bims-supasi 2024-11-24 papers

bims-supasi

Biomed News

on Sulfation pathways and signalling

Issue of 2024–11–24
ten papers selected by
Jonathan Wolf Mueller, University of Birmingham

Biocatalytic sulfation of aromatic and aliphatic alcohols catalyzed by arylsulfate sulfotransferases.
Efficacy of chondroitin sulfate as an emerging biomaterial for cancer-targeted drug delivery: A short review.
NeoMProbe: a new class of fluorescent cellular and tissue membrane probe.
Structural analysis and accelerating wound healing function of a novel galactosylated glycosaminoglycan from the snail Helix lucorum.
Delivery system for dexamethasone phosphate based on a Zn2+-crosslinked polyelectrolyte complex of diethylaminoethyl chitosan and chondroitin sulfate.
Co-Therapy with S1P and Heparan Sulfate Derivatives to Restore Endothelial Glycocalyx and Combat Pro-Atherosclerotic Endothelial Dysfunction.
P-selectin-targeted Polyguluronate sulfate-copper peroxide Nanomicelles for Chemodynamic therapy of breast Cancer.
Characterization of the mechanisms governing heparin-bovine serum albumin complex interactions and associated anticoagulant activity.
The mediatory role of androgens on sex differences in glucose homeostasis and incidence of type 2 diabetes: the KORA study.
Structural basis for the reaction cycle and transport mechanism of human Na+-sulfate cotransporter NaS1 (SLC13A1).

Appl Microbiol Biotechnol. 2024 Nov 19. 108(1): 520

Biocatalytic sulfation of aromatic and aliphatic alcohols catalyzed by arylsulfate sulfotransferases.

Isabel Oroz-Guinea, Marko Rath, Isabelle Tischler, Klaus Ditrich, Doreen Schachtschabel, Michael Breuer, Wolfgang Kroutil.

  Many relevant metabolites, as well as chemical commodities, contain at least one sulfate ester group. Consequently, biocatalytic strategies to attach sulfate to a molecule under mild conditions are of high interest. In order to expand the enzymatic toolbox available, five new arylsulfate sulfotransferases (ASSTs) were identified in this study. Overexpression in Escherichia coli and enzyme purification resulted in soluble proteins which catalyzed the sulfate transfer to an acceptor substrate using p-nitrophenyl sulfate (pNPS) as sulfate donor. Optimal reaction conditions were established with respect to temperature and pH, as well as their tolerance to organic co-solvents and melting temperature. Additionally, the kinetic parameters (Vmax, KM, and kcat) were determined. The substrate scope for the acceptor showed that a structurally diverse spectrum of alcohols is accepted. The substrates included phenolic alcohols with one, two, and three hydroxy groups, linear and cyclic aliphatic alcohols, and amines. The phenolic substrates were accepted reaching activities of up to 154 U/mg purified enzyme. Additionally, also the aliphatic alcohols (both linear and cyclic) were accepted at reduced activity, showing that these enzymes are not limited to phenolic alcohols. Moreover, catalytic activity was detected when using aniline as an acceptor substrate implying their ability to sulfate also amino groups. Finally, the consecutive sulfation of di- and trihydroxy compounds was observed, resulting in the detection of the corresponding disulfated molecules. KEY POINTS: • Five novel arylsulfate sulfotransferases were identified and characterized. • Accepted substrates included aromatic and aliphatic alcohols, as well as aniline. • Disulfation of di- and trihydroxy aromatic compounds was studied and confirmed.

Keywords:  Aliphatic alcohol sulfation; Amine sulfation; Arylsulfate sulfotransferase; Disulfated compounds; Enzymatic sulfation

DOI:  https://doi.org/10.1007/s00253-024-13354-5
Int J Biol Macromol. 2024 Nov 15. pii: S0141-8130(24)08514-3. [Epub ahead of print]283(Pt 2): 137704

Efficacy of chondroitin sulfate as an emerging biomaterial for cancer-targeted drug delivery: A short review.

Sekar Vijayakumar, Zaira I González-Sánchez, Mani Divya, Mohammed Amanullah, Esteban F Durán-Lara, Mingchun Li.

