bims-supasi 2026-06-21 papers

bims-supasi

Biomed News

on Sulfation pathways and signalling

Issue of 2026–06–21
eleven papers selected by
Jonathan Wolf Mueller, University of Birmingham

Regio- and Stereoselective Synthesis of the Biotin-Conjugated Keratan Sulfate Hexa- and Octasaccharides [-3)βGal6S(1-4)βGlcNAc6S(1-]3and4 in the Repeating Disaccharide Region.
A rapid transfer of virions coated with heparan sulfate from the ECM to CD151 defines an early step in the human papillomavirus infection cascade.
Novel aptamers targeting heparan sulfate for delivery of RNA therapeutics in Alzheimer's disease.
Dextran sulfate restores endotoxin detectability in human serum.
Microbial modulation of proteoglycan and glycosaminoglycan biosynthesis in a three-dimensional corneal epithelium model.
Effects of Arylsulfatase B and Pembrolizumab in combination on progression of metastatic melanoma in the B16F10 syngeneic mouse model.
Androgen profiling in adolescent girls with polycystic ovary syndrome.
Wholly enzymatic programmable sulfation in nonanimal heparin synthesis.
Degraded sulfated galactan derived from Gracilaria fisheri induces immunogenic cell death in MDA‑MB‑231 cells.
Marine sulfated polysaccharides as biofunctional agents for enhancing hemocompatibility and endothelialization of tissue-engineered vascular grafts.
Cardiovascular-kidney-metabolic syndrome through the lens of gut‑derived uremic toxins.

J Org Chem. 2026 Jun 16.

Regio- and Stereoselective Synthesis of the Biotin-Conjugated Keratan Sulfate Hexa- and Octasaccharides [-3)βGal6S(1-4)βGlcNAc6S(1-]3and4 in the Repeating Disaccharide Region.

Jun-Ichi Tamura, Rei Hattori, Chiaki Iwama, Yuna Uemura, Toshifumi Mizuta, Mizuki Yokono, Naoko Takeda-Okuda.

Keratan sulfate (KS) is an acidic linear polysaccharide belonging to the glycosaminoglycan family. The repeating disaccharide unit of KS consists of the sequence -4)-βGlcNAc(1→3)-βGal(1→, with varying sulfation patterns at the primary hydroxy groups. L4 is a subclass of KS in which both primary hydroxy groups are sulfated. Herein, we report an efficient synthesis of KS L4 hexa- and octasaccharides as biotin conjugates through coupling reactions employing partially protected glycosyl acceptors.

DOI: https://doi.org/10.1021/acs.joc.6c00722
Elife. 2026 Jun 16. pii: RP107139. [Epub ahead of print]14

A rapid transfer of virions coated with heparan sulfate from the ECM to CD151 defines an early step in the human papillomavirus infection cascade.

Annika Massenberg, Yahya Homsi, Carl Niklas Schneider, Snježana Mikuličić, Tatjana Döring, Luise Florin, Thorsten Lang.

  Human Papillomaviruses (HPVs) are the underlying cause of several types of cancer; albeit, they are mostly known for their association with cervical carcinoma. The virions reach their target cells through a break in the epithelial barrier. After binding to heparan sulfate (HS) of the extracellular matrix (ECM), they are recruited via actin-dependent mechanisms to the cell surface, where they co-internalize with the entry factor CD151. The in vivo occurring active recruitment from the ECM to the cell surface may be bypassed in cell culture, where virions reach the cell surface simply by passive diffusion. To specifically investigate these early events of the infection cascade, we use HaCaT keratinocytes as they produce a robust ECM enabling abundant virion binding to ECM components such as HS before transfer to cell surface receptors and infection. Employing microscopy, we focus on the basal membrane that for virions is difficult to access by diffusion. We block the active recruitment from ECM attachment sites to the cell body, release the blocking, and monitor the association of virions with CD151 or HS. We observe quick virion recruitment from the ECM to the cell body within 15 min. During recruitment, virions associate with the tetraspanin CD151 present at the cell border or at filopodia. These virions are decorated with HS, which they lose in the next few hours, presumably prior to endocytosis. Our observations reveal a rapid step in the HPV infection cascade: the transfer of HS-coated virions from the ECM to CD151. This step is too fast to account for the asynchronous uptake of HPVs, which is likely driven by glycan and capsid processing.

