bims-supasi 2025-01-26 papers

bims-supasi

Biomed News

on Sulfation pathways and signalling

Issue of 2025–01–26
nineteen papers selected by
Jonathan Wolf Mueller, University of Birmingham

Sulfated Glycosaminoglycans as Inhibitors for Chlamydia Infections: Molecular Weight and Sulfation Dependence.
Effects of Heparan Sulfate Trisaccharide Containing Oleanolic Acid in Attenuating Hyperphosphorylated Tau-Induced Cell Dysfunction Associated with Alzheimer's Disease.
Correlation Between Indoxyl Sulfate in Chronic Kidney Disease and Olfactory Dysfunction.
The interaction between antithrombin and endothelial heparan sulfate mitigates pulmonary thromboinflammation after trauma and hemorrhagic shock.
Targeting heparan sulfate proteoglycans as an effective strategy for inhibiting cancer cell migration and invasiveness compared to heparin.
The Role of Indoxyl Sulfate in Exacerbating Colorectal Cancer During Chronic Kidney Disease Progression: Insights into the Akt/β-Catenin/c-Myc and AhR/c-Myc Pathways in HCT-116 Colorectal Cancer Cells.
A Novel, Cell-Compatible Hyaluronidase Activity Assay Identifies Dextran Sulfates and Other Sulfated Polymeric Hydrocarbons as Potent Inhibitors for CEMIP.
Multifunctions of Sustainable Chondroitin Sulfates with Predominant Subtypes and Low Molecular Weights on Neurite Outgrowth.
Anti-obesity and gut microbiota modulation effects of chondroitin sulfate on obese mice induced by high-fat diet.
Understanding the Glycosylation Pathways Involved in the Biosynthesis of the Sulfated Glycan Ligands for Siglecs.
Dual-drug loaded chondroitin sulfate embolization beads enhance TACE therapy for HCC by integrating embolization, chemotherapy, and anti-angiogenesis.
Structural analysis of sulfated fucan from the sea cucumber Holothuria mexicana with the assistance of endo-1,3-fucanase.
Sulfated and Phosphorylated Agarose as Biomaterials for a Biomimetic Paradigm for FGF-2 Release.
Structure of a Sulfated Capsular Polysaccharide from the Marine Bacterium Cobetia marina KMM 1449 and a Genomic Insight into Its Biosynthesis.
Selenium-Chondroitin Sulfate Nanoparticles Inhibit Angiogenesis by Regulating the VEGFR2-Mediated PI3K/Akt Pathway.
Sexual dimorphism in exercise-induced response on steroid hormones to a 24-week supervised concurrent training intervention.
A shear-responsive and lubricating hyaluronic acid-chondroitin sulfate-decellularized matrix hydrogel for articular cartilage regeneration.
Indoxyl Sulfate Induces Ventricular Arrhythmias Attenuated by Secretoneurin in Right Ventricular Outflow Tract Cardiomyocytes.
Proteomic Identification and Functional Analysis of Babesia microti Reveals Heparin-Binding Proteins.

Macromol Biosci. 2025 Jan 21. e2400443

Sulfated Glycosaminoglycans as Inhibitors for Chlamydia Infections: Molecular Weight and Sulfation Dependence.

Sebastian Wintgens, Janita Müller, Felicitas Drees, Dominik Spona, Lorand Bonda, Laura Hartmann, Johannes H Hegemann, Stephan Schmidt.

  Glycosaminoglycans (GAGs) play a pivotal role in pathogen attachment and entry into host cells, where the interaction with GAGs is critical for a diverse range of bacteria and viruses. This study focuses on elucidating the specific interactions between sulfated GAGs and the adhesin OmcB (Outer membrane complex protein B) of Chlamydia species, examining how structural characteristics of GAGs, such as sulfation degree and molecular weight, influence their binding affinity and thereby affect bacterial infectivity. A surface-based binding assay is established to determine the binding constants of OmcB with various GAGs. It is shown that increased sulfation and higher molecular weight enhance GAG binding to OmcB. These findings are further validated using cell assays, which shows that the addition of sulfated GAGs reduces OmcB-cell binding and inhibits the attachment of C. pneumoniae elementary bodies (EBs), underscoring the pivotal role of specific GAGs in chlamydial infections. Notably, heparin exhibites a stronger inhibitory effect on OmcB compare to GAGs with similar sulfation degrees and molecular weights, suggesting that particular molecular architectures may optimize binding interactions.

Keywords:  GAGs; carbohydrate interaction; carrageenan; chlamydia pneumoniae; chondroitin sulfate; glycans; heparan sulfate; heparin; sulfation

DOI:  https://doi.org/10.1002/mabi.202400443
J Med Chem. 2025 Jan 22.

Effects of Heparan Sulfate Trisaccharide Containing Oleanolic Acid in Attenuating Hyperphosphorylated Tau-Induced Cell Dysfunction Associated with Alzheimer's Disease.

Sanyong Zhu, Zhenfeng Song, April Sweet Tapayan, Kartikey Singh, Kuang-Wei Wang, Hsiao-Tien Chien Hagar, Jicheng Zhang, Hyunbae Kim, Patty Thepsuwan, Min-Hao Kuo, Kezhong Zhang, Hien M Nguyen.

