bims-supasi 2026-03-01 papers

bims-supasi

Biomed News

on Sulfation pathways and signalling

Issue of 2026–03–01
nineteen papers selected by
Jonathan Wolf Mueller, University of Birmingham

Spatial Profiling of Glycosaminoglycans (GAGomics) from Laser Microdissected Mouse Brain.
Biomanufacturing of Therapeutically Relevant Chondroitin Sulfate C via Engineered Microbes.
Inclusion of Chondroitin Sulfate Into a Gelatin Hydrogel Shifts Local and Global Mechanical Behavior and Fibrochondrogenic Phenotype for Applications in Insertional Tissue Engineering.
Glycosaminoglycan binding to soluble CX3CL1 impacts monocyte migration in vitro.
Structure and Function of Ocular Proteoglycans: Essential Proteins for Vision.
Chondroitin Sulfate Proteoglycans in CNS Development and Pathophysiology.
Indoxyl Sulfate in the Gut-Kidney Axis: Pathophysiology and Clinical Significance in CKD-Associated Colorectal Cancer.
Elevated Indoxyl Sulfate Levels Correlate with Increased Aortic Stiffness in Patients Undergoing Kidney Transplantation.
HS6ST1 regulates acute myeloid leukemia chemotherapy resistance via TGF-β1 signaling.
Age-dependent reference intervals for cerebrospinal fluid and urine biomarkers of mucopolysaccharidoses.
Coarse-Grained Martini 3 Model of Chondroitin Sulfate A.
Chondroitin Sulfate Enrichment in the Extracellular Matrix Inhibits NETosis in a 3D Calcific Aortic Valve Disease Model.
Sulfated glycosaminoglycans inhibit LCMV entry and modulate antiviral immunity and pathology.
SRPX2 exhibits neuroprotective effects in neural stem cells: inhibition of OGD/R-stimulated apoptosis and oxidative stress.
Structural Characterization of Glycoprotein Glycans and Glycosaminoglycans of Brain Tissues in Slc35a3-Knockout Mice.
Probing Glycosaminoglycan-Protein Interactions: Applications of Surface Plasmon Resonance.
Uremic Toxin-Driven Vascular Calcification in Chronic Kidney Disease: Molecular Pathways and Integrated Phenotypes.
Sulfates Increase the Antioxidant Activity of Cowpea Subjected to Saline Stress.
Sea cucumber sulfated fucan protects against acute liver injury in mice: insights from inflammatory responses, gut microbiota and hepatic metabolic profile analyses.

Mol Cell Proteomics. 2026 Feb 19. pii: S1535-9476(26)00029-0. [Epub ahead of print] 101533

Spatial Profiling of Glycosaminoglycans (GAGomics) from Laser Microdissected Mouse Brain.

Elias Mernie, Joseph Zaia.

  Glycosaminoglycans (GAGs) are linear, negatively charged polysaccharides composed of repeating disaccharide units. Heparan sulfate (HS) and chondroitin sulfate (CS) are highly sulfated GAG classes, ubiquitously expressed in mammalian tissues, that play critical roles in cellular signaling, tissue homeostasis, and disease progression. Aside from their biological importance, the structural analysis of HS and CS remains limited to bulk tissue analysis due to their extensive heterogeneity, structural complexity, and the presence of isomers and epimers. In this work, we developed an integrated workflow combining laser microdissection (LMD), hydrophilic interaction liquid chromatography (HILIC), and cyclic ion mobility mass spectrometry (cIM-MS) for the identification and quantification of HS and CS disaccharides from small-scale and spatially resolved mouse brain tissue sections. Through sequential enzymatic digestion of HS and CS chains from the same sample, we profiled not only the common disaccharides that serve as structural signatures for HS and CS, but also rarely detected HS disaccharides containing saturated uronic acid (UA) residues, as well as lyase-resistant 3-O-sulfated HS tetrasaccharides. HILIC enabled the separation of HS and CS disaccharides based on their composition and hydrophilicity, while cIM-MS further enhanced the resolution of positional isomers. Quantitative analysis using linear calibration curves revealed disaccharide abundances in small-scale tissue sections collected by LMD. Overall, our finding highlighted the merit of the LMD-HILIC-cIM-MS workflow for HS and CS analysis in spatial GAGomics and its potential for biomarker discovery and therapeutic application studies.

Keywords:  Chondroitin sulfate (CS); Cyclic ion mobility mass spectrometry (cIM-MS); Heparan sulfate (HS); Laser microdissection (LMD)

DOI:  https://doi.org/10.1016/j.mcpro.2026.101533
ACS Synth Biol. 2026 Feb 23.

Biomanufacturing of Therapeutically Relevant Chondroitin Sulfate C via Engineered Microbes.

Aditi Dey Tithi, Hana Zeghal, Yuefan Song, Elena E Paskaleva, Sweta Vangaveti, Mattheos Koffas.

