bims-supasi 2023-02-19 papers

bims-supasi

Biomed News

on Sulfation pathways and signalling

Issue of 2023–02–19
nine papers selected by
Jonathan Wolf Mueller, University of Birmingham

Glycomics by ion mobility tandem mass spectrometry of chondroitin sulfate disaccharide domain in biglycan.
Treatment with semaglutide, a GLP-1 receptor agonist, improves extracellular matrix remodeling in the pancreatic islet of diet-induced obese mice.
A sulphated glycosaminoglycan extract from Placopecten magellanicus inhibits the Alzheimer's disease β-site amyloid precursor protein cleaving enzyme 1 (BACE-1).
Smart Chondroitin Sulfate Micelles for Effective Targeted Delivery of Doxorubicin Against Breast Cancer Metastasis.
Heparan sulfate regulates IL-21 bioavailability and signal strength that control germinal center B cell selection and differentiation.
Attenuation of indoxyl sulfate-induced cell damage by cinchonidine-a Cinchona alkaloid-through the downregulation of p53 signaling pathway by promoting MDM2 cytoplasmic-nuclear shuttling in endothelial cells.
Inhibition of human sulfotransferases (SULTs) by per- and polyfluoroalkyl substances (PFASs) and structure-activity relationship.
Directly mapping the O-sulfation sites within CCR2 via an engineered nanopore.
PHARMACOLOGY OF HEPARIN AND RELATED DRUGS: AN UPDATE.

J Mass Spectrom. 2023 Mar;58(3): e4908

Glycomics by ion mobility tandem mass spectrometry of chondroitin sulfate disaccharide domain in biglycan.

Mirela Sarbu, Raluca Ica, Edie Sharon, David E Clemmer, Alina D Zamfir.

  Biglycan (BGN), a small leucine-rich repeat proteoglycan, is involved in a variety of pathological processes including malignant transformation, for which the upregulation of BGN was found related to cancer cell invasiveness. Because the functions of BGN are mediated by its chondroitin/dermatan sulfate (CS/DS) chains through the sulfates, the determination of CS/DS structure and sulfation pattern is of major importance. In this study, we have implemented an advanced glycomics method based on ion mobility separation (IMS) mass spectrometry (MS) and tandem MS (MS/MS) to characterize the CS disaccharide domains in BGN. The high separation efficiency and sensitivity of this technique allowed the discrimination of five distinct CS disaccharide motifs, of which four irregulated in their sulfation pattern. For the first time, trisulfated unsaturated and bisulfated saturated disaccharides were found in BGN, the latter species documenting the non-reducing end of the chains. The structural investigation by IMS MS/MS disclosed that in one or both of the CS/DS chains, the non-reducing end is 3-O-sulfated GlcA in a rather rare bisulfated motif having the structure 3-O-sulfated GlcA-4-O-sulfated GalNAc. Considering the role played by BGN in cancer cell spreading, the influence on this process of the newly identified sequences will be investigated in the future.

Keywords:  biglycan; chondroitin sulfate; ion mobility tandem mass spectrometry; structural analysis; sulfation pattern

DOI:  https://doi.org/10.1002/jms.4908
Life Sci. 2023 Feb 14. pii: S0024-3205(23)00136-4. [Epub ahead of print] 121502

Treatment with semaglutide, a GLP-1 receptor agonist, improves extracellular matrix remodeling in the pancreatic islet of diet-induced obese mice.

Luiz E Macedo Cardoso, Thatiany Souza Marinho, Fabiane Ferreira Martins, Marcia Barbosa Aguila, Carlos A Mandarim-de-Lacerda.

   AIMS: The extracellular matrix (ECM) is fundamental for the normal endocrine functions of pancreatic islet cells and plays key roles in the pathophysiology of type 2 diabetes. Here we investigated the turnover of islet ECM components, including islet amyloid polypeptide (IAPP), in an obese mouse model treated with semaglutide, a glucagon-like peptide type 1 receptor agonist.
MAIN METHODS: Male one-month-old C57BL/6 mice were fed a control diet (C) or a high-fat diet (HF) for 16 weeks, then treated with semaglutide (subcutaneous 40 μg/kg every three days) for an additional four weeks (HFS). The islets were immunostained and gene expressions were assessed.
KEY FINDINGS: Comparisons refer to HFS vs HF. Thus, IAPP immunolabeling and beta-cell-enriched beta-amyloid precursor protein cleaving enzyme (Bace2, -40 %) and heparanase immunolabeling and gene (Hpse, -40 %) were mitigated by semaglutide. In contrast, perlecan (Hspg2, +900 %) and vascular endothelial growth factor A (Vegfa, +420 %) were enhanced by semaglutide. Also, semaglutide lessened syndecan 4 (Sdc4, -65 %) and hyaluronan synthases (Has1, -45 %; Has2, -65 %) as well as chondroitin sulfate immunolabeling, and collagen type 1 (Col1a1, -60 %) and type 6 (Col6a3, -15 %), lysyl oxidase (Lox, -30 %) and metalloproteinases (Mmp2, -45 %; Mmp9, -60 %).
SIGNIFICANCE: Semaglutide improved the turnover of islet heparan sulfate proteoglycans, hyaluronan, chondroitin sulfate proteoglycans, and collagens in the islet ECM. Such changes should contribute to restoring a healthy islet functional milieu and should reduce the formation of cell-damaging amyloid deposits. Our findings also provide additional evidence for the involvement of islet proteoglycans in the pathophysiology of type 2 diabetes.

