bims-supasi 2025-10-19 papers

bims-supasi

Biomed News

on Sulfation pathways and signalling

Issue of 2025–10–19
eleven papers selected by
Jonathan Wolf Mueller, University of Birmingham

Structural domain analysis of heparin and heparan sulfate combined with label-free quantitative proteomics to elucidate their functional diversity in liver cancer and APAP-induced liver injury.
Structure-function relationship of the GH168 fucanase reveals an unusual enzyme recognition mechanism for sulfated polysaccharide.
Kinetic Mechanism of Heparin-Induced Fibrillation of α-Synuclein.
The Impact of Dextran Sulfate on Anti-Xa Assay Outcomes after Unfractionated Heparin Reversal by Excessive Protamine.
Synthesis and Characterization of a Nanoscale Hyaluronic Acid-Specific Probe for Magnetic Particle Imaging and Magnetic Resonance Imaging.
The Implantable Electrode Co-Deposited with Iron Oxide Nanoparticles and PEDOT:PSS.
In Vivo Absorption of Iron Complexes of Chondroitin Sulfates with Different Molecular Weights and Their Anti-Inflammation and Metabolism Regulation Effects on LPS-Induced Macrophages.
Measurement of 11-Oxo-Androgens, A Novel Biomarker, in Females with Clinical Signs of Premature Adrenarche.
Pegmolesatide ameliorates indoxyl sulfate-induced cardiomyocyte hypertrophy through modulating the EPOR-CD131-dependent JAK2/STAT3 signaling pathway.
Associations Between Salivary Cortisol, DHEA-S, and Alpha-Amylase and Longitudinal Sleep Disruption in Shift-Working Healthcare Professionals: A Pilot Study.
Para-Cresol and the Brain: Emerging Role in Neurodevelopmental and Neurodegenerative Disorders and Therapeutic Perspectives.

Mol Cell Proteomics. 2025 Oct 14. pii: S1535-9476(25)00189-6. [Epub ahead of print] 101090

Structural domain analysis of heparin and heparan sulfate combined with label-free quantitative proteomics to elucidate their functional diversity in liver cancer and APAP-induced liver injury.

Zizhe An, Qingqing Chen, Changkai Bu, Lexin Chen, Deling Shi, Bin Zhang, Lan Jin, Lianli Chi.

  The precise structure of glycosaminoglycans is critical for their bioactivity and the development of glyco-pharmaceuticals. Herein, cellular and animal experiments were conducted to assess the differences in the activities of heparin (HP) and heparan sulfate (HS) against liver cancer and drug-induced liver injury (DILI). Label-free quantitative proteomics, bioinformatics, biolayer interferometry (BLI), and immunohistochemical analyses were used to determine key proteins with differential expression. As a result, HP demonstrated superior anti-liver cancer activity compared with HS, whereas HS exhibited strong potential in resisting acetaminophen (APAP)-induced liver injury. DIRAS family GTPase 2 (DIRAS2) was identified as a key HS-binding protein that was strongly associated with cell proliferation, and its expression levels in cells and tissues showed opposite trends following HP and HS administration. HP significantly reduced the abundance of DIRAS2 in the tumor tissue, thereby inhibiting tumor cell proliferation, whereas HS promoted proliferation by increasing DIRAS2 expression. Cluster sequencing revealed that consecutive GlcNS6S-IdoA2S domains in HP and IdoA2S-GlcNS6S, GlcA-GlcNS6S, and IdoA-GlcNAc domains in HS were required for affinity binding within the decasaccharide region. Molecular docking suggested that differences in the binding modes of HP and HS chains to DIRAS2 underlie their functional diversity. These findings indicate that HP and HS oligosaccharides with well-defined structures may serve as potential therapeutic agents for liver-related diseases.

