bims-supasi 2026-06-07 papers

bims-supasi

Biomed News

on Sulfation pathways and signalling

Issue of 2026–06–07
nine papers selected by
Jonathan Wolf Mueller, University of Birmingham

A long-chain heparan sulfate capture mechanism directs paracrine GDNF-GFRα1 signalling through RET.
Innate immune-regulated sulfated glycosaminoglycans are associated with progeny respiratory syncytial virus retention at the cell surface in immortalized cell lines.
Evaluatıon of Dhea-S (Dehydroepıandrosterone Sulfate) levels in patients with adrenal adenomas exhibiting autonomous cortisol secretion.
Analytical and clinical validation of a competitive ELISA for serum indoxyl sulfate and its clinical association with chronic kidney disease risk stratification.
Characterizing structure-function relationships for a homogeneous, highly 6-O-sulfated keratan sulfate from bovine cornea: collagen binding and anti-inflammatory potential.
Programmable core-shell microneedles with marine chondroitin sulfate core and chito-oligosaccharide shell disrupt the pathological microenvironment cycle for enhanced healing of infected burn wounds.
A novel PAPSS2 pathogenic variant: expanding the mutational spectrum and genotype-phenotype landscape in skeletal dysplasia.
Psychiatric Symptoms in Women with Mild Autonomous Cortisol Secretion Versus Non-Functioning Adrenal Adenomas: A Cross-Sectional Study.
An oral tyrosine challenge test for functional phenotyping of microbiota-derived phenyl sulfate production.

bioRxiv. 2026 May 21. pii: 2026.05.20.726209. [Epub ahead of print]

A long-chain heparan sulfate capture mechanism directs paracrine GDNF-GFRα1 signalling through RET.

Mia I Zol-Hanlon, Beatrice Rix, Salomé Bodet-Lefèvre, Miguel Zamora-Porras, David C Briggs, Andrea Nans, Annabel C Borg, Sarah L Maslen, Antonio Di Maio, Ten Feizi, Yan Liu, Pradeep Chopra, Geert-Jan Boons, Jelizaveta Pavljuk, Ralf P Richter, Benjamin Schumann, Neil Q McDonald.

The receptor tyrosine kinase RET is activated by GDNF and GFRα1 together as a bipartite ligand, driving receptor activation and signalling in developmental and neuroprotective contexts. Evidence from developmental and cell models has suggested that heparan sulfate (HS) functions as a fourth component in RET signalling by binding to GDNF, but the molecular details remain unclear. Here, we present the cryo-EM structure of the heterohexameric RET:GDNF:GFRα1 complex with a fully resolved heparin ligand, revealing an unexpected extended HS binding site spanning all three proteins. The architecture of the complex and binding mode of the HS chain in this complex enables the formation of a higher order 4:4:4 assembly bound to a single 30-saccharide HS chain which bridges two intimately bound complexes. This multi-protein interface selectively binds the highly sulfated domains of HS over other GAG classes, and is essential for RET activation in trans with soluble GFRα1, but not in cis when GFRα1 is membrane-bound. Our data suggest that HS shapes the dynamics of RET signalling at every stage, from ligand diffusion to signalling complex formation. Thus, GDNF-GFRa1 paracrine signalling reveals a surprising dependence for long-chain GAG function in which the glycan engages in both receptor complex assembly and clustering.

DOI: https://doi.org/10.64898/2026.05.20.726209
Virology. 2026 May 26. pii: S0042-6822(26)00189-3. [Epub ahead of print]623 110974

Innate immune-regulated sulfated glycosaminoglycans are associated with progeny respiratory syncytial virus retention at the cell surface in immortalized cell lines.

Keitaro Yoshida, Soh Yamamoto, Noriko Ogasawara, Kiyosu Taniguchi, Tetsuya Nosaka, Shin-Ichi Yokota.