  Chondroitin sulfate C (CS-C) is a biologically significant glycosaminoglycan in which a precise 6-O-sulfation pattern confers critical structural and signaling functions in connective and neural tissues. Here, we report the first functional expression of human chondroitin 6-O-sulfotransferase-1 (C6ST-1) in Escherichia coli, enabling cell-free biosynthesis of CS-C. By applying structure-guided protein engineering combining transmembrane truncation, His6 -MBP fusion, and PROSS-directed stabilizing mutations, we generated a soluble and catalytically active variant in E. coli Origami B (DE3) and modified Shuffle T7 Express. Under optimized reaction conditions (MES buffer pH 5.5, 30 °C, Mg2+/Ca2+/Mn2+ with protamine sulfate), the engineered enzyme catalyzed up to 67% sulfation of chondroitin (CS-O) to CS-C, verified via SAX-HPLC. Kinetic and molecular dynamics analyses revealed enhanced substrate affinity and catalytic efficiency for the M9 Δ131 mutant. This study establishes a sustainable, animal-free platform for high-purity CS-C biomanufacturing and provides a generalizable strategy for engineering eukaryotic sulfotransferases for functional expression in bacterial hosts.

Keywords:  chondroitin sulfate; glycosaminoglycan; protein engineering; sulfotransferase

DOI:  https://doi.org/10.1021/acssynbio.5c00780
J Biomed Mater Res A. 2026 Mar;114(3): e70057

Inclusion of Chondroitin Sulfate Into a Gelatin Hydrogel Shifts Local and Global Mechanical Behavior and Fibrochondrogenic Phenotype for Applications in Insertional Tissue Engineering.

Kyle B Timmer, Michael Xu, Brendan A C Harley.

  Glycosaminoglycans (GAGs) like chondroitin sulfate (CS) influence both mechanical properties and biological signals within the tissue microenvironment. CS modifications have been prevalent in a range of biomaterial design strategies, particularly those with a focus on wound healing. Here, we investigate the impact of CS incorporation within a thiolated gelatin (Gel-SH) hydrogel previously established as a promising biomaterial for tendon-to-bone entheseal repair, reporting a dual biological and mechanical effect. We show that CS inclusion increases mesenchymal stem cell metabolic activity and osteo-tendinous differentiation patterns in the Gel-SH biomaterial. Additionally, we demonstrate that inclusion of CS into a Gel-SH hydrogel insertional zone used to link dissimilar tendon and bone specific collagen scaffolds induces favorable local changes in stress-strain behavior. We further show that the mode of incorporation, free incorporation of CS versus covalent tethering of oxidized CS (CSO), clearly impacts these observed effects. Overall, these results highlight promising new motifs to modulate Gel-SH hydrogels for greater promotion of enthesis-associated behavior in resident hMSCs; further, they offer broad insight into design strategies and key considerations for modification of multicompartment materials, namely in consideration of incorporation methods and on the interplay of mechanical and biological properties.

Keywords:  cartilage; gelatin; oxidized chondroitin sulfate

DOI:  https://doi.org/10.1002/jbm.a.70057
Front Immunol. 2026 ;17 1747705

Glycosaminoglycan binding to soluble CX3CL1 impacts monocyte migration in vitro.

Maria Ennemoser, Paula Peinsipp, Tihana Novak, Clara Matteini, Dorian Tauschmann, Tanja Gerlza, Andreas J Kungl.

   Introduction: In addition to providing shear-resistant cell-cell adhesion in its natural membrane-bound form, the soluble variant of CX3CL1 (or fractalkine) promotes strong cell migration through signaling via its unique G-protein-coupled receptor CX3CR1 on monocytes, macrophages, T-cells, and NK-cells. To induce cell migration, most chemokines benefit from their interaction with the heterogenous group of glycosaminoglycans (GAGs), which act as coreceptors in chemotactic processes. While the interaction of many chemokines with their GAG counterparts has been investigated in detail, the potential interaction of CX3CL1 and GAGs has not yet received sufficient attention.
Results: Here, we show that the bioactive N-terminal, soluble chemokine domain of CX3CL1 (cdCX3CL1) binds to heparan sulfate (HS) as well as to dermatan sulfate (DS or CS-B), exhibiting Kd-values in the mid nanomolar range. Moreover, the removal of monocyte-surface HS reduced cdCX3CL1-induced cell migration, thereby strongly indicating a potential biological relevance of CX3CL1 binding to GAGs. Interaction studies taking into account the extracellular receptor-peptide of CX3CR1 showed that, in addition to binding CX3CL1, CX3CR1 was found to bind to HS as well. Cross-linking cdCX3CL1 and the CX3CR1 peptide led to a ten-fold higher HS binding affinity compared to the isolated proteins.
Discussion: These findings further strengthen the assumption of an extended interaction network, in which GPCR, chemokine, and GAGs affect each other simultaneously.

