bims-supasi 2025-05-25 papers

bims-supasi

Biomed News

on Sulfation pathways and signalling

Issue of 2025–05–25
twenty-two papers selected by
Jonathan Wolf Mueller, University of Birmingham

A semi-synthetic heparan sulfate material that potentiates BMP2-mediated osteogenesis.
Chondroitin sulfate reverses tibial dyschondroplasia, broiler chondrocyte proliferation and differentiation dysfunction via the CHST11/β-Catenin pathway.
Tetraphenylethene-carrying peptide probes for fluorescence "turn-on" sensing of chondroitin sulfate A.
Camptothecin-loaded chondroitin sulfate-celecoxib reduction-sensitive micelles for enhanced colon cancer treatment.
Maternal serum heparan sulfate in preeclampsia pathophysiology: Insights from a systematic review and meta-analysis.
Associations between urinary glycosaminoglycans and onset of acute respiratory distress syndrome in sepsis patients: a prospective exploratory study.
Discovery and Characterization of CcrSult1: A Novel Flavonoid Sulfotransferase from the Red Alga Chondrus crispus.
Crystal structure and catalytic mechanism of PL35 family glycosaminoglycan lyases with an ultrabroad substrate spectrum.
Influence of alkali treatment and ultrasonication on the bioactivities and rheological properties of sulfated polysaccharides.
Confirmation of a novel, stable estrogen metabolite, as 5a,6a-epoxy-estrone sulfate in stallion blood by LC-MS/MS.
Advances in fucoidan and fucoidan oligosaccharides: Current status, future prospects, and biological applications.
Natural product-based nano-antioxidant for the treatment of acute pancreatitis.
Indoxyl Sulfate Contributes to Selenium Deficiency and Renal Ferroptosis by Decreasing the Expression of Selenium Transport Protein SEPP1.
Elevated Dehydroepiandrosterone Sulfate Levels in 2 Patients With Prolactinomas: An Underrecognized Association.
Multi-cancer detection of circulating tumor cells by targeting oncofetal chondroitin sulfate.
Structural characterization of galactomannan sulfated modification products with different molecular weight fractions and their in vitro anti-lung cancer activities.
From Biosynthesis to Signaling: Unveiling the Multifaceted Roles of Phytosulfokine Peptide in Plants.
Advancement on heparin-based hydrogel/scaffolds in biomedical and tissue engineering applications: Delivery carrier and pre-clinical implications.
Investigation on the Detoxification of Indoxyl Sulfate (IS) and Indole-3-Acetic Acid (IAA) Protein-Bound Uremic Toxins (PBUTs) Using Trametes versicolor Biocompatible Laccase: In Situ Synchrotron Imaging, Experimental and Computational Studies.
Elucidation of Molecular Mechanisms of Sulfated Oligoguluronic Acid on Mitigating Intestinal Inflammation and Enhancing Epithelial Barrier Function.
Structure, function and catalytic mechanism of the carrageenan-sulfatases from the marine bacterium Zobellia galactanivorans DsijT.
Mining the heparinome for cryptic antimicrobial peptides that selectively kill Gram-negative bacteria.

Int J Biol Macromol. 2025 May 17. pii: S0141-8130(25)04901-3. [Epub ahead of print]314 144349

A semi-synthetic heparan sulfate material that potentiates BMP2-mediated osteogenesis.

Liam J Sargison, Amira Sargison, Susan M Carnachan, Raymond A A Smith, Alison M Daines, Simon F R Hinkley, Simon M Cool.

Heparan sulfate (HS) is a naturally occurring polysaccharide fundamental to eukaryotic life. It is currently under investigation in many contexts for its ability to modulate and potentiate the interactions of proteins in the extracellular matrix. Among other promising applications, heparan sulfate has been investigated as a material for potentiating Bone Morphogenetic Protein 2 (BMP2) activity in osteogenesis and bone repair, with encouraging results. However, isolating a structurally consistent, scalable, and economical source of heparan sulfate has been problematic. To address this, a series of semi-synthetic heparan sulfates were prepared from affordable, batch-consistent, commercially available heparin and were evaluated in their structural and BMP2-potentiating properties. These populations were also compared to a population of heparan sulfate previously optimised for bone repair - HS3. We show that a semi-synthetic process generates a heparan sulfate-like material that potentiates BMP2-mediated osteogenesis and warrants further investigation as a material for bone augmentation procedures.

DOI: https://doi.org/10.1016/j.ijbiomac.2025.144349
Int J Biol Macromol. 2025 May 21. pii: S0141-8130(25)05040-8. [Epub ahead of print] 144488

Chondroitin sulfate reverses tibial dyschondroplasia, broiler chondrocyte proliferation and differentiation dysfunction via the CHST11/β-Catenin pathway.

Yuanliang Li, Cong Li, Wenjing Xu, Jing Zhao, Kai Liu, Xiaoqing Liu, Ying Li, Zhaoxin Tang, Aoyun Li, Hui Zhang.

