bims-supasi 2025-11-30 papers

bims-supasi

Biomed News

on Sulfation pathways and signalling

Issue of 2025–11–30
fifteen papers selected by
Jonathan Wolf Mueller, University of Birmingham

The role of chondroitin sulfate in venous thrombosis, organization, and resolution.
Enzymatic Synthesis and Anticoagulant Evaluation of Fucosylated Chondroitin Sulfate Polysaccharides with Defined Sulfation Patterns.
Sulfatase modifying factors control the timing of zebrafish convergence and extension morphogenesis.
Exploring Phosphate Substitution in Heparan Sulfate Mimetics: Synthesis and Antiviral Evaluation.
Structural basis for human chondroitin sulfate chain polymerization.
Heparan Sulfate Proteoglycans (HSPGs) and Their Degradation in Health and Disease.
Infection-induced elevation of gut glycosaminoglycans fosters microbiota expansion in Drosophila melanogaster.
Structure-activity relationships of sulfated polysaccharides in inflammatory bowel disease: Sources, mechanisms, and therapeutic potential.
From Native Glycosaminoglycans to Mimetics: Design, Mechanisms, and Biomedical Applications.
An isotope dilution-liquid chromatography-tandem mass spectrometry-based candidate reference measurement procedure for the quantification of dehydroepiandrosterone sulfate in human serum and plasma.
Synthesis and Recovery of N-Sulfo Heparosan From Fermentation Broth.
Evidence for Early Evolution of Sulfated Peptide Signaling in Plant Development.
A CD25-chemokine receptor complex initiates non-canonical IL-2 signaling.
Factors influencing the removal of protein-bound uremic toxins in hemodiafiltration.
Impact of a High-Fat High-Carbohydrate (HFHC) Diet at a Young Age on Steroid Hormone Hair Concentrations in Mice: A Comparison with a Control Diet and Nutraceutical Supplementation.

Am J Physiol Heart Circ Physiol. 2025 Nov 24.

The role of chondroitin sulfate in venous thrombosis, organization, and resolution.

Felipe F Lamenza, Chase W Kessinger.



Keywords:  chondroitin sulfate; deep vein thrombosis; glycosaminoglycans; in vivo imaging; inflammation

DOI:  https://doi.org/10.1152/ajpheart.00855.2025
JACS Au. 2025 Nov 24. 5(11): 5381-5387

Enzymatic Synthesis and Anticoagulant Evaluation of Fucosylated Chondroitin Sulfate Polysaccharides with Defined Sulfation Patterns.

Rongfeng Li, Yuanjie Liu, Kaiqiang Li, Guantian Li, Huahua Yu, Song Liu, Ronge Xing.

  Fucosylated chondroitin sulfate (FCS), a uniquely structured glycosaminoglycan with outstanding anticoagulant activity and a lower risk of bleeding, is a promising anticoagulant candidate. However, the complex and heterogeneous structure of the natural FCS polysaccharide presents significant challenges in developing novel anticoagulant drugs and elucidating the structure-activity relationship. Herein, we developed an enzymatic system for the synthesis of FCS polysaccharides with defined sulfation and fucosylation patterns using bifunctional L-fucokinase-GDP-L-fucose pyrophosphorylase (BfFKP) and α1-3-fucosyltransferases mutant (Hpα1, 3-FucTM) and successfully synthesized FCS polysaccharides with α1-3-linked fucose (FCSA), 4-O-sulfated fucose (F4SCSA), 2, 4-O-disulfated fucose (F2S4SCSA), and natural-like mixed sulfated fucose (FNMSCSA), respectively. F2S4SCSA polysaccharide displayed excellent intrinsic anticoagulant activity, which is significantly stronger than clinical anticoagulant low molecular weight heparin and nature-like FCS. Additionally, we also elucidated the precise anticoagulant mechanism of FCS that its sulfation patterns play a crucial role in the anticoagulant activity. Specifically, FCS selectively binds to the positively charged arginine and lysine on the surface of the intrinsic factor IXa factor (K D(F2S4SCSA) = 1.05 × 10-8) predominantly by the negative-charged sulfate group of fucose on its side chain. This one-pot enzymatic cascade approach enables the high-yield synthesis of F2S4SCSA with defined structure and outstanding anticoagulant activity, thereby providing a promising route for the development of next-generation anticoagulant drugs.

