bims-supasi 2025-05-11 papers

bims-supasi

Biomed News

on Sulfation pathways and signalling

Issue of 2025–05–11
eighteen papers selected by
Jonathan Wolf Mueller, University of Birmingham

Recent analytical advances in the detection and characterization of 3-O-sulfated heparan sulfate.
Chondroitin sulfate regulates proliferation of Drosophila intestinal stem cells.
Engineering of lipid membranes asymmetrically functionalized with chondroitin sulfate.
Carbohydrate sulfation as a critical modulator of siglec-sialoglycan interactions.
Steroid sulfatase and the transporter of sulfated steroids are upregulated in granulose cells from women of POSEIDON group 4 in controlled ovarian hyperstimulation for in vitro fertilization cycles.
Chondroitin sulfate: From bioactive molecule to versatile drug delivery system for advancing regenerative medicine.
A sulfated fucopyranosyl-glucosamino-glucopyranose from marine heterotrophic Bacillus tequilensis regulates inflammatory cytokines in lipopolysaccharide-stimulated human monocyte THP-1 cells.
Cross-sectional and Longitudinal Relationship between Sex Hormones and Six Epigenetic Clocks in Older Adults: Results of the Berlin Aging Study II (BASE-II).
Inhibiting synovial inflammation and promoting cartilage repair in rheumatoid arthritis using a matrix metalloproteinase-binding hydrogel.
A comprehensive review of preparation and pharmacology of low molecular weight fucoidan.
Carbohydrate sulfotransferase 14 gene deletion induces dermatan sulfate deficiency and affects collagen structure and bowel contraction.
Chondroitin sulfate and Cys-Ala-Gly peptides coated ZE21B magnesium alloy for enhanced corrosion resistance and vascular compatibility.
Isolation, structural characterization, and antiviral activity of a sulfated polysaccharide (LJP-1) from Laminaria japonica.
Electrochemical Benzylic C-H Sulfation beyond the O-Sulfonation Limitation.
Transfer of SARS-CoV-2 nucleocapsid protein to uninfected epithelial cells induces antibody-mediated complement deposition.
The glycosaminoglycan chains of perlecan regulate the perivascular fluid transport.
Construction of safer hirudin-derived peptides with enhanced anticoagulant properties based on C-terminal active residue adaptation and modification.
Endogenous sex steroid hormones, sex hormone binding globulin and risk of all-cause and cause-specific mortality: a systematic review and dose-response meta-analysis of prospective cohort studies.

Anal Bioanal Chem. 2025 May 06.

Recent analytical advances in the detection and characterization of 3-O-sulfated heparan sulfate.

Elias Mernie, Joseph Zaia.

  Heparan sulfate (HS) is a linear, highly sulfated, and heterogeneous polysaccharide that covalently attaches to core proteins to form heparan sulfate proteoglycans (HSPGs). HSPGs are widely expressed in mammalian cells and are found on the cell surface and within the extracellular matrix (ECM). Structurally, HS consists of repeating disaccharide units composed of hexuronic acid (HexA) (either glucuronic acid (GlcA) or iduronic acid (IdoA)) linked to glucosamine (GlcN) units. The HS chain undergoes extensive post-polymerization modifications, including N-deacetylation of GlcN, C5-epimerization of HexA, and sulfation at various positions like 2-O-sulfation of HexA, as well as 3-O-, 6-O-, and N-sulfation of GlcN. Among these modifications, 3-O-sulfation of HS, produced by HS 3-O-sulfotransferase (HS3OST), is the rarest and most functionally significant. While 3-O-sulfated HS is well known for its anticoagulant properties through the activation of antithrombin, it also plays a critical role in various physiological and pathological processes, including cell differentiation, cancer progression, herpes simplex virus entry, and neuronal development. However, the precise mechanisms underlying these functions and their pathological implications remain inadequately characterized. This knowledge gap is primarily due to the low abundance of 3-O-sulfated HS and the lack of standardized analytical methods for its detection in biological samples. In this review, we summarize recent advancements in analytical techniques for the analysis of 3-O-sulfated HS and highlight potential future directions to improve its characterization and advance our understanding of its biological roles.

Keywords:  3-O-Sulfation; Heparan sulfate; Mass spectrometry; Proteoglycans

DOI:  https://doi.org/10.1007/s00216-025-05898-w
PLoS Genet. 2025 May;21(5): e1011686

Chondroitin sulfate regulates proliferation of Drosophila intestinal stem cells.

Collin Knudsen, Ayano Moriya, Eriko Nakato, Rishi Gulati, Takuya Akiyama, Hiroshi Nakato.

