bims-supasi 2025-09-14 papers

bims-supasi

Biomed News

on Sulfation pathways and signalling

Issue of 2025–09–14
fifteen papers selected by
Jonathan Wolf Mueller, University of Birmingham

Tumor promotion or suppression: Revisiting the role of EXT1 and Heparan sulfate.
The Sex Hormone Precursors Dehydroepiandrosterone (DHEA) and Its Sulfate Ester Form (DHEAS): Molecular Mechanisms and Actions on Human Body.
Heparanase-Neutralizing Monoclonal Antibody (mAb A54) Attenuates Tumor Growth and Metastasis.
Interaction studies by NMR on the multivalent interaction between chondroitin sulfate E derivatives and the langerin receptor.
Which came first - the messenger, the activator, or the receiver?
Antithrombin-binding heparan sulfate is ubiquitously expressed in epithelial cells and suppresses pancreatic tumorigenesis.
SDC2 and FN as cargo proteins in circulating extracellular vesicles in obese breast cancer patients with lymph node metastasis.
Association of obesity and adrenal androgen levels with bone age progression in boys with premature adrenarche.
Engineering an Injectable Scaffold with Enhanced ECM Mimicry for Cell Delivery and Tissue Regeneration.
The First Simplified Heparan Sulphate-Alginate Hybrid Trisaccharides: Synthesis and Biological Effects on Human Dermal Fibroblasts.
Stimulated Hyperinsulinemia Is Independently Associated with Higher Serum DHEAS in PCOS: A Retrospective Study.
Cathepsin K and glycosaminoglycans differentially regulate matrix metalloproteinase activity in dentin under various pH conditions.
Structural Insights into Fun174Sb from the GH174 Family Unravel Novel Subsite Specificities of the Endo-1,3-Fucanase.
Heparanase as a therapeutic target for mitigating cancer progression.
Developmental effects of sulfated thyroid hormones in sea urchin skeletogenesis suggest activation of non-canonical thyroid hormone signaling pathway.

Histol Histopathol. 2025 Sep 12. 18985

Tumor promotion or suppression: Revisiting the role of EXT1 and Heparan sulfate.

Ayumi Niwa, Hiroyuki Tomita, Akira Hara.

Heparan sulfate (HS), a linear sulfated polysaccharide attached to proteoglycans, modulates the availability and activity of growth factors and cytokines to regulate cell signaling, adhesion, and migration. Exostosin-1 (EXT1), a key glycosyltransferase for HS chain elongation, is increasingly implicated in cancer development and progression. Although originally identified as a tumor suppressor in hereditary multiple exostoses, EXT1 exhibits a complex, context-dependent role in cancer. The effects of EXT1 in cancer differ by cell and tumor type, exerting both tumor-suppressing and tumor-promoting effects. Notably, EXT1 also alters the tumor microenvironment via its expression in stromal fibroblasts and endothelial cells, further influencing tumor behavior. This review discusses the functions of HS and EXT1, emphasizing the roles of EXT1 in cancer and its microenvironment. A deeper understanding of these mechanisms may offer novel therapies targeting the HS biosynthetic pathway.

DOI: https://doi.org/10.14670/HH-18-985
Int J Mol Sci. 2025 Sep 03. pii: 8568. [Epub ahead of print]26(17):

The Sex Hormone Precursors Dehydroepiandrosterone (DHEA) and Its Sulfate Ester Form (DHEAS): Molecular Mechanisms and Actions on Human Body.

Hsin-Yi Lin, Jie-Hong Chen, Kuo-Hu Chen.

