in dogs and correlate DHEAS and eACTH concentrations. A multicenter, retrospective, cross-sectional study was conducted, including dogs diagnosed with CS. They were divided into groups according to suspected CS etiology, sex and neutered status. A total of 38 dogs were included; 33/38 (87 %) were classified as having PDH and 5/38 (13 %) ADH. There were 19 females and 19 males, of which 16 and 9 were neutered, respectively. Median DHEAS concentrations were significantly higher in intact males (2.45 ng/mL; interquartile range 1.02-7.80 ng/mL) than in neutered males (0.68 ng/mL; interquartile range 0.42-2.03 ng/mL; p = 0.017). Females showed a positive correlation between DHEAS and eACTH levels (r = 0.588; p = 0.008). There were no significant differences in DHEAS concentrations between PDH and ADH (p = 0.645). Moreover, ROC curve analysis demonstrated poor ability of DHEAS to differentiate PDH from ADH (AUC 0.430). In conclusion, DHEAS does not appear to be a relevant biomarker for determining CS etiology in dogs and ACTH may not be a major driver for its synthesis.

Keywords:  Adrenal-dependent hypercortisolism; Cushing’s syndrome; Dehydroepiandrosterone sulfate; Dog; Endogenous adrenocorticotropic hormone; Pituitary-dependent hypercortisolism

DOI:  https://doi.org/10.1016/j.domaniend.2025.106993
J Am Chem Soc. 2025 Dec 22.

Synthesis of Heparan Sulfate Hexadecasaccharides and Their Molecular Interaction with Mycobacterial Heparin-Binding Hemagglutinin for the Detection of Mycobacterium tuberculosis.

Krishnagopal Maiti, Guan-Wen Huang, Yun-Hao Zhuang, Chih-Hung Wang, Jia-Ru Chang, Medel Manuel L Zulueta, Jasper S Dumalaog, Chiao-Chu Ku, Shih-Ching Wang, Cheng-Hsiu Chang, Chia-Lin Chyan, Horng-Yunn Dou, Gwo-Bin Lee, Shang-Cheng Hung.

Heparin-binding hemagglutinin (HBHA), located on the surface of Mycobacterium tuberculosis, binds to heparan sulfate (HS) on respiratory epithelial cells, initiating extrapulmonary dissemination and contributing to the development of latent tuberculosis. Previous characterization suggested that the lysine-rich domain of HBHA may accommodate an HS chain that is approximately twice the length of an octasaccharide. Herein, we prepared eight HS-based hexadecasaccharides through convergent assembly of a precursor, followed by divergent functional group modifications to generate varying sulfonation patterns. The hexadecasaccharide with repeating trisulfonated disaccharide units exhibited the highest binding affinity. The regions of HBHA affected by the interaction were identified by circular dichroism and multidimensional nuclear magnetic resonance analysis. Biotin functionalization of the hexadecasaccharide facilitated attachment to streptavidin-coated magnetic beads. These beads with bound HS displayed the ability to capture mycobacteria via HBHA on an integrated microfluidic chip. Aided by propidium monoazide as a DNA-binding agent and on-chip polymerase chain reaction, a means for diagnosis of tuberculosis is demonstrated.

DOI: https://doi.org/10.1021/jacs.5c14234
Int J Biol Macromol. 2025 Dec 19. pii: S0141-8130(25)10330-9. [Epub ahead of print]338(Pt 2): 149773

Enzymatic and chemical depolymerization of Fucus evanescens fucoidan: Impact on structure and hemostatic activity.

Artem S Silchenko, Ilya V Taran, Anastasia O Zueva, Nikolay V Zvyagintsev, Mikhail I Kusaykin, Svetlana P Ermakova.

  Fucoidans are fucose-rich, sulfated polysaccharides with potent anticoagulant properties. However, their application is limited by the structural heterogeneity and the platelet-activating effects associated with their high molecular weight (Mw). Low-Mw derivatives alleviate these issues but often show diminished anticoagulant potency. In the present study, we systematically compared enzymatic and chemical depolymerization methods to generate low-Mw Fucus evanescens fucoidan derivatives and evaluated how structural modifications influence their anticoagulant and platelet-modulating activities. Fucoidan derivatives were produced using four GH107 endo-fucanases with different sulfation specificities, as well as mild acid hydrolysis and hydrogen peroxide treatment. The structural characterization of the obtained derivatives was carried out using size-exclusion chromatography (SEC), nuclear magnetic resonance (NMR) spectroscopy, and a novel enzyme-based sulfation pattern mapping assay. Hemostatic properties were assessed via coagulation assays, coagulation factors inhibition, platelet aggregation, and measurements of whole-blood clot stability. Short-duration acid hydrolysis (1 h) and controlled peroxide treatment (12 h) yielded low-Mw derivatives with only slight anticoagulant activity reductions, whereas prolonged chemical treatment substantially decreased potency. Enzymatic depolymerization produced more defined low- and medium-Mw derivatives with higher yields and structure-dependent activity. Structure-activity analysis revealed that anticoagulant efficacy primarily depends on sulfation pattern (notably 2,4-di-sulfation), and molecular weight thresholds (6-10 kDa), rather than total sulfate content. Similarly, depolymerization reduced platelet aggregation by >45 %, with activation absent below 10 kDa. However, elevated 2,4-di-sulfation correlated positively with platelet aggergation. These findings highlight the critical balance between Mw and 2,4-di-sulfation in regulating hemostasis, providing a framework for designing safer, more effective fucoidan-based therapeutics.