  The global increase in cancer incidence over the past decade highlights the urgent need for more effective therapeutic strategies. Conventional cancer treatments face challenges such as drug resistance and off-target toxicity, which affect healthy tissues. Chondroitin sulfate (CHDS), a naturally occurring bioactive macromolecule, has gained attention because of its biocompatibility, biodegradability, and low toxicity, positioning it as an ideal candidate for cancer-targeted drug delivery systems. This review highlights the potential of CHDS as an emerging biomaterial in cancer therapy, focusing on its unique biological properties and applications in drug delivery platforms. Furthermore, we discuss the advantages of CHDS-based biomaterials in enhancing cancer treatment efficacy and minimizing side effects, in order to provide a comprehensive reference for future research on CHDS-based cancer therapeutics.

Keywords:  Biomaterial; CHDS; Cancer; Targeted drug delivery

DOI:  https://doi.org/10.1016/j.ijbiomac.2024.137704
Chem Sci. 2024 Oct 30.

NeoMProbe: a new class of fluorescent cellular and tissue membrane probe.

Saurabh Anand, Preeti Ravindra Bhoge, Rakesh Raigawali, Srinivas Vinod Saladi, Raghavendra Kikkeri.

The development of long-lasting plasma membrane (PM) and basement membrane (BM) probes is in high demand to advance our understanding of membrane dynamics during differentiation and disease conditions. Herein, we report that the microheterogeneity of heparan sulfate (HS) on fluorescent neo-proteoglycans backbone offers a facile platform for designing membrane probes. Confocal live-cell imaging studies of cancer and normal cell lines with a panel of Cy5 fluorescently tagged neo-proteoglycans confirmed that highly sulfated HS ligands with an l-iduronic acid component (PG@ID-6) induce a prolonged and brighter expression on the PM compared to low-sulfated and uronic acid counterparts. Mono- and multi-photon microscopic imaging of tissue sections with NeoMProbe (PG@ID-6) allowed mapping BM and demonstrated staining efficacy equivalent to antibodies against the BM components. Finally, in vivo, whole-body imaging of NeoMProbe and subsequent tissue section imaging confirmed versatile and efficient membrane mapping by the probe. Overall, NeoMProbe offers a novel toolkit for cell biology and tissue biomembrane imaging.

DOI: https://doi.org/10.1039/d4sc06225f
Carbohydr Polym. 2025 Jan 15. pii: S0144-8617(24)01126-3. [Epub ahead of print]348(Pt B): 122900

Structural analysis and accelerating wound healing function of a novel galactosylated glycosaminoglycan from the snail Helix lucorum.

Ya Li, Xingzi Wang, Jiangyan Chen, Luyun Sun, Debing Pu, Lisha Lin, Lan Luo, Xi Gong, Junxue Pu, Mingyi Wu.

  Diabetic foot ulcers (DFUs) as a nonhealing wound remain a clinical challenge, and the development of pro-healing and cost-effective drugs is in urgent need. Herein, we reported a novel galactosylated glycosaminoglycan (GAG) from the snail Helix lucorum, as an effective pro-healing compound. The snail GAG is composed of a heparan sulfate-like main chain and galactose side chains at C-3 of GlcNAc residue. Its main chain has a repeating disaccharide structure of → 4)-α-D-GlcNAc-(1 → 4)-α-L-IdoA2S(1 →. This is the first example of glycosaminoglycan with galactose branches from mollusks. Pharmacological experiments showed that the H. lucorum GAG significantly promoted skin wound healing in both healthy and diabetic mice by accelerating granulation tissue regeneration, angiogenesis, and collagen deposition. The distinctive galactosylated substitution may play an important role on its pro-healing activity. Our discovery enriches the diversity of non-anticoagulant heparan sulfate-like glycosaminoglycans, and provides a potential candidate of pro-healing drug for treating diabetic wound.

Keywords:  Diabetic wound healing; Glycosaminoglycan; Heparan sulfate; Heparin; Snail

DOI:  https://doi.org/10.1016/j.carbpol.2024.122900
Carbohydr Polym. 2025 Jan 15. pii: S0144-8617(24)01125-1. [Epub ahead of print]348(Pt B): 122899

Delivery system for dexamethasone phosphate based on a Zn2+-crosslinked polyelectrolyte complex of diethylaminoethyl chitosan and chondroitin sulfate.

