bims-supasi 2025-08-10 papers

bims-supasi

Biomed News

on Sulfation pathways and signalling

Issue of 2025–08–10
eighteen papers selected by
Jonathan Wolf Mueller, University of Birmingham

Unravelling structure-function interactions between fluorinated heparan sulfate mimetics and signaling proteins.
Chondroitin sulfate A-selenium nanoparticles protect chondrocytes from T-2 toxin-induced oxidative stress and mitochondrial dysfunction through activating autophagy by the SIRT1-AMPK-FOXO3 pathway.
Case Report: Adrenocortical adenoma harboring atypical subclinical Cushing's syndrome with dehydroepiandrosterone sulfate transferase and cytochrome b5 expression in tumor cells.
Three positively charged binding sites on the eastern equine encephalitis virus E2 glycoprotein coordinate heparan sulfate- and protein receptor-dependent infection.
Quantitative HILIC-Q-TOF-MS Analysis of Glycosaminoglycans and Non-reducing End Carbohydrate Biomarkers via Glycan Reductive Isotopic Labeling.
Heparan sulfate fine-tuned interleukin-1 (IL-1) signaling inhibits insulin secretion of grafted pancreatic islets.
A selenium-enriched glycosaminoglycan from sturgeon cartilage: characterization and anti-metabolic syndrome potential.
Development of chondroitin sulfate-modified quinoa protein isolate-dihydromyricetin composite nanoparticles: Focus on naringenin delivery, cell cytoprotective ability and anti-inflammatory effects.
Possible Involvement of CSPG4 in Promoting Endothelial Cell Migration and Contributing to Angiogenesis during Skeletal Muscle Regeneration and Development in the Rat.
Six new bacterial species isolated from the phycosphere of marine macroalgae: a joint analysis based on taxonomy and polysaccharide utilization loci.
Microbial engineering for natural and unnatural glycosaminoglycans biosynthesis.
Structural insights into manganese-dependent arylsulfatase from Enterococcus faecium and its catalytic promiscuity.
Cholesterol sulfate alleviates functional dyspepsia in juvenile mice via modulating the gut microbiota-derived lactate.
A sulfonated cartilage interpenetrating polymer network reinforces and protects the extracellular matrix of degraded cartilage.
Sulfated dietary fiber protects gut microbiota from antibiotics.
In Vitro Evaluation of the Potential Interactions of Zearalenone-14-sulfate and Zearalenone-14-glucuronide with Human Cytochrome P450 Enzymes, Organic Anion Transporting Polypeptides, and ATP-Binding Cassette Multidrug Transporters.
The cleavage of indinavir sulfate: synthesis and characterization of a cis-1-amino-2-indanol salt.
The impact of lymphocyte count on male erectile dysfunction with clinical validations and its potential metabolic mechanisms through mendelian randomization analysis.

RSC Chem Biol. 2025 Jul 10.

Unravelling structure-function interactions between fluorinated heparan sulfate mimetics and signaling proteins.

Virendrasinh Mahida, Rakesh Raigawali, Paula González, Ana Gimeno, Shani Leviatan Ben-Arye, Saurabh Anand, Sandhya Mardhekar, Jesús Jiménez-Barbero, Vered Padler-Karavani, Raghavendra Kikkeri.

Fluorinated carbohydrates are emerging scaffolds in glycobiology, enabling the elucidation of the roles of the individual hydroxyl groups of a carbohydrate in protein binding and drug discovery. Herein, we report a divergent strategy to synthesize seven heparan sulfate (HS) mimetics featuring a fluorine atom at the C3 position of the glucuronic acid residue, with the objective of modulating structure-function relationships. The sensitivity of fluorine signals to sulfation patterns was confirmed via 19F-NMR spectroscopy, while 3 J HH coupling and NOE data demonstrated that the glucuronic acid residue retained its 4C1 conformation. Glycan microarray analysis and SPR binding studies revealed that a single hydroxyl-to-fluorine substitution in HS mimetics retains the binding of N-acetylated HS sequences for several growth factors and chemokines. Remarkably, GlcNAc6S-GlcA(3F) and GlcNS6S3S-GlcA(3F) exhibited binding properties comparable to those of highly N-sulfated native HS ligands. These findings provide valuable insights for the development of novel therapeutic agents targeting morphogens and cell signalling pathways.

DOI: https://doi.org/10.1039/d5cb00174a
Ecotoxicol Environ Saf. 2025 Aug 04. pii: S0147-6513(25)01142-X. [Epub ahead of print]303 118797

Chondroitin sulfate A-selenium nanoparticles protect chondrocytes from T-2 toxin-induced oxidative stress and mitochondrial dysfunction through activating autophagy by the SIRT1-AMPK-FOXO3 pathway.

Huan Deng, Jinyan Lin, Yude Jiang, Abebe Feyissa Amhare, Lichun Qiao, Jun Wang, Jing Han.