Keywords:  Coagulation inhibition; Fucoidan depolymerization; GH107 Endo-fucanases; Low molecular weight derivatives; Platelet aggregation; Sulfation pattern

DOI:  https://doi.org/10.1016/j.ijbiomac.2025.149773
Int J Biol Macromol. 2025 Dec 22. pii: S0141-8130(25)10369-3. [Epub ahead of print] 149812

Structure-activity relationships of acid-hydrolyzed Carrageenans: Molecular modifications and anticancer activity in colorectal Cancer cells.

Ellen Cristina Miranda Lacerda, Lucas de Freitas Pedrosa, Francisco Felipe Bezerra, Paulo Antônio de Souza Mourão, Gabriela Martins de Araújo, Fábio Ruiz Simões, João Paulo Fabi.

  Carrageenans are sulfated polysaccharides found in algae and certain plants, and are widely used in the food industry. By modifying their chemical structures through sulfation, polysaccharides can enhance their biological properties, including anticancer effects. Investigating the relationship between carrageenan structure and biological effects is essential to understanding how carrageenans may affect cancer cells. We chemically modified carrageenans by acid hydrolysis, evaluated their biological effects on colon cancer cells, and characterized their molecular structure. HPSEC-RID confirmed a decrease in molecular weight and polydispersity of carrageenans. Modified carrageenans decreased cell viability in a lineage-specific manner, distinct from that of the same non-modified ones. A- and B-mod carrageenan samples reduced cellular proliferation and increased p21 protein levels in a p53-independent manner, and B-mod increased the sub-G1 phase of HCT116 cells. FTIR and NMR structural analyses identified β-Gal4SO4 and 3,6-anhydro-α-Gal (DA) units in the A-mod sample; β-Gal4SO4 and 3,6-anhydro-α-Gal2SO4 units, and also DA units, resulting from a specific desulfation reaction at the 2-position of 3,6-anhydro-α-Gal, in the B-mod sample. Since B-mod showed higher-molecular-weight fragments and fewer low-molecular-weight fragments, it indicates greater potential for in vitro anticancer activity and requires further optimization for safer use.

Keywords:  Carrageenan; Chemical modification; Colorectal cancer; Structure-bioactivity; Sulfated polysaccharides

DOI:  https://doi.org/10.1016/j.ijbiomac.2025.149812
Biochem Soc Trans. 2025 Dec 24. 53(6): 1543-1554

Heparan sulphate and neural development: dissecting the roles of astrocyte-expressed heparan sulphate.

Martina Gyimesi, Rachel K Okolicsanyi, Larissa M Haupt.

  Astrocytes are key regulators of neurogenesis, synaptogenesis, synaptic transmission and the clearance of pathological factors within the brain, while maintaining homeostasis throughout life. They also aid in the establishment and maintenance of a neurogenic niche enriched with precisely balanced growth factors, morphogens and extracellular matrix proteoglycans (PGs) to support neuronal development and function. Membrane-bound heparan sulphate (HS) PGs consist of core proteins decorated with HS glycosaminoglycan side chains, whose highly variable sulphation patterns regulate cellular signalling pathways such as Wnt and fibroblast growth factor. However, the specific contributions of astrocyte-derived and/or neuronal HSPGs within this microenvironment remain unclear. This mini-review examined our current understanding of the regulatory role of astrocyte-expressed HSPGs and their associated HS side chain structural variability. In particular, their influence on prenatal brain development, ageing and the changes occurring that contribute to neurodegeneration. We focused on the emerging concept that HS aggregation and impaired neurogenesis may serve as important preclinical contributors to Alzheimer's disease pathology. Alterations in astrocyteexpressed HS and their HSPG landscape are discussed as potential precursors to pathological HS aggregation and reactivity, shifting the focus of disease initiation to the potential compromise of the supportive astrocytic environment. We suggest that neuronal dysfunction cannot be solely attributed to neurodegeneration but must also be considered in the context of a deteriorating support system, where cells that once nurtured neurogenesis and synaptic integrity become dysfunctional contributors to disease pathology.