Natallia V Dubashynskaya, Anton N Bokatyi, Andrey S Trulioff, Artem A Rubinstein, Veronika P Novikova, Valentina A Petrova, Elena N Vlasova, Alexey V Malkov, Igor V Kudryavtsev, Yury A Skorik.

  Hybrid nano- and microparticles based on metal ion crosslinked biopolymers are promising carriers for the development of drug delivery systems with improved biopharmaceutical properties. In this work, dexamethasone phosphate-containing particles based on chondroitin sulfate and chitosan or diethylaminoethyl chitosan additionally crosslinked with Zn2+ were prepared. Depending on the polycation/polyanion ratio in the system, anionic and cationic polyelectrolyte complexes (PECs) were obtained. The anionic Zn2+-containing and Zn2+-free PECs had sizes of 154 and 180 nm and ζ-potentials of -22.4 and -27.5 mV, respectively. The cationic Zn2+-containing and Zn2+-free PECs had sizes of 242 and 362 nm and ζ-potentials of 22.4 and 24.7 mV, respectively. The presence of Zn2+ in the system significantly prolonged the release of dexamethasone phosphate from the hybrid polyelectrolyte particle. The resulting release profiles of dexamethasone phosphate were in agreement with the Peppas-Sahlin kinetic model, which considers the combined effects of Fickian diffusion and polymer chain relaxation on the drug release rate. It was shown that the prolongation of drug release was mainly due to swelling and relaxation of the Zn2+ crosslinked polymers. The developed particles exhibited good mucoadhesive properties and pronounced anti-inflammatory activity, making them attractive candidates for biomedical applications.

Keywords:  Anti-inflammatory activity; Biohybrid drug delivery systems; Chitosan; Chondroitin sulfate; Dexamethasone phosphate; Diethylaminoethyl chitosan; Mucoadhesion

DOI:  https://doi.org/10.1016/j.carbpol.2024.122899
bioRxiv. 2024 Nov 08. pii: 2024.11.06.622347. [Epub ahead of print]

Co-Therapy with S1P and Heparan Sulfate Derivatives to Restore Endothelial Glycocalyx and Combat Pro-Atherosclerotic Endothelial Dysfunction.

Ronodeep Mitra, Kaleigh Pentland, Svilen Kolev, Matthew Eden, Erel Levine, Jessica M Oakes, Eno E Ebong.

Endothelial cell (EC) glycocalyx (GCX) shedding due to disturbed blood flow and chemical factors leads to low-density lipoprotein infiltration and reduced nitric oxide synthesis, causing vascular dysfunction and atherosclerosis. This study evaluates a novel therapy combining sphingosine-1-phosphate (S1P) and heparin (heparan sulfate derivative). We hypothesized that heparin/S1P would repair mechanically damaged EC GCX in disturbed flow (DF) regions and restore anti-atherosclerotic mechanotransduction function, addressing cardiovascular disease. We used a parallel-plate flow chamber to simulate flow conditions in vitro and a partial carotid ligation mouse model to mimic DF in vivo. Heparin and albumin-bound S1P were administered to assess their reparative effects on the endothelial GCX. Immunocytochemistry, fluorescent staining, confocal microscopy, cellular alignment studies, and ultrasound were performed to evaluate EC function and endothelial-dependent vascular function. Barrier functionality was assessed via macrophage uptake. Heparin/S1P mechanism-of-action insights were gained through fluid dynamics simulations and staining of GCX synthesis enzyme as well as S1P receptor. Statistical analyses validated results. In vitro data showed that heparin/S1P therapy improves the function of DF-conditioned ECs by restoring EC GCX and promoting EC alignment and elevated vasodilator eNOS (endothelial-type nitric oxide synthase) expression. The in vivo studies confirmed GCX degradation, increased vessel inflammation and hyperpermeability, and vessel wall thickening in the partially ligated left carotid artery. Heparin/S1P treatment restored GCX in the left carotid artery, enhancing GCX thickness and coverage of the blood vessel wall. This work advances a new approach to regenerating the EC GCX and restoring its function in ECs under DF conditions.