Keywords:  F2S4SCSA enzymatic synthesis; FCS; anticoagulant; fucosylated chondroitin sulfate

DOI:  https://doi.org/10.1021/jacsau.5c00818
bioRxiv. 2025 Oct 24. pii: 2025.10.09.681375. [Epub ahead of print]

Sulfatase modifying factors control the timing of zebrafish convergence and extension morphogenesis.

Ailen Soledad Cervino, Amrita Basu, Ryan J Weiss, Gursimran Kaur Bajwa, Rubén Marín Juez, Sandra Grimm, Cristian Coarfa, Margot Kossmann Williams.

To shape the emerging body plan, morphogenetic cell movements must be coordinated not only in space, but also in time. Convergence and Extension (C&E) movements that elongate the anteroposterior axis initiate with precise timing during vertebrate gastrulation, but the mechanisms controlling their onset remain unknown. We examined this question using zebrafish embryonic explants that faithfully recapitulate C&E cell movements and their precise timing in culture, in isolation from other gastrulation movements. We determined that new transcription is required at gastrulation onset for C&E in explants and identified sulfatase modifying factor 2 ( sumf2 ) as a candidate 'trigger' gene expressed at this time. sumf2 and its paralog sumf1 encode negative and positive regulators, respectively, of all sulfatase enzymes, which remove sulfate groups from their substrates, altering their biological activity. In zebrafish embryos and explants, sumf1 and sumf2 expression levels invert at gastrulation onset, predicting a reduction in sulfatase activity and consequent increase of substrate sulfation. We found that overexpressing sumf1 and sumf2 causes delayed or precocious C&E onset, respectively, whereas loss of sumf1 and sumf2 function shifts C&E timing in the opposite direction. We further identified Sulf1, an extracellular sulfatase that modifies heparan sulfate proteoglycans (HSPGs), as the key effector by which sumf1 and sumf2 control C&E timing. Accordingly, reduced or increased levels of sulfated heparan sulfate similarly shift C&E onset and suppress sumf1 and sumf2 mutant phenotypes. Together, our work supports a model in which sumf2 expression at zebrafish gastrulation onset reduces sulfatase activity, rewriting HSPG sulfation patterns to promote and/or permit C&E morphogenesis.

DOI: https://doi.org/10.1101/2025.10.09.681375
ChemMedChem. 2025 Nov 22. e202500764

Exploring Phosphate Substitution in Heparan Sulfate Mimetics: Synthesis and Antiviral Evaluation.

Arran W Stewart, Andrew J Marshall, Sam Spijkers-Shaw, Kathy A Keith, Scott H James, Lawrence D Harris, Olga V Zubkova, Benjamin J Compton.

  Heparan sulfate (HS) is a ubiquitously expressed glycosaminoglycan (GAG) found on most mammalian cells. Its heterogeneous structure and dense negative charge allow HS to interact with a wide range of proteins, regulating their stability, localization, and engagement with cell-surface receptors. Given the role of disrupted HS-protein interactions in numerous diseases, HS mimetics represent a promising avenue for therapeutic intervention. These mimetics are designed to reproduce the functional properties of native HS while offering improved stability, scalability, and selectivity. Whereas most HS mimetics exploit naturally occurring sulfate groups to provide anionic character, this study explores phosphates as a sulfate bioisostere. Using a dendrimer-based scaffold, a focused library of phosphorylated maltose constructs was synthesized, comprising four (dimer), six (trimer), or eight (tetramer) units, with lipid-modified variants prepared for the dimer and trimer series. In vitro screening against four clinically relevant DNA viruses reveal that these phosphorylated HS mimetics display antiviral activity, albeit with reduced potency relative to their sulfated analogs.

Keywords:  antiviral activity; bioisostere; heparan sulfate; mimetics

DOI:  https://doi.org/10.1002/cmdc.202500764
Nat Commun. 2025 Nov 26.

Structural basis for human chondroitin sulfate chain polymerization.

Poushalee Dutta, Rosa L Cordeiro, Mélanie Friedel-Arboleas, Marie Bourgeais, Sylvain D Vallet, Margot Weber, Margaux Molinas, Huazhang Shu, Magnus N N Grønset, Rebecca L Miller, Elisabetta Boeri Erba, Rebekka Wild.

