bims-supasi 2025-10-12 papers

bims-supasi

Biomed News

on Sulfation pathways and signalling

Issue of 2025–10–12
fifteen papers selected by
Jonathan Wolf Mueller, University of Birmingham

In vivo analysis of Drosophila chondroitin sulfate biosynthetic genes.
Chondroitin sulfate on leukocytes mediates thrombus resolution and organization: an in vivo imaging study.
Novel regulators of heparan sulfate proteoglycans modulate cellular uptake of α-synuclein fibrils.
SLC26A1 directs sulfate homeostasis in health and disease.
Review on seaweed derived sulfated and non-sulfated marine polysaccharides as multifunctional food ingredients: Structure-function relationships, bioactivities and applications in functional foods.
Elevated plasma levels of the uremic toxin indoxyl sulfate positively correlates with plasma arsenic levels in acute promyelocytic leukemia patients: Evidence of renal AQP7 suppression mediated by the aryl hydrocarbon receptor.
Dermatan sulfate-recognized UiO-66 metal-organic frameworks: An active and passive targeting nanomedicine for methotrexate delivery.
Glycocalyx shedding as a clinical biomarker in critical illness.
An ectopic Hedgehog signaling axis drives directional tumor outgrowth in a mouse model of hereditary multiple osteochondromas.
Molecular dynamics insights into glycosaminoglycan effects on the extracellular domains of syndecan 2 and 4 dimers.
Fibroblast growth factor-23 remodels vascular extracellular matrix via glycosaminoglycan induction: implications for calcification in chronic kidney disease.
Adipocyte Heparan Sulfate Determines Type 2 Diabetes Susceptibility in Mice via FGF1-Mediated Glucose Regulation.
Molecular mechanism underlying phosphate distribution by SULTR family transporter SPDT in Oryza sativa.
Potential of Heparan Sulphate Mimetics Integrated Into Collagen Scaffolds for Enhanced Skin Wound Healing.
Identification and evolution of the plant sulfotransferase family.

J Biol Chem. 2025 Oct 06. pii: S0021-9258(25)02635-3. [Epub ahead of print] 110783

In vivo analysis of Drosophila chondroitin sulfate biosynthetic genes.

Tomomi Izumikawa, Ayano Moriya, Eriko Nakato, Kako Yamamoto, Raiki Sano, Takuya Akiyama, Akiko Kinoshita-Toyoda, Hidenao Toyoda, Hiroshi Nakato.

  Chondroitin sulfate (CS) is an evolutionarily conserved class of glycosaminoglycans and is found in most animal species. Previous studies of CS-deficient Drosophila models, Chondroitin sulfate synthase (Chsy) and Chondroitin polymerizing factor (Chpf) mutants, demonstrated the importance of CS in structural integrity of the basement membrane and organ shape maintenance. However, biosynthetic mechanisms of Drosophila CS remain to be elucidated. To investigate the CS biosynthesis in Drosophila, we generated mutants for two additional biosynthetic enzyme genes, CS N-acetylgalactosaminyltransferase (Csgalnact) and CS 4-O sulfotransferase (C4st), using CRISPR/Cas9 mutagenesis. Csgalnact null mutants show moderate changes in CS biosynthesis, including reduced CS in the larval brain and altered CS chain length. We found that this gene is dispensable for normal viability and morphogenesis. On the other hand, C4st mutants show more severe defects, including a high level of lethality and a folded wing phenotype. The C4st mutation not only eliminates CS sulfation but increases production of unsulfated chondroitin, suggesting the existence of a compensatory feedback mechanism. Both Csgalnact and C4st mutants show impaired adult negative geotaxis behavior, consistent with CSPGs' roles in the neuromuscular systems. Our study revealed unique and poorly understood features of invertebrate CS biosynthesis and provides novel in vivo toolsets to investigate CSPG functions in development.

Keywords:  C4st; Chondroitin sulfate; Chpf; Chsy; Csgalnact; Drosophila

DOI:  https://doi.org/10.1016/j.jbc.2025.110783
Am J Physiol Heart Circ Physiol. 2025 Oct 07.

Chondroitin sulfate on leukocytes mediates thrombus resolution and organization: an in vivo imaging study.

Aditya Adinata, Tetsuya Hara, Arinal Chairul Achyar, Satomi Nadanaka, Yoko Suzuki, Hiroshi Kitagawa, Michihiro Igarashi, Ken-Ichi Hirata, Hiromasa Otake, Noriaki Emoto.

