bims-supasi 2026-01-04 papers

bims-supasi

Biomed News

on Sulfation pathways and signalling

Issue of 2026–01–04
twelve papers selected by
Jonathan Wolf Mueller, University of Birmingham

Characterization and biological activities of a high-yield galactosylated heparan sulfate from Bursatella leachii egg strings.
Keratan sulfate revisited: UPLC-MS/MS-based quantitative profiling reveals structural heterogeneity and deficiency in ocular pathologies.
Chondroitin Sulfate-Based Nanoplatforms: Advances and Challenges for Cancer Therapy.
Quercetin Feeding Ameliorates Increased Erythrocyte Syndecan-3 Expression in Dyslipidemic and Diabetic Rats and Correlates to Erythrocyte Adhesion.
An Intravenous Brain-Penetrant Enzyme Therapy for Mucopolysaccharidosis II.
The impact of the conjugation manner of targeting agent and tandem cell-penetrating peptide on the efficacy of mitomycin C liposomes in treating triple-negative breast tumors.
Structure-activity relationship of a potent anti-FXase and antithrombotic chondroitin sulfate-dermatan sulfate hybrid bearing 2,3-O-sulfated motifs from Anthenoides laevigatus.
Cortisol, DHEA-S, and cortisol/DHEA-S ratio in association with oxidative stress in Korean adults.
Sustainable biovalorization of invasive Sargassum horneri: Dual immunomodulatory and gut-protective effects of sulfated polysaccharides in zebrafish and Caco-2 models.
Heparin: Over 100 Years of Anticoagulation.
Graded isavuconazonium sulfate challenge in a patient with hypersensitivity to fluconazole.
SNRK3.15 Is a Crucial Component of the Sulfur Deprivation Response in Arabidopsis thaliana.

Carbohydr Polym. 2026 Mar 01. pii: S0144-8617(25)01544-9. [Epub ahead of print]375 124760

Characterization and biological activities of a high-yield galactosylated heparan sulfate from Bursatella leachii egg strings.

Yan Ma, Ying Pan, Lutan Zhou, Lige Cui, Xuewen Wu, Mengchen Ji, Dilihumaer Ruzemaimaiti, Wenwen Ma, Haitian Wang, Linxia Chen, Weilie Xiao, Ronghua Yin, Jinhua Zhao.

  Systematic analysis of the gelatinoid of the sea hare Bursatella leachii egg strings showed that the material almost entirely consisted of polysaccharides. Hot water treatment could efficiently and conveniently extract the acidic polysaccharides (BLP) almost completely, with a yield of up to 50 % of the dry weight of the egg strings. Physicochemical analysis revealed that BLP is composed of glucuronic acid, glucosamine, galactose, and sulfate groups in a molar ratio of 1.00: 1.00: 1.12: 2.40, with a molecular weight of 359.7 kDa. The sulfation degree is comparable to heparin and higher than that of heparan sulfate. NMR analysis revealed that the backbone of BLP was as 4)-D-GlcA(S)-(β1, 4)-D-GlcN (Ac/S3S)-(α1, within the glucosamine residues could be modified by sulfated Gal via an α1, 6-glycosidic bond, representing the first discovery of an HS derivative with extensive Gal side-chains. BLP exhibited certain anticoagulant activity and potent heparanase inhibition. It also effectively suppressed the migration and invasion of 4 T1 mammary carcinoma cells, with superior anti-metastatic effects demonstrated by its typical low-molecular-weight product dBLP-5. This study enriches our understanding of natural GAGs and offers a high-yield source for developing potent heparin-like therapeutic compounds.

Keywords:  Anticoagulation; Bursatella leachii; Galactosylation; Heparan sulfate; Heparanase inhibition; Structure

DOI:  https://doi.org/10.1016/j.carbpol.2025.124760
Carbohydr Polym. 2026 Mar 01. pii: S0144-8617(25)01569-3. [Epub ahead of print]375 124785

Keratan sulfate revisited: UPLC-MS/MS-based quantitative profiling reveals structural heterogeneity and deficiency in ocular pathologies.