Chondroitin sulfates are complex polysaccharide chains that regulate various biological processes at the cell surface and within the extracellular matrix. Here, we identify four heterodimeric complexes responsible for chondroitin sulfate chain polymerization in humans: CHSY1-CHPF, CHSY1-CHPF2, CHSY3-CHPF, and CHSY3-CHPF2. Using a custom-tailored in vitro glycosylation assay based on chemo-enzymatically synthesized fluorescent substrates, we demonstrate that all four complexes exhibit chain polymerization activity. The cryo-EM structure of the CHSY3-CHPF complex provides molecular insights into the chondroitin sulfate chain polymerization reaction. The architecture of the catalytic sites suggests that CHSY1 and CHSY3 are enzymatically active, while CHPF and CHPF2 primarily play a stabilizing role. Mutational analysis of purified enzyme complexes, combined with an in cellulo complementation assay, confirms that only CHSY1 and CHSY3 have bifunctional glycosyltransferase activities. Based on the spatial arrangement of the catalytic sites, we propose that chondroitin sulfate chain polymerization follows a non-processive, distributive mechanism.

DOI: https://doi.org/10.1038/s41467-025-66787-5
Biomolecules. 2025 Nov 14. pii: 1597. [Epub ahead of print]15(11):

Heparan Sulfate Proteoglycans (HSPGs) and Their Degradation in Health and Disease.

Nicola Greco, Valentina Masola, Maurizio Onisto.

  Heparan sulfate proteoglycans (HSPGs) are essential constituents of the extracellular matrix (ECM) and cell surface, orchestrating a wide range of biological processes, such as cell adhesion, migration, proliferation, and intercellular communication. Through their highly sulfated glycosaminoglycan chains, HSPGs serve as crucial modulators of bioavailability and signaling of growth factors, cytokines, and chemokines, thereby influencing tissue homeostasis. Their dynamic remodeling is mediated by numerous enzymes, with heparanase (HPSE) playing a predominant role as the only known human endo-β-D-glucuronidase that specifically cleaves heparan sulfate chains. Beyond its well-documented enzymatic activity in ECM degradation and the release of HS-bound molecules, HPSE also exerts non-enzymatic functions that regulate intracellular signaling cascades, transcriptional programs, and immune cell behavior. Dysregulated HPSE expression or activity has been implicated in various pathological conditions, including fibrosis, chronic inflammation, cancer progression, angiogenesis, metastasis, and immune evasion, positioning this enzyme as a pivotal driver of ECM plasticity in both health and disease. This review provides an updated overview of HSPG biosynthesis, structure, localization, and functional roles, emphasizing the activity of HPSE and its impact on tissue remodeling and disease pathogenesis. We further explored its involvement in the hallmark processes of cancer, the inflammatory tumor microenvironment, and its contribution to fibrosis. Finally, we summarize current therapeutic strategies targeting HPSE, outlining their potential to restore ECM homeostasis and counteract HPSE-driven pathological mechanisms. A deeper understanding of the HSPG/HPSE axis may pave the way for innovative therapeutic interventions in cancer, inflammatory disorders, and fibrotic diseases.

Keywords:  extracellular matrix (ECM); heparan sulfate proteoglycans (HSPGs); heparanase (HPSE)

DOI:  https://doi.org/10.3390/biom15111597
Cell Rep. 2025 Nov 21. pii: S2211-1247(25)01370-1. [Epub ahead of print]44(12): 116598

Infection-induced elevation of gut glycosaminoglycans fosters microbiota expansion in Drosophila melanogaster.

Aranzazu Arias-Rojas, Marko Rubinić, Jasmin Albiez, Dagmar Frahm, Robert Hurwitz, Igor Iatsenko.

  While host genetics influence the composition of intestinal microbial communities, host genetic factors controlling the abundance of intestinal commensals remain to be determined. We perform a genome-wide association study in Drosophila melanogaster to identify host genetic variants linked to the abundance of the gut commensal Lactiplantibacillus plantarum. Polymorphisms in genes involved in heparan sulfate synthesis are strongly associated with L. plantarum abundance. RNAi knockdown of these genes reduces both heparan sulfate synthesis and commensal load. Upon infection, host heparan sulfate synthesis is induced via activation of the nuclear factor κB immune signaling pathway, increasing L. plantarum populations and conferring colonization resistance against pathogens. Furthermore, heparan sulfate is required for infection-induced immune effector expression and prevention of intestinal dysplasia. These findings underscore heparan sulfate as a crucial modulator of intestinal homeostasis, pivotal in microbiota control, intestinal defense, and epithelial renewal.

