bims-supasi 2025-06-22 papers

bims-supasi

Biomed News

on Sulfation pathways and signalling

Issue of 2025–06–22
eleven papers selected by
Jonathan Wolf Mueller, University of Birmingham

Chondroitin sulfate polyelectrolyte nanoparticles for controlled release of dexamethasone: Improvement the anticancer activity of curcumin.
Expression of Heart Development Protein With EGF-Like Domains 1 (HEG1) Decorated With Low-Sulfated Keratan Sulfate in Human Malignant Pleural Mesothelioma.
Sulfation-dependent dual modulation of NF-κB and TGF-β/Smad pathways by enteromorpha prolifera polysaccharides accelerates scarless diabetic wound healing.
Age-related changes in fecal adrenal androgen levels in hylobatids.
Bioactive sulfated galactans from Gracilaria fisheri promote chondrogenic activity via integrin-β1/FAK/Akt signaling in human chondrocytes.
OX40-heparan sulfate binding facilitates CAR T cell penetration into solid tumors in mice.
Anti-lung cancer activities of polysaccharides from Laminaria japonica: Network pharmacology and structural insights.
Bionic bearing-inspired lubricating microspheres with Immunomodulatory effects for osteoarthritis therapy.
Targeting Oncofoetal Chondroitin Sulphate Allows Identification of Tumour-Derived Extracellular Vesicles.
Degradation of Sulfated Polysaccharides into Platform Chemicals: Catalysis Mechanism by a Bro̷nsted Acid and the Effect of Protonated Polar Additives.
Dermatan sulfate regulates apoptosis and osteogenic differentiation of hBMSCs through estrogen-like effects.

Int J Biol Macromol. 2025 Jun 11. pii: S0141-8130(25)05762-9. [Epub ahead of print] 145209

Chondroitin sulfate polyelectrolyte nanoparticles for controlled release of dexamethasone: Improvement the anticancer activity of curcumin.

Shima Eldurini, Bothaina M Abd El-Hady, Medhat W Shafaa, Nadia A Mohamed, Ayman M Ibrahim, Emad Tolba.

  Nanoparticle-based drug delivery systems have revolutionized oncology to overcome some critical burdens of conventional chemotherapy, such as non-specific toxicity, poor drug solubility, and rapid clearance. This study presents chondroitin sulfate (ChS)-based polyelectrolyte nanoparticles to achieve controlled release of dexamethasone (DEXA) while enhancing the anticancer efficacy of curcumin(Cur). The ChS polyelectrolyte nanoparticles (ChSNPs) were synthesized through electrostatic interactions between chitosan (Cs) and Chs polymers. The obtained ChSNPs were used to encapsulate DEXA at different concentrations (i.e. 2.5 %, 5 %, and 10 % w/w). The obtained ChSNPs exhibited spherical nanosize structures with average diameters of 345 ± 78 nm for ChSNPs, 114.83 ± 49 nm for DEXA2.5-ChSNPs, 72.83 ± 12 nm for DEXA5-ChSNPs, and 50.83 ± 12 nm for DEXA10-ChSNPs. The in vitro anticancer potential of Cur against HCT116 was further determined in the presence of DEXA-ChSNPs. the viability cells results reveal that the Cur IC₅₀ was decreased by 3.2-fold when delivered with DEXA5-ChSNPs. The Western blot data reveals a 2.5-fold increase in caspase-3 activity (OD 0.841 vs 0.332 for Cur alone) demonstrates a synthetic lethal interaction between DEXA and Cur in HCT116 cells. These results suggest that DEXA-ChSNPs improve Cur chemosensitivity in colon cancer cells, providing a promising approach for enhanced therapeutic outcomes and reduced side effects in cancer treatment.

Keywords:  Anticancer drugs; Curcumin; Dexamethasone; Functional nanoparticles; Polyelectrolytes

DOI:  https://doi.org/10.1016/j.ijbiomac.2025.145209
Pathol Int. 2025 Jun 17.

Expression of Heart Development Protein With EGF-Like Domains 1 (HEG1) Decorated With Low-Sulfated Keratan Sulfate in Human Malignant Pleural Mesothelioma.

Koki Nakashima, Hitomi Hoshino, Zui Zhang, Tomoya O Akama, Nobuyuki Kondo, Seiki Hasegawa, Yoshitaka Sekido, Mana Fukushima, Tamotsu Ishizuka, Motohiro Kobayashi.

