bims-supasi 2026-04-26 papers

bims-supasi

Biomed News

on Sulfation pathways and signalling

Issue of 2026–04–26
fourteen papers selected by
Jonathan Wolf Mueller, University of Birmingham

Enhanced Thermostability and Ligand Binding Affinity of an Improved Homo sapiens Chondroitin 6-O-Sulfotransferase for Chondroitin Sulfate C Synthesis by Deleting a Dynamic Surface Loop.
Heparan sulfate buffers the bone resorptive activity of cathepsin K in bone homeostasis.
Chondroitinase ABC enhances trastuzumab activity via cell-surface chondroitin sulfate cleavage in pancreatic cancer cells.
SARS-CoV-2 variant-specific enhancement of dendritic heparan sulfate mimetic antiviral activities.
Defining substrate specificities of N-acetylglucosamine-6-O-sulfotransferases for enzymatic modular assembly of sulfated O-glycans.
CSPG4 Mediates Inflammatory, Cell Death, and Senescence Responses in Enteric Glia Exposed to Clostridioides difficile Toxins.
Integrated physicochemical and therapeutic assessment of bovine hydroxyapatite-gelatin-vitamin D₃-chondroitin sulfate capsules in a rabbit osteochondral defect model with OA-like changes.
Association between high DHEAS in 7-year-old girls and metabolic features 4 years after menarche.
Adrenal Biomarkers of Stress in Transgender and Gender-Diverse Adolescents.
Association of Free Testosterone and DHEA-S with Dyslipidemia in Women with Polycystic Ovarian Syndrome- a case-control study.
A sulfated manno-glucuronan ameliorates β-cell dysfunction in type 2 diabetes by targeting ALDH1A3.
Structural characterization of a glycosaminoglycan sulfate from Sepia esculenta ink, and its apoptosis induction in MDA-MB-231 cells via miR-18a-5p/ORAI3 pathway mediated intracellular calcium overload.
The risk of acute thromboembolic cardiovascular events in association with use of chondroitin sulphate: A comparative, propensity score-matched cohort study using Swiss healthcare claims data.
Design, synthesis and biophysical evaluation of sialyl triazoles as glycomimetic ligands for Siglec-8. Sulfonate is a viable replacement for sulfate.

J Agric Food Chem. 2026 Apr 20.

Enhanced Thermostability and Ligand Binding Affinity of an Improved Homo sapiens Chondroitin 6-O-Sulfotransferase for Chondroitin Sulfate C Synthesis by Deleting a Dynamic Surface Loop.

Lu Wang, Jiajun Huang, Yuqing Wu, Jiayu Wang, Yangjin Yu, Qingtong Wu, Jinsong Zhao, Peng Jin.

  Chondroitin sulfate C (CSC), a 6-O-sulfated chondroitin sulfate, is widely used in osteoarthritis treatment. However, the soluble expression and catalytic efficiency of Homo sapiens chondroitin 6-O-sulfotransferase (HsC6ST), a key enzyme for CSC biosynthesis, remain limited. Here, soluble expression of HsC6ST in Escherichia coli BL21(DE3) was achieved by fusion with the trigger factor (TF). To further improve its performance, a dynamic surface loop was deleted to generate TF-HsC6ST-Δloop. The mutant exhibited enhanced thermostability, with the half-life increasing from 5.91 to 9.44 h and the melting temperature (Tm) increasing from 88 °C to 97 °C. In addition, its catalytic efficiency (kcat/Km) toward PAPS and chondroitin increased by 1.4-fold and 1.9-fold, respectively. Molecular simulation suggested stronger ligand binding, with ΔGbind decreasing from -24.47 kcal/mol to -40.1 kcal/mol. Consequently, the CSC conversion rate increased from 41.2% to 78.4%.