  T-2 toxin is known to cause tissue and cellular damage, with chondrocytes being particularly vulnerable. In contrast, chondroitin sulfate A-selenium nanoparticles (CSA-SeNP) have shown cartilage-protective properties, although the precise molecular mechanism remains incompletely elucidated. This study used T-2 toxin and CSA-SeNP to treat human C28/I2 chondrocytes, and studied their effects on SIRT1-AMPK-FOXO3 pathway and oxidative damage, mitochondrial dysfunction, impaired autophagy, and apoptosis. Autophagy was evaluated by acridine orange (AO) and dansylcadaverine (MDC) staining, transmission electron microscopy observation, and mRFP-GFP-LC3 adenovirus. Oxidative stress (ROS, MDA, SOD, CAT, T-AOC) and mitochondrial function (ATP, SDH, ATPases, membrane potential) were assessed. Western blotting analyzed the expression level of the SIRT1-AMPK-FOXO3 pathway, autophagy markers, and apoptosis. We found that 4-hour exposure to 5 and 20 ng/mL, as well as 12-hour exposure to 5 ng/mL of T-2 toxin, activated the SIRT1-AMPK-FOXO3 pathway compensatively, inducing autophagy but inhibiting degradation of autolysosome, leading to oxidative damage, mitochondrial dysfunction, and increased apoptosis. 12-hour exposure to 20 ng/mL T-2 toxin inhibited this pathway and autophagy, causing serious damage to chondrocytes. CSA-SeNP alleviated the inhibition of the SIRT1-AMPK-FOXO3 pathway induced by T-2 toxin, reducing oxidative damage, mitochondrial dysfunction and apoptosis, thereby restoring autophagy to protect chondrocytes. In summary, T-2 toxin's effects on chondrocyte autophagy were dose- and time-dependent. CSA-SeNP protected against T-2 toxin by activating the SIRT1-AMPK-FOXO3 pathway, suggesting its potential for chondrocyte protection. This study may provide new insights into the development of T-2 toxin detoxification strategies and the method for prevention and treatment of chondrocyte damage.

Keywords:  Autophagy; Chondroitin sulfate A‑selenium nanoparticles; Mitochondrial dysfunction; Oxidative stress; SIRT1-AMPK-FOXO3 pathway; T-2 toxin

DOI:  https://doi.org/10.1016/j.ecoenv.2025.118797
Front Endocrinol (Lausanne). 2025 ;16 1624396

Case Report: Adrenocortical adenoma harboring atypical subclinical Cushing's syndrome with dehydroepiandrosterone sulfate transferase and cytochrome b5 expression in tumor cells.

Ichiro Abe, Yuto Yamazaki, Ayuko Higashi, Kentaro Ochi, Keita Kubo, Yuya Fujita, Kaori Takeshita, Toshiaki Wada, Ryo Mitsuoka, Yo Yamashita, Ryoko Yoshida, Tamotsu Kato, Tadachika Kudo, Shigero Miyajima, Tatsu Ishii, Satoshi Nimura, Takashi Suzuki, Hironobu Sasano, Kunihisa Kobayashi.

  Subclinical Cushing's syndrome (SCS) is frequently encountered during the clinical evaluation of adrenal incidentalomas and is typically associated with reduced levels of serum dehydroepiandrosterone sulfate (DHEA-S). Cytochrome b5 is a component of the electron transfer system that enhances the activity of 17, 20-lyase relative to that of 17a-hydroxylase. Therefore, tumors harboring cytochrome b5 might be associated with dehydroepiandrosterone sulfotransferase (DHEA-ST) expression, resulting in unsuppressed serum DHEA-S levels. Here, we reported the first case of SCS with elevated serum DHEA-S levels in an incidentally detected adrenocortical adenoma showing immunohistochemical positivity for both cytochrome b5 and DHEA-ST.

Keywords:  cytochrome b5; dehydroepiandrosterone; electron transfer system; hypercortisonemia; subclinical Cushing’s syndrome

DOI:  https://doi.org/10.3389/fendo.2025.1624396
Nat Commun. 2025 Aug 05. 16(1): 7227

Three positively charged binding sites on the eastern equine encephalitis virus E2 glycoprotein coordinate heparan sulfate- and protein receptor-dependent infection.

Maria D H Alcorn, Chengqun Sun, Theron C Gilliland, Tetyana Lukash, Christine M Crasto, Saravanan Raju, Michael S Diamond, Scott C Weaver, William B Klimstra.

Naturally circulating strains of eastern equine encephalitis virus (EEEV) bind heparan sulfate (HS) receptors and this interaction has been linked to neurovirulence. Previous studies associated EEEV-HS interactions with three positively charged amino acid clusters on the E2 glycoprotein. One of these sites has recently been reported to be critical for binding EEEV to the very-low-density lipoprotein receptor (VLDLR), an EEEV receptor protein. The proteins apolipoprotein E receptor 2 (ApoER2) isoforms 1 and 2, and LDLR have also been shown to function as EEEV receptors. Herein, we investigate the individual contribution of each HS interaction site to EEEV HS- and protein receptor-dependent infection in vitro and EEEV replication in animals. We show that each site contributes to both EEEV-HS and EEEV-protein receptor interactions, providing evidence that altering these interactions can affect disease in mice and eliminate mosquito infectivity. Thus, multiple HS-binding sites exist in EEEV E2, and these sites overlap functionally with protein receptor interaction sites, with each type of interaction contributing to tissue infectivity and disease phenotypes.