Keywords:  filopodia; human; infectious disease; microbiology; primary attachment site; secondary receptor; tetraspanins; virus transport

DOI:  https://doi.org/10.7554/eLife.107139
Prog Biomed Eng (Bristol). 2026 Jun 17.

Novel aptamers targeting heparan sulfate for delivery of RNA therapeutics in Alzheimer's disease.

Arshad Mehmood, Amir Zaman Shah, Jesus Alejandro Martinez Juarez, Xiaohui Liu, Hui Jiang, Xuemei Wang.

  Heparan sulfate (HS) proteoglycans are abundant, sulfation-patterned glycosaminoglycans on brain cells and the neurovascular unit that interact with amyloid-β (Aβ) and tau, aggregate and propagate proteopathic species, and modulate cellular uptake pathways. Aptamers are short, chemically synthesized single-stranded nucleic acids that fold to form high-affinity ligands. Novel aptamers bind specific HS motifs for targeting ligands to deliver RNA therapeutics (siRNA, antisense oligonucleotides, mRNA, RNA aptamer-cargo hybrids) into the brain and diseased cells in Alzheimer's disease (AD). We cover diagnostic aptamers, SELEX approaches adapted for glycans and HS, chemistry, optimization (AI/machine-learning-enabled design), novel therapeutic applications, delivery vehicles and conjugation strategies, catalytic aptamers/ribozymes, and challenges for clinical translation. We propose a workflow-in-silico HS motif mapping and machine learning (ML)-guided sequence design through microfluidic/in-vivo SELEX, site-specific chemical modification for nuclease resistance and blood-brain barrier (BBB) transcytosis, to scalable GMP manufacture. Aptamer-HS technology could enable the precision delivery of RNA therapeutics in AD.

Keywords:  RNA therapeutics; SELEX; aptamer; heparan sulfate; machine learning

DOI:  https://doi.org/10.1088/2516-1091/ae7eb9
Anal Bioanal Chem. 2026 Jun 20.

Dextran sulfate restores endotoxin detectability in human serum.

Claudia Schildböck, Denisa Cont, Jens Hartmann, Stephan Harm.

  Accurate quantification of endotoxins in human serum is essential for both clinical diagnostics and biomedical research but is frequently compromised by low endotoxin recovery (LER) in Limulus amebocyte lysate (LAL) assays. Here, we systematically evaluated natural and synthetic polyanions as additives to neutralize HDPs and restore LAL-detectable endotoxin activity in human serum. Dextran sulfate, polyacrylic acid, fondaparinux, enoxaparin, and chondroitin sulfate were screened using complementary bacterial growth assays and kinetic chromogenic LAL measurements. Among all tested compounds, dextran sulfate (DS40) showed the highest efficacy in neutralizing serum-derived HDPs. At an optimized concentration of 0.06 mg/mL, DS40 consistently restored endotoxin recovery within pharmacopeial acceptance criteria (50-200%) for purified and naturally occurring endotoxins derived from Escherichia coli, Klebsiella pneumoniae, and Pseudomonas aeruginosa. Performance was comparable to unfractionated heparin, a previously established HDP-neutralizing additive. Importantly, DS40 did not interfere with assay linearity or sensitivity and fully complied with European Pharmacopoeia requirements for the absence of interfering factors. Compared to heparin, DS40 offers superior batch-to-batch consistency, lower cost, improved sustainability, and eliminates the use of animal-derived components. These findings establish DS40 as a robust, chemically defined additive for overcoming LER and enabling reliable endotoxin quantification in human serum, thereby improving the analytical performance of LAL-based assays.