Keywords:  Chondroitin sulfate C; chondroitin 6-O-sulfotransferase; ligand binding; thermostability

DOI:  https://doi.org/10.1021/acs.jafc.6c01008
Matrix Biol. 2026 Apr 21. pii: S0945-053X(26)00051-X. [Epub ahead of print] 102009

Heparan sulfate buffers the bone resorptive activity of cathepsin K in bone homeostasis.

Yin Luo, Xiaoxiao Zhang, Huanmeng Hao, Zhangjie Wang, Jian Liu, Ding Xu.

  To understand the physiological significance of the interaction between Cathepsin-K (CtsK) and heparan sulfate (HS) in bone resorption, we manipulated HS-CtsK interaction genetically by mutating three basic residues of CtsK responsible for binding HS. This knockin strain (CtskAAA) expresses an HS-binding deficient CtsK variant. In contrast to CtsK-KO mice, which display profound osteopetrosis, under C57BL/6 background CtskAAA/AAA mice display an osteoporotic phenotype due to enhanced bone resorption by the mutant osteoclasts. This phenotype is consistent with our finding that HS inhibits the collagenase activity of CtsK, suggesting that HS functions as a restraining mechanism to dampen CtsK activity. Surprisingly, under 129S1 background, CtskAAA/AAA mice display increased bone mass due to reduced bone resorptive activity of the mutant osteoclasts, opposite to the phenotype found under C57BL/6 background. This phenotype appears to reflect another biochemical property of HS-CtsK interaction, where HS can stabilize CtsK and extend its half-life. Combined, our data provide strong genetic evidence that CtsK-HS interaction is required for normal osteoclast activity in bone homeostasis through two mechanisms. Endogenous HS likely functions as a buffering agent to prevent excessive resorption and promote sustained resorption, and the balance point of the buffering can be greatly affected by genetic backgrounds.

Keywords:  Protease; cathepsin; collagenase; mandible; osteoclasts

DOI:  https://doi.org/10.1016/j.matbio.2026.102009
Biochem Biophys Res Commun. 2026 Apr 15. pii: S0006-291X(26)00538-3. [Epub ahead of print]818 153774

Chondroitinase ABC enhances trastuzumab activity via cell-surface chondroitin sulfate cleavage in pancreatic cancer cells.

Masao Nakamura, Kazuki Sasaki.

  Pancreatic ductal adenocarcinoma (PDAC) has a glycan-rich microenvironment that hampers therapeutic antibody access to a cell-surface target antigen. The poor outcomes of a clinical trial involving enzymatic degradation of the hyaluronan suggest additional glycan-dependent resistance mechanisms. In this study, we investigated whether chondroitin sulfate (CS) proteoglycans (CSPGs) enriched in PDAC act as glycan decoy receptors that impair trastuzumab (Tmab) engagement with human epidermal growth factor receptor 2 (HER2). Using a monoclonal IgM antibody-based high-sensitivity immunoblot platform, we found that CS-A-bearing CSPGs were more abundant in PDAC-derived cell lines and tissues than in their normal counterparts. Chondroitinase ABC (ChABC) cleaved the CS-A chains attached to CSPG core proteins, a major component of which turned out to be CD44, a HER2-masking receptor implicated in reduced Tmab binding. CS-A directly bound to Tmab and dose-dependently inhibited the antibody binding to HER2. Furthermore, CS-A, a CS subtype enriched in PDAC cells, but not CS-C, stabilized the higher-temperature transition of Tmab, consistent with interactions at the Fab and/or Fc-CH3 domains. In HER2-expressing Capan-1 cells, ChABC and Tmab cooperated to inhibit migration under conditions in which each agent alone had little effect, and ChABC pretreatment increased intracellular Tmab uptake. These findings support a model in which CS-A-bearing CSPGs on the surface of PDAC cells sequester Tmab and limit its productive engagement with HER2. Thus, enzymatic CS cleavage emerges as a glycan-editing strategy to potentiate Tmab activity in CS-A-rich tumors.

