bims-supasi 2025-08-03 papers

bims-supasi

Biomed News

on Sulfation pathways and signalling

Issue of 2025–08–03
twenty-two papers selected by
Jonathan Wolf Mueller, University of Birmingham

Structure-activity relationships study on inhibition of CRISPR-Cas9 by glycosaminoglycans.
3-O Sulfated Heparan Sulfate (G2) Peptide Ligand Impairs the Infectivity of Chlamydia muridarum.
Disrupting SARS-CoV-2 Spike-ACE2 Interactions via Glycosaminoglycans in a Pseudoviral Study of Heparan Sulfate and Enoxaparin.
Chemoenzymatic Synthesis and Biological Recognition of a Sulfonate Isostere of 6‑Sulfo-sialyl Lewisx.
Simple One-Step Deuterated Peracetylation-MALDI-MS/MS (OSDPM) Strategy for Structural Sequencing of Glycosaminoglycan Oligosaccharides.
Gamma-tocopherol vitamin E enhances the cytotoxicity of p-cresyl sulfate to renal tubular cells.
Investigating Protein-Glycosaminoglycan Interactions Using Paramagnetic Glycosaminoglycan Oligosaccharides.
Structural characterization and biological functions of echinoderm polysaccharides: A review.
Gut-derived uremic toxins and cardiovascular health in chronic kidney disease.
Predicted Adult Height Remained Normal in Children With Premature Adrenarche Despite Advanced Bone Age.
Bone development of broiler chickens supplemented with chondroitin sulfate and manganese.
Low-Molecular Weight Protamine Enhances Neuroprotection and Remyelination by Mitigating Chondroitin Sulfate Proteoglycan Inhibition in Models of Demyelination.
The sulfation pattern of glycosaminoglycans in human brain development and neurological disorders such as Alzheimer's disease.
Heparan sulfate binding protein treatment ameliorates neuropathology and behavioral abnormalities in mucopolysaccharidosis IIIB mice.
Heparin, Heparin-like Molecules, and Heparin Mimetics in Breast Cancer: A Concise Review.
Late-stage O-sulfation with a bioinspired sulfuryl donor.
Peripheral Leukocyte Syndecan-3 Is Elevated in Alzheimer's Disease: Evidence from a Human Study.
A pan-respiratory virus attachment inhibitor with high potency in human airway models and in vivo.
Expanding the pH-Shift Technique for Sequential Extraction of Intact Proteins and Sulfated Polysaccharide From Fish Heads: A Novel Biorefinery Approach.
Dopamine-functionalized chondroitin sulfate/gelatin-based composite hydrogels for enhancing wound healing and bone regeneration.
Serum p-Cresyl Sulfate Is Independently Associated with Aortic Stiffness in Non-Dialysis Chronic Kidney Disease Patients.
Higher p-Cresol sulfate and tumor necrosis factor (TNF)-α levels are associated with cognitive improvement through increased TNF receptor 2 in individuals with mild cognitive impairment: A cross-sectional mediation analysis.

Carbohydr Polym. 2025 Oct 15. pii: S0144-8617(25)00695-2. [Epub ahead of print]366 123912

Structure-activity relationships study on inhibition of CRISPR-Cas9 by glycosaminoglycans.

Yudi Cheng, Zhe Wang, Min Cao, Sirui Liu, Xinyue Zhang, Cheng Cheng, Chao Cai, Xing Zhang, Jie Zheng.

  The CRISPR-Cas9 system is a revolutionary genome editing system known for its precision, simplicity and efficiency, playing a crucial role in gene-editing. It has enabled applications ranging from biomedicine to agriculture. However, the uncontrollable activity of Cas9 has raised significant safety concerns in clinical settings, limiting its broader application. Consequently, regulating CRISPR-Cas9 activity holds substantial promise for enhancing the safety and efficacy of gene-editing technologies. In this study, we demonstrated that sulfated glycosaminoglycans (GAGs) exhibit inhibitory effects of Cas9. Specifically, both chondroitin sulfate (CS) and heparin (HP) can inhibit CRISPR/Cas9 activity, with heparin showing a stronger inhibitory effect that correlates positively with its concentration. Molecular dynamics simulations indicate that sulfated heparin residues might inhibit Cas9 function by binding to essential DNA-binding sites, which are crucial for functional interactions, potentially impairing activity. Additionally, higher molecular weight GAGs exhibit enhanced inhibitory effects under the same sulphation. Notably, the sulfation site also influenced activity. C6-sulfation of chondroitin sulfate is more favorable for Cas9 inhibition, and N-sulfation of heparin enhances its inhibitory effect on Cas9 activity. These findings provide valuable insights into the development of carbohydrate-based inhibitors for CRISPR-Cas9, offering a foundation for further exploration in this field.

Keywords:  CRISPR; Cas9; Glycosaminoglycans; Inhibitors; Structure-activity relationship

DOI:  https://doi.org/10.1016/j.carbpol.2025.123912
Biomolecules. 2025 Jul 12. pii: 999. [Epub ahead of print]15(7):

3-O Sulfated Heparan Sulfate (G2) Peptide Ligand Impairs the Infectivity of Chlamydia muridarum.

Weronika Hanusiak, Purva Khodke, Jocelyn Mayen, Kennedy Van, Ira Sigar, Balbina J Plotkin, Amber Kaminski, James Elste, Bajarang Vasant Kumbhar, Vaibhav Tiwari.

