bims-supasi 2026-09-06 papers

bims-supasi

Biomed News

on Sulfation pathways and signalling

Issue of 2026–09–06
fifteen papers selected by
Jonathan Wolf Mueller, University of Birmingham

Synthetic Heparan Sulfate-like Oligosaccharides as Tools to Decipher Growth Factor Recognition.
Chondroitin sulfate degradation bolsters Proteus mirabilis growth and colonization of the catheterized urinary tract.
Investigation of the Substrate Specificities of Dermatan Sulfate Epimerase 1 (DS-epi1) and 4-O-sulfotransferase (DS 4-OST) Using Synthetic Oligosaccharide Substrates.
Heparan Sulfate Proteoglycans: Master Regulators of Cellular Signaling, Tissue Development, and Neural Function.
Biomimetic HDL nanoparticles functionalized with bromelain and chondroitin sulfate for enhanced penetration and targeted therapy of liver fibrosis.
Depolymerized fucoidan derivatives anti-migratory activity, driven by structure-controlled uptake, overrides heparanase in breast cancer cells.
Engineered matrices reveal sulfation-mediated stress adaptation and drug-specific modulation of chemotherapeutic response.
Adrenal androgen mediates the association between obesity and accelerated skeletal maturation in children and adolescents.
Antioxidant status and dehydroepiandrosterone sulfate in aging: Evidence from MIDUS 3 biomarkers cohort.
Targeting the heparan sulfate proteoglycan/heparanase axis as a novel therapeutic strategy to drive adipogenesis and block tumor growth of dedifferentiated liposarcoma.
Adrenal androgens, estrone, and insulin-like growth factor 1 are associated with thelarche without gonadotropin activation in girls.
Precision chemoenzymatic tailoring of bioengineered low-molecular-weight heparins for protamine-reversible anticoagulation.
Glycocalyx degradation is associated with increased circulating unmeasured ions after cardiopulmonary bypass.
TPST Gene Knock-Out Eliminates Tyrosine Sulfation on a Recombinant Antibody Produced in CHO Cells.
Associations Between Renal Function, Uremic Toxins, and Cognitive Performance in Patients with Chronic Kidney Disease: A Pilot Study.

J Med Chem. 2026 Aug 20.

Synthetic Heparan Sulfate-like Oligosaccharides as Tools to Decipher Growth Factor Recognition.

Joseph Wakpal, Kartikey Singh, Michael Hotor, Livia Philip, Dylan Yost-Slinker, Junzhe Wang, Hawau Abdulsalam, Hien M Nguyen.

Heparan sulfate proteoglycans (HSPGs) facilitate interactions between growth factors and their receptors, regulating signaling pathways involved in angiogenesis and cell proliferation. However, the structural heterogeneity and synthetic inaccessibility of native heparan sulfate (HS) have limited systematic exploration of structure-activity relationships (SAR) and the discovery of HS-based inhibitors. Here, we developed 46 aminoglycoside-derived non-native HS mimetics spanning diverse structural and functional group patterns. SAR analysis identified N-acetylation and 6-O-sulfation as key determinants of HS-FGF2 and HS-VEGF165 interaction modulation. Compound 8, synthesized in two steps, competitively disrupted heparin binding to FGF2 (IC50 = 0.23 μM), FGFR1 (IC50 = 0.17 μM), and VEGF165 (IC50 = 0.66 μM), with >140-fold FGF2/FGF4 selectivity and substantially greater potency than native HS pentasaccharide fondaparinux. In NIH3T3 fibroblasts, compound 8 selectively reduced FGF2-induced proliferation in a dose-dependent manner without measurable cytotoxicity, highlighting aminoglycoside-derived HS mimetics as synthetically accessible platforms for modulating growth factor signaling.

DOI: https://doi.org/10.1021/acs.jmedchem.6c00760
Infect Immun. 2026 Sep 01. e0022326

Chondroitin sulfate degradation bolsters Proteus mirabilis growth and colonization of the catheterized urinary tract.

Benjamin C Hunt, Vitus Brix, Namrata Deka, Brian S Learman, Aimee L Brauer, Brianna M Shipman, Nicole J De Nisco, Chelsie E Armbruster.

