bims-supasi Biomed News
on Sulfation pathways and signalling
Issue of 2025–09–28
seventeen papers selected by
Jonathan Wolf Mueller, University of Birmingham
  1. Pan-Amyloid Reactive Peptides p5+14 and p5R Exhibit Specific Charge-Dependent Binding to Glycosaminoglycans.
  2. The Hydrophilic Domain of HSulf Endosulfatases: An Intrinsically Disordered Region Governing Enzyme Functions and Therapeutic Potential.
  3. Interaction Between Heparan Sulfate Oligosaccharide and the Receptor-Binding Domain of the Wild-Type and Omicron Variant of the SARS-CoV-2 Spike Protein.
  4. A Novel Marine Bacterium-Derived Heparinase with High Potential for the Structure-Function Studies of Heparin/Heparan Sulfate.
  5. Three semi-synthetic approaches to a set of curdlan sulfate polysaccharides with different sulfation patterns.
  6. Structural characterization and biological activities of sulfated polysaccharides from Antrodia cinnamomea.
  7. Expression of a nematode chondroitin hydrolase in Pichia pastoris for low-molecular-weight chondroitin preparation.
  8. Implantable Bioresorbable Scaffold with Fucosylated Chondroitin Sulfate as a Promising Device for Delayed Stimulation of Hematopoiesis.
  9. Structure and preliminary anti-inflammatory activity of a novel sulfated α-glucan from Volutharpa ampullacea perryi.
  10. Serum Indoxyl Sulfate as a Potential Biomarker of Aortic Stiffness in Persons with Type 2 Diabetes Mellitus.
  11. Adrenarche, social cognition, and the development and evolution of autism spectrum traits.
  12. Benchmark of Available Explicit Solvent Models in CHARMM36m to Characterize Glycosaminoglycans.
  13. Reactive Oxygen Species-Responsive Sulfated Polysaccharide-Based Nanogels for Ischemic Stroke: A Precision Therapy through Pathological Microenvironment Modulation.
  14. Enhanced soluble expression and improved catalytic efficiency of Heparinase II by fusion of GST tag to the backside of the active pocket.
  15. Sulfate biology genes are associated with mineralization in mouse and human.
  16. Serum P-Cresyl Sulfate Is Associated with Peripheral Arterial Stiffness in Chronic Hemodialysis Patients.
  17. Exosomal miR-27a-5p inhibits indoxyl sulfate-induced cardiac dysfunction by targeting the USF2/FUT8 axis.
  1. Pharmaceuticals (Basel). 2025 Sep 06. pii: 1340. [Epub ahead of print]18(9):
    Pan-Amyloid Reactive Peptides p5+14 and p5R Exhibit Specific Charge-Dependent Binding to Glycosaminoglycans.
    Trevor J Hancock, Angela D Williams, James S Foster, Jonathan S Wall, Emily B Martin.
      Background: Polybasic peptides are being developed as components of reagents for diagnosing and treating patients with systemic amyloidosis. In addition to fibrils, amyloid deposits ubiquitously contain heparan sulfate proteoglycans. We have hypothesized that pan amyloid-targeting peptides can specifically engage, in addition to fibrils, a subset of glycosaminoglycans (GAGs) with high negative charge density. In this study, we characterized the binding of peptides p5+14 (a PET imaging agent for amyloid [124I-evuzamitide]) and p5R (a fusion protein used in the therapeutic AT-02) to GAGs. Methods: The peptide structure was evaluated in the presence of low molecular weight heparin using circular dichroism, and their interaction with synthetic GAGs of varying length and charge was interrogated. The binding patterns of p5+14 and p5R were compared using correlation analyses. Results: The peptides exist as mixed structural-fractions in solution but adopt an α-helical structure in the presence of heparin. Both peptides preferentially recognize heparin and heparan sulfate GAGs with a linear positive correlation between binding and the total charge and charge density. Conclusions: These peptides have previously been shown to specifically target amyloid deposits in vivo. A component of this specificity is their preferential interaction with a subset of heparan sulfate GAGs that have high charge density, potentially related to the degree of 6-O-sulfation. These data support the hypotheses that amyloid-associated GAGs have unique sulfation patterns, thereby explaining why these peptides do not bind GAGs found on the plasma membrane and extracellular matrix of healthy tissues.
    Keywords:  PET imaging; amyloidosis; diagnostics; heparin binding peptides; pan-amyloid peptides; peptide p5+14; peptide p5R
    DOI:  https://doi.org/10.3390/ph18091340
  2. Glycobiology. 2025 Sep 26. pii: cwaf060. [Epub ahead of print]
    The Hydrophilic Domain of HSulf Endosulfatases: An Intrinsically Disordered Region Governing Enzyme Functions and Therapeutic Potential.