DOI: https://doi.org/10.1038/s41467-025-62513-3
Anal Chem. 2025 Aug 06.

Quantitative HILIC-Q-TOF-MS Analysis of Glycosaminoglycans and Non-reducing End Carbohydrate Biomarkers via Glycan Reductive Isotopic Labeling.

Amrita Basu, Stephanie Archer-Hartmann, Pradeep Chopra, Mehrnoush Taherzadeh Ghahfarrokhi, Xiaolin Dong, Neil G Patel, Yiwen Zhang, Biswa Choudhury, Kosuke Funato, Dhananjay Yellajoshyula, Geert-Jan Boons, Parastoo Azadi, Ryan J Weiss.

Glycosaminoglycans (GAGs) are linear, heterogeneous polysaccharides expressed on all animal cells. Sulfated GAGs, including heparan sulfate (HS) and chondroitin/dermatan sulfate (CS/DS), are involved in numerous physiological and pathological processes; therefore, precise and robust analytical methods for their characterization are essential to correlate structure with function. In this study, we developed a method utilizing hydrophilic interaction liquid chromatography coupled with time-of-flight mass spectrometry (HILIC-Q-TOF-MS) and glycan reductive isotopic reducing end labeling (GRIL) for the quantitative compositional analysis of HS and CS/DS polysaccharides. Lyase-generated disaccharides and commercial standards were chemically tagged on the reducing end with aniline stable isotopes, thus enabling the absolute quantification of HS and CS/DS disaccharides in complex biological samples. In addition, we adapted this workflow, in conjunction with new synthetic carbohydrate standards, for the quantification of disease-specific non-reducing end (NRE) carbohydrate biomarkers that accumulate in patients with mucopolysaccharidoses (MPS), a subclass of lysosomal storage disorders. As a proof of concept, we applied this method to measure NRE biomarkers in patient-derived MPS IIIA and MPS IIID fibroblasts, as well as in cortex tissue from a murine model of MPS VII. Overall, this method demonstrates improved sensitivity compared to previous GRIL-LC/MS techniques and, importantly, avoids the use of ion-pairing reagents, which are undesirable in certain mass spectrometry instrumentation and contexts. By combining the benefits of HILIC separation with isotopic labeling, our approach offers a robust and accessible tool for the analysis of GAGs, paving the way for advancements in understanding GAG structure and function.

DOI: https://doi.org/10.1021/acs.analchem.5c02338
Sci Adv. 2025 Aug 08. 11(32): eady8566

Heparan sulfate fine-tuned interleukin-1 (IL-1) signaling inhibits insulin secretion of grafted pancreatic islets.

Selina Wrublewsky, Sandra Rother, Franziska Pohlemann, Toni Radanovic, Fabian Junker, Anne S Boewe, Stefan Schunk, Leticia P Roma, Gloria Ruiz-Gómez, M Teresa Pisabarro, Patrick E MacDonald, Michael D Menger, Matthias W Laschke, Emmanuel Ampofo.

Islet-resident macrophages contribute to hypoxia-induced islet cell death during pancreatic islet transplantation. However, their specific role during this process remains elusive. Here, we report that interleukin-1α (IL-1α) and IL-1β are released by islet-resident macrophages, resulting in the suppression of insulin secretion. This may be due to a decreased inflammation-driven expression of pancreatic and duodenal homeobox 1 (PDX-1) and MafA in β cells. Islet-resident macrophages release significantly less IL-1α when compared to IL-1β. However, both cytokines inhibit insulin expression and secretion to a comparable extent. We identified heparan sulfate on the islet surface, which acts as a "molecular glue" potentiating the inhibitory action of IL-1α on insulin expression via specific binding to IL-1 receptor (IL-1R). In vivo analyses revealed that the loss of IL-1 signaling in isolated islets accelerates their revascularization and, thus, enhances their endocrine function. These findings indicate that heparan sulfate fine-tuned IL-1 signaling crucially determines the outcome of islet transplantation.

DOI: https://doi.org/10.1126/sciadv.ady8566
Int J Biol Macromol. 2025 Aug 06. pii: S0141-8130(25)07194-6. [Epub ahead of print] 146637

A selenium-enriched glycosaminoglycan from sturgeon cartilage: characterization and anti-metabolic syndrome potential.

Yanbin Gao, Jiaxi Lin, Dan Liu, Wenjuan Zhao, Jinjin Pei, A M Abd El-Aty.