  Broiler tibial dyschondroplasia (TD) is a prevalent disorder that impairs locomotion and disrupts feeding behaviors, thereby compromising production efficiency and causing significant economic losses. Consequently, there is a growing need for effective therapeutic interventions. Chondroitin sulfate (CS) has demonstrated potential to enhance bone development and improve growth performance. However, the molecular mechanisms underlying CS alleviates TD remain unclear, due to its multiple biological activities. This study revealed that CS significantly alleviates TD in broilers by enhancing the body weight, increasing tibial mass, and promoting repair of growth plate injuries. Specifically, CS treatment restored the normal morphology of the tibial growth plate and upregulated the expression of extracellular matrix components (ECM), including Col2α1, ACAN, and CHST11, in TD-affected chondrocytes, consequently activating the Wnt/β-Catenin pathway. Notably, the inhibition of CHST11 markedly suppressed ECM synthesis and chondrocytes proliferation, accompanied by a decrease in β-Catenin expression, replicating the pathological patterns observed in thiram-induced TD chondrocytes. Importantly, CS supplementation effectively counteracted CHST11 inhibition, restoring ECM synthesis and cellular proliferation through the upregulation of the CHST11/β-Catenin pathway. These findings point to the pivotal role of CHST11-mediated activation of the Wnt/β-Catenin pathway plays a vital role in the therapeutic effect of CS in broiler TD.

Keywords:  Chondroitin sulfate; Extracellular matrix; Tibial dyschondroplasia

DOI:  https://doi.org/10.1016/j.ijbiomac.2025.144488
Spectrochim Acta A Mol Biomol Spectrosc. 2025 May 15. pii: S1386-1425(25)00713-9. [Epub ahead of print]341 126407

Tetraphenylethene-carrying peptide probes for fluorescence "turn-on" sensing of chondroitin sulfate A.

Yusuke Sato, Kanta Kobayashi, So Fujita, Kotoha Okano, Seiichi Nishizawa.

  New class of fluorescence probes was developed for sensing of chondroitin sulfate A (CSA), a biologically important glycosaminoglycan (GAG). Three kinds of synthetic CSA-binding peptides were conjugated with a tetrahenylethene (TPE) unit for the probe design. Significantly, the TPE unit conjugated with TR peptide (TRTPPESYASVR) displayed an increase in the monomer emission upon binding to CSA, which stands in sharp contrast to typical TPE-carrying probes with aggregation-induced emission (AIE) response. It was shown that TPE-TR probe has the selectivity for CSA over other GAGs including hyaluronan and heparin. We found that the use of a hydrophilic aminoethoxy-ethoxy acetic acid (AEEA) spacer between TPE and TR peptide resulted in the improved "turn-on" sensing of CSA. The assay using the probe with AEEA spacer facilitated more rapid and sensitive detection of CSA compared to Alcian blue assay, a traditional assay for the quantification of CSA.

Keywords:  Fluorescent probe; Monomer emission; Peptide; chondroitin sulfate A

DOI:  https://doi.org/10.1016/j.saa.2025.126407
Int J Biol Macromol. 2025 May 21. pii: S0141-8130(25)05041-X. [Epub ahead of print] 144489

Camptothecin-loaded chondroitin sulfate-celecoxib reduction-sensitive micelles for enhanced colon cancer treatment.

Qiao Qiao, Jie Li, Chunying Tao, Meiyang Yang, Weijun Chen, Lipeng Qiu, Huiming Tu.

  Studies have shown that inflammation is closely linked to the cancer development, and the patients with inflammatory bowel disease (IBD) have a higher risk of colon cancer. Celecoxib (CXB) and camptothecin (CPT) showed potential treatment for IBD and colon cancers, respectively. However, their applications are limited by synchronous delivery, water insolubility, and off-target side effects. Herein, a glutathione (GSH) responsive chondroitin sulfate A (CSA)-SS-CXB micelle loaded with CPT (CSA-SS-CXB@CPT) was prepared as a targeted system to treat colon cancer by anti-inflammatory and antitumor synergistic effect. Specifically, CSA had tumor tumor-targeting effect due to colon cancer lesion-high expression of CD44 receptors. In vitro results verified that CSA-SS-CXB@CPT selectively internalized into colon cancer HT-29 cells and had strong reactive oxygen species (ROS) elimination ability. The CSA-SS-CXB@CPT could rapidly release CXB and CPT in the tumor microenvironment for playing an anti-tumor role. In vivo experiments illustrated that CSA-SS-CXB@CPT significantly targeted tumor tissues and suppressed tumor growth without producing serious side effects in tumor-bearing nude mice. Therefore, this work provides an opportunity for targeted co-delivery of anti-inflammatory and chemotherapy drugs to treat colon cancer.

Keywords:  Camptothecin; Chondroitin sulfate; Colon cancer

DOI:  https://doi.org/10.1016/j.ijbiomac.2025.144489
Placenta. 2025 May 09. pii: S0143-4004(25)00137-7. [Epub ahead of print]

Maternal serum heparan sulfate in preeclampsia pathophysiology: Insights from a systematic review and meta-analysis.

Alejandra María Gómez-Gutiérrez, Angela María Alvarez-Gómez, Juan Carlos Quintana-Castillo, Julio Cesar Bueno-Sánchez, Walter D Cardona Maya.

