bims-supasi 2026-02-15 papers

bims-supasi

Biomed News

on Sulfation pathways and signalling

Issue of 2026–02–15
eighteen papers selected by
Jonathan Wolf Mueller, University of Birmingham

C4ST-1 Overexpression Suppresses Osteoblast Differentiation via a Wnt/β-Catenin-p53 Axis.
Structural determinants of glycosaminoglycan oligosaccharides as LL-37 inhibitors in breast cancer.
Halofuginone Suppresses Hepcidin by a Heparan Sulfate-dependent Mechanism to Treat Iron Disorders in Mice.
Iduronate Ring Puckering Effects on Preferred Glycosidic Linkage Conformations in Heparin/Heparan Sulfate and Dermatan Sulfate Disaccharides.
Heparin-Modified Aligned Collagen Scaffolds Enhance In Vitro Myogenesis.
Engineering compartmentalized utilization of glycerol with glucose for high-level chondroitin production in Corynebacterium glutamicum.
Low-Molecular-Weight Sulfated Chitosan Microparticles Efficiently Bind HIV-1 In Vitro: Potential for Microbicide Applications.
Chondroitin sulfate doped poly(3, 4-ethylenedioxythiophene) for implantable supercapacitor with high conductivity and anti-inflammatory efficacy.
Tumour acidosis remodels the glycocalyx to control lipid scavenging and ferroptosis.
Informed mutation of western equine encephalitis virus to heparan sulfate binding: Implications for rational design of alphavirus live attenuated vaccines.
Integrating heparan sulfate mimetics into LbL nanofilms as extracellular matrix-like architectures to promote bone tissue regeneration.
Elevated vaginal heparan sulfate correlates with impaired neutrophil killing of Candida albicans in women with vulvovaginal candidiasis.
Apolipoprotein J-mediated hepato-renal crosstalk drives renal injury in chronic kidney disease.
Indole toxicity on removal of uremic toxin p-cresol, in-vitro study of Thauera aminoaromatica S2.
Heparan Sulfates Regulate Vascular Reactivity in Syndecan 1 Knockout Mice.
GAL3ST1-Mediated Histone Tyrosine Sulfation Induced by Cancer-Associated Fibroblasts Promotes Gastric Cancer Metastasis.
A novel peptide-based AIE probe for highly selective and ultrasensitive detection of heparin and its applications.
Peripheral Syndecan-3 and Neurofilament Light Chain as Complementary Blood Biomarkers for Alzheimer's Disease.

Biol Pharm Bull. 2026 ;49(2): 273-280

C4ST-1 Overexpression Suppresses Osteoblast Differentiation via a Wnt/β-Catenin-p53 Axis.

Toshiyasu Koike, Satomi Nadanaka, Hiroshi Kitagawa.

  Disruption of osteoblast differentiation can lead to severe bone diseases, such as osteoporosis and osteosclerosis. Our previous study showed that a reduced 4S/6S ratio promotes osteoblast differentiation, linking this specific chondroitin sulfate (CS) modification to bone pathology. This study investigated the effect of forced elevation of the 4S/6S ratio on differentiation. C4ST-1 was found to exhibit overexpression, increasing the 4S/6S ratio, significantly suppressing osteoblast differentiation, as evidenced by reduced Akp2 gene expression and ALP activity. This inhibition was far more potent than that caused by the enzymatic removal of CS. Notably, treating C4ST-1-overexpressing cells with chondroitinase reduced differentiation inhibition to a level similar to that in mock cells treated with chondroitinase. These results suggest that the strong inhibition was due to the excessive 4-sulfated CS produced by C4ST-1, implying a mechanism distinct from the inhibition caused by a lack of CS. To elucidate this mechanism, we investigated the potential feedback loop. The increase in 4-sulfated CS from C4ST-1 overexpression enhanced Wnt3a expression, which upregulated p53 expression. Pharmacological inhibition of β-catenin and p53 partially restored Akp2 expression, confirming their roles as key mediators. We propose that a high 4S/6S ratio activates a Wnt/β-catenin-p53 axis, where p53 acts as a brake on differentiation. Our findings highlight the critical role of CS sulfation patterns in fine-tuning the osteoblast fate.

Keywords:  Wnt3a; chondroitin sulfate; osteoblast differentiation; p53

DOI:  https://doi.org/10.1248/bpb.b25-00589
Glycobiology. 2026 Feb 12. pii: cwag010. [Epub ahead of print]

Structural determinants of glycosaminoglycan oligosaccharides as LL-37 inhibitors in breast cancer.

Chloe Le Fournis, Martyna Maszota-Zieleniak, Adam Kulesza, Pradeep Chopra, Geert-Jan Boons, Nicolas Aubrey, Franziska Liesecke, Sergey A Samsonov, Günther Weber.