Keywords:  chemokine; chemokine receptor; fractalkine; glycosaminoglycan; heparan sulfate; monocyte

DOI:  https://doi.org/10.3389/fimmu.2026.1747705
Int J Mol Sci. 2026 Feb 18. pii: 1943. [Epub ahead of print]27(4):

Structure and Function of Ocular Proteoglycans: Essential Proteins for Vision.

James Melrose.

  This narrative review outlines the structure and essential functions of ocular proteoglycans (PGs) in visual processing as documented in the extensive literature on this subject matter. The eye, as one of the most complex sensory organs, relies on the coordinated activity of various tissues and cell types, with PGs playing a central role in facilitating communication and maintaining tissue function. These molecules stabilise ocular tissues; for example, SPACRCAN (IMPG2) and hyaluronan aggregates in the interphotoreceptor matrix protect photoreceptors from oxidative stress. Specialised heparan sulfate PGs, such as pikachurin, eyes-shut, and the neurexin family, stabilise synapses and ensure synaptic specificity and plasticity. Pikachurin is particularly important for the rapid transmission of visual signals at the bipolar ribbon synapse. A diverse array of chondroitin sulfate (aggrecan, versican, neurocan, brevican, phosphacan, NG2), keratan sulfate (SV2), and heparan sulfate (perlecan, agrin, collagen XVIII) PGs are differentially expressed in ocular tissues, contributing to tissue stability and homeostasis. In the cornea, sclera, and choroid, small leucine-rich repeat PGs (SLRPs) maintain three-dimensional structure, corneal transparency, and tissue function through interactions with cytokines and growth factors. The vitreous humour contains opticin and nyctalopin, which support the nutrition of avascular regions and facilitate bipolar ribbon synapse signalling. Ultimately, the effectiveness of the eye as a visual organ depends significantly on the functional roles of its constituent PGs.

Keywords:  SLRPs; eyes-shut; hyaluronan; lecticans; neurexin; pikachurin; synapse; vision

DOI:  https://doi.org/10.3390/ijms27041943
J Neurosci Res. 2026 Mar;104(3): e70115

Chondroitin Sulfate Proteoglycans in CNS Development and Pathophysiology.

Seyed Mojtaba Hosseini, Soheila Karimi-Abdolrezaee.

  Chondroitin sulfate proteoglycans (CSPGs) are major components of the matrix in many tissues including the central nervous system (CNS). Interactions between extracellular CSPGs and different cell types are crucial for the development of the CNS as CSPGs are heavily involved in maintaining the pool of progenitors, neurogenesis, neuronal migration and maturation, cortical lamination, synapse formation and stabilization, neuronal plasticity, and memory formation. CSPGs play distinct roles in CNS development and pathology. While physiologic levels of CSPGs have key roles in CNS development, CNS pathologies result in upregulation of CSPGs that pose a barrier to neuroregeneration. Extensive evidence shows that pathologic CSPGs interfere with various regenerative mechanisms including axonal elongation, immunomodulation, synaptogenesis, cellular replacement, and remyelination. At the cellular level, CSPGs' effects are mainly mediated through activation of leukocyte common antigen-related receptor (LAR) and protein tyrosine phosphatase sigma (PTP-σ) receptors. Various approaches have been developed to overcome the inhibitory effects of pathologic CSPGs including enzymatic degradation of CSPGs, blocking CSPG/LAR/PTP-σ axis, and inhibition of CSPGs synthesis. Here, we will discuss the current understanding on the role and mechanisms of CSPGs in CNS development and pathologies and signaling pathways that mediate CSPGs' effects in the CNS. We will also review how CSPGs have been modulated in neurological disorders.

Keywords:  central nervous system; chondroitin sulfate proteoglycans; neurodevelopment; neuropathology; signaling and mechanisms

DOI:  https://doi.org/10.1002/jnr.70115
Toxins (Basel). 2026 Jan 30. pii: 72. [Epub ahead of print]18(2):

Indoxyl Sulfate in the Gut-Kidney Axis: Pathophysiology and Clinical Significance in CKD-Associated Colorectal Cancer.

Hidehisa Shimizu, Toshimitsu Niwa.

  Chronic Kidney Disease (CKD) and Colorectal Cancer (CRC) share a profound epidemiological link, supported by Mendelian randomization studies suggesting causality. This review articulates a refined Gut-Kidney Axis, focusing on the pathophysiology of indole-derived uremic toxins. CKD-induced dysbiosis drives hepatic synthesis and systemic accumulation of indoxyl sulfate, which is proposed to promote carcinogenesis via Aryl Hydrocarbon Receptor (AhR) and Akt signaling, ultimately upregulating c-Myc and EGFR. We propose a two-compartment model: while systemic indoxyl sulfate reflects the total gut indole pool (mainly from planktonic bacteria), adherent bacteria like Fusobacterium nucleatum may create high-concentration indole hotspots within the tumor microenvironment. Clinically, we advocate for protein-independent DNA methylation biomarkers (SEPT9, SDC2) to avoid renal confounding. Furthermore, we propose a novel diagnostic panel integrating serum indoxyl sulfate (systemic load) and urinary indoxyl sulfate (gut production) to guide therapy. Therapeutically, targeting upstream drivers (AhR/Akt) may bypass resistance to anti-EGFR therapies in KRAS-mutated tumors. We also discuss the repurposing of the oral adsorbent AST-120 and emerging bacteriophage therapies as strategies to disrupt this oncogenic axis. This review offers a comprehensive framework for stratified management of CKD-associated CRC.