Keywords:  heparan sulfate; heparin; liver cancer; liver injury; structural analysis

DOI:  https://doi.org/10.1016/j.mcpro.2025.101090
Nat Commun. 2025 Oct 17. 16(1): 9216

Structure-function relationship of the GH168 fucanase reveals an unusual enzyme recognition mechanism for sulfated polysaccharide.

Guangning Chen, Jingjing Shen, Xinyu Li, Menghui Sun, Sheng Dong, Ying Sun, Achiraya Khamleng, Xuanwei Mei, Yuying Zhang, Guanchen Liu, Fangyi Chen, Xiao Song, Kaimeng Liu, Yingang Feng, Changhu Xue, Yaoguang Chang.

Sulfated fucan is one of the most recalcitrant polysaccharides. The molecular mechanism underlying the endo-1,3-fucanase, which plays a critical role in the breakdown of sulfated fucan, remains unexplained. Here, we conduct a comprehensive structure-function relationship investigation on the endo-1,3-fucanases within a family space-GH168. The family can be divided into four subfamilies according to phylogenetic relationship and functional similarities. Subfamily I, Ⅱ and Ⅳ preferentially recognize Fucp2(OSO3-), Fucp2,4(OSO3-) and Fucp units at the +1 subsite, respectively, while consistently recognizing the Fucp2(OSO3-) unit at the -1 subsite. Remarkably, two-thirds of the interacting residues are dedicated to the recognition of sulfate groups along the glycoside chains. This mechanism is distinct from the direct recognition of the sugar backbone employed by neutral polysaccharide hydrolases. These findings unveil a critical enzyme recognition mechanism for sulfate polysaccharides and promote the application of endo-1,3-fucanases in the structural analysis and oligosaccharide production of sulfated fucan.

DOI: https://doi.org/10.1038/s41467-025-63891-4
ACS Chem Neurosci. 2025 Oct 12.

Kinetic Mechanism of Heparin-Induced Fibrillation of α-Synuclein.

Takashi Ohgita, Norihiro Namba, Nao Minami, Hiroyuki Saito.

  Deposition of fibrillar aggregates of α-synuclein (αS) in the brain is a hallmark of αS-associated neurodegenerative diseases. Heparin, a structural analog of cell-surface heparan sulfate, modulates the kinetics of αS fibrillation and the morphology of the resulting fibrils. In this study, we investigated the kinetic mechanism of heparin-induced αS fibrillation using physicochemical techniques. Thioflavin T fluorescence and fibril-pelleting assays demonstrated that heparin greatly induces αS fibril formation and increases the mass of fibrillar αS in a concentration-dependent manner. Atomic force microscopy revealed that higher concentrations of heparin promote the formation of longer fibrils. These findings suggest that elongation of αS fibrils reaches a dynamic equilibrium during the plateau phase and that heparin shifts this equilibrium toward elongation. Considering the fibril dissociation process, we developed a kinetic model for heparin-induced αS fibrillation based on the process by which fibrillar αS inversely converts to a monomeric state. This model successfully captured the kinetic behavior of heparin-induced αS fibrillation and indicated that heparin promotes fibril growth by favoring elongation over dissociation. Overall, our study suggests the potential mechanism by which heparin promotes fibrillation of αS, highlighting the critical role of the equilibrium between fibril elongation and dissociation in αS fibrillation.

Keywords:  Amyloid fibrils; Fibril dissociation; Finke−Watzky model; Heparin; Neurodegenerative diseases; α-Synuclein

DOI:  https://doi.org/10.1021/acschemneuro.5c00489
Indian J Hematol Blood Transfus. 2025 Oct;41(4): 973-977

The Impact of Dextran Sulfate on Anti-Xa Assay Outcomes after Unfractionated Heparin Reversal by Excessive Protamine.

Jiahong Zhang.