Keywords:  CP: microbiology; Drosophila; Lactiplantibacillus plantarum; epithelial renewal; genome-wide association study; glycosaminoglycans; heparan sulfate; infection; intestinal immunity; microbiota

DOI:  https://doi.org/10.1016/j.celrep.2025.116598
Carbohydr Polym. 2026 Jan 15. pii: S0144-8617(25)01358-X. [Epub ahead of print]372 124574

Structure-activity relationships of sulfated polysaccharides in inflammatory bowel disease: Sources, mechanisms, and therapeutic potential.

Wendong Liu, Mingyue Shen, Jiahui Li, Jianhua Xie.

  Inflammatory Bowel Disease (IBD), a chronic relapsing-remitting intestinal disorder, has emerged as a significant global health challenge with continuously rising incidence rates worldwide. Functionally active compounds and prebiotic supplements are increasingly recognized as effective strategies for improving gut health. Sulfated polysaccharides (SPs), derived from a wide range of sources, including animals, plants, microorganisms, and their metabolites, represent a class of beneficial functionally active compounds that have garnered substantial research attention for their potential therapeutic applications in IBD management. Nevertheless, the necessary analysis of the relationship between the structure of SPs and their anti-inflammatory bowel disease (anti-IBD) activity is currently lacking. This review comprehensively evaluates the evidence base regarding the sources of SPs, their anti-IBD activity (including in vitro and in vivo model systems), underlying mechanisms, and structure-activity relationships, highlighting the impact of the degree and the position of sulfate on IBD.

Keywords:  Gut microbiota; Immunomodulation; Inflammatory bowel disease; Sulfated polysaccharides; Sulfation modification; Therapeutic mechanisms

DOI:  https://doi.org/10.1016/j.carbpol.2025.124574
Biomolecules. 2025 Oct 27. pii: 1518. [Epub ahead of print]15(11):

From Native Glycosaminoglycans to Mimetics: Design, Mechanisms, and Biomedical Applications.

Fabian Junker, Sandra Rother.

  Glycosaminoglycans (GAGs) are essential regulators of numerous biological processes through their interactions with growth factors, chemokines, cytokines, and enzymes. Their structural diversity and heterogeneity, however, limit reproducibility and translational use, as native GAGs are typically obtained from animal-derived sources with notable batch-to-batch variability. To overcome these challenges, a wide range of GAG mimetics has been developed with the aim of replicating or modulating the biological functions of native GAGs while offering improved structural definition, accessibility, and therapeutic potential. Polysaccharide-based GAG mimetics, including derivatives of heparan sulfate, hyaluronan, dextran, and other natural glycans, represent one major strategy, whereas non-saccharide-based mimetics provide alternative scaffolds with enhanced stability and selectivity. Both approaches have yielded compounds that serve as valuable tools for dissecting GAG/protein interactions and as candidates for therapeutic development. Biomedical applications of GAG mimetics span diverse areas such as cancer, cardiovascular and inflammatory diseases, bone and cartilage regeneration, wound healing, and infectious diseases. This mini-review summarizes key developments in the design and synthesis of GAG mimetics, highlights their potential biomedical applications, and discusses current challenges and future perspectives in advancing them toward clinical translation.

Keywords:  anti-inflammatory agents; antiviral agents; cancer therapy; glycan/protein interaction; glycosaminoglycan mimetics; glycosaminoglycans; heparan sulfate mimetics; heparinase inhibitors; regenerative medicine

DOI:  https://doi.org/10.3390/biom15111518
Clin Chem Lab Med. 2025 Dec 01.

An isotope dilution-liquid chromatography-tandem mass spectrometry-based candidate reference measurement procedure for the quantification of dehydroepiandrosterone sulfate in human serum and plasma.

Sara Cheikh Ibrahim, Neeraj Singh, Katrin Gradl, Friederike Bauland, Daniel Köppl, Alexander Gaudl, Andrea Geistanger, Uta Ceglarek, Manfred Rauh, Christian Geletneky, Judith Taibon.