  Accumulating evidence suggest that deep vein thrombosis (DVT) is an inflammatory disease and that chondroitin sulfate glycosaminoglycans (CS-GAGs), a long unbranched polysaccharide, can modulate inflammation. Thus, we aimed to clarify CS-GAGs role in DVT pathophysiology by utilizing mice with target deletion of Chondroitin Sulfate N-acetylgalactosaminyltransferase-2 (ChGn-2 KO mice), in which CS-GAGs chain length is reduced. We found an impaired DVT resolution and organization in both stasis- and stenosis-induced DVT model, with a lower level of inflammation and neutrophil infiltration within DVT of ChGn-2 KO mice. Using serial in vivo imaging, we observed a reduced Ly6G/Ly6C-positive cells migration into DVT in ChGn-2 KO mice. After confirming expression of CS-GAGs on both leukocytes and venous endothelial cells, we performed leukocyte transfer experiments and demonstrated that rhodamine 6G-stained cells from ChGn-2 KO mice failed to invade into the thrombus in wild-type (WT) mice, while rhodamine 6G-stained cells from WT mice were capable to infiltrate the thrombus in ChGn-2 KO mice. Simultaneous imaging of rhodamine 6G-stained cells from WT and Hoechst 33342-stained cells from ChGn-2 KO mice confirmed that loss of ChGn-2 attenuated myeloid cell migration into the thrombus. Finally, CS disaccharide composition analysis revealed a shorter CS-GAGs on the leukocytes' cell membrane from ChGn-2 KO mice. Collectively, CS-GAGs on the cell surface of leukocytes and its regulation by ChGn-2 mediate their capability to infiltrate the thrombus, highlighting a potential innovative therapy by modulating CS-GAGs to enhance DVT resolution and organization.

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

DOI:  https://doi.org/10.1152/ajpheart.00318.2025
Commun Biol. 2025 Oct 06. 8(1): 1426

Novel regulators of heparan sulfate proteoglycans modulate cellular uptake of α-synuclein fibrils.

Benoît Vanderperre, Amitha Muraleedharan, Marie-France Dorion, Frédérique Larroquette, Esther Del Cid Pellitero, Nishani Rajakulendran, Carol X-Q Chen, Roxanne Larivière, Charlotte Michaud-Tardif, Thomas Goiran, Rony Chidiac, Damien Lipuma, Graham MacLeod, Rhalena Thomas, Zhangjie Wang, Wolfgang E Reintsch, Wen Luo, Irina Shlaifer, Fuming Zhang, Ke Xia, Zachary Steinhart, Robert J Linhardt, Jean-François Trempe, Jian Liu, Thomas M Durcan, Stephane Angers, Edward A Fon.

Synucleinopathies are characterized by the accumulation and propagation of α-synuclein (α-syn) aggregates throughout the brain, leading to neuronal dysfunction and death. In this study, we used an unbiased FACS-based genome-wide CRISPR/Cas9 knockout screening to identify genes that regulate the entry and accumulation of α-syn preformed fibrils (PFFs) in cells. We identified key genes and pathways specifically implicated in α-syn PFFs intracellular accumulation, including heparan sulfate proteoglycans (HSPG) biosynthesis and Golgi trafficking. All confirmed hits affected heparan sulfate (HS), a post-translational modification known to act as a receptor for proteinaceous aggregates including α-syn and tau. Intriguingly, deletion of SLC39A9 and C3orf58 genes, encoding respectively a Golgi-localized exporter of Zn2+, and the Golgi-localized putative kinase DIPK2A, specifically impaired the uptake of α-syn PFFs, by preventing the binding of PFFs to the cell surface. Mass spectrometry-based analysis of HS chains in SLC39A9-/- and C3orf58-/- cells indicated major defects in HS homeostasis. Additionally, Golgi accumulation of NDST1, a prime HSPG biosynthetic enzyme, was detected in C3orf58-/- cells. Interestingly, C3orf58-/- human iPSC-derived microglia and dopaminergic neurons exhibited a strong reduction in their ability to internalize α-syn PFFs. Altogether, our data identifies new modulators of HSPGs that regulate α-syn PFFs cell surface binding and uptake.

DOI: https://doi.org/10.1038/s42003-025-08786-2
Curr Opin Nephrol Hypertens. 2025 Oct 06.

