bims-supasi Biomed News
on Sulfation pathways and signalling
Issue of 2026–07–19
eleven papers selected by
Jonathan Wolf Mueller, University of Birmingham
  1. Bacterial-Derived Signals Selectively Remodel Glycosaminoglycan Biosynthetic Pathways in Reconstructed Human Corneal Epithelium.
  2. Exploring microbial-derived chondroitin sulfate as a suppressor of microglial inflammation and pyroptosis.
  3. Regio-selective sulfation of heparin mimicking polymers defines in vivo activity.
  4. Chemoenzymatic Synthesis of Heparan Sulfate Oligosaccharides by a Covalent Catch-and-Release Approach.
  5. Perspectives of Bacterial PAPS-Independent Aryl Sulfotransferases for Practical In Vitro Sulfation.
  6. Auranofin Suppresses Cancer Cell Invasion by Inhibiting Heparanase-1 Expression via the aPKC-NF-κB Pathway.
  7. Chondroitin sulfate reinforces mitochondrial redox homeostasis to enable integrated intervertebral disc regeneration.
  8. A Metrologically Traceable Candidate Reference Measurement Procedure (cRMP) for Dehydroepiandrosterone Sulfate in Human Serum Based on Isotope Dilution-Liquid Chromatography-Tandem Mass Spectrometry (ID-LC-MS/MS).
  9. Indoxyl Sulfate, a Gut Microbiota-Derived Metabolite, Modulates Hepatic Cholesterol Metabolism via SREBP-2/HMG-CoA Reductase Upregulation in Rats.
  10. Dehydroepiandrosterone (DHEA) and Dehydroepiandrosterone Sulfate (DHEA-S) in Broiler Plasma: Analytical Validation of Immunoassays and Comparative Overview Across Avian Species.
  11. Physiological and Behavioural Characterisation of a Novel Steroid Sulfatase-Deficient Mouse.
  1. Int J Mol Sci. 2026 Jul 06. pii: 6046. [Epub ahead of print]27(13):
    Bacterial-Derived Signals Selectively Remodel Glycosaminoglycan Biosynthetic Pathways in Reconstructed Human Corneal Epithelium.
    Noelia Blanco-Agudín, Natalia Vázquez, Suhui Ye, Cristina Sánchez-Fernández, Iván Fernández-Vega, Álvaro Meana, Jesús Merayo-Lloves, Luis M Quirós.
      Proteoglycans (PGs) and their glycosaminoglycan (GAG) chains play key roles in corneal epithelial physiology and host-microbe interactions. Although bacterial exposure has been shown to alter PG and GAG biosynthesis, the contribution of specific bacterial-derived signals remains unclear. In this study, reconstructed human corneal epithelia (QobuR) were exposed to bacterial extracellular vesicles (BEVs) from Pseudomonas aeruginosa and Staphylococcus epidermidis, as well as to lipopolysaccharide, peptidoglycan, and lipoteichoic acid. The expression of 72 genes involved in PG and GAG biosynthesis and remodeling was analyzed by quantitative real-time PCR. Only 22 genes showed significant transcriptional alterations, indicating a highly selective response. Most changes affected enzymes involved in the generation of heparan sulfate (HS) and chondroitin sulfate (CS) fine structure, particularly sulfotransferases. Notably, HS3ST4 and HS3ST5 were consistently upregulated under all experimental conditions, suggesting that modulation of HS 3-O-sulfation represents a conserved corneal epithelial response to bacterial-derived stimuli. Whereas microbial-associated molecular patterns induced broader transcriptional responses, BEVs elicited more restricted and species-dependent effects. Overall, these findings demonstrate that bacterial-derived signals selectively remodel GAG biosynthetic pathways and provide new insights into the molecular mechanisms underlying host-microbe interactions at the ocular surface.
    Keywords:  bacterial extracellular vesicles; corneal epithelium; glycosaminoglycans; heparan sulfate; host–microbe interactions; microbial-associated molecular patterns
    DOI:  https://doi.org/10.3390/ijms27136046
  2. Sci Rep. 2026 Jul 13.
    Exploring microbial-derived chondroitin sulfate as a suppressor of microglial inflammation and pyroptosis.