Keywords:  Aryl Hydrocarbon Receptor; Chronic Kidney Disease; Fusobacterium nucleatum; Liquid Biopsy; Tryptophan Metabolism; colorectal cancer; gut–kidney axis; indoxyl sulfate; tumor microenvironment; uremic toxins

DOI:  https://doi.org/10.3390/toxins18020072
Toxins (Basel). 2026 Jan 30. pii: 71. [Epub ahead of print]18(2):

Elevated Indoxyl Sulfate Levels Correlate with Increased Aortic Stiffness in Patients Undergoing Kidney Transplantation.

Hsiao-Hui Yang, Chin-Hung Liu, Yen-Cheng Chen, Bang-Gee Hsu.

  Although kidney transplantation (KT) restores renal function, residual uremic toxins, such as indoxyl sulfate (IS), may persist and contribute to vascular remodeling and aging. Aortic stiffness, reflected by carotid-femoral pulse wave velocity (cfPWV), is a strong predictor of cardiovascular events. This study enrolled KT recipients to examine the association of circulating IS with aortic stiffness. Using the SphygmoCor system, we assessed aortic stiffness, which was defined as cfPWV > 10 m/s. Serum IS concentrations were measured by liquid chromatography-tandem mass spectrometry. Of 94 KT recipients, 26 (27.7%) met the criteria for aortic stiffness. Compared with patients without aortic stiffness, those with aortic stiffness were older (p = 0.017) and had significantly higher systolic blood pressure (p = 0.011) and fasting glucose levels (p = 0.002), a higher prevalence of diabetes (p = 0.043), and higher IS levels (p = 0.002). According to multivariable logistic regression, serum IS remained independently associated with aortic stiffness (p = 0.017). According to stepwise linear regression, log-transformed IS further showed a positive correlation with cfPWV (p = 0.016). Serum IS remained an independent determinant of aortic stiffness in KT recipients, highlighting the burden of residual uremic toxins as a contributor to post-transplant vascular aging.

Keywords:  aortic stiffness; carotid–femoral pulse wave velocity; indoxyl sulfate; kidney transplantation; uremic toxins

DOI:  https://doi.org/10.3390/toxins18020071
Res Sq. 2026 Feb 13. pii: rs.3.rs-8725671. [Epub ahead of print]

HS6ST1 regulates acute myeloid leukemia chemotherapy resistance via TGF-β1 signaling.

Christina Termini, Kelsey Woodruff, Diya Patel, Jack Peplinski, Nicollette Setiawan, Matthew Hagen, Soheil Meshinchi.

Despite therapeutic advances, relapse remains the leading cause of death in patients with acute myeloid leukemia (AML). Growth factor signaling controls AML survival, proliferation, relapse, and chemotherapy resistance. Here, we studied heparan sulfate proteoglycans, a class of molecules that bind growth factors via their heparan sulfate chains to change their signaling ability. Heparan sulfate-growth factor interactions are controlled by the addition of sulfate groups catalyzed by heparan sulfotransferases, such as those encoded by HS2ST1 and HS6ST1 . Using AML patient cohort analyses, we demonstrate that increased HS6ST1 expression is associated with worse survival and increased relapse risk for AML patients harboring KMT2A -rearrangements. Using cell line derived xenografts, we show that AML cells depleted of HS2ST1 , but not HS6ST1 , have increased bone marrow leukemic burden. Further, AML cells depleted of HS6ST1 are more sensitive to cytarabine than Control cells, suggesting that HS6ST1 regulates AML chemotherapy resistance. Heparan sulfate antagonism with surfen synergized with cytarabine to further support AML cell death compared to cytarabine alone. Mechanistically, we demonstrate that HS6ST1 depletion in AML cells reduces TGF-β1-mediated signaling, which diminishes cell survival upon cytarabine treatment. Together, our data show that HS6ST1 promotes AML cell chemotherapy resistance by supporting TGF-β1 signaling.

DOI: https://doi.org/10.21203/rs.3.rs-8725671/v1
Mol Genet Metab. 2026 Feb 19. pii: S1096-7192(26)00145-9. [Epub ahead of print]147(4): 109862

Age-dependent reference intervals for cerebrospinal fluid and urine biomarkers of mucopolysaccharidoses.

Candice B Herber, Shaohua Xiao, Deborah S Gho, Ana-Claire L Meyer, Buyankhishig Tsogtbaatar, Jung H Suh, Meng Fang, Sarah Huntwork-Rodriguez, Fabian Model, Kyle Ireton, Yuda Zhu, Julie D Saba, Kristie L White, Akhil Bhalla.