SLC26A1 directs sulfate homeostasis in health and disease.

Felix Pitzken, Anna Köttgen, Peter S Aronson, Felix Knauf.

   PURPOSE OF REVIEW: Sulfate is essential for the sulfation of proteoglycans to maintain cell function. The mechanisms regulating the 'ins and outs' of systemic sulfate balance remain incompletely understood. SLC26A1 is an anion exchanger expressed in the kidney. It has recently been identified as a key regulator of plasma sulfate homeostasis in humans. This review summarizes current insights into SLC26A1 function and its role in human diseases.
RECENT FINDINGS: Slc26a1-knockout mouse models exhibit reduced plasma sulfate and abnormal sulfate and oxalate homeostasis, accompanied by augmented susceptibility to acetaminophen-induced liver injury and kidney stone disease, although findings on oxalate homeostasis are inconsistent. In humans, rare and common SLC26A1 variants are associated with hyposulfatemia, musculoskeletal abnormalities, and, in some cases, nephrolithiasis. Functional assays confirm disrupted sulfate and oxalate transport of damaging variants. However, the knockout mouse models have been incompletely characterized, and few patients with damaging SLC26A1 variants have been characterized regarding sulfate and oxalate homeostasis and associated diseases.
SUMMARY: SLC26A1 emerges as a key regulator of sulfate homeostasis, with potential roles in hepatic detoxification, skeletal integrity, and kidney stone disease. Additional mouse models with tissue-specific gene deletion are needed to delineate the role of SLC26A1 in sulfate and oxalate homeostasis as well as disease pathogenesis. Identification of additional patients with damaging variants in SLC26A1 as well as larger population studies may help to elucidate causal relationships of SLC26A1 activity with clinical outcomes.

Keywords:  SLC26A1; nephrolithiasis; oxalate transport; skeletal disease; sulfate homeostasis

DOI:  https://doi.org/10.1097/MNH.0000000000001123
Int J Biol Macromol. 2025 Oct 05. pii: S0141-8130(25)08628-3. [Epub ahead of print] 148071

Review on seaweed derived sulfated and non-sulfated marine polysaccharides as multifunctional food ingredients: Structure-function relationships, bioactivities and applications in functional foods.

Rinish Mortin John, Aishwarya Lakshmi Thasvanth Raj, Yuvaraj Dinakarkumar, Arokiyaraj Selvaraj, Muthezhilan Radhakrishnan.

  Seaweed-derived hydrocolloids encompass both sulfated and non-sulfated polysaccharides that play a pivotal role in food technology and human health. Sulfated polysaccharides such as carrageenan, fucoidan, ulvan, and porphyran exhibit distinctive structural features that confer potent bioactive properties, including antioxidant, immunomodulatory, antimicrobial, and prebiotic activities. Non-sulfated polysaccharides such as alginate and agar (although primarily a galactan, contains sulfated agaropectin fractions) are equally important for their remarkable gel-forming abilities, rheological modulation, and stabilization functions in diverse food matrices. The functionality of these compounds is governed by their macromolecular architecture, degree of sulfation or uronic acid content, and extraction methods, which collectively influence gelation behavior, viscosity, and bioavailability. Recent advances in green extraction and chemical/physical modification strategies have further enhanced both the techno-functional and bioactive performance of these hydrocolloids. This review critically examines the structure-function relationships of major sulfated and non-sulfated seaweed polysaccharides, highlighting their gel-forming capacity and multifunctional health benefits. By integrating insights from food chemistry, marine biotechnology, and nutrition, the manuscript underscores the potential of seaweed polysaccharides as next-generation functional food ingredients that combine technological versatility with bioactive value.

Keywords:  Marine hydrocolloid; Structure–function relationship; Techno-functional properties

DOI:  https://doi.org/10.1016/j.ijbiomac.2025.148071
Drug Metab Dispos. 2025 Sep 08. pii: S0090-9556(25)09168-8. [Epub ahead of print]53(10): 100159

Elevated plasma levels of the uremic toxin indoxyl sulfate positively correlates with plasma arsenic levels in acute promyelocytic leukemia patients: Evidence of renal AQP7 suppression mediated by the aryl hydrocarbon receptor.

Shuo Tian, Yangyi Hao, Chenli Yue, Wenlei Zhang, Longyu Li, Lijuan Yue, Kai Ren, Yutong Liu, Xin Hai.