  The glycoform of heart development protein with EGF-like domains 1 (HEG1) recognized by the SKM9-2 monoclonal antibody is a useful diagnostic marker for malignant pleural mesothelioma (MPM). The putative glycoform includes core 2 O-glycans carrying sialyl poly-N-acetyllactosamine (LacNAc), but sulfation modifications are undetermined. Since sialyl 6-sulfo LacNAc-capped core 2 O-glycans are expressed in MPM and their structure overlaps with low-sulfated keratan sulfate (KS), we asked whether low-sulfated KS is expressed in MPM and whether HEG1 is decorated with low-sulfated KS. We performed immunohistochemical analysis of 41 MPM cases using anti-KS monoclonal antibodies and endoglycosidases, reversed-phase ion-pair high-performance liquid chromatography analysis of KS/sulfated LacNAc isolated from human pleural tissue, and western blot analysis of HEG1·IgG recombinant fusion proteins secreted from low-sulfated KS-expressing human embryonic kidney cells. Most MPM tissues were stained with anti-low-sulfated KS antibodies and staining was eliminated by endo-β-galactosidase and keratanase II but not by peptide-N-glycosidase F. Disaccharide composition analysis revealed that mono-sulfated LacNAc disaccharide and di-sulfated LacNAc disaccharide accounted for 83.1% and 16.9% of pleural KS/sulfated LacNAc, respectively. Western blot analysis of HEG1·IgG glycoforms indicated that HEG1 functions as a core protein for low-sulfated KS. Thus, HEG1 protein decorated with low-sulfated KS is expressed in MPM.

Keywords:  heart development protein with EGF‐like domains 1 (HEG1); low‐sulfated keratan sulfate; malignant pleural mesothelioma; protein glycosylation

DOI:  https://doi.org/10.1111/pin.70033
Int J Biol Macromol. 2025 Jun 16. pii: S0141-8130(25)05848-9. [Epub ahead of print] 145293

Sulfation-dependent dual modulation of NF-κB and TGF-β/Smad pathways by enteromorpha prolifera polysaccharides accelerates scarless diabetic wound healing.

Luxi Li, Fei Jiang, Ruyi Ren, Xiang Ding, Lujuan Liu, Yun Su, Zhe Chi, Chenguang Liu.

  Chronic wounds in diabetic patients pose significant clinical challenges due to persistent inflammation and impaired healing, leading to delayed closure and excessive scarring. Since chemokines play a pivotal role in inflammatory cell recruitment and scar formation, precise regulation of their activity and distribution is critical. Enteromorpha prolifera polysaccharides (PEPs) exhibit anti-inflammatory, antioxidant, and tissue regenerative properties closely associated with their sulfate group content. In this study, we developed three sulfated PEPs (SPEPs)-SPEP-L, SPEP-M, and SPEP-H-with varying sulfate contents. Our results demonstrated that all three SPEPs exhibited significant anti-inflammatory and anti-scarring activities, with efficacy positively correlated to their sulfate content. Mechanistic studies showed that SPEPs bind to chemokines via electrostatic interactions, thereby attenuating their aberrant signaling and accumulation. This dual action suppresses NF-κB activation, downregulates proinflammatory cytokines (e.g., TNF-α and IL-1β), and reprograms macrophages toward an anti-inflammatory phenotype, collectively reducing inflammatory cell infiltration and accelerating wound repair. Additionally, SPEPs regulated the TGF-β/Smad signaling pathway by modulating Smad2, Smad3, and Smad7 expression, thereby correcting abnormal collagen deposition and inhibiting early scar formation. These results suggest that sulfated PEPs enhance biological activity, effectively targeting inflammation and scarring through well-defined molecular mechanisms, thus promoting rapid and scar-free healing in diabetic wounds.

Keywords:  Anti-inflammatory activity; Diabetic wound healing; Enteromorpha prolifera polysaccharide (PEP); Scar inhibition; Sulfate group modification

DOI:  https://doi.org/10.1016/j.ijbiomac.2025.145293
Gen Comp Endocrinol. 2025 Jun 11. pii: S0016-6480(25)00106-6. [Epub ahead of print]370 114766

Age-related changes in fecal adrenal androgen levels in hylobatids.

Emilee N Hart, Susan Margulis, Rafaela S C Takeshita.