  Glycosaminoglycans (GAGs) are negatively charged polysaccharides composed of repeating disaccharide units and are essential components of the extracellular matrix throughout numerous tissues. The bladder urothelium has a protective GAG layer that primarily consists of chondroitin sulfate (CS), heparan sulfate (HS), and hyaluronic acid (HA), and urinary tract pathogens must either degrade or otherwise circumvent this layer to infect the urothelium. In this study, we investigated GAG degradation by Proteus mirabilis, a common and persistent colonizer of the catheterized urinary tract. Almost all P. mirabilis urinary tract isolates harbor a putative chondroitin endolyase (PMI2127), exolyase (PMI2128), and sulfatase (PMI2124). By generating mutant and complemented strains of these genes, we determined that P. mirabilis strain HI4320 degrades multiple forms of CS under numerous culture conditions, including during growth in human urine, and can use CS degradation products as a carbon source. Sulfatase and endolyase activities were required for efficient degradation of all CS types, while the exolyase only contributed to using CS-B or CS-C as a carbon source. Interestingly, only endolyase activity contributed to colonization in a murine model of catheter-associated urinary tract infection (CAUTI), although the colonization defect was even more pronounced when both the endolyase and exolyase were disrupted. The colonization defect was specific to the CAUTI model, likely due to the impact of catheterization on the GAG landscape of the bladder. Limiting CS degradation by P. mirabilis may therefore reduce the risk of ascending infection in catheterized patients.

Keywords:  Proteus mirabilis; catheter; glycosaminoglycan; urinary tract infection

DOI:  https://doi.org/10.1128/iai.00223-26
ACS Chem Biol. 2026 Aug 31.

Investigation of the Substrate Specificities of Dermatan Sulfate Epimerase 1 (DS-epi1) and 4-O-sulfotransferase (DS 4-OST) Using Synthetic Oligosaccharide Substrates.

Yongmei Xu, Yi-Chi Wang, Eduardo Stancanelli, Haoran Wang, Jianxiang Zhang, Emil Tykesson, Anders Malmström, Jian Liu.

  Dermatan sulfate epimerase 1 (DS-epi1, DSE) and dermatan sulfate 4-O-sulfotransferase (DS 4-OST, CHST14) are critical enzymes involved in the biosynthesis of dermatan sulfate. In this study, structurally homogeneous chondroitin oligosaccharide substrates were used to investigate the substrate specificity of each individual enzyme, as well as their combined actions. The structures of the enzyme-modified oligosaccharides were confirmed by high-resolution mass spectrometry (MS) and NMR or determined by LC-MS-based sequencing analysis. Our results demonstrate that DS-epi1 catalyzes the reversible conversion between glucuronic acid (GlcA) and iduronic acid (IdoA), with GlcA being the predominant product once the reaction reaches equilibrium. DS 4-OST selectively sulfates the 4-hydroxyl group of N-acetylgalactosamine (GalNAc) residues that are linked to the reducing end of an IdoA unit (-IdoA-GalNAc-). Furthermore, DS-epi1 and DS 4-OST act in a concerted and ordered manner to generate clustered -IdoA-GalNAc4S- domains. During the reaction, the enzyme mixture initiates modifications at the non-reducing end of the saccharide chain and proceeds toward the reducing end consecutively. These findings provide new insights into the regulatory mechanisms governing dermatan sulfate biosynthesis and demonstrate the feasibility of synthesizing structurally defined dermatan sulfate oligosaccharides.

Keywords:  biosynthesis of dermatan sulfate; biosynthesis of iduronic acid; dermatan 4-O-sulfotransferase; dermatan sulfate epimerase 1; enzymatic synthesis of N-acetylgalactosamine 4-O-sulfate; enzymatic synthesis of dermatan sulfate; glycosaminoglycans

DOI:  https://doi.org/10.1021/acschembio.6c00533
J Neurosci Res. 2026 Sep;104(9): e70151

Heparan Sulfate Proteoglycans: Master Regulators of Cellular Signaling, Tissue Development, and Neural Function.

James Melrose.