  The human antimicrobial peptide LL-37 exerts a dual role in cancer, promoting tumor progression in breast carcinoma by stimulating calcium influx and enhancing cell migration. Its interactions with glycosaminoglycans (GAGs) provide an attractive therapeutic avenue for intervention. In this study, we investigated the ability of structurally distinct GAG oligosaccharides to inhibit LL-37-mediated responses in MDA-MB-231 breast cancer cells. Functional assays were performed to evaluate membrane depolarization, intracellular calcium mobilization, and migration capacity. When applied at a 1:1 stoichiometric ratio with LL-37, heparin emerged as the most effective inhibitor. This inhibitory activity required a minimum oligosaccharide length of 18 monosaccharide units and was strongly dependent on the degree of sulfation. Heparin displayed significantly higher efficacy than either chondroitin sulfate or dermatan sulfate. Binding studies using microscale thermophoresis demonstrated nanomolar affinity of LL-37 for heparin, whereas interactions with chondroitin and dermatan sulfate were weaker. Complementary molecular dynamics simulations reinforced these findings by highlighting the predominant role of electrostatic interactions in stabilizing LL-37/GAG complexes and by providing atomistic models of the binding interfaces. Binding studies on a heparin-derived synthetic oligosaccharide array revealed that, apart from the degree of sulfation, structural components in heparin contribute to its affinity for LL-37. Collectively, our results suggest that the structural optimization of GAG mimetics may represent a promising targeted strategy to block LL-37-driven tumor progression.

Keywords:  LL-37; breast cancer; glycosaminoglycans; metastasis; sulfation code

DOI:  https://doi.org/10.1093/glycob/cwag010
Blood Adv. 2026 Feb 11. pii: bloodadvances.2025017943. [Epub ahead of print]

Halofuginone Suppresses Hepcidin by a Heparan Sulfate-dependent Mechanism to Treat Iron Disorders in Mice.

Stephanie Leal, Andrea Denardo, Anna Van Echten, Hannah Jungnickel, Christopher Bradley Nelson, Daniel Sandoval, Jiannah-Maxine A Salvador, Jennifer Shin, Ahri Chung, Maiah Brush, Conner P Bennett, Ann Piermatteo, Patrick Secrest, Chun-Ling Jung, Tomas Ganz, Maura Poli, Philip Gordts.

Hepcidin, a liver-derived hormone, is the central regulator of systemic iron homeostasis. Elevated hepcidin levels contribute to iron-refractory iron deficiency anemia (IRIDA) and anemia of inflammation, both characterized by restricted iron availability. Current treatments, such as parenteral iron infusions, are often ineffective and pose risks of adverse reactions, underscoring the need for alternative therapeutic strategies targeting hepcidin. We previously identified a novel hepcidin regulatory pathway involving liver heparan sulfate (HS) proteoglycans (HSPGs), which modulate receptor-ligand interactions through their sulfated HS chains. Recently, we found that halofuginone impairs HS biosynthesis and considered whether it could be used as a hepcidin modulator. Here, we demonstrate that in human hepatoma (Hep3B) cells, halofuginone inhibits both basal and BMP6-induced hepcidin expression and p-SMAD1 signaling in a dose- and time-dependent manner. Consistently, Hep3B cells lacking HS (EXT1-/-) show no hepcidin suppression in response to halofuginone. In vivo administration of halofuginone reduces hepcidin expression in an iron-overload mouse model (8.3 g/kg carbonyl iron). This effect was absent in mice with impaired liver HS sulfation (Ndst1f/fAlbCre+), confirming that halofuginone suppresses hepcidin via HSPG-mediated mechanisms. Additionally, halofuginone decreased hepcidin expression in mice subjected to acute inflammation. These findings establish halofuginone as a potential therapeutic for mitigating hepcidin-driven iron restriction in anemic disorders.

DOI: https://doi.org/10.1182/bloodadvances.2025017943
Molecules. 2026 Feb 02. pii: 504. [Epub ahead of print]31(3):

Iduronate Ring Puckering Effects on Preferred Glycosidic Linkage Conformations in Heparin/Heparan Sulfate and Dermatan Sulfate Disaccharides.

Olgun Guvench.