  Preeclampsia (PE) is a hypertensive disorder that generally occurs after the first half of pregnancy, at delivery or even postpartum; it is associated with maternal organ dysfunction and significantly increases maternal, fetal, and newborn morbidity and mortality. During PE, the syncytiotrophoblast and endothelial cells are damaged, and molecules from the extracellular matrix, such as heparan sulfate (HS), can be released into the blood. Therefore, this study aimed to perform a systematic review and meta-analysis to assess the HS levels in serum from women with preeclampsia and normal pregnancy. To perform this systematic review and meta-analysis study, we comprehensively searched PubMed, ScienceDirect and LILACS and collected published studies about HS and preeclampsia. The risk of bias was assessed using the Newcastle-Ottawa Scale score. Upon search completion, 568 studies were identified, and 4 studies were retrieved for the present analysis. The forest plot showed an increase in serum HS in women with preeclampsia relative to non-preeclamptic women, standardized mean diference -SMD-with 95 % CI 1.2 (-0.41 to 2.81), and this relationship is maintained in early PE group (SMD 1.05; 95 % CI (0.22-2.32)). In conclusión, we presented here that HS possibly plays a vital role in the pathogenesis of preeclampsia since the results showed an increase in this molecule's levels in serum from women with preeclampsia.

Keywords:  Glycosaminoglycans; Heparan sulfate; Placenta; Preeclampsia; Pregnancy

DOI:  https://doi.org/10.1016/j.placenta.2025.04.026
Sci Rep. 2025 May 22. 15(1): 17783

Associations between urinary glycosaminoglycans and onset of acute respiratory distress syndrome in sepsis patients: a prospective exploratory study.

Ziyuan Shen, Zhengying Li, Hua Zhang, Xiaoyun Wei, Senhao Wei, Feng Zhao, Cui Yang, Zhukai Cong, Zhongnan Yin, Chenchen Ding, Cai Tie, Xi Zhu.

  The aim of the current study was to explore the association between urinary glycosaminoglycans and the onset of acute respiratory distress syndrome (ARDS) in sepsis patients. We conducted a prospective cohort study of 49 sepsis patients and collected clinical characteristics, urine, and blood samples within 24 h of admission to the Surgical Intensive Care Unit (SICU) of Peking University Third Hospital. Samples from patients who did not develop ARDS were collected from day 1 to day 7 after SICU admission, while samples from patients who developed ARDS were collected from day 1 to the day of onset, forming time-series data. A liquid chromatography-mass spectrometry (LC-MS) system was used to determine urinary dermatan sulfate (DS), chondroitin sulfate (CS), and heparan sulfate (HS) concentrations; enzyme-linked immunosorbent assay (ELISA) and cytometric bead array (CBA) were used to measure plasma inflammatory factors. The endpoint was the onset of ARDS. We used generalized estimating equations to identify associations between urinary glycosaminoglycans and ARDS onset in sepsis patients. Twenty-two of the 49 sepsis patients developed ARDS, and 132 plasma samples and 132 urine samples were obtained. Between the ARDS and non-ARDS groups, sex, pneumonia, Acute Physiology and Chronic Health Evaluation II (APACHE II), Lung Injury Prediction Score (LIPS), and PaO2/FiO2 showed statistically significant differences. Generalized estimating equations showed that DS and tumor necrosis factor-α (TNF-α) were independently associated with ARDS onset in sepsis patients, but their generalizability across ARDS subtypes warrants further validation.

Keywords:  Acute respiratory distress syndrome; Glycosaminoglycans; Inflammatory factors; Risk factors; Sepsis

DOI:  https://doi.org/10.1038/s41598-025-02109-5
J Agric Food Chem. 2025 May 22.

Discovery and Characterization of CcrSult1: A Novel Flavonoid Sulfotransferase from the Red Alga Chondrus crispus.

Wencui Chen, Zhijian Li, Tao Liu, Qianqian Lyu, Weizhi Liu.

  Sulfated flavonoids, prevalent in various plants, possess enhanced bioavailability due to the introduction of sulfonate groups, a process catalyzed by flavonoid sulfotransferases (SULTs). These enzymes serve as invaluable tools for exploring the structure-function relationships of sulfated flavonoids and for the preparation of biologically active derivatives. Despite their significance, flavonoid SULTs remain largely unexplored especially for those from marine environment. In this study, we report the discovery of CcrSULT1, the first flavonoid SULT from the red algaChondrus crispus. Substrate specificity tests revealed that CcrSULT1 exhibits a pronounced chemical selectivity preference for phenolic compounds, particularly flavonoids. More importantly, we discovered that CcrSULT1 may have unique regional selectivity toward mono phenolic hydroxyl groups (e.g., the 4'-OH of kaempferol, a flavonoid aglycone widely distributed in algae and various plants) in substrates, potentially leading to the specific production of monosulfated products. This hypothesis is further supported by the construction of a complex structural model. This study paves the way for the discovery of unknown algal sulfotransferases and provides a biological basis for understanding algal sulfation metabolism and biomass conversion.

Keywords:  cytosolic sulfotransferases; flavonoid; substrate specificity; sulfation; sulfotransferase

DOI:  https://doi.org/10.1021/acs.jafc.5c02656
Elife. 2025 May 19. pii: RP102422. [Epub ahead of print]13

Crystal structure and catalytic mechanism of PL35 family glycosaminoglycan lyases with an ultrabroad substrate spectrum.

Lin Wei, Hai-Yan Cao, Ruyi Zou, Min Du, Qingdong Zhang, Danrong Lu, Xiangyu Xu, Yingying Xu, Wenshuang Wang, Xiu-Lan Chen, Yu-Zhong Zhang, Fuchuan Li.