  Respiratory syncytial virus (RSV) and human metapneumovirus (hMPV), members of the Pneumoviridae family, are major causes of acute respiratory tract infections globally. Although glycosaminoglycans (GAGs), including heparan sulfate (HS), are implicated in viral attachment, their roles beyond entry remain incompletely defined. Here, we performed a genome-wide CRISPR/Cas9 knockout screen in interferon receptor-deficient cells to identify host factors commonly required for RSV and hMPV infection. The screen identified multiple genes involved in GAG biosynthesis and sulfation, including solute carrier family 35 member B2 (SLC35B2) and β-1,3-glucuronyltransferase 3 (B3GAT3). GAG sulfation promoted viral attachment and internalization of both viruses. Beyond entry, GAG sulfation influenced post-entry RSV dynamics. Genetic disruption of GAG biosynthesis or sulfation, as well as pharmacological inhibition, reduced cell-associated RSV while increasing infectious particles released into the supernatant, indicating that sulfated GAGs are associated with RSV particle retention at the cell surface in immortalized cell-line systems. This phenotype was not observed for hMPV, supporting a virus-specific requirement for GAG sulfation during RSV infection. Furthermore, RSV infection increased cell-surface GAG-reactive signal in a mitochondrial antiviral signaling protein (MAVS)-dependent manner. Loss of MAVS abolished this increase and was associated with increased released RSV titers, suggesting that innate immune signaling may influence viral release either directly through antiviral effects or indirectly through changes in GAG-related cell-surface properties. Collectively, our findings support a dual role for sulfated GAGs in Pneumoviridae infection in immortalized cell-line systems, facilitating viral entry for both RSV and hMPV while selectively restricting RSV dissemination through modulation of viral particle retention at the cell surface.

Keywords:  B3GAT3; Glycosaminoglycan sulfation; Human metapneumovirus; Innate immunity; Respiratory syncytial virus; SLC35B2

DOI:  https://doi.org/10.1016/j.virol.2026.110974
Steroids. 2026 Jun 03. pii: S0039-128X(26)00070-X. [Epub ahead of print] 109808

Evaluatıon of Dhea-S (Dehydroepıandrosterone Sulfate) levels in patients with adrenal adenomas exhibiting autonomous cortisol secretion.

Ulcaz Perihan Aksoydan Zubaroglu, Gamze Akkus, Bekir Tamer Tetiker.

   BACKGROUND: Autonomous cortisol secretion (ACS) is the most common hormonal dysfunction in adrenal incidentalomas and is associated with increased cardiometabolic morbidity. Dehydroepiandrosterone sulfate (DHEAS), an ACTH-dependent adrenal steroid, may decrease in ACS due to hypothalamic-pituitary-adrenal axis suppression. This study evaluated the diagnostic utility of DHEAS and DHEAS-based ratios, particularly within a dexamethasone suppression test (DST)-integrated framework, for differentiating ACS from non-functioning adrenal adenomas (NFA).
METHODS: In this retrospective single-center study, records of 433 patients followed for adrenal incidentaloma between 2015 and 2021 were reviewed. After applying predefined criteria, 67 patients were included: 35 with ACS and 32 with NFA. ACS was defined using a post-1 mg DST cortisol threshold of ≥ 1.8 µg/dL and confirmed with a two-day low-dose DST. Clinical, metabolic, biochemical, hormonal, and radiological parameters were analyzed. ROC analyses and logistic regression were performed, and internal validation was conducted using bootstrapping with 1,000 iterations.
RESULTS: Comorbidities were more frequent in ACS. ACTH, DHEAS, DHEAS/cortisol ratio, DHEAS/1-mg DST cortisol ratio, and TyG index differed significantly between groups. Post-1 mg DST cortisol showed the highest discriminatory performance (AUC = 0.967). Although DHEAS alone had limited diagnostic utility, the DHEAS/1-mg DST cortisol ratio showed good discrimination (AUC = 0.884, 95% CI: 0.802-0.966) and remained the only independent predictor of ACS (OR: 0.931, 95% CI: 0.895-0.968, p < 0.001). TyG showed moderate discrimination but was not an independent predictor.
CONCLUSION: The DHEAS/1-mg DST cortisol ratio may serve as a useful adjunctive marker for ACS-NFA differentiation, especially in borderline or ambiguous cases, but requires prospective external validation.

Keywords:  Adrenal incidentaloma; Autonomous cortisol secretion; DHEAS; Dexamethasone suppression test; TyG index

DOI:  https://doi.org/10.1016/j.steroids.2026.109808
Ren Fail. 2026 Dec;48(1): 2679793

Analytical and clinical validation of a competitive ELISA for serum indoxyl sulfate and its clinical association with chronic kidney disease risk stratification.

Yi-Chou Hou, Yung-Chun Chuang, Yu-Wei Cheng, Hsin-Yi Huang, Li-Yin Chen, Tzu-Ling Tseng, Kuo-Cheng Lu.