  The conformation of a glycosaminoglycan (GAG) carbohydrate biopolymer is dependent upon the ring puckering states of its constituent monosaccharide residues and the dihedral angles (φ, ψ) of the glycosidic linkages connecting these residues. In the context of GAGs, the monosaccharide residue iduronate (IdoA; the conjugate base of iduronic acid) is able to take on both chair and boat-like ring pucker states. All-atom explicit-solvent molecular dynamics simulations were applied to determine the extent to which IdoA ring pucker state affects the conformational preferences of (φ, ψ) in 16 different IdoA-containing disaccharides derived from the GAGs heparin/heparan sulfate and dermatan sulfate. Using the extended-system adaptive biasing force (eABF) method, the complete free-energy surface ΔG(φ, ψ) was computed for each disaccharide with its IdoA ring restrained separately to the 1C4, 2SO, B3,O, or 4C1 ring pucker state. Global-minimum ΔG(φ, ψ) values resided within broad ΔG(φ, ψ) basins, and both ring pucker state and sulfation status influenced basin shape and size. Various sulfoforms of the disaccharide IdoAα1-4GlcNS had prominent secondary-minimum basins distinct from the global-minimum basins, and these secondary-minimum basins may manifest as metastable states in standard (nonbiased) molecular dynamics simulations on the 1-microsecond timescale. As such, the present results provide a reference for assessing (φ, ψ) sampling in nonbiased molecular dynamics simulations of GAGs and demonstrate the interplay between IdoA ring puckering, glycosidic linkage dihedral rotation, and sulfation status in contributing to GAG conformational preferences.

Keywords:  CHARMM; IdoA2S; adaptive biasing force; biased sampling; free energy; glycosaminoglycan; glycosidic linkage; iduronate; molecular dynamics; ring pucker

DOI:  https://doi.org/10.3390/molecules31030504
J Biomed Mater Res A. 2026 Feb;114(2): e70048

Heparin-Modified Aligned Collagen Scaffolds Enhance In Vitro Myogenesis.

Geshani C Bandara, Ryann D Boudreau, William Wyatt, Steven R Caliari.

Biomaterial-based skeletal muscle tissue engineering approaches have largely focused on mimicking the 3D aligned architecture of native muscle, which is critical for guiding myotube formation and force transmission. In contrast, fewer studies incorporate glycosaminoglycan (GAG)-mediated biochemical cues despite their known role in regulating myogenesis and growth factor sequestration. In this study, we develop aligned collagen-GAG (CG) scaffolds using directional freeze-drying and systematically vary GAG type by incorporating GAGs of increasing sulfation levels (hyaluronic acid, chondroitin sulfate, and heparin). While all scaffold variants support myoblast adhesion, metabolic activity, and myotube alignment, heparin-modified CG scaffolds significantly enhance myoblast metabolic activity and myogenic differentiation as measured by myosin heavy chain (MHC) expression and myotube size. We additionally show that heparin-modified scaffolds sequester and retain significantly higher levels of insulin-like growth factor-1 (IGF-1), a potent promoter of myogenesis, compared to other scaffold groups. Together, these results highlight the importance of tailoring GAG type in CG scaffolds for targeted applications and underscore the promise of heparin-modified CG scaffolds as a material platform for skeletal muscle tissue engineering.

DOI: https://doi.org/10.1002/jbma.70048
Carbohydr Polym. 2026 Apr 15. pii: S0144-8617(26)00062-7. [Epub ahead of print]378 124946

Engineering compartmentalized utilization of glycerol with glucose for high-level chondroitin production in Corynebacterium glutamicum.

Zhuangzhuang Shi, Yue Ming, Jue Li, Yiting Lin, Weilong Wang, Wei Sha, Guoqiang Li, Mengmeng Wu, Ting Ma.

  Chondroitin sulfate (CS) is an important glycosaminoglycan widely used in biomedical and nutraceutical fields. However, its commercial production remains dependent on extraction from animal tissues. Microbial synthesis of its unsulfated precursor, chondroitin, followed by enzymatic sulfation, presents a sustainable alternative. Nevertheless, low chondroitin titer remains a major bottleneck for efficient biosynthesis. This study established an efficient Corynebacterium glutamicum cell factory for enhanced chondroitin production. The base chassis strain CgC25 was engineered by deleting lactic and acetic acid synthesis pathways and blocking glycolysis. To compensate for metabolic impairments, an optimized glycerol utilization pathway was implemented via an RBS library, establishing a parallel carbon metabolism system. Redox homeostasis was also reinforced to alleviate metabolic stress. The final strain CgC40 achieved a titer of 12.37 ± 0.51 g/L with a yield of 102.94 ± 4.90 mg/g carbon source, increased by 24.20% and 30.07%, respectively. This titer constitutes the highest level reported to date. Multi-omics analysis further confirmed the enhanced chondroitin synthesis and a corresponding reduction in TCA cycle activity. This work demonstrates an effective metabolic reprogramming strategy that coordinated carbon co-utilization to enhance bioproduction efficiency, providing a broadly applicable platform for synthesizing diverse high-value compounds.

Keywords:  Carbon source division; Chondroitin; Corynebacterium glutamicum; Glycerol; Synergetic utilization

DOI:  https://doi.org/10.1016/j.carbpol.2026.124946
Molecules. 2026 Jan 23. pii: 395. [Epub ahead of print]31(3):

Low-Molecular-Weight Sulfated Chitosan Microparticles Efficiently Bind HIV-1 In Vitro: Potential for Microbicide Applications.