  Background: Heparan sulfate (HS) is widely implicated as a receptor for Chlamydia cell attachment and infectivity. However, the enzymatic modification of HS modified by the 3-O sulfotransferase-3 (3-OST-3) enzyme in chlamydial cell entry remains unknown. Methodology: To rule out the possibility that host cell 3-O sulfated heparan sulfate (3-OS HS) plays a significant role in C. muridarum entry, a Chinese hamster ovary (CHO-K1) cell model lacking endogenous 3-OST-3 was used. In addition, we further tested the efficacy of the phage-display-derived cationic peptides recognizing heparan sulfate (G1 peptide) and the moieties of 3-O sulfated heparan sulfate (G2 peptide) against C. muridarum entry using human cervical adenocarcinoma (HeLa 229) and human vaginal epithelial (VK2/E6E7) cell lines. Furthermore, molecular dynamics simulations were conducted to investigate the interactions of the Chlamydia lipid bilayer membrane with the G1 and G2 peptides, focusing on their binding modes and affinities. Results: The converse effect of 3-OST-3 expression in the CHO-K1 cells had no enhancing effect on C. muridarum entry. The G2 peptide significantly (>80%) affected the cell infectivity of the elementary bodies (EBs) at all the tested concentrations, as evident from the reduced fluorescent staining in the number of inclusion bodies. The observed neutralization effect of G2 peptide on C. muridarum entry suggests the possibility of sulfated-like domains being present on the EBs. In addition, data generated from our in silico computational structural modeling indicated that the G2 peptide ligand had significant affinity towards the C. muridarum lipid bilayer. Conclusions: Taken together, our findings show that the pretreatment of C. muridarum with 3-O sulfated heparan sulfate recognizing G2 peptide significantly prevents the entry of EBs into host cells.

Keywords:  Chlamydia; computational modeling; infectivity; intracellular; molecular dynamics

DOI:  https://doi.org/10.3390/biom15070999
Biomolecules. 2025 Jun 26. pii: 931. [Epub ahead of print]15(7):

Disrupting SARS-CoV-2 Spike-ACE2 Interactions via Glycosaminoglycans in a Pseudoviral Study of Heparan Sulfate and Enoxaparin.

Virginia Fuochi, Salvatore Furnari, Filippo Drago, Pio Maria Furneri.

   BACKGROUND: The COVID-19 (coronavirus disease 19) pandemic has underscored the urgent need for effective antiviral agents targeting viral entry mechanisms. This study investigated the inhibitory effects of heparan sulfate (HS) and enoxaparin (EX) on the interaction between the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike protein and the angiotensin-converting enzyme 2 (ACE2) receptor.
METHODS: A pseudovirus model was employed to evaluate the efficacy of HS and EX under different treatment strategies: pre-treatment of host cells, pre-treatment of the viral particles, and simultaneous co-treatment.
RESULTS: Both compounds significantly inhibited viral entry. EX exhibited a dose-dependent effect under all treatment conditions. In cell pre-treatment, EX achieved the highest levels of inhibition, whereas HS demonstrated consistent inhibitory activity that was largely concentration-independent. Viral pre-treatment revealed that both compounds effectively reduced infectivity by interfering directly with viral particles. In the co-treatment experiments, HS demonstrated superior inhibitory activity at lower concentrations compared to EX.
CONCLUSIONS: The results suggested that HS and EX inhibit SARS-CoV-2 entry via distinct mechanisms. HS likely acts via competitive inhibition at the host cell surface, while EX may bind directly to the spike protein, thereby preventing engagement with the ACE2 receptor. These findings highlight the therapeutic potential of HS and EX as entry inhibitors targeting the early stages of SARS-CoV-2 infection. Further studies are warranted to evaluate their efficacy against emerging variants and in vivo models.

Keywords:  ACE2 receptor; SARS-CoV-2; enoxaparin; glycosaminoglycans; heparan sulfate; spike protein; viral entry inhibition

DOI:  https://doi.org/10.3390/biom15070931
JACS Au. 2025 Jul 28. 5(7): 3328-3338

Chemoenzymatic Synthesis and Biological Recognition of a Sulfonate Isostere of 6‑Sulfo-sialyl Lewisx.

Yunfei Wu, Julia Weber, Anne L M Kimpel, Luca Unione, Elif Uslu, Robert P de Vries, Geert-Jan Boons.

  Sulfation of N-acetylglucosamine (GlcNAc) moieties of glycans is a common modification that has been implicated in many biological and disease processes. Glycans having sulfate replaced by a stable analogue may find use as glycomimetic drugs. Here, we describe the synthesis of analogues of UDP-GlcNAc in which C-6 hydroxyl is replaced by a thiol or disulfide-protected thiol. It was found that UDP-GlcNAc-6-deoxy-6-SH is a donor substrate for GCNT1 and UDP-GlcNAc-6-deoxy-6-S-SMe for B3GnT2, allowing the preparation of glycopeptides and oligo-LacNAc derivatives having a GlcNAc-6-deoxy-6-S-R moiety, respectively. The disulfide can be reduced to a thiol, which can easily be oxidized to the corresponding sulfonates. Furthermore, oligosaccharides having a sulfonate or disulfide at C-6 are appropriate substrates for glycosyltransferases, providing access to a panel of glycomimetics. The sulfonates and several reference glycans and glycopeptides were printed as a glycan microarray that was used to examine binding selectivities of several lectins, Siglecs, and hemagglutinins of influenza A viruses. It was found that sulfonates can either be tolerated, enhance binding as in the case of Siglec-4, or abolish recognition as for Siglec-9. Molecular modeling studies of the complex of Siglec-4 with sulfated and sulfonated sialyl LacNAc indicate that plasticity of the binding site of the protein and a great charge on oxygens of a sulfonate are responsible for the higher binding affinity. Introduction of a 6-sulfonate gives better step economy than conventional enzymatic sulfation, is simpler to operate, provides compounds resistant to hydrolysis by sulfatases, and can modulate binding selectivities.