   OBJECTIVES: Dehydroepiandrosterone sulfate (DHEAS), the sulfate ester of dehydroepiandrosterone, is one of the most common steroid hormones in the human body and the precursor of several other androgens. It is primarily used as a diagnostic or prognostic indicator in adrenal and reproductive disorders. Present immunoassays for DHEAS lack sensitivity and specificity, being vulnerable to cross-reactivity with endogenous interferences. Therefore, an isotope dilution-liquid chromatography-tandem mass spectrometry (ID-LC-MS/MS)-based candidate reference measurement procedure (RMP) was developed to quantify DHEAS in human serum/plasma.
METHODS: We ensured traceability to the International System of Units by using quantitative nuclear magnetic resonance to characterize a commercially available DHEAS reference material used for assay calibration. To mitigate matrix effects and prevent interference co-elution, a two-dimensional heart-cut LC method was employed for LC-MS/MS, in combination with a solid phase extraction sample preparation protocol. Selectivity was determined by spiking the prepared internal standard with the interferences testosterone, epi-testosterone, dehydroepiandrosterone, 5α-dihydrotestosterone, and estrone, in analyte free matrix. A post-column infusion experiment and comparison of standard line slopes were performed to evaluate matrix effects. Precision and accuracy were assessed via a multi-day validation experiment, and variability components estimated using analysis of variance-based variance-components analysis. Measurement uncertainty (MU) was evaluated in compliance with current guidelines.
RESULTS: This RMP was suitable for analyzing DHEAS within the 0.800 to 8,400 ng/mL (2.17-22,800 nmol/L) range, demonstrating selectivity, sensitivity, and matrix-independence. Trueness and accuracy assessment revealed a relative bias (n=6) between -1.9 and 0.3 % for surrogate matrix samples (except for 5.9 % at the lowest level), -2.3 to 3.6 % for Li-heparin plasma samples and sample dilutions, and an overall bias between 0.7 and 1.8 % (n=60), indicating no statistically significant bias. The measurement process resulted in standard measurement uncertainties (MUs) ranging from 4.0 to 5.6 % for the low range and 3.5-4.2 % for the high range. At a 95 % confidence level (k=2), these uncertainties expanded to 7.9-11.1 % and 7.1-8.3 %, respectively. Reference values, determined from six measurements over multiple days (n=6), had standard MUs between 1.6 and 2.1 % for the low range and 0.9-1.7 % for the high range, with expanded MUs of 3.2-4.3 % and 1.9-3.5 %.
CONCLUSIONS: This RMP exhibited high analytical performance for DHEAS quantification and met requirements for measurement uncertainty. Additionally, it enabled differentiation between the DHEAS and other androgens. Consequently, this RMP is suitable for routine assay standardization and clinical sample evaluation.

Keywords:  SI units; dehydroepiandrosterone sulfate; isotope dilution-liquid chromatography-tandem mass spectrometry; qNMR characterization; reference measurement procedure; traceability

DOI:  https://doi.org/10.1515/cclm-2025-0179
Biotechnol J. 2025 Nov;20(11): e70159

Synthesis and Recovery of N-Sulfo Heparosan From Fermentation Broth.

Congxu Li, Xiaofeng Tang, Shuming Yuan, Changqian Shi, Chen Li, Xianxuan Zhou.

  Heparosan, a glycosaminoglycan (GAG) derived from bacterial capsular polysaccharide (CPS), shares a similar backbone with both clinically utilized heparin and heparan sulfate (HS). This facilitates its transformation into heparin/HS via chemoenzymatic strategies. Currently, the purification process of heparosan, followed by N-deacetylation and N-sulfation, requires executing several complex steps prone to the unintended loss of polysaccharides and environmental risks. In this study, heparosan extracted from fermentation broth underwent immediate N-deacetylation and N-sulfation before DEAE chromatography purification. The results showed that the recovery of N-deacetylated heparosan increased from less than 40% to 93.6% with negligible contaminants. After sulfation, the overall recovery yield of N-sulfo heparosan was 76.0%. The number average molecular weight (Mn) and weight average molecular weight (MW) of N-sulfo heparosan were ascertained to be 5.2 and 10.7, respectively, with a polydispersity index (PDI) value of 2.1. The assessment of elemental composition revealed that the efficiency of N-sulfation was 84%, which aligns with that of commercial heparin. The strategy delineated in this investigation avoids the substantial loss of N-deacetylated polysaccharides resulting from the complex procedures. Furthermore, the study avoids using harmful organic solvents in preparing heparosan, thereby promoting the in vitro green synthesis of heparin-like polysaccharides and analogous pharmaceutical compounds.