The basement membrane (BM) plays critical roles in stem cell maintenance and activity control. Here we show that chondroitin sulfate (CS), a major component of the Drosophila midgut BM, is required for proper control of intestinal stem cells (ISCs). Loss of Chsy, a critical CS biosynthetic gene, resulted in elevated levels of ISC proliferation during homeostasis, leading to midgut hyperplasia. Regeneration assays demonstrated that Chsy mutant ISCs failed to properly downregulate mitotic activity at the end of regeneration. We also found that CS is essential for the barrier integrity to prevent leakage of the midgut epithelium. CS is known to be polymerized by the action of the complex of Chsy and another critical protein, Chondroitin polymerizing factor (Chpf). We found that Chpf mutants show increased ISC division during midgut homeostasis and regeneration, similar to Chsy mutants. As Chpf is induced by a tissue damage during regeneration, our data suggest that Chpf functions with Chsy to facilitate CS remodeling and stimulate tissue repair. We propose that the completion of the repair of CS-containing BM acts as a prerequisite to properly terminate the regeneration process.

DOI: https://doi.org/10.1371/journal.pgen.1011686
Faraday Discuss. 2025 May 09.

Engineering of lipid membranes asymmetrically functionalized with chondroitin sulfate.

Teresa Rodríguez-García, Loretta Akakpo, Sadie L Nickles, Ryan J Schuck, Daiane S Alves, Katherine G Schaefer, Frederick A Heberle, Gavin M King, Francisco N Barrera.

One of the defining properties of the eukaryotic plasma membrane is the glycocalyx, which is formed by glycosylated lipids and proteins. The glycocalyx is arranged asymmetrically, as it is exclusive to the extracellular side of the membrane. Membrane asymmetry therefore includes both lipid and carbohydrate asymmetry, whereby the latter has the most skewed trans-leaflet imbalance. The glycocalyx plays a structural role that protects cell integrity and it also participates in mechanosensing and other cellular processes. However, our understanding of glycocalyx function is hampered by the lack of suitable model systems to perform biophysical investigation. Here, we describe the engineering of lipid bilayers that are chemically conjugated at the outer surface with one of the most abundant glycocalyx components, chondroitin sulfate (CS). Membranes were doped with a reactive phospholipid, which allowed thiol-maleimide conjugation of thiol-modified CS at the lipid headgroup. Our data show that we achieved CS conjugation of large unilamellar vesicles, supported lipid bilayers, and giant unilamellar vesicles. CS conjugation of vesicles allowed electrostatic recruitment of poly-L-lysine, which could recruit other CS-coated vesicles or CS in solution. Overall, we describe a simple and robust method for polysaccharide functionalization of vesicles which can be applied to gain new mechanistic understanding of the pathophysiological role of the glycocalyx.

DOI: https://doi.org/10.1039/d4fd00195h
Carbohydr Res. 2025 Apr 25. pii: S0008-6215(25)00128-4. [Epub ahead of print]553 109502

Carbohydrate sulfation as a critical modulator of siglec-sialoglycan interactions.

Jaesoo Jung, Edward N Schmidt, Matthew S Macauley.

Siglecs are sialic acid-binding immunomodulatory receptors that regulate immune homeostasis. Abnormal alterations in sialic acid-containing glycans (sialoglycans) on tissues or cells are key drivers of various diseases, including cancer, neurodegenerative disorders, allergies, and autoimmune diseases. Consequently, the role of Siglecs as immune checkpoints has gained increasing attention. To better understand Siglec biology, comprehensive approaches have been employed to elucidate Siglec ligands, including chemical synthesis for glycan microarrays and genetic manipulation of glycosyltransferases for understanding their biosynthesis process. These efforts have revealed that carbohydrate sulfation, catalyzed by carbohydrate sulfotransferases (CHSTs), fine-tunes Siglec-sialoglycan interactions by enhancing binding affinities. This review summarizes the latest insights into sulfated sialoglycan ligands for individual Siglecs.

DOI: https://doi.org/10.1016/j.carres.2025.109502
Steroids. 2025 May 01. pii: S0039-128X(25)00067-4. [Epub ahead of print]219 109626

Steroid sulfatase and the transporter of sulfated steroids are upregulated in granulose cells from women of POSEIDON group 4 in controlled ovarian hyperstimulation for in vitro fertilization cycles.

Karina Sequeira, Soledad Henríquez, Paulina Kohen, Ariel Fuentes, Alejandro Tapia-Pizarro, Pablo Céspedes, Ana Godoy, Luigi Devoto.