  This study develops a novel selenium-enriched chondroitin sulfate (CSSE) from selenium-rich sturgeon cartilage that has potent multitarget activity against high-carbohydrate/high-fat diet-induced metabolic syndrome. Structural analyses (NMR/MALDI-TOF MS) confirmed Se-O-SO₃ covalent bonds (δ 78.5 ppm in 13C NMR) and a molecular weight of 16.8 kDa, indicating hepatic targeting with lower renal toxicity. Compared with sodium selenite, CSSE showed superior antioxidant capacity (65-80 % vs. 30-45 % DPPH scavenging) and biocompatibility (89.5 % vs. 66.4 % cell viability) (p = 0.009). In high-carbohydrate/high-fat diet (HCHF)-fed mice, CSSE markedly decreased body weight gain (-35 %), fasting glucose (-55 %), and triglyceride levels (-44 %), outperforming inorganic selenium by 2.1-3.5-fold. Mechanistically, CSSE inhibited mammalian target of rapamycin complex 1 (mTORC1) activation (32.7 % phosphorylated mammalian target of rapamycin (p-mTOR)/mammalian target of rapamycin (mTOR)), restored insulin signaling via the phosphoinositide 3-kinase-protein kinase B (PI3K-Akt)/insulin receptor substrate 1 (IRS-1) (↑103 % phosphorylated Akt (p-Akt)/protein kinase B (Akt), and upregulated the fibroblast growth factor 21 (FGF21)/fibroblast growth factor 19 (FGF19) gut-liver axis (p = 0.028). CSSE enriched beneficial gut bacteria (e.g., Ligilactobacillus) while suppressing Allobaculum, increasing short-chain fatty acid (SCFA) production by 58.1 % and enhancing gut barrier function (↓49 % fluorescein isothiocyanate (FITC)-dextran leakage, p = 0.007). Fecal microbiota transplantation (FMT) has validated microbiota-mediated benefits. The dual antioxidant and lipid-lowering actions of CSSE, combined with its targeted delivery and safety, position it as a pioneering marine organoselenium therapy. This study also establishes a sustainable approach to transform aquaculture byproducts into precision nutraceuticals, advancing metabolic health through circular bioeconomic solutions.

Keywords:  Bioactivity; Characterization; Chondroitin sulfate selenium; Sturgeon

DOI:  https://doi.org/10.1016/j.ijbiomac.2025.146637
Food Chem. 2025 Jul 30. pii: S0308-8146(25)03012-2. [Epub ahead of print]493(Pt 2): 145761

Development of chondroitin sulfate-modified quinoa protein isolate-dihydromyricetin composite nanoparticles: Focus on naringenin delivery, cell cytoprotective ability and anti-inflammatory effects.

Ying-Ying Chen, Xue-Ying Li, Qiang-Ming Li, Li-Hua Pan, Jian-Ping Luo, Xue-Qiang Zha.

  The development of nanocarriers utilizing macromolecules as targeted delivery systems has received significant interests. In this study, chondroitin sulfate (CS), quinoa protein isolate (QPI), and dihydromyricetin (DHM) were selected to form ternary polysaccharide-protein-polyphenol complexes (DHgQC). The DHgQ/CS mass ratio of 2:1 and pH of 6.0 were optimized for fabricating nanocomplexes. We further investigated the potential of DHgQC nanocomplexes as carriers for encapsulating and delivering hydrophobic substance naringenin (Nar), achieving a high encapsulation efficiency (90.64 %) and loading capacity (13.27 %). Meanwhile, the Nar-encapsulated nanocomplex (Nar@DHgQC) demonstrated excellent photothermal stability, and controlled release characteristics. Furthermore, Nar@DHgQC exhibited remarkable capabilities in clearing RONS, maintaining cell viability, and mitigating oxidative stress. Importantly, cellular uptake assays confirmed the targeting of inflammatory macrophages by Nar@DHgQC nanoparticles, resulting in strong anti-inflammatory activity. This work presents a novel paradigm for the development of food-grade biopolymer nanoparticles as functional carriers for applications in the food and biomedicine fields.

Keywords:  Anti-inflammation; Chondroitin sulfate; Macrophage polarization; Macrophage targeting; Quinoa protein isolate

DOI:  https://doi.org/10.1016/j.foodchem.2025.145761
Anim Sci J. 2025 Jan-Dec;96(1):96(1): e70097

Possible Involvement of CSPG4 in Promoting Endothelial Cell Migration and Contributing to Angiogenesis during Skeletal Muscle Regeneration and Development in the Rat.

Riku Yamaguchi, Masanari Ikeda, Shiho Takeuchi, Katsuyuki Nakamura, Akbota Kurmangaliyeva, Naomi Teramoto, Hidetoshi Sugihara, Chihiro Kikawa, Takashi Matsuwaki, Masugi Nishihara, Keitaro Yamanouchi.