Keywords:  N‐deacetylation; N‐sulfation; heparin; heparosan; polysaccharide

DOI:  https://doi.org/10.1002/biot.70159
bioRxiv. 2025 Nov 07. pii: 2025.11.07.687175. [Epub ahead of print]

Evidence for Early Evolution of Sulfated Peptide Signaling in Plant Development.

Devin V Tulio, Alexandra M Shigenaga, Shu-Zon Wu, Pamela C Ronald, Magdalena Bezanilla.

In plants, the cell wall fixes the position of each cell; therefore, during development, plants rely on cellular proliferation and expansion for tissue patterning and organ formation. How plant cells communicate with neighboring cells to coordinate expansion for properly patterned tissues and organs is not well understood. In seed plants, organ growth is known to be modulated by sulfotyrosyl peptide signaling. Here, we report that the activity of TYROSYL PROTEIN SULFOTRANSFERASE (TPST), which is responsible for the post-translational modification of sulfotyrosyl peptides, is essential for expansion during development in the non-vascular plant, Physcomitrium patens . Plants that harbor a null mutation in the gene encoding TPST ( Δtpst ) were smaller, and while they formed gametophore initials, the gametophores did not fully expand. Mutational analysis of P. patens TPST identified the residue Histidine 124, a candidate catalytic residue, as essential for TPST function. Notably, addition of the sulfated signaling peptide, PSY1 from either P. patens or Arabidopsis thaliana , rescued all Δtpst developmental deficits. Taken together, these data suggest that TPST functions to sulfate PSY, and this activity is necessary for plant growth and development. Furthermore, since addition of AtPSY fully rescues Δtpst and PpPSY promotes root elongation in Arabidopsis and rice, these findings suggest that PSY signaling is evolutionarily conserved.

DOI: https://doi.org/10.1101/2025.11.07.687175
J Biol Chem. 2025 Nov 25. pii: S0021-9258(25)02833-9. [Epub ahead of print] 110981

A CD25-chemokine receptor complex initiates non-canonical IL-2 signaling.

Hosup Lee, Sarah Hyun Ji Kim, Javid Aceil, Amelia Meecham, Alexandre Gingras, Klaus Ley, Jamie B Spangler, Mark H Ginsberg.

  An anti-mouse CD25 antibody, PC61, induces a complex formed by the IL-2-dependent association of CD25 with CCR7 and an alternative IL-2 signaling pathway that results in integrin activation in CD4+CD25HiFoxp3+ regulatory T cells (Treg). Here, we used structure-based design together with combinatorial screening to identify a human IL-2 mutant (IL-2(E52K)) that disrupts CD25-CCR7 complex formation while retaining the full CD25 affinity of the parent molecule. An anti-human CD25, 7G7B6, drove formation of IL-2-dependent human CD25-CCR7, CD25-CXCR4, and CD25-CCR5 complexes and induced integrin activation in human CD25-expressing IL-2Rα+ YT-1 cells, Jurkat T cells and primary Tregs. IL-2(E52K) failed to support activation in CCR5Lo Jurkat T cells and primary Tregs. In contrast, IL-2(E52K) supported activation in CCR5Hi IL-2Rα+ YT-1 cells which was blocked by the CCR5-specific antagonist, Maraviroc. Heparan sulfate (HS), a physiological ligand of IL-2, induced IL-2-dependent CD25-CCR7 association and IL-2(E52K) failed to support HS-induced CD25-CCR7 complex formation and integrin activation in Jurkat cells. Both HS and 7G7B6 did not block canonical IL-2 signaling. CD122 was present in the 7G7B6-induced CCR7-CD25 complex. CD122 forms a heterodimer with CD132 (the common γ chain) that triggers canonical IL-2 signaling. Thus, both anti-CD25 antibody and HS require formation of a chemokine receptor-CD25 complex to initiate alternative IL-2 signaling. In addition, our findings suggest that alternative and canonical IL-2 signaling receptors can be incorporated into the same multi-protein assembly, allowing for a single complex to mediate divergent effects on downstream signaling.

Keywords:  CCR5; CCR7; CD25; CXCR4; Integrin; Interleukin 2; T cell biology; chemokine receptor; heparan sulfate; signaling

DOI:  https://doi.org/10.1016/j.jbc.2025.110981
Nefrologia (Engl Ed). 2025 Nov 24. pii: S2013-2514(25)00169-5. [Epub ahead of print] 501391

Factors influencing the removal of protein-bound uremic toxins in hemodiafiltration.