   BACKGROUND: Indoxyl sulfate (IS), a protein-bound uremic toxin derived from tryptophan metabolism, accumulates in patients with chronic kidney disease (CKD) and contributes to renal, vascular, and systemic injury. Conventional detection using LC-MS/MS is accurate but resource-intensive. To simplify IS quantification, Leadgene Biomedical developed a competitive enzyme-linked immunosorbent assay (ELISA) that employs anti-IS monoclonal antibodies capable of recognizing both free and protein-bound IS forms.
METHODS: Serum samples from 188 participants -classified as low-risk (healthy or CKD ≤ stage 2, n = 79) and high-risk (CKD stage G3a and above (eGFR <60 mL/min/1.73 m2, n = 109) - were analyzed using the Leadgene® IS ELISA Kit. Diagnostic performance was assessed through ROC analysis, precision by nested-ANOVA (total %CV < 10%), and accuracy by comparison with LC-MS/MS.
RESULTS: Mean age was higher in the high-risk group (65.17 ± 11.66 vs 57.96 ± 13.88 years, p < 0.001). The ELISA demonstrated excellent diagnostic performance with an area under the curve of 0.96 and an optimal cutoff of 2.233 µg/mL, yielding sensitivity 0.872 (95% confidence interval (CI) 0.816-0.912) and specificity 0.940 (95% CI 0.856-0.977). The Pearson correlation coefficient between the ELISA and LC-MS/MS results was 0.964, confirming high analytical concordance.
CONCLUSION: The Leadgene® IS ELISA Kit provides a rapid and accessible platform for serum indoxyl sulfate quantification with validated analytical performance and significant association with higher-risk CKD classification.

Keywords:  ELISA; Indoxyl sulfate; LC–MS/MS; chronic kidney disease; diagnostic performance; protein-bound uremic toxins

DOI:  https://doi.org/10.1080/0886022X.2026.2679793
Carbohydr Polym. 2026 Aug 15. pii: S0144-8617(26)00586-2. [Epub ahead of print]386 125469

Characterizing structure-function relationships for a homogeneous, highly 6-O-sulfated keratan sulfate from bovine cornea: collagen binding and anti-inflammatory potential.

Yan Sun, Xin Zhou, You Wang, Mingzhi Song, Litao Zhang, Qiang Ren.

  A structurally homogeneous keratan sulfate (KS) was purified from bovine cornea using an optimized method integrating enzymatic digestion and ion-exchange chromatography. Comprehensive structural analyses, including 1D/2D NMR, FT-IR, and disaccharide profiling, demonstrated a highly sulfated, linear polymer composed of repeating [-3Galβ1-4GlcNAcβ1-] units, with predominant 6-O-sulfation on both galactose and N-acetylglucosamine residues, comprising nearly equal proportions of disulfated (Gal6S-GlcNAc6S, 48.63%) and monosulfated (GlcNAc6S, 51.11%) disaccharides, with only trace amounts of non-sulfated units (<0.3%). HPGPC confirmed a narrow molecular weight distribution centered at approximately 43 kDa. Fluorescence quenching spectroscopy demonstrated that KS interacts with collagen with moderate affinity, a 1:1 stoichiometric ratio, and an enthalpy-driven mechanism. Circular dichroism analysis further suggested that KS association induces partial destabilization of the collagen triple-helical structure. At the single-molecule level, fluorescence correlation spectroscopy confirmed the formation of the KS-collagen complex, with further mechanistic insights provided by molecular docking and molecular dynamics simulations. Functionally, KS attenuated LPS-induced pro-inflammatory cytokine expression in RAW 264.7 macrophages, with network pharmacology implicating multi-target regulation of the TLR4/NF-κB pathway. This study establishes a direct link between the fine structure of corneal KS and its biological functions, providing a quantitative framework for understanding stromal matrix organization and guiding KS-based biomaterial design.

Keywords:  Anti-inflammatory; Collagen; Interaction; Keratan sulfate; Structural characterization

DOI:  https://doi.org/10.1016/j.carbpol.2026.125469
Int J Biol Macromol. 2026 Jun 02. pii: S0141-8130(26)02787-X. [Epub ahead of print] 152860

Programmable core-shell microneedles with marine chondroitin sulfate core and chito-oligosaccharide shell disrupt the pathological microenvironment cycle for enhanced healing of infected burn wounds.