   PURPOSE: The reduced circulating levels of dehydroepiandrosterone sulphate (DHEA-S) are associated with women with poor ovarian response, > 35 years old and low ovarian reserve (POSEIDON group 4, PG4) in cycles of controlled ovarian hyperstimulation. In the ovary, the uptake of DHEA-S is facilitated by the transmembrane organic anion-transporting polypeptide, OATP2B1, whereas in the cytoplasm, the hydrolysis of the inactive precursor DHEA-S into the biologically active steroid DHEA is catalyzed by the steroid sulfatase enzyme (STS). The objective of the present study was to evaluate DHEA and DHEA-S in serum and follicular fluid as well as the expression levels for STS and OATP2B1 in granulosa cells from women in PG4 compared to a control group (control) of age matched women with normal ovarian reserve and response to controlled ovarian hyperstimulation.
METHODS: Prospective study which included 23 women who underwent in vitro fertilization. We compared women in PG4 (n = 13) with a control (n = 8). Transcript levels and the cellular distribution of STS and OATP2B1 transporter were determined by qPCR and immunofluorescence respectively in granulosa cells collected at the time of oocyte pick-up. Gene expression was analyzed according to age, circulating AMH, antral follicle count (AFC) along with DHEA-S and DHEA in serum and follicular fluid.
RESULTS: Serum and follicular fluid analysis showed that DHEA-S was significantly decreased in PG4 compared to control, whereas no differences in DHEA concentrations were observed. Women in PG4 had significantly higher expression of STS and OATP2B1 mRNA (n = 13, p < 0.05) compared with those of the control.
CONCLUSION: Our results suggest that up-regulation of STS and OATP2B1 in granulosa cells from women in PG4 could be a compensatory mechanism to overcome the decreased circulating levels of DHEA-S possibly required as substrate for intraovarian production of DHEA.

Keywords:  Androgens; Dehydroepiandrosterone Sulphate; In vitro Fertilization; Ovarian Reserve; Poor Ovarian Response

DOI:  https://doi.org/10.1016/j.steroids.2025.109626
Int J Biol Macromol. 2025 May 02. pii: S0141-8130(25)04298-9. [Epub ahead of print]311(Pt 2): 143746

Chondroitin sulfate: From bioactive molecule to versatile drug delivery system for advancing regenerative medicine.

Aparna Rajesh, Devika Sajeev, Nethish Kumaar R, Jayakumar Rangasamy, Sreeja C Nair.

  Regenerative medicine, a rapidly advancing field, holds immense promise for restoring and revitalizing damaged tissues and organs resulting from aging, diseases, or injuries, ultimately improving patient well-being. Chondroitin Sulfate (CS), a naturally occurring glycosaminoglycan, is a compelling biomaterial due to its natural origin, well-established biocompatibility, and structural complexity. Renowned for its biocompatibility, structural complexity, and varied bioactivities, CS provides significant applications beyond its recognized function in joint health and osteoarthritis treatment. Recent breakthroughs demonstrate its potential in treating complicated disorders such as interstitial cystitis, psoriasis, dry eye syndrome, and cardiovascular diseases by controlling inflammation, facilitating wound healing, and improving tissue repair. Notwithstanding its therapeutic potential, CS remains inadequately investigated in regenerative medicine and tissue engineering. Its capacity to modulate cellular signaling, promote extracellular matrix remodeling, and improve scaffold integration establishes it as a crucial facilitator of sophisticated therapeutic approaches. This review elucidates the progression of CS-based drug delivery systems, encompassing hydrogels, microparticles, nanoparticles, composites, and beads while underscoring their effectiveness in addressing conventional drug delivery obstacles such as non-specific targeting and off-target effects. Integrating CS into advanced platforms enables regulated drug release, accurate targeting, and enhanced cellular absorption while maintaining biodegradability and compatibility with tissue engineering scaffolds. Its inherent antioxidant, anti-inflammatory, and immune-modulating characteristics augment its attractiveness for individualized therapeutic applications. Recent studies highlight the adaptability of CS in developing multimodal drug delivery systems designed for regenerative medicine. Nonetheless, substantial deficiencies persist, especially in clinical validation and extensive applications. Overcoming these hurdles may fully realize CS's potential in transforming drug delivery, establishing a solid basis for the progression of regenerative therapies. By integrating biomaterial science with clinical medicine, CS-based systems are set to transform treatment approaches in regenerative medicine, providing precision, efficiency, and adaptability for individualized care.

Keywords:  Biomaterials; Chondroitin sulfate; Drug delivery; Glycosaminoglycan; Regenerative medicine; Tissue engineering

DOI:  https://doi.org/10.1016/j.ijbiomac.2025.143746
Int J Biol Macromol. 2025 May 07. pii: S0141-8130(25)04605-7. [Epub ahead of print] 144053

A sulfated fucopyranosyl-glucosamino-glucopyranose from marine heterotrophic Bacillus tequilensis regulates inflammatory cytokines in lipopolysaccharide-stimulated human monocyte THP-1 cells.

Sumayya Asharaf, Kajal Chakraborty, Chesvin Varghese, Rekha Devi Chakraborty, Silpa Kunnappilly Paulose, Shubhajit Dhara.