  Recently, a new class of glycosaminoglycan (GAG) lyases (GAGases) belonging to PL35 family has been discovered with an ultrabroad substrate spectrum that can degrade three types of uronic acid-containing GAGs (hyaluronic acid, chondroitin sulfate and heparan sulfate) or even alginate. In this study, the structures of GAGase II from Spirosoma fluviale and GAGase VII from Bacteroides intestinalis DSM 17393 were determined at 1.9 and 2.4 Å resolution, respectively, and their catalytic mechanism was investigated by the site-directed mutant of their crucial residues and molecular docking assay. Structural analysis showed that GAGase II and GAGase VII consist of an N-terminal (α/α)6 toroid multidomain and a C-terminal two-layered β-sheet domain with Mn2+. Notably, although GAGases share similar folds and catalytic mechanisms with some GAG lyases and alginate lyases, they exhibit higher structural similarity with alginate lyases than GAG lyases, which may present a crucial structural evidence for the speculation that GAG lyases with (α/α)n toroid and antiparallel β-sheet structures arrived by a divergent evolution from alginate lyases with the same folds. Overall, this study not only solved the structure of PL35 GAG lyases for the first time and investigated their catalytic mechanism, especially the reason why GAGase III can additionally degrade alginate, but also provided a key clue in the divergent evolution of GAG lyases that originated from alginate lyases.

Keywords:  biochemistry; catalytic mechanism; chemical biology; crystal structure; glycosaminoglycan lyases; none; polysaccharide lyase 35 family

DOI:  https://doi.org/10.7554/eLife.102422
Int J Biol Macromol. 2025 May 15. pii: S0141-8130(25)04674-4. [Epub ahead of print]314 144122

Influence of alkali treatment and ultrasonication on the bioactivities and rheological properties of sulfated polysaccharides.

Clarisa Naa Shormeh Darko, Benny Arthur, Kadri Saluri, Helerin Lepik, Laura Punak, Marju Robal, Kert Martma, Rando Tuvikene.

  The rheological, antioxidant and anticoagulant properties of 17 different structurally uniform and hybrid sulfated polysaccharides are presented in this study. Alkali treatment was used to modify carrageenan precursors, while ultrasonication was employed to partially depolymerize polysaccharide chains. Native and modified sulfated polysaccharides with well-resolved molecular structures were characterized by size exclusion chromatography and dynamic rheometry methods. Extensive ultrasonication (1-64 min) reduced the molecular weights of the samples from approximately 384-1156 kDa to 47-95 kDa. Their rheological properties showed strong dependence on molecular weight, with gelling ability decreasing in the order: furcellaran, kappa carrageenan > iota carrageenan, funoran > lambda carrageenan > theta carrageenan, sulfated chitosan. The anticoagulant activity, measured via aPTT assay, followed the order: lambda carrageenan > iota carrageenan, kappa/iota carrageenan, carrageenan mixture, sulfated chitosan > theta carrageenan > kappa carrageenan, funoran. Among the antioxidant properties determined using Folin-Ciocalteu, DPPH, ABTS, OH radical, and FRAP assays, OH radical scavenging activity was particularly noteworthy, being inherent to all polysaccharides and displaying a correlation with molecular weight. These results validate the interdependence of alkali treatment and the molecular weights of both natural and chemically sulfated polysaccharides in influencing their respective anticoagulant and antioxidant activities measured using in-vitro assays.

Keywords:  Anticoagulation; Antioxidants; Carrageenan; Chitosan; Sonication; Sulfated polysaccharides

DOI:  https://doi.org/10.1016/j.ijbiomac.2025.144122
J Steroid Biochem Mol Biol. 2025 May 20. pii: S0960-0760(25)00116-5. [Epub ahead of print] 106788

Confirmation of a novel, stable estrogen metabolite, as 5a,6a-epoxy-estrone sulfate in stallion blood by LC-MS/MS.

James I Raeside, Heather L Christie, Tracey Chenier, Dyanne Brewer, Armen Charchoglyan.

  Mass spectrometry (MS) has become pivotal for accurately delineating intricate molecular structures for steroids present in minute quantities within biological samples. This study utilized liquid chromatography-high resolution tandem mass spectrometry (LC-HRMS/MS) to identify and characterize a 'new' estrogen metabolite, 5α,6α-epoxy-estrone sulfate, in stallion serum from three animals. The estrogen structure was predicted previously using radiolabeled steroids. HRMS/MS, in combination with a seamless sample preparation involving liquid-liquid extraction and chromatographic separation, enabled accurate mass spectrometric identification of the target metabolite. A distinct chromatographic peak corresponding to the metabolite displayed a fragmentation pattern consistent with its predicted structure. Fragment ions at m/z 79.9 and 285.1 resulting from precursor ion m/z 365.5 [M-H]- suggested the presence of a sulfated group and epoxy form of estrone, with an additional oxygen atom when compared with those for a reference standard of estrone sulfate. The assignment of other fragment ions from the target ion further elucidated the predicted structure. Evidence for a structure unique from any other estrogen metabolite on record was demonstrated on two different LC-QTOF instruments. Its identification in the blood circulation ensures distribution throughout the body. The potential significance for future physiological/pathological investigations is discussed.

Keywords:  LC-HRMS/MS; epoxide sulfate; estrone metabolite; serum; stallion

DOI:  https://doi.org/10.1016/j.jsbmb.2025.106788
Carbohydr Polym. 2025 Jun 15. pii: S0144-8617(25)00340-6. [Epub ahead of print]358 123559

Advances in fucoidan and fucoidan oligosaccharides: Current status, future prospects, and biological applications.