Alzheimer's disease (AD) is the most common form of dementia, marked by progressive brain degeneration and cognitive decline. A major pathological feature of AD is the accumulation of hyperphosphorylated tau (p-tau) in the form of neurofibrillary tangles (NFTs), which leads to neuronal death and neurodegeneration. P-tau also induces endoplasmic reticulum (ER) stress and activates the unfolded protein response, causing inflammation and apoptosis. Additionally, p-tau spreads in the brain through interactions with heparan sulfate (HS) proteoglycans, promoting aggregation and internalization. Targeting the tau-HS interaction offers a potential therapeutic strategy for AD. We present a novel HS mimetic with a lipophilic oleanolic acid linker and a sulfated trisaccharide, which shows strong cytoprotective effects against p-tau. Moreover, this compound alleviates p-tau-induced ER stress and inflammation. Molecular docking studies indicate that the conjugation of oleanolic acid enhances binding between the ligand and tau protofilament cores, facilitating protective interactions. These findings provide a foundation for the development of novel HS mimetics, enabling further investigation of tau-HS interactions in AD and other tauopathies.

DOI: https://doi.org/10.1021/acs.jmedchem.4c02563
Iran J Otorhinolaryngol. 2025 ;37(1): 19-25

Correlation Between Indoxyl Sulfate in Chronic Kidney Disease and Olfactory Dysfunction.

Irnanda-Warda-Rizki Nasution, Tengku-Siti-Hajar Haryuna, Delfitri Munir, Syafrizal Nasution, Putri-Chairani Eyanoer, Siti Nursiah, Ramlan Sitompul.

   Introduction: Olfactory dysfunction is prevalent among individuals with chronic kidney disease (CKD), with prevalence escalating alongside disease severity. The uremic toxin we observed in this study is Indoxyl sulfate (IS), a potent uremic toxin that markedly accumulates in the plasma of patients with chronic insufficiency. Olfactory damage may occur in the setting of neuronal damage due to renal failure.
Materials and Methods: 27 patients, a total sample in this study with diagnosed chronic kidney disease within stage 5 on regular hemodialysis, were examined for indoxyl sulfate levels in blood plasma and then examined for their olfactory function using the Sniffin' Sticks test. A correlation analysis was conducted between indoxyl sulfate levels and olfactory function test results in patients with CKD.
Results: The Pearson correlation test revealed a strong, significant negative correlation between indoxyl sulfate levels and olfactory function (r = -0.613; p = 0.001). Additionally, correlations were found between indoxyl sulfate levels and each component of olfactory function: threshold value (r = -0.408; p = 0.035), discrimination (r = -0.807; p = 0.001), and identification (r = -0.703; p = 0.001).
Conclusion: Olfactory function is compromised in individuals with chronic renal disease and correlates with the level of accumulation of the uremic toxin indoxyl sulfate.

Keywords:  Chronic kidney disease; Indoxyl sulfate; Olfactory dysfunction; Sniffin’ stick test

DOI:  https://doi.org/10.22038/ijorl.2024.77737.3632
Shock. 2025 Jan 23.

The interaction between antithrombin and endothelial heparan sulfate mitigates pulmonary thromboinflammation after trauma and hemorrhagic shock.

Maria Del Pilar Huby Vidaurre, Ava K Mokhtari, Baron K Osborn, Bryan A Cotton, Yao-Wei Wang, Yongmei Xu, Katelyn Arnold, Jian Liu, Jillian R Richter, Jessica C Cardenas.

INTRODUCTION: Trauma and hemorrhagic shock (T/HS) are associated with multiple organ injury. Antithrombin (AT) has anti-inflammatory and organ protective activity through its interaction with endothelial heparan sulfate containing a 3-O-sulfate modification. Our objective was to examine the effects of T/HS on 3-O-sulfated (3-OS) heparan sulfate expression and determine whether AT-heparan sulfate interactions are necessary for its anti-inflammatory properties.
METHODS: Male Sprague Dawley rats underwent laparotomy, gut distension and fixed-pressure hemorrhagic shock (HS) and resuscitation. Liquid chromatography-coupled mass spectrometry analyses were performed to measure pulmonary and plasma heparan sulfate di/tetrasaccharides. Pulmonary mRNA levels were assessed by nCounter panel. Rats were treated with vehicle or surfen (1 mg/kg), a small molecule heparan sulfate antagonist, to block the interaction between AT and endothelial cells prior to T/HS and resuscitated with fresh frozen plasma (FFP), lactated Ringer's (LR), or AT-supplemented LR. Lung injury was assessed histologically for injury and fibrin deposition and immunostained for myeloperoxidase (MPO). Plasma was assessed for circulating inflammatory biomarkers.
RESULTS: T/HS significantly reduced pulmonary expression of 6-O and 3-O sulfated heparan sulfate, which was associated with reduced pulmonary 6-O- and 3-O-sulfotransferase mRNA levels. Surfen increased fibrin deposition and inflammatory cell infiltration into pulmonary tissue in T/HS rats resuscitated with FFP but had no effect in LR resuscitated rats. Although T/HS and LR resuscitation worsened histologic lung injury compared to sham, regardless of surfen treatment, lung injury was notably improved in FFP resuscitated rodents pre-treated with vehicle but not surfen. Surfen abrogated the anti-inflammatory effects of FFP, indicated by notable increases in circulating levels of multiple pro-inflammatory mediators compared to rats pre-treated with vehicle. Finally, we observed significant increases in pulmonary fibrin and MPO staining in rats pre-treated with surfen followed by resuscitation with LR supplemented with AT compared to vehicle, which was associated with notable increases in lung injury scores.
CONCLUSIONS: T/HS causes pronounced reductions in pulmonary expression of 3-OS heparan sulfate, which is essential to AT's anti-thrombotic and anti-inflammatory activity. Blocking the interaction between AT and the endothelium attenuates the anti-thromboinflammatory and organ protective properties of FFP, suggesting that AT-endothelial anticoagulant function and anti-inflammatory signaling is important for organ protection during T/HS.