This narrative review examines the essential roles of heparan sulfate proteoglycans (HSPGs) in brain development, synaptic function, axonal guidance, synapse formation and stabilization, and the establishment of correctly interconnected neural networks. Distinct HSPG profiles help shape precise neural circuits, whereas HSPG dysregulation is associated with impaired neurodevelopmental processes, cognitive decline, and pathological changes in brain tissues. These findings emphasize the importance of HSPGs in normal brain function and in disease-associated tissue dysfunction. HSPGs are a diverse group of proteins with critical roles in the CNS and PNS, including synaptic function, neurodevelopment, neurodegeneration, cell migration, and regulation of neuroprogenitor stem cell niches in the subventricular ependymal zone and subgranular dentate gyrus. Together, the diverse functions of HSPGs place them as master regulators of tissue form and function in health and disease.

DOI: https://doi.org/10.1002/jnr.70151
Int J Biol Macromol. 2026 Sep 02. pii: S0141-8130(26)04283-2. [Epub ahead of print] 154337

Biomimetic HDL nanoparticles functionalized with bromelain and chondroitin sulfate for enhanced penetration and targeted therapy of liver fibrosis.

Yuxin Zhao, Kai Liu, Long Xie, Jia Luo, Huan Gu, Xiaofang Li.

  Activated hepatic stellate cells (aHSCs) play a central role in liver fibrosis by promoting excessive extracellular matrix (ECM) deposition, while oxidative products in fibrotic livers perpetuate their activation. The treatment of liver fibrosis remains challenging because the ECM barrier limits drug uptake by aHSCs. To overcome this challenge, we developed high-density lipoprotein (HDL) nanoparticles loaded with silybin (SIL), and modified them with chondroitin sulfate (CS) and bromelain (BRO). The resulting formulation, denoted as BRO/CS-SIL@HDL nanoparticles (BCSH), was designed to enhance hepatic enrichment, facilitate penetration through the collagen-rich ECM, and enable CD44 receptor-mediated targeting. BCSH showed efficient internalization even in the presence of a collagen barrier. BCSH treatment markedly reduced inflammation, oxidative stress, collagen deposition, and HSC activation. Then RNA seq was further performed to explore the potential molecular mechanisms underlying the therapeutic effects of the nanoparticles, revealing alterations in multiple signaling pathways and biological processes related to liver fibrosis. In conclusion, these results suggest that BCSH represents a promising therapeutic strategy for liver fibrosis.

Keywords:  Hepatic stellate cells; High-density lipoprotein; Liver fibrosis

DOI:  https://doi.org/10.1016/j.ijbiomac.2026.154337
Biomed Pharmacother. 2026 Sep 04. pii: S0753-3322(26)00931-5. [Epub ahead of print]203 119895

Depolymerized fucoidan derivatives anti-migratory activity, driven by structure-controlled uptake, overrides heparanase in breast cancer cells.

C Manseur, J Saliba, R Mersni-Achour, F Le Joubioux, M Porta Zapata, B Musnier, El Yazidi-Belkoura, B Colin, R Havret, P-E Bodet, C Dabbadie, J Cherfan, S Ali-Moussa, N Bridiau, D Le Cerf, T Varacavoudin, T Maugard, I Fruitier-Arnaudin, H Groult.

  Depolymerized Fucoidan derivatives (DFd) are emerging anticancer agents, yet their relationship with heparanase (HPSE) remains unclear. H2O2-assisted depolymerization of native fucoidan (Fucus vesiculosus) generates DFd characterized by reduced number- and weight-average molecular masses (Mn and Mw) and degree of sulfation (DS) with oxidative structural modifications, resulting in heterogeneous yet bioactive compounds with reduced anticoagulant activity compared to the native fucoidan. Their inhibitory effect on HPSE in vitro was associated with both Mn and DS, although no dominant factor was identified. Biologically, DFd decreased mitochondrial metabolic activity and migration in breast cancer models according to Mn and DS reductions, with differential responses between MCF7 and MDA-MB-231 cells. Despite minor cell line-specific changes in HPSE expression, heparan sulfate (HS) levels remained unchanged, suggesting that these effects are not driven by altered HPSE expression or extracellular matrix degradation. This study provides a key original contribution by tracking DFd cellular internalization for the first time in these cell lines, revealing a dependence on Mn/DS and a correlation with the observed migration inhibition for the MCF7 cells treated with the smallest DFd. These findings highlight cellular uptake as a critical determinant of fucoidan bioactivity and open new perspectives for understanding and optimizing their anticancer mechanisms.