  Dehydroepiandrosterone (DHEA) and its sulfate ester form DHEAS, are multifunctional steroid hormones primarily produced in the adrenal cortex, with additional synthesis in peripheral tissues. DHEA/DHEAS serve as precursors to sex steroids and exhibit neuroprotective, anti-inflammatory, and immune-modulating effects. DHEA levels decline significantly with age, a phenomenon termed "adrenopause", prompting interest in supplementation to mitigate age-related symptoms. Particularly in postmenopausal women, DHEA has shown potential benefits in treating genitourinary syndrome of menopause (GSM), including improved vaginal health, lubrication, and sexual function. While intravaginal DHEA appears effective and safer than systemic estrogen therapy, especially for women with estrogen sensitivity, results remain mixed for oral administration. DHEA and DHEAS exhibit diverse neuroactive properties through modulation of GABA-A, NMDA, and sigma-1 receptors. These neurosteroids contribute to neuroprotection, synaptic plasticity, and mood regulation. Altered DHEA/DHEAS levels have been implicated in neurodegenerative disorders and depression, with emerging evidence supporting their potential therapeutic value. In addition, DHEA plays a multifaceted role in aging-related physiological changes. It supports muscle anabolism, bone density maintenance, cardiovascular protection, and immune regulation. Though supplementation shows potential benefits, especially in conjunction with resistance training, results remain discrepant. Current evidence has revealed that the therapeutic effects of DHEA supplementation are inconsistent in different human systems among different studies. The diversity of results is mainly due to heterogeneous receptor distribution, various action pathways, and distinct tissue responses in different systems. Further research is needed to define its efficacy and dosage across various systems.

Keywords:  DHEA; DHEAS; dehydroepiandrosterone; dehydroepiandrosterone sulfate

DOI:  https://doi.org/10.3390/ijms26178568
Cells. 2025 Sep 04. pii: 1379. [Epub ahead of print]14(17):

Heparanase-Neutralizing Monoclonal Antibody (mAb A54) Attenuates Tumor Growth and Metastasis.

Uri Barash, Malik Farhoud, Maali Odeh, Eliezer Huberman, Liang Wu, Israel Vlodavsky.

  Heparanase is the only human enzyme responsible for heparan sulfate (HS) breakdown, an activity that remodels the extracellular matrix (ECM) and strongly drives cancer metastasis and angiogenesis. Compelling evidence implies that heparanase promotes essentially all aspects of the tumorigenic process, namely, tumor initiation, vascularization, growth, metastasis, and chemoresistance. A key mechanism by which heparanase accelerates cancer progression is by enabling the release and bioavailability of HS-bound growth factors, chemokines, and cytokines, residing in the tumor microenvironment and supporting tumor growth and metastasis. The currently available heparanase inhibitors are mostly HS/heparin-like compounds that lack specificity and exert multiple off-target side effects. To date, only four such compounds have progressed to clinical trials, and none have been approved for clinical use. We have generated and characterized an anti-heparanase monoclonal antibody (A54 mAb) that specifically inhibits heparanase enzymatic activity (ECM degradation assay) and cellular uptake. Importantly, A54 mAb attenuates xenograft tumor growth and metastasis (myeloma, glioma, pancreatic, and breast carcinomas) primarily when administered (syngeneic or immunocompromised mice) in combination with conventional anti-cancer drugs. Co-crystallization of the A54 Fab fragment and the heparanase enzyme revealed that the interaction between the two proteins takes place adjacent to the enzyme HS/heparin binding domain II (HBDII; Pro271-Ala276), likely hindering heparanase from interacting with HS substrates via steric occlusion of the active site cleft. Collectively, we have generated and characterized a novel mAb that specifically neutralizes heparanase enzymatic activity and attenuates its pro-tumorigenic effects in preclinical models, paving the way for its clinical examination against cancer, inflammation, and other diseases.

Keywords:  combination therapy; heparan sulfate; heparanase; neutralizing monoclonal antibody; pancreatic cancer; tumor growth inhibition; tumor xenograft

DOI:  https://doi.org/10.3390/cells14171379
Org Biomol Chem. 2025 Sep 10.

Interaction studies by NMR on the multivalent interaction between chondroitin sulfate E derivatives and the langerin receptor.

M José García-Jiménez, Sergi Gil, Pedro Domínguez-Rodriguez, Laura Roldán, Michel Thepaut, Francisco Arrabal-Campos, Ignacio Fernandez, Franck Fieschi, Javier Rojo, José L de Paz, Pedro M Nieto.

