bims-supasi 2026-08-02 papers

bims-supasi

Biomed News

on Sulfation pathways and signalling

Issue of 2026–08–02
nineteen papers selected by
Jonathan Wolf Mueller, University of Birmingham

Bioactive Glycosaminoglycans from Caranx crysos: A Structure-Function Study of Selective Anticoagulant Activity.
A heparan sulfate-mimetic derivative of botryosphaeran with antiviral activity against herpes simplex virus.
Site-Specific Tyrosine Sulfation of Triabin via Semi-Synthesis Enhances Thrombin Inhibition through Synergistic Multiple-Mode Interactions.
Changes in Expression of Syndecans and Heparan Sulfate Biosynthesis Enzymes in Short-Term Streptozotocin-Induced Diabetic Rat Kidneys.
Heparan Sulfate Controls Nanoscale Assembly of GPC3-Wnt Receptor Complexes.
Discovery of a Functional Sequon for Chondroitin Sulfate Glycosylation.
Effect of sequential oxidation-reduction-sulfation on the conformation and anticoagulant properties of ulvan from Ulva fasciata.
High Humidity Exacerbates Rheumatoid Arthritis in Mice via Prevotella stercorea-Mediated Chondroitin Sulfate Degradation.
Fabrication of Chondroitin Sulfate-Copper/Zinc Complexes and Antibacterial Activity Involving Hydrogel Application in Infected Wound Healing.
Increases in fecal testosterone precede increases in fecal dehydroepiandrosterone in wild male mountain gorillas (Gorilla beringei beringei).
The Content and Location of 3-O-Sulfated Glucosamine Enable Differentiation of Ovine, Bovine and Porcine Heparins.
Keratan Sulfate: An Electroconductive Glycosaminoglycan at the Interface of Sensory Perception and Neural Signaling.
Phosphatidylserine lipids reduce the adsorption of chondroitin sulphate at the membrane surface.
Effect of Dietary Aryl Hydrocarbon Receptor Ligands on Indoxyl Sulfate-Induced Endothelial Activation.
Saccharina japonica sulfated fucans alleviate intestinal ageing-associated epithelial deterioration and regenerative decline.
SLC26A11 is an atypical solute carrier with dual transport-channel function mediating lysosomal sulfate transport.
Uremic Toxin Trajectories in Septic Shock-Associated Acute Kidney Injury and Patient Outcomes: The Tox-AKI Study.
Renal Ischemia-Reperfusion and Uremic Toxins Modulate the Aortic Adenosinergic Axis in Acute Kidney Injury.
Sulfated polysaccharides target RANK Lys97 to inhibit osteoclast differentiation and reverse osteoporosis.

Mar Drugs. 2026 Jul 03. pii: 234. [Epub ahead of print]24(7):

Bioactive Glycosaminoglycans from Caranx crysos: A Structure-Function Study of Selective Anticoagulant Activity.

Ranim Kroumi, Soumaya Alimi, Fabiana Esposito, Asma Haffouz, Basma Hadjkacem, Angela Casillo, Anissa Haddar, Assaad Sila, Emiliano Bedini, Ali Bougatef.

  Glycosaminoglycans (GAGs) are the carbohydrate portion of proteoglycans (PGS), a family of complex biomacromolecules ubiquitously found in the extracellular matrix and on cell surfaces that play critical roles in a plethora of physiological and pathological processes. In the present work, chondroitin sulfate (CS) and dermatan sulfate (DS) were extracted and purified from the head (GCB) and skin (GDB) of blue runner fish (Caranx crysos) to explore their structural features and biological properties. GCB and GDB were purified by ion-exchange chromatography with yields of 0.82% and 0.61%, respectively. Chemical and structural analysis showed that GCB and GDD demonstrated quite similar sulfation degrees (4.45% and 4.24%, respectively). The molecular weight values obtained for GCB and GDB as estimated by high-performance size exclusion chromatography coupled with a triple detector array (HP-SEC-TDA) were 48.9 and 28.54 KDa, respectively. Structural features were elucidated using FT-IR and 2D NMR spectroscopy. GCB was mainly identified as chondroitin sulfate, containing 82% GlcA and minor proportions of IdoA and IdoA2S (scoring 18% dermatan-like structures). In contrast, GDB was predominantly dermatan sulfate, with a higher unsulfated IdoA content (54%) and a lower GlcA percentage (17%). In vitro anticoagulant activity, evaluated using APTT and PT assays, demonstrated that both GAGs exhibit significant anticoagulant potential. In addition, both fractions exhibited no antiplatelet activity, suggesting that the isolated glycosaminoglycans selectively target the coagulation cascade without affecting platelet aggregation. Furthermore, hemolytic assays confirmed that neither GCB nor GDB showed any hemolytic activity at the tested concentrations. Cytotoxicity assessment in HEK293 and HUVEK cell lines further confirmed the absence of detectable toxicity even at high concentration. Overall, these marine-derived GAGs present promising therapeutic potential as a source of anticoagulant drugs.