  Mucopolysaccharidoses (MPSs) are characterized by deficient activity of lysosomal hydrolase enzymes, leading to progressive accumulation of glycosaminoglycans. These glycosaminoglycans can be assayed in biofluids as potential markers of disease severity and response to disease-modifying therapies. This study sought to calculate control reference intervals in a largely pediatric population for key MPS biomarkers: heparan sulfate (HS) and dermatan sulfate (DS) in cerebrospinal fluid (CSF) and urine, and CSF monosialic gangliosides GM2 and GM3. We also explored the effect of age on biomarker levels. Biomarker levels were measured using liquid chromatography-tandem mass spectrometry in CSF and urine samples from pediatric and young adult donors and were compared with baseline CSF and urine biomarker levels from an ongoing Phase 1/2 study of children with MPS II. Age-specific reference intervals were estimated for CSF HS, DS, and GM2, and for urine HS, DS, and the sum of HS and DS, after observing that levels of these markers decreased with age. CSF GM3 levels were not found to be age dependent, therefore a single reference interval was estimated for the reference population. In patients with MPS II, levels of HS and DS, respectively, were 6- and 7-fold higher in CSF, and 13- and 30-fold higher in urine than the upper reference interval limits. Establishing age-specific reference intervals will help to optimize biomarker use in clinical studies.

Keywords:  Biomarker; Ganglioside; Glycosaminoglycan; Mucopolysaccharidosis; Pediatric; Reference interval

DOI:  https://doi.org/10.1016/j.ymgme.2026.109862
J Chem Theory Comput. 2026 Feb 23.

Coarse-Grained Martini 3 Model of Chondroitin Sulfate A.

Paulius Greicius, Frauke Gräter, Fabian Grünewald, Camilo Aponte-Santamaría.

Chondroitin sulfate A (CSA) is a negatively charged linear glycosaminoglycan that plays a vital role in many biological processes. Research on CSA has been challenging due to its size, chemical heterogeneity, and multitude of binding partners. To address these issues, we developed a model of CSA for coarse-grained molecular dynamics simulations based on the Martini 3 force field. We demonstrate that this model is capable of reproducing atomistic properties of the repeating CSA disaccharide unit, including its molecular volume, bonded interactions, and structural polymer properties of CSA chains of different lengths. In particular, for biologically relevant long chains and despite using an explicit solvent, the computational cost is significantly reduced, relative to the cost equivalent atomistic simulations would require. The compatibility of the model with the Martini Go̅ protein model was tested by retrieving the force-response relationship of the CSA-malaria adhesin VAR2CSA complex. Importantly, we explored the influence of electrostatics on CSA aggregation. We show that the default Martini 3 parameters lead to overaggregation. We provide at least three different strategies to alleviate this issue, making use of a bigger bead for sodium cations, reflecting their hydration shell, partial ionic charges as a mean-field resource to take into account electronic polarizability, and, optionally, particle mesh Ewald summation as a more robust treatment of long-range electrostatics. Our model enables predictive modeling of CSA and potentially other chondroitin sulfates with the Martini 3 force field. In addition, this model provides insights for the further development of coarse-grained models of highly charged systems.

DOI: https://doi.org/10.1021/acs.jctc.5c01743
Adv Healthc Mater. 2026 Feb 22. e04972

Chondroitin Sulfate Enrichment in the Extracellular Matrix Inhibits NETosis in a 3D Calcific Aortic Valve Disease Model.

Thayana Torquato, Yasmin Mirzaalikhan, Manijeh Khanmohammadi, Chanly Chheang, Habiba Danish, Azadeh Mirabedini, Shadi Houshyar, Jonathan McQualter, Karlheinz Peter, Sara Baratchi.

  Calcific aortic valve disease (CAVD) is the most common valvular disorder in high-income countries, and its prevalence is projected to rise with an aging population. No pharmacological therapies currently exist to halt or reverse progression, reflecting the complex and poorly understood pathophysiology. A hallmark of CAVD is extracellular matrix (ECM) remodeling and accumulation of proteoglycans such as chondroitin sulfate (CS). CAVD is also recognized as an inflammatory disease, with emerging evidence implicating neutrophils and their extracellular traps (NETs) as active contributors to disease progression. However, the impact of CS enrichment on neutrophil behavior remains unclear. Here, we developed a disease-inspired 3D ECM hydrogel model to investigate how ECM composition regulates neutrophil function and NET formation. Human neutrophils were encapsulated in type I collagen hydrogels enriched with CS, mimicking healthy and diseased valve tissue. CS enrichment impaired neutrophil effector functions, including actin cytoskeleton remodeling and NETosis. Neutrophils in CS-rich matrices showed disrupted actin dynamics, reduced chromatin decondensation, and diminished histone H3 citrullination, resulting in suppressed NET release in response to NADPH oxidase-dependent and calcium-mediated stimuli. These findings identify CS enrichment as a regulator of neutrophil function through disruption of actin cytoskeleton remodeling. Beyond CAVD, this study highlights the importance of ECM composition in modulating immune responses.

