bims-supasi Biomed News
on Sulfation pathways and signalling
Issue of 2026–02–22
seventeen papers selected by
Jonathan Wolf Mueller, University of Birmingham



  1. J Pharm Biomed Anal. 2026 Feb 18. pii: S0731-7085(26)00084-1. [Epub ahead of print]274 117416
      Heparin, an essential anticoagulant in clinical practice, is susceptible to contamination with chondroitin sulfate (CS) and dermatan sulfate (DS). Ensuring the reliable quantification of these polysaccharides in crude heparins is critical for product safety and for monitoring the purification process, yet remains challenging due to their structural similarity and heterogeneous composition. ¹H NMR and Independent Component Analysis (ICA) were used to resolve the overlapping acetyl signals of CS and DS. Samples of crude heparin and synthetic mixtures were measured on a 500 MHz high-field NMR and an 80 MHz benchtop instrument. The ICA yielded models with root mean square errors (RMSEs) ≤ 1.7 % w/w (500 MHz) and ≤ 2.1 % w/w (80 MHz) for the synthetic mixtures (concentration range of 3-19 % w/w for CS and 3-40 % w/w for DS). The accuracy of the ICA method was confirmed by the conventional enzymatic digestion method for crude heparin samples. While the 500 MHz model completely conformed with the results of the enzymatic method, the 80 MHz benchtop system is best suited for screening applications where impurity levels are from moderate to high. The ICA-NMR workflow surpasses the traditional enzymatic assay in speed and simplicity, and opens the way towards the development of an automated and validated on‑site heparin quality control method.
    Keywords:  1H NMR; Benchtop NMR; Chemometrics; Chondroitin; Dermatan; Heparin; ICA
    DOI:  https://doi.org/10.1016/j.jpba.2026.117416
  2. Commun Chem. 2026 Feb 14.
      Glycosaminoglycans use positional sulfation to encode binding specificity onto its sequence. Understanding these sulfation patterns constitute a major challenge. Previous studies hinted that sulfate groups can migrate along glycans during collision-induced dissociation in mass spectrometry (MS) experiments, forming isomeric fragments that can lead to incorrect structural assignments. We use ion-mobility - mass spectrometry to investigate the mechanism of this phenomenon in heparin sulfate disaccharides. The sulfate group migrates from the non-reducing to reducing end of the sugar, and the degree of migration does not depend on the structure of the label. The migration product has a sulfate group attached to either 6O- or 3O-position of GlcNAc, and the migration mechanism consists of multiple steps, with the sulfate group first shifting from the iduronic acid to the 6O-position of GlcNAc, and next to the 3O-position. The presented data offer insight into the complexity and unpredictability of sulfated sugar fragmentation in tandem MS and extensive investigations is required to determine whether this represents a singular case or a general phenomenon characteristic of deprotonated sulfated glycans.
    DOI:  https://doi.org/10.1038/s42004-026-01939-2
  3. Anal Chem. 2026 Feb 16.
      Deciphering rare 3-O-sulfated motifs in heparan sulfate (HS) is the key to understanding critical biological processes, such as viral infection and tumor progression. However, the structural analysis of these elusive structures remains highly challenging due to their low abundance and the limitations of conventional analytical approaches. In this study, we report the application of human lysosomal arylsulfatase G (ARSG), a sulfatase specifically targeting 3-O-sulfated glucosamine residues, as a novel enzymatic tool, which, in combination with heparinase and heparanase digestion, facilitates the identification of 3-O-sulfated glucosamine moieties within HS. Coupling ARSG-mediated regioselective desulfation with hydrophilic interaction liquid chromatography-mass spectrometry (HILIC-MS) enables the efficient detection and quantification of 3-O-sulfated oligosaccharides in HS and heparin derivatives. This approach overcomes a major analytical barrier in HS characterization and provides new insights into the distribution and functional roles of 3-O-sulfation. The integration of ARSG expands the enzymatic toolkit available for HS structural characterization and represents a significant advance toward elucidating the structure-function relationships of HS in health and disease.