Hamed I Hamouda, Tang Li, Samah Shabana, Amr H Hashem, Heng Yin.

  Sulfated polysaccharides (SPS) derived from seaweeds are precious bioactive compounds of diverse biological activities. Fucoidan is a complex SPS composed of L-fucose and sulfate groups, can be extracted from brown seaweeds, as well as microbial, insect, plant glycans, and marine invertebrates. It has gained considerable attention due to its anti-inflammatory, anticancer, antiviral, antithrombotic, hypolipidemic, and immune-modulatory properties. Recent research has focused on the extraction and extensive characterization of fucoidan. Its structural complexity, influenced by species, sources, and harvesting conditions, directly influences its bioactivity, with higher sulfation and lower molecular weight enhancing its activity. Interestingly, fucoidan oligosaccharides (FOs) play a critical role in various metabolic processes and hold significant potential in disease diagnostics. This comprehensive review explores the current status of fucoidan research, covering its sources, extraction and purification techniques, structural variations and biological activities. Additionally, we highlight its potential health benefits, providing insights for researchers interested in sulfated polysaccharides.

Keywords:  Biological activities; Brown seaweeds; Extraction; Fucoidan; Fucoidan oligosaccharides; Purification

DOI:  https://doi.org/10.1016/j.carbpol.2025.123559
Regen Biomater. 2025 ;12 rbaf012

Natural product-based nano-antioxidant for the treatment of acute pancreatitis.

Xiaoluan Lu, Ze Gao, Yanling Yu, Lang Zhang, Jing Huang, Xiaoming Zhang, Pei Jing, Shiyong Zhang, Mei Zeng.

  Acute pancreatitis (AP) is a potentially highly fatal inflammatory disease characterized by the generation of high level of reactive oxygen species (ROS) of mass recruited inflammatory macrophages in pancreatic tissue. Many natural product antioxidants have been explored to treat AP due to their superiority in biosafety while the therapeutic application is restricted by their low ROS elimination as well as the rapid metabolism caused by small molecular weight and fast absorption. Herein, a new natural product-based nano-antioxidant (FA@zein-CS) that can overcome these problems was developed for the treatment of AP by encapsulating ferulic acid (FA) into the zein based nanoparticles and then hybridizing of chondroitin sulfate (CS). The FA@zein-CS would not only efficiently target to the inflamed pancreatic tissue by the specific binding of CS to CD44, but also effectively initiate the release of FA and zein degradation product in response to intracellular pH/GSH/ROS to achieve synergistic antioxidant effect. In addition, thanks to the fact that all components were derived from natural products, the FA@zein-CS held the excellent biocompatibility. In vivo results disclosed that the FA@zein-CS significantly reduced pancreatic structural damage and restored the pancreatic function with serum amylase and lipase reduced by 61.8% and 82.8%, respectively. This natural product-based nano-antioxidant holds great clinic potential for AP.

Keywords:  CD44 targeting; acute pancreatitis; multi-responsibility; nano-antioxidant; natural product; synergistic anti-oxidation

DOI:  https://doi.org/10.1093/rb/rbaf012
Kidney360. 2025 May 22.

Indoxyl Sulfate Contributes to Selenium Deficiency and Renal Ferroptosis by Decreasing the Expression of Selenium Transport Protein SEPP1.

Takehiro Nakano, Yutaka Kitazato, Takumu Ogawa, Kai Tokumaru, Yuhi Shintani, Takuma Yoshitake, Kohei Yasuno, Hitoshi Maeda, Motoko Tanaka, Kazutaka Matsushita, Toru Maruyama, Hiroshi Watanabe.

BACKGROUND: The relationship between the progression of chronic kidney disease (CKD) and trace element deficiencies has attracted considerable attention. However, many aspects of trace element deficiency and the molecular mechanisms of CKD pathology remain unclear. Here, we hypothesized that uremic toxins are involved in trace element deficiencies, which contribute to the progression of CKD.
METHODS: Adenine-induced CKD mice were used for in vivo study. Cultured hepatocytes were used for in vitro study.
RESULTS: Seventeen trace elements in the plasma of CKD mice were measured using inductively coupled plasma mass spectrometry. Among these, selenium was identified as the trace element most significantly affected by the administration of AST-120, an oral spherical activated carbon. CKD mice displayed reduced levels of selenium in the plasma, which was restored after the administration of AST-120. In vivo and in vitro experiments showed the uremic toxin indoxyl sulfate (IS) decreased expression of the selenium transport protein SEPP1 in liver. IS suppressed SEPP1 expression through increased production of reactive oxygen species (ROS) via the OATP/AhR/NADPH oxidase pathway. Increased ROS led to the downregulation of transcription factors for SEPP1, such as AMPK/PGC1-α and miR-34a/HNF4α. Analysis of serum from hemodialysis patients also suggested that IS is involved in reducing serum SEPP1 levels and exacerbating selenium deficiency. Combination therapy with AST-120 and sodium selenite restored the supply of selenium to the kidneys and increased GPX4 expression, thereby exerting renoprotective effects via suppression of ferroptosis.
CONCLUSIONS: This study highlights the key role IS plays in selenium deficiency and renal ferroptosis by suppressing hepatic SEPP1 expression. The findings suggest potential therapeutic strategies that target IS and selenium deficiency for the management of CKD.