Xinping Wang, Han Zhou, Xi Liang, Yue Li, Shimei Shen, Yuxin Li, Qingfeng Niu, Bi Ning Zhang, Shuying Xu, Guangli Yu, Guoyun Li.

  Keratan sulfate (KS) is a structurally unique glycosaminoglycan involved in various physiological processes. Dysregulated KS levels and sulfation modifications are associated with the development of various disorders. However, the absence of commercial KS standards and specific hydrolases has hindered accurate quantification and functional studies. To overcome these limitations, we prepared two structurally distinct KS disaccharide standards (Gal-GlcNAc6S and Gal6S-GlcNAc6S) from corneal and cartilaginous tissues, and obtained recombinant KS hydrolase through heterologous expression. Given that the total abundance of various sulfated KS disaccharides reflects overall KS content, a robust UPLC-MS/MS method was further developed for simultaneous quantification of multiple sulfated KS disaccharides. The developed methodology demonstrated exceptional sensitivity, achieving KS quantification from minimal biological inputs (500-1,000 cells or 1 mg tissue). Quantitative analysis revealed significant variation in KS distribution among distinct human ocular cell populations, with stromal cells exhibiting the highest abundance, followed by endothelial and epithelial cells. Notably, total KS expression in corneal specimens from macular corneal dystrophy (MCD) patients was reduced by over 90 % relative to keratoconus (KC). This study establishes a comprehensive platform for KS quantification and offers novel insights into its structure-function relationships within ocular tissues.

Keywords:  Keratan sulfate; Ocular cell heterogeneity; Ocular pathologies; Quantitative profiling; UPLC–MS/MS

DOI:  https://doi.org/10.1016/j.carbpol.2025.124785
Molecules. 2025 Dec 16. pii: 4798. [Epub ahead of print]30(24):

Chondroitin Sulfate-Based Nanoplatforms: Advances and Challenges for Cancer Therapy.

Ludovica Scorzafave, Marco Fiore, Giuseppe Cirillo, Fiore Pasquale Nicoletta, Francesca Iemma, Manuela Curcio.

  Chondroitin sulfate (CS)-based nanoparticles have emerged as versatile and multifunctional platforms for cancer therapy, integrating effective drug delivery with diagnostic capabilities. Their ability to exploit the enhanced permeability and retention (EPR) effect enables selective accumulation within tumor tissues, while surface modification with CS enhances targeting efficiency through strong conformational and electrostatic affinity for CD44 receptors, which are overexpressed in many cancer cells. In addition, CS interacts with E-selectin, providing dual-targeting capabilities superior to those of other polysaccharides such as hyaluronic acid. A wide variety of CS-derived nanostructures-including micelles, nanogels, hybrid liposomes, and CS-drug conjugates-have shown great potential not only in drug delivery but also in advanced therapeutic modalities such as photodynamic, sonodynamic, and immunotherapy. This review discusses recent advances (2020-2025) in CS-based nanoplatforms for cancer therapy, with particular emphasis on the role of CS within nanostructures. It highlights how the functionalization of nanoparticles with CS represents a powerful strategy to improve colloidal stability, pharmacokinetics, and receptor-mediated uptake, thereby enabling controlled, site-specific drug release and reducing off-target toxicity. Ultimately, these advances open new opportunities for cancer treatment, with the potential for bench-to-clinic translation through the integration of AI-guided design, organelle-specific targeting, multi-pathway modulation, and immune system engagement.

Keywords:  cancer therapy; chondroitin sulfate; drug targeting; smart nanoparticles

DOI:  https://doi.org/10.3390/molecules30244798
J Biochem Mol Toxicol. 2026 Jan;40(1): e70660

Quercetin Feeding Ameliorates Increased Erythrocyte Syndecan-3 Expression in Dyslipidemic and Diabetic Rats and Correlates to Erythrocyte Adhesion.

Smitha Honnalagere Mallanna, Nandini D Chilkunda.