  Marine macroalga or seaweed-associated bacterial exopolysaccharides, particularly (1 → 3)-linked β-glucans, possess potential ability to reduce inflammatory responses by targeting various cytokines. In this direction, a sulfated exopolysaccharide (BP-2), characterized as fucopyranosyl glucosamino-glucopyranose, was isolated from the heterotrophic bacterium Bacillus tequilensis MTCC13043, associated with the brown seaweed Sargassum wightii. The whole-genome analysis of B. tequilensis MTCC13043 (accession number: JAKGAV000000000) revealed that 97 % of its genome consisted of biosynthetic gene clusters for specific saccharin molecules. Administration of BP-2 (50 μg/mL) on lipopolysaccharide (LPS) induced THP-1 monocytic cell line resulted in a substantial reduction in overexpressed nitric oxide (~56 %), tumor necrosis factor (TNF-α) (~81 %), interleukins (IL-6, IL-12 and IL-1β) (~50-66 %). Significant downregulation of mRNA expression of IL-2 (1.65-fold) and interferon-gamma (IFN-γ) (2.15-fold) was observed in BP-2 (50 μg/mL) treated cells, in comparison with LPS-treated cells (3.81-5.06-fold), whereas the expression of inflammation regulatory transforming growth factor (TGF)-β was upregulated (~80 %, 4.85-fold) upon treatment with BP-2 (50 μg/mL). The structure-activity correlations revealed that (1 → 3) β-glycosidic linkage, along with C-6/C-4,6 sulfation patterns in BP-2 are likely responsible for its prospective anti-inflammatory property. These findings clearly indicate the potential of the isolated bacterial exopolysaccharide (BP-2) as a promising anti-inflammatory agent.

Keywords:  (1 → 3) β-glycosidic linkage; Anti-inflammatory activity; Exopolysaccharide; Seaweed-associated Bacillus tequilensis

DOI:  https://doi.org/10.1016/j.ijbiomac.2025.144053
J Gerontol A Biol Sci Med Sci. 2025 May 09. pii: glaf106. [Epub ahead of print]

Cross-sectional and Longitudinal Relationship between Sex Hormones and Six Epigenetic Clocks in Older Adults: Results of the Berlin Aging Study II (BASE-II).

Hannah Schmid, Valentin Max Vetter, Jan Homann, Vivien Bahr, Christina M Lill, Vera Regitz-Zagrosek, Lars Bertram, Ilja Demuth.

  Beyond their essential roles in regulating reproduction and development, sex hormones play a crucial role in the aging processes. Observational studies have indicated that low sex hormone concentrations in older age are associated with adverse health events. DNA methylation age acceleration (DNAmAA) estimated from epigenetic clocks quantifies differences in biological aging. DNAmAA was previously shown to be associated with age at menopause, ovariectomy, hormone replacement therapy and testosterone level. We analysed the relationship between estradiol, dehydroepiandrosterone sulfate (DHEAS) and the Free Androgen Index (FAI) with DNAmAA estimators from six epigenetic clocks (Horvath's, Hannum's, 7-CpG clock, PhenoAge, GrimAge, DunedinPACE) in 1,404 participants of the Berlin Aging Study II (BASE-II, mean age at baseline 68.7 ±3.7 years, 48% women). The relationship was investigated in multiple linear regression models cross-sectionally at two time points and longitudinally over on average 7.3 years of follow-up. We did not observe any consistent associations between the sex hormones and DNAmAA estimators investigated. However, we found several nominal associations (alpha=0.05) of unclear relevance. For instance, we identified an inverse association between DHEAS and Horvath's DNAmAA, i.e. a reduced biological age with higher DHEAS levels in men at baseline. In women we found an inverse association between estradiol and DunedinPACE (baseline) and a positive association with GrimAge (follow-up). In longitudinal analyses, ΔDHEAS and ΔDunedinPACE were inversely associated in both sexes. Our results suggest that sex hormones play at best a minor role with respect to biological aging in the older population studied here.

Keywords:  DHEAS; Free Androgen Index; epigenetic aging; estradiol

DOI:  https://doi.org/10.1093/gerona/glaf106
Mater Today Bio. 2025 Jun;32 101792

Inhibiting synovial inflammation and promoting cartilage repair in rheumatoid arthritis using a matrix metalloproteinase-binding hydrogel.

Zhanpeng Xue, Nan Li, Kaijun Du, Jianxiong Shu, Zhenwen Huang, Zhifei Gao, Xiaobo Xie, Qi Li, Yao Lu.

  Originating from synovial tissue, matrix metalloproteinase-9 (MMP-9) is a key inflammatory factor that promotes the formation and invasion of synovial pannus, leading to cartilage matrix destruction in rheumatoid arthritis (RA). However, clinical trials of systemic use of MMP-9 inhibitors are not successful due to severe side effects. Thus, locally inhibiting MMP-9 may be an alternative in the treatment of RA. Herein, we developed MMP-9 binding peptide-functionalized copper sulfide nanoparticles (CuS-T NPs) and delivered them with light crosslinking chondroitin sulfate methacrylate (ChSMA) hydrogel. We found that the CuS NP-doped hydrogels could inhibit synovial inflammation. Specifically, the CuS-T/ChSMA hydrogel could rapidly bind to MMP-9, thereby inhibiting not only the invasion of RA fibroblast-like synoviocytes but also the polarization of inflammatory M1-type macrophages. The underlying mechanism involved the inhibition of the MAPK pathway. Moreover, ChSMA hydrogel provided a cartilage matrix-mimic microenvironment and synergistically promoted the generation of collagen-2 and aggrecan with CuS NPs. In an adjuvant-induced arthritis mouse model, the intra-articular injection of ChSMA/CuS-T hydrogel significantly alleviated synovial inflammation and accelerated cartilage repair without causing any side effects, killing two birds with one stone in RA therapy.