    DOI:  https://doi.org/10.1021/acs.analchem.5c05985
  4. Acc Chem Res. 2026 Feb 16.
      ConspectusHeparan sulfate (HS), a highly sulfated glycosaminoglycan, varies in its disaccharide units, chain length, and sulfation patterns. HS structural diversity and its localization at cell surfaces and in the extracellular matrix enable HS interaction with a breadth of HS-binding proteins (HSBPs), HS thus being a co-receptor for other proteins and initiating various biological responses. Several designed and studied HS mimetics modulate HSBP activity implicated in various diseases. A key HSBP is heparanase (HPSE), which can cleave HS into smaller fragments, facilitating release of angiogenic growth factors, activating biological signals that may contribute to pathological conditions (promoting tumor development and metastasis), and enabling autoreactive immune cells to target insulin-producing β-cells. Thus, HPSE serves as a crucial target for disease therapy strategies. Several saccharide-based HS mimetics, designed as HSPE inhibitors, have advanced to clinical trials, but these sugar molecules were discontinued or suspended due to adverse effects from off-target HSBP interactions. Glycopolymers engineered to incorporate functionalized glycan residues into their polymeric backbones are a promising approach to retain endogenous HS' native biological activity, thereby enhancing therapeutic efficacy. Stereoselective formation of α-1,2-cis-glycosidic linkages that connect the glucosamine unit to the uronic acid disaccharide core is challenging during development of HS mimetics as HPSE inhibitors. Computational modeling and a stereoselective catalytic glycosylation method were used to design and synthesize glycopolymer-based HS mimetics with repeating units of the glucosamine-glucuronic acid disaccharide core and a controlled degree of polymerization and incorporate glycan residues with precisely tailored sulfation patterns. This strategy ensures targeted biological activity and maintains structural specificity toward its intended HSBP. Glycopolymers were synthesized using ring-opening metathesis polymerization with the third-generation Grubbs catalyst, enabling precise control over both the degree of polymerization and molecular weight by tuning the catalyst loading. The most potent glycopolymer displayed superior potency and selectivity compared to previously reported monovalent and polymeric HPSE inhibitors and demonstrated remarkable antimetastatic activity in models of mammary carcinoma and myeloma cancer. It also protected pancreatic β-cells and human islets from HPSE-induced damage, suggesting a possible diabetes therapeutic agent. Prioritizing multivalency and precise structural control in polymeric HS mimetics facilitates targeted interactions with specific HSBPs and enhances their potential for precision therapeutic applications.
    DOI:  https://doi.org/10.1021/acs.accounts.5c00844
  5. Neuropharmacology. 2026 Feb 17. pii: S0028-3908(26)00058-4. [Epub ahead of print]289 110885
      Alcohol Use Disorder is a leading preventable cause of morbidity and mortality, yet knowledge of mechanisms driving ethanol-related neuroplasticity remains incomplete. While research has traditionally focused on neuronal signaling, emerging evidence implicates astrocytes in addiction-related adaptations. Here, we investigated the astrocyte-specific molecular consequences of chronic ethanol consumption in the prefrontal cortex and nucleus accumbens, two brain regions critical for executive control and reward processing. Using Translating Ribosome Affinity Purification RNA-seq and bulk RNA-seq in Aldh1l1-EGFP/Rpl10a mice, expressing an EGFP tag on astrocyte ribosomes, we identified hundreds of differentially translated astrocytic genes following chronic continuous two-bottle choice ethanol drinking. Sex-specific analyses revealed a higher number of astrocytic changes in the female PFC and male NAc. Pathway enrichment highlighted extracellular matrix remodeling, synaptic signaling, mitochondrial function, and immune-related pathways. Analyses of individual drinking levels further demonstrated distinct correlations between ethanol intake and astrocytic translation. The major components of the brain extracellular matrix are chondroitin sulfate proteoglycans, produced primarily by astrocytes and covalently bound to chondroitin sulfate glycosaminoglycan chains. Complementary mass spectrometry/liquid chromatography analyses of chondroitin sulfate, heparan sulfate, and hyaluronic acid glycosaminoglycan disaccharides revealed ethanol-induced alterations in chondroitin sulfate glycosaminoglycan sulfation patterns, with additional baseline differences identified between selectively bred high- and low-ethanol preference lines. Together, these findings indicate that astrocytes undergo profound sex- and region-specific adaptations to chronic ethanol, implicating extracellular matrix and glycosaminoglycan remodeling as key risk-factors for and mediators of chronic ethanol-related neuroplasticity.