  This study investigated the effects of indoxyl sulfate (IS), an endogenous metabolite and uremic toxin, on arsenic trioxide pharmacokinetics in acute promyelocytic leukemia patients with varying renal function. Plasma IS levels demonstrated a significant positive correlation with monomethylarsonic acid and dimethylarsinic acid concentrations in patients (P < .0001). In adenine-induced renally impaired rats, IS similarly correlated with elevated plasma inorganic arsenic (iAs), monomethylarsonic acid, and dimethylarsinic acid levels. Protein expression analysis indicated a downregulation of renal aquaporin (AQP) 7 and AQP3. In vitro studies confirmed that IS selectively inhibits AQP7 expression (62.1% reduction at 100 μM) through aryl hydrocarbon receptor activation in human embryonic kidney 293T cells, while AQP3 remained unaffected. Collectively, IS increases plasma arsenic concentration in renally impaired acute promyelocytic leukemia patients via aryl hydrocarbon receptor-mediated suppression of renal AQP7. SIGNIFICANCE STATEMENT: This study reveals that indoxyl sulfate inhibits renal aquaporin 7 via aryl hydrocarbon receptor activation, increasing plasma arsenic in arsenic trioxide-treated acute promyelocytic leukemia patients with renal impairment. As the first demonstration of this mechanism, to our knowledge, it provides crucial insights for optimizing therapy and reducing toxicity risks.

Keywords:  Aquaporin 7; Arsenic trioxide; Concentration; Indoxyl sulfate; Renal impairment

DOI:  https://doi.org/10.1016/j.dmd.2025.100159
Int J Biol Macromol. 2025 Oct 04. pii: S0141-8130(25)08672-6. [Epub ahead of print]330(Pt 2): 148115

Dermatan sulfate-recognized UiO-66 metal-organic frameworks: An active and passive targeting nanomedicine for methotrexate delivery.

Amin Mahoutforoush, Monireh Rasoulzadehzali, Elghar Ashrafi, Mohammadreza Tajik, Elham Golpayegani, Mohammad Mehramiz, Hamed Hamishehkar, Fahimeh Kazeminava, Siamak Javanbakht.

  This study introduces a novel drug delivery system (DDS) by integrating zirconium-based metal-organic frameworks (UiO-66) with glycosaminoglycans, specifically dermatan sulfate (DS), to achieve an active and passive targeting nanomedicine. The synthesized UiO-66/DS nanocomposite demonstrated successful structural validation and exhibited a pH-dependent release profile for methotrexate (MTX), with 75 % release at acidic pH 4.5 (simulating acidic environment of intracellular compartments) versus <30 % at physiological pH 7.4 over 96 h. Cytotoxicity assays revealed enhanced cancer cell apoptosis in MCF-7 cell line via CD44 receptor-mediated uptake, coupled with minimal hemolytic activity (<4 %), underscoring the system's therapeutic safety. These findings highlight the potential of UiO-66/DS nanocomposite as a dual-targeted platform for anticancer therapies, taking advantage of its pH-responsive behavior in acidic tumor microenvironments and its enhanced cellular interactions mediated by conjugating sulfated polysaccharide.

Keywords:  Dermatan sulfate; Drug delivery; Metal-organic framework; Methotrexate; Receptor-mediated

DOI:  https://doi.org/10.1016/j.ijbiomac.2025.148115
Exp Mol Pathol. 2025 Oct 03. pii: S0014-4800(25)00047-4. [Epub ahead of print]144 104997

Glycocalyx shedding as a clinical biomarker in critical illness.

Ayako Inoda, Keiko Suzuki, Hiroyuki Tomita, Hideshi Okada.

  The endothelial glycocalyx, a carbohydrate-rich layer lining the vascular endothelium, plays a critical role in maintaining vascular homeostasis by regulating permeability, leukocyte adhesion, and inflammatory signaling. Its degradation has been implicated in endothelial dysfunction and organ damage in various diseases. Biomarkers derived from glycocalyx components, particularly Syndecan-1 (SDC-1) and heparan sulfate (HS), can be detected in blood and urine, providing a potential window into vascular injury. In this narrative review, we explore the clinical potential of glycocalyx-derived biomarkers, with a focus on SDC-1, in a broad spectrum of conditions, including sepsis, coronavirus disease, acute respiratory distress syndrome, kidney diseases, cardiovascular disorders, autoimmune diseases, cancer, trauma, and pregnancy-related complications. We highlight the pathophysiological mechanisms of glycocalyx degradation, assess the diagnostic and prognostic utility of SDC-1, and summarize emerging therapeutic strategies to preserve glycocalyx integrity. Given their strong association with disease severity and outcomes, glycocalyx-derived biomarkers may enable earlier diagnosis, improved risk stratification, and personalized treatment, supporting more informed clinical decision-making across diverse medical conditions.