  Our earlier study demonstrated that metabolic disorders increase the expression of Syndecan-3 (Sdc-3), a heparan sulfate proteoglycan (HSPG) in erythrocytes, contributing to adhesion through the glycosaminoglycan chain. Reactive oxygen species (ROS) could be one of the factors for increased expression. This study aimed to determine whether quercetin, a bioactive antioxidant commonly found in food, could modulate Sdc-3 expression. Male Wistar rats were made dyslipidemic and diabetic, after which they were treated with quercetin at doses of 50 and 100 mg/kg body weight for a duration of 2 months. Sdc-3 expression in erythrocytes was assessed by Western blot, and erythrocyte adhesion to fibronectin was evaluated in-vitro. The quercetin-supplemented diet reduced circulating lipids, blood glucose, and MDA levels, mitigated changes in Sdc-3 expression, and decreased erythrocyte adhesion to fibronectin. These effects may be attributed to quercetin's antioxidant properties, as was seen by the positive correlation between MDA levels and Sdc-3 expression. Sdc-3 levels in erythrocytes could serve as a prognostic marker for assessing the impact of dietary compounds on complications linked to metabolic disorders.

Keywords:  diabetes; erythrocyte adhesion; high‐fat diet; metformin; quercetin; syndecan‐3

DOI:  https://doi.org/10.1002/jbt.70660
N Engl J Med. 2026 Jan 01. 394(1): 39-50

An Intravenous Brain-Penetrant Enzyme Therapy for Mucopolysaccharidosis II.

Joseph Muenzer, Barbara K Burton, Paul Harmatz, Deepa S Rajan, Simon A Jones, Johanna M P van den Hout, John J Mitchell, Akhil Bhalla, Natalie J Engmann, Imanol Zubizarreta, Wei Dong, Fabian Model, Ryan J Watts, Matthew D Troyer, Peter S Chin, Carole Ho.

BACKGROUND: Tividenofusp alfa, comprising iduronate-2-sulfatase fused to an engineered transferrin receptor-binding Fc domain, has been developed to treat neurologic and peripheral manifestations of mucopolysaccharidosis type II (MPS II), a rare lysosomal disorder causing progressive multisystem and neurologic decline.
METHODS: We conducted a phase 1-2, open-label study in which male participants up to 18 years of age with MPS II received weekly intravenous tividenofusp alfa for 24 weeks, followed by an 80-week safety extension and a 157-week open-label extension. The primary objective was to evaluate the safety of tividenofusp alfa. Secondary objectives were to evaluate central nervous system and peripheral effects as assessed by cerebrospinal fluid (CSF) and urinary heparan sulfate levels, adaptive behavior (as assessed with the Vineland Adaptive Behavior Scales), and liver volume.
RESULTS: A total of 47 male participants were enrolled. At the 24-week primary analysis, all 47 participants reported at least one adverse event that emerged during the treatment period, most commonly infusion-related reactions. Pyrexia, urticaria, and vomiting were the most frequently reported symptoms of infusion-related reactions, occurring in more than 40% of the participants, despite routine premedication. Three participants had serious treatment-related adverse events; all continued to receive treatment. CSF and urinary heparan sulfate levels appeared to be reduced from baseline by 91% and 88%, respectively. Across all study periods, adverse events remained common. Reductions in heparan sulfate levels appeared to be maintained through week 153, adaptive behavior stabilized or improved, and liver volumes normalized or remained normal.
CONCLUSIONS: In participants with MPS II, tividenofusp alfa treatment was commonly associated with adverse events. Heparan sulfate, the primary substrate that accumulates in the CSF and urine in persons with MPS II, appeared to decrease to levels within the range of unaffected children. A randomized trial is ongoing to further evaluate these effects. (Funded by Denali Therapeutics; ClinicalTrials.gov number, NCT04251026; EudraCT number, 2019-004909-27.).

DOI: https://doi.org/10.1056/NEJMoa2508681
Int J Pharm X. 2025 Dec;10 100457

The impact of the conjugation manner of targeting agent and tandem cell-penetrating peptide on the efficacy of mitomycin C liposomes in treating triple-negative breast tumors.

Mehrnaz Salahi, Jaleh Varshosaz, Mahboubeh Rostami, Salar Nasr Esfahani, Arsham Hekmat, Ali Jahanian-Najafaabadi, Mohsen Minayian.