Keywords:  Siglec; chemoenzymatic synthesis; glycan microarray; glycomimetic; glycosyltransferases; influenza A

DOI:  https://doi.org/10.1021/jacsau.5c00443
Anal Chem. 2025 Jul 28.

Simple One-Step Deuterated Peracetylation-MALDI-MS/MS (OSDPM) Strategy for Structural Sequencing of Glycosaminoglycan Oligosaccharides.

Zhonghua Li, Yuxiao Zhang, Fan Bai, Yi Lasanajak, Qing Zhang, Maomao Yan, Lauren Byrd-Leotis, David A Steinhauer, Haojie Lu, Xuezheng Song.

Heparin and heparan sulfate (HP/HS), characterized by heterogeneous sulfation motifs, uronic acid epimerization (GlcA/IdoA), and variations in N-acetyl and N-sulfo groups, play pivotal roles in regulating physiological and pathological processes. This inherent structural complexity, resulting from sulfation heterogeneity and epimeric diversity, poses significant challenges for the HP/HS structural analysis. Current labor-intensive multistep derivatization methods coupled with LC-MS/MS or MSn usually require a substantial amount of sample (>50 μg) and prolonged processing times, which severely limit their applicability to scarce HP/HS samples. Herein, we develop a one-step deuterated peracetylation-MALDI-MS/MS (OSDPM) analytical strategy that enables high-throughput structural characterization of HP/HS oligosaccharides with ng- to sub-μg-level sensitivity. Additionally, this OSDPM approach simultaneously determines the oligosaccharide composition and sulfation patterns and distinguishes between GlcA2S/IdoA2S epimers. We successfully applied this method to characterize the structures of 17 natural HP/HS glycans separated from porcine intestinal mucosa, and their glycan microarray data further validated the structural accuracy of OSDPM-derived sequencing results. The simplicity, sensitivity, and efficiency of our OSDPM strategy provide a valuable solution for HP/HS structural characterization.

DOI: https://doi.org/10.1021/acs.analchem.5c01615
Eur J Med Res. 2025 Jul 26. 30(1): 673

Gamma-tocopherol vitamin E enhances the cytotoxicity of p-cresyl sulfate to renal tubular cells.

Chyou-Wei Wei, Lin Jian, Shu-Cing Wu, Yi-Lin Chen, Ying-Ru Pan, Yi-Chung Chien, Jia-Yan Wu, Yung-Luen Yu, Giou-Teng Yiang.

   BACKGROUND: The protein-bound uremic toxins p-cresyl sulfate (PCS) and indoxyl sulfate (IS) are commonly found at elevated levels in patients with chronic kidney disease and can promote oxidative stress leading to the progression of renal disease. However, whether PCS or IS can directly cause renal-cell damage remains unknown. Vitamin E is comprised of eight major forms, one of which (gamma-tocopherol, γ-tocopherol) is commonly found in various cooking oils such as corn oil and soybean oil. Many studies have shown that γ-tocopherol has antioxidant effects although previous studies also indicated that it can induce cytotoxicity. The presence of γ-tocopherol in cooking oils raises the possibility that it may increase the cytotoxicity of protein-bound uremic toxins that can induce renal damage.
METHODS: We studied the cytotoxic effects of different uremic toxins on renal cells and further investigated whether combinations of uremic toxins and γ-tocopherol had synergistic or antagonistic effects.
RESULTS: Our result showed that γ-tocopherol is not cytotoxic to rat renal tubular epithelial NRK-52E cells, however, γ-tocopherol exerts cytotoxic effects on human renal tubular epithelial HK-2 cells through apoptotic death pathway. Moreover, γ-tocopherol can enhance the PCS-induced cytotoxic effects on NRK-52E and HK-2 cells.
CONCLUSION: In this study, our results constitute the first demonstration that γ-tocopherol may cause renal-cell damage and enhance PCS-induced toxicity to renal cells via the apoptotic cell-death pathway.

Keywords:  gamma-tocopherol; indoxyl sulfate; p-cresyl sulfate; renal tubular cells synergistic effects.

DOI:  https://doi.org/10.1186/s40001-025-02942-4
Methods Mol Biol. 2025 ;2961 77-86

Investigating Protein-Glycosaminoglycan Interactions Using Paramagnetic Glycosaminoglycan Oligosaccharides.

Eathen Ryan, Shundene Key, Hoa Nguyen, Xu Wang.

  Glycosaminoglycan (GAG) is a family of linear, sulfated polysaccharides ubiquitous to all mammals. GAG plays important roles in many biological processes, including cell differentiation, growth, and mobility. Much of GAG's activity is intimately linked to its interaction with proteins. As a powerful structural biology tool, solution NMR has played a crucial role in investigating protein-GAG interactions. One especially useful tool in solution NMR studies of protein-GAG interactions is the use of paramagnetically-labeled GAG oligosaccharides. Paramagnetism provides a sensitive and information-rich method to identify both the binding site as well as the binding orientations of GAG. In this chapter, we will detail the procedure for the purification of heparin oligosaccharides and their paramagnetic functionalization, as well as the subsequent nuclear magnetic resonance (NMR) experiments needed to quantify the paramagnetic effect of the GAG oligosaccharide on the target protein.