Keywords:  Biomarker; Endothelial glycocalyx; Heparan sulfate; Syndecan-1; Vascular dysfunction

DOI:  https://doi.org/10.1016/j.yexmp.2025.104997
Sci Signal. 2025 Oct 07. 18(907): eadu6357

An ectopic Hedgehog signaling axis drives directional tumor outgrowth in a mouse model of hereditary multiple osteochondromas.

Sarah E Catheline, Christina Mundy, Cheri Saunders, Sadhana Ramesh, Kelly A Shaughnessy, Juliet Chung, Eiki Koyama, Maurizio Pacifici.

Osteochondromas characterize the rare pediatric disorder hereditary multiple osteochondromas (HMO). The tumors originate from the growth plate perichondrium along skeletal elements, appear first as ectopic cartilage, and then grow unidirectionally, colliding with and damaging surrounding structures. HMO is caused by mutations that affect the heparan sulfate (HS) synthases EXT1 or EXT2, leading to HS deficiency and aberrant activity of HS-binding growth factors. We investigated the signaling pathways and mechanisms underlying tumor growth in HMO using mice with conditional Ext1 deficiency in the growth plate and perichondrium. Developing tumors displayed active Hedgehog (Hh) signaling within their cartilaginous moiety and the presence of parathyroid hormone-related protein (PTHrP) at their distal edge, generating an ectopic Hh-PTHrP axis orthogonal to the one directing normal bone lengthening at the adjacent growth plate. In Ext1 mutants, loss of the Hh signaling effector Smoothened (Smo) reduced tumor growth, whereas heterozygous loss of the Smo inhibitor Patched1 (Ptch1) increased tumor growth. Two HS-binding growth factors that promote normal cartilage growth in the growth plate, BMP2 and activin A, did not exert their normal prochondrogenic activity when Hh signaling was blocked, demonstrating that Hh signaling is essential for chondrogenesis. Together, our findings show that osteochondromas usurp a physiological signaling mechanism to guide and propel their directional outgrowth, enabling them to damage surrounding tissues, and suggest potential targets for therapeutic intervention.

DOI: https://doi.org/10.1126/scisignal.adu6357
Carbohydr Res. 2025 Sep 30. pii: S0008-6215(25)00316-7. [Epub ahead of print]558 109690

Molecular dynamics insights into glycosaminoglycan effects on the extracellular domains of syndecan 2 and 4 dimers.

Sergey A Samsonov, Sylvie Ricard-Blum.

  The four mammalian syndecans (1-4) are transmembrane proteoglycans, which all bear three heparan sulfate chains covalently attached to their core protein. They contribute to cell signaling, and play a role in numerous diseases. The syndecans dimerize via their transmembrane domains, and their cytoplasmic domains form a compact intertwined dimer. This computational study aims at building models of the dimers of the extracellular domain of syndecans 2 and 4, and to determine if and how the glycosaminoglycan (GAG) chains attached to their core proteins affect the dimer structural and dynamic properties. The GAGosylation was mimicked by adding three heparin hexadecasaccharide chains to each extracellular domain. The initial conformations of the dimers, and specifically the distances between the C-termini of the extracellular domains, were defined using our SAXS experimental data and literature data. The four generated models (i.e., dimers of the extracellular domains of syndecans 2 and 4 with or without GAG chains) were then subjected to multiple independent microsecond-scale molecular dynamics simulations in implicit solvent, and their trajectories were analyzed. The structural and dynamic descriptors calculated from the ensembles of the four models followed unimodal distributions. No well-defined conformational states were observed. GAGosylation increased the compactness of the dimer of extracellular domain of syndecan 2, but not of the dimer of syndecan 4. Our computational approach provides novel structural insights into syndecan 2 and 4 dimers and the structural role of GAGs on conformations of proteoglycan core proteins, which remains challenging to investigate experimentally, and even more challenging when attached to disordered core proteins such as those of syndecans.