In this paper, we present the NMR analysis of multivalent compounds displaying chondroitin sulfate E (CS-E) disaccharide ligands and their interaction with langerin. The disaccharides correspond to the two alternative sequences of CS-E: GlcA-GalNAc and GalNAc-GlcA. Firstly, we studied the conformation of the two corresponding series of glycodendrimers free in solution and in the presence of langerin. The NMR structures of the free compounds are compatible with the expected ones. Both sequences exhibit very similar conformations with a rigid moiety, the disaccharides, and a flexible region corresponding to the rest of the molecule. A key aspect of this work is the detailed analysis of how different compounds interact with distinct regions of the langerin receptor as a function of the spatial distribution of the same binding epitope. This allows us to gain unique insights into the receptor's binding behavior and the specific interactions mediated by different ligand multivalency. We conducted transferred NOESY experiments in the presence of langerin, concluding that the conformations of the bound disaccharides were the same as the free ones. In addition, we performed STD-NMR experiments and analyzed the binding epitope, demonstrating that the monovalent compound with GlcA at the non-reducing end can interact with langerin through the Ca2+ cation, while the reverse sequence does not. The corresponding trimers 2 and 6 interact mainly via the central aromatic core, independent of the disaccharide sequence. In the case of tetramer 3, the interaction takes place mainly by the GalNAc proton in position 4 and in the hexamer, significant spin diffusion prevents epitope analysis, although the interaction with langerin is clearly observed. The STD-NMR experiments in the absence of Ca2+ showed a lack of binding for both monovalent compounds 1 and 5. In contrast, in the case of multivalent compounds 2, 3 and 6, STD peak characteristics of binding were found with similar pattern epitope maps to those obtained in the presence of Ca2+. We also performed DOSY experiments for the first series of GlcA-GalNAc compounds individually, in the presence and absence of langerin, and for the mixture of all the compounds in the same NMR tube. Finally, we performed MD simulations for the monovalent and trivalent compounds, corroborating the NMR analysis for the compounds in the absence of langerin.

DOI: https://doi.org/10.1039/d5ob00845j
Trends Plant Sci. 2025 Sep 06. pii: S1360-1385(25)00226-2. [Epub ahead of print]

Which came first - the messenger, the activator, or the receiver?

Amalie Scheel Tost, Frederik Grønbæk Tidemand, Anja Thoe Fuglsang.

  Plants have developed sophisticated signaling mechanisms to adapt to environmental changes, and secreted peptides play crucial roles. Sulfated tyrosine (sTyr) peptides are important regulators of plant growth, nutrient uptake, defense responses, and seed development. This study delves into the evolution of sTyr peptides, their receptors, and the enzyme tyrosylprotein sulfotransferase (TPST) that is responsible for their activation. By exploring the evolutionary timeline of sTyr peptide function, we aim to determine their significance in the emergence of land plants. We map the distribution of sTyr peptides, their receptors, and TPST across different plant species, and identify key sites essential for their activity. These findings provide a comprehensive overview of the functional and evolutionary significance of sTyr peptidesand offer insights into their potential agricultural applications.

Keywords:  agricultural application; evolution; leucine-rich repeat receptor kinases (LRR-RKs); signaling; sulfated peptides; tyrosylprotein sulfotransferase (TPST)

DOI:  https://doi.org/10.1016/j.tplants.2025.07.017
J Clin Invest. 2025 Sep 16. pii: e184172. [Epub ahead of print]

Antithrombin-binding heparan sulfate is ubiquitously expressed in epithelial cells and suppresses pancreatic tumorigenesis.

Thomas Mandel Clausen, Ryan J Weiss, Jacob R Tremblay, Benjamin P Kellman, Joanna Coker, Leo A Dworkin, Jessica P Rodriguez, Ivy M Chang, Timothy Chen, Vikram Padala, Richard Karlsson, Hyemin Song, Kristina L Peck, Satoshi Ogawa, Daniel R Sandoval, Hiren J Joshi, Gaowei Wang, L Paige Ferguson, Nikita Bhalerao, Allison Moores, Tannishtha Reya, Maike Sander, Thomas C Caffrey, Jean L Grem, Alexandra Aicher, Christopher Heeschen, Dzung Le, Nathan E Lewis, Michael A Hollingsworth, Paul M Grandgenett, Susan L Bellis, Rebecca L Miller, Mark M Fuster, David W Dawson, Dannielle D Engle, Jeffrey D Esko.