    Önder Otlu, Mehmet Erdem, Şeniz Erdem, Ahmet Alver, Ayşe Şebnem Erenler.
      Neuroinflammation is a protective immune response in the central nervous system (CNS), primarily regulated by glial cells such as microglia, astrocytes, and oligodendrocytes. Microglia serve as the main innate immune cells, initiating responses to pathological stimuli through mechanisms including inflammasome activation. The NLRP3 inflammasome plays a central role in promoting inflammation and pyroptosis. Chondroitin sulfate (CS), a sulfated glycosaminoglycan found in the extracellular matrix, exhibits anti-inflammatory, anticoagulant, and antioxidant properties. This study investigates the anti-neuroinflammatory potential of microbial chondroitin sulfate (MCS), a novel compound developed by our team, in comparison to commercial CS (CCS). N9 mouse microglial cells were treated with MCS and CCS. We evaluated cytotoxicity and cell viability using LDH and CCK-8 assays. Levels of pro-inflammatory cytokines IL-1β and IL-18 were measured via ELISA. Western blotting and flow cytometry were used to assess the expression of NLRP3, caspase-1, GSDMD, and GSDMD-N, key proteins involved in inflammasome activation and pyroptosis. MCS significantly reduced LDH release and increased cell viability, indicating protection against cytotoxicity. It also suppressed IL-1β and IL-18 secretion and downregulated NLRP3, caspase-1, and GSDMD activation. Notably, MCS achieved effects comparable to CCS at doses approximately 200 times lower. This is the first study to demonstrate that MCS effectively inhibits NLRP3 inflammasome activation and pyroptosis in microglial cells. These findings highlight MCS as a potent anti-neuroinflammatory agent and a promising candidate for therapeutic development in CNS inflammatory disorders.
    Keywords:  Chondroitin sulfate; Inflammasome; Microglia; Neuroinflammation; Pyroptosis
    DOI:  https://doi.org/10.1038/s41598-026-61795-x
  3. bioRxiv. 2026 Jul 10. pii: 2026.07.09.737190. [Epub ahead of print]
    Regio-selective sulfation of heparin mimicking polymers defines in vivo activity.
    Madeline K Loffredo, Hyun Ok Ham, Maria Varghese, Carolyn A Haller, Elliot L Chaikof, Mark W Grinstaff.
      Heparin, a naturally derived glycosaminoglycan, is the most commonly used anti-thromboembolic in the world. However, the biological origin of heparin inherently results in batch-to-batch variability, large dispersity indexes, and potential contamination, leading to inconsistent activity and patient-dependent dose-response. As such, new synthetic anticoagulants are of keen interest, particularly those that mimic heparin while being amenable to alterations in polymer structure and composition for performance optimization. Herein, we report the strategy, synthesis, and evaluation of well-defined, regioselectively functionalized di-sulfated polyamidosaccharides ( disulPASs ) including exploration of the structure-function relationship of molecular weight and sulfation density on anticoagulant activity. Polymerization of an orthogonally protected ý-lactam monomer via anionic ring-opening, followed by selective deprotection and sulfation reactions affords disulPAS. Similar to heparin, disulPAS s elongate clotting time through the intrinsic and extrinsic pathways, showing molecular weight and dose-dependent responses in clotting time; are non-cytotoxic and non-hemolytic, partially neutralized by protamine sulfate, and unlike heparin, are not degraded by heparinases. As compared to less sulfated and randomly sulfated iterations of PAS, disulPAS performs superiorly, with in vitro and in vivo clotting activity most similar to native heparin.
    DOI:  https://doi.org/10.64898/2026.07.09.737190
  4. Angew Chem Int Ed Engl. 2026 Jul 13. e2903805
    Chemoenzymatic Synthesis of Heparan Sulfate Oligosaccharides by a Covalent Catch-and-Release Approach.