Keywords:  Caranx crysos; anticoagulant activity; antiplatelet activity; chemical characterization; chondroitine sulfate; cytotoxicity; dermatan sulfate; glycosaminoglycans; hemolytic activity

DOI:  https://doi.org/10.3390/md24070234
Carbohydr Res. 2026 Jul 24. pii: S0008-6215(26)00241-7. [Epub ahead of print]568 110052

A heparan sulfate-mimetic derivative of botryosphaeran with antiviral activity against herpes simplex virus.

Flávia Deduch Kikuchi, Mario Gabriel Lopes Barboza, André Luiz Dyna, Marcelle de Lima Ferreira Bispo, Aneli M Barbosa-Dekker, Robert F H Dekker, Ligia Carla Faccin-Galhardi, Alexandre Orsato.

  Herpes is a viral disease with high worldwide prevalence. The lack of herpes vaccines and the growing viral resistance to acyclovir and its analogues create an urgent need for new treatment strategies. Anionic polysaccharides, especially sulfated derivatives, can inhibit herpes simplex virus (HSV) infection by interfering with viral attachment to heparan sulfate on host cells. Building on our previous work, we designed and prepared a heparan sulfate-mimetic derivative of botryosphaeran, a fungal β-glucan, by sequential oxidation and sulfonation. Firstly, oxidation converted approximately one-half of the C-6 primary hydroxyl groups into carboxyl groups, yielding BOTOX. Subsequent sulfonation yielded the heparan sulfate mimetic (BOTOX/SULF) with a degree of sulfonation of 0.3 and sulfate groups mainly at C-6 of the remaining glucose units. In vitro assays showed that BOTOX/SULF had high anti-HSV-1 activity, while BOTOX was inactive. The antiviral effect of BOTOX/SULF was comparable to that of previously reported botryosphaeran sulfonated derivatives with a higher degree of sulfonation, suggesting that the combined presence of carboxylate and sulfate groups contributes to activity. These results support heparan sulfate mimicry as a promising strategy for designing entry inhibitors against enveloped viruses.

Keywords:  Entry inhibitors; Oxidized polysaccharides; Sulfonated polysaccharides; β-D-glucans

DOI:  https://doi.org/10.1016/j.carres.2026.110052
Org Lett. 2026 Jul 26.

Site-Specific Tyrosine Sulfation of Triabin via Semi-Synthesis Enhances Thrombin Inhibition through Synergistic Multiple-Mode Interactions.

Zhenbang Xiao, Zeyuan Mo, Litong Lin, Chunmao He.

Herein, we report the semisynthesis of site-specifically sulfated triabin─a 142-amino-acid lipocalin protein─at Tyr124. Functional assays reveal that sulfation enhances anticoagulant activity by ∼5-fold, demonstrating that even rigid scaffolds can benefit from this modification. Modeling studies uncover a synergistic mechanism wherein the sulfate group engages in a hydrogen-bond network, electrostatic bridging, and charge-complementary interactions with thrombin exosite I, while the hydrophobic core (notably Phe106 and Val126) remains the primary driving force.

DOI: https://doi.org/10.1021/acs.orglett.6c02797
Cells. 2026 Jul 16. pii: 1277. [Epub ahead of print]15(14):

Changes in Expression of Syndecans and Heparan Sulfate Biosynthesis Enzymes in Short-Term Streptozotocin-Induced Diabetic Rat Kidneys.

Tanja Čujić, Anita Racetin, Natalija Filipović, Sandra Kostić, Nela Kelam, Petar Todorović, Katarina Vukojević.

   BACKGROUND: The aim of this study was to determine the temporal expression patterns of syndecan family members (SDC1, SDC2, SDC4) and heparan sulfate biosynthesis enzymes (NDST1, NDST2) in kidneys of diabetic rats and age-matched controls.
METHODS: Male Sprague-Dawley rats received intraperitoneal streptozotocin (55 mg/kg; DM1 group) or citrate buffer (control group). Kidney samples were harvested after 2 weeks and 2 months and processed for immunofluorescence.
RESULTS: SDC1 showed significant temporal upregulation in controls that was abolished in diabetic animals. SDC2 exhibited high early expression in the control group with significant decline as the kidneys matured but remained elevated in diabetic kidneys at 2 months compared to controls. SDC4 showed no significant difference between groups, though an age-related decrease was observed in controls. NDST1 was significantly upregulated in diabetic rats at 2 weeks, followed by profound suppression at 2 months (p < 0.0001). NDST2 showed modest but significant early elevation in diabetic animals. Transcript-level analysis of two independent public datasets of streptozotocin-induced diabetic rat renal cortex reproduced the principal directional findings-an early increase in SDC1 and a progressive elevation of SDC2-while indicating post-transcriptional regulation of SDC4 and the early NDST response.
CONCLUSIONS: Diabetes disrupts normal temporal expression of syndecans and heparan sulfate biosynthesis enzymes in rat kidneys. Early compensatory upregulation of NDST1 and NDST2, followed by progressive NDST1 suppression, suggests a deteriorating heparan sulfate biosynthetic capacity, potentially contributing to the progression of diabetic nephropathy.