    C Demongin, J Tao, N El Omrani, K Uchimura, N Basdevant, R Daniel.
      Human extracellular endosulfatases HSulf-1 and HSulf-2 catalyze the selective 6-O-desulfation of heparan sulfate (HS), critically shaping the sulfation code that governs glycosaminoglycan (GAG)-mediated signaling. A unique feature of these enzymes is their hydrophilic domain (HD), an intrinsically disordered, non-conserved segment absent from all other human sulfatases. Despite lacking homology to known protein domains, the HD has emerged as a key regulatory module for substrate recognition, enzyme localization, and processive activity along HS chains. In this review, we dissect the structural and functional roles of the HD, with emphasis on its dynamic interaction with HS motifs and potential modulation of protein-GAG complexes. We also explore how its intrinsically disordered nature may confer conformational flexibility advantageous for navigating the complex landscape of extracellular glycans. Given the implication of HSulfs in diverse physiological and pathological contexts, including cancer, the HD presents a promising therapeutic target for the selective inhibition of endosulfatase activity. We discuss the challenges and perspectives in targeting intrinsically disordered regions (IDRs) in GAG-binding proteins, and highlight how the HD of HSulfs provides a paradigmatic example of non-canonical domains orchestrating fine-tuned GAG editing in the extracellular matrix.
    Keywords:  HSulf endosulfatases; cancer therapeutics; heparan sulfate (HS); hydrophilic domain (HD); intrinsically disordered regions (IDRs)
    DOI:  https://doi.org/10.1093/glycob/cwaf060
  3. Biomolecules. 2025 Sep 19. pii: 1343. [Epub ahead of print]15(9):
    Interaction Between Heparan Sulfate Oligosaccharide and the Receptor-Binding Domain of the Wild-Type and Omicron Variant of the SARS-CoV-2 Spike Protein.
    Marco Mandalari, Michela Parafioriti, Minghong Ni, Francesca Benevelli, Monica Civera, Stefano Elli, Marco Guerrini.
      Heparan sulfate proteoglycans serve as initial attachment sites for several viruses and bacteria. Recent studies suggest that SARS-CoV-2 similarly exploits these glycosaminoglycans, facilitating conformational changes in the spike protein that promote the interaction between the receptor-binding domain (S1-RBD) and the cellular angiotensin-converting enzyme 2 receptor (ACE2), thereby triggering the virus internalization process. The molecular details that drive this process, particularly the co-receptor role of heparan sulfate (HS), remain incompletely understood. The interaction between an HS hexasaccharide (hexa) and the N343 glycosylated S1-RBD of the wild-type (WT) and Omicron variant of SARS-CoV-2 was investigated. The conformational properties of hexa with these S1-RBDs in unbound and bound states are explored using multiple independent MD simulations; the protein binding epitope of hexa, as well as the details of its interaction with S1-RBD of the Omicron variant, are characterized by comparing experimental and theoretical 1H STD NMR signals. This investigation identifies the role played by the glycosyl moiety at N343 in potentially affecting this interaction in both WT and Omicron S1-RBD, explaining the observed low specificity and multi-modal nature of the interaction between HS oligosaccharides and these S1-RBDs.
    Keywords:  1H-STD NMR spectroscopy; SARS-CoV-2; glycosylation; heparan sulfate; heparin; molecular dynamic simulation; molecular recognition; recognition protein S spike
    DOI:  https://doi.org/10.3390/biom15091343
  4. J Agric Food Chem. 2025 Sep 20.
    A Novel Marine Bacterium-Derived Heparinase with High Potential for the Structure-Function Studies of Heparin/Heparan Sulfate.
    Xiangyu Xu, Qingdong Zhang, Xiaoyu Cui, Yuan Liu, Yingying Xu, Xu Wang, Lin Wei, Ruiqing Cheng, Wenshuang Wang, Xiying Zhang, Fuchuan Li.