    Francesco Palmieri, Chin Huang, Digantkumar Chapla, Kelley W Moremen, Geert-Jan Boons.
      A covalent catch-and-release approach is described for the chemoenzymatic synthesis of HS oligosaccharides. It exploits that a glycan modified by a hydrazide tag can under mild acidic conditions efficiently be reacted with an aldehyde-containing resin to give an immobilized hydrazone product. The hydrazone is stable under neutral conditions, allowing stringent washing conditions to remove all other components. The product can be released by transiminolysis using aqueous hydroxylamine, which, after evaporation, yields a compound that can be immediately employed in the next cycle of modification. As many as 11 consecutive transformations could be performed to give a homogenous octasaccharide having a complex pattern of sulfation and epimerization. The methodology provides opportunities to prepare convenient collections of biologically important HS oligosaccharides for structure-function studies.
    Keywords:  carbohydrates; chemoenzymatic; enzymes; heparan sulfate; hydrazones; solid‐phase extraction
    DOI:  https://doi.org/10.1002/anie.2903805
  5. J Agric Food Chem. 2026 Jul 16.
    Perspectives of Bacterial PAPS-Independent Aryl Sulfotransferases for Practical In Vitro Sulfation.
    Katerina Brodsky, Barbora Petránková, Kristýna Slámová, Pavla Bojarová, Kateřina Valentová.
      PAPS-independent bacterial aryl sulfotransferases (ASTs) do not require the costly and unstable cofactor PAPS like mammalian sulfotransferases. Instead, they use simple aromatic sulfuryl donors. Originally discovered in intestinal bacteria, ASTs display remarkable substrate diversity, catalyzing sulfation of phenols, alcohols, amines, sugars, and polyphenols, including flavonoids and flavonolignans. Among them, AST from Desulfitobacterium hafniense (DhAST) is particularly notable for its stability and broad substrate range. Structural and mechanistic studies reveal that ASTs follow a ping-pong bibi mechanism with transient enzyme sulfation. Recent identification of new ASTs from diverse bacterial species and advances in recombinant expression have broadened the potential of these enzymes for selective and scalable synthesis of sulfated metabolites in vitro. Expanding the available AST library has deepened the understanding of bacterial sulfation pathways and supports their applications in biocatalysis, metabolite synthesis, and production of sulfated bioanalytical standards.
    Keywords:  (poly)phenols; Desulfitobacterium hafniense; aryl sulfotransferases (ASTs); in vitro; sulfation
    DOI:  https://doi.org/10.1021/acs.jafc.6c01204
  6. Int J Mol Sci. 2026 Jun 23. pii: 5646. [Epub ahead of print]27(13):
    Auranofin Suppresses Cancer Cell Invasion by Inhibiting Heparanase-1 Expression via the aPKC-NF-κB Pathway.
    Masahiro Komeno, Rin Miyajima, Kanami Miyashita, Masato Suzuki, Toshinao Matoba, Ayuna Miwa, Shoo Katsumoto, Ryosuke Yasumura, Kenta Ko, Hitoshi Kotani, Shoma Tamori, Shoko Itakura, Kosuke Kusamori, Makiya Nishikawa, Kazunori Akimoto, Takashi Suda, Chiaki Takahashi, Nobuaki Higashi, Fuming Zhang, Toshihiko Toida, Kyohei Higashi.