Keywords:  astrocytes; brain development; neurodegeneration; neurogenesis; proteoglycans

DOI:  https://doi.org/10.1042/BST20253088
Biomed Mater. 2025 Dec 23.

Enhancing the efficiency of bone tissue regeneration by using a 3D printed scaffold optimized with heparan sulfate proteoglycan 2.

Chung-Yao Ku, Yin-Hsiu Chen, Chih-Ming Lin, Yin-Hung Chu, Ying-Jui Ho, Li-Ling Liu, Ying-Chieh Huang, Kentaro Okuyama, Chiung-Hui Liu, Wen-Chieh Liao.

  Craniofacial bone deficiencies caused by trauma or disease pose clinical challenges as the shape of the damaged area varies between people. Although bone grafts are effective, they face issues such as poor drug retention and potential immune responses. Polylactic acid (PLA) scaffolds possess therapeutic potential owing to their size, mechanical properties, stability, and biocompatibility. However, PLA scaffolds inherently lack bioactive molecules necessary to promote osteogenesis. Heparan sulfate proteoglycans (HSPG2), also known as perlecan (Pln), are a basement membrane-specific glycosaminoglycan (GAG)-containing core protein. Pln is a reservoir for heparin-binding growth factors, such as fibroblast growth factor (FGF), through GAG chains in domain I. For these reasons, we designed an HSPG2-coated PLA scaffold to enhance FGF delivery and promote cranial bone regeneration. Our results suggested an ideal scaffold with a 0.3 mm pore size and 60% porosity, enabling MG 63 cell proliferation and osteogenesis. HSPGs help modulate FGF signalling during MG63 cell differentiation, motivating further studies on the microenvironment involved in neo-bone formation. We used 3D-printed PLA scaffolds coated with HSPG2 to create an osteoconductive environment. Advanced quantitative tests, computed tomography, and confocal microscopy confirmed the efficacy of the scaffold in reducing cranial bone-gap distances. Customised PLA scaffolds repaired diverse bone defects and regulated FGF delivery via HSPG2/FGF signalling, consequently promoting cranial bone regeneration. This study demonstrated promising applications for the treatment of cranial bone defects.&#xD.

Keywords:  Extracellular matrix; Fibroblast growth factor; Glycosaminoglycans; Heparan sulfate proteoglycan 2; Polylactic acid

DOI:  https://doi.org/10.1088/1748-605X/ae30bd
Cells. 2025 Dec 05. pii: 1934. [Epub ahead of print]14(24):

Cervical Glycosaminoglycans and Extracellular Matrix Remodeling: New Insights and the Therapeutic Promise of Tafoxiparin.

Wojciech Flis, Mateusz Wartęga, Julia Sowińska, Maciej W Socha.

  Cervical ripening is a multifaceted process involving endocrine, inflammatory, and biomechanical signals that act on the cervical extracellular matrix. While previous reviews have focused on hormonal and immune mechanisms, the specific role of cervical glycosaminoglycans (GAGs)-particularly hyaluronan and heparan sulfate-has received limited dedicated attention. This review addresses that gap by exploring how these GAGs function as integrators of hormonal cues, immune activation, and extracellular matrix remodeling during pregnancy and labour. We conducted a narrative synthesis of experimental, translational, and clinical studies on GAG composition, metabolism, and signaling, with particular attention to tafoxiparin, a heparan-sulfate-based compound with minimal anticoagulant activity. Available evidence suggests that alterations in hyaluronan and heparan sulfate content influence collagen disorganization, tissue hydration, immune cell infiltration, and prostaglandin production-collectively contributing to cervical softening and dilatation. Although tafoxiparin may replicate some actions of endogenous GAGs, current clinical data remain sparse and inconclusive. Thus, targeting cervical GAG biology represents a mechanistic yet still investigational strategy, requiring further studies to determine its therapeutic value.

Keywords:  cervical ripening; extracellular matrix; glycosaminoglycans; heparan sulfate; hyaluronan; inflammation; labour induction; tafoxiparin

DOI:  https://doi.org/10.3390/cells14241934
Ann Thorac Surg Short Rep. 2025 Dec;3(4): 1146-1147

Use of Andexanet Alfa to Reverse Heparin After Cardiopulmonary Bypass.

David Niehaus, Michael Javorski, Elliot Kay, Abigail Rhoades, Hilary Raidt, Rob Dowling.