Keywords:  Antibody activity; Chondroitin sulfate A; Chondroitinase ABC; Pancreatic ductal adenocarcinoma; Trastuzumab

DOI:  https://doi.org/10.1016/j.bbrc.2026.153774
Virology. 2026 Apr 15. pii: S0042-6822(26)00130-3. [Epub ahead of print]620 110915

SARS-CoV-2 variant-specific enhancement of dendritic heparan sulfate mimetic antiviral activities.

Blake Sullivan-Hill, Shabihah Shahrudin, Caroline L Ashley, Nicholas J Shields, Sam Spijkers-Shaw, Ye Li, Rory Devlin, Phillip M Rendle, Carol Wang, Megan Steain, Olga V Zubkova, John A Taylor, Natalie E Netzler.

  SARS-CoV-2 continues to impose a substantial burden to healthcare systems, economies, and communities. While several antivirals are approved for COVID-19 treatment, their use is limited by contraindications and uptake, and vaccines provide only partial and waning protection against infection. Therefore, additional antivirals are urgently needed to combat SARS-CoV-2. This study evaluated dendritic heparan sulfate (HS) mimetics as antivirals using pseudoviruses and wildtype SARS-CoV-2 spanning different lineages. Using immunofluorescence and plaque reduction assays, we identified HS mimetics that potently inhibited the Omicron BA.1 variant (IC50 values 0.74 - 15.26 μM) with no impacts on cell viability up to 200 μM. One mimetic, Tet-ST-12 demonstrated nanomolar inhibition of the Omicron BA.1 subvariant, however all test compounds had reduced antiviral efficacy against ancestral variants of SARS-CoV-2 (Wuhan D614G, Mu and Delta, IC50 values > 100 μM). These findings highlighted the variant-specific differences in HS mimetics' binding affinities and showcase their potential for development as antivirals against SARS-CoV-2. Furthermore, an examination of the direct-acting antiviral nirmatrelvir in combination with Tet-ST-12 revealed strong synergy (Bliss score >20), enabling significant dose reductions to achieve similar inhibition of Omicron BA.1 infectivity, while raising the barrier to the evolution of antiviral resistance. This study demonstrates the potential for the dendritic HS mimetics as antiviral candidates against SARS-CoV-2 and its evolving variants.

Keywords:  Antivirals; Heparan sulfate mimetics; Heparin; Nirmatrelvir; SARS-CoV-2 evolution; Synergy

DOI:  https://doi.org/10.1016/j.virol.2026.110915
Org Chem Front. 2026 Apr 13.

Defining substrate specificities of N-acetylglucosamine-6-O-sulfotransferases for enzymatic modular assembly of sulfated O-glycans.

Shuquan Fan, Jinghua Han, Tangliang Shen, MohammadHossein Shabahang, Zhenming Du, Jun Pan, Guitao Bai, Shumin Bao, Avinash Ittuveetil, Lei Li.

Sulfated O-glycans are widely distributed and play key roles in a wide range of physiological and disease processes, yet their synthesis remains challenging due to difficulties in regioselective sulfation. Here, we systematically characterized two human GlcNAc-6-O-sulfotransferases, CHST2 and CHST6, revealing their strong preference towards O-glycans (including O-GalNAc and O-mannosyl glycans) over N-glycans and poly-LacNAc chains. Both enzymes favored β1-6 branched GlcNAc residues, with CHST6 showing higher activity and broader substrate tolerance than CHST2. Guided by these insights, we established a modular enzymatic assembly platform for efficient synthesis of 32 well-defined sulfated O-GalNAc, O-mannosyl glycans, and O-glycopeptides. This streamlined strategy enables versatile access to sulfated O-glycans and provides a general route for constructing other classes of sulfated glycans.