DOI: https://doi.org/10.1097/SHK.0000000000002543
Front Cell Dev Biol. 2024 ;12 1505680

Targeting heparan sulfate proteoglycans as an effective strategy for inhibiting cancer cell migration and invasiveness compared to heparin.

Lorenzo Depau, Jlenia Brunetti, Chiara Falciani, Elisabetta Mandarini, Marta Zanchi, Maria Francesca Paolocci, Marta Garfì, Alessandro Pini, Luisa Bracci.

  By virtue of their ability to bind different growth factors, morphogens and extracellular matrix proteins, heparan sulfate proteoglycans (HSPGs) play a determinant role in cancer cell differentiation and migration. Despite a strong conceptual basis and promising preclinical results, clinical trials have failed to demonstrate any significant advantage of administering heparin to oncology patients. We exploited our anti-heparan sulfate branched peptide NT4 to test the opposite approach, namely, targeting HSPGs to interfere with their functions, instead of using heparin as a soluble competitor in human cell lines from pancreas adenocarcinoma, colon adenocarcinoma, rhabdomyosarcoma and two different breast cancers. We found that the anti-heparan sulfate peptide NT4 is more effective than heparin for inhibiting cancer cell adhesion, directional migration, colony formation and even cell growth, suggesting that targeting cell membrane HSPGs may be a more effective anti-metastatic strategy than using soluble heparin. Analysis of NT4 effects on cancer cell directional migration, associated to cellular distribution of HSPGs and cadherins in different migrating cancer cell lines, provided further indications on the molecular basis of HSPG functions, which may explain the efficiency of the HSPG targeting peptide.

Keywords:  cancer cell migration; extracellular matrix; heparan sulfate proteoglycans; peptide; tumor target

DOI:  https://doi.org/10.3389/fcell.2024.1505680
Toxins (Basel). 2025 Jan 01. pii: 17. [Epub ahead of print]17(1):

The Role of Indoxyl Sulfate in Exacerbating Colorectal Cancer During Chronic Kidney Disease Progression: Insights into the Akt/β-Catenin/c-Myc and AhR/c-Myc Pathways in HCT-116 Colorectal Cancer Cells.

Yu Ichisaka, Chihiro Takei, Kazuma Naito, Manami Higa, Shozo Yano, Toshimitsu Niwa, Hidehisa Shimizu.

  Epidemiological studies suggest an increased risk of colorectal cancer (CRC) aggravation in patients with chronic kidney disease (CKD). Our previous study demonstrated that indoxyl sulfate, a uremic toxin whose concentration increases with CKD progression, exacerbates CRC through activation of the AhR and Akt pathways. Consequently, indoxyl sulfate has been proposed to be a significant link between CKD progression and CRC aggravation. The present study aimed to investigate the roles of c-Myc and β-Catenin, which are hypothesized to be downstream factors of indoxyl sulfate-induced AhR and Akt activation, in CRC cell proliferation and EGF sensitivity in HCT-116 CRC cells. Indoxyl sulfate significantly induced CRC cell proliferation at concentrations exceeding 62.5 µM, a process suppressed by the c-Myc inhibitor 10058-F4. Indoxyl sulfate activated the Akt/β-Catenin/c-Myc pathway as evidenced by the Akt inhibitor MK2206, which decreased both β-Catenin and c-Myc protein levels, and the β-Catenin inhibitor XAV-939, which reduced c-Myc protein levels. The AhR antagonist CH223191 also inhibited c-Myc upregulation, indicating involvement of the AhR/c-Myc pathway. MK2206 partially attenuated the indoxyl sulfate-induced AhR transcriptional activity, suggesting that Akt activation influences the AhR/c-Myc pathway. MK2206, CH223191, and 10058-F4 suppressed the increase in EGFR protein levels induced by indoxyl sulfate, indicating that the Akt/β-Catenin/c-Myc and AhR/c-Myc pathways enhance the sensitivity of HCT-116 CRC cells to EGF. These findings indicate that the elevation of indoxyl sulfate levels in the blood, due to CKD progression, could worsen CRC by promoting the proliferation of CRC cells and enhancing EGF signaling. Therefore, indoxyl sulfate could potentially serve as a therapeutic target for CRC aggravation in patients with CKD.