      Heparanase 1 (HPSE1) is the only mammalian endoglycosidase that cleaves heparan sulfate (HS), a glycosaminoglycan (GAG), and is frequently upregulated in cancers, thereby promoting tumor progression. Despite extensive efforts to develop inhibitors of its HS-degrading activity, its non-enzymatic functions limit therapeutic efficacy and pose a major challenge for therapeutic development. Thus, inhibiting HPSE1 expression is critical for controlling its enzymatic and non-enzymatic functions; however, no FDA-approved inhibitors are currently available. Here, we identify auranofin (AUF), an oral gold-containing drug used to treat rheumatoid arthritis, as a potent inhibitor of HPSE1 promoter activity. High-throughput screening revealed that an atypical protein kinase C (aPKC)-NF-κB signaling axis is a key regulator of HPSE1 expression. Notably, AUF treatment reduced HPSE1 expression and significantly suppressed the invasive capacity of MDA-MB-231 cells in a Transwell migration assay. We then investigated the role of HPSE1 in the invasive activity of MDA-MB-231 cells, which produce higher levels of hyaluronan (HA) and HS than non-invasive cells. Neither HS degradation, HA supplementation in Matrigel during Transwell migration, nor HPSE1 overexpression alone was sufficient to drive invasion, suggesting that invasive capacity depends on mesenchymal features and coordinated induction of HPSE1 and GAGs rather than HS degradation. Collectively, our findings demonstrate that AUF-mediated inhibition of aPKC suppresses HPSE1 expression, thereby inhibiting both its enzymatic and non-enzymatic functions and limiting cancer progression, metastasis, and angiogenesis. These results highlight the therapeutic potential of AUF for targeting HPSE1-driven tumor progression and support its repurposing for cancer treatment.
    Keywords:  atypical protein kinase C; auranofin; cancer invasion; epithelial–mesenchymal transition; heparan sulfate; heparanase-1; hyaluronan
    DOI:  https://doi.org/10.3390/ijms27135646
  7. Regen Biomater. 2026 ;13 rbag134
    Chondroitin sulfate reinforces mitochondrial redox homeostasis to enable integrated intervertebral disc regeneration.
    Xin Wang, Yixue Huang, Yilin Yang, Yesheng Jin, Yun Xiao, Hao Liu, Yong Xu, Yijie Liu.
      Intervertebral disc degeneration (IVDD), characterized by oxidative stress, mitochondrial dysfunction and extracellular matrix (ECM) breakdown, is a major contributor to low back pain. Current regenerative strategies often fail to address both the biological and structural aspects of IVDD in an integrated manner. Here, we demonstrate that chondroitin sulfate (CS) exerts a dual therapeutic role by enhancing endogenous antioxidant defenses and promoting anabolic ECM synthesis in both annulus fibrosus cells (AFCs) and nucleus pulposus cells (NPCs). Mechanistically, CS activates the integrin α4β1-PI3K-Akt signaling pathway, preserving mitochondrial integrity and restoring redox homeostasis. Furthermore, we developed an injectable, multifunctional PVA/collagen (Col)/CS hydrogel that integrates mechanical support, bioactivity and targeted CS delivery to enable unified repair of the disc's biphasic structure. In a rat IVDD model, this hydrogel effectively preserved disc architecture, restored disc height and MRI signal and upregulated key matrix and antioxidant markers, demonstrating coordinated repair of both the annulus fibrosus (AF) and the nucleus pulposus (NP). Our study establishes CS as a potent dual-function agent and presents an integrated hydrogel-based strategy for functional disc regeneration.
    Keywords:  PI3K-Akt pathway; chondroitin sulfate; intervertebral disc degeneration; mitochondrial function; oxidative stress
    DOI:  https://doi.org/10.1093/rb/rbag134
  8. J Mass Spectrom. 2026 Aug;61(8): e70088
    A Metrologically Traceable Candidate Reference Measurement Procedure (cRMP) for Dehydroepiandrosterone Sulfate in Human Serum Based on Isotope Dilution-Liquid Chromatography-Tandem Mass Spectrometry (ID-LC-MS/MS).
    Liping Yang, Bingling Gao, Tao Yang, Liping Tang, Ying Kan, Keqi Sun, Peng Xiao.