DOI: https://doi.org/10.1039/d6qo00226a
FASEB J. 2026 Apr 30. 40(8): e71806

CSPG4 Mediates Inflammatory, Cell Death, and Senescence Responses in Enteric Glia Exposed to Clostridioides difficile Toxins.

Francisco M S Marques, Deiziane V S Costa, Conceição S M Rebouças, Gerly A C Brito, Cirle A Warren, Renata F C Leitão.

  Clostridioides difficile infection (CDI) is a persistent public health problem worldwide. C. difficile toxins A (TcdA) and B (TcdB) can affect enteric glial cells, an important component of the enteric nervous system. Here, we aimed to identify the profile of C. difficile toxin receptors expressed by enteric glia and investigate the contribution of the chondroitin sulfate proteoglycan receptors (CSPG4) in mediating inflammatory response, cell death, and senescence in enteric glia exposed to TcdA or TcdB. We found that human, mouse, and rat enteric glia express all of the previously recognized C. difficile toxin receptors. However, in vitro, C. difficile toxins significantly increased CSPG4 expression in enteric glia. In vivo, CDI also increased CSPG4 expression in colonic and cecal tissues. Blockage of CSPG4 significantly decreased IL-6 and S100B gene expression, as well as reduced the nuclear translocation of NFκB and STAT3 in enteric glia exposed to TcdB, but not TcdA. Interestingly, blockade of CSPG4 also decreased senescence-associated beta-galactosidase (SA-β-galactosidase) activity and other senescence markers (γH2AX, p16 and p21) in enteric glia exposed to TcdA or TcdB. However, CSPG4 blockade reduced cell death promoted by TcdA, but not TcdB. Taken together, these findings show that enteric glia, by expressing all known C. difficile toxin receptors, can respond directly to TcdA or TcdB. However, CSPG4 seems to play an important role in cell death and inflammatory response promoted by TcdA and TcdB, respectively, as well as senescence induced by both toxins.

Keywords:   Clostridioides difficile ; cell death; chondroitin sulfate proteoglycan; enteric glia; senescence

DOI:  https://doi.org/10.1096/fj.202600333R
Sci Rep. 2026 Apr 21.

Integrated physicochemical and therapeutic assessment of bovine hydroxyapatite-gelatin-vitamin D₃-chondroitin sulfate capsules in a rabbit osteochondral defect model with OA-like changes.

Fani Deapsari, Yusuf Alif Pratama, Hazna Mariskha Afra, Adisti Ratna Sari, Hanni Prihhastuti Puspitasari, Aniek Setiya Budiatin.

  Osteoarthritis (OA) is a degenerative joint disease marked by cartilage degradation and subchondral bone remodeling, while most nutraceuticals focus on cartilage and overlook bone health. We developed a capsule containing bovine hydroxyapatite (BHA), gelatin, vitamin D₃, and chondroitin sulfate and evaluated its physicochemical quality and in vivo effectiveness. Formulations were tested for organoleptic properties, moisture, weight uniformity, disintegration time, microbial contamination, heavy metals, and active-ingredient identification in accordance with Indonesian Food and Drug Agency regulations; all specifications were met. Efficacy was assessed in a rabbit osteochondral defect model (post-traumatic degeneration/repair model) with negative control, positive control, and test groups treated for 28 days, followed by radiography, histology (H&E quantification of osteoblasts, osteoclasts, osteocytes, and chondrocytes), and immunohistochemistry (type II collagen and MMP-13). Compared with untreated controls, the test group showed improved cartilage architecture, higher osteoblast, osteocyte, and chondrocyte counts, fewer osteoclasts, increased type II collagen expression, and reduced MMP-13, with outcomes comparable or superior to the positive control. These findings indicate the formulated nutraceutical supports both cartilage and subchondral bone and may serve as a complementary strategy for OA management, warranting confirmation in longer, dose-responsive, and translational studies.