Keywords:  calcific aortic valve disease; chondroitin sulfate; extracellular matrix remodeling; inflammation; neutrophil extracellular traps

DOI:  https://doi.org/10.1002/adhm.202504972
EMBO Mol Med. 2026 Feb 23.

Sulfated glycosaminoglycans inhibit LCMV entry and modulate antiviral immunity and pathology.

Michal Gorzkiewicz, Soha Noseir, Mandar Vengurlekar, Mitrajit Ghosh, Ichiro Katahira, Džiuljeta Abromavičiūtė, Ulla Gerling-Driessen, Lorand Bonda, Nick Rähse, Marco Lapsien, Sabrina Bockholt, Ann Kathrin Bergmann, Konstantina Kostadinovska, Hafssa Fraii, Karl S Lang, Lisa Oestereich, Holger Gohlke, Laura Hartmann, Philipp A Lang.

  Viral infections remain a major challenge due to the limited availability and efficacy of current treatments. Existing antivirals primarily target viral replication but are often virus-specific and can lead to drug resistance. Sulfated glycosaminoglycans (GAGs) have emerged as promising broad-spectrum agents that block viral binding and entry into host cells. Here, we show that highly sulfated GAGs restrict the infectivity of both pathogenic and non-pathogenic Arenaviruses. Using the lymphocytic choriomeningitis virus (LCMV) model, we demonstrate that GAG exposure reduces viral entry and infection in cell lines and bone marrow-derived dendritic cells, impairing their ability to activate antiviral T cells. In vivo, early exposure of LCMV to dextran sulfate suppressed immune activation, leading to diminished T-cell responses, prolonged infection, and increased immunopathology. By contrast, administering dextran sulfate during the acute infection phase decreased viral load, improved effector T-cell function, and reduced liver pathology. These findings highlight the therapeutic potential of sulfated GAGs against Arenavirus infections and the importance of treatment timing for clinical efficacy.

Keywords:  Arenavirus; Dextran Sulfate; GAGs; Infection; LCMV

DOI:  https://doi.org/10.1038/s44321-026-00387-8
Open Life Sci. 2026 Jan;21(1): 20251182

SRPX2 exhibits neuroprotective effects in neural stem cells: inhibition of OGD/R-stimulated apoptosis and oxidative stress.

Pan Li, Jie Hua.

  Hypoxic-ischemic encephalopathy (HIE) is a major cause of infant morbidity as well as mortality. Neural stem cells (NSCs) is essential for brain development and function, and the role of NSCs in HIE is crucial and deserves further study. Sushi repeat-containing protein X-linked 2 (SRPX2) is a novel chondroitin sulfate proteoglycan which has multiple biological functions, such as cell growth and adhesion. However, SRPX2 is rarely reported in HIE process, and the mechanism is unclear. Herein, we aimed to uncover the role of SRPX2 in the progression of HIE. The oxygen-glucose deprivation/reoxygenation (OGD/R) model was established as a HIE cell model. We revealed that SRPX2 improves survival of OGD/R-stimulated NSCs. SRPX2 inhibited apoptosis of OGD/R-stimulated NSCs. Further data confirmed SRPX2 restrained oxidative stress of OGD/R-stimulated NSCs. Mechanically, SRPX2 activated the Wnt/beta-catenin pathway, and therefore suppressed the apoptosis as well as oxidative stress of OGD/R-stimulated NSCs. Collectively, SRPX2 suppressed apoptosis as well as oxidative stress of OGD/R-stimulated NSCs by activating Wnt/β-Catenin pathway.

Keywords:  apoptosis; hypoxic-ischemic encephalopathy (HIE); oxidative stress; sushi repeat-containing protein X-linked 2 (SRPX2); wnt/β-catenin pathway

DOI:  https://doi.org/10.1515/biol-2025-1182
Int J Mol Sci. 2026 Feb 08. pii: 1643. [Epub ahead of print]27(4):

Structural Characterization of Glycoprotein Glycans and Glycosaminoglycans of Brain Tissues in Slc35a3-Knockout Mice.

Ikumi Hirose, Hisatoshi Hanamatsu, Shuji Mizumoto, Rina Yamashita, Shuhei Yamada, Jun-Ichi Furukawa, Tatsuya Furuichi, Hirokazu Yagi.