DOI: https://doi.org/10.34067/KID.0000000837
JCEM Case Rep. 2025 Jul;3(7): luaf111

Elevated Dehydroepiandrosterone Sulfate Levels in 2 Patients With Prolactinomas: An Underrecognized Association.

Joseph Arguinchona, Aditi Kumar, Divya Yogi-Morren, Mona Vahidi Rad, Krupa Doshi.

  While adrenal androgen production is primarily regulated by ACTH, some data suggest a less common association between hyperprolactinemia and elevated dehydroepiandrosterone sulfate (DHEA-S). We describe 2 patients with this underrecognized connection. Patient 1, a 60-year-old male, was incidentally found to have bilateral adrenal masses on computed tomography during evaluation of gastrointestinal complaints. Further workup revealed elevated levels of DHEA-S and prolactin, with pituitary macroadenoma identified as the cause, given normalization of both prolactin and DHEA-S on cabergoline therapy. Patient 2, a 38-year-old male, presented with visual field defects, and subsequent pituitary magnetic resonance imaging confirmed a macroadenoma. He also had markedly elevated levels of DHEA-S and prolactin. Both patients were treated with cabergoline, leading to rapid normalization of both prolactin and DHEA-S levels. These cases demonstrate an association between hyperprolactinemia and elevated DHEA-S, supported by the normalization of levels with medical treatment of prolactinoma. Although hyperprolactinemia in the context of a prolactinoma is an uncommon cause of elevated DHEA-S, it should be considered once other etiologies have been excluded.

Keywords:  DHEA-S; adrenal androgens; hyperprolactinemia; prolactinoma

DOI:  https://doi.org/10.1210/jcemcr/luaf111
NPJ Precis Oncol. 2025 May 16. 9(1): 144

Multi-cancer detection of circulating tumor cells by targeting oncofetal chondroitin sulfate.

Caroline Løppke, Randi Ugleholdt, Christine F Secher, Nicolai T Sand, Joana Mujollari, Tobias Gustavsson, Robert Dagil, Thor G Theander, Ali Salanti, Kristoffer S Rohrberg, Mette Ø Agerbæk.

Liquid biopsies for the detection of circulating tumor cells (CTCs) are a promising strategy for personalized cancer management. However, traditional CTC detection platforms are often constrained to epithelial cancers, vulnerable to phenotypic changes, and rely on specialized devices for standardized detection, restricting the clinical utility across diverse cancer types and healthcare settings. In this study, we present a tumor-agnostic, platform-independent CTC detection strategy based on recognition of the cancer-specific glycosylation, oncofetal chondroitin sulfate (ofCS). Through coupling of the ofCS-binding protein, VAR2CSA, to a fluorophore-carrying dextran polymer, we successfully detected ofCS-positive CTCs from blood samples in two diverse and independent cohorts comprising early- and late-stage cancer patients of both epithelial and non-epithelial tumor origin. In addition, no ofCS-positive cells were detected in non-malignant controls. Thus, targeting of ofCS has the potential to expand the range of patients who could benefit from CTC analysis, enhancing the clinical utility in various cancer settings.

DOI: https://doi.org/10.1038/s41698-025-00936-3
Int J Biol Macromol. 2025 May 17. pii: S0141-8130(25)04878-0. [Epub ahead of print]315(Pt 1): 144326

Structural characterization of galactomannan sulfated modification products with different molecular weight fractions and their in vitro anti-lung cancer activities.

Ying Lv, Yubo Zhou, Ziyi Jin, Chenhuan Lai, Yanan Chen, Qiang Yong.

The degradation of polysaccharides and the introduction of surface functional groups have been shown to significantly enhance the solubility and bioactivity of polysaccharides. This study aimed to compare the structural characteristics of three galactomannans with varying molecular weights (GMG0, GMG1, and GMG2) and their sulfated derivatives (S-GMG0-P, S-GMG1-P, and S-GMG2-P; P = 1-4), and to assess their potential anticancer effects on the A549 lung cancer cell line. The results indicated that a reduction in molecular weight facilitated the sulfation modification process, with the sulfated polysaccharides exhibiting higher molecular weights and more dynamic solution conformations. In vitro antitumor assays revealed that S-GMG0-4 exhibited the most potent antiproliferative effect compared to both the three polysaccharides and other sulfated derivatives. Furthermore, S-GMG0-4 and S-GMG1-4 significantly induced apoptosis in A549 cells and triggered G1-phase cell cycle arrest. The anticancer mechanisms of S-GMG0-4 and S-GMG1-4 were linked to the modulation of key apoptosis- and cell cycle-related genes, including p53, caspase 9, and Bcl-2. Additionally, both S-GMG0-4 and S-GMG1-4 effectively inhibited A549 cell migration. These findings provide a solid foundation for further exploration of sulfated galactomannans as promising candidates for the development of novel anticancer therapies.

DOI: https://doi.org/10.1016/j.ijbiomac.2025.144326
J Exp Bot. 2025 May 23. pii: eraf230. [Epub ahead of print]

From Biosynthesis to Signaling: Unveiling the Multifaceted Roles of Phytosulfokine Peptide in Plants.

Changqi Wu, Raheel Munir, Fangfang Li, Pingfang Li, Yi Cai, Kai Shi.