  3-O-sulfation of heparan sulfate (HS) is the key determinant for binding and activation of Antithrombin III (AT). This interaction is the basis of heparin treatment to prevent thrombotic events and excess coagulation. Antithrombin-binding HS (HSAT) is expressed in human tissues, but is thought to be expressed in the subendothelial space, mast cells, and follicular fluid. Here we show that HSAT is ubiquitously expressed in the basement membranes of epithelial cells in multiple tissues. In the pancreas, HSAT is expressed by healthy ductal cells and its expression is increased in premalignant pancreatic intraepithelial neoplasia lesions (PanINs), but not in pancreatic ductal adenocarcinoma (PDAC). Inactivation of HS3ST1, a key enzyme in HSAT synthesis, in PDAC cells eliminated HSAT expression, induced an inflammatory phenotype, suppressed markers of apoptosis, and increased metastasis in an experimental mouse PDAC model. HSAT-positive PDAC cells bind AT, which inhibits the generation of active thrombin by tissue factor (TF) and Factor VIIa. Furthermore, plasma from PDAC patients showed accumulation of HSAT suggesting its potential as a marker of tumor formation. These findings suggest that HSAT exerts a tumor suppressing function through recruitment of AT and that the decrease in HSAT during progression of pancreatic tumorigenesis increases inflammation and metastatic potential.

Keywords:  Cancer; Cell biology; Coagulation; Glycobiology; Oncology

DOI:  https://doi.org/10.1172/JCI184172
Sci Rep. 2025 Sep 12. 15(1): 32498

SDC2 and FN as cargo proteins in circulating extracellular vesicles in obese breast cancer patients with lymph node metastasis.

Liali Yousef Talat, Ghada Mohamed, Maher H Ibraheem, Amr Ahmed WalyEldeen, Hebatallah Hassan, Sherif Abdelaziz Ibrahim.

  Lymph node metastasis (LNM) is a pivotal determinant of breast cancer (BC) patient prognosis and treatment efficacy. Cell surface heparan sulfate proteoglycans (HSPGs), namely, syndecan-1 (SDC1), SDC2, and SDC4, are involved in cancer progression, metastasis, and regulate extracellular vesicles (EVs) biogenesis, including the microvesicles (MVs). This study analyzed MV-enriched EVs isolated from blood plasma of BC patients with negative (n = 19) and positive (n = 20) LNM (nLNM and pLNM, respectively) using differential centrifugation. Western blot analysis revealed significantly elevated SDC2 levels in MV-enriched EVs from pLNM cases compared to nLNM. Additionally, fibronectin (FN), a SDC2-interacting protein identified through STRING analysis, was also upregulated in pLNM MV-enriched EVs. In contrast, qRT-PCR showed reduced SDC2 (P < 0.01) and FN (P < 0.05) mRNA levels in tumor tissues of pLNM patients compared to nLNM. ROC analysis highlighted the diagnostic value of SDC2 (AUC: 0.8376) and FN (AUC: 0.8803) mRNA in differentiating LNM status. Bioinformatics analyses further confirmed the association of SDC2 and FN expression with BC staging and prognosis. These findings underscore the potential of circulating MV-enriched EV-associated SDC2 and FN, along with their tumor tissue mRNA expression, as potential predictive biomarkers for LNM and chemotherapy response in chemotherapy-naïve obese BC patients.

Keywords:  Breast cancer; Extracellular vesicles; FN; Metastasis; Microvesicles; SDC2

DOI:  https://doi.org/10.1038/s41598-025-17638-2
Ann Pediatr Endocrinol Metab. 2025 Aug;30(4): 175-181

Association of obesity and adrenal androgen levels with bone age progression in boys with premature adrenarche.