Keywords:  Chondroitin sulfate methacrylate; Copper sulfide nanoparticles; Matrix metalloproteinase-9; Rheumatoid arthritis

DOI:  https://doi.org/10.1016/j.mtbio.2025.101792
Int J Biol Macromol. 2025 May 07. pii: S0141-8130(25)04528-3. [Epub ahead of print] 143976

A comprehensive review of preparation and pharmacology of low molecular weight fucoidan.

Ping Luo, Huazhong Liu.

  Fucoidan is a type of sulfated fucans originated from many marine animals and algae, its unique molecular characteristics rich in L-fucose and sulfate ester group give it a wide range of biological properties. The natural polysaccharide has been used as a clinical drug for kidney disease for many years. However, high molecular weight associated defects, low water solubility and high viscosity, reduce its bioavailability. Consequently, low molecular weight fucoidan (LMWF) with better physicochemical properties originally has been widely studied its biological properties and once regarded as a substitute of heparin for its anticoagulant activity. Presently, large number of researches reported its various bioactivities, including anti-coagulation, anti-oxidation, anti-inflammation, anti-tumor, etc., but the LMWFs prepared by different methods from various species possess distinct molecular characteristics, which results in discrepant biological activities and the underlying mechanisms. Based on the research progress of LMWF, this review article comprehensively overviewed the preparation methods, toxicity, and pharmacology, which highlights LMWF as a valuable marine active substance for developing marine functional foods and drugs.

Keywords:  LMWF; Molecular targets; Pharmacodynamics; Pharmacokinetics; Preparation

DOI:  https://doi.org/10.1016/j.ijbiomac.2025.143976
PLoS One. 2025 ;20(5): e0320943

Carbohydrate sulfotransferase 14 gene deletion induces dermatan sulfate deficiency and affects collagen structure and bowel contraction.

Fumiko Ono, Yuki Takahashi, Shin Shimada, Shuji Mizumoto, Shinji Miyata, Yuko Nitahara-Kasahara, Shuhei Yamada, Takashi Okada, Tomoki Kosho, Takahiro Yoshizawa.

Dermatan sulfate (DS) is a type of glycosaminoglycan present in the extracellular matrix, and which is related to tissue strength, structure, and healing. Dermatan 4-O-sulfotransferase 1 (D4ST1) is an enzyme that catalyzes the transfer of a sulfate group to the N-acetylgalactosamine residue of dermatan, resulting in mature DS. Biallelic loss-of-function variants in the carbohydrate sulfotransferase 14 (CHST14) gene encoding D4ST1, induce defective DS biosynthesis. DS deficiency causes severe connective tissue fragility and deformities in humans (musculocontractural Ehlers-Danlos Syndrome [mcEDS]) and mice (Chst14 gene knockout [Chst14-/-] mice). Many patients with mcEDS experience gastrointestinal symptoms such as constipation, diverticula, diverticulitis, and perforation. However, pathogenesis of these symptoms has not been systematically investigated. Therefore, we sought to determine the effects of DS deficiency on the colon using Chst14-/- mice. We found that collagen fibrils were abnormally arranged in the submucosa of the colon. The mice also exhibited accelerated colonic contraction. Unexpectedly, no significant aggravation of dextran sulfate sodium-induced colitis was observed in Chst14-/- mice compared with wild-type mice. These findings suggest a physiological role of DS in the colon and may shed light on the potential mechanisms underlying the gastrointestinal symptoms of mcEDS.

DOI: https://doi.org/10.1371/journal.pone.0320943
Int J Biol Macromol. 2025 May 02. pii: S0141-8130(25)04447-2. [Epub ahead of print]311(Pt 3): 143895

Chondroitin sulfate and Cys-Ala-Gly peptides coated ZE21B magnesium alloy for enhanced corrosion resistance and vascular compatibility.

Xinyu Wang, Yuan Zhao, Yunwei Gu, Lingchuang Bai, Lan Chen, Shaokang Guan.