Keywords:  AhR; Akt; EGFR; Indoxyl sulfate; c-Myc; chronic kidney disease; colorectal cancer; gut microbiota; indole derivative; tryptophan metabolites; β-Catenin

DOI:  https://doi.org/10.3390/toxins17010017
Cells. 2025 Jan 11. pii: 101. [Epub ahead of print]14(2):

A Novel, Cell-Compatible Hyaluronidase Activity Assay Identifies Dextran Sulfates and Other Sulfated Polymeric Hydrocarbons as Potent Inhibitors for CEMIP.

Anja Schmaus, Sofia Spataro, Paul Sallmann, Stephanie Möller, Leonardo Scapozza, Marco Prunotto, Jonathan P Sleeman.

  Hyaluronan (HA) levels are dynamically regulated homeostatically through biosynthesis and degradation. HA homeostasis is often perturbed under disease conditions. HA degradation products are thought to contribute to disease pathology. The hyaluronidase CEMIP requires the presence of living cells for its HA depolymerizing activity. CEMIP is overexpressed in a variety of pathological conditions, and the inhibition of its hyaluronidase activity therefore has therapeutic potential. To identify novel inhibitors of the CEMIP hyaluronidase activity, we established here a cell-compatible, medium-throughput assay for CEMIP-dependent HA depolymerization. The assay employs ultrafiltration plates to separate low- from high-molecular-weight HA, followed by quantification of HA fragments using an HA ELISA-like assay. Using this assay, we tested a range of compounds that have been reported to inhibit other hyaluronidases. Thereby, we identified several sulfated hydrocarbon polymers that inhibit CEMIP more potently than other hyaluronidases. One of these is heparin, a sulfated glycosaminoglycan produced by mast cells that constitutes the first described physiological CEMIP inhibitor. The most potent inhibitor (IC50 of 1.8 nM) is dextran sulfate, a synthetic sulfated polysaccharide. Heparin and dextran sulfate are used in numerous established and experimental biomedical applications. Their ability to inhibit CEMIP needs to be taken into account in these contexts.

Keywords:  CEMIP; HYBID; dextran sulfate; heparin; hyaluronan; hyaluronidase; polystyrene sulfonate; sulfated hyaluronan

DOI:  https://doi.org/10.3390/cells14020101
Biomacromolecules. 2025 Jan 21.

Multifunctions of Sustainable Chondroitin Sulfates with Predominant Subtypes and Low Molecular Weights on Neurite Outgrowth.

Shuqin Xu, Meiling Qiu, Liyuan Liang, Yue Chen, Yajia Wang, Jing Wu, Jinghua Chen.

Three chondroitin sulfate (CS) analogues with predominant subtypes (A, C, and E) were prepared from engineered Escherichia coli K4 combined with regioselective sulfation. CS with the designed sulfates as the main components was characterized by nuclear magnetic resonance spectroscopy, elementary analysis, and disaccharide analysis. CS prepared from the native or degraded capsular polysaccharide had molecular weights of 1.55 × 104-1.90 × 104 and 5.6 × 103-7.4 × 103, respectively. We found that CS with dual sulfates promoted the outgrowth and survival of hippocampal neurons, whereas CS with monosulfate had an inhibitory effect. CS interacted with the nerve growth factor (NGF) and tyrosine kinase (TrkA), which activated the extracellular signal-regulated kinase (ERK) signaling pathway to modulate the outgrowth of hippocampal neurons. This work clarified the multiple effects of CS on neurite outgrowth based on nonanimal-sourced glycosaminoglycans, which would benefit efforts in discovering their novel functions and therapeutic applications.

DOI: https://doi.org/10.1021/acs.biomac.4c01713
Int J Biol Macromol. 2025 Jan 16. pii: S0141-8130(25)00517-3. [Epub ahead of print]298 139968

Anti-obesity and gut microbiota modulation effects of chondroitin sulfate on obese mice induced by high-fat diet.

Qingshan Shen, Xudong Qi, Yilin Liu, Zhuang Yang, Chengzhi Hu, Lei Zhao, Huan Zhan, Hua Bian, Yanli Ma.

  Despite the extensive application of chondroitin sulfate (CS), a type of biological macromolecule, in various fields, including biomedicine, cosmetics, food, and pharmaceuticals, research into its potential anti-obesity properties remains limited. In this study, the impacts of CS on obese mice induced by a high-fat diet (HFD) were investigated. The results showed that supplementing CS effectively controlled body weight gain and fat accumulation (perirenal fat and epididymal fat) compared to the control group of obese mice. Furthermore, supplementation with CS reduced the levels of glucose and triglyceride in the serum. Analysis of 16S ribosomal RNA sequencing data illustrated that the diet supplemented with CS modified the composition of gut microbiota, particularly resulting in a reduction of Desulfobacterota and an increase in Bacteroides abundance. Correlation analysis suggested significant associations between specific gut microbiota taxa and obese phenotypes. Overall, these findings highlight that dietary intervention with CS may provide a promising strategy to mitigate obesity and its related symptoms, likely involving the role of gut microbiota in obese mice. This research offers compelling scientific evidence supporting the anti-obesity potential of CS as a dietary supplement.