Keywords:  Bone diseases; Bone regeneration; Bovine Hydroxyapatite, Subchondral Bone; Chronic osteoarthritis; Drug delivery

DOI:  https://doi.org/10.1038/s41598-026-49088-9
J Endocr Soc. 2026 May;10(5): bvaf211

Association between high DHEAS in 7-year-old girls and metabolic features 4 years after menarche.

Ana Pereira, Gordon B Cutler, German Iñiguez, Verónica Mericq.

   Background: Premature adrenarche is linked to increased adiposity, enhanced adrenal 11-oxygenated C19 androgen production, and adverse metabolic profiles in childhood. However, it remains unclear whether early elevations in dehydroepiandrosterone sulfate (DHEAS) predict metabolic dysfunction in adolescence or young adulthood.
Methods: This longitudinal study included girls from the Growth and Obesity Chilean Cohort Study, all with normal birth weight. DHEAS was measured at ∼7 years (n = 504, 68% follow-up), and participants were reevaluated 4 years after menarche (4YPM, ∼16 years). Girls were classified as having high DHEAS (HD; >75th percentile) or normal DHEAS (ND; ≤75th percentile). Anthropometric, metabolic, and hormonal parameters, including 11-oxygenated C19 steroids, were compared between groups.
Results: At 4YPM, HD girls (n = 96) showed higher body mass index SD score (P < .01), waist-to-height and waist-to-hip ratios (P < .05), and 47% higher mean DHEAS levels (P < .001) than ND girls (n = 249). No differences were observed in glucose, insulin, homeostatic model assessment for insulin resistance, lipid profile, testosterone, SHBG, free androgen index, or 11-oxosteroid concentrations. HD girls exhibited slightly higher mean blood pressure but no increased prevalence of metabolic syndrome in crude or adjusted models (adjusted for birth weight SD score, age at menarche, and body mass index at ∼7 years). Among HD girls, DHEAS at 7 years was not correlated with 11-oxosteroids at 4YPM. Serum 11KA4 was inversely associated with glucose after adjustment (β -.02; 95% CI, -0.04 to -0.006).
Conclusion: Elevated DHEAS at adrenarche persists after puberty without higher bioactive 11-oxosteroids or significant metabolic deterioration, suggesting attenuation of early adverse metabolic features by mid-adolescence.

Keywords:  11 oxo steroids; DHEAS; adrenarche; metabolic syndrome; metabolism; obesity

DOI:  https://doi.org/10.1210/jendso/bvaf211
Dev Psychobiol. 2026 May;68(3): e70156

Adrenal Biomarkers of Stress in Transgender and Gender-Diverse Adolescents.

Simone Coslovich, Stefania Tonetto, Giulia Bragato, Gianluca Tamaro, Alice Fachin, Paolo Dalena, Lorenzo Zandonà, Antonella Fabretto, Egidio Barbi, Gianluca Tornese.