Keywords:  Breast cancer; Depolymerization; Fucoidan derivatives; Heparanase; Modulation

DOI:  https://doi.org/10.1016/j.biopha.2026.119895
Biomater Sci. 2026 Sep 01.

Engineered matrices reveal sulfation-mediated stress adaptation and drug-specific modulation of chemotherapeutic response.

Sevgi Sarıca, Ece Öztürk.

Engineering biomimetic extracellular matrices that isolate specific biochemical cues is essential for understanding how matrix chemistry regulates tumor cell behavior and therapeutic response. Aberrant sulfation due to proteoglycan expression is a hallmark of lung tumor matrices, yet its functional impact is difficult to study using conventional materials where mechanical and biochemical variables are coupled. To address this, mechanically matched sulfated alginate hydrogels are engineered to mimic the elevated sulfated glycosaminoglycan (sGAG) content of malignant ECM, enabling sulfation to be examined as a single, tunable variable. Within this system, ECM sulfation is shown to enhance tumor cell proliferation, promote oxidative and mitochondrial stress tolerance, suppress apoptotic signaling and attenuate the efficacy of cisplatin, gemcitabine and paclitaxel. Sulfated matrices preserve mitochondrial membrane potential, limit ROS accumulation, shift apoptotic gene expression toward a survival-favoring profile, selectively upregulate ABCB1-mediated efflux and modulate drug response through the PI3K/Akt-ABCB1 signaling axis. Functional inhibition of PI3K and ABCB1 uncovers drug-specific dependencies, while dual pathway targeting completely restores chemotherapeutic sensitivity. These findings identify ECM sulfation as a potent regulator of stress adaptation and therapeutic efficacy in lung adenocarcinoma and underscore the importance of biomimetic ECM design in controlling tumor cell fate and drug response.

DOI: https://doi.org/10.1039/d6bm01195k
Front Endocrinol (Lausanne). 2026 ;17 1883721

Adrenal androgen mediates the association between obesity and accelerated skeletal maturation in children and adolescents.

Youngha Choi, Eunju Lee, Hye Sun Lee, Eun Jae Hwang, Youn Kyoung Kim, Seo Jung Kim, Kyoung Won Cho, Sujin Kim, Kyungchul Song, Junghwan Suh, Eun Byoul Lee, Hyun Wook Chae.

   Background: Childhood obesity is associated with advanced bone age (BA), but the underlying endocrine mechanisms remain unclear. We investigated the mediating role of dehydroepiandrosterone sulfate (DHEA-S) in the relationship between adiposity and skeletal maturation.
Methods: This retrospective study included 1,252 children aged 4-12 years from a single center. Skeletal maturation was assessed using the BA-to-chronological age (CA) ratio. Advanced maturation was defined as BA/CA > 1.1. Mediation analysis was performed to evaluate whether DHEA-S explains the association between BMI SDS and skeletal maturation.
Results: Body mass index standard deviation score (BMI SDS) and DHEA-S were independently associated with the BA/CA ratio (p < 0.05). In boys younger than 9 years, DHEA-S demonstrated good discriminative performance for advanced maturation (Area under the curve = 0.817). Mediation analysis showed that DHEA-S significantly mediated the association between BMI and BA/CA in boys < 9 years (β = 0.512, p = 0.024) and in girls ≥ 8 years (β = 0.377, p = 0.003). In young boys, the direct effect of BMI became non-significant after inclusion of DHEA-S, consistent with substantial mediation by adrenal androgens.
Conclusions: Adrenal androgen activity, reflected by DHEA-S, represents a significant endocrine pathway linking obesity to accelerated skeletal maturation. The magnitude of this mediation varies by age and sex, highlighting developmentally specific windows of endocrine-metabolic interaction in growing children.