Kyeongmi Lee, Jinjoo Choi, Yunsoo Choe, Seung Yang.

   PURPOSE: Both premature adrenarche (PA) and obesity are closely linked to increases in bone age (BA). However, the mechanisms underlying these associations are unclear as research data, particularly in boys, are lacking. Therefore, our aim in this study was to test for an association between obesity and BA progression in boys with PA and to assess the role of adrenal androgen in the mediation of any identified association.
METHODS: We retrospectively analyzed data from medical records of prepubertal boys with PA. Participants were categorized into 2 groups based on the difference between their BA and chronological age (CA), BA-CA≥1 and BA-CA<1.
RESULTS: Among 67 boys having a mean age of 8.3±0.7 years, the 27 boys in the BA-CA≥1 group had significantly higher body mass index (BMI) z-scores (1.7±0.9 vs. 1.0±1.3, P=0.022) and dehydroepiandrosterone sulfate (DHEA-S) z-scores (1.7±1.3 μg/dL vs. 1.1±0.7 μg/dL, P=0.020), than the 40 boys in the BA-CA<1 group. Multivariate regression analyses revealed a significant association between BMI z-score and BA progression for the BA-CA≥1 group, even after adjusting for DHEA-S z-score, odds ratio=1.605 with P=0.048. Mediation analyses indicated that the direct effect of BMI z-score on BA-CA was statistically significant, β=0.2190 with P=0.039; however, the indirect effect of BMI z-score on BA-CA through DHEA-S z-score was not significant.
CONCLUSION: In boys with PA, higher DHEA-S z-scores and BMI z-scores were associated with BA-CA. However, DHEA-S did not mediate the relationship between obesity and BA progression. Our data suggested that in boys with obesity and PA, the rapid progression of skeletal maturation is primarily the result of a direct impact of obesity on BA and not due to an increase in adrenal androgen levels.

Keywords:  Androgen; Bone age; Dehydroepiandrosterone sulfate; Obesity; Premature adrenarche

DOI:  https://doi.org/10.6065/apem.2448248.124
ACS Biomater Sci Eng. 2025 Sep 09.

Engineering an Injectable Scaffold with Enhanced ECM Mimicry for Cell Delivery and Tissue Regeneration.

Shrikant S Kirwale, Ritika Jaiswal, Prajnadipti Sahu, Vagesh Verma, Sushil K Yadav, Aniruddha Roy.

  The development of biomimetic scaffolds that emulate the extracellular matrix (ECM) is critical for advancing cell-based therapies and tissue regeneration. This study reports the formulation of CHyCoGel, a novel injectable, ECM-mimetic hydrogel scaffold composed of chitosan, hyaluronic acid, chondroitin sulfate, and an amphiphilic stabilizer. CHyCoGel addresses key limitations of existing scaffolds, offering improved structural uniformity, injectability, and in situ gelation suitable for cell encapsulation and minimally invasive delivery. Primary dermal fibroblasts (PDFs) isolated from neonatal rat skin were grafted into CHyCoGel, which supported high cell viability, well-organized cytoskeletal structures, and modulation of genes involved in tissue remodeling, including α-SMA, fibronectin, Col1A1, and TGF-β. In vivo application of PDF-loaded CHyCoGel significantly enhanced wound healing, epithelialization, and the regeneration of skin appendages. Notably, CHyCoGel promoted angiogenesis by upregulating VEGF and facilitated balanced ECM remodeling through enhanced type I collagen expression with reduced total collagen accumulation. These findings highlight CHyCoGel's potential as a cytocompatible, bioactive scaffold capable of directing reparative cellular behavior and promoting structurally and functionally integrated tissue regeneration, particularly in chronic and complex wound settings.

Keywords:  ECM-mimetic scaffold; cell encapsulation; chitosan; chondroitin sulfate; hyaluronic acid; polyelectrolyte complexes; tissue regeneration

DOI:  https://doi.org/10.1021/acsbiomaterials.5c00958
Int J Mol Sci. 2025 Aug 27. pii: 8305. [Epub ahead of print]26(17):

The First Simplified Heparan Sulphate-Alginate Hybrid Trisaccharides: Synthesis and Biological Effects on Human Dermal Fibroblasts.