  Adrenarche, or the postnatal activation of the adrenal gland, is a phenomenon exclusive to some primates that is evidenced by high levels of the hormones dehydroepiandrosterone (DHEA) and its sulfated form (DHEAS), independent of the onset of puberty. Within primates, two patterns of adrenal secretions occur: a prepubertal increase in DHEAS levels (adrenarche) that has been reported in humans and great apes, and a continuous postnatal decline on DHEAS levels with age, observed in cercopithecines (e.g., macaques and baboons). Our research seeks to determine the pattern of DHEAS secretion during hylobatid development. DHEAS was measured by enzyme immunoassay in cross-sectional fecal samples from 35 female and 29 male zoo-housed hylobatids (Hylobates, Nomascus, Symphalangus) ranging from age 1 to 54 years. Additionally, we measured longitudinal fecal samples from 7 female hylobatids under human care (6 Nomascus, 1 Hoolock). Our study tested the effects of age, sex, and genus on fecal DHEAS levels using generalized linear mixed-effects models. The models were separated by genus and showed that age was positively correlated with a prepubertal increase in fecal DHEAS across all genera, indicating that the hylobatids exhibit delayed adrenarche. A significant effect of sex was only identified in the Symphalangus model. Results from adult and old hylobatids did not exhibit decreasing DHEAS associated with adrenal senescence, which is characteristic of humans and other primates. The evidence of a delayed DHEAS increase observed across all hylobatid genera suggests a shared developmental characteristic among all ape species.

Keywords:  Adrenal steroids; Adrenarche; Dehydroepiandrosterone-sulfate; Fecal steroids; Hylobatids; Lesser apes; Small apes

DOI:  https://doi.org/10.1016/j.ygcen.2025.114766
Int J Biol Macromol. 2025 Jun 16. pii: S0141-8130(25)05877-5. [Epub ahead of print] 145322

Bioactive sulfated galactans from Gracilaria fisheri promote chondrogenic activity via integrin-β1/FAK/Akt signaling in human chondrocytes.

Boottoh Nambunruang, Ruedee Hemstapat, Aungkura Supokawej, Alita Kongchanagul, Tulyapruek Tawonsawatruk, Kanokpan Wongprasert.

  Osteoarthritis (OA) is characterized by progressive cartilage degradation and limited tissue regeneration, commonly affecting older adults. Current treatment strategies mainly alleviate symptoms without effectively restoring cartilage integrity. Sulfated polysaccharides derived from marine algae have attracted attention for their potential biological effects in promoting cartilage repair. This study examined the chondrogenic activity of sulfated galactans (SG) isolated from the marine red alga Gracilaria fisheri in human C28/I2 chondrocytes, using transforming growth factor-beta 3 (TGF-β3) as a comparative control. SG treatment significantly increased the synthesis of essential cartilage extracellular matrix (ECM) components, such as type II collagen and aggrecan. These effects were mediated through the integrin β1/FAK/Akt signaling pathway, as demonstrated by reduced ECM synthesis following treatment with the Akt inhibitor, MK2206. Additionally, SG improved chondrocyte adhesion and proliferation. These results suggest that sulfated galactans from Gracilaria fisheri may support cartilage ECM synthesis and exhibit potential as biologically active components for osteoarthritis management.

Keywords:  Akt pathway; Chondrocytes; ECM; Integrin β1; Sulfated galactans; Type II collagen

DOI:  https://doi.org/10.1016/j.ijbiomac.2025.145322
Sci Transl Med. 2025 Jun 18. 17(803): eadr2151

OX40-heparan sulfate binding facilitates CAR T cell penetration into solid tumors in mice.

Huihui Zhang, Runbo Zhong, Wanting Wang, Yue Huang, Fanlin Li, Jie Liang, Junshi Zhang, Zekun Yu, Hua Zhong, Shun Lu, Enkhsaikhan Lkhagvasuren, Ariunzaya Bat-Erdene, Gansukh Choijilsuren, Tsogtsaikhan Sandag, Xuanming Yang.

Although chimeric antigen receptor (CAR)-modified T cells have shown great success in treating B cell malignancies, they have demonstrated only limited efficacy against solid tumors. Here, we designed a CAR by integrating an antigen-independent OX40 that showed superior antitumor efficacy against multiple solid tumors. We unexpectedly found, through a CRISPR-Cas9-based whole-genome screen, that heparan sulfate is a ligand for OX40. We found that heparan sulfate can directly bind OX40 at the biochemical and cellular levels and that the interaction of heparan sulfate and OX40 activated the AKT, MAPK, and NF-κB signaling pathways. Functionally, the heparan sulfate-OX40 interaction enhanced cell adhesion and CAR T cell functional binding avidity to tumor cells. In vivo, OX40-expressing CAR T cells exhibited increased solid tumor infiltration and persistence dependent on the OX40-heparan sulfate interaction. Our findings provide insights into a glycan-costimulation interaction that is capable of regulating T cell immunity and has potential application in CAR T cell optimization.