Keywords:  Dextran sulfate; Endotoxemia; Endotoxin neutralization; Host defense peptides; Limulus amebocyte lysate; Polyanions

DOI:  https://doi.org/10.1007/s00216-026-06624-w
Front Cell Infect Microbiol. 2026 ;16 1804227

Microbial modulation of proteoglycan and glycosaminoglycan biosynthesis in a three-dimensional corneal epithelium model.

Noelia Blanco-Agudín, Francisco Pérez-Rastrollo, Natalia Vázquez, Suhui Ye, Cristina Sánchez-Fernández, María Daniela Corte-Torres, Jesús Merayo-Lloves, Iván Fernández-Vega, Luis M Quirós.

   Background: Recently, a three-dimensional in vitro corneal epithelium model, designated QobuR, was developed. This model aims to reproduce the complex cellular interactions observed in vivo and to provide an alternative to animal models for toxicity testing and ophthalmic drug development. However, the corneal epithelium, like other exposed epithelia, is continuously exposed to microorganisms present on the ocular surface, although the existence and extent of a stable corneal microbiota remain areas of ongoing investigation. Nonetheless, microbial exposure may exert a significant influence on its physiology. During microbial interaction with epithelial surfaces, cell-surface proteoglycans and glycosaminoglycans act as key mediators, and this interaction can induce changes in their biosynthesis and structure. As these molecules function as specific receptors for numerous ligands and regulate essential cellular processes, their interaction with the microbiota may contribute to the maintenance of tissue homeostasis.
Methods: In this study, we analyzed the transcriptional profiles of genes involved in PG and GAG biosynthesis in the QobuR model following controlled co-culture with individual bacterial species and with a mixed microbial consortium designed to represent the ocular surface microbiota. Expression changes were assessed by qRT-PCR and complemented by immunohistochemical analysis.
Results: Distinct bacterial species induced specific patterns of gene expression, predominantly affecting enzymes involved in late-stage sulfation of heparan sulfate and chondroitin sulfate chains. Exposure to the microbial consortium resulted in broader and more complex transcriptional modulation, incorporating most changes observed in individual conditions while introducing additional alterations. Notably, the transcriptional profile of microbiota-exposed QobuR showed increased similarity to donor-derived corneal epithelium. These observations were supported by immunohistochemical analyses.
Conclusions: These findings demonstrate that corneal epithelial cells exhibit dynamic transcriptional responses to microbial exposure under controlled in vitro conditions. The results highlight the relevance of incorporating host-microbe interaction components into three-dimensional epithelial models, while also emphasizing that the interpretation of these responses should consider the experimental framework and the current uncertainties regarding the composition and the functional role of the ocular surface microbiota.

Keywords:  chondroitin sulfate; corneal epithelium; glycosaminoglycans; heparan sulfate; host–microbe interaction; ocular surface; proteoglycans; three-dimensional cell culture

DOI:  https://doi.org/10.3389/fcimb.2026.1804227
Front Oncol. 2026 ;16 1820206

Effects of Arylsulfatase B and Pembrolizumab in combination on progression of metastatic melanoma in the B16F10 syngeneic mouse model.

Sumit Bhattacharyya, Insug O-Sullivan, Joanne K Tobacman.