  Skeletal muscle regeneration is a complex process that requires coordinated interactions between myogenic and vascular cells. Chondroitin sulfate proteoglycan 4 (CSPG4), a cell surface proteoglycan, had been shown to be expressed around immature myofibers in patients with Duchenne muscular dystrophy, suggesting its role in muscle regeneration. In the present study, we found that CSPG4 is transiently expressed by regenerating myofibers upon muscle injury in the rat. We generated the CSPG4 knockout (KO) rats to investigate its role in muscle regeneration. In CSPG4 KO rats, skeletal muscle development was perturbed with impaired angiogenesis. When muscle regeneration was induced, CSPG4 KO rats showed a reduced number of CD31-positive cells at the regenerating site. These results suggest the role of CSPG4 in angiogenesis during muscle regeneration and development. In vitro, coculture of CSPG4-expressing mesenchymal progenitor cells (MPC) promoted vascular endothelial cell migration, whereas the KO of CSPG4 in MPC abrogated the upregulation of endothelial cell migration. Our findings identify CSPG4 as a key regulator of vascular endothelial cell recruitment during muscle vascular remodeling and highlight its potential as a therapeutic target for Duchenne muscular dystrophy, which is characterized by impaired angiogenesis.

Keywords:  angiogenesis; chondroitin sulfate proteoglycan4; rat; regeneration; skeletal muscle

DOI:  https://doi.org/10.1111/asj.70097
Front Microbiol. 2025 ;16 1642517

Six new bacterial species isolated from the phycosphere of marine macroalgae: a joint analysis based on taxonomy and polysaccharide utilization loci.

De-Chen Lu, Ying Yuan, Xin-Yun Tan, Le Liu, Jin-Hao Teng, Xue Cui, Tian-He Liu, Jing Zhang, Zong-Jun Du, Ming-Yi Wang.

  Marine macroalgae-associated Bacteroidota play crucial roles in global carbon cycling through polysaccharide degradation, yet their taxonomic and functional diversity remains understudied. Here, we describe six novel species (strains 3-376T, 4-2040T, 2-473AT, 4-528T, 4-911T and 463T) within the families Flavobacteriaceae, Crocinitomicaceae, and Cytophagaceae isolated from macroalgal surfaces in the coastal area of Weihai, China. Metagenomic read recruitment and 16S rRNA abundance analyses demonstrated host-specific associations. Integrative taxonomic analyses, including phylogenomics (120 conserved proteins), 16S rRNA sequencing, and chemotaxonomy (e.g., MK-6 quinones, phosphatidylethanolamine lipids, and iso-C15:0 fatty acids), confirmed their novel status, with average amino acid identity (AAI), percentage of conserved proteins (POCP) distinguishing them from related taxa. Genomes (3.3-7.1 Mb; G + C 31.7-45.3%) revealed diverse polysaccharide utilization loci (PULs) targeting algal glycans like laminarin, alginate, and sulfated polymers (ulvan, chondroitin sulfate). Cytophagaceae 463T harbored the richest CAZyme/PUL repertoire (131 CAZymes, 15 PULs), while Crocinitomicaceae 4-911T lacked PULs, highlighting family-level specialization. This study expands the known diversity of core phycosphere Bacteroidota, linking PUL evolution to habitat specialization. The novel species' distinct degradative capacities underscore their ecological roles in algal carbon processing and potential for biotechnological applications. Our integrated taxonomy-genomics approach advances understanding of microbial contributions to marine ecosystem dynamics.

Keywords:  Bacteroidota; Flavobacteriaeae; core phycosphere families; novel species; polysaccharide utilization loci

DOI:  https://doi.org/10.3389/fmicb.2025.1642517
Nat Prod Rep. 2025 Aug 05.

Microbial engineering for natural and unnatural glycosaminoglycans biosynthesis.

Chunlei Zhao, Jinyi Qian, Xiulai Chen.

Covering: up to 2025Microbial synthesis of glycosaminoglycans (GAGs) facilitates sustainable biomanufacturing using cost-effective carbon feedstocks. This transformative framework is driven by three core innovations: de novo GAGs biosynthesis, sulfation engineering, and new-to-nature GAGs analogs creation. Despite these advances, critical challenges hinder industrial-scale efficiency, such as suboptimal distribution of metabolic flux, insufficient sulfation environments, and host incompatibility with unnatural analogs. In this review, we present a systematic analysis of microbial hosts, biosynthetic pathways, and microbial engineering strategies for GAGs production. We first describe how strategic host optimization and pathway manipulation can tap the full potential of microorganisms for efficient GAGs biosynthesis. Then, we analyze the development of microbial cell factories (MCFs) for GAGs biosynthesis from the simple pathway transplantation to systemic de novo construction of metabolic systems, thereby establishing programmable platforms to surpass natural biosynthesis limits. Next, we present a tripartite engineering framework for GAGs sulfation that integrates precursor synthesis modules, sulfate donor accumulation systems, and sulfotransferase networks, thereby progressing sulfation control from biomimetic mechanisms to programmable artificial systems. Further, we discuss the microbial synthesis of new-to-nature GAGs analogs through the incorporation of unnatural precursors or the reprogramming of natural precursors, thereby enabling MCFs to construct non-canonical glycopolymers with designed function. Finally, we prospect the development of multifunctional customized MCFs to drive breakthroughs in industrial-scale GAGs bioproduction.

