bims-supasi 2026-09-13 papers

bims-supasi

Biomed News

on Sulfation pathways and signalling

Issue of 2026–09–13
fifteen papers selected by
Jonathan Wolf Mueller, University of Birmingham

R17 Drives Heparan Sulfate Clearance via Endolysosomal Trafficking.
Chondroitin sulfate and collagen peptides co-derived from sturgeon cartilage: Characterization and combined effects on IL-1β-induced chondrocyte inflammation in vitro.
Sulfated polysaccharides and their utilization mechanisms by microorganisms: A review.
Endothelial glycocalyx glycan expression in lymphatic vasculature in mice.
Chondroitin sulfate modulates gut microbiota to improve bone metabolism and reduce locomotion problems in yellow-feathered broilers.
EFN-4/Ephrin converges with SAX-3/Robo, UNC-6/Netrin, and Heparan Sulfate Proteoglycan signaling to control MAB-5/Hox-dependent posterior Q neuroblast migration in Caenorhabditis elegans.
Characterization and Immunomodulatory Activity of a Sulfated Polysaccharide from Natto-Derived Bacillus subtilis.
A Simplified and Robust LC-MS/MS Method for Simultaneous Quantification of Six Steroid Hormones Associated With Polyendocrine Metabolic Ovarian Syndrome.
Priming Cells with Modulators of Cellular Signaling Ensures Enhanced Selectivity of HSPG-Specific Protein-Drug Conjugate Delivery.
Self-assembly non-covalent binding mechanism of lycopene-protein-chondroitin sulfate ternary nanoparticles: Multidimensional characterization and molecular dynamics simulation.
Exploring the impact of syndecans in prostate cancer: Stage-specific roles and therapeutic implications.
Sulfated Polysaccharides in Wound Healing: From Bioactive Materials Design to Regenerative Therapeutics.
Glypican-1 in Rhabdomyosarcoma: A Multi-omics Exploration of a Targetable Biomarker.
Uremic toxin-induced pathological signaling in sinus node cells is attenuated by probenecid.
Vitamin D alleviates indoxyl sulfate-induced inflammatory and cholesterol dysregulation in macrophages: Implications for vascular health in patients receiving hemodialysis.

Isr J Chem. 2026 Jul;66(4): e70016

R17 Drives Heparan Sulfate Clearance via Endolysosomal Trafficking.

Pranali Bedekar, Alexander Lin, Abigail E Reeves, Meg Critcher, Gil-Suk Yang, Sean Hui, Daved H Fremont, Mia L Huang.

  Heparan sulfate (HS) proteoglycans are information-rich macromolecules that can orchestrate extracellular signaling and cargo uptake across diverse cellular contexts. Ligands that can engage cell surface HS possess significant potential as probes to investigate or manipulate cell-matrix interactions. Here, we show that R17, an HS-binding protein from the rodent herpesvirus Peru, actively remodels the glycocalyx of pancreatic cancer cells. Recombinant R17 bound heparin in vitro and associated with the surface of pancreatic cancer cells to promote the dose-dependent clearance of HS via trafficking to lysosomes. R17 also reduced wound closure without detectable cytotoxicity, indicative of the ability of R17 to suppress cellular migration. Notably, HS depletion persisted upon cation-independent mannose-6-phosphate receptor knockdown, suggesting that clearance is independent of this mechanism. These findings identify R17 as an exogenous HS-binding protein that can drive HS clearance via endolysosomal trafficking and suggest an alternative approach to modulate HS-dependent functions.

Keywords:  endocytosis; endolysosomal trafficking; glycosaminoglycans; heparan sulfate; heparan sulfate proteoglycans; lysosome; pancreatic cancer

DOI:  https://doi.org/10.1002/ijch.70016
Int J Biol Macromol. 2026 Sep 06. pii: S0141-8130(26)04115-2. [Epub ahead of print]382(Pt 1): 154169

Chondroitin sulfate and collagen peptides co-derived from sturgeon cartilage: Characterization and combined effects on IL-1β-induced chondrocyte inflammation in vitro.

Cheng Ji, Chunyu Niu, Qi Liu, Yan Chen, Qi Zeng, Yin Chen.