  In this report, experiments assessed how Arylsulfatase B (ARSB; N-acetylgalactosamine-4-sulfatase) treatment might interact with Pembrolizumab and improve therapeutic responses in melanoma. ARSB acts to remove 4-sulfate groups from chondroitin 4-sulfate (C4S; chondroitin sulfate A; CSA). ARSB is required for the degradation of C4S, identified as an oncofetal, tumor-agnostic antigen. Previous reports showed that in syngeneic B16F10 mouse melanomas, ARSB inhibited progression of subcutaneous and metastatic pulmonary melanomas and improved survival by direct effects on melanoma cells. ARSB enhanced apoptosis, which was mediated by increased expression of Constitutive Photomorphogenic (COP)1, an E3 ubiquitin ligase. Combined treatment by recombinant human ARSB, directed at melanoma cells, and Pembrolizumab, directed at infiltrating cytotoxic lymphocytes, can lead to increased apoptosis by different mechanisms, to declines in metalloproteinases and invasiveness, and to altered expression of cytokines. The apparent synergism between effects of ARSB and Pembrolizumab may further inhibit the progression of melanoma and improve treatment outcomes.

Keywords:  Arylsulfatase B; apoptosis; checkpoint inhibition; chondroitin 4-sulfate; invasiveness; melanoma

DOI:  https://doi.org/10.3389/fonc.2026.1820206
Front Endocrinol (Lausanne). 2026 ;17 1817505

Androgen profiling in adolescent girls with polycystic ovary syndrome.

Xuan Zhang, Yanan Zhang, Hemeng Chong, Yutong Xing, Xuehan Gao, Yueqiu Qin, Xujing Kong, Susu Cai, Baorong Chen, Xue Yan, Huifeng Zhang.

   Objective: To characterize global steroid hormone dysregulation and the androgen profile in adolescent girls with polycystic ovary syndrome (PCOS), and to explore adrenal versus ovarian androgen origins using a dexamethasone suppression test combined with liquid chromatography-tandem mass spectrometry (LC-MS/MS).
Methods: We consecutively enrolled 37 adolescent PCOS patients and 22 age-matched healthy controls. PCOS diagnosis followed the 2023 international evidence-based recommendations. All participants underwent clinical evaluation and LC-MS/MS steroid profiling; 24 PCOS patients also received a dexamethasone suppression test.
Results: Compared with healthy controls, the PCOS group had elevated levels of multiple androgens, including dehydroepiandrosterone (DHEA), dehydroepiandrosterone sulfate (DHEA-S), androstenedione (AD), total testosterone (TT), androsterone (ADT), dihydrotestosterone (DHT), 11β-hydroxyandrostenedione (11-OHAD), 11β-hydroxytestosterone (11-OHT), and epitestosterone (EpiT), as well as estrone, pregnenolone, and 17-hydroxyprogesterone, along with decreased sex hormone-binding globulin (SHBG). Spearman correlation showed that DHEA-S explained only limited variation in 11-OHAD (rs = 0.629, P < 0.001). ROC analysis identified the free androgen index (FAI) as the best diagnostic marker (AUC = 0.976, sensitivity 91.7%, specificity 87.0% at cutoff 4.27). FAI alone was elevated in 86.5% of PCOS patients; adding total testosterone and androstenedione increased detection to 97.3%. In the dexamethasone suppression test, DHEA, DHEA-S, and 11-oxygenated androgens were markedly suppressed (median inhibition 81.9%-92.2%), whereas testosterone suppression was minimal (14.0%, P = 0.522). Notably, baseline DHEA-S was not elevated in most patients with significant androgen suppression, indicating discordance between suppression-test-defined adrenal dominance and traditional DHEA-S criteria.
Conclusion: Adolescent girls with PCOS exhibit widespread androgen abnormalities. FAI demonstrates the highest diagnostic value, and the addition of total testosterone and androstenedione modestly improves detection. The dexamethasone suppression test suggests that most 11-oxygenated androgens are of adrenal origin, whereas testosterone suppression is minimal. Elevated DHEA-S levels are not consistently aligned with adrenal-origin androgen dominance defined by the suppression test. These findings warrant further validation in larger populations.

Keywords:  adrenal glands; androgens; dexamethasone suppression test; liquid chromatography–mass spectrometry; ovary

DOI:  https://doi.org/10.3389/fendo.2026.1817505
Trends Biotechnol. 2026 Jun 17. pii: S0167-7799(26)00184-8. [Epub ahead of print]

Wholly enzymatic programmable sulfation in nonanimal heparin synthesis.