DOI: https://doi.org/10.1039/d5np00043b
mBio. 2025 Aug 08. e0003125

Structural insights into manganese-dependent arylsulfatase from Enterococcus faecium and its catalytic promiscuity.

Lulu Guo, Xuanjia Dong, Zetao Hu, Ling Zeng, Zhaohui Jin, Lin Jiang, Wenting Dai, Jinbiao Ma, Shili Chen, Ying Huang.

  Catalytic promiscuity, wherein enzymes catalyze multiple distinct reactions by stabilizing various transition states, is well documented in the alkaline phosphatase superfamily. In this study, we determined the crystal structure of an arylsulfatase from Enterococcus faecium (EfAS), revealing a homotetrameric assembly with a windmill-like architecture not observed in other known arylsulfatases or phosphonoester hydrolases. This quaternary structure is stabilized by hydrogen bonding, salt bridges, and hydrophobic interactions, while retaining full accessibility to the catalytic groove. Moreover, by incorporating a manganese ion in its active site, EfAS provides the first crystallographically confirmed example of a Mn²+-dependent arylsulfatase, addressing previous uncertainties regarding metal specificity. Functional assays and site-directed mutagenesis showed that EfAS hydrolyzes sulfates, phosphates, and phosphonates, indicating broad substrate specificity. Furthermore, high-performance liquid chromatography-mass spectrometry demonstrated that EfAS removes sulfate groups from key bioactive molecules, such as caerulein and estrone sulfate. Collectively, these findings establish EfAS as an atypical member of the alkaline phosphatase superfamily, featuring a distinct oligomeric organization and broad substrate scope, and suggest its potential role in modulating sulfation of bioactive compounds.IMPORTANCEThis work provides the first crystallographically confirmed Mn²+-dependent arylsulfatase, unveiling a unique "windmill-like" homotetrameric architecture and demonstrating catalytic promiscuity toward sulfates, phosphates, and phosphonates. These findings address longstanding uncertainties about metal specificity in arylsulfatases, highlight the structural and functional diversity of the alkaline phosphatase superfamily, and suggest new strategies for modulating the sulfation of bioactive molecules.

Keywords:  Enterococcus faecium; arylsulfatase; biomolecule; catalytic promiscuity; crystal structure; gut microbiome

DOI:  https://doi.org/10.1128/mbio.00031-25
Eur J Pharmacol. 2025 Aug 06. pii: S0014-2999(25)00805-2. [Epub ahead of print] 178051

Cholesterol sulfate alleviates functional dyspepsia in juvenile mice via modulating the gut microbiota-derived lactate.

Aitong Liu, Guangtao Yan, Jun Xie, Zichen He, Tianhao Yang, Xiaodan Huang, Jianhui Xie, Qingfeng Xie, Ziren Su, Yuhong Liu.

  The overall global pooled prevalence of functional dyspepsia (FD) was 8.4%, affecting 3-27 % of children. Currently, no specific medication exists for FD, especially in pediatric cases. Cholesterol sulfate (CHS), a bioactive compound derived from sea cucumber, shows potential in protecting the gastrointestinal tract, but its effects on pediatric FD remain unknown. This study assessed the pharmacological effects of CHS using a juvenile mice model of FD induced by repeated low-dose cisplatin. Results indicated that CHS significantly enhanced gastrointestinal motility and alleviated inflammation, marked by increased serum gastrin (GAS) and motilin (MTL), elevated interleukin-4 (IL-4), and reduced interleukin-1β (IL-1β) in intestines of FD juvenile mice. CHS restrained FD-induced gut dysbiosis by reducing the Firmicutes/Bacteroidotas (F/B) ratio and suppressing Lactobacillus dominance. Notably, CHS decreased lactate and lactate dehydrogenase (LDH) levels in serum and the intestines of FD juvenile mice. Elevated lactate suppresses ghrelin production through G protein-coupled receptor (GPR81) receptor signaling, impairing intestinal motility, which highlights the significance of reducing lactate levels. Ghrelin enhances gastrointestinal motility by activating intestinal cholinergic neurons and potentiating serotonin (5-HT) signaling. After CHS treatment, GPR81 expression was downregulated while acetylcholinesterase (AChE) expression, ghrelin and 5-HT levels were upregulated in intestines, as well as heightened serum AChE activity. The co-administration of CHS with antibiotics(ABX) significantly attenuated its therapeutic efficacy, confirming that CHS alleviates FD in juvenile mice by inhibiting gut microbiota-derived lactate metabolism. In conclusion, our study provides evidence to support the utilization of CHS for regulating gastrointestinal motility for pediatric FD patients.