  Glycosylation depends on luminal nucleotide sugars delivered by solute carrier 35 (SLC35) transporters. SLC35A3 is a uridine diphosphate N-acetylglucosamine (UDP-GlcNAc) transporter. In humans, biallelic mutations in SLC35A3 cause arthrogryposis, mental retardation, and seizures (AMRS). To define how loss of SLC35A3 function reshapes the neural glycome, we profiled N-, O-, and glycosaminoglycans (GAGs) in Slc35a3 knockout mouse brains. N- and O-glycans were analyzed by MALDI-TOF MS, and GAG disaccharides were quantified by anion-exchange HPLC. Knockout mouse brains exhibited attenuation of complex-type N-glycans with a reciprocal rise in high-mannose species, as revealed by MALDI-TOF MS profiling. In contrast, ConA lectin blotting showed no significant change, consistent with its preferential detection of mannose-rich glycans. Branching analysis revealed loss of tri- and tetra-antennary structures compared with biantennary species. O-glycan profiling showed core-2-type species (Hex2HexNAc2 backbone) decreased. The dominant disialyl core-1 remained stable. Total GAG output (chondroitin/dermatan sulfate, heparan sulfate, and hyaluronan) was preserved. These findings support a microdomain model in which SLC35A3 acts as a locally effective supplier of UDP-GlcNAc to MGAT4 (branching N-acetylglucosaminyltransferase that installs the β1,4-GlcNAc arm) in the brain, while alternative routes buffer UDP-GlcNAc delivery for GAG and mucin-type O-glycan biosynthesis. Accordingly, AMRS may be attributed to impaired higher-order N-glycan branching in the brain.

Keywords:  Core-2 O-glycan (GCNT1/C2GnT); MALDI-TOF-MS; MGAT4-dependent N-glycan branching; SLC35A3; UDP-GlcNAc transporter; glycosaminoglycan

DOI:  https://doi.org/10.3390/ijms27041643
Biosensors (Basel). 2026 Jan 25. pii: 71. [Epub ahead of print]16(2):

Probing Glycosaminoglycan-Protein Interactions: Applications of Surface Plasmon Resonance.

Changkai Bu, Lin Pan, Lianli Chi, Vitor H Pomin, Jonathan S Dordick, Chunyu Wang, Fuming Zhang.

  Glycosaminoglycans (GAGs) are highly negatively charged polysaccharides that play essential roles in numerous physiological and pathological processes through their interactions with proteins. These interactions govern cellular signaling, inflammation, coagulation, and recognition. Surface Plasmon Resonance (SPR) has emerged as a key biophysical technique for label-free, real-time characterization of biomolecular interactions, offering insights into binding kinetics, affinity, and specificity. SPR-based approaches to glycosaminoglycan-protein interaction studies offer powerful tools for elucidating the roles of GAGs in a wide range of physiological and pathological processes. In this review, we systematically discuss experimental strategies, data analysis methods, and representative applications of SPR-based glycosaminoglycan-protein interactions. Special attention is given to the challenges associated with GAG heterogeneity and immobilization, as well as recent technological advances that enhance sensitivity and throughput. To our knowledge, this review represents one of the first systematic and up-to-date summaries specifically focused on recent advances in applying SPR to the study of glycosaminoglycan-protein interactions.

Keywords:  binding kinetics; biosensor; extracellular matrix; glycomics; glycosaminoglycan; heparin; protein interactions; surface plasmon resonance

DOI:  https://doi.org/10.3390/bios16020071
Toxins (Basel). 2026 Feb 21. pii: 112. [Epub ahead of print]18(2):

Uremic Toxin-Driven Vascular Calcification in Chronic Kidney Disease: Molecular Pathways and Integrated Phenotypes.

Rodolfo Fernando Rivera, Maria Teresa Sciarrone Alibrandi, Nadia Edvige Foligno, Lorenza Magagnoli, Paola Ciceri, Mario Cozzolino.

   BACKGROUND: Vascular calcification (VC) affects up to 90% of patients with end-stage renal disease and increases cardiovascular mortality 3- to 5-fold. Once considered passive mineral deposition, VC is now recognized as an active, toxin-driven process orchestrating vascular smooth muscle cell transdifferentiation, endothelial dysfunction, and matrix remodeling. However, current uremic toxin classifications remain biochemically oriented, providing limited clinical guidance for risk stratification and therapeutic selection.
METHODS: This comprehensive review reframes uremic toxin-driven VC through an integrated phenotypic lens, synthesizing molecular mechanisms, clinical biomarkers, and therapeutic targets into a unified translational framework.
RESULTS: We propose five mechanistic-clinical phenotypes representing distinct biological trajectories of vascular injury. These include (1) inflammatory-oxidative (dominated by indoxyl sulfate, p-cresyl sulfate, NLRP3 inflammasome activation), (2) mineral-metabolic (hyperphosphatemia, FGF23 excess, Klotho deficiency), (3) epigenetic-senescent (histone modifications, microRNA dysregulation, cellular senescence), (4) endocrine cross-talk (vitamin D, PTH, gut-derived metabolites), and (5) integrated toxic continuum (convergence of multiple pathways in advanced disease). A comprehensive biomarker panel spanning inflammatory markers, mineral metabolism parameters, epigenetic indicators, and endocrine-gut metabolites enables phenotypic stratification and therapeutic monitoring. Emerging therapies-including tissue-nonspecific alkaline phosphatase inhibition, ectonucleotide pyrophosphatase/phosphodiesterase 1 enzyme replacement, vitamin K2 activation, senolytic agents, and SNF472 crystal-growth blockade-are mapped to their optimal phenotypic contexts.
CONCLUSIONS: This phenotype-oriented paradigm transforms VC from an inevitable complication into a targetable and potentially reversible manifestation of uremic toxicity, establishing a translational foundation for precision-based vascular medicine in chronic kidney disease. The framework enables biomarker-guided patient stratification, rational therapeutic selection, and phenotype-enriched clinical trial design.