Keywords:  adolescent; bone age; child; dehydroepiandrosterone sulfate; obesity

DOI:  https://doi.org/10.3389/fendo.2026.1883721
Nutr Health. 2026 Sep 03. 2601060261483849

Antioxidant status and dehydroepiandrosterone sulfate in aging: Evidence from MIDUS 3 biomarkers cohort.

Laith Ashour, Leen Altiti, Rand Khawaldeh, Batool Abuqudaira, Rakan Hani Wadi, Mera Jaber, Basae'r Najadat, Shaima Jaber, Rand Ibrahim Awwad, Tuqa Waleed Smadi, Sara Jamal Mohammad.

  BackgroundDehydroepiandrosterone sulfate (DHEAS) has been consistently linked to cardiovascular and skeletal health; however, the relationship between circulating antioxidant concentrations, including vitamins, and DHEAS levels in older adults has been insufficiently examined.AimTo assess associations between serum DHEAS and five antioxidants: β-cryptoxanthin, total lycopene, α-tocopherol, γ-tocopherol, and retinol.MethodsData from the Midlife in the United States (MIDUS3) Biomarker Project (2017-2022) were analyzed in a cross-sectional design. Analyses evaluated associations between DHEAS, antioxidant levels, and demographic and metabolic characteristics, including age, sex, smoking history, creatinine, HbA1c, total cholesterol, body mass index, dietary quality, alcohol intake, physical activity, and sleep quality. Multivariable linear regression models adjusting for all antioxidants and potential confounders were conducted following square-root transformation of DHEAS.SummaryThe analytical sample comprised 747 participants (55.8% female) with a mean age of 66.0 years (SD = 9.64). In adjusted models, higher α-tocopherol concentrations were associated with lower DHEAS levels (β = -0.09; 95% CI: [-0.172 to -0.009], P < 0.031) whereas retinol demonstrated a positive association with DHEAS (β = 0.081; 95% CI: [0.009-0.154], P = 0.029). None of the other antioxidants had a significant association with serum DHEAS. Increasing age, female sex, and poorer sleep quality were significantly associated with lower DHEAS concentrations. In conclusion, in older adults, serum retinol levels are positively associated with DHEAS concentrations, whereas α-tocopherol shows an inverse association. Conversely, no significant associations were observed between serum DHEAS levels and β-cryptoxanthin, total lycopene, or γ-tocopherol.

Keywords:  Antioxidants; aging; dehydroepiandrosterone sulfate; older adults

DOI:  https://doi.org/10.1177/02601060261483849
Int J Biol Sci. 2026 ;22(13): 7173-7190

Targeting the heparan sulfate proteoglycan/heparanase axis as a novel therapeutic strategy to drive adipogenesis and block tumor growth of dedifferentiated liposarcoma.

Cinzia Lanzi, Enrica Favini, Laura Dal Bo, Monica Tortoreto, Stefano Percio, Valentina Zuco, Gian Paolo Dagrada, Silvia Brich, Paola Collini, Loris De Cecco, Dario Callegaro, Roberta Sanfilippo, Alessandro Gronchi, Nadia Zaffaroni, Yehuda G Assaraf, Sandro Pasquali, Giuliana Cassinelli.

  Dedifferentiated liposarcoma (DDLPS) is an aggressive mesenchymal malignancy coexisting with a low grade well-differentiated component. Pathways implicated in liposarcoma growth and dedifferentiation are promoted by heparan sulfate (HS) proteoglycans (HSPG) and their modifying enzymes including heparanase. HSPGs serve as co-receptors enhancing tyrosine kinase signaling and tumor aggressiveness. Targeting these interactions bears promise in attenuating liposarcoma growth. We employed an investigational HS mimetic, the non-anticoagulant heparin CX-01 (dociparstat), to assess its HS competition impact on deregulated adipogenic differentiation and growth of human DDLPS cell lines and patient-derived xenografts (PDXs). Remarkably, CX-01 reduced colony formation and invasive capacities of DDLPS cell lines, inducing cytoskeleton remodeling, lipid accumulation and reactivation of adipogenic program. Mechanistic studies into the anti-DDLPS activity of CX-01 unveiled Syndecan 1 (SDC1)/heparanase system and receptor tyrosine kinase-AKT signaling as targets of cell growth inhibition and induction of differentiation. CX-01 treatment of mice harboring DDLPS PDXs attenuated tumor growth, enhanced lipid content and consistently altered the transcriptome, modulating pathways associated with tumor dedifferentiation (adipogenesis and fatty acid metabolism) and tumor-microenvironment interaction (TGFβ signaling, inflammatory response). In two independent cohorts of DDLPS patients, genes downregulated in CX-01-treated PDXs (SDC1, TIMP1, FN1, COL5A1, and MMP14), were found preeminently expressed in the dedifferentiated, compared to the well-differentiated tumor component and normal fat. This suggests a role for these genes in disease progression. Collectively, this study demonstrates the remarkable potential of HS competition to simultaneously block multiple anti-adipogenic players representing metabolic vulnerabilities, and to promote a differentiated tumor phenotype markedly less aggressive.