  Currently, the anti-Xa assay is the "gold standard" for monitoring heparin activity; however, dextran sulfate (DS) addition to analytical reagents can lead to overestimated heparin activity following unfractionated heparin (UFH) reversal by protamine (Pr), often leading to improper UFH management. We investigated the impact of DS on anti-factor Xa assay outcomes after UFH was reversed by excessive Pr. Normal pooled plasma samples were spiked with UFH and Pr to prepare samples with varying Pr to UFH (P: H) ratios of different UFH concentrations. A chromogenic method was used to detect anti-Xa activity using two reagents: HemosIL liquid anti-Xa with DS (HemosIL) and STA liquid anti-Xa without DS (STA). When the P: H ratio was ≥ 1.0, i.e., Pr was equal or in excess, anti-Xa activity was detected by the HemosIL reagent, and did not decrease as expected, with dose-dependent effects with increasing UFH concentrations, while anti-Xa activity using STA reagent was almost undetectable. Meanwhile, both APTT and TT were within reference ranges, indicating that UFH had been completely neutralized. Therefore, when using HemosIL reagent (with DS) to detect anti-Xa activity from UFH reversal by excessive Pr, clinicians must be aware of potential DS interference and consider alternative monitoring strategies to accurately assess anticoagulant status.
Supplementary Information: The online version contains supplementary material available at 10.1007/s12288-025-01971-7.

Keywords:  Anti-Xa assay; Dextran sulfate; Protamine; Unfractionated heparin

DOI:  https://doi.org/10.1007/s12288-025-01971-7
Nanomaterials (Basel). 2025 Oct 01. pii: 1505. [Epub ahead of print]15(19):

Synthesis and Characterization of a Nanoscale Hyaluronic Acid-Specific Probe for Magnetic Particle Imaging and Magnetic Resonance Imaging.

Harald Kratz, Dietmar Eberbeck, Frank Wiekhorst, Matthias Taupitz, Jörg Schnorr.

  Glycosaminoglycans (GAGs) are part of the extracellular matrix (ECM) and play a major role in maintaining their physiological function. During pathological processes, the ECM is remodeled and its GAG composition changes. Hyaluronic acid (HA) is one of the GAGs that plays an important role in pathological processes such as inflammation and cancer and is therefore an interesting target for imaging. To provide iron oxide nanoparticles (IONP) that bind to hyaluronic acid (HA) as specific probes for molecular imaging, a peptide with high affinity for HA was covalently bound to the surface of commercial IONP (synomag®-D, NH2) leading to hyaluronic acid-specific iron oxide nanoparticles (HAIONPs). Affinity measurements using a quartz crystal microbalance (QCM) showed a very high affinity of HAIONP to HA, but not to the control chondroitin sulfate (CS). HAIONPs exhibit a very high magnetic particle spectroscopy (MPS) signal amplitude, which predestines them as HA-selective tracers for magnetic particle imaging (MPI). The high relaxivity coefficient r2 also makes HAIONP suitable for magnetic resonance imaging (MRI) applications. HAIONP therefore offers excellent prerequisites for further development as a probe for the specific quantitative imaging of the HA content of the ECM in pathological areas.

Keywords:  chondroitin sulfate; extracellular matrix; glycosaminoglycans; hyaluronic acid; iron oxide nanoparticles; quartz crystal microbalance

DOI:  https://doi.org/10.3390/nano15191505
Nanomaterials (Basel). 2025 Oct 02. pii: 1511. [Epub ahead of print]15(19):

The Implantable Electrode Co-Deposited with Iron Oxide Nanoparticles and PEDOT:PSS.

Yiyang Liu, Hui Wu, Sheng Wang, Quanwei Yang, Baolin Zhang.

  Iron oxide nanoparticles (IONs) exhibit biocompatibility, ease of drug loading, and potential for generating forces and heat in a magnetic field, enhancing Magnetic Resonance Imaging (MRI). This study proposes coating IONs on electrode surfaces to improve performance and neuron bonding. Methods included synthesizing IONs, grafting chondroitin sulfate (CS), and co-depositing with poly(3,4-ethylenedioxythiophene):poly(styrenesulfonate) (PEDOT:PSS). Results showed reduced impedance, increased charge storage, and improved signal quality in vivo.