  Transgender and gender diverse (TGD) adolescents are frequently exposed to minority stress, which may influence the hypothalamic-pituitary-adrenal (HPA) axis during critical developmental windows. Altered cortisol dynamics have been described in populations facing chronic stress, yet evidence in TGD youth is limited. Understanding adrenal function in this context is essential for clarifying potential biological pathways linking social stressors to developmental and health outcomes. In the present study, identifying as TGD serves as an indirect proxy of exposure to minority stressors, which were not directly measured. We conducted a retrospective, case-control study at a tertiary pediatric center, including 48 TGD adolescents and 298 controls referred for evaluation of premature pubarche with nonclassical congenital adrenal hyperplasia excluded. All participants underwent a standard dose synacthen test (SDST; 250 µg tetracosactide iv, sampling at baseline and 60 min, 8:00 a.m.), which assesses adrenal responsiveness to pharmacological ACTH stimulation. Serum cortisol, DHEAS, ACTH, and 17-hydroxyprogesterone were assayed. Statistical analyses included nonparametric group comparisons, correlations, and multivariable regression adjusting for age and sex assigned at birth. TGD individuals demonstrated significantly higher baseline cortisol levels (293 vs. 214 nmol/L; p < 0.001) and a reduced cortisol response to SDST (Δcortisol: 354 vs. 446 nmol/L; p < 0.001). In the full sample, basal DHEAS levels were higher in TGD youth (231 vs. 142 nmol/L; p = 0.362), whereas the DHEAS-to-cortisol ratio did not differ significantly between groups. In an age-matched subsample (1:2 matching), the DHEAS-to-cortisol ratio was significantly lower in TGD adolescents (0.72 vs. 1.03; p = 0.004). Multivariate analysis confirmed an independent association between TGD status and higher basal cortisol, lower Δcortisol, and a reduced DHEAS-to-cortisol ratio after adjustment for covariates (all p < 0.001). Our findings provide preliminary evidence of altered adrenal responsiveness in TGD adolescents, potentially reflecting the biological embedding of minority stress during development. Although exploratory, these results highlight the need for prospective, longitudinal studies integrating psychosocial and neuroendocrine measures to clarify mechanisms linking stress, HPA axis function, and developmental outcomes in gender-diverse youth.

Keywords:  adolescent; adrenal; gender dysphoria; gender incongruence ; stress; transgender and gender diverse

DOI:  https://doi.org/10.1002/dev.70156
EJIFCC. 2026 Mar;37(2): 211-218

Association of Free Testosterone and DHEA-S with Dyslipidemia in Women with Polycystic Ovarian Syndrome- a case-control study.

K Lavanya, N Palaniappan, Santhi Silambanan, V M Vinodhini, Mahesh Kumar.

Background: Polycystic ovarian syndrome (PCOS) is a multisystem disorder presenting with menstrual irregularities, infertility, and features of hyperandrogenism. Hyperandrogenism predisposes to the critical clinical features of PCOS. This find aimed to study the association of androgenic hormones such as dehydroepiandrosterone sulfate (DHEA-S) and free testosterone with lipid profile in PCOS women.
Methods: This case-control study was conducted in the Department of Biochemistry at a tertiary care hospital in Chennai. Patients were recruited from the Department of Obstetrics and Gynecology. Participants were aged 18-40 years. Blood samples were collected for analysis of lipid profile, DHEA-S, and free testosterone. DHEA-S and free testosterone were analyzed by ELISA. Ethics approval and written informed consent were obtained. Based on the distribution of the data, appropriate statistical tools were used. P-value ≤ 0.05 was considered statistically significant.
Results: Most of the participants were aged between 21 and 30 years. HDL-c was decreased in PCOS patients compared to healthy individuals; however, no statistically significant difference was found. Free testosterone showed an association with triglyceride. The areas under the curves of DHEA-S and free testosterone were 0.638 and 0.765, respectively.
Conclusion: DHEA-S and free testosterone showed good area under the curves. But free testosterone performed better with a higher area under the curve as well as its association with triglyceride. The cut-off values to diagnose PCOS were 3.0 μg/mL and 2.5 pg/mL for DHEA-S and free testosterone, respectively, with adequate sensitivity and specificity. Since free testosterone performed better in ROC curve than DHEA-S, free testosterone is considered to be a potential biomarker of identifying hyperandrogenism in PCOS women.

Keywords: DHEA-S; PCOS; androgen; dyslipidemia; free testosterone; infertility; insulin resistance
Carbohydr Polym. 2026 Jun 15. pii: S0144-8617(26)00344-9. [Epub ahead of print]382 125227

A sulfated manno-glucuronan ameliorates β-cell dysfunction in type 2 diabetes by targeting ALDH1A3.

Wenjing Zhang, Fuming Zhang, Xiaoting Zou, Nan Wu, Sunyue He, Lusi Lu, Chunyi Xu, Weiying Xu, Weihua Jin, Jiaqiang Zhou.