Keywords:  AKT; CX-01; adipogenesis; c-Met; dedifferentiated liposarcoma; syndecan-1

DOI:  https://doi.org/10.7150/ijbs.133802
Horm Res Paediatr. 2026 Sep 01. 1

Adrenal androgens, estrone, and insulin-like growth factor 1 are associated with thelarche without gonadotropin activation in girls.

Saija Burtsov, Anna Viitasalo, Sonja P Soininen, Merja R Häkkinen, Seppo Auriola, Aino Mäntyselkä, Raimo Voutilainen, Jarmo Jääskeläinen, Timo A Lakka.

INTRODUCTION: Although a well-known phenomenon, the hormonal mechanism of thelarche in the absence of gonadotropin activation remains unclear. To reveal the biological mechanisms of such thelarche we assessed serum concentrations of several hormones potentially related to breast development, as well as clinical signs of androgen action.
METHODS: A population-based sample of 175 girls aged 9-11 was divided into those without thelarche (Tanner breast stage 1) and those with thelarche (Tanner breast stage ≥ 2). The girls were further categorized based on basal serum luteinizing hormone (LH) using a cut-off of 0.3 IU/L. This resulted in three groups: 114 girls with low LH without thelarche, 32 girls with low LH and thelarche, and 29 girls with higher LH and thelarche. Serum concentrations of sex steroids and insulin-like growth factor-1 (IGF-1) and clinical signs of androgen action were assessed at ages 7-9 and 9-11 years.
RESULTS: Girls with low LH and thelarche had higher levels of dehydroepiandrosterone sulfate (DHEAS) (0.80 vs. 0.60 µmol/L, p=0.03 at 7-9 years; 0.97 vs. 0.72 µmol/L, p=0.03 at 9-11 years), testosterone (0.18 vs. 0.14 nmol/L, p=0.02; 0.27 vs. 0.22 nmol/L, p=0.02), estrone (14.5 vs. 11.5 pmol/L, p=0.02; 24.3 vs. 18.2 pmol/L, p=0.002), and IGF-1 (28.6 vs. 23.6 nmol/L, p=0.001; 35.9 vs. 31.1 nmol/L, p=0.006) than girls with low LH without thelarche. Differences in DHEAS, testosterone, and IGF-1 diminished after further adjustment for body fat percentage. Girls with low LH and thelarche also had more clinical signs of androgen action at both ages than girls with low LH without thelarche. There were no statistically significant differences in hormonal concentrations at 7-9 years between girls with low LH and thelarche and those with higher LH and thelarche. However, at 7-9 years, girls with low LH and thelarche had more signs of androgen action than girls with higher LH and thelarche. At 9-11 years, girls with higher LH and thelarche had higher hormonal concentrations except for DHEAS than girls with low LH and thelarche.
CONCLUSION: Thelarche with low LH is associated with elevated DHEAS, testosterone, estrone, and IGF-1 concentrations, which is partly explained by BF%, suggesting that aromatization of adrenal androgens to estrogens in adipose tissue is one hormonal mechanism of thelarche in girls without gonadotropin activation.