Katalin Kútvölgyi, Zsófia Peleskei, Fruzsina Demeter, Roland A Barta, Attila Mándi, Eszter Homoki, Attila Oláh, János Hajkó, Mihály Herczeg, Erika Lisztes.

  Glycosaminoglycans (GAGs) are linear, high molecular weight polydisperse heteropolysaccharides consisting of repeating disaccharide units, which always contain a uronic acid building block (e.g., d-glucuronic acid or l-iduronic acid). Their analogues containing d-mannuronic acid were not known until now. Another important class of the linear negatively charged polisaccharides are alginates, which are also present in the cell surface in the cell wall. They are composed of blocks of 1,4-linked β-d-mannuronic acid and its C-5 epimer α-l-guluronic acid in alternating or random order. Both groups of molecules have significant biological activity (e.g., cell growth inhibitory activity, anti-inflammatory effect, etc.). In the course of our research, we combined the structural characteristics of these two groups of molecules and produced a series of heparan sulphate analogue trisaccharides containing d-mannuronic acid, with a simplified structure, in which α- and β-mannosidic bonds are also found. Since trisaccharides may exert diverse biological effects and alginate derivatives can influence wound healing processes, we investigated the effects of the synthesized compounds on primary human dermal fibroblasts. We found that, when applied at 10 μM, none of the compounds influenced viability or spontaneous collagen production; however, some derivatives exhibited anti-inflammatory activity and suppressed the poly(I:C)-induced release of interleukin 6.

Keywords:  alginate; anti-inflammatory; dermal fibroblasts; heparan sulphate; mannuronic acid; trisaccharides

DOI:  https://doi.org/10.3390/ijms26178305
J Clin Med. 2025 Sep 04. pii: 6246. [Epub ahead of print]14(17):

Stimulated Hyperinsulinemia Is Independently Associated with Higher Serum DHEAS in PCOS: A Retrospective Study.

Nicoleta Baculescu, Serban Radian, Dana Manda, Cristina Georgiana Serban, Dan Alexandru Niculescu, Monica Livia Gheorghiu, Florin Grigorescu, Catalina Poiana.

  Background/Objectives: Increased dehydroepiandrosterone sulfate (DHEAS) is used as a diagnostic marker of hyperandrogenism in women with polycystic ovary syndrome (PCOS). The mechanisms of adrenal hyperandrogenism in PCOS include hyperinsulinism as a potential stimulator, but results of studies associating insulinemia with DHEAS in PCOS are conflicting. The objective of this study was to evaluate the factors associated with DHEAS levels in PCOS, focusing on insulinemia. Methods: We performed a cross-sectional retrospective study in a total of 257 patients with PCOS (Rotterdam criteria) evaluated in our tertiary center of endocrinology. Clinical and biochemical parameters included body mass index (BMI), serum DHEAS, total testosterone and sex hormone-binding globulin (SHBG), insulin and glycaemia at fasting and 2 h during the oral glucose tolerance test (OGTT), and homeostasis model assessment for insulin resistance (HOMA-IR) was calculated. Results: The comparative analysis of PCOS divided into DHEAS tertiles revealed that patients in the upper tertile were younger (p < 0.05) and had higher 2 h insulin in the OGTT (p < 0.05) than the lower tertile, while fasting insulin and HOMA-IR were not different. DHEAS correlated negatively with age (r = -0.146, p < 0.05) and positively with 2 h insulinemia (r = 0.246, p < 0.001), while fasting insulin and HOMA-IR did not correlate with DHEAS in all PCOS. In stepwise linear regression models, 2 h insulin remained a positive independent predictor for DHEAS only in non-obese PCOS (p < 0.0001). Conclusions: Our data indicate a positive association between stimulated insulin and DHEAS in PCOS. Two-hour insulin in OGTT was an independent predictor of DHEAS in non-obese PCOS, suggesting that DHEAS might be a reliable marker for the stimulatory insulin effect on adrenal steroidogenesis in non-obese PCOS patients.