Keywords:  Glycosaminoglycan; Paramagnetically labeled GAG oligosaccharides; Protein-GAG interactions

DOI:  https://doi.org/10.1007/978-1-0716-4722-6_6
Int J Biol Macromol. 2025 Jul 28. pii: S0141-8130(25)06757-1. [Epub ahead of print] 146200

Structural characterization and biological functions of echinoderm polysaccharides: A review.

Yunhan Li, Chong Yu, Xinhong Wang, Man Zhang, Juan Zhang, Haifeng Wang.

  Echinoderm polysaccharides are integral to the biology of these organisms and have significant implications for ecological interactions and potential applications in science and medicine. Understanding their structure and function can provide insights into marine biology and contribute to the development of new biomaterials and therapeutic agents. Various echinoderm polysaccharides have been discovered, but the structure and functional rules of echinoderm polysaccharides have not been elucidated. This review focuses on the identified structures of polysaccharides reported in recent years, summarizing their structural patterns (including composition, nuclear magnetic resonance, infrared spectroscopy, etc.) This review summarizes several representative structures of polysaccharides from echinoderms (including fucan sulfate, fucosylated chondroitin sulfate and glucan) and their structure-activity relationships. Meanwhile, this review also focuses on the various biological functional activities of polysaccharides from echinoderms, including their anticoagulant, immune regulatory, anticancer and anti-tumor effects, improvement of glucose and lipid metabolism, and antioxidant effects. This review offers valuable reference for the development of these polysaccharides as functional ingredients in food biotechnology and as therapeutic agents in the pharmaceutical industry. Future research into the mechanisms underlying their bioactivity, as well as the factors affecting their efficacy, will further expand their potential applications.

Keywords:  Biological functions; Echinoderm polysaccharide; Mechanisms; Structural characterization

DOI:  https://doi.org/10.1016/j.ijbiomac.2025.146200
Tzu Chi Med J. 2025 Jul-Sep;37(3):37(3): 264-274

Gut-derived uremic toxins and cardiovascular health in chronic kidney disease.

Ming-Chun Chen, Chiu-Huang Kuo, Yu-Li Lin, Bang-Gee Hsu.

  Uremic toxins (UTs) are bioactive compounds that accumulate in chronic kidney disease (CKD) due to impaired renal clearance, exacerbating disease progression and cardiovascular (CV) complications. These toxins originate from endogenous metabolism, gut microbiota, and dietary intake and include protein-bound UTs such as p-cresyl sulfate, indoxyl sulfate, and indole acetic acid, as well as small, water-soluble toxins such as trimethylamine-N-oxide and phenylacetylglutamine. Their accumulation promotes oxidative stress, inflammation, and endothelial dysfunction, contributing to vascular damage and associated with CV risk. Current management strategies focus on dietary interventions, prebiotics, probiotics, oral sorbents, emerging pharmacological approaches, and advanced dialysis techniques, but clinical outcomes remain inconsistent. Recent trials have demonstrated the potential of agents such as sevelamer, high-amylose-resistant starch, and AST-120 to reduce UT levels and improve certain vascular markers. However, more robust, long-term studies are necessary to fully establish the therapeutic efficacy and optimize treatment strategies to mitigate the impact of gut-derived UTs on CKD and CV health.

Keywords:  Chronic kidney disease; Gut-derived uremic toxins; Indole acetic acid; Indoxyl sulfate; Phenylacetylglutamine; Trimethylamine-N-oxide; p-cresyl sulfate

DOI:  https://doi.org/10.4103/tcmj.tcmj_293_24
Acta Paediatr. 2025 Jul 28.

Predicted Adult Height Remained Normal in Children With Premature Adrenarche Despite Advanced Bone Age.

Eetu Kanniainen, Jarmo Jääskeläinen, Jani Liimatta.

   AIM: Aetiological factors affecting the phenotype of adrenarche are largely unknown. This study investigated the phenotypic variability of premature adrenarche.
METHODS: In this cross-sectional retrospective registry study, data on 91 mainly Caucasian children diagnosed with premature adrenarche were retrieved from patient records. Hormonal and growth-related variables were analysed, and the data were further divided into subgroups to explore variations in different phenotypes of premature adrenarche.
RESULTS: We studied 91 children with premature adrenarche (23% boys) with median ages of 7.5 years (range 4.5-8.9) for boys and 6.8 years (4.3-8.0) for girls. They displayed increased height and weight, elevated androgen levels, and clinical signs of androgen action. Bone age was advanced by approximately 1 year, with overweight children showing more advanced bone age and linear growth. Adult heights predicted with bone age were comparable to mean parental heights. Girls with more advanced bone age had higher dehydroepiandrosterone sulfate (DHEAS) levels. Interestingly, early (< 6 years) diagnosed children exhibited higher height standard deviation scores but lower DHEAS levels compared to those diagnosed later (≥ 6 years).
CONCLUSIONS: Despite advanced bone age, predicted adult heights remained normal in premature adrenarche. Subgroup differences suggested the heterogeneity of aetiological factors in premature adrenarche.