  Osteoarthritis (OA) is a major joint disorder characterized by cartilage matrix degradation and inflammatory responses. Chondroitin sulfate and collagen peptides are major components of cartilage extracellular matrix and have potential relevance to OA-related inflammation. Sturgeon cartilage, a major processing by-product, is an underutilized source of these bioactive fractions. However, their extraction, characterization, and combined effects on chondrocyte inflammatory responses remain insufficiently studied. In this study, chondroitin sulfate and collagen peptides were separately extracted from sturgeon cartilage. Chondroitin sulfate fraction 1 (CS-1) was obtained by ion-exchange chromatography, whereas collagen peptide fraction 3 (CP-F3) was prepared by enzymatic hydrolysis, ultrafiltration, and gel filtration chromatography. CS-1 was predominantly chondroitin 4-sulfate, with a weight-average molecular weight of approximately 3.0 × 105 Da. CP-F3 was a low-molecular-weight collagen peptide fraction enriched in peptide-related ions below m/z 500. In an IL-1β-induced inflammatory model in SW1353 chondrocyte-like cells, combined treatment with CS-1 and CP-F3 increased proteoglycan and type II collagen retention, reduced NO, iNOS, COX-2, PGE2, and IL-6 levels, and restored the MMP-3/MMP-13/TIMP-1 balance. These effects may be associated with modulation of the TLR4/MyD88/NF-κB signaling pathway. Overall, these findings provide preliminary in vitro evidence that CS-1 and CP-F3, particularly in combination, may attenuate inflammatory and matrix-degrading responses. Further in vivo and mechanistic studies are required to clarify their relevance to cartilage protection.

Keywords:  Chondroitin sulfate; Collagen peptides; Osteoarthritis

DOI:  https://doi.org/10.1016/j.ijbiomac.2026.154169
Int J Biol Macromol. 2026 Sep 10. pii: S0141-8130(26)04377-1. [Epub ahead of print] 154431

Sulfated polysaccharides and their utilization mechanisms by microorganisms: A review.

Wanshuang Li, Xiaolin Chen, Cong Lin, Ronge Xing, Song Liu, Huahua Yu.

  Sulfated polysaccharides (SPS) are a class of biomacromolecules bearing a large negative charge; due to their structural complexity and diverse biological activities, they had become a hot topic in glycoscience research. This paper focused on recent advances in the study of SPS, systematically discussing both natural and synthetic sources. It explored the structural composition of four typical SPS namely heparin, chondroitin sulfate, fucoidan, and fondaparinux sodium, as well as their biological activities, including antiviral, antioxidant, antitumor, anticoagulant, and immunomodulatory effects. Subsequently, the paper analyzed the degradation mechanisms of these polysaccharides by various types of microorganisms, particularly gut microbiota, with a particular emphasis on the degradation of SPS by the Bacteroidetes phylum (Sus-like system), Lactic acid bacteria (LAB), and Micrococcus, then compared their degradation strategies. The roles of various active enzymes in the degradation process were analyzed, and the role of SPS synthesized by microorganisms themselves in their survival and development was discussed. The unique structure of SPS and their corresponding biological activities gave them enormous application potential in fields such as synthetic biology, metabolic engineering, and healthcare.

Keywords:  Carbohydrate-active enzymes; Gut microbiota; Polysaccharide utilization loci; Sulfate esterases; Sulfated polysaccharides

DOI:  https://doi.org/10.1016/j.ijbiomac.2026.154431
Front Cell Dev Biol. 2026 ;14 1910204

Endothelial glycocalyx glycan expression in lymphatic vasculature in mice.

Issahy Cano, Esak Lee.