Keywords:  Anti-obesity effect; Chondroitin sulfate; Gut microbiota

DOI:  https://doi.org/10.1016/j.ijbiomac.2025.139968
ACS Chem Biol. 2025 Jan 21.

Understanding the Glycosylation Pathways Involved in the Biosynthesis of the Sulfated Glycan Ligands for Siglecs.

Jaesoo Jung, Edward N Schmidt, Hua-Chien Chang, Zeinab Jame-Chenarboo, Jhon R Enterina, Kelli A McCord, Taylor E Gray, Lauren Kageler, Chris D St Laurent, Chao Wang, Ryan A Flynn, Peng Wu, Kay-Hooi Khoo, Matthew S Macauley.

Carbohydrate sulfation plays a pivotal role in modulating the strength of Siglec-glycan interactions. Recently, new aspects of Siglec binding to sulfated cell surface carbohydrates have been discovered, but the class of glycan presenting these sulfated Siglec ligands has not been fully elucidated. In this study, the contribution of different classes of glycans to cis and trans Siglec ligands was investigated within cells expressing the carbohydrate sulfotransferase 1 (CHST1) or CHST2. For some Siglecs, the glycan class mediating binding was clear, such as O-glycans for Siglec-7 and N-glycans for Siglec-2 and Siglec-9. Both N-glycans and mucin-type O-glycans contributed to ligands for Siglec-3, -5, -8, and -15. However, significant levels of Siglec-3 and -8 ligands remained in CHST1-expressing cells lacking complex N-glycans and mucin-type O-glycans. A combination of genetic, pharmacological, and enzymatic treatment strategies ruled out heparan sulfates and glycoRNA as contributors, although Siglec-8 did exhibit some binding to glycolipids. Genetic disruption of O-mannose glycans within CHST1-expressing cells had a small but significant impact on Siglec-3 and -8 binding, demonstrating that this class of glycans can present sulfated Siglec ligands. We also investigated the ability of sulfated cis ligands to mask Siglec-3 and Siglec-7. For Siglec-7, cis ligands were again found to be mucin-type O-glycans. While N-glycans were the major sulfated trans ligands for Siglec-3, disruption of complex mucin-type O-glycans had the largest impact on Siglec-3 masking. Overall, this study enhances our knowledge of the types of sulfated glycans that can serve as Siglec ligands.

DOI: https://doi.org/10.1021/acschembio.4c00677
Mater Today Bio. 2025 Feb;30 101419

Dual-drug loaded chondroitin sulfate embolization beads enhance TACE therapy for HCC by integrating embolization, chemotherapy, and anti-angiogenesis.

Jin-Xin Huang, Rui Yang, Huan Long, Jie Kong, Guo-Qiang Shao, Fei Xiong.

  Hepatocellular carcinoma (HCC) is a major public health threat due to its high incidence and mortality rates. Transcatheter arterial chemoembolization (TACE), the primary treatment for intermediate-to-advanced hepatocellular carcinoma (HCC), commonly utilizes embolic agents loaded with anthracycline-based cytotoxic drugs. Post-TACE, the hypoxic microenvironment in the tumor induced by embolization stimulates the formation of new blood vessels, potentially leading to revascularization and diminishing TACE's efficacy. In clinical practice, combined therapy for liver cancer using TACE and oral targeted drugs often encounters the limitation that targeted drugs cannot efficiently reach the tumor site following TACE. We have developed chondroitin sulfate microspheres (CMs) capable of encapsulating both the cytotoxic drug idarubicin (Ida) and the vascular inhibitor Lenvatinib (Len), thereby achieving a triple therapeutic effect on liver cancer: embolic starvation, drug toxicity, and efficient inhibition of neovascularization.

Keywords:  Chondroitin sulfate microspheres; Hepatocellular carcinoma; Lenvatinib; Neovascularization; Transcatheter arterial chemoembolization

DOI:  https://doi.org/10.1016/j.mtbio.2024.101419
Carbohydr Polym. 2025 Mar 15. pii: S0144-8617(25)00012-8. [Epub ahead of print]352 123231

Structural analysis of sulfated fucan from the sea cucumber Holothuria mexicana with the assistance of endo-1,3-fucanase.

Achiraya Khamleng, Guangning Chen, Jingjing Shen, Yaoguang Chang, Yaowapha Waiprib, Xinyu Li.

  Sulfated fucan from sea cucumber has received growing interest in recent decades. Insight into the primary structure of sulfated fucan is fundamental to elucidate their bioactivity. The sea cucumber Holothuria mexicana possesses a high market demand, while the structure of its sulfated fucan (Hm-FUC) remains unclear. This study investigates the structural characteristics of Hm-FUC, especially using a tool enzyme of heterologously expressed endo-1,3-fucanase (Fun168D). Hm-FUC demonstrated a 6.12 ± 0.45 % yield from the body wall of dried sea cucumber and a molecular weight of 475.2 ± 0.5 kDa. A set of procedures including enzymatic degradation, glycomics, and NMR analyses were introduced into the structural identification of Hm-FUC. The structure of Hm-FUC was determined to comprise a tetrafucose repeating unit [→3-α-l-Fucp2,4S-1 → 3-α-l-Fucp-1 → 3-α-l-Fucp2S-1 → 3-α-l-Fucp2S-1→]. The well-defined primary structure is beneficial for its application as nutritional component in foods and therapeutic agent in drugs.