Keywords:  Cholesterol sulfate; Functional dyspepsia; Gastrointestinal motility; Gut microbiota; Lactate

DOI:  https://doi.org/10.1016/j.ejphar.2025.178051
bioRxiv. 2025 Jul 31. pii: 2025.07.28.667232. [Epub ahead of print]

A sulfonated cartilage interpenetrating polymer network reinforces and protects the extracellular matrix of degraded cartilage.

Christian D DeMoya, Pierson Husted, Dev R Mehrotra, Michael B Albro, Brian D Snyder, Mark W Grinstaff.

Cartilage extracellular matrix (ECM) comprises a type-II collagen fibril network that affords structure and tensile strength, complemented by a negatively charged, sulfated glycosaminoglycan (GAG) matrix that retains interstitial water. These components act synergistically, bestowing the rheological and tribological material properties essential to cartilage function. At the onset of osteoarthritis, a disease characterized by cartilage degeneration, GAGs diminish from the ECM reducing interstitial fluid load support ( IFLS ) and transferring load to the collagen fibril network, which subsequently breaks down, culminating in increased hydraulic permeability, and decreased cartilage stiffness. We restore the material properties of damaged cartilage critical to diarthrodial joint function by forming an interpenetrating polymer network (IPN) with the native collagen using a synthetic, hydrophilic, and biocompatible GAG-mimetic polymer. Upon visible light activation, the monomer, 3-sulfopropylmethacrylate (SPM), and the crosslinker, polyethylene glycol diacrylate (PEGDA), form a sulfonated and anionic IPN that entangles and fills the existing porous degraded collagen matrix. Mechanistically, the highly sulfated, anionic SPM IPN retards water transport, reestablishes collagen fibril network integrity, and restores tissue IFLS , thereby returning the stiffness and viscoelastic properties of degraded cartilage to healthy levels. Additionally, the SPM IPN protects cartilage from further degradation by reducing the infiltration of inflammatory cytokines that upregulate catabolic matrix metalloproteinases and downregulate GAG production.
Statement of significance: Amelioration of OA requires a comprehensive approach: neutralize or impede catabolic enzymes that degrade cartilage and reconstitute damaged cartilage by augmenting tissue ECM constituents. Currently, there are no clinical treatments that restore the viscoelastic material properties of hyaline cartilage tissue critical to its mechanical function and impart chondroprotection after OA induction. This work suggests that reconstituting GAG-depleted cartilage using a synthetic sulfonated interpenetrating polymer to reestablish IFLS that can be instilled into the joint and polymerized with white light during conventional arthroscopy represents a novel, minimally invasive, clinical treatment for early OA.

DOI: https://doi.org/10.1101/2025.07.28.667232
Microbiome. 2025 Aug 06. 13(1): 183

Sulfated dietary fiber protects gut microbiota from antibiotics.

Fuqing Wu, Xiaoqian Annie Yu, David Angeles-Albores, Susan E Erdman, Eric J Alm.

   BACKGROUND: Antibiotics, while essential for combating pathogens, also disrupt commensal bacteria, leading to gut microbiota imbalance and associated diseases. However, strategies to mitigate such collateral damage remain largely underexplored.
RESULT: In this study, we found that fucoidan, a marine polysaccharide derived from brown seaweed, provides broad-spectrum growth protection against multiple classes of antibiotics for human gut microbial isolates in vitro and for fecal communities ex vivo. This protective effect is dependent on the structural integrity, molecular weight, and sulfur content of the polysaccharide. Transcriptomic analysis showed that while fucoidan had minimal impact on baseline gene expression, it counteracted about 60% of the genes induced by kanamycin, suggesting a potential inhibition of kanamycin. Mass spectrometry results further showed that this inhibition may be due to the non-specific binding of fucoidan to kanamycin in solution. Finally, animal model experiments revealed that fucoidan facilitated the recovery of gut microbes following antibiotic treatment in vivo.
CONCLUSION: These findings suggest fucoidan could serve as a potential intervention to help protect gut microbiota during antibiotic therapy. Further studies are needed to evaluate its clinical potential and ensure it does not compromise antimicrobial efficacy. Video Abstract.

Keywords:  Antibiotics; Dietary fiber; Fucoidan; Gut microbiome; Microbial community; Sulfated polysaccharide

DOI:  https://doi.org/10.1186/s40168-025-02176-w
ACS Omega. 2025 Jul 29. 10(29): 32466-32475

In Vitro Evaluation of the Potential Interactions of Zearalenone-14-sulfate and Zearalenone-14-glucuronide with Human Cytochrome P450 Enzymes, Organic Anion Transporting Polypeptides, and ATP-Binding Cassette Multidrug Transporters.

Ágnes Telbisz, Hana Kaci, Éva Bakos, Zoltán Nagymihály, Eszter B Both, Nándor Lambert, Csilla Özvegy-Laczka, Miklós Poór.