Sergio A Bucarey, Verónica Ramos, Alejandro A Hidalgo, Victor Neira, Andrónico Neira-Carrillo, Pablo Ferrer.

   BACKGROUND: Human Immunodeficiency Virus type 1 (HIV-1) remains a major global health challenge. Despite advances in antiretroviral therapy, new prevention strategies are needed, particularly topical microbicides capable of blocking the earliest steps of viral entry. HIV-1 attachment relies on interactions with heparan sulfate proteoglycans on host cell surfaces; therefore, sulfated heparan-mimetic polymers have been explored as antiviral agents. In this context, sulfated chitosan microparticles are designed to mimic natural glycosaminoglycan receptors, acting as biomimetic decoys that prevent viral attachment and entry.
METHODS: Low-molecular-weight sulfated chitosan (LMW Chi-S) microparticles were synthesized and characterized (SEM, EDS, DLS, FTIR) following US Patent No. 11,246,839 B2. Their antiviral activity was evaluated by incubating the microparticles with high-viral-load HIV-1-positive plasma (~3.5 × 106 copies/mL) to enable viral binding and removal by pull-down. The performance of the synthesized Chi-S microparticles was compared with established heparinoid controls, including soluble heparin and heparin microparticles.
RESULTS: Chi-S microparticles exhibited stronger virus-binding and neutralizing capacity than all heparinoid comparators, achieving up to 70% reduction in viral load relative to untreated HIV-1 plasma. In comparison, soluble heparin and heparin microparticles reduced viral load by approximately 53% and 60%, respectively. Subsequent evaluation across multiple tested concentrations confirmed a consistent antiviral effect, indicating that the synthesized Chi-S microparticles maintain robust virus-particle interactions throughout the concentration range examined.
CONCLUSIONS: These findings demonstrate that LMW Chi-S microparticles possess potent antiviral properties and outperform classical heparinoid materials, supporting their potential application as topical microbicides targeting early HIV-1 entry mechanisms.

Keywords:  HIV-1 entry inhibition; biomimetic microbicide; heparan sulfate mimetics; sulfated chitosan microparticles; virus-binding decoy strategy

DOI:  https://doi.org/10.3390/molecules31030395
Int J Biol Macromol. 2026 Feb 09. pii: S0141-8130(26)00784-1. [Epub ahead of print] 150858

Chondroitin sulfate doped poly(3, 4-ethylenedioxythiophene) for implantable supercapacitor with high conductivity and anti-inflammatory efficacy.

Yumeng Wang, Meimei Yu, Suting Zhou, Xiangya Wang, Zhijiang Sun, Yanfeng Wei, Dongliang Chen, Fen Ran.

  Once an implantable device enters the human body, its direct contact with wounds or tissues can initiate various biological responses. These reactions may not only compromise the performance of the energy storage device but also potentially trigger inflammatory cascades, induce autoimmune reactions, and pose risks to human health. Therefore, this study aims to design supercapacitors with anti-inflammatory properties by doping poly(3,4-ethylenedioxythiophene) (PEDOT) with chondroitin sulfate (CS). CS, a known anti-inflammatory molecule, is employed as a counterion to dope PEDOT, thereby enhancing its conductivity. PEDOT: CS, an anti-inflammatory bioelectrode material, is synthesized via chemical oxidation polymerization. An integrated anti-inflammatory supercapacitor is then fabricated using in-situ polymerization, with PEDOT: CS as the electrode material and polyvinyl alcohol/tannic acid as the electrolyte. Through the incorporation of CS, the supercapacitor demonstrates outstanding electrochemical performance and biocompatibility. The PEDOT: CS electrode delivers a specific capacitance of 307.9 F g-1 at 0.5 A g-1, and the integrated device exhibits a capacitance retention of 88.7% after 8, 000 cycles. Immunofluorescence assays reveal a decrease in CD 86 expression and a higher distribution of CD 206, indicating the creation of an anti-inflammatory environment supportive of tissue repair. The clotting time reaches 32 s, confirming excellent anticoagulant performance.

Keywords:  Biocompatibility; Bioelectronic; Conductive polymer; Conductivity; Implantable supercapacitor

DOI:  https://doi.org/10.1016/j.ijbiomac.2026.150858
Nat Cell Biol. 2026 Feb 11.

Tumour acidosis remodels the glycocalyx to control lipid scavenging and ferroptosis.

Anna Bång-Rudenstam, Myriam Cerezo-Magaña, Marton Horvath, Hugo Talbot, Emma Gustafsson, Stevanus Jonathan, Chaitali Chakraborty, Itzel Nissen, Kelin Gonçalves de Oliveira, Axel Boukredine, Sarah Beyer, Julio Enriquez Perez, Maria C Johansson, Lena Kjellén, Emil Tykesson, Anders Malmström, Toin H van Kuppevelt, Karin Forsberg-Nilsson, Jeffrey D Esko, Silvia Remeseiro, Johan Bengzon, Valeria Governa, Mattias Belting.