Keywords:  PEDOT:PSS; coating; electrophysiological signal transmission; implantable neural electrodes; iron oxide nanoparticles

DOI:  https://doi.org/10.3390/nano15191511
Foods. 2025 Sep 27. pii: 3356. [Epub ahead of print]14(19):

In Vivo Absorption of Iron Complexes of Chondroitin Sulfates with Different Molecular Weights and Their Anti-Inflammation and Metabolism Regulation Effects on LPS-Induced Macrophages.

Qianqian Du, Jiachen Zheng, Fanhua Kong, Xiuli Wu, Chunqing Ai, Shuang Song.

  The present study investigated the effects of hierarchical molecular weights and iron chelation on the in vivo absorption and the inflammatory bioactivity of chondroitin sulfate (CS). Firstly, CS, chondroitin sulfate-iron complex (CS-Fe), and low-molecular-weight chondroitin sulfate-iron complex (LCS-Fe) were fluorescently labeled and characterized. Then, the plasma concentration-time profiles and fluorescence imaging results demonstrated that LCS-Fe was more efficiently absorbed into the bloodstream and showed a higher Cmax (415.16 ± 109.50 μg/mL) than CS-Fe (376.60 ± 214.10 μg/mL) and CS (135.27 ± 236.82 μg/mL), and it clearly accumulated in the liver. Furthermore, the anti-inflammatory effect of CS-Fe and LCS-Fe was assayed in LPS-induced macrophages, and LCS-Fe and CS-Fe both showed a better inhibitory effect on NO production, COX-2 and IL-1β gene expression levels compared to CS. Additionally, targeted metabolic analysis of macrophages using LC-MS/MS revealed that CS, CS-Fe, and LCS-Fe could reverse approximately one quarter of the LPS-induced differential metabolites, and the biosynthesis of valine, leucine, and isoleucine was the most significantly involved metabolic pathway. Notably, the molecular weight reduction and iron chelation could both enhance the bioavailability and anti-inflammatory efficacy of CS.

Keywords:  anti-inflammation; chondroitin sulfate; in vivo absorption; iron complex; metabolic analysis; tissue distribution

DOI:  https://doi.org/10.3390/foods14193356
J Clin Res Pediatr Endocrinol. 2025 Oct 15.

Measurement of 11-Oxo-Androgens, A Novel Biomarker, in Females with Clinical Signs of Premature Adrenarche.

Liana Gabriel, Jorge Mejia-Corletto, Beatriz Blinov, Meredith Akerman, Jacklyn Frank, Paul Saenger.

   Background: Endocrine findings in premature adrenarche have been characterized by elevated DHEAS levels in the past.
Methods: We reviewed 44 female patients, aged 4 to 8 years, with premature adrenarche who were seen at our center between 2019 and 2023. Data were collected on the traditional androgens (DHEA and DHEAS) and novel 11-oxo-androgens. 11-oxo-androgens, DHEAS, and DHEA levels were measured using Liquid chromatography/tandem mass spectrometry (LC/MS-MS) assays in commercial laboratories (Lab Corp).
Results: The majority, 89% of patients from the youngest group (4-5year olds), presented with apocrine odor as the only symptom of premature adrenarche. We have demonstrated that DHEA and DHEAS levels were within the normal range in many girls with premature adrenarche, whereas 11-oxo-androgens, particularly 11-hydroxyandrostenedione and 11β-hydroxytestosterone, were elevated. Out of those with normal DHEAS, 75 % had elevated 11-hydroxyandrostenedione, and 77.8% of those patients with normal DHEA had the same elevated oxo-adrogen. Additionally, advanced bone age greater than 1 year compared to chronological age was positively associated with 11-ketotestosterone (Spearman correlation coefficient = 0.32, 95% CI: 0.01-0.57, p=0.0429) and 11β-hydroxy testosterone (Spearman correlation coefficient=0.32, 95% CI: 0.01-0.58, p=0.0395).
Conclusion: We propose that 11-oxoandrogens are a more sensitive steroid to be measured in premature adrenarche.