Keywords:  diabetes; heparan sulfate biosynthesis enzymes; kidneys; rats; syndecan family members

DOI:  https://doi.org/10.3390/cells15141277
bioRxiv. 2026 Jul 22. pii: 2026.07.21.739947. [Epub ahead of print]

Heparan Sulfate Controls Nanoscale Assembly of GPC3-Wnt Receptor Complexes.

Shaoli Lin, David A Ball, Mohamadreza Fazel, Tatiana S Karpova, Mitchell Ho.

Glypican-3 (GPC3) is a heparan sulfate proteoglycan that is highly expressed in hepatocellular carcinoma and promotes tumor progression through Wnt3a/β-catenin signaling. However, how the nanoscale organization of GPC3 at the cell surface controls signaling remains unclear. Here, we combined nano-resolution MINFLUX imaging, single-molecule tracking, and functional assays to define the spatial architecture and dynamics of GPC3 on hepatoma cells. We found that GPC3 exists as both single molecules and nanoscale clusters and switches between confined and free diffusions on the plasma membrane. Heparan sulfate (HS) chains create nanoscale corrals that limit GPC3 movement, whereas removal of HS increases diffusive heterogeneity and disrupts confinement. Wnt3a stimulation induces the formation of higher-order GPC3 assemblies and enhances β-catenin signaling, while loss of HS markedly reduces this response. MINFLUX DNA-PAINT further revealed that HS chains orchestrate the spatial distribution of Wnt3a and promote its association with the Wnt receptor, Frizzled-1, an essential step for pathway activation. Collectively, these findings reveal that HS controls the nanoscale organization and dynamics of GPC3 to promote Wnt receptor assembly and efficient β-catenin signaling in hepatoma cells.

DOI: https://doi.org/10.64898/2026.07.21.739947
Res Sq. 2026 Jul 16. pii: rs.3.rs-10307688. [Epub ahead of print]

Discovery of a Functional Sequon for Chondroitin Sulfate Glycosylation.

Yoshiko Takeda-Uchimura, Mayumi Ishihara-Aoki, Ayano Moriya, Kazuchika Nishitsuji, Shuji Mizumoto, Midori Ikezaki, Yuki Takechi-Haraya, Eriko Nakato, Hassan Lemjabbar-Alaoui, Fabrice Allain, Yoshito Ihara, Shuhei Yamada, Michael Tiemeyer, Hiroshi Nakato, Kazuhiro Aoki, Kenji Uchimura.

The amino acid sequence requirements that instruct the modification of proteins with chondroitin sulfate (CS) have been unknown, precluding predictions or opportunities for precise protein engineering. This study identified an essential amino acid motif for CS addition, the "CS-sequon" (EDQDDKDGGDFSGWGG), by comparing the secreted sulfatases SULF1 and SULF2, where only SULF2 is CS-modified. A cluster of seven amino acids plus a nearby tryptophan are critical for CS attachment; inserting the CS-sequon into SULF1 enabled it to gain CS modification. This sequon recruits the activity of the CS-initiating xylosyltransferase to the peptide modification site and CS addition enhances SULF1/2 extracellular abundance and enzymatic activity. These findings were validated across human and non-human cells and in Drosophila, providing a foundational resource for engineering CS modifications into proteins.

DOI: https://doi.org/10.21203/rs.3.rs-10307688/v1
Int J Biol Macromol. 2026 Jul 29. pii: S0141-8130(26)03745-1. [Epub ahead of print] 153799

Effect of sequential oxidation-reduction-sulfation on the conformation and anticoagulant properties of ulvan from Ulva fasciata.

Lauri Alves Junior, Mariana M de Carvalho, Danielly Caetano, Jaqueline Carneiro, Diogo R B Ducatti, Alan Guilherme Gonçalves, Miguel D Noseda, Maria Eugênia R Duarte.

  Ulvans are sulfated polysaccharides from green macroalgae of the Ulva genus, widely studied for their anticoagulant properties and potential biomedical applications. In this study, oversulfated ulvan derivatives were synthesized using two distinct strategies: (i) direct sulfation of native ulvan and (ii) a sequential process involving periodate oxidation, NaBH₄ reduction, and subsequent sulfation. These routes generated derivatives with distinct degrees of sulfation (DS), molar mass (Mw), and structural features. Structural characterization by NMR spectroscopy confirmed successful chemical modifications, while circular dichroism revealed the loss of the native exciton couplet, suggesting disruption of the ordered helical arrangement upon sulfation and partial depolymerization. Anticoagulant assays (APTT, TT, and PT) demonstrated that activity correlated positively with both DS and Mw, and remained preserved even after partial cleavage of CC bonds in the polysaccharide backbone. All sulfated derivatives exhibited stronger anticoagulant effects than native ulvan. Notably, P2r-S retained thrombin inhibition despite its lower DS (1.4) compared with UF-S (1.8) and P1r-S (1.9), suggesting that factors beyond DS, such as sulfate distribution and Mw, contribute to its activity profile. Overall, the results highlight sulfation as the primary driver of anticoagulant enhancement and demonstrate how combined variations in DS, sulfate patterning, and molar mass shape ulvan bioactivity. These findings advance the understanding of structure-activity relationships in ulvans and support their development as promising marine-derived anticoagulant agents.