  Coronary stents are widely used in the interventional treatment of cardiovascular disease. Biodegradable magnesium alloy stents are ideal candidates to replace traditional non-biodegradable stents due to their excellent mechanical properties and biodegradation. However, too fast degradation and poor biocompatibility limit the further clinical application of magnesium alloy stents. Herein, a composite coating consisting of an MgF2 layer, PDA layer, ChS, and CAG peptide was constructed on the Mg-Zn-Y-Nd (ZE21B) alloy to enhance its corrosion resistance, hemocompatibility, and cytocompatibility. The MgF2 and PDA layers in the composite coating could collectively enhance the corrosion resistance of ZE21B alloy, and the ChS and CAG peptides in the composite coating could improve the anticoagulant and pro-endothelialization capacity of ZE21B alloy. The corrosion current density of the modified ZE21B alloy was much lower than that of bare ZE21B alloy, proving the better corrosion resistance. Moreover, the excellent hemocompatibility of modified ZE21B alloy was verified by the lower levels of hemolysis rate, fibrinogen adsorption and denaturation, and platelet adhesion and activation. Furthermore, the composite coating could selectively promote the adhesion, proliferation, migration, and competitive growth of endothelial cells rather than smooth muscle cells on the ZE21B alloy owing to the synergistic biological effects of ChS and CAG peptides. The ChS/CAG modified samples also exhibited excellent biosafety and histocompatibility in vivo implantation experiments. The composite coating significantly improved the corrosion resistance and biocompatibility of ZE21B alloy, and provided a simple and effective strategy for developing degradable vascular stents.

Keywords:  CAG peptides; Chondroitin sulfate; Cytocompatibility; Hemocompatibility; Magnesium alloy stents

DOI:  https://doi.org/10.1016/j.ijbiomac.2025.143895
Int J Biol Macromol. 2025 May 05. pii: S0141-8130(25)04495-2. [Epub ahead of print] 143943

Isolation, structural characterization, and antiviral activity of a sulfated polysaccharide (LJP-1) from Laminaria japonica.

Luming Deng, Pan Zhou, Yuting Yi, Yuan Li, Hongyu Zheng, Xia Wu, Chunlan Cai, Lishuang Zhou, Zhuo Luo, Kefeng Wu, Hui Luo.

  Herpes simplex virus type 1 (HSV-1) represents a widespread and prevalent human pathogen that leads to various conditions, including herpes labialis, herpes keratitis, and neonatal encephalitis. In this study, sulfated polysaccharide (LJP-1) with a molecular weight of 272,231 Da was isolated from Laminaria japonica, a species of brown algae recognized for its medicinal and nutritional properties. The monosaccharide composition, FT-IR, methylation, GC-MS, and NMR analysis revealed that the backbone structure of LJP-1 was composed of 1,4-α-D-GlcpA, 1,6-β-D-Galp, and 1,4,6-β-D-Galp. The sulfate groups were located at the C-4 position of T-β-D-Xylp unit. Besides, the antiviral efficacy of LJP-1 against HSV-1 was evaluated using Vero cells in vitro and a mouse model of skin zosteriform infection in vivo. Our findings revealed that LJP-1 exhibited significant inhibitory effects on HSV-1 attachment, penetration, and viral particle activation. Moreover, LJP-1 alleviated the symptoms associated with skin disorders induced by HSV-1 and inhibited the replication of HSV-1 by reducing the expression levels of ICP27 and gB. Furthermore, the viral titer of HSV-1 was significantly decreased in the skin tissues of infected mice. Collectively, these results indicate that LJP-1 has huge potential as an anti-HSV-1 agent for applications in the functional food and pharmaceutical industries.

Keywords:  Anti-HSV-1 activity; Laminaria japonica polysaccharide; Structural elucidation

DOI:  https://doi.org/10.1016/j.ijbiomac.2025.143943
Angew Chem Int Ed Engl. 2025 May 07. e202507048

Electrochemical Benzylic C-H Sulfation beyond the O-Sulfonation Limitation.

Wei Sheng, Huanhuan Peng, Ben Gao, Chunlang Song, Jiakun Li.

  Direct C-H sulfation represents a valuable transformation for the synthesis of organosulfates. However, it has been challenging to achieve owing to the presence of multiple C-H bonds with comparable strengths and steric environments. Current methods for producing organosulfates primarily rely on O-sulfonation, which limits their applicability to hydroxyl-containing compounds. Herein, we report a practical and cost-efficient method for the electrochemical sulfation of benzylic C-H bonds. This reaction avoids the need for strong oxidants, demonstrating broad substrate scope, excellent chemoselectivity and site selectivity. The orthogonal reactivity of this protocol is particularly evident in the transformation of alcohol substrates.

Keywords:  C-H oxidation; O-sulfonation; electrooxidation; sulfation

DOI:  https://doi.org/10.1002/anie.202507048
Cell Rep. 2025 May 08. pii: S2211-1247(25)00283-9. [Epub ahead of print]44(5): 115512

Transfer of SARS-CoV-2 nucleocapsid protein to uninfected epithelial cells induces antibody-mediated complement deposition.

Jamal Fahoum, Maria Billan, Julia K Varga, Dan Padawer, Yelena Britan-Rosich, Maya Elgrably-Weiss, Pallabi Basu, Miri Stolovich-Rain, Leah Baraz, Einav Cohen-Kfir, Sujata Kumari, Esther Oiknine-Djian, Manoj Kumar, Orly Zelig, Guy Mayer, Michail N Isupov, Dana G Wolf, Shoshy Altuvia, Reuven Wiener, Ora Schueler-Furman, Alexander Rouvinski.