Aggressive tumours are defined by microenvironmental stress adaptation and metabolic reprogramming. Within this niche, lipid droplet accumulation has emerged as a key strategy to buffer toxic lipids and suppress ferroptosis. Lipid droplet formation can occur via de novo lipogenesis or extracellular lipid-scavenging. However, how tumour cells coordinate these processes remains poorly understood. Here we identify a chondroitin sulfate (CS)-enriched glycocalyx as a hallmark of the acidic microenvironment in glioblastoma and central nervous system metastases. This CS-rich glycocalyx encapsulates tumour cells, limits lipid particle uptake and protects against lipid-induced ferroptosis. Mechanistically, we demonstrate that converging hypoxia-inducible factor and transforming growth factor beta signalling induces a glycan switch on syndecan-1-replacing heparan sulfate with CS-thereby impairing its lipid-scavenging function. Dual inhibition of CS biosynthesis and diacylglycerol O-acyltransferase-1, a critical enzyme in lipid droplet formation, triggers catastrophic lipid peroxidation and ferroptotic cell death. These findings define glycan remodelling as a core determinant of metabolic plasticity, positioning the dynamic glycocalyx as a master regulator of nutrient access, ferroptotic sensitivity and therapeutic vulnerability in cancer.

DOI: https://doi.org/10.1038/s41556-026-01879-y
PLoS Pathog. 2026 Feb 09. 22(2): e1013941

Informed mutation of western equine encephalitis virus to heparan sulfate binding: Implications for rational design of alphavirus live attenuated vaccines.

Tetyana Lukash, Shishir Poudyal, Theron C Gilliland, Thomas Klose, Chengqun Sun, Shauna N Vasilatos, Jessica L Farren, Long Kwan Metthew Lam, Richard J Kuhn, William B Klimstra.

Encephalitogenic alphaviruses are mosquito-borne viruses that can cause fatal disease in humans and equines. Currently, there are no licensed vaccines or antiviral treatments for these infections. Western equine encephalitis virus (WEEV) is a member of this group that had not produced a human infection in over a decade. However, an outbreak of WEEV encephalitis in humans and equines was reported recently in South America, indicating a need for additional countermeasures. Blind passage approaches to generation of RNA virus live attenuated vaccines (LAVs) frequently result in acquisition of positively charged amino acid mutations that confer heparan sulfate (HS) binding and that are attenuating factors in resultant LAVs. To develop an informed approach for creation of alphavirus LAVs, we have utilized the WEEV McMillan (McM) strain as an HS weak/non-binding platform into which we have placed positively charged amino acid substitution mutations at positions in the E2 glycoprotein previously shown to confer HS-dependent infection upon other alphaviruses. This approach yielded four mutants with high efficiency HS binding and avirulence in mice, which were further subjected to yield optimization by in vitro selection of second-site mutations. Interestingly, the original mutations concomitantly increased HS interactions and reduced infection promoted by VLDLR and PCDH10 protein receptors, while the second site mutations improved infectivity mediated by VLDLR. Further, we report a newly generated 4.1Å cryo-EM reconstruction of WEEV McM strain into which we have mapped the mutations to provide an E2 glycoprotein domain-based representation of receptor binding site location.

DOI: https://doi.org/10.1371/journal.ppat.1013941
Carbohydr Polym. 2026 Apr 15. pii: S0144-8617(26)00038-X. [Epub ahead of print]378 124922

Integrating heparan sulfate mimetics into LbL nanofilms as extracellular matrix-like architectures to promote bone tissue regeneration.

E Bullier-Marchandin, L Rossignol, A Echalard, S Morin-Grognet, J Maucotel, A Arabo, D Barritault, G Ladam, B Labat.

  Biomimetic surfaces are increasingly needed to enhance the effectiveness of biomaterials in bone tissue repair. The Layer-by-Layer (LbL) technique is a particularly attractive method due to its versatility and ability to incorporate a wide range of bioactive molecules under mild conditions. While numerous LbL systems have been developed, those integrating glycosaminoglycans (GAG) are often reported to rapidly degrade, which limits their potential in tissue integration. To address this limitation, we investigated the incorporation of ReGeneraTing Agents® (RGTA®) into LbLs. RGTA® are glycanase-resistant analogues of heparan sulfate, designed to protect and stabilize growth factors. To date, their use is restricted to soluble formulations or adsorptions onto biomaterial surfaces. Here, we propose a novel approach to immobilize two RGTA® (OTR4120 and OTR4131) within LbL architectures to produce bone extracellular matrix-like microenvironments. We revealed that OTR4120 potentiated much more in vitro bone formation over OTR4131, with the synthesis of a mature mineralized hydroxyapatite-rich matrix only atop OTR4120 films. Subsequent in vivo translation of OTR4120 LbL films validated the osteogenic potentializing effect. This new strategy aimed at combining the regenerative potential of OTR4120 with the structural and functional advantages of the LbL assemblies, offering a new avenue for the development of biomimetic osteogenic materials.