    Keywords:  Alcohol drinking; Astrocyte; Extracellular matrix; Glycosaminoglycans; Nucleus accumbens; Prefrontal cortex; RNA-Seq
    DOI:  https://doi.org/10.1016/j.neuropharm.2026.110885
  6. PLoS One. 2026 ;21(2): e0342242
      Osteoarthritis (OA) is a prevalent degenerative joint disease with no curative treatment currently available. Recent evidence suggests that chondrocyte ferroptosis contributes to OA progression. Chondroitin sulfate (CS), widely used in OA management, exhibits anti-inflammatory and antioxidant properties, yet its role in modulating ferroptosis remains unclear. In this study, we investigated whether CS alleviates OA by inhibiting chondrocyte ferroptosis and explored the underlying mechanisms. Using an in vitro ferroptosis model induced by RSL3 in rat chondrocytes, we found that CS significantly restored cell viability and ameliorated ferroptosis-related changes, including reduction of intracellular and mitochondrial ROS, lipid peroxidation, and iron overload. CS also downregulated the expression of ferroptosis markers PTGS2 and ACSL4, while upregulating SLC7A11 and HSPA8 in a dose-dependent manner. Network pharmacology and transcriptomic analysis identified HSPA8 as a key overlapping gene among CS targets, OA-related differentially expressed genes, and ferroptosis-related genes. In a rat OA model induced by modified Hulth surgery, CS treatment attenuated cartilage degradation, as evidenced by improved OARSI scores, restored COL2A1 expression, and suppressed MMP13. Immunohistochemistry confirmed that CS upregulated SLC7A11 and HSPA8 while downregulating ACSL4. These findings demonstrate that CS mitigates OA progression by inhibiting chondrocyte ferroptosis, potentially through upregulation of HSPA8 and subsequent enhancement of SLC7A11 expression. Our study provides novel insights into the mechanism of CS in OA treatment and highlights ferroptosis as a promising therapeutic target.
    DOI:  https://doi.org/10.1371/journal.pone.0342242
  7. Carbohydr Polym. 2026 May 01. pii: S0144-8617(26)00152-9. [Epub ahead of print]379 125036
      Safe, potent, and low-bleeding anticoagulants remain an unmet medical need. Here we report a homogeneous glycosaminoglycan (GAG), designated TPG, isolated from the brittlestar Trichaster palmiferus. TPG (30.3 kDa, 32% sulfate) is composed of an almost equimolar ratio of L-Iduronic acid (IdoA) and N-acetyl-D-galactosamine (GalNAc) together with minor D-glucosamine (GlcN), D-galacturonic acid (GalA), and D-galactose (Gal). These physicochemical properties are distinct from heparin, dermatan sulfate, and chondroitin sulfate. Using one- and two-dimensional NMR of its desulfated derivative, free-radical depolymerized fragments, and oligosaccharide fractions generated by partial N-deacetylation-deamination cleavage, we established that the polymer backbone is built from four repeating disaccharides: L-IdoA2S3S-α-1,3-D-GalNAc4S/6S-β-1,4-, L-IdoA2S-α-1,3-D-GalNAc4S/6S-β-1,4-, D-GalA-α-1,3-D-GalNAc4S-β-1,4-, and D-GalNAc4S-β-1,4-GlcN0S/6S-α-1,3-. The IdoA2S3S and GalA residues and the D-GalNAc4S-β-1,4-GlcN0S/6S-α-1,3- unit are rare in natural GAGs, rendering TPG resistant to chondroitinase ABC. NMR detected terminal Gal in desulfated TPG and large oligosaccharide fragments, but its connection pattern remains unclear. TPG prolongs clotting times by simultaneously blocking intrinsic factor Xase and potentiating HCII-mediated thrombin inhibition, and it achieves potent antithrombotic efficacy in vivo with virtually no bleeding, an advantage over enoxaparin. These findings establish a brittlestar GAG whose unusual sulfation pattern defines a new class of high-efficacy, low-bleeding anticoagulants.