DOI: https://doi.org/10.1159/hrp/adaag012
Eur J Med Chem. 2026 Aug 31. pii: S0223-5234(26)00720-8. [Epub ahead of print]319 119275

Precision chemoenzymatic tailoring of bioengineered low-molecular-weight heparins for protamine-reversible anticoagulation.

Lin Wang, Yali Wang, Fengyan Tang, Yanzhen Cheng, Ziyi Zhou, Qiuhan Xu, Jiukun Liu, Chunhui Liu.

  Animal-derived low-molecular-weight heparins (LMWHs) are essential anticoagulants but are associated with supply chain vulnerabilities and contamination risks, alongside incomplete protamine reversibility in clinical practice. Herein, we report the precision chemoenzymatic tailoring of bioengineered LMWHs from Escherichia coli K5 capsular polysaccharide (heparosan) to achieve protamine-reversible anticoagulation. Through the integration of chemical N-deacetylation/N-sulfation, precisely regulated C5-epimerization/2-O-sulfation, controlled β-eliminative depolymerization, and sequential enzymatic 6-O/3-O-sulfation, the molecular weight distribution and specific sulfation patterns were rationally modulated. The representative bioengineered product, L3S-2, exhibited potent anti-factor Xa activity, an optimized anti-factor Xa/anti-factor IIa ratio, and pharmacokinetic properties comparable to enoxaparin following subcutaneous administration. Crucially, L3S-2 demonstrated significantly improved protamine reversibility both in vitro and in vivo compared to commercial enoxaparin. In rat thrombosis models, L3S-2 potently inhibited venous and arterial thrombus formation, demonstrating efficacy comparable to enoxaparin. These findings establish a rational design framework for bioengineered anticoagulants, demonstrating that optimizing multivalent electrostatic interactions with protamine via tailored sulfation and molecular weight yields highly reversible agents with optimized therapeutic indices.

Keywords:  Anticoagulant activity; Chemoenzymatic synthesis; Heparosan; Low-molecular-weight heparin; Protamine reversibility

DOI:  https://doi.org/10.1016/j.ejmech.2026.119275
J Crit Care. 2026 Aug 29. pii: S0883-9441(26)00310-2. [Epub ahead of print]97 155732

Glycocalyx degradation is associated with increased circulating unmeasured ions after cardiopulmonary bypass.

PRIME study group

  Unmeasured anions are commonly detected in critically ill patients, yet their nature remains unclear. We examined whether endothelial glycocalyx degradation may be related to this unexplained anionic burden through release of polyanionic heparan sulfate fragments. In a prospective subanalysis embedded in a randomized trial of cardiopulmonary bypass priming, 34 patients undergoing coronary artery bypass grafting with cardiopulmonary bypass were studied. A total of 150 serial measurements of strong ion gap, heparan sulfate, and syndecan-1 were obtained at five timepoints from post-induction to the first 24 h of intensive care unit admission. In mixed-effects models accounting for repeated measurements and timepoint effects, strong ion gap was associated with heparan sulfate (β = 0.20, 95%CI 0.06-0.33; p = 0.005), but not syndecan-1. These findings suggest that glycocalyx-derived heparan sulfate may be related to persistent unmeasured anions extending from cardiopulmonary bypass into the subsequent intensive care unit admission, a period characterized by acute inflammation and volume loading. The absence of an association with syndecan-1 suggests a specific association to circulating polyanionic glycosaminoglycans rather than all glycocalyx degradation products. These findings are hypothesis-generating and suggest a possible relationship between circulating glycocalyx degradation and a persistent strong ion gap in critically ill patients, although comprehensive gap fractionation is required to quantify the contribution of heparan sulfate and determine whether it can be modified by resuscitation strategy.

Keywords:  Acid-base; Acidosis; Anion gap; Strong ion difference; Strong ion gap

DOI:  https://doi.org/10.1016/j.jcrc.2026.155732
Biotechnol J. 2026 Sep;21(9): e70302

TPST Gene Knock-Out Eliminates Tyrosine Sulfation on a Recombinant Antibody Produced in CHO Cells.

Jacqualyn Schulman, Rachel Egan, Lakshmi Kandari, Nandakumar Madayiputhiya, David Mahon, Li Tao, Hao Luo, Kendall Condon, John N Feder, Dan Huang, Anurag Khetan.