  Lymphatic vessels are crucial for the drainage and transport of interstitial fluids, cells, and macromolecules. Like all other cells, lymphatic endothelial cells express a cell-surface glycocalyx, composed of carbohydrate-enriched molecules, that contributes to endothelial barrier maintenance and cell-cell communication. Although the endothelial glycocalyx has been increasingly studied in blood endothelium, little has been done to characterize it in lymphatics. In this study, among a variety of tested fixatives, Carnoy's fixative, a solution of ethanol, chloroform, and acetic acid, was determined to best preserve endothelial glycocalyx epitopes in lymphatics-on-chip microfluidic devices and mouse tissue sections. Dermal, lung, and lymph node tissues were isolated from male C57BL/6J mice and fixed with Carnoy's fixative. We aimed to determine the presence of prominent glycocalyx components, including heparan sulfate and chondroitin sulfate, across different mouse organs to characterize organ-specific differences. We hypothesized that, due to the different organ environment demands for fluid clearance and immune surveillance, the expression of major glycocalyx components would be heterogeneous. However, immunofluorescence imaging of these tissues demonstrated the presence of these glycans within LYVE-1-positive structures across the tested tissues. This conclusion provides a basis for further characterization and understanding of the composition, function, and potential alterations of the lymphatic endothelial glycocalyx across very distinct organs/tissues and conditions.

Keywords:  LYVE-1; carnoy’s fixative; chondroitin sulfate; heparan sulfate; initial lymphatics; lymphatic glycocalyx; lymphatic vessel-on-chip; microfluidic device

DOI:  https://doi.org/10.3389/fcell.2026.1910204
Anim Nutr. 2026 Dec;27 92-113

Chondroitin sulfate modulates gut microbiota to improve bone metabolism and reduce locomotion problems in yellow-feathered broilers.

Yuyang Xue, Min Yao, Xiangjian Peng, Fang Wang, Shanshan Nan, Wei Jing, Fei Zhang, Xueqiang Liu, Zhonglin Liu, Cunxi Nie, Wenju Zhang.

  Chondroitin sulfate (CS) is known to promote bone health, but its effects on skeletal development and gut microbiota in yellow-feathered broilers remain largely unexplored. This study aimed to evaluate the effects of CS on bone health, growth performance, and intestinal flora in broilers. A total of 720 one-d-old Jinling yellow-feathered broilers (initial body weight 37.0 ± 0.5 g) were randomly divided into four treatment groups, each with nine replicates of 20 birds. The control group was fed a basal diet (CON), while the experimental group was supplemented with low (LCS), medium (MCS), or high CS (HCS) levels (0.05%, 0.15%, or 0.30%) for 30 d. Samples were collected every 10 d during a supplementation period of 30 d and again at 63 d to investigate the effect of early supplementation of CS on bone development later in life. Chondroitin sulfate supplementation improved broiler growth performance only at the beginning of the study. Compared with the CON group, the MCS group significantly increased tibial weight and length, and improved mid-segment geometric parameters, including vertical wall thickness (WTv), cross-sectional moment of inertia (CSMI), and cross-sectional area (CSA) (P < 0.05). The MCS group optimized bone trabecular structure, increased bone volume/tissue volume (BV/TV) and trabeculae thickness (Tb.Th) (P < 0.05); promoted new bone formation, and enhanced bone Ca and P deposition, compared with the CON. Chondroitin sulphate supplementation significantly decreased serum bone resorption markers tartrate resistant acid phosphatase (TRAP), elevated bone formation markers bone specific alkaline phosphatase (BALP) at 30 d, and down-regulated the expression levels of bone resorption-related genes (TRAP and RANKL) (P < 0.05). Compared with the CON group, the MCS group significantly increased the abundance of p_Bacillota_A_368345, Faecalibacterium, and Brotaphodocola (P < 0.05); and decreased the abundance of harmful bacterial genera. Functional prediction showed that the MCS group down-regulated some pro-inflammatory and tricarboxylic acid (TCA) cycle-related pathways and up-regulated carbohydrate degradation pathways (P < 0.05), compared with the CON group. In conclusion, CS supplementation improved bone quality, and altered the composition of intestinal flora during broiler growth.

Keywords:  Bone development; Bone health; Broiler; Chondroitin sulphate; Gut microbiology

DOI:  https://doi.org/10.1016/j.aninu.2026.03.008
PLoS Genet. 2026 Sep 08. 22(9): e1012303

EFN-4/Ephrin converges with SAX-3/Robo, UNC-6/Netrin, and Heparan Sulfate Proteoglycan signaling to control MAB-5/Hox-dependent posterior Q neuroblast migration in Caenorhabditis elegans.