    Keywords:  Anticoagulant activity; Antithrombotic activity; Brittlestars; Glycosaminoglycans; Polysaccharides
    DOI:  https://doi.org/10.1016/j.carbpol.2026.125036
  8. Carbohydr Polym. 2026 May 01. pii: S0144-8617(26)00099-8. [Epub ahead of print]379 124983
      Acute liver injury (ALI) caused by acetaminophen (APAP) has a high incidence rate worldwide, and severe cases may cause liver failure or even death. N-acetylcysteine (NAC), as an effective treatment drug approved for clinical application in ALI, has limitations such as a short half-life and the requirement for high-dose injections. Consequently, it is imperative to optimize new administration method of NAC and promote alternative therapeutic strategies for ALI. Herein, hydrogel patches ONC composed of oxidized chondroitin sulfate (OCS) and NAC-grafted CMCS were developed, and their reparative effects on APAP-induced ALI were investigated. ONC hydrogels exhibited excellent biocompatibility and appropriate biodegradability, and favorable hemostatic effects in the liver. In vitro experiments demonstrated that ONC could promote the proliferation and migration of hepatocytes, as well as the angiogenesis of HUVECs. By establishing an APAP-induced ALI model in mice, liver enzymes after ONC hydrogel patches treatment recovered to near-normal levels. Moreover, histological examination, RT-qPCR, and transcriptome sequencing results demonstrated that ONC patches could reduce the expression of inflammatory factors and apoptosis in the liver, while simultaneously activating antioxidant-related signaling pathways, thereby promoting the regeneration and functional repair of damaged tissues. Therefore, ONC hydrogel patches may be a promising alternative strategy for treating ALI.
    Keywords:  Acute liver injury; Carboxymethyl chitosan; Chondroitin sulfate; Hydrogel patch; N-acetylcysteine
    DOI:  https://doi.org/10.1016/j.carbpol.2026.124983
  9. Int Microbiol. 2026 Feb 21.
      
    Keywords:   H. pylori ; Cholesterol sulfate; M-coccoid; Signaling; Spiral; Transformation
    DOI:  https://doi.org/10.1007/s10123-026-00784-6
  10. Int J Pharm. 2026 Feb 18. pii: S0378-5173(26)00148-1. [Epub ahead of print] 126700
      Microneedles (MNs), a novel transdermal drug delivery approach, are known for their convenience, dosing accuracy, and ability to enhance patient compliance. Conventional single layer MNs, however, have a drawback: most of the drug resides in the backing layer, which can't permeate the skin, leading to low drug utilization. Herein, to address the limitations of conventional MNs in drug delivery, we proposed a tip-concentrated dissolving microneedle combined with photothermal nanoparticles. Natural biopolymer compounds chondroitin sulfate and carboxymethyl chitosan serve as the matrix. Via a layered design, the drug is concentrated at the tips, with photothermal nanoparticles distributed along the shaft and in the backing layer. The photothermal effect is harnessed to accelerate drug release and enhance transdermal penetration. Compared to traditional MNs, this novel system, through optimized drug distribution and photothermal response, significantly improves drug utilization and delivery efficiency. It also excels in transdermal performance and adaptability to curved skin surfaces. This research not only overcomes the single loading function limitation of single layer MNs but also offers innovative ideas and technical support for developing precise drug delivery systems.
    Keywords:  Carboxymethyl chitosan; Chondroitin sulfate; Dissolvable microneedles; Drug delivery; Photothermal effect
    DOI:  https://doi.org/10.1016/j.ijpharm.2026.126700
  11. Toxicon. 2026 Feb 14. pii: S0041-0101(26)00051-6. [Epub ahead of print] 109033
      Low molecular mass compounds are the least understood among the components of spider venom. Sulfated fucosyl-guanosines originally detected from Hololena curta McCook are unique and rarely found in nature. While their synthetic counterparts are widely used as antibiotics. The present work compiles the current knowledge of these molecules, exploring their potential biogenetic origin. Additional topics highlight biochemistry and their significance as natural products with potential for pharmaceutical developments.