Keywords:  Fucanase; Holothuria mexicana; Sulfated fucan

DOI:  https://doi.org/10.1016/j.carbpol.2025.123231
Biomimetics (Basel). 2024 Dec 30. pii: 12. [Epub ahead of print]10(1):

Sulfated and Phosphorylated Agarose as Biomaterials for a Biomimetic Paradigm for FGF-2 Release.

Aurelien Forget, V Prasad Shastri.

  Cardiovascular diseases such as myocardial infarction or limb ischemia are characterized by regression of blood vessels. Local delivery of growth factors (GFs) involved in angiogenesis such as fibroblast blast growth factor-2 (FGF-2) has been shown to trigger collateral neovasculature and might lead to a therapeutic strategy. In vivo, heparin, a sulfated polysaccharide present in abundance in the extracellular matrix (ECM), has been shown to function as a local reservoir for FGF-2 by binding FGF-2 and other morphogens and it plays a role in the evolution of GF gradients. To access injectable biomaterials that can mimic such natural electrostatic interactions between soluble signals and macromolecules and mechanically tunable environments, the backbone of agarose, a thermogelling marine-algae-derived polysaccharide, was modified with sulfate, phosphate, and carboxylic moieties and the interaction and release of FGF-2 from these functionalized hydrogels was assessed by ELISA in vitro and CAM assay in ovo. Our findings show that FGF-2 remains active after release, and FGF-2 release profiles can be influenced by sulfated and phosphorylated agarose, and in turn, promote varied blood vessel formation kinetics. These modified agaroses offer a simple approach to mimicking electrostatic interactions experienced by GFs in the extracellular environment and provide a platform to probe the role of these interactions in the modulation of growth factor activity and may find utility as an injectable gel for promoting angiogenesis and as bioinks in 3D bioprinting.

Keywords:  angiogenesis; biomimetic; controlled release; growth factors; regenerative medicine

DOI:  https://doi.org/10.3390/biomimetics10010012
Mar Drugs. 2025 Jan 08. pii: 29. [Epub ahead of print]23(1):

Structure of a Sulfated Capsular Polysaccharide from the Marine Bacterium Cobetia marina KMM 1449 and a Genomic Insight into Its Biosynthesis.

Maxim S Kokoulin, Yulia V Savicheva, Alina P Filshtein, Ludmila A Romanenko, Marina P Isaeva.

  Some marine and extremophilic microorganisms are capable of synthesizing sulfated polysaccharides with a unique structure. A number of studies indicate significant biological properties of individual sulfated polysaccharides, such as antiproliferative activity, which makes them a promising area for further research. In this study, the capsular polysaccharide (CPS) was obtained from the bacterium Cobetia marina KMM 1449, isolated from a marine sediment sample collected along the shore of the Sea of Japan. The CPS was isolated by saline solution, purified by a series of chromatographic procedures, and studied by chemical methods along with 1D and 2D 1H and 13C NMR spectroscopy. The following new structure of the CPS from C. marina KMM 1449 was established and consisted of sulfated and simultaneously phosphorylated disaccharide repeating units: →4)-α-L-Rhap2S-(1→3)-β-D-Manp6PGro-(1→. To elucidate the genetic basis of the CPS biosynthesis, the whole genomic sequence of C. marina KMM 1449 was obtained. The CPS biosynthetic gene cluster (BGC) of about 70 genes composes four regions encoding nucleotide sugar biosynthesis (dTDP-Rha and GDP-Man), assembly (GTs genes), translocation (ABC transporter genes), sulfation (PAPS biosynthesis and sulfotransferase genes) and lipid carrier biosynthesis (wcb operon). Comparative analysis of the CPS BGCs from available Cobetia genomes showed the presence of KMM 1449-like CPS BGC among strains of all three Cobetia species. The study of new natural sulfated polysaccharides, as well as the elucidation of the pathways of their biosynthesis, provides the basis for the development of potential anticancer drugs.

Keywords:  Cobetia; NMR; biosynthetic gene cluster; genome sequence; marine bacteria; sulfated capsular polysaccharide

DOI:  https://doi.org/10.3390/md23010029
Mar Drugs. 2025 Jan 02. pii: 22. [Epub ahead of print]23(1):

Selenium-Chondroitin Sulfate Nanoparticles Inhibit Angiogenesis by Regulating the VEGFR2-Mediated PI3K/Akt Pathway.

Xia Zheng, Xiaofei Liu, Zhuo Wang, Rui Li, Qiaoli Zhao, Bingbing Song, Kit-Leong Cheong, Jianping Chen, Saiyi Zhong.