Keywords:  Dimerization; Glycosaminoglycans; Glycosylation; Intrinsic disorder; Molecular dynamics; Syndecans

DOI:  https://doi.org/10.1016/j.carres.2025.109690
Ren Fail. 2025 Dec;47(1): 2567528

Fibroblast growth factor-23 remodels vascular extracellular matrix via glycosaminoglycan induction: implications for calcification in chronic kidney disease.

Christian Freise, Tia Jernej, Susanne Metzkow, Jörg Schnorr, Matthias Taupitz.

  Chronic kidney disease (CKD) leads to accumulation of uremic toxins, which contribute to cardiovascular disease (CVD) and mortality. Among these, fibroblast growth factor 23 (FGF-23), a bone-derived hormone, is associated with arterial stiffness, vascular calcification, and left ventricular hypertrophy. However, the mechanisms linking elevated FGF-23 levels to vascular alterations remain poorly understood. We hypothesized that FGF-23 modulates the expression of sulfated glycosaminoglycans (sGAGs) and hyaluronic acid (HA) in vascular cells. Rat vascular smooth muscle cells (VSMCs) and human endothelial cells (ECs) were treated with FGF-23 ± its co-receptor Klotho and analyzed using qPCR, Western blotting, Blyscan assay, Alcian blue staining, ELISA, and reporter assays. FGF-23 significantly increased sGAG (2.5-fold) and HA (1.6-fold) levels in VSMCs, and sGAG (50-fold) and HA (3.7-fold) levels in ECs. Klotho alone induced a ∼72-fold rise in sGAGs in ECs but had no effect in VSMCs. FGF-23 also upregulated GAG-specific gene expressions of carbohydrate sulfotransferase 1 and xylosyltransferase 2 ∼1.6-fold and increased HA-specific hyaluronan synthase-2 and -3 protein expression. These effects were mediated by ERK and NF-κB signaling. To evaluate biological relevance, we assessed calcium- and phosphate-induced calcification in VSMCs. FGF-23 significantly enhanced calcification by ∼65%, which paralleled elevated sGAG levels. Inhibition of GAG sulfation with NaClO3 significantly reduced sGAGs and prevented FGF-23-induced calcification. Similarly, the FGFR inhibitor AZD4547 abolished FGF-23-induced increases in sGAGs and calcification in both VSMCs and ECs. These findings indicate that FGF-23 modulates vascular GAG composition and promotes calcification, thereby contributing to pathological vascular remodeling in CKD.

Keywords:  Chronic kidney disease; cardiovascular disease; extracellular matrix; fibroblast growth factor 23; glycosaminoglycans; vascular calcification

DOI:  https://doi.org/10.1080/0886022X.2025.2567528
Mol Metab. 2025 Oct 08. pii: S2212-8778(25)00174-7. [Epub ahead of print] 102267

Adipocyte Heparan Sulfate Determines Type 2 Diabetes Susceptibility in Mice via FGF1-Mediated Glucose Regulation.

Chung-Jui Yu, Ariane R Pessentheiner, Sihao Liu, Sarah Wax, Marissa L Maciej-Hulme, Chelsea D Painter, Bastian Ramms, Daniel R Sandoval, Anthony Quach, Natalie DeForest, G Michelle Ducasa, Chiara Tognaccini, Caroline Labib, Norah Al-Azzam, Friederike Haumann, Greg Trieger, Patrick Secrest, Amit Majithia, Aaron C Petrey, Kamil Godula, Annette R Atkins, Michael Downes, Ronald M Evans, Philip L S M Gordts.

Obesity is the principal driver of insulin resistance, and lipodystrophy is also linked with insulin resistance, emphasizing the vital role of adipose tissue in glucose homeostasis. The quality of adipose tissue expansion is a critical determinant of insulin resistance predisposition, with individuals suffering from metabolic unhealthy adipose expansion exhibiting greater risk. Adipocytes are pivotal in orchestrating metabolic adjustments in response to nutrient intake and cell intrinsic factors that positively regulate these adjustments are key to prevent Type-2 diabetes. Employing unique genetic mouse models, we established the critical involvement of heparan sulfate (HS), a fundamental element of the adipocyte glycocalyx, in upholding glucose homeostasis during dietary stress. Genetic models that compromise adipocyte HS accelerate the development of high-fat diet-induced hyperglycemia and insulin resistance, independent of weight gain. Mechanistically, we show that perturbations in adipocyte HS disrupts endogenous FGF1 signaling, a key nutrient-sensitive effector. Furthermore, compromising adipocyte HS composition detrimentally impacts FGF1-FGFR1-mediated endocrinization, with no significant improvement observed in glucose homeostasis. Our data establish adipocyte HS composition as a determinant of Type 2 diabetes susceptibility and the critical dependency of the endogenous adipocyte FGF1 metabolic pathway on HS.