  SARS-CoV-2 infection triggers a strong antibody response toward nucleocapsid protein (NP), suggesting its extracellular presence beyond intravirion RNA binding. Our co-culture experiments show NP decorates infected and proximal uninfected cell surfaces. We propose a mechanism whereby extracellular NP on uninfected cells contributes to COVID-19 pathogenicity. We show that NP binds to cell-surface sulfated glycosaminoglycans using its RNA-binding sites, facilitated by the flexible, positively charged linker. Coating uninfected lung-derived cells with NP attracted anti-NP IgG from lung fluids and sera of COVID-19 patients. Immune recognition was significantly higher in moderate versus mild COVID-19. Binding of anti-NP IgG in sera generated clusters, triggering C3b deposition via the classical complement pathway on SARS-CoV-2 non-susceptible cells co-cultured with infected cells. The heparin analog enoxaparin outcompeted NP binding, rescuing cells from anti-NP IgG-mediated complement deposition. Our findings reveal how extracellular NP may exacerbate COVID-19 damage and suggest preventative therapy avenues.

Keywords:  C3b complement deposition; COVID-19 severity; CP: Immunology; SARS-CoV-2 antibodies; SARS-Cov-2 Nucleocapsid protein; classical complement pathway; electrostatic interactions; enoxaparin; flexible linker; heparan sulfate proteoglycans; sulfated glycosaminoglycans

DOI:  https://doi.org/10.1016/j.celrep.2025.115512
Fluids Barriers CNS. 2025 May 08. 22(1): 48

The glycosaminoglycan chains of perlecan regulate the perivascular fluid transport.

Abhishek Singh, Mika Kaakinen, Harri Elamaa, Vesa Kiviniemi, Lauri Eklund.

   BACKGROUND: The perivascular conduct pathway that connects the cerebrospinal fluid spaces with the interstitial fluid in the parenchyma are of importance for solute clearance from the brain. In this pathway, the relatively wide perivascular space (PVS) surrounding the pial arteries provides a low-resistant passage while around the perforating arteries, the solute movement is along the basement membrane (BM), that prevents the free exchange of interstitial fluids and solutes. We hypothesize that this selectivity involves specific components of the vascular BM, which is mainly composed of type IV collagen (Col IV) and laminin networks interconnected by nidogens and heparan sulphate proteoglycans (HSPGs). Perlecan is the major HSPG in the BM that binds to Col IV and laminin via glycosaminoglycan (GAG) chains to form a molecular sieve. GAGs may also provide the charge selectivity required for filtration, and also a scaffold for amyloid-β (Aβ) aggregation. The purpose of this study was the functional characterization of perivascular fluid transport and brain clearance in mice lacking perlecan GAG chains.
METHODS: We generated a novel mouse line (Hspg2∆3∆91) lacking perlecan GAG side chains and investigated perivascular flow and brain clearance in these mice using intravital multiphoton and fluorescence recovery after photobleaching techniques, and functional assays with various tracers. Potentially deleterious effects on brain homeostasis were investigated using transcriptomic, proteomic and immunohistochemical methods. The Hspg2∆3∆91 mice were crossed with a 5xFAD line to examine the importance of GAGs in Aβ aggregation.
RESULTS: We observed a delayed inflow of CSF tracer into the Hspg2∆3∆91 brain with no changes in the clearance of parenchymal injected tracers. Quantification of the Aβ plaques revealed fewer and smaller plaques in the walls of the pial arteries at six months of age, but not in the brain parenchyma. Surprisingly, perlecan GAG deficiency had no severe deleterious effects on brain homeostasis in transcriptomic and proteomic analyses.
CONCLUSIONS: Potential brain clearance mechanisms are dependent on the flow through special ECM structures. BM is mainly known for its barrier function, whereas very little is known about how passage along the perivascular ECM is established. This study shows that the GAG composition of the BM affects the solute dynamics and Aβ deposition in the periarterial space.

Keywords:  Amyloid beta; Basement membrane; Cerebrospinal fluid; Extracellular matrix; Glycosaminoglycans; Heparan sulphate proteoglycan; Perivascular space; Perlecan

DOI:  https://doi.org/10.1186/s12987-025-00648-7
J Adv Res. 2025 May 02. pii: S2090-1232(25)00289-9. [Epub ahead of print]

Construction of safer hirudin-derived peptides with enhanced anticoagulant properties based on C-terminal active residue adaptation and modification.

Xiaozhe Yi, Xiaoli Wu, Erhuan Zang, Xiaoli He, Xinyi Chang, Jinxin Liu, Linchun Shi.