Keywords:  Oxo-androgens; adrenarche; child; premature

DOI:  https://doi.org/10.4274/jcrpe.galenos.2025.2025-3-20
Int Immunopharmacol. 2025 Oct 14. pii: S1567-5769(25)01634-0. [Epub ahead of print]167 115643

Pegmolesatide ameliorates indoxyl sulfate-induced cardiomyocyte hypertrophy through modulating the EPOR-CD131-dependent JAK2/STAT3 signaling pathway.

Xinyu Zhang, Sufang Li, Tingru Lin, Liangying Gan, Li Zhu, Li Zuo.

   BACKGROUND: Cardiovascular events remain the leading cause of mortality in chronic kidney disease (CKD). Pegmolesatide(P), a novel long-acting EPO receptor modulator, shows cardiovascular benefits in clinical studies. This study aims to demonstrate Pegmolesatide suppressed the formation of EPOR-CD131 heterodimer and to explore its cardioprotective mechanisms against indoxyl sulfate (IS)-induced cardiomyocyte hypertrophy.
METHODS: H9c2 cardiomyocytes were assigned to different treatment groups (vehicle, IS, IS+P, P) and RNA sequencing was performed to identify dysregulated signaling pathways. Mechanistic exploration groups supplemented with CD131 agonist ARA290, STAT3 activator Colivelin, or STAT3 inhibitor Stattic for rescue experiments. Analyses included real-time qPCR/Western blot for cardiac hypertrophy markers and EPOR-CD131/JAK2/STAT3 axis components, phalloidin staining for cell size and co-immunoprecipitation (Co-IP) for EPOR-CD131 heterodimerization.
RESULTS: Pegmolesatide significantly attenuated IS-induced cardiomyocyte hypertrophy, as evidenced by suppressed expression of cardiac hypertrophy markers (ANP, BNP, and β-MHC), reduced cell surface area, and improved cytoskeletal organization(P < 0.05). Mechanistically, Pegmolesatide upregulated EPOR expression while suppressing CD131 expression and activation of the JAK2/STAT3 signaling. Co-IP analysis demonstrated that Pegmolesatide suppressed the formation of EPOR-CD131 heterodimer. Functional rescue experiments showed that the cardioprotective effects of Pegmolesatide were reversed by CD131 agonist ARA290 or STAT3 activator Colivelin. Notably, combined treatment with ARA290 and STAT3 inhibitor Stattic partially restored its anti-hypertrophic activity.
CONCLUSION: Pegmolesatide exerts protective effects against IS-induced cardiomyocyte hypertrophy by inhibiting the EPOR-CD131/JAK2/STAT3 signaling axis. It may be a promising strategy for CKD-related cardiovascular complications.

Keywords:  Cardiomyocyte hypertrophy; EPOR-CD131 heterodimer; Indoxyl sulfate; JAK2/STAT3 signaling pathway; Pegmolesatide

DOI:  https://doi.org/10.1016/j.intimp.2025.115643
Nat Sci Sleep. 2025 ;17 2611-2623

Associations Between Salivary Cortisol, DHEA-S, and Alpha-Amylase and Longitudinal Sleep Disruption in Shift-Working Healthcare Professionals: A Pilot Study.

Mohammed F Salahuddin, Karn Sukararuji, Mahsa Sharifi, Kingsley Anetor Francis Odia, Md Dilshad Manzar, Seithikurippu R Pandi-Perumal, Ahmed S BaHammam.