      Dehydroepiandrosterone sulfate (DHEAS), a crucial steroid hormone for adrenal function and pubertal development, is highly associated with related diseases. This study aims to develop and validate an isotope dilution liquid chromatography tandem mass spectrometry (ID-LC-MS/MS)-based candidate reference measurement procedure (cRMP) for quantifying serum DHEAS. Serum samples were prepared by protein precipitation with acetonitrile and separated on a reversed phase column. Assay validation was conducted under the guidance of standard documents, including C62-A, EP6-A, EP10-A3, and C50-P endorsed by the Clinical and Laboratory Standards Institute (CLSI). The cRMP was established and proven to be highly specific without significant matrix effect and able to accurately quantify DHEAS in human serum. The intra-assay and inter-assay imprecision ranged from < 0.1 to 1.0% and from 1.0 to 1.1%, respectively. Trueness was assessed by recovery rate from 99.6 to 101.2%. The limit of detection (LoD) was 0.270 nmol/L, and the lower limit of the measuring interval (LLMI) was 12.1 nmol/L. A linear correlation ranged from 7.60 to 41 858 nmol/L was observed with a correlation coefficient > 0.999. R2 value of linear regression analysis between this method and clinical immunoassays was ≥ 0.990. The relative expanded uncertainty was 1.5%-2.5% over the concentration range of 12.1-33 043 nmol/L. This study developed an ID-LC-MS/MS-based cRMP, which provided high specificity, trueness, and precision for serum DHEAS quantification, contributing to the DHEAS measurement standardization and traceability.
    Keywords:  dehydroepiandrosterone sulfate; isotope dilution‐liquid chromatography–tandem mass spectrometry; reference measurement procedure; traceability
    DOI:  https://doi.org/10.1002/jms.70088
  9. Nutrients. 2026 Jul 03. pii: 2160. [Epub ahead of print]18(13):
    Indoxyl Sulfate, a Gut Microbiota-Derived Metabolite, Modulates Hepatic Cholesterol Metabolism via SREBP-2/HMG-CoA Reductase Upregulation in Rats.
    Mateusz Szudzik, Mikołaj Zajdel, Anna Laskowska, Tomasz Hutsch, Marcin Ufnal.
       BACKGROUND: A high-fat diet (HFD) contributes to cardiometabolic disease. Gut microbiota-derived metabolites may participate in this process, but their contribution to lipid regulation is not well defined. Indoxyl sulfate (IS), a microbiota-derived metabolite, has been linked to vascular and metabolic dysfunction. Its role in lipid metabolism remains unclear.
    METHODS: In Part A, plasma and urinary concentrations of IS were measured in plasma and urine from HFD-fed rats in which dyslipidemia had developed, together with controls. In Part B, HepG2 cells were exposed to IS, and cell viability and selected cholesterol metabolism-related transcripts and proteins were assessed. In Part C, 10-week-old, male Sprague-Dawley rats maintained on a standard diet received vehicle or IS at two doses for 8 weeks. Hepatic expression of LDLR, SREBP-2, HMG-CoA reductase, and related cholesterol metabolism markers were measured by quantitative real-time PCR and Western blotting.
    RESULTS: In Part A, higher plasma IS concentrations and higher daily urinary IS excretion were found in samples collected from HFD-fed rats compared to controls. In HepG2 cells, IS reduced cell viability at higher concentrations and increased LDLR mRNA and protein expression. In IS-treated rats, total cholesterol, LDL-cholesterol, and triglycerides increased in a dose-dependent manner. Hepatic SREBP-2 and HMG-CoA reductase protein levels were increased at both IS doses, whereas LDLR protein abundance was increased at the higher dose. Moreover, serum PCSK9 levels were reduced in IS-treated rats.
    CONCLUSION: IS increased in HFD-fed rats. IS altered cholesterol metabolism-related pathways in HepG2 cells and in rats. In vivo IS administration increased circulating lipids and hepatic proteins involved in cholesterol synthesis and uptake. These findings indicate that IS may contribute to disturbed lipid homeostasis, although its role in HFD-induced dyslipidemia requires further mechanistic confirmation.
    Keywords:  LDL; bacterial metabolites; dyslipidemia; indoxyl sulfate
    DOI:  https://doi.org/10.3390/nu18132160
  10. Animals (Basel). 2026 Jun 27. pii: 1990. [Epub ahead of print]16(13):
    Dehydroepiandrosterone (DHEA) and Dehydroepiandrosterone Sulfate (DHEA-S) in Broiler Plasma: Analytical Validation of Immunoassays and Comparative Overview Across Avian Species.