      Heparinases are crucial for deciphering heparin/heparan sulfate (HP/HS) structures; yet most known heparinases from terrestrial sources share similar properties. Here, we identify a novel heparinase, HD1492, from HP-cultured marine bacterial metagenomes. Although phylogenetically classified as heparinase II, its exhibits unique enzymatic properties by preferentially cleaving sulfated regions in HP/HS and generating resistant oligosaccharides from low-sulfated HS. These oligosaccharides have a signature feature: one or several nonsulfated disaccharides linked to an N-sulfated disaccharide at the reducing end. This property enables HD1492 to reveal the distribution and composition of nonsulfated domains in HP/HS─overcoming the limitation of conventional disaccharide analysis─as validated in mouse organ-derived GAGs and the drug sulodexide. Overall, the unique enzymatic properties of HD1492 confer innovative value that distinguishes it from terrestrial heparinases, providing a much-needed tool for the resolution of HP/HS structural and functional domains and the development and quality control of related products.
    Keywords:  heparan sulfate; heparin; heparinase; marine bacteria; substrate selectivity
    DOI:  https://doi.org/10.1021/acs.jafc.5c08686
  5. Front Mol Biosci. 2025 ;12 1635564
    Three semi-synthetic approaches to a set of curdlan sulfate polysaccharides with different sulfation patterns.
    Fabiana Esposito, Agnieszka Zabłocka, Serena Traboni, Alfonso Iadonisi, Sabina Górska, Emiliano Bedini.
       Introduction: Curdlan is a linear homopolysaccharide composed of β-1→3-linked glucose units. It is extracted from some bacteria as an exopolysaccharide and employed in the food industry due to its remarkable rheological and thermal behaviors. Furthermore, its ability to form gel encapsulations with several drugs and its roles in innate and adaptive immunity have fueled an increasing interest in pharmaceutical applications of curdlan and its derivatives. Among them, curdlan sulfate derivatives disclosed not only a highly enhanced water solubility concerning native curdlan but also an efficient immunomodulatory potential in both in vitro and in vivo assays.
    Methods: To detect the effects of the sulfation degree and sulfation pattern on the immunological activity of curdlan sulfate, a set of regioselectively sulfated curdlan polysaccharides was semi-synthesized and fully characterized utilizing nuclear magnetic resonance (NMR) spectroscopy techniques.
    Results: Although some regioselectively sulfated curdlan derivatives were already reported some years ago, in this work, a comprehensive semi-synthetic study was developed by investigating three different, complementary approaches based on direct regioselective sulfation or desulfation reactions or multistep protection-sulfation-deprotection procedures.
    Discussion: Some of the semi-synthesized curdlan sulfate derivatives were selected as representatives of different sulfation degrees and patterns and subjected to a panel of immunological assays to define some structure-activity relationships.
    Keywords:  curdlan; glycans; immunological assays; regioselective sulfation; semi-synthesis; sulfation pattern
    DOI:  https://doi.org/10.3389/fmolb.2025.1635564
  6. Int J Biol Macromol. 2025 Sep 19. pii: S0141-8130(25)08358-8. [Epub ahead of print]329(Pt 1): 147801
    Structural characterization and biological activities of sulfated polysaccharides from Antrodia cinnamomea.
    Chia-I Jen, Wei-Lun Qiu, Chi-Hsein Chao, Mei-Kuang Lu.
      Antrodia cinnamomea, an edible and medicinal mushroom, has been widely used for functional foods and dietary supplements in Taiwan. This study discovered β-1,6-linked sulfated galactoglucans with or without branches from A. cinnamomea mycelia, and elucidated their anti-inflammatory and anti-cancer potentials. Results showed that K1, a sulfated polysaccharide (SPS) isolated from A. cinnamomea mycelia cultured for 49 days with 1 mM potassium sulfate, possessed potential anti-inflammation in that K1 100 μg/ml suppressed tumor necrosis factor-α (TNF-α) production by 49%, and anti-cancer activity with K1 800 μg/ml suppressed lung cancer H1975 cells by 57%. Based on the molecular weight distribution, three SPS fractions (K1 F1, K1 F2, and K1 F3) were purified from K1. Among the three fractions, K1 F2 and K1 F3 were found to contain high sulfate content with values of 4.46 and 3.77 mmol/g, respectively. The representative repeating unit of K1 F2 contained a sulfated β-1,6-linked glucosyl backbone with a long α-/β-galactoglucose branch attached at the 3-O position of backbone, while the proposed repeating unit of K1 F3 included an unbranched sulfated β-1,6-linked glucosyl residue. K1 F2 and K1 F3 attenuated the LPS-induced inflammation in RAW264.7 cells via p38 and AKT pathways, respectively. K1 F2 possessed potential anti-cancer activity against H1975 lung cancer cells through TGFβRI and apoptotic pathways. In conclusion, K1 F2, a long-branched sulfated galactoglucan, and K1 F3, an unbranched sulfated glucan, may be good candidates for anti-inflammatory and anti-cancer applications.