Víctor Joaquín Escudero-Saiz, Elena Cuadrado-Payán, María Rodríguez-García, Gregori Casals, Lida María Rodas, Néstor Fontseré, José Jesús Broseta, Francisco Maduell.

   INTRODUCTION: Protein-bound uremic toxins (PBUTs) have a high affinity for albumin and they are associated with increased cardiovascular morbidity and mortality in hemodialysis patients. Among them, p-cresyl sulfate (pCS) and indoxyl sulfate (IS) stand out due to their high toxicity. Postdilution hemodiafiltration (HDF) is one of the dialysis techniques that has shown the greatest benefits in terms of patient survival.
MATERIALS AND METHODS: This observational, single-center, cross-sectional study evaluated PBUT clearance in 137 patients undergoing post-dilution HDF, analyzing the factors that influence their removal. Reduction ratios (RRs) of IS and pCS were measured, as well as their correlation with dialysis parameters and clinical variables.
RESULTS: The mean RR for IS was 53.4% ± 9.3%, and for pCS, 48.2% ± 11.3%. A significant correlation was observed between the RR of both toxins (r = 0.606; P < .01), suggesting similar elimination mechanisms. In addition, total convective volume showed a positive correlation with the RR of pCS (r = 0.19; P = .027) and a weak correlation with the RR of IS (r = 0.155; P = .07). A significant difference in clearance was found according to sex, with higher RRs in women (P < .001 for IS and P = .008 for pCS).
CONCLUSIONS: The clearance of PBUTs is primarily diffusive. Enhancing all variables related to this physical principle will improve the elimination of these toxins. Postdilution HDF with high convective volume slightly increases this clearance. However, the results remain insufficient given the high toxicity of these molecules. New strategies, such as the use of adsorptive membranes and competitive molecules, are needed to optimize their removal and reduce the negative cardiovascular impact in hemodialysis patients.

Keywords:  Convección; Convection; Hemodiafiltración; Hemodiafiltration; Indoxyl sulfate; P-cresyl sulfate; Protein-bound uremic toxins; Sulfato de indoxilo; Sulfato de p-cresol; Toxinas urémicas unidas a proteínas

DOI:  https://doi.org/10.1016/j.nefroe.2025.501391
Life (Basel). 2025 Nov 07. pii: 1722. [Epub ahead of print]15(11):

Impact of a High-Fat High-Carbohydrate (HFHC) Diet at a Young Age on Steroid Hormone Hair Concentrations in Mice: A Comparison with a Control Diet and Nutraceutical Supplementation.

Isabella Pividori, Tanja Peric, Antonella Comin, Natalia Rosso, Silvia Gazzin, Mirco Corazzin, Alberto Prandi.

  An unhealthy prepubertal diet can have long-lasting effects throughout life. This study investigated hair concentrations of adrenal and sex steroids, in an in vivo mouse model of juvenile obesity subjected to control (CTRL), obesogenic (HFHC) diet, or nutraceutical supplementation (silymarin or coconut oil) diets. 87 3-week-old C57BL/6 mice (42 females, 45 males) were fed CTRL or HFHC diets for 8 weeks. Afterward, the CTRL group continued on CTRL diet while the HFHC diet group was divided into five groups: HFHC, HFHC→CTRL, HFHC→CTRL + silymarin (SIL), HFHC→HFHC + SIL and HFHC→HFHC + Coconut oil. At 4 weeks, the HFHC group showed increased cortisol/dehydroepiandrosterone (DHEA) ratio compared to CTRL group. At 20 weeks, the HFHC→HFHC group showed higher levels of progesterone (P4) and dehydroepiandrosterone sulfate (DHEA-S) and lower levels of estradiol (E2) compared to the CTRL→CTRL group. The switch from HFHC→CTRL was the optimal therapy because the body weight and almost all the hormones were close to those observed for the CTRL diet group. Supplement with SIL or Coconut oil reduced DHEA-S and increased in E2 compared with the endocrine setting seen with the HFHC diet. These interventions should be considered as supportive measures rather than substitutes for dietary correction.

Keywords:  17-β-oestradiol; DHEA; DHEA-S; coconut oil; cortisol; mouse; progesterone; silymarin; testosterone

DOI:  https://doi.org/10.3390/life15111722