  Chondroitin sulfate (CS), a class of glycosaminoglycans covalently attached to proteins to form proteoglycans, is widely distributed in the extracellular matrix and cell surface of animal tissues. In our previous study, CS was used as a template for the synthesis of seleno-chondroitin sulfate (SeCS) through the redox reaction of ascorbic acid (Vc) and sodium selenite (Na2SeO3) and we found that SeCS could inhibit tumor cell proliferation and invasion. However, its effect on angiogenesis and its underlying mechanism are unknown. In this study, we analyzed the effect of SeCS on tube formation in vitro, based on the inhibition of tube formation and migration of human umbilical vein endothelial cells (HUVECs), and evaluated the in vivo angiogenic effect of SeCS using the chick embryo chorioallantoic membrane (CAM) assay. The results showed that SeCS significantly inhibited the angiogenesis of chicken embryo urothelium. Further mechanism analysis showed that SeCS had a strong inhibitory effect on VEGFR2 expression and its downstream PI3K/Akt signaling pathway, which contributed to its anti-angiogenic effects. In summary, SeCS showed good anti-angiogenic effects in an HUVEC cell model and a CAM model, suggesting that it may be a potential angiogenesis inhibitor.

Keywords:  VEGFR2 protein; angiogenesis; chick embryo chorionic allantoic assay; human umbilical vein endothelial cells; selenium–chondroitin sulfate

DOI:  https://doi.org/10.3390/md23010022
Eur J Clin Invest. 2025 Jan 20. e14377

Sexual dimorphism in exercise-induced response on steroid hormones to a 24-week supervised concurrent training intervention.

Lourdes Herrera-Quintana, Héctor Vázquez-Lorente, Jonatan R Ruiz, Francisco J Amaro-Gahete.

   BACKGROUND: Steroid hormones are key mediators of adaptative responses to exercise, a stimulus that may concurrently affect their blood concentrations. However, the chronic endocrine adaptations and whether these potential changes are dependent on exercise intensity remain undetermined. Moreover, it is also unknown if the exercise-induced effects on steroid hormonal status are related to the participant' sex.
METHODS: This study aimed to investigate the intensity effects of a 24-week supervised concurrent training intervention on steroid hormones in sedentary young men and women. A total of 106 untrained young adults (68% women) aged 18-25 years were randomly assigned to one of the three groups: (I) Control group (no exercise; n = 35); (II) Ex-Moderate group (concurrent training at moderate intensity; n = 36); (III) Ex-Vigorous group (concurrent training at vigorous intensity; n = 35). Steroid hormones (i.e. cortisol, testosterone and dehydroepiandrosterone sulfate (DHEAS)) were measured in plasma through a chemiluminescent method. Body composition parameters were determined using a dual-energy X-ray absorptiometry scanner.
RESULTS: No significant changes in steroid hormones levels were observed after the intervention (all p ≥ .129). However, a time x group interaction was noted in the testosterone/cortisol ratio (T/C ratio) only in women (p = .044). Concretely, our data showed a significant decrement of T/C ratio in both the Ex-Moderate group and in the Ex-Vigorous compared with the control group (Δ = -24.2 ± 2.0% and Δ = -38.9 ± 45.4%, respectively).
CONCLUSION: Our 24-week supervised concurrent training intervention showed no significant changes in steroid hormone levels. However, a significant decrement of T/C ratio was observed only in women, indicating a sexual dimorphism in the effect on T/C ratio.

Keywords:  DHEAS; T/C ratio; aerobic and resistance training; body composition; cortisol; steroid hormones; testosterone

DOI:  https://doi.org/10.1111/eci.14377
Carbohydr Polym. 2025 Mar 15. pii: S0144-8617(24)01397-3. [Epub ahead of print]352 123171

A shear-responsive and lubricating hyaluronic acid-chondroitin sulfate-decellularized matrix hydrogel for articular cartilage regeneration.

Haofeng Qiu, Gaoke Pan, Xufeng Mao, Ximing Cai, Lei Song, Lei Shao, Haijiao Mao, Rong Wang, Dangsheng Xiong.

  The high-dynamic, high-loading environment in the joint cavity puts urgent demands on the cartilage regenerative materials with shear responsiveness and lubrication. Here, a new type of injectable hydrogel composed of oxidized hyaluronic acid (OHA), adipic dihydrazide-grafted hyaluronic acid (HA-ADH), oxidized chondroitin sulfate (OChs), and decellularized extracellular matrix methacrylate (dECMMA) was fabricated. The aldehyde groups in OHA and OChs reacted with the amino groups in HA-ADH to form a dynamic hydrogel, which was then covalently crosslinked with dECMMA to create a dual-crosslinked hydrogel with sufficient mechanical strength. This hydrogel possesses injectability and self-healing capabilities, making it suitable for use in the dynamic and high-frequency loading environment of joint cartilage. dECMMA fibers in this hydrogel could be oriented and aligned under certain shear forces, together with the biopolymers, giving the hydrogel lubricity and low strain-liquid transition properties that do not interfere with the daily mobility of the joint. In vitro and in vivo experiments showed that the hydrogel has sufficient tissue adhesion and excellent biocompatibility, promotes chondrocyte migration, and induces stem cell differentiation. The animal experiments demonstrated that the hydrogel promoted cartilage repair, and the lubricating effect of the newborn cartilage was close to that of normal cartilage.

Keywords:  Cartilage regeneration; Dual-crosslinking; Injectable; Lubrication; Polysaccharide hydrogels; Shear-responsive

DOI:  https://doi.org/10.1016/j.carbpol.2024.123171
Cardiovasc Toxicol. 2025 Jan 21.