    Keywords:  Anti-inflammation; Anti-lung cancer; Antrodia cinnamomea; Galactoglucan; Sulfated polysaccharide
    DOI:  https://doi.org/10.1016/j.ijbiomac.2025.147801
  7. Int J Biol Macromol. 2025 Sep 23. pii: S0141-8130(25)08426-0. [Epub ahead of print]329(Pt 2): 147869
    Expression of a nematode chondroitin hydrolase in Pichia pastoris for low-molecular-weight chondroitin preparation.
    Ziyang Ye, Shuiyuan Zhou, Xiangzhao Mao, Yin Li, Taicheng Zhu.
      Chondroitin sulfate (CS) is widely used in dietary supplements and pharmaceuticals due to its biological activities. However, the large molecular size of high-molecular-weight CS limits its bioavailability and therapeutic efficacy, necessitating the production of low-molecular-weight CS or oligosaccharides to enhance absorption and bioactivity. Here, we report the heterologous expression of recombinant chondroitin hydrolase (rCeChnase) from Caenorhabditis elegans in the methylotrophic yeast Pichia pastoris. This expression system offers an environmentally friendly and cost-effective alternative to animal-derived hyaluronidases, with rCeChnase demonstrating significantly higher catalytic efficiency. The enzyme exhibited optimal activity at 37 °C and pH 5.0, with the highest stability at 25 °C and pH 5.0. A five-fold increase in enzymatic activity production, reaching over 40,000 U/mL, was achieved by lowering the culture temperature to 25 °C. rCeChnase showed a strong preference for non-sulfated chondroitin, with minimal activity towards CS and hyaluronic acid. The enzyme was used to efficiently degrade high-molecular-weight chondroitin into low-molecular-weight chondroitin and oligosaccharides, which were verified by agarose gel electrophoresis and LC-MS. rCeChnase's endo-β1,4-hydrolysis activity was confirmed, and the major product was chondroitin tetrasaccharides. This study highlights the industrial potential of rCeChnase as a promising tool for the production of native low-molecular-weight chondroitin and oligosaccharides.
    Keywords:  Pichia pastoris; chondroitin hydrolase; low-molecular-weight chondroitin
    DOI:  https://doi.org/10.1016/j.ijbiomac.2025.147869
  8. Mar Drugs. 2025 Aug 28. pii: 344. [Epub ahead of print]23(9):
    Implantable Bioresorbable Scaffold with Fucosylated Chondroitin Sulfate as a Promising Device for Delayed Stimulation of Hematopoiesis.
    Natalia Y Anisimova, Olga V Rybalchenko, Natalia S Martynenko, Georgy V Rybalchenko, Elena A Lukyanova, Maria I Bilan, Anatolii I Usov, Mikhail V Kiselevskiy, Nikolay E Nifantiev.
      The aim of this study was to evaluate the prospects of using natural fucosylated chondroitin sulfate (FCS) from the sea cucumber Cucumaria japonica as the active component of an implantable biodegradable scaffold to stimulate hematopoiesis in mice with cyclophosphamide (CPh)-induced myelosuppression. The scaffolds were based on bioresorbable Fe-Mn-C and Fe-Mn-Pd alloys after equal-channel angular pressing (ECAP). The efficiency of the developed constructs with FCS was compared with the activity of the same scaffolds loaded with recombinant human granulocyte colony stimulating factor, as well as solutions of these active compounds administered subcutaneously after the end of the cyclophosphamide (CPh) course. It was found that implantation of the Fe-Mn-C scaffold loaded with FCS most effectively stimulated hematopoiesis, providing a complex effect. This design of the developed constructs contributed to an increase in the concentration not only of leukocytes and neutrophils, but also platelets in the blood, promoted the proliferation of bone marrow cells, increasing the concentration of Ki-67(+) cells, and contributed to the restoration of the morphology of the animals' spleen.
    Keywords:  fucosylated chondroitin sulfate; hemo-stimulation; implant; scaffold
    DOI:  https://doi.org/10.3390/md23090344
  9. Int J Biol Macromol. 2025 Sep 19. pii: S0141-8130(25)08363-1. [Epub ahead of print] 147806
    Structure and preliminary anti-inflammatory activity of a novel sulfated α-glucan from Volutharpa ampullacea perryi.
    Yiling Chen, Yong Qin, Haixin Yi, Xiaoyu Cui, Xu Wang, Xiangyu Xu, Yongmei Chen, Fuchuan Li, Wenshuang Wang.