    Keywords:  Spider venom; sulfated fucosyl-guanosines; sulfated nucleosides; understudied venom compounds
    DOI:  https://doi.org/10.1016/j.toxicon.2026.109033
  12. NPJ Aging. 2026 Feb 20.
      Subjective and objective markers are important in describing healthy aging, yet little is known about their relationships. This study analysed the time-dependent association of dehydroepiandrosterone sulfate (DHEAS) with subjective health. At baseline, DHEAS was measured in participants aged 45-83 randomly selected from the general population. Subjective mental and physical health were assessed using the 12-item Short Form (SF-12) questionnaire at baseline and two follow-ups. In sex-specific linear regression models controlled for age, weight, tobacco consumption, Charlson Comorbidity Index, depression, and testosterone levels, the associations of DHEAS with the subscores of the SF-12 were analysed. DHEAS showed a positive cross-sectional association with subjective physical health, which was stronger in women and remained relevant after multivariable adjustment. However, longitudinal analyses revealed no long-term effect of DHEAS on subjective health. These findings suggest that the association between DHEAS and subjective physical health is temporary and that an underlying causality is unlikely.
    DOI:  https://doi.org/10.1038/s41514-026-00346-0
  13. Ren Fail. 2026 Dec;48(1): 2628465
      Radial-artery to cephalic-vein end-to-side arteriovenous fistulae (RCAVF) are the first-line vascular access for hemodialysis, yet early stenosis or thrombosis reduces its long-term patency. Indoxyl sulfate (IS), a protein-bound uremic toxin with diverse vascular effects, may impede fistula maturation. We conducted a single-center prospective cohort study enrolling 113 stage 5 chronic kidney disease patients who underwent RCAVF creation between February 2023 and August 2024. Patients were stratified by IS tertiles to assess fistula outcomes. Multivariable Cox regression, Kaplan-Meier analyses, and nomogram construction were used to identify risk factors and patency. Additionally, multiplex tyramide signal amplification immunofluorescence was applied to 40 samples of cephalic vein to quantify aryl hydrocarbon receptor (AHR) and tissue factor (TF) expression. After a median follow-up of 12 months, serum IS was higher in the dysfunction group (p = 0.005). Elevated IS (p = 0.013) and diabetes mellitus (p = 0.006) were independent risk factors for RCAVF dysfunction. Restricted cubic spline analysis showed a linear relationship between IS and risk. Kaplan-Meier curves revealed decreasing primary patency with increasing IS tertiles (p < 0.05), consistent in diabetic patients. The 1-year patency nomogram had good predictive performance (AUC = 0.87). Histopathology showed upregulated AHR and TF expression in veins from dysfunctional fistulas, with correlated fluorescence intensities (r = 0.60, p < 0.05), though neither correlated directly with serum IS (p > 0.05). In conclusion, elevated serum IS independently predicts RCAVF dysfunction, and the aberrant IS-AHR-TF signaling axis may contribute to its pathogenesis.
    Keywords:  Arteriovenous fistulas; aryl hydrocarbon receptor; indoxyl sulfate; tissue factor; vascular access dysfunction