Keywords:  Anticoagulant activity; Structure–activity relationship; Sulfated polysaccharides

DOI:  https://doi.org/10.1016/j.ijbiomac.2026.153799
Microorganisms. 2026 Jul 14. pii: 1540. [Epub ahead of print]14(7):

High Humidity Exacerbates Rheumatoid Arthritis in Mice via Prevotella stercorea-Mediated Chondroitin Sulfate Degradation.

Mingzhu Wang, Qianqian He, Yiwu Qiu, Lin Huang, Yun Zhang, Ding Ye, Zhixing He, Chengping Wen.

  Background: Rheumatoid arthritis (RA) is influenced by environmental exposures. High humidity has been clinically associated with worsened joint symptoms, but the microbial and metabolic mechanisms remain unclear. We investigated whether a gut microbiota-metabolism axis contributes to humidity-associated aggravation of collagen-induced arthritis (CIA). Methods: CIA mice were maintained under normal or high relative humidity. We integrated 16S rRNA and metagenomic sequencing, liquid chromatography-tandem mass spectrometry metabolomics, and intestinal barrier assessments. Fecal microbiota transplantation (FMT) was performed to evaluate microbiota dependency. Based on multi-omics findings, we quantified chondroitin sulfate (CS) and conducted functional experiments involving Prevotella stercorea (P. stercorea) supplementation, CS administration, and in vitro degradation assays. Results: High humidity aggravated arthritis severity and systemic inflammation, including increased interleukin-6, interleukin-17A, and granulocyte colony-stimulating factor, and was accompanied by impaired intestinal barrier integrity. FMT supported a microbiota-dependent contribution. Metagenomic analysis identified enrichment of P. stercorea and glycosaminoglycan degradation pathways under high humidity. CS abundance was reduced in articular cartilage, P. stercorea degraded CS in vitro and was associated with cartilage CS loss in vivo, and CS supplementation attenuated arthritis under high humidity and reduced the arthritis-promoting effects associated with P. stercorea. Conclusions: High humidity is associated with microbiota-dependent functional remodeling, enhanced CS degradation, and aggravated arthritis in CIA mice. These findings suggest that humidity-associated alterations in microbial CS metabolism may link environmental exposure to cartilage disruption and joint inflammation.

Keywords:  Prevotella stercorea; chondroitin sulfate; collagen-induced arthritis; glycosaminoglycan; humidity; rheumatoid arthritis

DOI:  https://doi.org/10.3390/microorganisms14071540
Gels. 2026 Jul 15. pii: 633. [Epub ahead of print]12(7):

Fabrication of Chondroitin Sulfate-Copper/Zinc Complexes and Antibacterial Activity Involving Hydrogel Application in Infected Wound Healing.

Qingshan Shen, Jiarui Wu, Jiawen Li, Yujie Dong, Yang Liu, Lei Zhao, Huan Zhan, Yanli Ma.

  The escalating prevalence of bacterial infections has intensified the search for innovative antimicrobial strategies, particularly for infected wound management. Chondroitin sulfate (CS), a naturally occurring glycosaminoglycan with established biocompatibility, presents an attractive scaffold for developing metal ion-functionalized biomaterials. This study reports the fabrication of chondroitin sulfate-copper complex (CSCu) and chondroitin sulfate-zinc complex (CSZn) through an ion exchange method, wherein Cu2+ and Zn2+ ions bind to the groups of carboxylate, sulfate, or N-acetyl from the CS backbone. The resulting complexes exhibited copper or zinc loading capacities of about 6.6% and demonstrated potent antibacterial activity against E. coli and S. aureus. The integration of CSCu or CSZn with sodium alginate yielded a hydrogel system with a higher apparent viscosity, possessing injectability and spreadability on the skin surface and a porous three-dimensional internal structure conducive to wound healing applications. In a murine model of S. aureus-infected full-thickness wounds, topical application of CSCu and CSZn hydrogels substantially accelerated wound closure, achieving 97.46% and 98.11% healing, respectively, by day 10. Additionally, treatment with CSCu or CSZn hydrogels significantly attenuated systemic inflammatory responses, as reflected in lowered serum TNF-α, IL-1β, and IL-6 alongside increased IL-10. Histological evaluation confirmed enhanced re-epithelialization and stratum spinosum formation in treated wounds. These findings establish CSCu and CSZn as a promising bioactive agent for addressing bacterial wound infections through a dual mechanism of direct antibacterial action and immunomodulatory effects, offering a valuable alternative to conventional antibiotic therapies.