   INTRODUCTION: Hirudin exerts anticoagulant effects by inhibiting the binding and catalytic activity of thrombin to fibrinogen. However, its rigid N-terminal region irreversibly occupies the thrombin catalytic center, raising concerns about potential bleeding.
OBJECTIVES: In this study, a novel lead compound, WPHVC_V1, which is based on the competitive binding mechanism of the hirudin variant WPHV_C, was developed and validated for in vitro and in vivo activity and safety.
METHODS: Saturation mutagenesis, molecular dynamics simulations and mutant protein activity assays were used to elucidate the competitive anticoagulant mechanism between WPHV_C and thrombin. Next, a recombinantly expressed tyrosylprotein sulfotransferase was used to modify and confirm the sulfation site on the C-terminal tyrosine of hirudin. Finally, a multisite aromatic amino acid mutation strategy was implemented to design and synthesize the lead anticoagulant, WPHVC_V1.
RESULTS: The acidic amino acid cluster in WPHV_C formed strong electrostatic interactions with the positively charged thrombin exosite I, blocking fibrinogen binding. The introduction of aromatic amino acids further stabilized the complex through π-π stacking and π-cation interactions. For example, mutation of 13E to A decreased the free energy of dissociation (ΔG) from 19.27 to 10.93 kcal·mol-1 and shortened the thrombin time (TT) from 42.00 s to 30.94 s, whereas mutation of 26 K to W increased the ΔG to 24.70 kcal·mol-1 and prolonged TT to 51.92 s. In addition, the aromatic effect of 20Y, combined with sulfation, synergistically enhanced binding. Based on these findings, the newly designed WPHVC_V1 showed a ΔG of 37.24 kcal·mol-1 and, at 0.1 mg/ml, increased TT/APTT/PT from 41.72/14.38/15.86 s (WPHV_C) to 62.08/23.38/22.22 s. In in vivo studies, WPHVC_V1 achieved tail thrombus inhibition in the mouse tail by reducing the length of the thrombus from 3.562 cm in CK to 1.853 cm (1.729 cm for sodium heparin and 2.530 cm for WPHV_C), completely inhibited thrombus formation in a carotid artery model and reduced tail bleeding time by 35.2 s compared with heparin sodium. Safety evaluations revealed that WPHVC_V1 did not cause hemolysis, had no significant effect on blood pressure or cause pathological changes in major organs.
CONCLUSION: These findings provide an initial foundation and sequence reference for the development of safe and effective anticoagulant drugs with potential for clinical translation.

Keywords:  Anticoagulant activity; Direct thrombin inhibitors; Hirudin variant; Molecular dynamic; Tyrosine sulfation

DOI:  https://doi.org/10.1016/j.jare.2025.04.045
J Clin Endocrinol Metab. 2025 May 07. pii: dgaf262. [Epub ahead of print]

Endogenous sex steroid hormones, sex hormone binding globulin and risk of all-cause and cause-specific mortality: a systematic review and dose-response meta-analysis of prospective cohort studies.

Hamidreza Raeisi-Dehkordi, Mojgan Amiri, Sara Beigrezaei, Hugo G Quezada-Pinedo, Farnaz Khatami, Fadi Alijla, Marinka Steur, Beatrice Minder, Angeline Chatelan, Trudy Voortman, Yvonne T van der Schouw, Oscar H Franco, Taulant Muka.

   BACKGROUND: While abundant research suggests a sex-specific role of endogenous sex steroid hormones in chronic diseases, research on mortality remains inconclusive. We quantified the sex-specific associations of endogenous sex steroid hormones including total testosterone (TT), free testosterone, bioavailable testosterone, estradiol (E2), dehydroepiandrosterone, and dehydroepiandrosterone-sulphate and sex hormone binding globulin (SHBG) with risk of all-cause and cause-specific mortality in the general population.
METHODS: Embase, Medline, Web of Science, and Cochrane Central were searched and population-based cohort studies investigating the association of interested were included. The risk of bias was assessed using the ROBINS-E tool. The certainty of evidence was evaluated using GRADE framework. Pooled hazard ratios (HRs) and 95% confidence intervals (CI) were calculated using a random effects model for the top versus bottom tertile of sex hormones and risk of mortality.
RESULTS: 53 publications with 359,047 participants were included in the systematic review. A significant association was observed between higher level of TT and risk of all-cause mortality (HR (95%CI): 0.89 (0.83 to 0.97), n=19 studies) in men, while no association was found in women. Dose-response analysis suggested a significant U-shaped association between TT and all-cause mortality in men and a J-shaped association in women. Higher level of SHBG was significantly associated with higher risk of all-cause mortality in women (1.25 (1.13 to 1.39), n=3) and no association was observed in men. Additionally, higher DHEAs levels were associated with lower risk of all-cause mortality in men (0.72 (0.57 to 0.91), n=6) and no association was observed in women.
CONCLUSIONS: This meta-analysis reveals a dose-response link between endogenous sex steroid hormones and mortality, highlighting the need for sex-specific studies on hormone modulation's impact on mortality and longevity.
SOURCE OF FUNDING: None.
PROSPERO REGISTRATION CODE: CRD42022329605.

Keywords:  Androgens; Death; Estradiol; SHBG; Sex differences; Testosterone

DOI:  https://doi.org/10.1210/clinem/dgaf262