Yi Li, Jian-Qun Deng, An-Qi Wang, Si-Yu Xin, Li-Li Sheng, Yu-Han Zhao, Xin-Yu Li, Chao-Yue Li, Feng-Shan Wang, Hua-Rong Shao, Ju-Zheng Sheng.

  Heparin is a critically important clinical anticoagulant. The biosynthesis of heparin using Escherichia coli-based multienzyme cascades represents a promising alternative to animal-derived production. However, efficient deployment of heparin-synthesizing enzymes faces significant challenges, particularly in achieving recombinant expression of functionally active heparin N-deacetylase/N-sulfotransferase (NDST) enzymes in bacterial systems. In this article, we implement a strategy termed model animal-guided sequence-structure-activity to discover functional NDST orthologs compatible with prokaryotic expression. Coupled with computationally assisted focused rational iterative site-specific mutagenesis, we engineered the high-performance variant NDST-M8, which exhibited a 10.65-fold increase in activity and a 3.84-fold improvement in stability relative to the truncated variant AgNDST-M0. This methodology enabled an E. coli multienzyme cascade that synthesizes bioactive heparin from heparosan backbones, with tunable N-sulfation levels (30-90%) that precisely modulate anticoagulant activity. Our work resolves critical bottlenecks in enzymatic heparin production, establishing a scalable, nonanimal platform for the industrial manufacturing of activity-graded heparin therapeutics.

Keywords:  anticoagulant polysaccharides; biocatalysis; heparin; programmable sulfation; protein engineering

DOI:  https://doi.org/10.1016/j.tibtech.2026.04.028
Mol Med Rep. 2026 Aug;pii: 231. [Epub ahead of print]34(2):

Degraded sulfated galactan derived from Gracilaria fisheri induces immunogenic cell death in MDA‑MB‑231 cells.

Tawut Rudtanatip, Yada Polsan, Waraporn Sakaew, Somsuda Somintara, Jenjiralai Phanphak, Jamal El-Abid, Kanokpan Wongprasert, Choowadee Pariwatthanakun.

  Sulfated galactan (SG) isolated from Gracilaria fisheri has demonstrated promise for cancer therapy and prevention through inhibition of cancer cell proliferation and migration. However, its structure‑activity relationship remains to be elucidated. The present study evaluated the microstructural characteristics and anticancer activity, particularly immunogenic cell death (ICD)‑inducing potential, of SG and its degraded derivative (DSG) in triple‑negative breast cancer cells. SG and DSG were prepared and structurally characterized using gel permeation chromatography, nuclear magnetic resonance, Fourier‑transform infrared and scanning electron microscopy coupled with energy‑dispersive X‑ray spectroscopy. ICD induction was assessed in human MDA‑MB‑231 breast cancer cells using an MTT assay, phase‑contrast microscopy, Hoechst/propidium iodide dual staining, intracellular reactive oxygen species (ROS) generation assay, and transmission electron microscopy (TEM). In addition, western blot analysis, immunofluorescence staining, and reverse transcription‑quantitative PCR were performed. Structural analyses revealed that SG and DSG share similar backbone structures but differ markedly in sulfate content and molecular weight. Both compounds were non‑toxic to normal breast epithelial MCF‑10A cells and exhibited mild cytotoxicity toward MDA‑MB‑231 cells. DSG treatment induced notable morphological changes in cancer cells, with reduced cell numbers, increased membrane permeability and elevated intracellular ROS levels. TEM revealed DSG‑induced ultrastructural changes consistent with cellular stress and cytotoxicity. DSG also markedly upregulated ICD‑associated proteins [calreticulin (CRT) and Fas receptor (Fas‑R)] and endoplasmic reticulum stress‑related genes (protein kinase RNA‑like endoplasmic reticulum kinase, inositol‑requiring enzyme 1, activating transcription factor (ATF)6, ATF4, eukaryotic initiation factor 2 α subunit, CRT and Fas‑R), with effects similar to the positive control doxorubicin. Therefore, these findings indicated that DSG enhances ICD in triple‑negative breast cancer cells and may potentially serve as a promising ICD‑inducing adjuvant for cancer immunotherapy.