Keywords:  adrenal cortex; adrenarche; adult height; bone age; dehydroepiandrosterone sulfate

DOI:  https://doi.org/10.1111/apa.70252
Vet Anim Sci. 2025 Sep;29 100485

Bone development of broiler chickens supplemented with chondroitin sulfate and manganese.

Julian Andres Muñoz, Taiane da Silva Martins, Pollyana Leite Matioli Garbossa, Laura Barbosa Ferreira Pimentel, Caio Bertasi Barbalho, Monica Márcia da Silva, André Felipe de Arruda, Silvana Martinez Baraldi-Artoni, Cristiane Soares da Silva Araújo, Angélica Simone Cravo Pereira.

  Musculoskeletal disorders in broiler chickens are often related to immature connective tissue. This study aimed to evaluate the effects of dietary supplementation with chondroitin sulfate (CS) and manganese (Mn) on performance, bone quality, and the optimal CS:Mn ratio for skeletal development in broilers. A total of 1152 male Cobb chicks were reared for 47 days in a completely randomized 4 × 3 factorial design comprising four CS levels (0.00, 0.06, 0.12, and 0.18 % w/w) and three Mn levels (0, 40, and 80 mg/kg), resulting in 12 treatments with eight replicates of 12 birds each. Supplementation with CS and Mn did not affect (P > 0.10) feed intake, body weight, weight gain, bone mineral content, bone mineral density, phosphorus and manganese levels, ash content, absolute bone weight, or diaphyseal perimeter of the tibiotarsus. A significant interaction between CS and Mn levels was observed for feed conversion (FC), which increased linearly with Mn inclusion in diets lacking CS (P = 0.003). In diets without Mn, CS levels exhibited a quadratic effect on FC (P = 0.003). Flock viability and productive efficiency index increased linearly with increasing CS inclusion. A significant CS × Mn interaction was also observed for maximum bone breaking strength, with a linear decrease with increasing Mn in diets containing 0.12 % CS (P = 0.019). CS had a quadratic effect on the Seedor index, bone area, and morphometric traits of the proximal and distal tibiotarsus, with 0.06-0.12 % CS yielding optimal outcomes. Mn supplementation showed quadratic effects on bone area (P = 0.09) and calcium content (P = 0.005), with peak values at 40 mg Mn/kg. The results suggest that supplementation with CS and the inclusion of 40 mg Mn/kg in broiler diets could be used as a nutritional strategy to improve tibiotarsal bone quality, particularly morphometric attributes, calcium content, and breaking strength. Furthermore, CS supplementation may contribute to reducing mortality and improving productivity metrics in broilers.

Keywords:  Chondrocyte density; Glycosaminoglycans; Morphometric traits; Poultry; Tibiotarsus

DOI:  https://doi.org/10.1016/j.vas.2025.100485
Neuropharmacology. 2025 Jul 29. pii: S0028-3908(25)00326-0. [Epub ahead of print] 110618

Low-Molecular Weight Protamine Enhances Neuroprotection and Remyelination by Mitigating Chondroitin Sulfate Proteoglycan Inhibition in Models of Demyelination.

Tapani K Koppinen, Carolina R Reyes, Liam Beckett, Jinhan Nam, Tuomas A E Kallionpää, Saila Medina Leskinen, Nadine Huber, Annakaisa Haapasalo, Francisco J Rivera, Merja H Voutilainen, Heikki Rauvala.

Chondroitin sulfate proteoglycans (CSPGs) are inhibitory molecules deposited in the extracellular matrix of lesions in multiple sclerosis (MS). CSPGs maintain ongoing inflammatory processes and prevent oligodendrocyte progenitor cell (OPC) differentiation, resulting in impaired remyelination and chronic pathology in MS. Here, we profile low-molecular weight protamine (LMWP) as a small, positively charged peptide that binds to the negatively charged inhibitory sections of CSPGs. We show that LMWP overcomes CSPG inhibition of OPC differentiation and increases remyelination following toxin-based focal demyelination. Moreover, LMWP ameliorates disease progression in experimental autoimmune encephalomyelitis (EAE) model. LMWP is blood brain barrier-penetrant, and peripheral administration in EAE mice results in significantly lowered concentrations of serum neurofilament light-chain. Additionally, tissue analyses show increased myelin thickness and a reduction in axonal degeneration with LMWP treatment in EAE mice, supporting its role as a neuroprotective compound. Finally, LMWP reduces microgliosis and fibrosis in EAE, most likely, favoring tissue repair. Thus, LMWP supports remyelination as well as neuroprotection resulting in a promising strategy for the treatment of demyelinating disease, such as MS.

DOI: https://doi.org/10.1016/j.neuropharm.2025.110618
Am J Physiol Cell Physiol. 2025 Jul 31.

The sulfation pattern of glycosaminoglycans in human brain development and neurological disorders such as Alzheimer's disease.

Kazumi Hirano, Hideo Egawa, Shoko Nishihara.