Keywords:  Beta-cell; Heparanase; Islet amyloid polypeptide; Perlecan; Syndecan

DOI:  https://doi.org/10.1016/j.lfs.2023.121502
Carbohydr Res. 2023 Jan 26. pii: S0008-6215(23)00009-5. [Epub ahead of print]525 108747

A sulphated glycosaminoglycan extract from Placopecten magellanicus inhibits the Alzheimer's disease β-site amyloid precursor protein cleaving enzyme 1 (BACE-1).

Courtney J Mycroft-West, Anthony J Devlin, Lynsay C Cooper, Scott E Guimond, Patricia Procter, Gavin J Miller, Marco Guerrini, David G Fernig, Edwin A Yates, Marcelo A Lima, Mark A Skidmore.

  The clinically important anticoagulant heparin, a member of the glycosaminoglycan family of carbohydrates that is extracted predominantly from porcine and bovine tissue sources, has previously been shown to inhibit the β-site amyloid precursor protein cleaving enzyme 1 (BACE-1), a key drug target in Alzheimer's Disease. In addition, heparin has been shown to exert favourable bioactivities through a number of pathophysiological pathways involved in the disease processes of Alzheimer's Disease including inflammation, oxidative stress, tau phosphorylation and amyloid peptide generation. Despite the multi-target potential of heparin as a therapeutic option for Alzheimer's disease, the repurposing of this medically important biomolecule has to-date been precluded by its high anticoagulant potential. An alternative source to mammalian-derived glycosaminoglycans are those extracted from marine environments and these have been shown to display an expanded repertoire of sequence-space and heterogeneity compared to their mammalian counterparts. Furthermore, many marine-derived glycosaminoglycans appear to retain favourable bioactivities, whilst lacking the high anticoagulant potential of their mammalian counterparts. Here we describe a sulphated, marine-derived glycosaminoglycan extract from the Atlantic Sea Scallop, Placopecten magellanicus that displays high inhibitory potential against BACE-1 (IC50 = 4.8 μg.mL-1) combined with low anticoagulant activity; 25-fold less than that of heparin. This extract possesses a more favourable therapeutic profile compared to pharmaceutical heparin of mammalian provenance and is composed of a mixture of heparan sulphate (HS), with a high content of 6-sulphated N-acetyl glucosamine (64%), and chondroitin sulphate.

Keywords:  Alzheimer's disease; Amyloid-β; BACE-1; Chondroitin sulphate; Glycosaminoglycan; Heparan sulphate; Heparin; Placopecten magellanicus; β-secretase; β-site amyloid precursor protein cleaving enzyme 1

DOI:  https://doi.org/10.1016/j.carres.2023.108747
Int J Nanomedicine. 2023 ;18 663-677

Smart Chondroitin Sulfate Micelles for Effective Targeted Delivery of Doxorubicin Against Breast Cancer Metastasis.

Jingmou Yu, Xin Xie, Liangliang Wang, Wenbo Liu, Huifeng Xu, Xiangmei Lu, Xiaofan Li, Jin Ren, Weidong Li.