Vedant D Jain, Andrew M Johannesen, Felipe L Teixeira, Erik A Lundquist.

Hox genes have been broadly implicated in nervous system development, but the molecular and genetic mechanisms that act downstream of Hox factors remain to be identified. The MAB-5 antennapedia-like Hox transcription factor is both necessary and sufficient to cause posterior migration of the Q neuroblast descendants in Caenorhabditis elegans. In response to MAB-5, the left-side QL descendants QL.a and QL.ap undergo a three-stage migration process, with each stage characterized by a posterior lamellipodial protrusion followed by cell body migration. The QL.ap cell differentiates into the PQR neuron posterior to the anus. Previous studies showed that the MAB-5-regulated gene efn-4/Ephrin was required for the third and final stage of QL.ap migration, with efn-4 mutation resulting in placement of PQR immediately anterior to the anus. This subtle and previously-undescribed phenotype opens the possibility that other known neuronal development genes could be involved. In this work, we screened known signaling mutants for third-stage PQR migration defects. We found that mutations in SAX-3/Robo signaling, UNC-6/Netrin signaling, and heparan sulfate proteoglycans (HSPGs) all displayed third-stage PQR migration defects. The effects in single mutants were weak compared to efn-4, and double mutant analysis revealed lack of genetic synergy, consistent with all of these molecules converging on a common pathway. This genetic analysis is consistent with physical interaction studies in vitro from another group that suggest that these molecules form connected communities of interacting extracellular domains, raising the possibility that they are all components of a large extracellular signaling complex required for posterior QL.ap migration. In this model, we envision that MAB-5/Hox drives EFN-4/Ephrin expression in QL.ap, which then seeds the formation of an extracellular signaling complex containing SAX-3/Robo signaling, UNC-6/Netrin signaling, and HSPGs that drives posterior lamellipodial formation and posterior migration.

DOI: https://doi.org/10.1371/journal.pgen.1012303
Appl Biochem Biotechnol. 2026 Sep 08.

Characterization and Immunomodulatory Activity of a Sulfated Polysaccharide from Natto-Derived Bacillus subtilis.

Aitian Tian, Hongliang Gao, Yanfang Sun, Jingyu Zhang, Shuchang Wang, Yanning Niu, Chunjing Zou, Caifeng Jia, Zhongyi Chang, Jing Huang, Deming Jiang.

  Sulfated polysaccharides with significant biological activities were widely applied in functional food, cosmetic, biomedical and pharmaceutical industries. In this study, we established a practical high-throughput screening workflow for sulfated polysaccharide-producing bacteria and applied it to natto-derived isolates. Using this approach, a sulfated polysaccharide produced by Bacillus subtilis var. natto GX10-35 with the yield of 0.86 mg/mL was isolated and a purified polysaccharide fraction, GX10-35-P1, was obtained from its fermentation broth. Chemical analyses showed the sulfate content of the sulfated polysaccharide GX10-35-P1 was 12.02%. Spectroscopic analyses suggests that GX10-35-P1 is a sulfated exopolysaccharide with distinct structural features, with a proposed backbone consisting of α-D-Galp-(1→6)-α-D-Glcp-(1→→6)-α-D-Glcp-(1→→6)-α-D-Glcp-(1→6)-α-D-Galp3S-(1→6)-α-D-Glcp-(1→6)-α-D-Glcp-(1→6)-α-D-Glcp-(1→, indicating it could be classified as an unreported type of water-soluble sulfated exopolysaccharide from bacteria. Moreover, GX10-35-P1 could induce murine macrophage cells RAW264.7 to proliferation, phagocytic, release nitric oxide and promote the mRNA expression of TNF-α, IL-1β, IL-6 and IL-10 cytokines. These results indicate that GX10-35-P1 is a promising bacterial sulfated polysaccharide with potential for further investigation as an immunomodulatory agent.

Keywords:   Bacillus subtilis ; Immunoregulatory activity; Natto; Sulfated polysaccharide

DOI:  https://doi.org/10.1007/s12010-026-05912-6
Biomed Chromatogr. 2026 Oct;40(10): e70609

A Simplified and Robust LC-MS/MS Method for Simultaneous Quantification of Six Steroid Hormones Associated With Polyendocrine Metabolic Ovarian Syndrome.