Keywords:  Biomimetic mineralization; Bone regeneration; Glycosaminoglycans GAG; Layer-by-Layer (LbL) assembly; RGTA®

DOI:  https://doi.org/10.1016/j.carbpol.2026.124922
Infect Immun. 2026 Feb 09. e0070925

Elevated vaginal heparan sulfate correlates with impaired neutrophil killing of Candida albicans in women with vulvovaginal candidiasis.

Junko Yano, Nicole A Woznicki, Jack D Sobel, Mary C Meyaski-Schluter, Paul L Fidel.

  Recurrent vulvovaginal candidiasis (RVVC), primarily caused by the fungal pathogen Candida albicans, is a common infection affecting a significant number of women worldwide. Despite a robust inflammatory response by polymorphonuclear neutrophils (PMNs) with potent antifungal properties during symptomatic episodes, fungal clearance often fails, leading to persistent overgrowth and PMN-associated immunopathology. Studies in an established animal model demonstrated that elevated vaginal heparan sulfate (HS) interferes with PMN-C. albicans interactions, thereby impairing fungal clearance. This study investigated the presence and inhibitory effects of HS in women diagnosed with RVVC. Vaginal conditioned medium (VCM) was prepared from swab samples obtained from symptomatic VVC patients, women in asymptomatic remission, and healthy controls. Results from ELISA and immunostaining showed significantly elevated HS levels in VCM-containing vaginal secretions and epithelial cells from symptomatic women compared to those from asymptomatic and healthy controls. PMN killing assays further revealed significantly reduced antifungal activity in the presence of VCM from symptomatic women compared to asymptomatic and healthy control VCM, resulting in a significant negative correlation between vaginal HS concentrations and PMN antifungal activity. The inhibitory effect of HS was further confirmed in vitro by impaired PMN killing in control VCM spiked with purified HS, and by the restoration of PMN function following heparanase (HS lyase) treatment of both symptomatic VCM and HS-spiked controls. These findings support the results from the animal studies and provide the first clinical evidence that elevated HS in the vaginal environment contributes to PMN dysfunction, leading to persistent C. albicans colonization and VVC-associated immunopathology.

Keywords:  Candida albicans; inflammation; vulvovaginal candidiasis

DOI:  https://doi.org/10.1128/iai.00709-25
Free Radic Biol Med. 2026 Feb 10. pii: S0891-5849(26)00115-2. [Epub ahead of print]

Apolipoprotein J-mediated hepato-renal crosstalk drives renal injury in chronic kidney disease.

Jiayi Pi, Hau-Chern Jan, Nong Qin, Cheng-Pin Huang, Mei-Chi Huang, Ye Qiu, Shuen-Ru Yang, Shuangdi Duan, Liyang Shi, Hung-Yu Sun.

  Chronic kidney disease (CKD) is characterized by multi-organ dysfunction and the systemic accumulation of toxic metabolites. Apolipoprotein J (ApoJ), a stress-responsive chaperone primarily synthesized in the liver, has emerged as a biomarker of disease severity; however, its mechanistic role in CKD pathogenesis remains unclear. Here, we identify ApoJ as a mediator of pathological hepato-renal crosstalk. ApoJ was markedly increased in experimental and human CKD and was closely associated with transcriptional signatures regulated by the aryl hydrocarbon receptor (AhR). Mechanistically, ApoJ stabilized AhR by preventing its ubiquitination, thereby enhancing renal tubular AhR activation, oxidative injury, and epithelial-mesenchymal transition. In the liver, ApoJ induced sulfotransferase 1A1 expression, promoting overproduction of the uremic tryptophan metabolite indoxyl sulfate, which further aggravated kidney injury. Hepatocyte-specific ApoJ deletion or pharmacologic blockade with the ApoJ antagonist peptide MK53 attenuated renal damage, suppressed tubular AhR signaling, and reduced hepatic uremic toxin generation. In human CKD specimens, tubular ApoJ accumulation correlated with injury, and mediation analyses indicated that circulating ApoJ amplifies the nephrotoxic impact of tryptophan metabolites. These findings identify ApoJ as a pathogenic driver of CKD that coordinates toxicological signaling between liver and kidney, and they highlight ApoJ inhibition as a potential therapeutic strategy.

Keywords:  Apolipoprotein J; chronic kidney disease; liver-to-kidney axis; renal injury; uremic toxin

DOI:  https://doi.org/10.1016/j.freeradbiomed.2026.02.018
bioRxiv. 2026 Jan 31. pii: 2026.01.30.702922. [Epub ahead of print]

Indole toxicity on removal of uremic toxin p-cresol, in-vitro study of Thauera aminoaromatica S2.