      Glucans, as versatile biomacromolecules, hold significant application potential across various industries. Volutharpa ampullacea perryi, an affordable deep-sea gastropod, demonstrates considerable commercial promise. In this study, a novel sulfated α-glucan (VpG) was isolated and identified from Volutharpa ampullacea perryi for the first time. Compared to other α-sulfated glucans, it has a high degree of sulfation (18.6 %) and an ultra-high molecular weight of approximately 2250 kDa. Further NMR analysis, including 1H, 13C, COSY, TOCSY, HSQC and HMBC, revealed that the anomeric signals at 5.35 ppm dominated. Therefore, VpG is mainly consisted of a repeating α-(1 → 4)-linked glucose backbone with β-(1 → 6) and β-(1 → 3)-linked glucosyl branches. Furthermore, bioactivity evaluation demonstrated that VpG significantly alleviates inflammation in dextran sulfate sodium-induced mouse models of ulcerative colitis, effectively inhibiting body weight loss by 20 % and colon shortening by 31.26 %. The strong anti-inflammatory activity of VpG indicates its potential in pharmaceutical development and provides a novel approach for the high-value utilization of Volutharpa ampullacea perryi.
    Keywords:  Anti-inflammatory activity; Structural characterization; Sulfated α-glucan; Volutharpa ampullacea perryi
    DOI:  https://doi.org/10.1016/j.ijbiomac.2025.147806
  10. Medicina (Kaunas). 2025 Sep 05. pii: 1607. [Epub ahead of print]61(9):
    Serum Indoxyl Sulfate as a Potential Biomarker of Aortic Stiffness in Persons with Type 2 Diabetes Mellitus.
    I-Min Su, Yi-Yen Teng, Jer-Chuan Li, Chin-Hung Liu, Du-An Wu, Bang-Gee Hsu.
      Background and Objectives: Indoxyl sulfate (IS), a gut microbiota-derived metabolite of tryptophan, is implicated in vascular dysfunction through oxidative stress and inflammation. This study evaluated the association between serum IS levels and aortic stiffness (AS) in patients with type 2 diabetes mellitus (T2DM). Materials and Methods: This cross-sectional study enrolled 80 patients with T2DM from a medical center in eastern Taiwan, excluding patients with malignancy, acute infection, heart failure, or recent cardiovascular events. Serum IS concentrations were quantified using liquid chromatography-mass spectrometry. AS was assessed using carotid-femoral pulse wave velocity (cfPWV), with values > 10 m/s indicating AS. Results: A total of 30 patients (37.5%) had AS. IS levels were significantly higher in the AS group than in the control group (p < 0.001). After multivariate adjustment, IS remained an independent predictor of AS (odds ratio: 2.565, 95% confidence interval: 1.145-5.748, p = 0.022). Linear regression analysis confirmed IS as an independent contributor to cfPWV values (β = 0.261, p = 0.019). Receiver operating characteristic analysis showed fair discriminatory ability (area under the curve = 0.739, p < 0.001). Conclusions: In patients with T2DM, serum IS is an independent predictor of AS and may serve as a promising nontraditional biomarker for cardiovascular risk stratification.
    Keywords:  aortic stiffness; carotid–femoral pulse wave velocity; indoxyl sulfate; type 2 diabetes mellitus
    DOI:  https://doi.org/10.3390/medicina61091607
  11. Front Psychiatry. 2025 ;16 1576392
    Adrenarche, social cognition, and the development and evolution of autism spectrum traits.
    Cory Szakal, Bernard Crespi.
      Autism Spectrum Disorder (ASD) is a heterogeneous neurodevelopmental condition characterized by underdeveloped social cognition, along with restricted interests and repetitive behaviors. ASD manifests through a range of genetic, environmental, and psychosocial factors, which influence brain development and lead to maladaptive social and behavioral processes. While early diagnosis is common, ASD traits can develop and express themselves through various stages of childhood, driven by dynamic changes in cognitive and social abilities in relation to stressors and challenges. A recent study reports genomic and psychological evidence for two different age-related trajectories of autism development, one early, and one later and near the time of adrenarche and middle childhood, around ages 7 - 10. Given that middle childhood represents a key period for the development of social cognition including complex theory of mind and peer relationships, that adrenarche mediates the origin and social adaptations of middle childhood, and that social challenges increase with its onset, we hypothesize that autism onset, expression and diagnoses during this period may involve alterations to adrenarche, and to its endocrinological and neurological bases. Adrenarche involves onset and increase in secretion of the androgens dehydroepiandrosterone (DHEA) and its sulfate (DHEAS). A series of systematic reviews was conducted to evaluate the hypothesis that DHEA or DHEAS levels are associated with ASD, autism spectrum traits, or aspects of brain development relevant to autism. The reviews showed that: (1) higher DHEA demonstrated evidence of positive associations with aspects of internalizing and externalizing, including social anxiety, with especially notable effects in girls, and (2) higher DHEA showed evidence of association with ASD diagnoses overall, as also indicated by a recent meta-analysis. These findings provide initial support for the hypothesis that alterations to the social adaptations associated with adrenarche, and DHEA levels in middle childhood may underlie a subtype of autism with diagnosis during this developmental period.