Keywords:  DHEAS; PCOS; adrenal hyperandrogenism; hyperinsulinemia

DOI:  https://doi.org/10.3390/jcm14176246
Int J Biol Macromol. 2025 Sep 05. pii: S0141-8130(25)08043-2. [Epub ahead of print]327(Pt 2): 147486

Cathepsin K and glycosaminoglycans differentially regulate matrix metalloproteinase activity in dentin under various pH conditions.

Xiujiao Lin, Yiying Chen, Bingjie Zhong, Hao Yu.

  This study examined the pH-dependent (3, 5, and 7) regulation of matrix metalloproteinase (MMP) activity by cathepsin K (catK) and glycosaminoglycans (GAGs) using sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE), fluorescence assays, and human dentin slice experiments. The direct effects of catK were evaluated in the catK-active, catK-deficient, and odanacatib (ODN)-inhibited groups, whereas indirect GAG/tissue inhibitor of metalloproteinase (TIMP)-mediated regulation was assessed in the catK-active, ODN-inhibited, and chondroitin sulfate (CS)-treated groups through dimethylmethylene blue (DMMB) assays, in situ zymography, and immunofluorescence staining. CatK directly activated MMP-2 (62 kDa) and MMP-9 (82 kDa) at all pH values, with no activation observed in the ODN-inhibited or catK-deficient groups. MMP activity was significantly higher at pH 5/7 than at pH 3. ODN treatment reduced the amount of liberated GAGs, particularly at pH 5. A comparative analysis revealed a consistent activity gradient of ODN-inhibited < catK-active < CS-treated for gelatinase activity across all pH values, and significantly lower collagenase intensity in the ODN group than in the catK/CS groups at pH 5. TIMP-1 and TIMP-2 levels were increased in ODN-inhibited slices at pH 3 and 5 respectively, compared with those in controls. These results demonstrate the dual regulatory mechanism of catK involving direct MMP activation and GAG-mediated TIMP modulation, which is strongly pH dependent. The increased efficacy of ODN under acidic conditions suggests its therapeutic potential for preventing dentin erosion when it is applied following acidic challenges.

Keywords:  Cathepsin K; Chondroitin sulfate; Dentin enzymes; Dentin erosion; Glycosaminoglycans; MMPs; pH conditions

DOI:  https://doi.org/10.1016/j.ijbiomac.2025.147486
J Agric Food Chem. 2025 Sep 09.

Structural Insights into Fun174Sb from the GH174 Family Unravel Novel Subsite Specificities of the Endo-1,3-Fucanase.

Guangning Chen, Xinyu Li, Ziyue Yan, Xuanwei Mei, Fangyi Chen, Changhu Xue, Yaoguang Chang.

  Sulfated fucan has attracted growing attention due to its diverse biological properties. Endo-1,3-fucanases are valuable tools for the degradation of sulfated fucan. This study characterized an endo-1,3-fucanase Fun174Sb from the GH174 family, utilizing a combination of protein crystallography, mutagenesis, computational biology, and nuclear magnetic resonance techniques. The complex structure of Fun174Sb revealed that the enzyme primarily relies on hydrophobic and electrostatic interactions to bind the ligand. Mutations showed that several residues─F145, Y152, W230, and R320─are essential for substrate recognition. Notably, the 2-O-sulfate group of the fucosyl residue at the -1 subsite does not interact with any enzyme residues but instead sterically fits into an open space, enabling the -1 subsite to accommodate both Fucp and Fucp2(OSO3-). This study enhances the understanding of the subsite specificity of endo-1,3-fucanases, facilitating their application in the research and development of sulfated fucan.

Keywords:  GH174; X-ray diffraction; fucanase; glycoside hydrolase; sulfated fucan

DOI:  https://doi.org/10.1021/acs.jafc.5c08386
Biochim Biophys Acta Rev Cancer. 2025 Sep 08. pii: S0304-419X(25)00183-0. [Epub ahead of print]1880(5): 189441

Heparanase as a therapeutic target for mitigating cancer progression.