Pei-Hsin Wang, Prakit Saingam, Rosita Rasyid, Bruce J Godfrey, Jonathan Himmelfarb, Mari Karoliina Henriikka Winkler.

Protein-bound uremic toxins, such as indoxyl sulfate and p -cresyl sulfate, are major contributors to chronic kidney disease (CKD) complications and are poorly removed by dialysis due to strong albumin binding. Targeting their gut-derived microbial precursors offers a promising strategy to reduce systemic toxin load. Thauera aminoaromatica S2 is known to anaerobically degrade p -cresol, but its response to indole and its potential as an orally administered microbial therapy remain poorly characterized. Here, we investigated the activity of Thauera aminoaromatica S2 under exposure to both p -cresol and indole in planktonic and hydrogel-encapsulated forms. Low indole levels (0.25 mM) enhanced planktonic growth in the presence of 2 mM p -cresol, whereas co exposure inhibited p-cresol degradation in hydrogel systems, likely due to restricted diffusion and elevated local indole concentrations. Nonetheless, encapsulation enabled tolerance to conditions (2 mM p -cresol + 0.5 mM indole) that abolished planktonic growth, suggesting microenvironmental protection. Incorporation of activated carbon into the hydrogel restored p -cresol removal despite indole exposure, likely through localized indole sequestration. These results highlight the potential of combining encapsulation with adsorptive additives to stabilize microbial function and support the development of microbial therapies aimed at mitigating uremic toxin precursors in CKD.

DOI: https://doi.org/10.64898/2026.01.30.702922
Int J Mol Sci. 2026 Jan 30. pii: 1386. [Epub ahead of print]27(3):

Heparan Sulfates Regulate Vascular Reactivity in Syndecan 1 Knockout Mice.

Simone R Potje, Aishwarya Katiki, Paulo W Pires, Andreia Zago Chignalia.

  Heparan sulfates (HS) are polysaccharides abundantly expressed in the extracellular matrix and the glycocalyx of endothelial cells, having a putative role in vascular function. The role of HS in vascular reactivity remains unclear. Herein, we sought to determine whether HS regulate the vascular tone in physiological conditions. Using male, 6-8-weeks-old, CD1, C57BL/6, syndecan 1 (Sdc1-/-) and glypican 1 (Gpc1-/-) knockout mice, we investigated if the degradation of HS with heparinase III altered vascular reactivity to norepinephrine (NE), acetylcholine (ACh) and potassium chloride (KCl). Our findings indicate that HS are crucial players in the vascular response to NE and ACh in CD1, C57BL/6, and Sdc1-/- but not in Gpc1-/- mice. Both Sdc1-/- and Gpc1-/- showed increased compensatory expression of syndecan 2 and syndecan 4. However, while Sdc1-/- showed decreased expression of glypican 1, Gpc1-/- showed increased expression of syndecan 1 in aortic homogenates. The lack of response to the vascular reactivity effects of heparinase III in Gpc1-/- suggests a differential role of HS to proteoglycan function in the regulation of the vascular tone. Our data demonstrate a physiological role for HS in the regulation of the vascular tone in physiological conditions.

Keywords:  glypican 1; heparan sulfate; heparinase III; syndecan 1; vascular reactivity

DOI:  https://doi.org/10.3390/ijms27031386
Cancer Res. 2026 Feb 13.

GAL3ST1-Mediated Histone Tyrosine Sulfation Induced by Cancer-Associated Fibroblasts Promotes Gastric Cancer Metastasis.

Yifan Lu, Xiongyan Wu, Baolong Li, Lizhong Yao, Junyi Hou, Beiqin Yu, Jianfang Li, Chen Li, Min Yan, Zhongyin Yang, Chao Yan, ZhengGang Zhu, Bingya Liu, Kaiwen Tang, Tao Pan, Zhenjia Yu, Zhijian Jin, Liping Su.

Gastric cancer (GC) metastasis involves the interaction between tumor cells and their stromal microenvironment. Cancer-associated fibroblasts (CAFs) play a pivotal role in this process, and elucidation of the molecular mechanisms underlying GC cell-CAF interactions could uncover potential therapeutic targets to block metastatic progression. Here, through transcriptomic profiling of GC cell-CAF communications, we identified galactose-3-O-sulfotransferase 1 (GAL3ST1) as a key regulator of CAF-induced GC cell metastatic potential. Mechanistically, GAL3ST1 functioned as a histone sulfotransferase to sulfate nascent histone H3 at tyrosine 99 (H3Y99sulf) in the cytosol of GC cells. The sulfated histones were subsequently translocated to the nucleus via AP2B1, where they recruited KAT2A to establish H3K56 acetylation marks that resulted in activation of β-catenin transcription and drove epithelial-mesenchymal transition (EMT). Furthermore, CAF-derived SEMA7A engaged ITGB1 on GC cells and initiated ERK1/2-CEBPB signaling to transcriptionally upregulate GAL3ST1. Collectively, these findings reveal a role for GAL3ST1 in histone sulfation-mediated epigenetic regulation and elucidate the SEMA7A/GAL3ST1/H3Y99sulf axis as a crucial mediator of tumor-stromal crosstalk in GC metastasis.