    Keywords:  DHEA; DHEAS; adrenarche; autism; evolutionary; juvenile stage; middle childhood
    DOI:  https://doi.org/10.3389/fpsyt.2025.1576392
  12. J Phys Chem B. 2025 Sep 24.
    Benchmark of Available Explicit Solvent Models in CHARMM36m to Characterize Glycosaminoglycans.
    P A Wesołowski, D J Wales, K K Bojarski.
      Heparin is a highly sulfated glycosaminoglycan (GAG) with essential roles in anticoagulation, angiogenesis, cell signaling, and host-pathogen interactions, mediated largely through electrostatic binding to diverse protein targets. While the TIP3P water model is commonly used in molecular simulations of GAGs, the influence of solvent representation on HP structure within the CHARMM36m force field remains poorly understood. Here, we report 5 μs molecular dynamics simulations of an HP dodecamer in five explicit solvent models: TIP3P, TIP4P, TIP5P, SPC/E, and OPC. TIP3P and SPC/E yield stable HP conformations, whereas TIP4P, TIP5P, and OPC introduce greater structural variability. Comparison with GLYCAM06 reveals that CHARMM36m preserves global HP architecture but differs in sampling specific glycosidic linkages. These findings highlight the critical impact of water model choice on GAG conformational dynamics and offer practical guidance for the accurate simulation of sulfated carbohydrates.
    DOI:  https://doi.org/10.1021/acs.jpcb.5c04919
  13. Acta Biomater. 2025 Sep 24. pii: S1742-7061(25)00698-1. [Epub ahead of print]
    Reactive Oxygen Species-Responsive Sulfated Polysaccharide-Based Nanogels for Ischemic Stroke: A Precision Therapy through Pathological Microenvironment Modulation.
    Dingfu Wang, Dan Li, Xiaolin Liu, Shixin Wang, Yile Fan, Ling Lu, Chuanbin Shen, Chunxia Li.
      Thrombolytic therapy for cardiovascular and cerebrovascular diseases is significantly limited by the short half-life, inadequate targeting specificity, and hemorrhagic complications of conventional therapeutic agents. To overcome these challenges, we developed a dual-functional nanogel (PGS-SP@UK) that integrates P-selectin-mediated thrombus targeting with ROS-responsive drug release. Taking advantage of the P-selectin targeting capability of polyguluronate sulfate (PGS), we synthesized the sulfated polysaccharide with selenocystamine and pinacol phenylboronate (PBAP) to construct an amphiphilic copolymer capable of encapsulating urokinase (UK). Notably, this nanogel exhibited H2O2-triggered UK release (85.79%) while maintaining great stability under physiological conditions. In vitro studies confirmed its neuroprotective effects through modulation of the ferroptosis signaling pathway in an OGD/R-induced model. In vivo studies revealed efficient blood-brain barrier penetration and thrombus-specific accumulation, achieving 84.3% recovery in cerebral infarct area through synergistic thrombolysis and oxidative stress mitigation. Our study presents an innovative drug delivery system with significant potential for clinical ischemic stroke treatment. STATEMENT OF SIGNIFICANCE: Conventional thrombolytic agents suffer from poor targeting specificity and severe bleeding complications, limiting their clinical efficacy in ischemic stroke treatment. We designed a dual-functional nanogel (PGS-SP@UK) that uniquely integrates P-selectin-mediated active targeting with ROS-responsive drug release mechanisms. This innovative design represents a system to combine polyguluronate sulfate-based thrombus recognition with oxidative stress-triggered urokinase liberation. Our nanogel achieves unprecedented selectivity through dual targeting: bioactive targeting via P-selectin binding and microenvironmental responsiveness to pathological ROS levels. In vivo validation demonstrated exceptional therapeutic outcomes with 84.3% cerebral infarct recovery while eliminating systemic hemorrhagic risks. This breakthrough establishes a new therapeutic paradigm that transcends current limitations through synergistic thrombolysis and neuroprotection, offering transformative potential for precision medicine in thrombotic disorders.