  Tyrosine sulfation is a post-translational modification that has been reported to occur infrequently on recombinant monoclonal antibodies (mAbs). We recently demonstrated that tyrosine sulfation occurred on a bispecific antibody (bsAb) produced in Chinese hamster ovary (CHO) cells, using a multi-enzymatic approach in combination with intact mass and peptide-based mass spectrometry analysis supplemented with the use of synthetic peptides. Tyrosine sulfation needs to be controlled during the manufacturing process due to potential undesired effects, such as impact on potency and immunogenicity. Here, we report that tyrosine sulfation was not significantly inhibited by the addition of chemical inhibitors, such as sodium chlorate. Individual knockout and double knockout (DKO) of two key genes in the tyrosine sulfation pathway were carried out sequentially. Tyrosyl protein sulfotransferase 1/2 (TPST1/2) DKO by CRISPR/Cas9 (clustered regularly interspaced short palindromic repeats/CRISPR-associated protein-9 nuclease)-mediated gene editing eliminated tyrosine sulfation while maintaining cell growth, antibody production, and overall product quality.

Keywords:  CRISPR; Chinese hamster ovary cells; biotherapeutics; bispecific; post‐translational modification; product quality attributes; tyrosine sulfation

DOI:  https://doi.org/10.1002/biot.70302
Int J Med Sci. 2026 ;23(9): 2899-2910

Associations Between Renal Function, Uremic Toxins, and Cognitive Performance in Patients with Chronic Kidney Disease: A Pilot Study.

Te-Wei Cheng, Kevin Li-Chun Hsieh, Chih-Chin Kao, Hsun-Hua Lee, Yen-Chung Lin, Chien-Hung Lai.

   Background: Patients with chronic kidney disease (CKD) often experience cognitive decline. However, the associations between renal dysfunction, uremic toxins, and cerebrovascular changes remain unclear.
Aim: This study investigated the associations between renal function, uremic toxins, cerebrovascular imaging markers, and cognitive performance in patients with CKD plus early cognitive decline through integrated biochemical, neuropsychological, and neuroimaging assessments.
Design: An observational pilot study.
Setting: Outpatient clinic of the physical medicine and rehabilitation department at a tertiary hospital.
Population: Adult patients with stage 3-5 CKD who exhibited early cognitive decline and could complete CANTAB-based cognitive assessments.
Methods: This study included 12 patients with stage 3-5 CKD who were not undergoing hemodialysis and had early cognitive decline (Clinical Dementia Rating score: 0.5 or 1.0). Cognitive performance was assessed using the CANTAB. Serum levels of total indoxyl sulfate (IS) and total p-cresyl sulfate (pCS) were measured. Brain magnetic resonance imaging was performed to evaluate qualitative imaging markers potentially associated with cognitive impairment, such as arterial stenosis of the circle of Willis. Pearson correlations between the aforementioned biomarkers were explored.
Results: Both IS and pCS levels were negatively correlated with estimated glomerular filtration rate (IS: r = -0.301, p = 0.469; pCS: r = -0.461, p = 0.250). A higher estimated glomerular filtration rate was correlated with better spatial working memory strategy performance (r = 0.695, p = 0.012). However, no clear correlation was observed between cognitive performance and arterial stenosis severity.
Conclusion: This pilot study suggests that renal function is associated with selected cognitive domains in patients with CKD. The overall burden of qualitative MRI lesions was low in this cohort, although structural brain abnormalities were still observed. Integration of biochemical, neuropsychological, and brain imaging biomarkers may provide a comprehensive evaluation of cognitive function in these patients.
Clinical Rehabilitation Impact: Integrating multidomain cognitive assessments with uremic toxin profiling and noninvasive brain imaging may facilitate early identification of cognitive deficits in patients with CKD, thereby supporting individualized cognitive evaluation in rehabilitation practice.Trial Registration: NCT07272733.

Keywords:  Cambridge Neuropsychological Test Automated Battery; chronic kidney disease; cognitive decline; magnetic resonance imaging

DOI:  https://doi.org/10.7150/ijms.133922