Mengxue Feng, Yan Song, Xueqing Qian.

  Polyendocrine metabolic ovarian syndrome (PMOS), formerly known as polycystic ovary syndrome (PCOS), is characterized by dysregulation of multiple steroid hormones. Accurate quantification of these analytes is essential for laboratory evaluation; however, currently may involve complex sample-preparation workflows or provide insufficient analytical coverage, particularly for dehydroepiandrosterone sulfate (DHEAS). A liquid chromatography-tandem mass spectrometry (LC-MS/MS) assay was established for the simultaneous measurement of six steroid hormones associated with PMOS. Sample preparation combined liquid-liquid extraction with protein precipitation. Chromatographic separation was completed within 6 min. Validation followed international recommendations and included linearity, sensitivity, precision, accuracy, matrix effects, selectivity, and specificity. All analytes showed excellent linearity (R = 0.9959-0.9995), with intra- and inter-day CVs ≤ 5.6%. Spike recovery ranged from 85.2% to 114.9%. Accuracy was further supported by third-party QC materials and successful participation in an external quality assessment program. The assay provided an expanded linear range for DHEAS (20-20,000 ng/mL). This validated LC-MS/MS assay provides rapid, sensitive, and reproducible quantification of six PCOS-related steroid hormones and is suitable for routine laboratory implementation.

Keywords:  dehydroepiandrosterone sulfate (DHEAS); liquid chromatography–tandem mass spectrometry (LC–MS/MS); polycystic ovary syndrome (PCOS); polyendocrine metabolic ovarian syndrome (PMOS); serum; steroids

DOI:  https://doi.org/10.1002/bmc.70609
J Am Chem Soc. 2026 09 09. 148(35): 37884-37908

Priming Cells with Modulators of Cellular Signaling Ensures Enhanced Selectivity of HSPG-Specific Protein-Drug Conjugate Delivery.

Aleksandra Chorążewska, Krzysztof Ciura, Magdalena Milczarek, Dagmara Kłopotowska, Adam Pomorski, Anna Więch-Walów, Błażej Łukianowski, Paweł Gajdzis, Artur Krężel, Rafał Bartoszewski, Joanna Wietrzyk, Liliana Schaefer, Natalia Porębska, Łukasz Opaliński.

Protein-drug conjugates (PDCs) constitute a rapidly growing group of precise anticancer agents. Receptor-mediated endocytosis is a critical step in PDC action, which ensures the delivery of PDCs into the interior of cancer cells. Here, we report TriFHS-MMAE, the first multivalent PDC specifically targeting heparan sulfate proteoglycans (HSPGs) overexpressed by pancreatic cancer cells, which induces ultrafast and highly efficient aggregation-dependent endocytosis (ADE) of HSPGs. Using high-content screening with a near-kinome-wide library of inhibitors, we identified signaling pathways that govern ADE of HSPGs and discovered cascades that selectively operate in pancreatic cancer cells versus healthy cells. We show that priming cells with identified endocytic chemical modulators improves the targeting of the TriFHS-MMAE conjugate in vitro and in vivo. Overall, these findings provide insights into the interplay among signaling, endocytosis, and PDCs and support the development of specific therapies for pancreatic cancer.

DOI: https://doi.org/10.1021/jacs.6c08409
Food Chem. 2026 Sep 03. pii: S0308-8146(26)03119-5. [Epub ahead of print]528 150959

Self-assembly non-covalent binding mechanism of lycopene-protein-chondroitin sulfate ternary nanoparticles: Multidimensional characterization and molecular dynamics simulation.

Weiyu Yan, Qian Cui, Tian Qiu, Xiaofu Liang, Mengju Xu, Zijian Qiu, Meijia Guo, Yongmin Zhang, Jiaping Zhou, Mingyuan Li.