    Keywords:  Ischemic Stroke; P-selectin; Responsive targeted drug delivery system; Urokinase
    DOI:  https://doi.org/10.1016/j.actbio.2025.09.031
  14. Int J Biol Macromol. 2025 Sep 24. pii: S0141-8130(25)08434-X. [Epub ahead of print] 147877
    Enhanced soluble expression and improved catalytic efficiency of Heparinase II by fusion of GST tag to the backside of the active pocket.
    Yu-Ting Li, Jia-Lu Pei, Tong Huan, Yue Wu, Ye-Wang Zhang.
      Although heparinase II has been widely used in the structural analysis of heparin and HS, it suffers from low activity and inefficient expression and purification. In this study, heparinase II from Mariniphaga anaerophila (MaHepII) was cloned, and the GST tag was fused to the backside of the enzyme's active pocket. The fusion protein GST-MaHepII was efficiently expressed in the recombinant Escherichia coli BL21. Afterward, Ni-NTA affinity chromatography was used to purify GST-MaHepII, with an enzymatic activity recovery yield of 70.3 % and a specific activity of 7.5 U mg-1 toward heparin. When HS was used as the substrate, the enzyme exhibited a specific activity of 11.1 U mg-1. Additionally, the influence of the GST tag on the enzymatic properties of MaHepII was evaluated. After removal of the GST tag by proteolytic cleavage, MaHepII was purified by GSH affinity chromatography. Characterization of the enzymatic properties indicated that the GST tag improved the catalytic efficiency of MaHepII by 3.1-fold toward heparin and 1.4-fold toward HS. Molecular docking revealed that the GST tag fusion might increase the flexibility of the protein structure and alter the size or shape of the substrate channel. These changes facilitate substrate access to the active site and enhance the catalytic efficiency of MaHepII.
    Keywords:  Characterization; Expression; Fusion protein; GST tag; Heparinase II; Molecular docking
    DOI:  https://doi.org/10.1016/j.ijbiomac.2025.147877
  15. JBMR Plus. 2025 Oct;9(10): ziaf130
    Sulfate biology genes are associated with mineralization in mouse and human.
    Kun-Di Lee, Paul A Dawson, Kim M Summers.
      Sulfate plays a critical role in bone health and development. More than 90 sulfate-related genes are highly conserved across mammalian species, but very few of these genes have been linked to adverse bone phenotypes in humans. To extend our knowledge of sulfate-related gene expression dynamics during mineralization, this study leveraged 6 publicly available transcriptomic datasets, covering human osteosarcoma cell line Saos-2 mineralization, 2 mouse calvarial osteoblast mineralization models, vascular smooth muscle cell (VSMC) calcification, and 2 neurogenic heterotopic ossification datasets. We focused on a total of 12 sulfate-related genes that were upregulated during mineralization of Saos-2 cells. Six of these genes (Slc26a11, Sgsh, Sqor, Sult1a1, Tpst1, and Ust) were also consistently upregulated during mouse osteoblast and VSMC mineralization. Additionally, 3 genes (Cth, Got1, and Sulf1) were upregulated in Saos-2 mineralization but downregulated in mouse primary osteoblasts. Cbs, Chst3, and Chst13 were unchanged in the mouse primary cell models. Cbs, Chst13, Sgsh, Sulf1, and Ust also increased in models of heterotopic ossification. We have now identified several genes (CHST13, TPST1, UST, SULF1, GOT1, SLC26A11, and SULT1A1) that have not previously been considered for adverse bone conditions in humans, suggesting that additional sulfate biology genes may be linked with human skeletal conditions. Network analysis showed large co-expression clusters of genes, including sulfate biology and bone genes, that were upregulated across the calcification time courses. Gene ontology term enrichment analysis demonstrated significant enrichment in terms associated with mineralization, including ossification, bone mineralization, cartilage development, and extracellular matrix organization for these clusters of genes. This study provides a collated list of sulfate-related genes and networks that are associated with mineralization, which will facilitate future functional studies of sulfation pathways associated with bone pathology.
    Keywords:  bone; mineralization; sulfate; sulfate biology genes; transcriptomics
    DOI:  https://doi.org/10.1093/jbmrpl/ziaf130
  16. Diagnostics (Basel). 2025 Sep 16. pii: 2353. [Epub ahead of print]15(18):
    Serum P-Cresyl Sulfate Is Associated with Peripheral Arterial Stiffness in Chronic Hemodialysis Patients.