DOI: https://doi.org/10.1126/scitranslmed.adr2151
Int J Biol Macromol. 2025 Jun 13. pii: S0141-8130(25)05695-8. [Epub ahead of print] 145142

Anti-lung cancer activities of polysaccharides from Laminaria japonica: Network pharmacology and structural insights.

Weihua Jin, Chenghui Lu, Lin Sun, Jing Hou, Zhongshang Zhang, Sanying Wang, Fuming Zhang, Genxiang Mao, Tong Hu.

  This study investigates the anti-lung cancer activities of polysaccharides extracted from Laminaria japonica, focusing on their bioactive components and molecular mechanisms. Using a network pharmacology approach, key bioactive compounds were identified, and their associated therapeutic targets were predicted. Experimental validation through in vitro assays on human adenocarcinoma (A549) and Lewis Lung Cancer (LLC) cell lines demonstrated that specific polysaccharide fractions, particularly the S-C fraction, exhibited significant inhibitory effects on cancer cell viability, migration, and invasion. In vivo studies further confirmed the S-C fraction's potential in reducing lung metastasis in a mouse model. The results also highlight the structural features of the polysaccharides, particularly their sulfated galactofucan composition, which contributes to their anti-cancer activities. Overall, the study provides an evaluation of L. japonica polysaccharides as promising natural agents for lung cancer therapy, supporting their potential as adjuncts to conventional treatments.

Keywords:  Anti-lung cancer activity; Laminaria japonica polysaccharides; Sulfated galactofucan

DOI:  https://doi.org/10.1016/j.ijbiomac.2025.145142
J Nanobiotechnology. 2025 Jun 20. 23(1): 457

Bionic bearing-inspired lubricating microspheres with Immunomodulatory effects for osteoarthritis therapy.

Xu He, Xingzhi Liu, Xinyi Cheng, Can Zhu, Yida Chen, Yi Wang, Yun Zhou, Hao Shen, Huilin Yang, Yong Xu, Qin Shi, Junjie Niu.

  Inflammatory infiltration and inappropriate friction remain the two main challenges in treating osteoarthritis (OA). An effective treatment platform is anticipated to lubricate the cartilage and ameliorate intra-articular inflammation. Herein, injectable hydrogel microspheres with chondroitin sulfate (Chs)/sericin methacryloyl (SerMA) designed as the core and grafted with folic acid (FA)- and 78c-modified liposomes (78c@Lipo-FA) by DSPE-PEG2k-GPLGLAGQC (DPG) peptides, namely LFDCS, was formed by thin-film hydration and microfluidic methods. Physically, LFDCS exhibited cartilage lubrication and adhesion capability as the bionic bearings. Meanwhile, with the degradation of LFDCS, Chs were set out to promote chondrocyte function. Physiologically, 78c@Lipo-FA were released from LFDCS enzymatically responsible to matrix metalloprotein-9 (MMP9) due to the split of DPG motif, which specifically bound to classical-activated macrophages (M1) by ligating to FA receptor through FA and inhibit M1 function by 78c, consequently rescued cartilage from degradation by inflammation. Mechanically, an RNA sequencing analysis revealed that the LFDCS could ameliorate chondrocyte dysfunction by down-regulating PI3K/AKT signaling and inflammation response. LFDCS greatly reduced friction on articular surfaces, suppressed M1-induced inflammation and attenuated chondrocyte dysfunction in OA rats. In conclusion, the bionic bearing-inspired lubricating microspheres characterized by M1-phenotype macrophage-targeted addresses the unfavorable factors of both the physical and physiological microenvironments in macrophage-mediated diseases.

Keywords:  Cartilage adhesion; Chondroitin sulfate; Inflammatory; Microspheres; Osteoarthritis; Sericin methacryloyl

DOI:  https://doi.org/10.1186/s12951-025-03544-2
J Extracell Vesicles. 2025 Jun;14(6): e70106

Targeting Oncofoetal Chondroitin Sulphate Allows Identification of Tumour-Derived Extracellular Vesicles.

Agustin Enciso-Martinez, Caroline Løppke, Joyce J Koene, Jade Ebbelaar, Meike van der Geest, Mandy Los, Emma P E M Boerrigter, Robert Dagil, Tobias Gustavsson, Elena E Vidal-Calvo, Ton G van Leeuwen, Roman I Koning, Nick van Es, Ali Salanti, Edwin van der Pol, Rienk Nieuwland, Mette Ø Agerbæk, Peter Ten Dijke.