  Phytosulfokine (PSK) is a secreted peptide that plays a pivotal role in regulating plant growth, development, and environmental adaptability. PSK biosynthesis begins with a preproprotein precursor that undergoes sulfation by tyrosylprotein sulfotransferase in the cis-Golgi apparatus, followed by proteolytic cleavage by subtilases in the apoplast to yield the mature PSK. This mature peptide is recognized by membrane-bound leucine-rich repeat receptor kinases, known as PSK receptors (PSKRs), which subsequently activate diverse signaling cascades, including cGMP-dependent signaling, phosphorylation events, Ca2+ signaling, MAPK pathways, and transcriptional regulation. This review consolidates recent advances in PSK biosynthesis, biological functions, signaling mechanisms, and crosstalk with other plant hormones. By summarizing these insights, we aim to provide a theoretical framework for developing PSK-based strategies to enhance crop resilience and productivity in response to environmental challenges.

Keywords:  growth factor; leucine-rich repeat receptor kinase; peptide hormone; phosphorylation; phytosulfokine; plant peptide; subtilases; tyrosine sulfation

DOI:  https://doi.org/10.1093/jxb/eraf230
Int J Pharm. 2025 May 19. pii: S0378-5173(25)00570-8. [Epub ahead of print] 125733

Advancement on heparin-based hydrogel/scaffolds in biomedical and tissue engineering applications: Delivery carrier and pre-clinical implications.

Shubhrajit Mantry, Prabhat Kumar Das, Jonna Sankaraiah, Satyajit Panda, Kotaiah Silakabattini, Ashok Kumar Reddy Devireddy, Chandra Sekhar Barik, Mohammad Khalid.

  The advancement of biomaterials utilization in biomedical and tissue regenerative applications has emerged progressively. Hydrogels are three-dimensional, hydrophilic polymeric networks that replicate the natural extracellular matrix (ECM), establishing a hydrated porous milieu that emulates biological functions such as proliferation and differentiation of cellular components. The application of biological macromolecules, particularly Heparin-based hydrogel, has garnered considerable interest owing to various intrinsic biological and mechanical properties. This comprehensive review paper is designed to elucidate the derivation of heparin and its purification method for biomedical uses. The article briefly outlines the diverse physiochemical and biological properties of heparin derivative-based hydrogels/scaffolds and emphasizes their significance as vehicles for growth factors, genes, and cells in complex biomedical and tissue engineering applications. This publication also summarizes the potential concerns associated with heparin-based derivatives, efforts to address these issues, and current clinical perspectives. This represents the inaugural instance of an extensive summarization of heparin-based hydrogels in biomedical applications, emphasizing pre-clinical and clinical investigations, which will further assist the scientific community in addressing the challenges associated with heparin-based hydrogels in biomedical contexts.

Keywords:  Biological macromolecules; Biomedical applications; Glycosaminoglycans; Heparin; Heparin sulfate; Hydrogel

DOI:  https://doi.org/10.1016/j.ijpharm.2025.125733
Appl Biochem Biotechnol. 2025 May 19.

Investigation on the Detoxification of Indoxyl Sulfate (IS) and Indole-3-Acetic Acid (IAA) Protein-Bound Uremic Toxins (PBUTs) Using Trametes versicolor Biocompatible Laccase: In Situ Synchrotron Imaging, Experimental and Computational Studies.

Sana Daneshamouz, Shaghayegh Saadati, Sishi Zhu, Denis Kalugin, Ahmed Shoker, Amira Abdelrasoul.

  The removal of protein-bound uremic toxins (PBUTs), such as indoxyl sulfate (IS) and indole-3-acetic acid (IAA), from hemodialysis (HD) patients remains a significant challenge due to their strong binding to serum proteins, such as albumin. This study aimed to evaluate the potential of using the enzyme laccase, derived from Trametes versicolor, for the decomposition and removal of IS and IAA during HD. Molecular docking was utilized to investigate the interactions between laccase and the toxins, identifying key functional groups involved. To assess the detoxification efficacy, liquid chromatography-mass spectrometry (LC-MS) and gas chromatography-mass spectrometry (GC-MS) were employed, allowing for the identification of decomposition byproducts and their toxicity assessment. Additionally, in situ synchrotron radiation micro-computed tomography (SR-µCT) at the Canadian Light Source (CLS) was used to analyze the binding of human serum albumin (HSA) with IS and IAA before and after laccase treatment. Our findings revealed that laccase effectively decomposed IAA into five byproducts, including indole, as confirmed by GC-MS, while IS remained unaffected. The byproducts exhibited lower toxicity ratings than IAA and were more easily eliminated through HD. However, synchrotron-based μ-CT analysis showed reduced HSA-IAA adsorption on the HD membrane post-laccase treatment, with no impact on HSA-IS adsorption. Notably, the transformation of indole into IS in the liver suggests that laccase may not be suitable for IAA detoxification in HD. Despite the lack of expected outcomes, these results provide valuable insights into toxin-enzyme interactions and guide future research toward alternative strategies for PBUTs removal in HD.

Keywords:  Detoxification; GC–MS; Indole-3-acetic acid; Indoxyl sulfate; Laccase; Molecular docking

DOI:  https://doi.org/10.1007/s12010-025-05235-y
J Agric Food Chem. 2025 May 23.

Elucidation of Molecular Mechanisms of Sulfated Oligoguluronic Acid on Mitigating Intestinal Inflammation and Enhancing Epithelial Barrier Function.

Decheng Bi, Jinfeng Huang, Nanting Zhu, Lijun Yao, Yan Wu, Yong Peng, Guobing Chen, Beiwei Zhu, Xu Xu.