Keywords:  Gracilaria fisheri; degraded sulfated galactan; immunogenic cell death; triple‑negative breast cancer

DOI:  https://doi.org/10.3892/mmr.2026.13941
Mater Horiz. 2026 Jun 10.

Marine sulfated polysaccharides as biofunctional agents for enhancing hemocompatibility and endothelialization of tissue-engineered vascular grafts.

Gabriele Obino, Antonio J Lepedda, Lorenzo Moroni.

Small-diameter vascular grafts (≤6 mm) continue to face high failure rates due to thrombosis, intimal hyperplasia, and inadequate endothelialization. While bioresorbable and hybrid materials offer promising alternatives to conventional prostheses, challenges in hemocompatibility and host integration remain. Marine sulfated polysaccharides (MSPs)-including fucoidans, carrageenans, and fucosylated chondroitin sulfates-have emerged as biofunctional agents capable of modulating coagulation, inflammation, and vascular cell behavior. These structurally diverse, highly sulfated glycans mimic features of the native endothelial glycocalyx, enabling interactions with coagulation factors and promoting endothelial regeneration. This review brings together current insights into MSPs structure-function relationships, anticoagulant mechanisms, and endothelial support, and discusses how these features can be strategically harnessed for vascular graft design and clinical translation. We examine recent strategies for MSPs functionalization of electrospun and 3D-printed scaffolds and evaluate emerging evidence from in vitro and in vivo studies. Finally, we explore current challenges and future directions for the clinical application of MSP-functionalized vascular biomaterials. Collectively, these insights position marine sulfated polysaccharides as a versatile and underexplored class of biomolecules with the potential to address long-standing barriers in vascular tissue engineering.

DOI: https://doi.org/10.1039/d6mh00404k
Gut Microbes. 2026 Dec 31. 18(1): 2685906

Cardiovascular-kidney-metabolic syndrome through the lens of gut‑derived uremic toxins.

Chudan Xu, Matthew Snelson, Francine Z Marques.

  Cardiovascular-Kidney-Metabolic (CKM) syndrome represents a complex, interconnected cluster of cardiovascular disease, chronic kidney disease, and metabolic disorders such as obesity and type 2 diabetes. These conditions share overlapping metabolic, inflammatory, and vascular pathways, with the gut microbiome increasingly recognised as a key contributor and common underlying risk factor. Uremic toxins, traditionally considered waste products of host and microbial metabolism, are now recognised as active mediators of tissue damage across the CKM spectrum, particularly in the context of impaired renal function. Their production and accumulation are amplified by disrupted intestinal barrier integrity, chronic inflammation, and reduced renal clearance, collectively driving systemic toxicity throughout the CKM continuum. This review explores the origins and impact of gut-derived uremic toxins, including trimethylamine-N-oxide (TMAO), indoxyl sulfate (IS), p-cresol sulfate (PCS) and its associated metabolites, p-cresol and p-cresol glucuronide (PCG), phenylacetylglutamine (PAGln), and imidazole propionate (ImP) within the context of CKM syndrome. These toxins originate from an imbalanced gut microbiome, often shaped by poor diets, such as low-fibre and high-meat intake. We discuss their production by the microbiome and their roles from cardiovascular, renal, and metabolic perspectives and highlight emerging microbiome-targeted strategies to mitigate their pathogenic effects.

Keywords:  Gut microbiome; cardiovascular-kidney-metabolic syndrome; microbiome-targeted therapy; uremic toxins

DOI:  https://doi.org/10.1080/19490976.2026.2685906