DOI: https://doi.org/10.1101/2024.11.06.622347
Int J Biol Macromol. 2024 Nov 18. pii: S0141-8130(24)08628-8. [Epub ahead of print] 137818

P-selectin-targeted Polyguluronate sulfate-copper peroxide Nanomicelles for Chemodynamic therapy of breast Cancer.

Dingfu Wang, Xiaolei Qiu, Lihua Hao, Zirui Fan, Shixin Wang, Chunxia Li.

  The exploration of efficient and safe chemodynamic therapy (CDT)-based cancer treatment is expected but still faces challenges. Herein, a kind of multifunctional nanomicelles was constructed for CDT, combined with biocompatible polysaccharides as nanocarriers, pH responsiveness and active targeting of P-selectin overexpressed tumors. The P-selectin-targeted ligand, polyguluronate sulfate (PGS), complexed with copper peroxide to form PGS-Cu nanomicelles by electrostatic interactions. Under acidic conditions, PGS-Cu nanomicelles released copper ions with H2O2 and were able to produce •OH by Fenton-like reaction. In vitro data demonstrated PGS-Cu nanomicelles had high selectivity targeting P-selectin over-expressed cancer cells and induced cell death via CDT. In vivo evaluation showed PGS-Cu nanomicelles were enriched in tumor tissues and significantly inhibited tumor growth. This study identified that PGS-Cu nanomicelles could be a highly effective strategy for CDT cancer treatment.

Keywords:  Anti-breast cancer; Chemodynamic therapy; P-selectin targeting; Polyelectrolyte nanomicelles; Polyguluronate sulfate

DOI:  https://doi.org/10.1016/j.ijbiomac.2024.137818
Carbohydr Polym. 2025 Jan 15. pii: S0144-8617(24)01023-3. [Epub ahead of print]348(Pt A): 122797

Characterization of the mechanisms governing heparin-bovine serum albumin complex interactions and associated anticoagulant activity.

Lei Zhang, Si-Ya Wang, Yun-Tao Zhang, Qiang Ren.

  Heparin's interactions with body proteins affect its bioavailability and anticoagulant efficacy, resulting in variable clinical outcomes. This study focused on enhancing the specificity of heparin-BSA (bovine serum albumin) interactions to stabilize anticoagulant effects. We examined the impact of heparin-BSA complexes on coagulation indices such as activated partial thromboplastin time (APTT), prothrombin time (PT), thrombin time (TT), and activated clotting time (ACT). The enoxaparin sodium-BSA complex demonstrated enhanced anticoagulant activity at an optimized 1 × 10-3 mol/L concentration. Fluorescence spectroscopy revealed a single binding site between heparin and BSA, with binding affinities ranging from 3.9 × 103 to 7.2 × 104 L/mol, where enoxaparin sodium showed the highest affinity. The interactions were predominantly non-covalent, driven by van der Waals forces and hydrogen bonding, as indicated by negative ΔH° and ΔS° values. Advanced imaging techniques suggested structural changes in BSA and its microenvironment post-binding. Scanning electron microscopy confirmed tighter encapsulation of enoxaparin within BSA. Molecular docking identified the primary heparin disaccharide unit, △UA,2S-GlcNS,6S (IS), binding at Sudlow sites I and II, enhancing understanding of the interaction mechanisms. These findings provide insights into designing more effective anticoagulant therapies. This study elucidates the interaction mechanism between heparin and BSA, thereby providing a theoretical foundation for efforts to devise new anticoagulant drugs.

Keywords:  Anticoagulant; Bovine serum albumin; Heparin; Heparin-BSA complex

DOI:  https://doi.org/10.1016/j.carbpol.2024.122797
Cardiovasc Diabetol. 2024 Nov 15. 23(1): 411

The mediatory role of androgens on sex differences in glucose homeostasis and incidence of type 2 diabetes: the KORA study.

Hamidreza Raeisi-Dehkordi, Barbara Thorand, Sara Beigrezaei, Annette Peters, Wolfgang Rathman, Jerzy Adamski, Angeline Chatelan, Yvonne T van der Schouw, Oscar H Franco, Taulant Muka, Jana Nano.