    DOI:  https://doi.org/10.1080/0886022X.2026.2628465
  14. NPJ Sci Food. 2026 Feb 16.
      Chronic kidney disease (CKD) is characterized by progressive attenuation of kidney functions, resulting in the accumulation of uremic toxins. Various symptoms for CKD are closely associated with the gut-kidney axis, which represents the interaction between gut microbiota and CKD. In this study, we investigated the effects of Lactobacillus acidophilus (L. acidophilus) KBL409 on uremic toxin concentrations using a multi-center, randomized, double-blind, placebo-controlled study. Participants in the L. acidophilus KBL409 group received a daily capsule containing 1 × 1010 colony-forming units of L. acidophilus KBL409 or placebo. The per protocol analysis included 34 participants in the L. acidophilus KBL409 group and 30 participants in the placebo group. After 16 weeks, the serum indoxyl sulfate (IS) concentration was significantly lower in the L. acidophilus KBL409 group than in the placebo group (p < 0.05). Additionally, significant reductions in the genera Blautia, Butyricicoccus, Lachnospiraceae UCG-004, and Megamonas were observed in the L. acidophilus KBL409 group. These bacteria exhibited positive correlations with predicted functional genes linked to uremic toxin synthesis pathways, suggesting that L. acidophilus KBL409 reduced serum IS by altering gut microbial compositions. Therefore, L. acidophilus KBL409 could be used as an effective probiotic for improving kidney health through gut microbiota modulation.
    DOI:  https://doi.org/10.1038/s41538-026-00755-1
  15. Sci Rep. 2026 Feb 20.
      Progression occurs in more than 10% of melanoma patients initially diagnosed with local disease, emphasizing the need for improved risk stratification even in early stages. In this study, we used an enrichment method based on recombinant Plasmodium falciparum VAR2CSA protein to enable the capture of rare circulating tumor cells (CTCs) from a single blood draw in early-stage (AJCC I-II) melanoma patients. CTCs were subsequently identified using fluorescent antibodies targeting tumor initiating and melanoma specific cell markers. In parallel, we investigated circulating tumor DNA (ctDNA) in these patients. Among 92 early-stage melanoma patients, CTCs were detected in 21 patients (22.8%) at time of initial diagnosis. The presence of CTCs was significantly associated with an unfavorable clinical outcome, such as disease progression or death related to melanoma disease, with a median observation time of 30 months (IQR 24.0-36.0) (p = 0.043). Furthermore, when combining CTC with ctDNA detection, a highly significant correlation with disease progression was observed (p = 0.014) underlining the role of early tumor cell dissemination in melanoma disease. These findings suggest that CTC assessment, particularly when combined with ctDNA analysis, may represent a valuable biomarker to facilitate risk stratification of early-stage melanoma patients to improve personalized treatment approaches.
    Keywords:  Cell free DNA; Circulating tumor cells; Liquid biopsy; Massively parallel sequencing; Melanoma; VAR2CSA
    DOI:  https://doi.org/10.1038/s41598-026-40072-x
  16. J Steroid Biochem Mol Biol. 2026 Feb 16. pii: S0960-0760(26)00033-6. [Epub ahead of print]259 106967
      Estrogens play an important role throughout a woman's life; therefore, disrupting their physiological production will alter hormonal balance with consequences for estrogen-related conditions, such as endometriosis and adenomyosis. The gut microbiome (GM) plays a critical role in regulating systemic estrogen concentrations, since a number of microorganisms present in the GM possess the enzyme β-glucuronidase (β-GLC), a key factor in regulating host estrogen metabolism. Although most studies have focused on the conversion of estrogen glucuronides to active estrogens by β-GLC in gut bacteria, it is known that the GM also contains steroid sulfatases (STS), which are able to convert inactive sulfated estrogens to active ones. This is especially important because estrone (E1) sulfate (E1S) is quantitatively the most important estrogen in the human and can be readily converted to E1 and estradiol (E2). It has been shown that estrogen sulfates are present in bile and can therefore reach the intestines, raising the possibility of biologically active E1 and E2 formation in the intestine by bacterial enzyme transformation. Everything depends on the presence of sulfatases in the GM, and in this respect, STS have been found in a variety of microbial species. This means that sulfatases are poised to reactivate estrogens, which are then capable of undergoing enterohepatic recirculation and exerting systemic effects throughout the body. Given that estrogen sulfates represent the largest component of circulating estrogens that are secreted by the liver into the intestines via the bile, the role of gut microbial sulfatases may be superior to that of β-GLC.
    Keywords:  Arylsulfatases; Beta-glucuronidases; Conjugated estrogens; Estrobolome; Gut microbiome
    DOI:  https://doi.org/10.1016/j.jsbmb.2026.106967