Keywords:  antibacterial activity; chondroitin sulfate–metal complex; hydrogel; wound healing

DOI:  https://doi.org/10.3390/gels12070633
J Comp Physiol B. 2026 Jul 27.

Increases in fecal testosterone precede increases in fecal dehydroepiandrosterone in wild male mountain gorillas (Gorilla beringei beringei).

Ella R Brown, Rose Umuhoza, Carine Uwamahoro, Alliance Umwizerwa, Winnie Eckardt, Tara S Stoinski, Michael D Cherney, Richard J Auchus, Stacy Rosenbaum.

  Testosterone (T) and dehydroepiandrosterone sulfate (DHEAS) are two steroids integral to male primate development. For humans, both are high in early infancy (for T, this is known as minipuberty) then rapidly decline. DHEAS then increases beginning in early childhood, resulting in a process known as adrenarche, which signals the maturation of the zona reticularis of the adrenal gland. T increases a few years thereafter, marking the beginning of puberty. These processes are relatively well-studied in humans, but data is lacking for the other great apes. Particularly for adrenarche, strikingly little is known about its distribution across the primate order. Here, we draw on a large sample of wild male mountain gorilla fecal samples collected over the full course of the gorilla lifespan to examine how the hormones T and DHEAS change with age. We use enzyme-linked immunosorbent assays to quantify metabolites of both hormones, and validate these assays using high-performance liquid chromatography-tandem mass spectrometry analyses. We find that both hormones are high in male gorilla infancy, and then decline before T rises again at 9.3 years of age. Surprisingly, DHEAS rises afterwards at 10.7 years old, showing a departure from the human developmental pattern. T then peaks at 18 years of age, while DHEAS plateaus at ~ 23 years of age. More research is needed to assess intra-order variation in primate hormonal development.

Keywords:  Adrenarche; DHEAS; Male development; Mountain gorillas; Puberty; Testosterone

DOI:  https://doi.org/10.1007/s00360-026-01702-y
Biomolecules. 2026 Jul 14. pii: 1025. [Epub ahead of print]16(7):

The Content and Location of 3-O-Sulfated Glucosamine Enable Differentiation of Ovine, Bovine and Porcine Heparins.

Arianna Somma, Elena Urso, Michela Parafioriti, Marco Guerrini, Antonella Bisio.

  Heparin, the naturally occurring, highly sulfated glycosaminoglycan drug, acts as a regulator of diverse biological processes by interacting with diverse specific proteins through a variety of sulfated structural motifs with varying degrees of affinity. Despite its rarity, 3-O-sulfation of glucosamine plays a key role in several biological activities, especially anticoagulant activity mediated by interaction with antithrombin (AT), a mechanism that has been extensively studied. The present work primarily focuses on sequences containing 3-O-sulfated glucosamine that are not involved in anticoagulant activity, analysing their relative abundance and structural environments in heparins derived from distinct animal origins. Three heparin samples derived from bovine, ovine and porcine intestinal mucosa (BMH, OMH and PMH) were fractionated by affinity chromatography on AT-Sepharose into no affinity (NA) and high affinity (HA) fractions. Parent heparins and derived NA and HA fractions were enzymatically depolymerised using either a cocktail of heparinases I, II and III or heparinase II alone, and the resulting mixtures of di- and oligosaccharides were analysed by liquid chromatography coupled with mass spectrometry. Digestion with heparinase II, which preserves heparin sequences containing 3-O-sulfated glucosamine, produced a series of 3-O-sulfated trisaccharides containing two glucosamine residues either side of a uronic acid, located at the non-reducing end (NRE) of heparin chains. Treatment with a heparinase cocktail, which cleaves these trisaccharides, released NRE glucosamine monosaccharides, including 3-O-sulfated species. Notably, both the number of NRE trisaccharide species and the overall proportion of 3-O-sulfated monosaccharides were markedly higher in OMH compared to BMH or PMH. Using 1H/13C bi-dimensional nuclear magnetic resonance spectroscopy, the higher proportion of NRE 3-O-sulfated glucosamine in ovine heparin relative to bovine and porcine heparins was found to be preferentially located in chains lacking affinity for AT. These results offer new insights into the localisation of most 3-O-sulfated heparin sequences that are not associated with anticoagulant activity and, importantly, also reveal a possible structural marker that indicates the ovine origin of heparin. Additionally, a tetrasaccharide species was detected that may be indicative of a highly sulfated AT-binding site in BMH.

Keywords:  AT-affinity chromatography; bovine; liquid-chromatography mass spectrometry; nuclear magnetic resonance spectroscopy; ovine; porcine heparins

DOI:  https://doi.org/10.3390/biom16071025
J Neurosci Res. 2026 Aug;104(8): e70149

Keratan Sulfate: An Electroconductive Glycosaminoglycan at the Interface of Sensory Perception and Neural Signaling.

James Melrose.