  This study investigates the protective role of sulfated oligoguluronic acid (SOGA), synthesized from polyguluronic acid (PG)-derived oligoguluronic acid (OGA), against intestinal inflammation and barrier dysfunction. In vitro, SOGA significantly reduced LPS-induced proinflammatory cytokine secretion in THP-1 cells, whereas PG and OGA were ineffective. Mechanistic investigations revealed that SOGA effectively inhibited the activation of LPS-induced NF-κB, JNK MAPK, and NLRP3 inflammasome signaling pathways. In Caco-2 monolayers, SOGA effectively restored mitochondrial function, preserved tight junction integrity, and reduced paracellular permeability. In comparison, this effect was absent for PG and OGA. Additionally, SOGA significantly suppressed the secretion of proinflammatory cytokines in a coculture model of Caco-2/THP-1 cells. In vivo, SOGA ameliorated ulcerative colitis symptoms in mice by reducing inflammation, enhancing tight junction protein expression, and improving mitochondrial function. These findings underscore the potential of SOGA in inflammatory bowel disease treatment by targeting key aspects of inflammation and intestinal barrier dysfunction.

Keywords:  intestinal inflammation; mitochondrial function; sulfated oligoguluronic acid; tight junction integrity

DOI:  https://doi.org/10.1021/acs.jafc.5c03269
Carbohydr Polym. 2025 Jun 15. pii: S0144-8617(25)00268-1. [Epub ahead of print]358 123487

Structure, function and catalytic mechanism of the carrageenan-sulfatases from the marine bacterium Zobellia galactanivorans DsijT.

Antonin Chevenier, Mathieu Fanuel, Ekaterina Sokolova, Diego Mico Latorre, Diane Jouanneau, Alexandra Jeudy, Aurélie Préchoux, Marie-Katherin Zühlke, Jürgen Bartel, Dörte Becher, Mirjam Czjzek, David Ropartz, Gurvan Michel, Elizabeth Ficko-Blean.

  Carrageenans are highly diverse sulfated galactans found in red seaweeds. They play various physiological roles within macroalgae, but also serve as carbon sources for heterotrophic marine bacteria living at their surface. Carrageenan sulfatases catalyze the removal of sulfate esters from the glycans to expose the saccharide chain for further enzymatic processing. In the marine flavobacterium Zobellia galactanivorans, three carrageenan sulfatase genes are localized within a carrageenan utilization locus, belonging to three distinct SulfAtlas S1 (formylglycine-dependent sulfatases) subfamilies (S1_19, ZgCgsA; S1_7, ZgCgsB1; and S1_17, ZgCgsC). In this study we combined several techniques to characterize the detailed desulfurylation steps in the catabolic pathway of carrageenan in this model marine bacterium. High resolution UHPLC-MS/MS sequencing of the reaction species provides precise chemical localization of the enzymatic activities for the three carrageenan sulfatases on carrageenan polysaccharides and oligosaccharides. High resolution structures of the S1_19 endo-/exo-lytic carrageenan sulfatase (ZgCgsA) in complex with oligocarrageenan products show substrate plasticity which involve enzyme and glycan conformational rearrangements. A sulfo-enzyme covalent-intermediate sheds light on the catalytic mechanism and highlights the unique chemistry of formylglycine, an essential post-translationally modified catalytic residue in the active site of S1 family sulfatases.

Keywords:  Carrageenan sulfatases; Catalysis; Conformational change; Covalent-intermediate; Formylglycine; Substrate plasticity

DOI:  https://doi.org/10.1016/j.carbpol.2025.123487
Mol Syst Biol. 2025 May 23.

Mining the heparinome for cryptic antimicrobial peptides that selectively kill Gram-negative bacteria.

Roberto Bello-Madruga, Daniel Sandín, Javier Valle, Jordi Gómez, Laura Comas, María Nieves Larrosa, Juan José González-López, María Ángeles Jiménez, David Andreu, Marc Torrent.

  Glycosaminoglycan (GAG)-binding proteins regulating essential processes such as cell growth and migration are essential for cell homeostasis. As both GAGs and the lipid A disaccharide core of Gram-negative bacteria contain negatively charged disaccharide units, we hypothesized that GAG-binding proteins could also recognize LPS and enclose cryptic antibiotic motifs. Here, we report novel antimicrobial peptides (AMPs) derived from heparin-binding proteins (HBPs), with specific activity against Gram-negative bacteria and high LPS binding. We used computational tools to locate antimicrobial regions in 82% of HBPs, most of those colocalizing with putative heparin-binding sites. To validate these results, we synthesized five candidates [HBP-1-5] that showed remarkable activity against Gram-negative bacteria, as well as a strong correlation between heparin and LPS binding. Structural characterization of these AMPs shows that heparin or LPS recognition promotes a conformational arrangement that favors binding. Among all analogs, HBP-5 displayed the highest affinity for both heparin and LPS, with antimicrobial activities against Gram-negative bacteria at the nanomolar range. These results suggest that GAG-binding proteins are involved in LPS recognition, which allows them to act also as antimicrobial proteins. Some of the peptides reported here, particularly HBP-5, constitute a new class of AMPs with specific activity against Gram-negative bacteria.

Keywords:  Antimicrobial Peptide; Glycosaminoglycans; Heparin; Heparin-binding Protein; Lipopolysaccharide

DOI:  https://doi.org/10.1038/s44320-025-00120-6