  To overcome lycopene's (LYC's) poor water solubility, oxidative instability, and low bioaccessibility, chondroitin sulfate (CS) was used as a stabilizing layer to construct LYC-Protein-CS nanoparticles (LYC-Protein-CS NPs) using different proteins. Their structures and delivery performance were compared to clarify how protein structure influences the delivery of lipophilic bioactives. Zein's layered folding and hydrophobic-hydrophilic partitioning promoted assembly with CS, forming a compact core-shell network. Consequently, LYC-Zein-CS showed superior encapsulation, dispersion stability, antioxidant activity, and gastrointestinal release behavior. Compared with free LYC, this system increased apparent bioaccessibility by 12.95-fold in the gastric phase and 14.87-fold in the intestinal phase during simulated digestion. These findings reveal how protein structural differences regulate the performance of protein-polysaccharide nanoparticles and provide theoretical and technical insights into the precise design and practical application of delivery systems for LYC and other lipophilic bioactive compounds.

Keywords:  Chondroitin sulfate; Lycopene; Protein-polysaccharide nanoparticles; Stability

DOI:  https://doi.org/10.1016/j.foodchem.2026.150959
Eur J Cell Biol. 2026 Sep 04. pii: S0171-9335(26)00042-7. [Epub ahead of print]105(4): 151571

Exploring the impact of syndecans in prostate cancer: Stage-specific roles and therapeutic implications.

Ranyelison Silva Machado, Rodrigo Esaki Tamura, Martin Götte, Jessica Oyie Sousa Onyeisi.

  Syndecans (SDCs) 1-4 are a family of transmembrane heparan sulfate proteoglycans (HSPGs) that regulate cell-cell communication, adhesion, extracellular matrix organization, and signaling pathways involved in tumor biology. In prostate cancer (PCa), accumulating evidence suggests that SDCs contribute to tumor progression, therapeutic resistance, and interactions within the tumor microenvironment. However, their specific, stage-dependent roles remain incompletely understood. This review provides an integrated synthesis of current experimental and clinical evidence on SDC1-SDC4 in PCa, complemented by exploratory analyses of publicly available transcriptomic, genomic, and proteomic datasets. In contrast, copy-number alteration (CNA) strata dichotomized by the mean for SDC1, SDC2, and SDC4 showed differences in progression-free interval. Specific CNA subclasses and relationships between CNA values and SDC mRNA or protein abundance could not be determined. Proteomic pseudotime analysis further suggested that SDC4 expression increases during PCa progression, supporting its potential involvement in advanced disease. We discuss the regulation and modulation of SDCs by androgen deprivation therapy (ADT), enzymatic shedding, integrin-mediated signaling, extracellular matrix interactions, lipid signaling pathways, and microRNA networks. In particular, SDC1-microRNA interactions may influence PCa cell proliferation, cellular senescence, epithelial-mesenchymal transition (EMT), and intracellular signaling pathways. Overall, this review highlights SDCs as context-dependent regulators of PCa biology with potential relevance as biomarkers or therapeutic targets. However, clinical translation will require independent validation, standardized assays, compartment-resolved analyses, and mechanistic confirmation.

Keywords:  Prognosis; Prostate cancer; Proteoglycans; Syndecans

DOI:  https://doi.org/10.1016/j.ejcb.2026.151571
Int J Nanomedicine. 2026 ;21 615075

Sulfated Polysaccharides in Wound Healing: From Bioactive Materials Design to Regenerative Therapeutics.

Guangyun Hu, Ling Li, Ronglan Ouyang, Xiaosheng Ke, Shurun Huang, Peng Yang, Can Huang.

  Sulfated polysaccharides (SPs) are emerging as a versatile class of bioactive macromolecules for wound healing, owing to their intrinsic roles in cell signaling, immunomodulation, tissue repair, and host defense. As wound healing is a dynamic and tightly coordinated process, particularly in chronic and refractory wounds, a central question is how SP-based biomaterials can be engineered to modulate the wound microenvironment with spatiotemporal precision. Natural and engineered SPs offer distinct advantages, including structural diversity, inherent bioactivity, and tunable physicochemical properties. Mechanistically, SPs regulate key aspects of repair through macrophage polarization, sequestration and presentation of heparin-binding proteins and growth factors, antimicrobial activity, and extracellular matrix (ECM) remodeling. Recent advances have enabled SP-based platforms in the form of hydrogels, microneedles, microspheres, and nanofibrous scaffolds, which provide biochemical and mechanical cues to orchestrate inflammation resolution, angiogenesis, infection control, and tissue regeneration. This Review outlines the sources, structural features, and engineering strategies of SPs, highlights the transition from natural to engineered systems, and discusses recent progress and translational challenges in SP-based wound therapeutics.