DOI: https://doi.org/10.1158/0008-5472.CAN-25-2452
Spectrochim Acta A Mol Biomol Spectrosc. 2026 Feb 08. pii: S1386-1425(26)00142-3. [Epub ahead of print]353 127571

A novel peptide-based AIE probe for highly selective and ultrasensitive detection of heparin and its applications.

Xinlin Cao, Shiyang Li, Chunmei Pu, Shiyi Xiong, Peng Wang.

  Heparin is a highly sulfated linear glycosaminoglycan with anticoagulant properties, and its excessive use may lead to many diseases. Therefore, developing sensitive detection techniques for precise detection of heparin is of utmost importance. Herein, we reported a novel peptide-based fluorescent probe (TPE-GRGRG) based on tetraphenylethylene (TPE)-labeled pentapeptide (Gly-Arg-Gly-Arg-Gly-NH2) for the highly selective and outstanding sensitive detection of heparin. TPE-GRGRG exhibited a large Stokes shift (132 nm) and typical aggregation-induced emission (AIE) characteristics in DMSO/H2O binary mixtures. TPE-GRGRG demonstrated a significant enhancement of fluorescence intensity in the presence of heparin with a response time of under 30 s and the limit of detection (LOD) as low as 0.30 nM. A series of characterizations revealed that TPE-GRGRG and heparin formed nanoaggregates via electrostatic interactions, including fluorescence spectroscopy, UV-Vis, FTIR, CD, zeta potential, DLS measurements and fluorescence lifetime analyses, which in turn restricted the intramolecular rotation and triggered the fluorescence enhancement. TPE-GRGRG enabled heparin detection over a wide pH range and exhibited good biocompatibility, and was successfully applied to image heparin in living cells and zebrafish larvae. Furthermore, this study established detection platforms based on swab tests for visual qualitative analysis and smartphone RGB analysis, thereby achieving portable and visual heparin monitoring with the LOD of 0.93 μM. Finally, heparin detection was achieved in 0.1% fetal bovine serum with the LOD of 1.46 nM. TPE-GRGRG offers a reliable strategy for point-of-care testing of heparin, holding potential application value in clinical diagnosis and biosensing.

Keywords:  AIE-active fluorescent probe; Bioimaging; Heparin; Pentapeptide; Smartphone-based sensing platform

DOI:  https://doi.org/10.1016/j.saa.2026.127571
Int J Mol Sci. 2026 Feb 06. pii: 1600. [Epub ahead of print]27(3):

Peripheral Syndecan-3 and Neurofilament Light Chain as Complementary Blood Biomarkers for Alzheimer's Disease.

Anett Hudák, Annamária Letoha, Tamás Letoha.

  Reliable and disease-specific blood biomarkers are critically needed for Alzheimer's disease (AD), particularly in early stages when interventions are most effective. Although phosphorylated tau and neurofilament light chain (NfL) are widely used, their diagnostic specificity has been reported to decrease in elderly populations with multimorbidities. Syndecan-3 (SDC3), a heparan sulfate proteoglycan implicated in amyloid and tau aggregation, has recently emerged as a mechanistically relevant biomarker candidate. In this clinically realistic cohort study, we examined 46 participants, including 23 clinically diagnosed AD patients and 23 age-matched non-AD individuals with psychiatric and/or metabolic comorbidities. SDC3 expression was quantified in peripheral blood mononuclear cells (PBMCs), while soluble SDC3 and NfL were measured in plasma. Both PBMC-expressed and plasma SDC3 levels were elevated in AD compared with non-AD participants and showed a strong intercorrelation, whereas plasma NfL was likewise increased in AD. Individually, PBMC-SDC3, plasma SDC3, and NfL demonstrated moderate discriminatory performance. However, multivariable models integrating SDC3 (PBMC or plasma), NfL, and age achieved substantially improved discrimination (AUC > 0.8). SDC3 did not correlate with NfL, consistent with a biological signal distinct from neuroaxonal injury and reflective of peripheral immune-metabolic remodeling. Together, these findings identify SDC3 as a blood-based biomarker associated with systemic immune remodeling that complements established neuronal markers in a clinically realistic AD versus non-AD comparison. While exploratory, this study supports further investigation of SDC3 within integrated, multi-domain biomarker strategies in larger and independent cohorts.

Keywords:  Alzheimer’s disease; biomarker; immune remodeling; neurofilament light chain; neuroinflammation; peripheral blood mononuclear cells; syndecan-3

DOI:  https://doi.org/10.3390/ijms27031600