  Glycosaminoglycans (GAGs) are modified by various sulfotransferases and endosulfatases. The resulting sulfation patterns are formed, influencing numerous functions. Sulfation leads to a strong negative charge on GAGs, inducing specific interactions with proteins such as signaling ligands and pathogenicity factors, impacting cellular functions and disease onset. While a long history of research has greatly advanced our understanding of GAGs and the sulfation patterns in model organisms, studies of human brain development and the pathogenesis of neurological diseases are in their infancy. To elucidate the role of the sulfation patterns in the human brain, it is necessary to determine the interplay of factors such as core proteins, GAG elongation enzymes and sulfotransferases in a hierarchical manner. In recent years, technological advances in, for example, genomic mutation analysis, single cell analysis, and in vitro brain development models, are beginning to inform our understanding of the role of the sulfation patterns in human brain development and neurological disorders such as Alzheimer's disease.

Keywords:  brain organoids; glycosaminoglycan; human brain; neurological disease; sulfation

DOI:  https://doi.org/10.1152/ajpcell.00842.2024
Cell Death Discov. 2025 Aug 01. 11(1): 362

Heparan sulfate binding protein treatment ameliorates neuropathology and behavioral abnormalities in mucopolysaccharidosis IIIB mice.

Serenella Anzilotti, Melania Scarcella, Mariangela Ciampa, Noemi Di Muraglia, Camilla Anastasio, Chiara Fiorentino, Federica Rossin, Luigi Avallone, Giuseppe Pignataro, Luigi Michele Pavone, Valeria De Pasquale.

Mucopolysaccharidosis IIIB (MPS IIIB) is a metabolic neurodegenerative disorder caused by a deficiency of the lysosomal enzyme α-N-acetylglucosaminidase (NAGLU), which is involved in the degradation of heparan sulfate (HS). Affected patients exhibit progressive neurodegeneration, behavioral disturbances, and a shortened lifespan. Currently, there is no effective treatment for MPS IIIB. We have recently developed a new therapeutic strategy based on the use of the HS-binding protein NK1, a spliced variant of hepatocyte growth factor. Here, we demonstrate that treating Naglu-/- mice with recombinant NK1 ameliorates neuropathology by reducing HS storage, lysosomal dysfunction, autophagy imbalance, and neuroinflammation in the cortex and hippocampus of MPS IIIB mouse brains. Furthermore, we found that recombinant NK1 treatment improves cognitive behavior and motor activity in Naglu-/- mice, as assessed using open field, object recognition, and T-maze tests. Our findings suggest that recombinant NK1 is a promising candidate for the treatment of MPS IIIB and other lysosomal storage diseases associated with central nervous system dysfunction.

DOI: https://doi.org/10.1038/s41420-025-02648-w
Biomolecules. 2025 Jul 17. pii: 1034. [Epub ahead of print]15(7):

Heparin, Heparin-like Molecules, and Heparin Mimetics in Breast Cancer: A Concise Review.

Diego R Gatica Portillo, Yishu Li, Navneet Goyal, Brian G Rowan, Rami A Al-Horani, Muralidharan Anbalagan.

  Heparin and heparan sulfate are essential in various biological processes relevant to cancer biology and pathology. Given the clinical importance of breast cancer, it is of high interest to seek more effective and safer treatment. The application of heparins (UFH, LMWH, ULMWH, fondaparinux) and heparin mimetics as potential treatments is particularly interesting. Their use led to promising results in various breast cancer models by exhibiting anti-angiogenic and anti-metastatic properties. This article concisely reviews studies involving heparins and mimetics in both in vitro and in vivo breast cancer settings. We highlight molecules, conjugates, delivery systems, and combinations involving heparin or its mimetics. We also survey several potential biological targets such as VEGF, FGF-2, TGFβ-1, PDGF-B, NPP-1, CXCL12-CXCR4 axis, and CCR7-CCL21 axis. Overall, heparins and their mimetics, conjugates, and combinations represent a powerful strategy to effectively and safely treat breast cancer, which is the most common cancer diagnosed in women worldwide and the fifth leading cause of cancer-related deaths worldwide.

Keywords:  LMWH; anti-angiogenic; anti-metastatic; breast cancer; heparin; heparin mimetics

DOI:  https://doi.org/10.3390/biom15071034
Nat Commun. 2025 Jul 27. 16(1): 6920

Late-stage O-sulfation with a bioinspired sulfuryl donor.

Ye Zheng, Li Huang, Chunlan Song, Jiakun Li.

O-sulfation is a widespread modification of both endogenous and exogenous biomolecules, where the primary objective is to identify effective sulfuryl donors. In nature, 3'-phosphoadenosine-5'-phosphosulfate (PAPS) and p-nitrophenyl sulfate (PNPS) are efficient sulfuryl donors. However, most chemical sulfuryl donors in O-sulfation, typically require harsh conditions and have not been demonstrated in complex molecules. Here we report a biomimetic O-sulfation method that is compatible with complex natural products and pharmaceutical scaffolds. Key to this approach is the use of tetrabutylammonium (nBu4N+) as a counterion for intrinsically anionic PNPS donor. The role of nBu4N+ goes far beyond simple charge balance; the coordination of nBu4N+ with sulfate in PNPS activates the sulfuryl donor by elongating the S-O bond and enhancing the leaving ability of nitrophenolate group. This unique activation model facilitates the transfer of sulfuryl group to diverse alcohols and phenols under simple and mild reaction conditions, thereby demonstrating its utility for site-selective O-sulfation with multiple hydroxyl groups.

DOI: https://doi.org/10.1038/s41467-025-62093-2
Int J Mol Sci. 2025 Jul 09. pii: 6587. [Epub ahead of print]26(14):

Peripheral Leukocyte Syndecan-3 Is Elevated in Alzheimer's Disease: Evidence from a Human Study.