Keywords:  biomaterials; regenerative therapy; sulfated polysaccharides; wound healing

DOI:  https://doi.org/10.2147/IJN.S615075
Recent Pat Anticancer Drug Discov. 2026 Aug 31.

Glypican-1 in Rhabdomyosarcoma: A Multi-omics Exploration of a Targetable Biomarker.

Belal Al-Zu'bi, Fatemah Ofo Alshammari, Randa AlQaisi, Jaber H Jaradat, A A Al-Abadleh, Rashed J Gousous, Abulmaaty M Elsayed, Yousef M Al-Saraireh, Mohammad Salem Hareedy.

   INTRODUCTION: Glypican-1 (GPC1), a heparan sulfate proteoglycan found on the cell surface, has been associated with carcinogenesis and chemoresistance in several malignancies. However, its function in rhabdomyosarcoma remains poorly understood.
METHODS: GPC1 protein expression was evaluated in rhabdomyosarcoma tissue microarrays using immunohistochemistry and quantified using the Allred scoring system. Transcriptomic analysis was performed using the GSE108022 dataset, and protein-protein interaction networks were analyzed using STRING. Structural features were assessed using AlphaFold, and drug sensitivity associations were explored using CTRP data.
RESULTS: GPC1 protein expression was detected in 61.5% (64/104) of rhabdomyosarcoma cases, while 75% of normal skeletal muscle samples were negative. A significant association was observed between GPC1 expression and tumor subtype (p = 0.002, Cramér's V = 0.403), as well as sex (p = 0.025, Cra-mér's V = 0.219). Transcriptomic analysis showed significantly higher GPC1 expression in rhabdomyosarcoma compared to normal muscle (p < 0.001). Protein interaction analysis revealed enrichment in pathways related to cell adhesion, growth factor signaling, and extracellular matrix organization. Drug-sensitivity analysis indicated that higher GPC1 expression was associated with resistance to PI3K and HDAC inhibitors and increased sensitivity to vincristine, topotecan, and alisertib.
DISCUSSION: GPC1 is aberrantly expressed in rhabdomyosarcoma, influencing neoplastic signaling and treatment responses, and new patents emphasize its potential for therapeutic targeting and diagnostic purposes Conclusion: GPC1 is aberrantly overexpressed, readily accessible to ligands or other molecules, and is a functionally significant biomarker in rhabdomyosarcoma, with emerging potential for diagnostic purposes and targeted therapy development.

Keywords:  Rhabdomyosarcoma; biomarker; drug sensitivity; glypican-1; immunohistochemistry; structural modeling

DOI:  https://doi.org/10.2174/0115748928472096260821102954
Cardiorenal Med. 2026 Sep 07. 1

Uremic toxin-induced pathological signaling in sinus node cells is attenuated by probenecid.

Dal-Ah Kim, Chor Ho Jo, Mi-Ran Lee, Jung-Hwa Ryu, Kyoung Hye Kong.