   Background: Shift work is a well-established disruptor of sleep, yet the biological mechanisms driving sleep disturbances remain poorly understood. Salivary cortisol (HPA axis), α-amylase (sympathetic-adrenomedullary output), and DHEA-S (adrenal androgen with anti-glucocorticoid/resilience properties) are candidate indicators of stress-related sleep disruption. We therefore examined whether changes in these biomarkers were associated with 6-month sleep trajectories in health professionals.
Methods: In a prospective 6-month repeated-measures design, 52 healthcare professionals (daytime vs rotating shifts; mean age 31.4 ± 9.4 years; 57% female) completed validated sleep assessments, PROMIS Sleep Disturbance, PROMIS Sleep Impairment, the Sleep-Wake Disorder Index (SWDI), and the NIH 7-day Sleep Diary, at baseline and six-month follow-up. Salivary cortisol, Dehydroepiandrosterone Sulfate (DHEA-S), and alpha-amylase were collected on the morning of Day 7 of each diary period. Change scores (Δ = follow-up - baseline) were computed. Repeated-measures ANOVA, Pearson correlations, and multivariable regressions assessed group differences and biomarker-sleep associations.
Results: Compared with daytime workers, rotating shift workers reported significantly greater increases in sleep disturbance, impairment, and reduced sleep efficiency over time (all p < 0.05). Reductions in cortisol and alpha-amylase were significantly associated with worsening PROMIS Sleep Disturbance and SWDI scores (r = -0.65 and -0.53, respectively; p < 0.05). Multivariable regression showed that decreased cortisol (β = -41.845, p = 0.0064) and increased DHEA-S (β = 0.001, p = 0.0405) associated with worsening PROMIS Sleep Impairment. A combined model including reduced cortisol, and increased DHEA-S associated with greater PROMIS Sleep Disturbance (adjusted R² = 0.698).
Conclusion: In this pilot, changes in salivary cortisol and DHEA-S were associated with longitudinal changes in sleep. These results suggest potential utility for biomarker-informed risk stratification, warranting confirmation in larger, controlled studies.

Keywords:  cortisol; psychological; shift work schedule; sleep diary; sleep wake disorders; stress

DOI:  https://doi.org/10.2147/NSS.S555134
ACS Pharmacol Transl Sci. 2025 Oct 10. 8(10): 3432-3452

Para-Cresol and the Brain: Emerging Role in Neurodevelopmental and Neurodegenerative Disorders and Therapeutic Perspectives.

Laura Bertarini, Federico Imbeni, Virginia Brighenti, Isabella Martusciello, Federica Pellati, Silvia Alboni.

  p-Cresol (pC) is a phenolic compound to which humans can be exposed through both environmental sources, such as a pollutant, and endogenous production by the gut microbiota. Among microbial contributors, Clostridioides difficile appears to be a major source of pC within the body. Once absorbed, pC is highly protein-bound in plasma and predominantly circulates in its hepatic conjugated forms: p-cresyl sulfate (pCS) and p-cresol glucuronide (pCG), which are mainly excreted in urine. Accumulation of these metabolites, particularly pCS, classified as a protein-bound uremic toxin, has been associated with the progression of chronic kidney disease (CKD) and related complications, due to its pro-oxidant, pro-inflammatory, and pro-apoptotic properties. CKD patients are at increased risk for cognitive impairment, affective disorders, and central nervous system (CNS) dysfunctions. In recent years, increasing evidence has suggested a potential role of pC and its metabolites in CNS diseases. Here, we summarize current knowledge on the involvement of these compounds in the pathogenesis and progression of autism spectrum disorder, Parkinson's disease, Alzheimer's disease, and post-traumatic stress disorder. We also discuss how modulating systemic levels of pC may represent a promising strategy to improve pathological phenotypes in the context of neurodevelopmental and neurodegenerative disorders.

Keywords:  Alzheimer’s disease; Parkinson’s disease; autism; brain; p-cresol; stress

DOI:  https://doi.org/10.1021/acsptsci.5c00289