Anett Hudák, Annamária Letoha, Tamás Letoha.

  Syndecan-3 (SDC3), a transmembrane heparan sulfate proteoglycan involved in cell signaling and endocytosis, has recently been implicated in the pathogenesis of neurodegenerative disorders. While preclinical studies have demonstrated its role in Alzheimer's disease (AD), its diagnostic relevance in peripheral blood remains unexplored. In this human cohort study, we measured SDC3 expression in peripheral blood mononuclear cells (PBMCs) from 22 clinically diagnosed AD patients and 20 cognitively unimpaired non-AD controls using a custom ELISA. The findings were compared with plasma p-tau217 levels and a panel of systemic laboratory markers. PBMC-expressed SDC3 was significantly elevated in AD patients and moderately correlated with AD status (r = 0.309, p = 0.0465) independent of age. Notably, SDC3 levels were inversely correlated with systemic inflammatory markers, including C-reactive protein (CRP; r = -0.421, p = 0.0055) and D-dimer (r = -0.343, p = 0.038), suggesting an AD-associated immune phenotype distinct from acute-phase or vascular inflammation. Conversely, plasma p-tau217 levels did not significantly differ between groups but correlated with markers of tissue injury and inflammation (LDH, GOT, and ferritin), potentially reflecting systemic influences in non-AD controls. A multivariable logistic regression model incorporating SDC3, p-tau217, and age demonstrated high diagnostic accuracy (AUC = 0.85). These findings identify PBMC-expressed SDC3 as a promising blood-based biomarker candidate for AD, warranting further validation in larger, biomarker-confirmed cohorts.

Keywords:  Alzheimer’s disease; biomarker; immune remodeling; neuroinflammation; p-tau217; peripheral blood mononuclear cells; syndecan-3

DOI:  https://doi.org/10.3390/ijms26146587
Sci Adv. 2025 Aug;11(31): eadv9311

A pan-respiratory virus attachment inhibitor with high potency in human airway models and in vivo.

Gregory Mathez, Paulo Jacob Silva, Vincent Carlen, Charlotte Deloizy, Clémentine Prompt, Anaïs Hubart, Joana Rocha-Pereira, Marie Galloux, Ronan Le Goffic, Francesco Stellacci, Valeria Cagno.

Respiratory viruses can cause severe infections, often leading to hospitalization or death, and pose a major pandemic threat. No broad-spectrum antiviral is currently available. However, most respiratory viruses use sialic acid or heparan sulfates as attachment receptors. Here, we report the identification of a pan-respiratory antiviral strategy based on mimicking both glycans. We synthesized a modified cyclodextrin that simultaneously mimics heparan sulfate and sialic acid. This compound demonstrated broad-spectrum antiviral activity against important human pathogens: parainfluenza virus 3, respiratory syncytial virus, influenza virus H1N1, and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). In addition, the compound is active against avian strains of influenza virus, revealing its importance for pandemic preparedness. The compound retains broad-spectrum activity in ex vivo models of respiratory tissues and in vivo against respiratory syncytial virus and influenza virus, using prophylactic and therapeutic strategies. These findings contribute to the development of future treatments and preventive measures for respiratory viral infections.

DOI: https://doi.org/10.1126/sciadv.adv9311
Food Sci Nutr. 2025 Aug;13(8): e70673

Expanding the pH-Shift Technique for Sequential Extraction of Intact Proteins and Sulfated Polysaccharide From Fish Heads: A Novel Biorefinery Approach.

Shahab Naghdi, Masoud Rezaei, Mehdi Tabarsa, Mehdi Abdollahi.

  The pH-shift technology was successfully expanded for the sequential recovery of proteins and sulfated polysaccharides (SPs) from rainbow trout heads. Adjusting the pH of the remaining process water after protein recovery at their isoelectric point to 8 enabled precipitation and recovery of SPs with the aid of ethanol at both alkaline and acid process versions and named SP-11.5 and SP-2.5, respectively. The mass yield of SPs recovered using the alkaline process version was 3.25%, nearly double that of SP (1.75%) from the acid version. SP-11.5 contained higher levels of carbohydrates (61.22%), proteins (13.29%), and sulfates (12.13%) compared to SP-2.5. FTIR, DSC, and XRD analyses showed no significant differences in the structural properties of the recovered SPs as a function of the pH-shift process version. However, SP-11.5 exhibited better antioxidant activity in DPPH, ABTS, and metal chelating tests and superior antibacterial properties against Listeria monocytogenes and Escherichia coli than SP-2.5. This study suggests that the pH-shift process can be effectively extended for sequential extraction of both protein isolates and SPs from fish by-products for a multiple product biorefinery where the alkaline version outperformed.

Keywords:  bioactive and functional properties; fish by‐products; pH shift; protein isolates; sequential extraction; sulfated polysaccharides

DOI:  https://doi.org/10.1002/fsn3.70673
Carbohydr Polym. 2025 Oct 15. pii: S0144-8617(25)00592-2. [Epub ahead of print]366 123809

Dopamine-functionalized chondroitin sulfate/gelatin-based composite hydrogels for enhancing wound healing and bone regeneration.

Jian Yang, Jiale Jin, Haojie Yu, Yun Wang, Li Wang, Xiaowei Liu, Dongyu Wang, Yudi Huang, Chenguang Ouyang, Yu Wang, Yichuan Hong, Shuning Ren, Jian Hu, Jingyi Feng.