  Triple-negative breast cancer (TNBC) remains one of the most aggressive subtypes with limited therapeutic options. To address this unmet need, this study aimed to enhance the cellular uptake and cytotoxicity of mitomycin C (MMC) using surface-modified nanoliposomes functionalized with poly-L-arginine (PLA), a cell-penetrating peptide, and chondroitin sulfate (CS), a CD44-targeting ligand. Another object was to investigate how the conjugation manner of the targeting agent-chondroitin sulfate (CS), a CD44-targeting ligand, and a tandem cell-penetrating peptide (CPP) made of poly-L-arginine (PLA)-affects the enhancement of cellular uptake and anti-tumor effects of Mitomycin C (MMC) nanoliposomes in triple-negative breast cancer (TNBC). We synthesized and characterized four liposomal formulations; CS-liposomes, PLA-liposomes, PLA-CS-liposomes, and CS-PLA-liposomes and their particle size, polydispersity index, zeta potential, encapsulation efficiency, and drug release were evaluated. In vitro studies on 4 T1 TNBC cells included cytotoxicity (MTT), cellular uptake, apoptosis, cell cycle arrest, and caspase-3/8 expression (qRT-PCR). In vivo efficacy was tested in BALB/c mice bearing orthotopic 4 T1 tumors by monitoring tumor growth, body weight, and histopathology (H&E and Ki-67). Optimized PLA-CS liposomes had a mean particle size of 144.0 ± 2.4 nm, a PDI of 0.31 ± 0.02, and 73 % encapsulation efficiency, with sustained MMC release over 24 h. PLA-functionalized liposomes showed significantly greater cytotoxicity and uptake than free MMC and non-targeted controls. They induced G1 cell cycle arrest and strongly upregulated caspase-3 (+64-fold in CS-PLA, +13-fold in PLA-CS), consistent with activation of the intrinsic apoptosis pathway. Animal studies revealed PLA-CS liposomes produced the strongest tumor suppression (Ki-67 index 6 %), reduced tumor grade to 1, and showed no liver or kidney metastasis. All liposomal formulations performed better than free MMC in tumor control and safety. PLA-CS-liposomes provide a potent and well-tolerated delivery platform for MMC in TNBC, combining improved tumor targeting, enhanced apoptotic response, and favorable organ safety.

Keywords:  Cell-penetrating peptide; Chondroitin sulfate; Mitomycin C; Poly-L-arginine; Targeted liposomes

DOI:  https://doi.org/10.1016/j.ijpx.2025.100457
Carbohydr Polym. 2026 Mar 01. pii: S0144-8617(25)01536-X. [Epub ahead of print]375 124752

Structure-activity relationship of a potent anti-FXase and antithrombotic chondroitin sulfate-dermatan sulfate hybrid bearing 2,3-O-sulfated motifs from Anthenoides laevigatus.

Xiang Shi, Minghao Shi, Jiewen Fu, Xusheng Lv, Liang Zhang, Qingxia Yuan, Longyan Zhao, Baoshun Zhang.

  This study isolated a homogeneous polysaccharide ALHX-2M from the body wall of the starfish Anthenoides laevigatus (South China Sea). Structural characterization identified it as a chondroitin sulfate-dermatan sulfate (CS-DS) hybrid chain with a 38.53 % sulfate content and unique 2,3-di-O-sulfate motifs, mainly constituted by the repeating disaccharide units -L-IdoA2S3S-α1,3-D-GalNAc4S(6S)-β1,4- and -D-GlcA2S3S-β1,3-D-GalNAc4S-β1,4- disaccharide with a molar ratio of approximately 2:1. ALHX-2M potently inhibited the intrinsic and common coagulation pathway, as evidenced by significantly prolonged APTT/TT without affecting PT. In vivo, 1.8 mg/kg ALHX-2M achieved 89.7 % thrombus inhibition in tissue thromboplastin-induced rat venous thrombosis (equivalent to 3.6 mg/kg LMWH) and exhibited strong efficacy in carrageenan-induced mouse tail thrombosis, with significantly lower bleeding risk than LMWH. It displayed potent FXase inhibition (IC50 = 57.1 ± 9.3 ng/mL, three-fold more potent than LMWH) and bound FIXa, a serine protease integral to the FXase complex, with high affinity (KD = 2.47 × 10-9 M). Structure-activity relationships confirmed: (1) activity requires a critical molecular size; (2) sulfate groups are essential; and (3) carboxyl groups are critical for FXase targeting. This unusual CS-DS hybrid chain represents a novel low-bleeding-risk anticoagulant candidate, providing an experimental basis for marine antithrombotic drug development and South China Sea biological resource utilization.