    Laura Menchetti, Olimpia Barbato, Giovanni Ricci, Marco Gobbi, Roberta Stocchi, Seyedalireza Kasaiyan, Renzo Galli, Luca Todini.
      This study validated immunoassays for measuring circulating DHEA and DHEA-S in broiler plasma and compared the two biomarkers. A commercially available RIA kit for DHEA and a species-independent ELISA kit for DHEA-S were tested against each other and available literature data. Blood samples were collected from 68 female broilers at slaughter. Most sample concentrations were close to the lower calibration range. DHEA concentrations ranged from 52 to 354 pg/mL, whereas DHEA-S values ranged from 76 to 7320 pg/mL. Both assays showed satisfactory validation results, including good precision (intra- and inter-assay CV ≤ 15%), accuracy (recovery ≥ 99%), linearity (R2 > 0.9; run test p > 0.1), and parallelism between calibrator curves and sample dilutions (ANCOVA p > 0.1). However, the DHEA-S assay showed high cross-reactivity with DHEA (160%), making quantitative DHEA-S determination unreliable; therefore, values should be interpreted as an estimate of combined DHEA/DHEA-S concentrations. Consequently, the higher concentrations measured with the DHEA-S ELISA compared with the DHEA RIA (Bland-Altman bias: -525.8 pg/mL) do not indicate a true predominance of DHEA-S. Nevertheless, both assays may represent useful tools for comparative evaluations among samples, although they do not provide reliable information on the physiological interconversion between the two steroids.
    Keywords:  animal welfare; dehydroepiandrosterone (DHEA); immunoassay validation; poultry; steroid hormones
    DOI:  https://doi.org/10.3390/ani16131990
  11. Genes Brain Behav. 2026 Aug;25(4): e70061
    Physiological and Behavioural Characterisation of a Novel Steroid Sulfatase-Deficient Mouse.
    Trevor Humby, Freya R Shepherd, Talia Elgie, Libby Anderson-Watkins, Lucy I Beevors, Angela E Taylor, Paul A Foster, William Davies.
      Steroid sulfatase (STS) cleaves sulphate groups from steroid hormones. In humans, STS deficiency is associated with X-linked ichthyosis, an increased predisposition to neurodevelopmental and mood conditions (including Attention Deficit Hyperactivity Disorder, autism, depression and anxiety), and cardiac arrhythmia risk. Until recently, no single-gene 'knockout' mammalian model existed; previous work in such a model is limited to skin phenotypes. We generated a novel C57BL/6J mouse model with a deletion in exon 2 of Sts. We examined gene expression and enzyme activity in liver and brain samples of homozygous mice, and assessed the breeding performance and health of male and female deletion-carriers. Subsequently, we compared performance across a range of behavioural paradigms in wildtype and homozygous male and female mice: elevated plus maze, open field, rotarod, spontaneous alternation, and acoustic startle/prepulse inhibition. We also investigated serum steroid hormone levels by liquid chromatography-mass spectrometry and measured heart weights and two morphological indices (bodyweight/tibia length) post mortem. Homozygous mice almost completely lacked STS expression/activity. Genetically-altered mice exhibited grossly-normal breeding performance, health, and endocrinology. Homozygous mice were more active and had higher normalised heart weights than wildtype mice. We also found significant genotype × sex interactions on bodyweight and on two behavioural measures (potentially reflecting lower anxiety in homozygous males and heightened anxiety in homozygous females). The 'Sts-deletion' mouse represents an experimentally-tractable model in which to identify and characterise phenotypes associated with STS deficiency. The mechanistic basis of the associations described here requires further investigation, and whether these translate to humans remains to be tested.
    Keywords:  Xp22.31; atrial fibrillation; attention deficit hyperactivity disorder; dehydroepiandrosterone sulphate
    DOI:  https://doi.org/10.1111/gbb.70061
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