  Severe trauma not only damages the skin, but also affects the bones, causing osteoarthritis or bone defects. Traditional treatment strategies (such as sutures, metal stents, etc.) have problems with the need for a second surgery and difficulty in degradation, which cannot meet the treatment expectations of clinical doctors well. As the novel biomedical material, hydrogels have great potential in the treatment of bone defects due to the advantages of seamless filling, degradability and easy operation. Here, we designed a composite hydrogel (Gel-Gym/HS-Dopa) composed of glycidyl methacrylate-modified gelatin (Gel-Gym) and dopamine-functionalized chondroitin sulfate (HS-Dopa). The hydrogel exhibited good tissue adhesion, self-healing, biodegradability, anti-inflammatory and biocompatibility. In animal experiments, Gel-Gym/HS-Dopa hydrogel could significantly promote the rat skin wound healing and bone defect reconstruction in vivo. Therefore, the hydrogel was promising as a potential deep trauma dressing.

Keywords:  Bone defect; Chondroitin sulfate; Dopamine; Gelatin; Wound dressing

DOI:  https://doi.org/10.1016/j.carbpol.2025.123809
Life (Basel). 2025 Jul 16. pii: 1116. [Epub ahead of print]15(7):

Serum p-Cresyl Sulfate Is Independently Associated with Aortic Stiffness in Non-Dialysis Chronic Kidney Disease Patients.

Yahn-Bor Chern, Ken Lee Chia, Chin-Hung Liu, Yu-Li Lin, Jen-Pi Tsai, Bang-Gee Hsu.

  p-Cresyl sulfate (PCS), a gut-derived uremic toxin with proinflammatory and cytotoxic effects, has been implicated in cardiovascular injuries among patients with chronic kidney disease (CKD). Aortic stiffness (AS), assessed by carotid-femoral pulse wave velocity (cfPWV), is a recognized predictor of cardiovascular risk. This study investigated the association between serum PCS levels and AS in patients with nondialysis-dependent CKD. In total, 165 patients with nondialysis-dependent CKD were enrolled. Clinical data and fasting blood samples were collected. Arterial stiffness (AS) was assessed bilaterally by measuring carotid-femoral pulse wave velocity (cfPWV) on both the left and right sides. A value above 10 m/s was considered indicative of increased stiffness. Serum PCS levels were quantified using high-performance liquid chromatography-mass spectrometry. Fifty patients (30.3%) had AS. The AS group was significantly older and had higher diabetes prevalence, systolic blood pressure, fasting glucose, urinary protein-creatinine ratio, and PCS levels than the control group. In the multivariate analysis, both PCS (odds ratio [OR]: 1.097; 95% confidence interval [CI]: 1.024-1.175; p = 0.008) and age (OR: 1.057; 95% CI: 1.025-1.090; p < 0.001) were independently associated with AS. In conclusion, elevated serum PCS and older age were independently associated with AS. Thus, PCS is a potential early marker of vascular damage in CKD.

Keywords:  aortic stiffness; biomarker; carotid–femoral pulse wave velocity; chronic kidney disease; p-Cresyl sulfate

DOI:  https://doi.org/10.3390/life15071116
J Alzheimers Dis Rep. 2025 Jan-Dec;9:9 25424823251362483

Higher p-Cresol sulfate and tumor necrosis factor (TNF)-α levels are associated with cognitive improvement through increased TNF receptor 2 in individuals with mild cognitive impairment: A cross-sectional mediation analysis.

Alzheimer’s Disease Neuroimaging Initiative

   Background: Neuroinflammation in neurocognitive disorders is driven by the release of tumor necrosis factor (TNF)-α from brain immune cells in response to injury, infection, or p-Cresol sulfate (p-CS)-a metabolite associated with chronic kidney disease and linked to TNF-α activity. However, the underlying mechanisms through which TNF-α and p-CS influence cognitive performance remain unclear.
Objective: This study investigated the impact of TNF-α and p-CS on cognition, focusing on the role of TNF Receptor 2 (TNFR2) in cognitively normal individuals (CN; n = 36), Alzheimer's disease patients (AD; n = 85), and those with mild cognitive impairment (MCI; n = 219).
Methods: Cognitive status was assessed with ADAS-Cog 13, p-CS measured via MxP® Quant 500, and TNF-α/TNFR2 quantified using Human DiscoveryMAP®. Mediation analysis explored TNFR2's role in linking p-CS, TNF-α, and cognition, with significance set at p < 0.05 and FDR controlled by the Benjamini-Hochberg method.
Results: The results showed that TNF-α levels were slightly higher in AD than in MCI, while TNFR2 levels were lowest in MCI, higher in CN, and highest in AD. After adjusting for age, gender, and APOE ɛ3/ɛ4 status, higher TNF-α levels were associated with higher TNFR2 levels in both MCI and AD. In MCI, elevated TNFR2 correlated with better cognitive function, indicating a possible neuroprotective role at this stage of cognitive decline. Further analysis revealed that both p-CS and TNF-α contributed to increased TNFR2 levels, which in turn supported cognitive performance.
Conclusions: In short, p-CS and TNF-α may improve cognitive performance via TNFR2 in individuals with MCI.

Keywords:  Alzheimer's disease; TNF receptor 2; cognitive performance; mild cognitive impairment; neuroinflammation; p-Cresyl sulfate; tumor necrosis factor-alpha

DOI:  https://doi.org/10.1177/25424823251362483