Keywords:  Anticoagulant and antithrombotic activity; Chondroitin sulfate–dermatan sulfate hybrid chains; Glycosaminoglycans; Starfish

DOI:  https://doi.org/10.1016/j.carbpol.2025.124752
Front Endocrinol (Lausanne). 2025 ;16 1708007

Cortisol, DHEA-S, and cortisol/DHEA-S ratio in association with oxidative stress in Korean adults.

Sat Byul Park.

   Background: Oxidative stress can result from redox reactions involving hemoglobin (Hb) and nitric oxide (NO), forming toxic peroxynitrite when NO reacts with superoxide during Hb autoxidation. γ-glutamyltranspeptidase (GGT) also contributes to reactive oxygen species generation in the presence of transition metals like iron. The hypothalamic-pituitary-adrenal axis is central to the body's stress response and immunomodulation. This study aimed to investigate the relationships between cortisol, dehydroepiandrosterone sulphate (DHEA-S), the cortisol/DHEA-S ratio, and oxidative stress markers such as Hb and GGT in a Korean population.
Methods: Data from 1,341 adults collected between January 2018 and March 2023 were analyzed. Sociodemographic and lifestyle data were gathered via questionnaires. Body composition, blood pressure, and metabolic variables, including cortisol and DHEA-S levels, were evaluated.
Results: The mean age of participants was 52.6 ± 11.9 years. Higher cortisol and DHEA-S levels were significantly linked to elevated Hb and GGT levels. Conversely, the cortisol/DHEA-S ratio was negatively correlated with Hb levels. Logistic regression confirmed that higher Hb levels were associated with increased cortisol (P = 0.038) and DHEA-S levels (P < 0.001). The GGT level had no significant association with the cortisol/DHEA-S ratio.
Conclusions: Elevated cortisol and DHEA-S levels are associated with markers of oxidative stress in Korean adults, independent of age and body mass index.

Keywords:  Cortisol; DHEA-S; GGT; Hemoglobin; cortisol/DHEA-S ratio; oxidative stress

DOI:  https://doi.org/10.3389/fendo.2025.1708007
Int Immunopharmacol. 2025 Dec 31. pii: S1567-5769(25)02112-5. [Epub ahead of print]171 116123

Sustainable biovalorization of invasive Sargassum horneri: Dual immunomodulatory and gut-protective effects of sulfated polysaccharides in zebrafish and Caco-2 models.

Fengqi Yang, Young-Sang Kim, Dandan Xiao, Xueyu Wang, Hyo-Geun Lee, Seon-Heui Cha, You-Jin Jeon.

  Inflammatory bowel disease (IBD) is a chronic condition characterized by persistent intestinal inflammation and disruption of the epithelial barrier, with limited effective treatments currently available. The present study was designed to assess the immunomodulatory and intestinal barrier-protective effects of sulfated polysaccharides extracted from Sargassum horneri (SHCPs) using both in vitro Caco-2 cell models and an in vivo dextran sulfate sodium (DSS)-induced zebrafish colitis model. SHCPs exhibited moderate activation of the NF-κB signaling pathway, which facilitated the balanced upregulation of key cytokines IL-6, IL-8, and IL-10, enhancing mucosal immune readiness without eliciting harmful inflammation. In Caco-2 cells, SHCPs significantly protected against DSS-induced decreases in cell viability and attenuated the DSS-induced upregulation of pro-inflammatory mediators, including PGE2, TNF-α, IL-6, and IL-1β. Zebrafish treated with SHCPs demonstrated reduced intestinal epithelial cell death, diminished nitric oxide production, attenuation of mucus hypersecretion, and improved gut motility, collectively mitigating hallmark features of IBD pathology. These bioactivities are closely linked to the distinct sulfation patterns and fucosylated backbone of SHCPs. Taken together, our findings highlight SHCPs as promising natural marine polysaccharides with the potential to restore intestinal immune homeostasis and alleviate inflammation-related gut disorders. Further investigations involving mammalian systems and clinical trials are necessary to validate their efficacy and clarify the underlying molecular mechanisms.