  Impairment of pancreatic β-cell function is a primary etiology of type 2 diabetes mellitus (T2DM). The sulfated manno-glucuronan (GMn) was found to possess a backbone structure consisting of interspersing 1, 3-linked β-D-GlcpA residues and alternating 1, 2-linked α-D-Manp residues and 1, 4-linked β-D-GlcpA residues. Additionally, random sulfation occurs at the C6 position of the Man residues. GMn demonstrated no detectable cytotoxicity in MIN6 cells and attenuated palmitic acid (PA)-induced decreases in cell viability in a dose-dependent manner. Furthermore, GMn effectively reversed PA-impaired glucose-stimulated insulin secretion (GSIS) in a dose-dependent manner in both MIN6 cells and primary mouse islets. In vivo, GMn treatment significantly attenuated glycemic levels in high-fat diet/streptozotocin-induced type 2 diabetic mice, elevated β-cell insulin content, and decreased the proportions of α-, δ-, and pancreatic polypeptide (PP)-cells. Mechanistically, GMn significantly suppressed aldehyde dehydrogenase 1A3 (ALDH1A3)-mediated retinol metabolism and increased the expression of key β-cell identity/function markers, including PDX1, NKX6.1, MAFA, and NeuroD1, in pancreatic islets. Consistently, in vitro studies demonstrated that GMn counteracted PA-induced upregulation of ALDH1A3, while promoting the expression of the same set of β-cell transcription factors. Collectively, these findings indicate that GMn may enhance β-cell proliferation and reduces β-cell differentiation by downregulating ALDH1A3 expression.

Keywords:  ALDH1A3; Differentiation; Pancreatic β-cell; Sulfated manno-glucuronan; Type 2 diabetes

DOI:  https://doi.org/10.1016/j.carbpol.2026.125227
Int J Biol Macromol. 2026 Apr 17. pii: S0141-8130(26)02029-5. [Epub ahead of print] 152103

Structural characterization of a glycosaminoglycan sulfate from Sepia esculenta ink, and its apoptosis induction in MDA-MB-231 cells via miR-18a-5p/ORAI3 pathway mediated intracellular calcium overload.

Jiayi Wu, Xiaomei Yang, Wei Xiao, Zhen Lin, Ping Luo, Yipeng Gu, Huazhong Liu.

  Based on our previous findings regarding anti-TNBC activity of SIP4, this study aims to further explore the antitumor mechanisms of the marine polysaccharide. Firstly, this study simplified the preparation methods of SIP4 based on our report, and identified the polysaccharide as a polymer of the repeating units of 5 sugars, -4GalpNAc1-2GlcAp1-4(GalpNAc1-4GlcpNAc1-3)Fucp1- that consists of trisaccharide backbone, a disaccharide branch and an unlocated sulfate ester group. SIP4 induced overexpression of ORAI3 and excessive calcium ion accumulation in MDA-MB-231 cells, and resulted in apoptosis. Exposure of miR-18a mimic promoted overexpression of ORAI3, augmentation of calcium ion content, and consequent apoptosis in MDA-MB-231 cells, although miR-18a inhibitor did not change the indicators. Moreover, combination of SIP4 and miR-18a significantly enhanced the promotion of ORAI3 expression, calcium concentration and apoptosis in the TNBC cells. But the blockage using inhibitor of miR-18a markedly decreased the enhancement by SIP4. Comprehensively, SIP4 mediated apoptosis in MDA-MB-231 cells via activating miR-18a/ORAI3 pathway to induce intracellular calcium overload is an important anti-TNBC mechanism.

Keywords:  Apoptosis; MDA-MB-231 cells; SIP4; miR-18a-5p/ORAI3

DOI:  https://doi.org/10.1016/j.ijbiomac.2026.152103
Osteoarthr Cartil Open. 2026 Jun;8(2): 100791

The risk of acute thromboembolic cardiovascular events in association with use of chondroitin sulphate: A comparative, propensity score-matched cohort study using Swiss healthcare claims data.