Yogesh Kumar, Lokesh Gambhir, Gaurav Sharma, Asha Sharma, Neha Kapoor.

  Cancer has been one of the primary causes of mortality for the last three decades across the globe, with contemporary treatment modalities often falling short due to limitations viz. drug resistance, toxicity, and the inability to target molecular mechanisms of tumor progression. Among various intracellular mediators implicated in cancer progression, heparanase, a heparan sulfate degrading enzyme, has been pivotal by facilitating tumor invasion, angiogenesis, and metastasis. Inhibiting the activity of heparanase is a promising therapeutic approach that can potentially curtail tumor growth and metastasis, offering a novel strategy to curb cancer progression. The present review underpins the discovery, structural features, and functional roles of heparanase, with a focus on its differential expression in normal and cancer cell state. Further, the review provides an insight in several classes of heparanase inhibitors including nucleic acid-based inhibitors, polysulfated saccharides, vaccines, miRNA, monoclonal antibodies, natural compounds and small molecule inhibitors along with their mechanism of action and potential benefits in cancer therapy. Recent advancements in heparanase inhibitor development, especially those agents that have moved into clinical trials and received patents is also highlighted thereby underscoring their therapeutic potential and commercial viability. The present review emphasizes over the potential of heparanase as a therapeutic agent and provides an extensive summary of actual endeavors to develop effective inhibitors that may substantiate the forthcoming landscape of cancer treatment.

Keywords:  Cancer therapeutics; Clinical trials; Heparanase; Heparanase inhibitor; Targeted therapy

DOI:  https://doi.org/10.1016/j.bbcan.2025.189441
Front Endocrinol (Lausanne). 2025 ;16 1648899

Developmental effects of sulfated thyroid hormones in sea urchin skeletogenesis suggest activation of non-canonical thyroid hormone signaling pathway.

Katherine Tieman, Andreas Heyland.

  Thyroid hormones (THs) are essential regulators of metabolism, homeostasis, and development in metazoans. The canonical genomic pathway involves THs binding to nuclear thyroid hormone receptors (NTHRs), which modulate gene expression in vertebrates. In contrast, non-genomic pathways involve THs interacting with membrane-bound or cytoplasmic receptors. One such pathway includes TH binding to the RGD-binding integrin dimer αVβ3, which activates the Mitogen-Activated Protein Kinase (MAPK) cascade, influencing cancer cell proliferation, metastasis, and angiogenesis. Both T4 and sulfated thyroid hormones (STHs) have been identified as actual and putative ligands in this pathway respectively. In the sea urchin Strongylocentrotus purpuratus, T4 and to a lesser extent T3 accelerate biomineralization-the formation of skeletal structures during embryonic and larval development-by modulating the activity of key transcription factors involved in this process. RGD peptides, potential ligands for the sea urchin integrin αPβG, can inhibit T4-induced effects, suggesting a role for integrin-mediated MAPK signaling (ERK1/2). This study examines whether STHs have developmental roles in sea urchin embryonic skeletogenesis and whether they bind to the αPβG integrin dimer in silico, a TH receptor candidate in sea urchins. Our findings show that STHs, like T4, accelerate the onset of skeletogenesis and increase the frequency of ectopic spicule formation, particularly near ectodermal cells. Homology modeling indicates that the αPβG integrin binds both T4 and STHs with high affinity, whereas no strong binding was observed between TH metabolites and the NTHR in sea urchins. We conclude that STHs have a developmental function in sea urchin skeletogenesis, likely mediated by the αPβG integrin rather than the NTHR. This represents the first documented developmental role of STHs and highlights the importance of non-canonical TH signaling in invertebrate development, encouraging further exploration of TH pathways in non-chordate animals.

Keywords:  AlphaFold; binding affinity; integrin receptor; non-genomic; sea urchin embryo; skeletogenesis; thyroid hormone metabolites

DOI:  https://doi.org/10.3389/fendo.2025.1648899