Keywords:  Immunomodulation; Inflammatory bowel disease; NF-κB signaling pathway; Sargassum horneri; Sulfated polysaccharides

DOI:  https://doi.org/10.1016/j.intimp.2025.116123
Handb Exp Pharmacol. 2025 Dec 30.

Heparin: Over 100 Years of Anticoagulation.

John Hogwood, Elaine Gray.

  This chapter provides an overview of heparin, including discovery, structure, mechanism of action, and principal use for anticoagulation. For over 100 years, heparin has a central role in prophylaxis and treatment of prothrombotic states, be it used in the event of pulmonary embolism or maintaining blood fluidity during dialysis. Indeed, heparin had a role in enabling the development of cardiopulmonary bypass for the surgical treatment of cardiopulmonary diseases. The development of heparin depolymerization which produced low molecular weight heparin further enhanced the usefulness of this anticoagulant, where this type of heparin can be self-administered. There has been much written about heparin over the last century, and this chapter provides a concise overview.

Keywords:  Anticoagulant; Heparin; Low Molecular Weight Heparin; Venous Thromboembolism

DOI:  https://doi.org/10.1007/164_2025_780
IDCases. 2025 ;42 e02355

Graded isavuconazonium sulfate challenge in a patient with hypersensitivity to fluconazole.

Mark Biagi, Michael Pierce, Wendy Harney, Otavio Pereira-Rodrigues, Geoffrey Tsaras.

  Hypersensitivity reactions to triazole antifungals are uncommonly reported and cross-reactivity between these agents is poorly understood. We describe our experiences in a patient who previously developed a full body rash after receiving fluconazole who was initially successfully challenged and treated with isavuconazole without experiencing any adverse effects and was later separately re-challenged and treated successfully with a full-course of isavuconazole 8 months later. She received a third course of isavuconazole approximately 10 months after her second course, and developed rash, chest tightness, dyspnea, and facial flushing.

Keywords:  Candidiasis; Fluconazole; Hypersensitivity; Isavuconazole; Isavuconazonium sulfate; Rechallenge

DOI:  https://doi.org/10.1016/j.idcr.2025.e02355
Plant Direct. 2026 Jan;10(1): e70132

SNRK3.15 Is a Crucial Component of the Sulfur Deprivation Response in Arabidopsis thaliana.

Anastasia Apodiakou, Elmien Heyneke, Saleh Alseekh, Pinnapat Pinsorn, Sabine Metzger, Stanislav Kopriva, Waltraud Schulze, Rainer Hoefgen, Sarah J Whitcomb.

  Sulfate deprivation (-S) results in numerous metabolic and phenotypic alterations in plants. Kinases are often key players in transducing nutrient status signals to molecular components involved in metabolic and developmental program regulation, but despite the physiological importance of sulfur, to date, no signaling kinases have been identified in sulfur-deficiency signaling response programs. Here, we show that the serine/threonine protein kinase CIPK14/SNRK3.15 plays a regulatory role in the -S response in Arabidopsis thaliana seedlings. Multiple molecular and physiological responses to -S are attenuated in snrk3.15 mutants, including both early adaptive responses and later emergency salvage processes including nutrient deficiency induced senescence. When grown in soil with sufficient sulfur supply, snrk3.15 mutants showed no clear phenotypes, including no difference in seed sulfur content. Lastly, the proteome dataset generated from Col-0 and snrk3.15.1 Arabidopsis seedlings under -S conditions for this project is the first of its kind and will be a valuable research resource.

Keywords:  CIPK14/SNRK3.15 (AT5G01820); O‐acetylserine (OAS)‐cluster genes; chlorophyll; nutrient deficiency induced senescence (NuDIS); proteomics; sulfate

DOI:  https://doi.org/10.1002/pld3.70132