This narrative review highlights the functional attributes of keratan sulfate (KS), a glycosaminoglycan integral to structural support, hydration, and diverse tissue functions. KS has roles in cell signaling and regulates cellular adhesion, proliferation, and differentiation. The electroconductive properties of KS stabilize ion fluxes and electrochemical gradients at the cell surface essential for membrane polarization that directs neuronal activation and neurotransmission. KS interacts with a diverse collection of kinases, growth factors, morphogens, and neuro-modulatory proteins, facilitating axonal guidance and correctly inter-connected neural networks essential for control of tissue function. The ability of KS to capture and transport protons assists in neuronal signaling and provides an ultrasensitive system that allows neurons to participate in neurosensory processes and contribute to neurosensory perception. The roles of some KS-proteoglycans are highlighted and encourage further studies in innovative areas of sensory perception and tissue function.

DOI: https://doi.org/10.1002/jnr.70149
J Colloid Interface Sci. 2026 Jul 22. pii: S0021-9797(26)01366-4. [Epub ahead of print]724(Pt 3): 141189

Phosphatidylserine lipids reduce the adsorption of chondroitin sulphate at the membrane surface.

Brigida Romano, Roberto Menichetti, Nicolò Paracini, Philipp Gutfreund, Brenda Bracco, Paola Sassi, Andrea Orecchini, Raffaello Potestio, Alessandra Luchini.

  Hypothesis Chondroitin sulphate (CS) is a linear polysaccharide typically found on the surface of cells and contributing to the structure of the extracellular matrix. Because of its proximity to the plasma membrane, the outermost cellular barrier, CS can interact with the phospholipids forming the structural scaffold of this cellular membrane. We hypothesise that the lipid composition of the plasma membrane, and specifically the exposure of phosphatidylserine (PS) lipids (an event that is detected in cancer cells and also associated to apoptosis and inflammation), affects the structural conformation of CS at the cell surface. Experiments We combined experimental data obtained with different techniques, i.e., quartz crystal microbalance with dissipation monitoring, neutron reflectometry and infrared spectroscopy, with molecular dynamics (MD) simulations to investigate the adsorption of CS at the surface of lipid bilayers prepared with either phosphatidylcholine (PC) lipids or a mixture of PC and PS lipids. Experiments were designed to identify the molecular groups that are involved in the CS-lipid interaction. Findings Our results indicate that CS adsorbs and remains stably attached to the lipid bilayer without PS lipids, due to stabilising interactions between the negatively charged sulphate groups on CS and positively charged choline groups within PC. The addition of POPS strongly reduces the CS-bilayer association: detecting experimentally CS chains attached to the bilayer was challenging, and the MD simulations suggest a weaker binding of CS to a PC-PS membrane.

Keywords:  Chondroitin sulphate; Infrared spectroscopy; Molecular dynamics simulations; Neutron reflectometry; Supported lipid bilayers

DOI:  https://doi.org/10.1016/j.jcis.2026.141189
Toxins (Basel). 2026 Jul 10. pii: 298. [Epub ahead of print]18(7):

Effect of Dietary Aryl Hydrocarbon Receptor Ligands on Indoxyl Sulfate-Induced Endothelial Activation.

Flora Lefevre, Rania Chermiti, Julien Cebile, Nathalie McKay, Stanislas Bataille, Stéphane Burtey, Laetitia Dou.

  Patients with chronic kidney disease (CKD) are exposed to high levels of uremic toxins and have an increased risk of cardiovascular disease. Among these toxins, indolic compounds such as indoxyl sulfate (IS) are predictors of cardiovascular events and mortality in CKD patients and induce a procoagulant and proinflammatory vascular phenotype through activation of the aryl hydrocarbon receptor (AhR). Targeting AhR activation by indolic toxins may therefore help prevent cardiovascular complications in CKD. To this end, we investigated in vitro whether natural dietary AhR ligands (galangin, quercetin, curcumin and indole-3-carbinol) could antagonize IS-induced AhR activation and the associated inflammatory response in endothelial cells. The activation of the AhR genomic pathway was assessed by measuring the expression of AhR target genes (CYP1A1, CYP1B1, and AHRR) in endothelial cells and by evaluating AhR-dependent transcriptional activity using a CALUX-AHRE luciferase reporter assay in HG40/6 cells. In parallel, endothelial inflammation was evaluated by analyzing the expression of AhR-related inflammatory genes: F3/tissue factor, PTGS2/COX-2, CCL2/MCP-1, and CXCL8/IL-8. Quercetin was the only ligand capable of antagonizing IS-induced AhR transcriptional activity, as well as the upregulation of the endothelial AhR target genes CYP1A1 and CYP1B1. In contrast, galangin, curcumin, and I3C exhibited no inhibitory effects. Moreover, none of the tested dietary AhR ligands suppressed the IS-induced upregulation of endothelial inflammatory genes; instead, they tended to potentiate IS-induced inflammatory responses at high concentrations. In conclusion, among the AhR ligands tested, quercetin was the only one that attenuated IS-induced activation of the AhR genomic pathway in endothelial cells. However, it may also enhance IS-mediated endothelial inflammation, an effect also observed at specific concentrations of galangin, curcumin, and I3C. These findings suggest that the potential beneficial effects of natural dietary AhR ligands should be carefully considered in the context of CKD patients exhibiting high levels of indolic uremic toxins.