Min Li, Yong Jiang, Jiqing Dong, Linlin Ma, Yuehao Xu, Xiangyan Chen, Yantao Li.

  Infected burn wounds are difficult to heal due to a self-sustaining cycle of infection, inflammation, oxidative stress, and pain that disrupts orderly tissue regeneration. Herein, we develop a programmable marine polysaccharide-based core-shell microneedle patch (CC-MN) that effectively disrupts this pathological cycle through stage-specific therapeutic regulation. The CC-MN integrates a chito-oligosaccharide (COS) shell and a chondroitin sulfate (CS) core. Its programmability is encoded by the core-shell architecture, enabling rapid COS shell dissolution for early-stage antibacterial intervention, followed by sustained CS core release for prolonged immunomodulatory and pro-regenerative regulation. Specifically, CC-MN achieved antibacterial inhibition rates of 94.0%, 98.8%, and 99.5% against Staphylococcus aureus, Escherichia coli, and Pseudomonas aeruginosa, respectively. Meanwhile, sustained CS release attenuated inflammation, scavenged excessive reactive oxygen species, reduced pain-associated inflammatory mediators including prostaglandin E2, and promoted macrophage polarization toward a pro-regenerative phenotype. In a Pseudomonas aeruginosa-infected burn wound model, CC-MN treatment reduced wound bacterial burden to ~0.5% of the untreated control and accelerated wound closure to 96.1% by day 16, accompanied by decreased inflammatory cytokine expression, enhanced angiogenesis, and improved collagen remodeling. This work presents a translatable and programmable microneedle platform for comprehensive management of infected burn wounds.

Keywords:  Antibacterial therapy; Burn wounds; Core-shell microneedles; Marine polysaccharides; Oxidative stress

DOI:  https://doi.org/10.1016/j.ijbiomac.2026.152860
J Pediatr Endocrinol Metab. 2026 Jun 03.

A novel PAPSS2 pathogenic variant: expanding the mutational spectrum and genotype-phenotype landscape in skeletal dysplasia.

Behiye Sarıkaya Özdemir, Naz Güleray Lafcı, Betül Emine Derinkuyu, Semra Çetinkaya, Merve Şakar, Melikşah Keskin, Nursel Muratoğlu Şahin, Zehra Aycan, Şenay Savaş Erdeve.

   OBJECTIVES: The biosynthesis of 3'-phosphoadenosine 5'-phosphosulfate (PAPS), a universal sulfate donor, is catalyzed by two isoenzymes: PAPS synthetase 1 (PAPSS1) and PAPS synthetase 2 (PAPSS2). While PAPSS1 is ubiquitously expressed, PAPSS2 shows tissue-specific expression and plays a key role in cartilage development and adrenal steroid metabolism. PAPSS2 deficiency impairs dehydroepiandrosterone sulfation (DHEA-S), leading to increased bioactive androgens and hyperandrogenism. Biallelic PAPSS2 variants cause skeletal dysplasias from brachyolmia (BO) to severe spondyloepimetaphyseal dysplasia (SEMD). This study aimed to expand the PAPSS2 mutational spectrum and explore potential genotype-phenotype correlations, including the distribution of variants across functional domains.
CASE PRESENTATION: Two siblings with disproportionate short stature underwent clinical, radiological, and biochemical evaluation. Targeted next-generation sequencing of skeletal dysplasia-associated genes was performed. Serum DHEA-S levels were measured to assess steroid sulfation. A literature review of previously reported PAPSS2 variants was conducted to explore genotype-phenotype correlations. A novel homozygous missense variant, c.1466C>G (p.Pro489Arg), in the ATP sulfurylase domain of PAPSS2, was identified in both siblings. The male proband exhibited a severe SEMD phenotype, while his sister presented with milder BO features. Both had markedly reduced DHEA-S levels (4.04 μg/dL and 31.8 μg/dL), consistent with impaired adrenal androgen sulfation. Review of the literature indicates an enrichment of SEMD-associated variants within the ATP sulfurylase domain, although phenotypic overlap with BO is evident, as also observed in the present family.
CONCLUSIONS: This study expands the known PAPSS2 mutational spectrum by identifying a novel pathogenic variant. The observed intrafamilial variability highlights the complexity of genotype-phenotype relationships, particularly in the context of limited case numbers, while low DHEA-S levels represent a robust biochemical marker of impaired steroid sulfation.