    Yahn-Bor Chern, Chih-Hsien Wang, Chin-Hung Liu, Hung-Hsiang Liou, Jen-Pi Tsai, Bang-Gee Hsu.
      Background/Objectives: Arterial stiffness is a major cardiovascular risk factor in patients with hemodialysis (HD). We conducted a cross-sectional study aimed at determining the relationship between serum p-Cresyl sulfate (PCS) and peripheral arterial stiffness (PAS), defined via the cardio-ankle vascular index (CAVI), in 110 patients receiving chronic HD. Methods: Participants were divided into PAS (CAVI ≥ 9.0) and control (CAVI < 9.0) groups. Serum PCS level was measured by high-performance liquid chromatography-mass spectrometry. Results: PAS was detected in 37 (33.6%) patients. The PAS patients were older and had higher SBP, more diabetes, and higher serum PCS and C-reactive protein (CRP) than the control group. Upon multivariate analysis, PAS was significantly associated with PCS (adjusted odds ratio: 1.238 per 1 mg/L increase, 95% confidence interval [CI]: 1.119-1.371, p < 0.001). The CAVI, advanced age, and CRP demonstrated a significant correlation with PCS, as evidenced by the correlation analysis conducted. Area under the receiver operating characteristic curve analysis showed that PCS had a good diagnostic value for PAS (AUC: 0.872, 95% CI: 0.805-0.939; p < 0.001), and the optimal cutoff value was 24.29 mg/L. Conclusions: PCS demonstrates great potential as a biomarker in the diagnosis of arterial stiffness.
    Keywords:  C-reactive protein; cardio-ankle vascular index; hemodialysis; p-Cresyl sulfate; peripheral arterial stiffness
    DOI:  https://doi.org/10.3390/diagnostics15182353
  17. Free Radic Biol Med. 2025 Sep 22. pii: S0891-5849(25)00997-9. [Epub ahead of print]241 268-286
    Exosomal miR-27a-5p inhibits indoxyl sulfate-induced cardiac dysfunction by targeting the USF2/FUT8 axis.
    Kun Xiao, Jiaojiao Hao, Nan Wang, Nan Shen, Bo Jiang, Longkai Li, Xu Zhang, Weidong Wang, Hui He, Ziran Wang, Huiyi Song, Qingzhu Tang, Biaojie Qin, Xiangning Du, Fan Yang, Shuni Chen, Xianan Guo, Shuang Meng, Hongli Lin.
      Uremic cardiomyopathy (UCM) is the leading cause of hemodialysis patient mortality. Indoxyl sulfate (IS), a key uremic toxin, activates multiple signaling pathways, causing cardiac hypertrophy and apoptosis. We previously demonstrated that core fucosylation (CF), a post-translational modification, is crucial in activating these pathways. Additionally exosome-mediated cardiac microvascular endothelial cell (CMEC)-cardiomyocyte (CM) crosstalk is important for UCM progression. However, the characteristics and roles of CF modification in IS-induced CMEC-derived exosomes (IS-Exos) that cause CM injury remain unexplored. Our studies have revealed that hemodialysis patients had significantly higher serum IS and α1,6-fucosyltransferase (FUT8), which were positively correlated with the severity of cardiac injury. Using a microfluidic chip model of IS-induced cardiac injury, we visualized exosome transfer from CMECs to CMs, which caused mitochondrial impairment, hypertrophy and apoptosis in CMs, with elevated CF levels playing critical roles. To investigate this further, we performed FUT8 knockout in IS-mice treated with IS-Exos and transfected FUT8 siRNA into CMs exposed to IS-Exos. We found that the inhibition of FUT8 leads to a reduction in ARG2 expression, which consequently diminishes reactive oxygen species (ROS) and ameliorates cardiac hypertrophy and apoptosis. Mechanistically, miR-27a-5p was markedly downregulated in IS-Exos. CD44 on IS-Exos interacts with EGFR in CMs, enhancing cardiac injury. Supplementation with miR-27a-5p in vivo and in vitro specifically targets USF2, leading to a downregulation of FUT8 expression. This cascade leads to a diminished expression of ARG2, alleviation of ROS, and the reversal of cardiac hypertrophy and apoptosis. Our findings offer new insights, suggesting that targeting CF modification may represent a promising therapeutic strategy for alleviating UCM in the future.
    Keywords:  Core fucosylation; Indoxyl sulfate; Intracellular communication; Reactive oxygen species; Uremic cardiomyopathy; miRNA-27a-5p
    DOI:  https://doi.org/10.1016/j.freeradbiomed.2025.09.040
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