Keywords:  aryl hydrocarbon receptor; chronic kidney disease; dietary AhR ligands; indolic uremic toxins

DOI:  https://doi.org/10.3390/toxins18070298
J Sci Food Agric. 2026 Jul 27.

Saccharina japonica sulfated fucans alleviate intestinal ageing-associated epithelial deterioration and regenerative decline.

Biqian Wei, Dehua Wang, Houyang Sun, Pengfei Ren, Yinfeng Wang, Yaoguang Chang, Yuming Wang, Qingjuan Tang.

   BACKGROUND: Intestinal ageing is characterized by progressive epithelial deterioration, barrier dysfunction and impaired regenerative capacity, which together contribute to age-related intestinal decline. Sulfated fucans derived from Saccharina japonica (SJ-FUC) are marine polysaccharides with potential bioactivities, although their role in intestinal ageing remains unclear. This study investigated the protective effects of SJ-FUC in a D-galactose-induced ageing mouse model.
RESULTS: Administration of SJ-FUC significantly alleviated intestinal ageing-associated phenotypes by reducing oxidative stress, suppressing senescence-associated secretory phenotype-related inflammatory cytokines, and downregulating the senescence markers P53, P16 and P21. Histological analysis showed marked improvement in ileal architecture and epithelial barrier integrity. SJ-FUC also mitigated ageing-associated regenerative decline, as indicated by increased expression of intestinal stem cell-related markers Lgr5, Ascl2 and Olfm4, elevated numbers of Olfm4-positive and Ki67-positive cells in ileal crypts, and restoration of Wnt/β-catenin signalling. In addition, SJ-FUC promoted goblet and Paneth cell differentiation. 16S rRNA sequencing further showed that SJ-FUC remodelled gut microbial composition, characterized by enrichment of beneficial taxa such as Lactobacillus and reduction of potentially detrimental bacteria including Bacteroides.
CONCLUSION: Sulfated fucans from Saccharina japonica alleviate intestinal ageing by preserving epithelial integrity and restoring regenerative capacity, supporting their potential as functional marine polysaccharides for improving age-related intestinal dysfunction. © 2026 Society of Chemical Industry.

Keywords:  Saccharina japonica; epithelial integrity; gut microbiota; intestinal ageing; regenerative capacity; sulfated fucans

DOI:  https://doi.org/10.1002/jsfa.70908
Nat Commun. 2026 07 27. pii: 7407. [Epub ahead of print]17(1):

SLC26A11 is an atypical solute carrier with dual transport-channel function mediating lysosomal sulfate transport.

Benedikt T Kuhn, Peter Kovermann, Bassam G Haddad, Tim Rasmussen, Tamsanqa T Hove, Stefanie Bungert-Plümke, Bettina Böttcher, Jan-Philipp Machtens, Christoph Fahlke, Eric R Geertsma.

Membrane transporters and channels are generally assumed to be based on distinct structural and functional principles. SLC26A11, a solute carrier with high expression levels in the brain, has been proposed to function as either an anion transporter or a channel. Here, we resolve this apparent discrepancy by demonstrating that SLC26A11 is a dual-function protein capable of operating as both a sulfate transporter and a chloride channel. By resolving its structure and combining biochemical studies and molecular dynamics simulations, we show that SLC26A11 exhibits all the hallmarks of a secondary transporter. The mechanistic basis for its selective ion transport identifies the protein as the elusive lysosomal sulfate exporter. Additionally, we demonstrate that SLC26A11 exhibits an uncoupled, channel-like chloride conductance gated by proton:sulfate symport. Our finding that the chloride-conducting state arises from the transport cycle may contribute to the development of therapeutic strategies for treating brain edema, and the identification of its role in lysosome sulfate efflux may provide new approaches to study and treat lysosomal storage diseases.

DOI: https://doi.org/10.1038/s41467-026-75749-4
Kidney360. 2026 Jul 28.

Uremic Toxin Trajectories in Septic Shock-Associated Acute Kidney Injury and Patient Outcomes: The Tox-AKI Study.

Dimitri Titeca-Beauport, Sandra Bodeau, Clément Brault, Momar Diouf, Touria Mernissi, Camille André, Olivier Varennes, Charlotte Durand-Maugard, Alexis Lambour, Yoann Zerbib, Loay Kontar, Michel Slama, Youssef Bennis, Gabriel Choukroun, Julien Maizel.