  Tumour-derived extracellular vesicles (tdEVs) are widely studied for their contribution to tumour progression and metastasis. These studies are hampered by the lack of specific markers to identify the tdEVs. Here, we show that oncofoetal chondroitin sulphate, a malignancy-associated glycosaminoglycan modification, is present on tdEVs and can be targeted by the malaria VAR2CSA protein or C9 antibody. Using a fluorescently labelled recombinant VAR2CSA protein, we identified EVs from cancer cells in vitro by super-resolution fluorescence microscopy and flow cytometry, as well as in a proof-of-concept study using plasma samples from pancreatic adenocarcinoma patients. Thus, the binding of VAR2CSA offers a tool to identify tdEVs, and can be used to explore their function and biomarker potential in cancer.

Keywords:  VAR2CSA; biomarker; cancer; extracellular vesicles; liquid biopsy; pancreatic adenocarcinoma

DOI:  https://doi.org/10.1002/jev2.70106
J Agric Food Chem. 2025 Jun 14.

Degradation of Sulfated Polysaccharides into Platform Chemicals: Catalysis Mechanism by a Bro̷nsted Acid and the Effect of Protonated Polar Additives.

Weifeng Xu, Jiankai Ou, Jinbao Huang, Liming Tai, Shi Yan, Hao Cheng, Li Jin, Hong Wang, Yingwei Liu, Yanbing Ma.

  Sulfated polysaccharides (SPSs) are the main components of algal biomass, which represents a promising feed stock for biorefinary. Molecular-level understanding of the Bro̷nsted acid-catalyzed conversion of SPS into platform chemicals is essential for efficient algal biomass utilization. The calculated results reveal that SPS tends to break the glycosidic bond through the Koshland mechanism in the liquid phase, leading to the formation of monomers. The participation of Cl- ions significantly increases the reaction rate. Thereafter, the Bro̷nsted acid displays favorable catalytic activity in a series of cascading steps for the conversion of the monosaccharides to furfurans, including isomerization, dehydration, decarbonylation, and desulfuration. The rate-determining steps are related to the [1,2]-H shift between C1 and C2 for the stepwise isomerism mechanism. We first proposed the formation pathways of 4-hydroxyvaleric acid (HVA) and succinic acid (SA) initiated from acyclic intermediates, which include site-selective C-C bond fission, dehydration, isomerization, hydration, and SN2 reactions. The concerted dehydration mechanism is the rate-controlling step for the formation of HVA or SA. It is found that the synergistic effect between the products leads to the formation of acid platform compounds. The effect of polar solvent additives is evaluated, and the result suggests that DMSO and THF can promote the formation of furan products and inhibit the formation of acid products.

Keywords:  Bro̷nsted acid; hydrolysis mechanism; platform chemicals; reaction kinetics; sulfated polysaccharide

DOI:  https://doi.org/10.1021/acs.jafc.5c02355
Int J Biol Macromol. 2025 Jun 18. pii: S0141-8130(25)05923-9. [Epub ahead of print] 145368

Dermatan sulfate regulates apoptosis and osteogenic differentiation of hBMSCs through estrogen-like effects.

Junyan Cai, Zili Sun, Qing Yang, Wangjing Xiao, Shukun Deng.

  Although dermatan sulfate (DS) has been known to have an impact on bone development, its effects on the apoptosis and osteogenic differentiation of human bone marrow mesenchymal stromal cells (hBMSCs) are still poorly understood. The present study investigated these effects and the underlying mechanism. Transcriptomic analysis revealed that DS significantly altered gene expression patterns associated with apoptosis and osteogenesis. Functionally, DS promoted hBMSC proliferation, reduced apoptosis, and potently enhanced osteogenic differentiation and mineralization. Crucially, knockdown of ESR1 attenuated these pro-osteogenic and anti-apoptotic effects of DS. Molecular docking analysis further indicated that DS binds to estrogen receptor α (ERα) with affinity comparable to estradiol. Collectively, our results demonstrate that DS exerts estrogen-like effects, primarily mediated through ERα, to promote hBMSC survival and osteogenic differentiation. This novel mechanism highlights the therapeutic promise of DS for enhancing bone formation in estrogen-deficient conditions, such as postmenopausal osteoporosis (PMOP).

Keywords:  Apoptosis; Cell cycle; Dermatan sulfate; Estrogen; Osteogenic differentiation

DOI:  https://doi.org/10.1016/j.ijbiomac.2025.145368