DOI: https://doi.org/10.1016/j.molmet.2025.102267
Sci Adv. 2025 Oct 10. 11(41): eady3442

Molecular mechanism underlying phosphate distribution by SULTR family transporter SPDT in Oryza sativa.

Sunzhenhe Fang, Yang Zhao, Xue Zhang, Fang Yu, Peng Zhang.

Phosphorus (P) limitation severely affects crop yields. To address the molecular basis of inorganic phosphate (Pi) specific transport within the sulfate transporter (SULTR) family, we determined the cryo-electron microscopy structures of Oryza sativa SULTR-like phosphorus distribution transporter (OsSPDT), a key Pi transporter for grain allocation, in apo- and Pi-binding states. OsSPDT forms a domain-swapped homodimer with each protomer containing an N-terminal domain (NTD), a transmembrane domain (TMD) divided into core and gate subdomains, and a C-terminal sulfate transporter and antisigma factor (STAS) domain. The structure adopts a cytoplasm-facing conformation with Pi coordinated at the core-gate interface. Key residues, including SPDT-unique Ser170, mediate Pi specificity within the binding pocket, distinguishing it evolutionarily from sulfate transporters within the SULTR family. Domain-swapping and mutational studies demonstrate functional interdependence of the NTD, TMD, and STAS domains. This work elucidates Pi selectivity in plant SULTR transporters and provides a molecular basis for developing low-phytate rice via OsSPDT gene editing.

DOI: https://doi.org/10.1126/sciadv.ady3442
Wound Repair Regen. 2025 Sep-Oct;33(5):33(5): e70096

Potential of Heparan Sulphate Mimetics Integrated Into Collagen Scaffolds for Enhanced Skin Wound Healing.

Nancy Avila-Martinez, Roman Krymchenko, Merel Gansevoort, Maren Pfirrmann, Sofia Aparicio, Agnes Choppin, Franck Chiappini, Denis Barritault, Martijn Verdoes, Toin H van Kuppevelt, Bouke K H L Boekema, Willeke F Daamen.

  Optimal healing of full-thickness skin wounds remains a clinical challenge. While current skin substitutes aid burn wound management, there is still a need to effectively minimize scarring. Therefore, we developed type I collagen scaffolds with covalently bound ReGeneraTing Agent (RGTA) OTR4120 (OTR), a synthetic heparan sulphate analogue resistant to glycanase degradation (Col I + OTR). To further stimulate skin regeneration, collagen scaffolds with and without OTR4120 were subsequently loaded with sonic hedgehog (SHH), a key effector molecule in embryogenesis. The presence of OTR4120 and SHH in scaffolds was biochemically and histologically confirmed after crosslinking and sterilization. SHH was found deeper into collagen scaffolds in the presence of OTR4120. Addition of SHH to scaffolds showed lower expression of M1-like cell surface markers, while Col I + OTR significantly enhanced IL-10 production. The potential of OTR4120 in wound healing was further evaluated in vivo using a rat full-thickness wound model over 28 days. By day 14, macroscopic images revealed that OTR-treated wounds better maintained the original wound shape. Histological analysis showed increased blood vessel formation, fewer scaffold remnants and more contiguous sebaceous glands in the granulation tissue with Col I + OTR scaffolds. This study demonstrates that OTR4120 could be a promising addition to acellular skin substitutes for improving acute wound healing.

Keywords:  OTR4120; biomaterials; macrophages; rat model; sonic hedgehog

DOI:  https://doi.org/10.1111/wrr.70096
BMC Genomics. 2025 Oct 08. 26(1): 895

Identification and evolution of the plant sulfotransferase family.

Shuangxin Han, Zhujun Chen, Quanlong Liu, Yueying Ding, Jia Wang, Hongbo Liu, Junyang Zou, Zhiying Hong, Hongmei Zhang, Wenping Yang, Lan Zhang, Hongwei Liu, Min Yuan.



Keywords:  Green plants; HGT; Lineage-specific; Origin; Sulfotransferases; TD

DOI:  https://doi.org/10.1186/s12864-025-12117-4