Indoxyl Sulfate Induces Ventricular Arrhythmias Attenuated by Secretoneurin in Right Ventricular Outflow Tract Cardiomyocytes.

Yuan Hung, Chen-Chuan Cheng, Yen-Yu Lu, Shih-Yu Huang, Yao-Chang Chen, Fong-Jhih Lin, Wei-Shiang Lin, Yu-Hsun Kao, Yung-Kuo Lin, Shih-Ann Chen, Yi-Jen Chen.

  Ventricular arrhythmias (VAs) are major causes of sudden cardiac death in chronic kidney disease (CKD) patients. Indoxyl sulfate (IS) is one common uremic toxin found in CKD patients. This study investigated whether IS could induce VAs via increasing right ventricular outflow tract (RVOT) arrhythmogenesis. Using conventional microelectrodes and whole-cell patch clamps, we studied the action potentials (APs) and ionic currents of isolated rabbit RVOT tissue preparations and single cardiomyocytes before and after IS (0.1 and 1.0 μM). Calcium fluorescence imaging was performed in RVOT cardiomyocytes treated with and without IS (1.0 μM) to evaluate the calcium transient and the calcium leak. In rabbit RVOT tissues, IS (0.1 and 1.0 μM) attenuated the contractility and shortened the AP durations in a dose-dependent manner. In addition, IS (0.1 and 1.0 μM) enhanced the pro-arrhythmia effects of isoproterenol (ISO, 1.0 μM) and rapid ventricular pacing in RVOT (before versus after ISO, 25% versus 83%, N = 12). In RVOT cardiomyocytes, IS (1.0 μM) significantly decreased the L-type calcium currents but increased the sodium-calcium exchanger and sodium window currents. Cardiomyocytes treated with IS (1.0 μM) had lower calcium transients but higher diastolic calcium and calcium leak than those without IS treatment. Pretreatment with secretoneurin (SN, 30 nM, a potent neuropeptide, suppressing CaMKII) or KN-93 (0.1 μM, a CaMKII inhibitor) prevented IS-induced ionic current changes and arrhythmogenesis. In conclusion, IS modulates RVOT electrophysiology and arrhythmogenesis via enhanced CaMKII activity, which is attenuated by SN, leading to a novel therapeutic target for CKD arrhythmias.

Keywords:  Ca2+/calmodulin-dependent protein kinase II; Chronic kidney disease; Indoxyl sulfate; Secretoneurin; Ventricular arrhythmias

DOI:  https://doi.org/10.1007/s12012-025-09963-9
J Trop Med. 2025 ;2025 8821002

Proteomic Identification and Functional Analysis of Babesia microti Reveals Heparin-Binding Proteins.

Yu Chun Cai, Bin Xu, Yan Hong Chu, Ying Fang Yu, Jia Hui Sun, Zi Ran Mo, Han Yin Yang, Shu Ning Yan, Mu Xin Chen, Jia Xu Chen.

  Glycosaminoglycan (GAG) molecules on the surface of red blood cells play an important regulatory role in the invasion of merozoites of apicomplexan protozoa. Heparan sulfate, a type of GAG molecule, has been identified as an important receptor facilitating the invasion of red blood cells by these parasites. Proteins in the parasite that exhibit strong affinity for heparin may play a pivotal role in this invasion process. This study aims to use proteomics to identify Babesia microti proteins with high binding affinity to heparin. Bioinformatics was utilized to analyze the subcellular localization and biological functions of these proteins. Candidate genes encoding proteins with strong heparin affinity will be expressed in a prokaryotic system to produce recombinant proteins. The interaction between these recombinant proteins and heparin will be characterized through heparin-binding experiments and other methods. Initially, a mouse model of B. microti was established and high-density B. microti were obtained. Heparin affinity chromatography was then used to purify natural B. microti proteins that can bind to heparin, identifying 186 B. microti proteins via ESI-MS that specifically interact with heparin. Further studies were carried out to analyze those specific proteins with unique peptide segments of two or more, yielding 15 B. microti proteins, most of which are cell surface proteins and secretory proteins. Based on mass spectrometry identification and subsequent analyses, BMSA5-1-1, B. microti peptidyl-prolyl cis-trans isomerase (BmPPIase), and chaperonin were selected for further study due to their potential impact on the invasion of red blood cells by B. microti. These candidate proteins were expressed as recombinant proteins using a prokaryotic expression system. In vitro heparin-binding assays demonstrated that these recombinant proteins specifically bind to heparin. Notably, BmPPIase and chaperonin recombinant proteins exhibited activity in specific heparin binding. Molecular interaction studies further confirmed the strong interaction between BmPPIase and heparin. In conclusion, this study used proteomic methods to identify 186 specific B. microti proteins with specific binding affinity to heparin, providing in-depth analysis of 15 key proteins. The findings confirmed that BmPPIase and chaperonin specifically bind to heparin, with molecular interaction experiments substantiating the strong interaction between BmPPIase and heparin.

Keywords:  Babesia microti; Babesiosis; heparin-binding protein; invasion of host; protein-protein interaction

DOI:  https://doi.org/10.1155/jotm/8821002