Keywords:  chronic kidney disease; indoxyl sulfate; phenotypic clusters; precision medicine; therapeutic targets; uremic toxins; vascular calcification

DOI:  https://doi.org/10.3390/toxins18020112
ACS Omega. 2026 Feb 17. 11(6): 9145-9159

Sulfates Increase the Antioxidant Activity of Cowpea Subjected to Saline Stress.

Vladimir Rubiano González, Alison Rocha de Aragão, Letycia de Lima Costa, Maria Aparecida Dos Santos Morais, Lucilândia de Souza Bezerra, Jackson Silva Nóbrega, Nildo da Silva Dias, Patrícia Lígia Dantas de Morais.

Water scarcity for irrigation presents significant challenges to agriculture. The use of saline water from deep wells can induce salt stress in crops, negatively impacting their growth and productivity. Nutritional management using sulfates has emerged as a promising strategy to mitigate the adverse effects of salinity. Therefore, this study aimed to evaluate the effect of sulfate application as a salt stress attenuator in cowpea plants (cv. BRS Tumucumaque). The experiment was conducted in a greenhouse using a randomized block design in a 2 × 4 factorial arrangement, consisting of two irrigation water electrical conductivity levels (ECw = 0.6 and 4.5 dS m-1) and four sulfate treatments: no sulfate (control), calcium sulfate, potassium sulfate, and ammonium sulfate. Irrigation with water at 4.5 dS m-1 reduced the cowpea growth and yield. However, it also stimulated pigment synthesis and the enzymatic activities of catalase (CAT) and ascorbate peroxidase (APX), particularly when combined with calcium and potassium sulfate, respectively. In contrast, ammonium sulfate intensified salt stress, increasing electrolyte leakage and lipid peroxidation in cowpea plants. Leaf Na+ concentrations remained stable, while calcium and potassium sulfate increased Mg2+ and K+ levels, respectively. The Na+/K+ ratio was lower with the potassium sulfate application. Overall, the application of calcium and potassium sulfates enhanced cowpea performance by alleviating the detrimental effects of salinity on growth, pigment production, yield, and antioxidant enzyme activity.

DOI: https://doi.org/10.1021/acsomega.5c08126
Food Funct. 2026 Feb 25.

Sea cucumber sulfated fucan protects against acute liver injury in mice: insights from inflammatory responses, gut microbiota and hepatic metabolic profile analyses.

Feifei Shi, Liting Zheng, Luoyu Wang, Bin Liu, Weiling Guo, Peng Liang.

As a natural polysaccharide, sulfated fucan from sea cucumber possesses multiple biological activities, but its protective effect on acute liver injury (ALI) is still unclear. The aim of this study was to clarify the protective effects of sulfated fucan from sea cucumber on lipopolysaccharide (LPS)-induced ALI in mice. After administering sulfated fucan from sea cucumber (100 mg kg-1 d-1) to mice via gavage for 14 days, an ALI model was induced by intraperitoneal injection of LPS. The results showed that pretreatment with sulfated fucan from sea cucumber significantly reduced serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), and alkaline phosphatase (ALP) levels, alleviated histopathological liver damage, suppressed the expression of pro-inflammatory factors (tumor necrosis factor (TNF)-α, interleukin (IL)-1β and IL-6), elevated the anti-inflammatory factor level (IL-10), and enhanced the activity of antioxidant enzymes (superoxide dismutase (SOD), glutathione peroxidase (GSH-Px) and catalase (CAT)). Additionally, FUC suppressed the toll-like receptor 4 (TLR4)/myeloid differentiation primary response 88 (MyD88)/nuclear factor-kappa B (NF-κB) pathway and activated the nuclear factor erythroid 2-related factor 2 (Nrf2)/heme oxygenase (HO)-1 pathway gene expression. 16S rRNA sequencing indicated that sulfated fucan from sea cucumber mainly increased the proportions of Lachnospiraceae_NK4A136_group and Christensenellaceae_R-7_group. Liver metabolomics analysis revealed that FUC reversed LPS-induced disturbances in purine metabolism, arachidonic acid metabolism, and tryptophan metabolism. This study demonstrates that sulfated fucan from sea cucumber exerts hepatoprotective effects by modulating the "gut-liver axis", providing a scientific basis for its use as a functional food or dietary supplement in the prevention of ALI.

DOI: https://doi.org/10.1039/d5fo04947d