INTRODUCTION: Uremic toxins, including indoxyl sulfate (IS) and p-cresyl sulfate (PCS), contribue to cardiac fibrosis and maladaptive remodeling in chronic kidney disease (CKD). Although their roles in ventricular and vascular pathology are well established, their effects on sinus node cells and the associated molecular alterations remain poorly defined. Understanding how the uremic milieu affects sinus node cell homeostasis may provide insight into CKD-associated conduction abnormalities.
METHODS: To investigate uremic toxin-induced stress responses, H9C2 cardiomyocytes were used as a comparative cardiac stress-model, whereas primary sinus node cells served as the principal pacemaker-relevant model. Both cell types were treated with IS and PCS. Profibrotic, pro-apoptotic, and stress-related signaling pathways were evaluated by protein and mRNA analyses, together p38 and ERK activation. In parallel, a CKD mouse model was generated by 2-week adenine feeding, and sinus node cells were isolated for molecular analysis. The effects of probenecid were examined in cultured cells and ex vivo using primary sinus node cells isolated from adenine-fed mice. Results IS and PCS induced profibrotic, pro-apoptotic, and remodeling-associated signaling in both H9C2 cardiomyocytes and primary sinus node cells, indicating activation of shared cardiac stress pathways. Conclusions regarding pacemaker-relevant molecular alterations were based primarily on primary sinus node cell findings, including cells isolated from 2-week adenine-fed mice., In primary sinus node cells, uremic toxin exposure increased fibronectin accumulation, altered the Bax/Bcl-2 balance, and activated p38 and ERK signaling, whereas TBX3 expression remained unchanged. changes occurred without overt loss of this pacemaker identity marker. These findings indicate apoptosis-associated, profibrotic, and stress-responsive molecular alterations rather than direct evidence of functional pacemaker impairment. Sinus node cells isolated from adenine-fed mice showed similar remodeling-associated molecular marker changes. Probenecid attenuated fibronectin accumulation, Bax/Bcl-2 imbalance, and stress kinase activation in primary sinus node cells, with similar effects observed ex vivo in cells isolated from adenine-fed mice.
CONCLUSION: These findings suggest that uremic toxin-driven stress signaling is associated with molecular remodeling signatures in sinus node cells under CKD-related conditions. Although the functional consequences of these molecular alterations were not assessed, probenecid attenuated uremic toxin-associated profibrotic, pro-apoptotic, and stress kinase signaling, suggesting that targeting molecular stress pathways may help strategy sinus node cell homeostasis in CKD.

DOI: https://doi.org/10.1159/crm/abtag008
PLoS One. 2026 ;21(9): e0357984

Vitamin D alleviates indoxyl sulfate-induced inflammatory and cholesterol dysregulation in macrophages: Implications for vascular health in patients receiving hemodialysis.

Kyoung Hye Kong, Kyungwon Yang, Jung-Hwa Ryu.

Indoxyl sulfate (IS) is a protein-bound uremic toxin that accumulates in patients with chronic kidney disease (CKD) and promotes oxidative stress, endothelial dysfunction, vascular smooth muscle cell proliferation, and fibrosis, thereby contributing to vascular stenosis in patients receiving hemodialysis. CKD is also commonly associated with vitamin D deficiency, which is linked to vascular calcification, immune dysregulation, and inflammation. This study aims to investigate the preventive effects of 1,25(OH)2D3 (active vitamin D) against IS-induced macrophage inflammatory activation and cholesterol dysregulation. Macrophages were pretreated with 30 nM 1,25(OH)2D3 for 12 and 24 h, followed by exposure to IS at concentrations of 125 and 250 µg/mL for 24 h. Morphological changes were observed under a microscope. To assess macrophage phenotype-associated changes, qPCR was performed to analyze the expression of M1-like/pro-inflammatory markers (TNF-α and IL-1β) and M2-like/anti-inflammatory phenotype-associated markers (CD163 TGF-β and IL-10). Cholesterol metabolism was assessed using a cholesterol efflux assay, qPCR analysis of ABCA1 and ABCG1 and Oil Red O staining for intracellular lipid accumulation. Protein expression of inflammatory mediators, TGF-β1, and cholesterol efflux transporters was further evaluated by western blotting. 1,25(OH)2D3 pretreatment modulated IS-associated inflammatory responses, as reflected by changes in selected M1-like/pro-inflammatory mediators, including iNOS, IL-6 and IL-1β. Conversely, 1,25(OH)2D3 increased selected M2-like/anti-inflammatory phenotype-associated markers, including CD163 and IL-10. Furthermore, 1,25(OH)2D3 pretreatment preserved cholesterol efflux capacity and modulated ABCA1 and ABCG1 expression in a time- and transporter-dependent manner, accompanied by reduced intracellular lipid accumulation as shown by Oil red O staining. These findings suggest that 1,25(OH)2D3 may protect macrophages against IS-induced inflammatory activation and cholesterol dysregulation, highlighting its potential as a preventive or modulatory approach for macrophage-mediated vascular dysfunction in CKD.

DOI: https://doi.org/10.1371/journal.pone.0357984