BACKGROUND: Emerging evidence suggests that uremic toxins (UTs) may exacerbate organ dysfunction in septic-shock-associated AKI. However, the dynamic changes in serum concentrations of these solutes and their specific prognostic implications remain largely unexplored.
METHODS: This prospective study enrolled 114 patients with septic shock and AKI, alongside 15 non-AKI septic shock controls. We measured serum levels of seven UTs (indoxyl sulfate, indole-3-acetic acid, para-cresyl sulfate, para-cresyl glucuronide, hippuric acid, 3-carboxy-4-methyl-5-propyl-2-furanpropionate (CMPF), and trimethylamine N-oxide ) daily from Day 0 to Day 6. We analysed toxin kinetics and their relationship with 28-day mortality and the time to successful liberation from vasopressor and invasive mechanical ventilation, using joint modelling for longitudinal and survival data.
RESULTS: Upon inclusion, 30% of patients had Stage 1, 30% Stage 2, and 40% Stage 3 AKI. Except for CMPF, all toxins accumulated significantly compared to controls and remained significantly higher in severe AKI throughout the observation period (p<0.001). Indoxyl sulfate showed the strongest longitudinal correlations with serum creatinine (r=0.67, p<0.001). Daily kidney replacement therapy (KRT) status was associated with lower levels of most UTs, with the notable exceptions of indoxyl sulfate (unaffected) and hippuric acid (positively associated). Forty-four patients (39%) died within 28 days. After adjusting for baseline SAPS II and nonrenal SOFA scores, UT trajectories were not significantly associated with 28-day mortality or the time to successful liberation from organ support.
CONCLUSIONS: Changes in serum UT concentrations correlated with the severity and trajectory of AKI during septic shock, and exhibited variable clearance during KRT, but were not independently associated with 28-day mortality or organ support dependence.

DOI: https://doi.org/10.34067/KID.0000001293
Int J Mol Sci. 2026 Jul 15. pii: 6296. [Epub ahead of print]27(14):

Renal Ischemia-Reperfusion and Uremic Toxins Modulate the Aortic Adenosinergic Axis in Acute Kidney Injury.

Ana Carolina da Costa Peres, Jackeline Rodrigues Ramos, Jeferson Stabile, Carmen Lucia Sanz Alarta, Lia Sumie Nakao, Fernanda Tibolla Viero, Henning Ulrich, Cristina Ribas Fürstenau.

  Acute kidney injury (AKI) is characterized by a rapid decline or sudden loss of renal function over hours to days. Pathophysiological triggers such as renal ischemia-reperfusion (IR) injury and the accumulation of uremic toxins (UTs), notably indoxyl sulfate (IS), can initiate AKI and affect vascular beds distant from the ischemic site, like the aorta. In this context, purinergic signaling becomes relevant, since its components regulate vascular tone and inflammatory responses. This study aimed to evaluate the impact of AKI induced by IR with or without IS administration on purinergic signaling in the aorta of mice. Renal ischemia was induced by the occlusion of the left renal pedicle for 60 min, followed by reperfusion for 8 days (IR 8) or 15 days (IR 15). Some animals were also treated with saline solution or IS for 15 days. The IR15 group exhibited increased plasma IS concentrations and upregulated adenosine receptor gene expression. Furthermore, in the IR+IS group, there was increased expression of A1, A2a, NTPDase 1, and 2. This shift toward an adenosine-enriched signaling environment may represent a key mechanism linking renal injury to systemic vascular inflammation.

Keywords:  adenosine; aorta; indoxyl sulfate; inflammation; kidney-vessel communication

DOI:  https://doi.org/10.3390/ijms27146296
Nat Biomed Eng. 2026 Jul 30.

Sulfated polysaccharides target RANK Lys97 to inhibit osteoclast differentiation and reverse osteoporosis.

Xiaogang Wang, Luli Ji, Yuanman Yu, Jiaze Yu, Jing Wang, Changsheng Liu.

Current osteoporosis treatments fail to balance bone resorption and formation. Here we show that engineered 2-N,6-O-sulfated chitosan (26SCS), a synthetic pentasaccharide, restores 115% bone mass (therapeutic) and prevents 66% bone loss, surpassing bisphosphonates by simultaneously suppressing osteoclastogenesis and promoting vascularized osteogenesis. Mechanistically, 26SCS targets K97 in receptor activator of nuclear factor-κB (RANK) through geometrically matched sulfate pairs, blocking RANK ligand (RANKL) signalling to arrest preosteoclast fusion while enhancing platelet-derived growth factor-BB (PDGF-BB) secretion via preserved preosteoclast viability to drive angiogenesis-coupled mineralization. Structural and functional analyses reveal that carboxyl groups in natural glycosaminoglycans such as heparin competitively bind K97, disrupting therapeutic specificity-a limitation overcome by 26SCS's carboxyl-free design and sequence-controlled sulfation. Unlike monosulfated analogues (2SCS/6SCS) that oversuppress osteoclastogenesis or lack pro-osteogenic effects, 26SCS's dual sulfation balances inhibition with trophic support. Thus, this work redefines glycosaminoglycan therapeutics via sulfation-patterned, topology-engineered biomaterials harmonizing bone metabolism.

DOI: https://doi.org/10.1038/s41551-026-01744-1