   BACKGROUND: Sex differences exist in type 2 diabetes (T2D), and androgens have been implicated in the etiology of T2D in a sex-specific manner. We therefore aimed to investigate whether androgens play a role in explaining sex differences in glucose homeostasis and incidence of T2D.
METHODS: We used observational data from the German population-based KORA F4 study (n = 1975, mean age: 54 years, 41% women) and its follow-up examination KORA FF4 (median follow-up 6.5 years, n = 1412). T2D was determined through self-reporting and confirmed by contacting the physicians and/or reviewing the medical charts. Multivariable linear and logistic regression models were employed to explore associations. Mediation analyses were performed to assess direct effects (DE) and indirect effects (IE), and the mediating role of androgens (total testosterone (TT), dehydroepiandrosterone (DHEA), dehydroepiandrosterone-sulfate (DHEAs)) in the association between sex (women vs. men) and glucose- and insulin-related traits (cross-sectional analysis) and incidence of T2D (longitudinal analysis).
RESULTS: After adjustment for confounders, (model 1: adjusted for age; model 2: model 1 + smoking + alcohol consumption + physical activity), women had lower levels of TT, DHEAs, fasting glucose levels, fasting insulin levels, 2 h-glucose levels and HOMA-IR, compared to men. An inverse association was observed for TT and glucose- and insulin-related traits in men, while a positive association was observed for TT and fasting glucose levels in women. We found a mediatory role of TT on the association of sex with fasting glucose levels (IE: β = 3.08, 95% CI: 2.04, 4.30), fasting insulin levels (IE: β = 0.39, 95% CI:0.30, 0.47), 2 h-glucose levels (IE: β = 12.77, 95% CI: 9.01, 16.03) and HOMA-IR (IE: β = 0.41, 95% CI: 0.33, 0.50). Also, the inconsistent mediatory role of TT was seen on the association of sex with incidence of T2D (DE: 0.12, 95% CI: 0.06, 0.20 and IE: OR = 7.60, 95% CI: 3.43, 24.54). The opposing DE and IE estimates suggest that the association between sex and either glucose homeostasis or the incidence of T2D may differ when TT is considered as a potential mediator, with higher TT levels being beneficial for glucose metabolism or incidence of T2D in men, while in women, detrimental. No mediatory role was observed for either DHEA or DHEAs on glucose homeostasis or the incidence of T2D.
CONCLUSIONS: The dimorphic mediatory role of TT highlights its complex role in metabolic health, contributing differently to the glucose dysregulation and risk of T2D in men and women.

Keywords:  Androgens; Glycemic control; Mediation analysis.; Sex differences; Sex hormones; Type 2 diabetes

DOI:  https://doi.org/10.1186/s12933-024-02494-7
Sci Adv. 2024 Nov 22. 10(47): eado6778

Structural basis for the reaction cycle and transport mechanism of human Na+-sulfate cotransporter NaS1 (SLC13A1).

Xudong Chen, Youqi Zhang, Jian Yin, Chang Liu, Min Xie, Yixue Wang, Meiying Chen, Rui Zhang, Xinyi Yuan, De Li, Xiangmei Chen, Xin Gao, Guangyan Cai, Sensen Zhang, Boda Zhou, Maojun Yang.

Sulfate (SO42-) is a pivotal inorganic anion with essential roles in mammalian physiology. NaS1, a member of solute carrier 13 family and divalent anion/sodium symporter family, functions as a Na+-sulfate cotransporter, facilitating sulfate (re)absorption across renal proximal tubule and small intestine epithelia. While previous studies have linked several human disorders to mutations in the NaS1 gene, its transport mechanism remains unclear. Here, we report the cryo-electron microscopy structures of five distinct conformations of the human NaS1 at resolutions of 2.7 to 3.3 angstroms, revealing the substrates recognition mechanism and the conformational change of NaS1 during the Na+-sulfate cotransport cycle. Our studies delineate the molecular basis of the detailed dynamic transport cycle of NaS1. These findings advance the current understanding of the Na+-sulfate cotransport mechanism, human sulfate (re)absorption, and the implications of disease-associated NaS1 mutations.

DOI: https://doi.org/10.1126/sciadv.ado6778