Heparin is the primary anticoagulant used for cardiopulmonary bypass and requires reversal to prevent postoperative bleeding. Protamine sulfate is the only United States Food and Drug Administration-approved heparin reversal agent and therefore is routinely used after cardiopulmonary bypass. Severe intraoperative protamine reactions are infrequent but may preclude full heparin reversal. Andexanet alfa has demonstrated effective in vitro heparin reversal, but clinical use has not been reported. We review the preclinical data on andexanet alfa as a heparin reversal agent and report a clinical case of andexanet alfa infusion, with complete laboratory and clinical evidence of heparin reversal.

DOI: https://doi.org/10.1016/j.atssr.2025.06.023
Mar Drugs. 2025 Dec 18. pii: 486. [Epub ahead of print]23(12):

Precision-Engineered Dermatan Sulfate-Mimetic Glycopolymers for Multi-Targeted SARS-CoV-2 Inhibition.

Lihao Wang, Lei Gao, Chendong Yang, Mengfei Yin, Jiqin Sun, Luyao Yang, Chanjuan Liu, Simon F R Hinkley, Guangli Yu, Chao Cai.

  The ongoing COVID-19 pandemic, caused by SARS-CoV-2, continues to pose major global health challenges despite extensive vaccination efforts. Variant escape, waning immunity, and reduced vaccine efficacy in immunocompromised populations underscore the urgent need for complementary antiviral therapeutics. Here, we report the design, synthesis, and biological evaluation of precision-engineered dermatan sulfate (DS)-mimetic glycopolymers as multi-targeted inhibitors of SARS-CoV-2. Guided by molecular docking and virtual screening, sulfation at the C2 and C4 positions of iduronic acid was identified as critical for binding to the viral spike protein and inhibiting host and viral enzymes, including heparanase (HPSE) and main protease (Mpro). Chemically synthesized DS disaccharides were covalently grafted onto polymer scaffolds via a post-modification strategy, yielding glycopolymers with well-defined assembly that form uniform nanoparticles under physiological conditions. Surface plasmon resonance and pseudovirus assays revealed strong binding to the viral spike protein (KD ≈ 177 nM), potent viral neutralization, and minimal cytotoxicity. Cellular uptake studies further demonstrated efficient internalization of nanoparticles and intracellular inhibition of HPSE and Mpro. These results establish a modular, non-anticoagulant, and glycosaminoglycan-mimetic platform for the development of broad-spectrum antiviral agents to complement vaccination and enhance preparedness against emerging coronavirus variants.

Keywords:  anti-SARS-CoV-2; dermatan sulfate; disaccharide; glycopolymer; synthesis

DOI:  https://doi.org/10.3390/md23120486
Forensic Sci Int. 2025 Dec 17. pii: S0379-0738(25)00427-X. [Epub ahead of print]379 112783

Postmortem correlation of ethanol and minor metabolites ethylglucuronide and ethylsulfate in blood, vitreous humor and bile.

Ersin Göl, Ali Erkan Aşcı, Arwa M Amin, Yusuf Atan, Mehmet Tokdemir.

  Accurate determination of ethanol use in postmortem cases is crucial in forensic investigations. While vitreous humor (VH) is considered a stable matrix that lacks endogenous alcohol production and serves as a reliable confirmatory sample, challenges arise when VH is unavailable or only blood samples are present. In such cases, interpreting the presence of ethanol becomes difficult due to the potential forpostmortem ethanol production. Ethyl glucuronide (EtG) and ethyl sulfate (EtS), minor non-oxidative metabolites of ethanol, have been proposed as alternative biomarkers. However, the significance of their levels, especially when only one metabolite is detected, remains uncertain. This study analyzed ethanol, EtG, and EtS levels in blood, VH, and bile samples from 40 postmortem cases with blood ethanol levels ranging from 0.11 to 4.35 g/L. Ethanol concentrations were measured using HS-GC-FID, while EtG and EtS were quantified via LC-ESI-MS/MS. The highest ethanol level was found in blood (4.35 g/L), while bile contained the highest concentrations of EtG (4.98 mg/L) and EtS (0.76 mg/L). Very strong to moderate correlations were observed for ethanol and its minor metabolites across all matrices, as well as between blood and bile EtG, indicating that bile EtG is a reliable surrogate biomarker for antemortem ethanol assessment. There were no weak or non-significant correlations present. These findings suggest that ethanol and its minor metabolites in VH, blood, and bile can be reliably used in postmortem assessments. Moreover, combined analysis of EtG and EtS may enhance the interpretation of antemortem alcohol consumption in forensic cases.

Keywords:  Alcohol; Bile; Ethanol; Ethyl glucuronide; Ethyl sulfate; Vitreous Humor

DOI:  https://doi.org/10.1016/j.forsciint.2025.112783