Tamino Zappalà, Theresa Burkard, Carola A Huber, Christoph R Meier, Julia Spoendlin.

   Objective: We aimed to evaluate the risk of acute thromboembolic cardiovascular events in new chondroitin (sulphate) users compared to new users of intraarticular (IA) steroids in a propensity score (PS)-matched cohort study.
Method: Using Swiss healthcare claims data (2013-2022, study period), we identified new users of chondroitin and IA steroids aged 40-99 years. Primary outcome was an inpatient-diagnosed myocardial infarction, ischemic stroke, or transient ischemic attack. The secondary outcome additionally included all-cause mortality. After PS matching, we calculated incidence rates (IRs) and estimated hazard ratios (HRs) with 95% confidence intervals (CIs). In a sensitivity analysis, we restricted to patients with imaging of the hip/knee and a claim for NSAIDs within 365 days before cohort entry to increase likelihood of them having osteoarthritis (OA).
Results: After matching, we included 36,659 chondroitin users and 37,501 IA steroid users. Matched IRs for the primary outcome were 9.6 for chondroitin and 11.9/1000 py for IA steroids, yielding a matched (m)HR of 0.81 (95% CI 0.69-0.95). The sensitivity analysis yielded a mHR of 0.79 (95% CI 0.56-1.11). IRs for the secondary outcome were 18.9 and 29.2/1000 py for chondroitin and IA steroid users, resulting in a mHR of 0.67 (95% CI 0.60-0.75).
Conclusion: Chondroitin use was associated with a slightly lower risk of cardiovascular events compared to IA steroid use. However, residual confounding by patient frailty may explain the finding to some degree, given the excess mortality in the comparison group. Further research is needed to corroborate or refute a potential cardioprotective effect of chondroitin.

Keywords:  Cardiovascular events; Chondroitin sulphate; Drug safety study; Healthcare claims data

DOI:  https://doi.org/10.1016/j.ocarto.2026.100791
Eur J Med Chem. 2026 Apr 02. pii: S0223-5234(26)00235-7. [Epub ahead of print]312 118790

Design, synthesis and biophysical evaluation of sialyl triazoles as glycomimetic ligands for Siglec-8. Sulfonate is a viable replacement for sulfate.

Kishan Mandal, Tobias Mühlethaler, Maria Pia Lenza, Alessia Stornaiuolo, Xiaohua Jiang, Alba Silipo, Beat Ernst, Paul V Murphy.

Ligand design and synthesis for Siglec-8 is important due to its roles in immune responses to allergens, chronic inflammatory disorders and malignancies. Here the synthesis, from readily accessible intermediates, of glycomimetics of Neu5Acα2-3 (6-O-sulfo-Gal), the minimal glycan ligand for Siglec-8, is reported. The mimetics retain Neu5Ac, while replacing the 6-O-sulfo-Gal component by a triazole containing linker presenting either carboxylate or sulfonate groups. Isothermal calorimetry (ITC) measurements showed that the sialyl triazole derivatives were ligands for Siglec-8, with a Kd of 45.5 μM established for the best ligand from the series. The ITC measurements showed that sulfonate was better than carboxylate as a replacement for sulfate, while the incorporation of the naphthylsulfonate group at the Neu5Ac C-9 of the ligands gave affinity improvement, consistent with earlier research. An NMR based binding study supports the conformational change to Siglec-8 to accommodate the 9-naphthylsulfonate group and indicates a similar mode of binding for the highest affinity triazole derivative to previously reported cyclohexane based glycomimetics. The perturbation of NMR signals, docking and binding pose metadynamics support binding of the ligand to the carbohydrate recognition domain. The research provides new Siglec-8 ligands from readily accessible intermediates as a basis for further development.

DOI: https://doi.org/10.1016/j.ejmech.2026.118790