Zearalenone (ZEN) is a mycotoxin that is typically produced by Fusarium strains. ZEN and its derivatives are common food contaminants and known xenoestrogens. Previous studies demonstrated the interactions of ZEN and zearalenols with certain cytochrome P450 (CYP) enzymes, organic anion transporting polypeptides (OATPs), and ATP-binding cassette (ABC) multidrug transporters. However, no data are available regarding the conjugated metabolites of the mycotoxin. Therefore, in the current study, we aimed to investigate the potential interactions of zearalenone-14-sulfate (Z14S) and zearalenone-14-glucuronide (Z14GA) with these proteins using in vitro assays. Our major observations/conclusions are the following: Z14S was a weak inhibitor of CYP2C9 and CYP3A4, while Z14GA did not affect the activity of the CYP enzymes examined. Z14S inhibited OATP1A2 and OATP1B3 at low micromolar concentrations, and it showed even stronger effects on OATP1B1 and OATP2B1 with nanomolar IC50 values. In contrast, Z14GA proved to be a weak inhibitor of OATPs tested, except OATP2B1. Among the ABC transporters investigated, we noticed the most relevant interactions of ZEN with MDR1, Z14S with BCRP, and Z14GA with MRP2. Our novel observations may contribute to the deeper understanding of the toxicokinetic interactions of Z14S and Z14GA.

DOI: https://doi.org/10.1021/acsomega.5c05217
Acta Crystallogr C Struct Chem. 2025 Sep 01.

The cleavage of indinavir sulfate: synthesis and characterization of a cis-1-amino-2-indanol salt.

Tebogo M L Mokoto, Andreas Lemmerer, Yasien Sayed, Kgaugelo C Tapala, Itumeleng B Setshedi, Mark G Smith.

  The HIV-1 protease inhibitor indinavir sulfate was cleaved via a one-pot reflux synthesis using 1-propanol, yielding the salt bis(2-hydroxy-2,3-dihydro-1H-inden-1-aminium) sulfate, 2C9H12NO+·SO42-. Single-crystal X-ray diffraction (SC-XRD) revealed that the salt crystallizes in the monoclinic space group P21. The structure consists of two conformationally distinct cations and one sulfate anion, stabilized through an extensive hydrogen-bonding network. Thermal analysis showed minor solvent loss around 200 °C, followed by a two-step decomposition process commencing at 306.6 °C. Hirshfeld surface analysis revealed dominant O...H/H...O (44.4-41.0%) and H...H (45.2-40.1%) intermolecular contacts, with minor contributions from C...H/H...C and C...O/O...C interactions. These contact percentages were calculated for each of the two independent cations. The van der Waals surface area (687.30 Å2) accounts for 71.43% of the unit cell. These results provide structural and thermal evidence for the transformation of indinavir sulfate under alcoholytic conditions, highlighting the formation and stabilization of the resulting salt.

Keywords:  chemical transformations; crystal structure; indinavir; salt crystal structure; slow evaporation; solvation crystallization; surface analysis; thermal analysis

DOI:  https://doi.org/10.1107/S2053229625005807
Aging Male. 2025 Dec;28(1): 2541694

The impact of lymphocyte count on male erectile dysfunction with clinical validations and its potential metabolic mechanisms through mendelian randomization analysis.

Haoyang Dong, Yong Liu, Dong Di, Tingsong Bian.

   BACKGROUND: Erectile dysfunction (ED) is on the rise globally, affecting people's lives. This article uses Mendelian randomization (MR) to analyze the causal relationship between clinical indicators and ED, and explores the potential metabolic mechanisms involved.
METHOD: Two-sample MR analysis was performed to analyze the causal relationships between 1,400 metabolites and clinical data and ED for revealing its potential metabolic mechanisms using GWAS (Genome-wide association studies) data. The stability of MR analysis was assessed using sensitivity analysis. We then used clinical data to confirm the MR analysis results.
RESULTS: The research results indicated that elevated lymphocyte count (LC) can lead to ED risks. To confirm that LC and ED are causally related, we gathered clinical data. We further revealed potential metabolic mechanisms and found that LC can not only reduce the metabolite 4-methylcatechol sulfate levels, lowering the metabolite 4-methylcatechol sulfate levels to increase the risk of ED, and can also increase the metabolite X-24801 levels, raising the metabolite X-24801 levels to increase the risk of ED.
CONCLUSIONS: A rise in LC could raise the risks of ED by negatively regulating the metabolite 4-methylcatechol sulfate levels and positively controlling the metabolite X-24801 levels.HighlightsThis article uses Mendelian randomization analysis to determine the causal relationship between lymphocyte count and erectile dysfunction, and uses sensitivity analysis to determine its stabilityRevealed the potential mechanism by which lymphocyte count increases the risk of erectile dysfunctionCollecting clinical data validated the results of Mendelian randomization analysisAt present, the methods and efficacy of treating erectile dysfunction in clinical practice are limited. This study provides new ideas for clinical diagnosis and treatment of erectile dysfunction.

Keywords:  Mendelian randomization; clinical indicators; erectile dysfunction; lymphocyte count; metabolite

DOI:  https://doi.org/10.1080/13685538.2025.2541694