Keywords:  DHEA-S; PAPSS2; brachyolmia; spondyloepimetaphyseal dysplasia (SEMD)

DOI:  https://doi.org/10.1515/jpem-2025-0640
Horm Metab Res. 2026 Jun 02.

Psychiatric Symptoms in Women with Mild Autonomous Cortisol Secretion Versus Non-Functioning Adrenal Adenomas: A Cross-Sectional Study.

Ilkay Cakir, Fuat Mısıroğlu, Zeynep Elustu Belten, Didem Acarer, Hamide Piskinpasa, Seda Karslı, Yusuf Ezel Yildirim, Meral Mert, Sema Ciftci, Esra Hatipoglu.

Abstract: The potential association between mild autonomous cortisol secretion and psychopathological symptoms remains inadequately studied. This study aimed to investigate whether women with mild autonomous cortisol secretion exhibit greater psychological symptom severity and distress compared with patients with nonfunctional adrenal adenomas, as assessed by multidimensional self-report scales including the Beck Depression Inventory-II, Beck Anxiety Inventory, and Symptom Checklist‑90. A cross-sectional study was conducted at the endocrinology department of a tertiary-care hospital in Turkey between June 2022 and 2025. The study cohort included 91 women with adrenal adenomas, comprising 50 patients with mild autonomous cortisol secretion and 41 patients with nonfunctional adrenal adenoma. Questionnaire-derived scores from the 10 subscales and Global Severity Index of the Symptom Checklist-90, as well as the Beck Anxiety Inventory and Beck Depression Inventory-II, along with hormonal parameters, including morning cortisol, adrenocorticotropic hormone, dehydroepiandrosterone sulfate, 1-mg dexamethasone-suppressed cortisol, 24-hour urinary free cortisol, the dehydroepiandrosterone sulfate ratio, and the cortisol/dehydroepiandrosterone sulfate ratio, were compared between the groups. Women with mild autonomous cortisol secretion exhibited higher overall psychological distress, as measured by the Global Severity Index of the Symptom Checklist-90. Depressive (Beck Depression Inventory-II) and anxiety (Beck Anxiety Inventory) symptoms did not differ significantly between groups, although a non-significant pattern suggested that depressive symptom severity may increase with higher basal cortisol levels. No significant associations were found between hormonal parameters and psychological scores. These findings indicate that patients with mild autonomous cortisol secretion may experience increased general psychological distress, highlighting the importance of considering mental health in their clinical evaluation and warranting further research into the relationship between mild cortisol excess and specific psychiatric symptoms.

DOI: https://doi.org/10.1055/a-2874-9528
NPJ Metab Health Dis. 2026 Jun 02. pii: 20. [Epub ahead of print]4(1):

An oral tyrosine challenge test for functional phenotyping of microbiota-derived phenyl sulfate production.

Ting-Yun Lin, Szu-Chun Hung, Takaaki Abe.

Phenyl sulfate (PS), a gut microbiota-derived metabolite implicated in the pathogenesis of diabetic kidney disease, is generated through microbial conversion of dietary tyrosine to phenol, followed by hepatic sulfation via SULT1A1. We developed an oral tyrosine challenge test (OTyCT) to phenotype individual PS-producing capacity. Forty-eight healthy adults underwent a standardized tyrosine load with serial plasma PS levels measured over 48 h using LC-MS. OTyCT revealed substantial interindividual variability of PS production independent of baseline PS levels, highlighting marked heterogeneity in host-microbiome metabolic interactions. Sixteen participants in the highest tertile of the incremental area under the curve of PS were defined as high-PS producers. High PS producers exhibited distinct gut microbial signatures despite comparable abundances of known phenol-biosynthetic genes and host SULT1A1 genotypes. These findings suggest that susceptibility to PS-related complications may vary according to gut microbial profiles, supporting OTyCT as a practical tool for metabolic phenotyping and microbiome-informed precision nutrition. Clinical Trial registry name and registration number: Identification of P-Cresyl Sulfate Producer Phenotype by Oral Tyrosine Challenge Test: Interactions Among Diet, Gut Microbiota, and Host Genome, NCT04204174.

DOI: https://doi.org/10.1038/s44324-026-00114-4