   Introduction: Metastasis is a major challenge in breast cancer therapy. The successful chemotherapy of breast cancer largely depends on the ability to block the metastatic process. Herein, we designed a dual-targeting and stimuli-responsive drug delivery system for targeted drug delivery against breast cancer metastasis.
Methods: AS1411 aptamer-modified chondroitin sulfate A-ss-deoxycholic acid (ACSSD) was synthesized, and the unmodified CSSD was used as the control. Chemotherapeutic drug doxorubicin (DOX)-containing ACSSD (D-ACSSD) micelles were prepared by a dialysis method. The ACSSD conjugate was confirmed by Fourier transform infrared spectroscopy (FTIR), nuclear magnetic resonance (NMR), dynamic light scattering (DLS), and transmission electron microscopy (TEM). In vitro cellular uptake and cytotoxicity of D-ACSSD micelles were studied by confocal laser scanning microscopy (CLSM) and MTT assay in breast tumor cells. The inhibition capability of D-ACSSD micelles in cell migration and invasion was carried out in 4T1 cells. In vivo antitumor activity of DOX-containing micelles was investigated in metastatic 4T1-bearing Balb/c mice.
Results: D-ACSSD and DOX-loaded CSSD (D-CSSD) micelles exhibited high drug encapsulation content and reduction-responsive characteristics. D-ACSSD micelles were spherical in shape. Compared with D-CSSD, D-ACSSD showed higher cellular uptake and more potent killing activity in 4T1 and MDA-MB-231 cells. Additionally, D-ACSSD exhibited stronger inhibitory effects on the invasion and migration of highly metastatic 4T1 cells than unmodified D-CSSD. Among the DOX-containing formulations, D-ACSSD micelles presented the most effective inhibition of tumor growth and lung metastasis in orthotopic 4T1-bearing mice in vivo. It also revealed that ACSSD micelles did not exhibit obvious systemic toxicity.
Conclusion: The smart D-ACSSD micelles could be a promising delivery system for the therapy of metastatic breast cancer.

Keywords:  breast cancer therapy; drug delivery; dual-targeting; metastasis; reduction-sensitive micelles

DOI:  https://doi.org/10.2147/IJN.S398802
Sci Immunol. 2023 Feb 24. 8(80): eadd1728

Heparan sulfate regulates IL-21 bioavailability and signal strength that control germinal center B cell selection and differentiation.

Zhian Chen, Yanfang Cui, Yin Yao, Bo Liu, Joseph Yunis, Xin Gao, Naiqi Wang, Pablo F Cañete, Zewen Kelvin Tuong, Hongjian Sun, Hao Wang, Siling Yang, Runli Wang, Yew Ann Leong, David Simon Davis, Jiahuan Qin, Kaili Liang, Jun Deng, Conan K Wang, Yen-Hua Huang, Jonathan A Roco, Sam Nettelfield, Huaming Zhu, Huajun Xu, Zhijia Yu, David Craik, Zheng Liu, Hai Qi, Christopher Parish, Di Yu.

In antibody responses, mutated germinal center B (BGC) cells are positively selected for reentry or differentiation. As the products from GCs, memory B cells and antibody-secreting cells (ASCs) support high-affinity and long-lasting immunity. Positive selection of BGC cells is controlled by signals received through the B cell receptor (BCR) and follicular helper T (TFH) cell-derived signals, in particular costimulation through CD40. Here, we demonstrate that the TFH cell effector cytokine interleukin-21 (IL-21) joins BCR and CD40 in supporting BGC selection and reveal that strong IL-21 signaling prioritizes ASC differentiation in vivo. BGC cells, compared with non-BGC cells, show significantly reduced IL-21 binding and attenuated signaling, which is mediated by low cellular heparan sulfate (HS) sulfation. Mechanistically, N-deacetylase and N-sulfotransferase 1 (Ndst1)-mediated N-sulfation of HS in B cells promotes IL-21 binding and signal strength. Ndst1 is down-regulated in BGC cells and up-regulated in ASC precursors, suggesting selective desensitization to IL-21 in BGC cells. Thus, specialized biochemical regulation of IL-21 bioavailability and signal strength sets a balance between the stringency and efficiency of GC selection.

DOI: https://doi.org/10.1126/sciimmunol.add1728
Life Sci. 2023 Feb 14. pii: S0024-3205(23)00111-X. [Epub ahead of print] 121477

Attenuation of indoxyl sulfate-induced cell damage by cinchonidine-a Cinchona alkaloid-through the downregulation of p53 signaling pathway by promoting MDM2 cytoplasmic-nuclear shuttling in endothelial cells.

Ruei-Dun Teng, Chih-Hao Yang, Chi-Li Chung, Joen-Rong Sheu, Cheng-Ying Hsieh.

  Renocardiac syndromes are a critical concern among patients with chronic kidney disease (CKD). High level of indoxyl sulfate (IS), a protein-bound uremic toxin, in plasma is known to promote the pathogenesis of cardiovascular diseases by impairing endothelial function. However, the therapeutic effects of the adsorbent of indole, a precursor of IS, on renocardiac syndromes is still debated. Therefore, novel therapeutic approaches should be developed to treat IS-associated endothelial dysfunction. In the present study, we have found that cinchonidine, a major Cinchona alkaloid, exhibited superior cell-protective effects among the 131 test compounds in IS-stimulated human umbilical vein endothelial cells (HUVECs). IS-induced cell death, cellular senescence, and impairment of tube formation in HUVECs were substantially reversed after treatment with cinchonidine. Despite the cinchonidine did not alter reactive oxygen species formation, cellular uptake of IS and OAT3 activity, RNA-Seq analysis showed that the cinchonidine treatment downregulated p53-modulated gene expression and substantially reversed IS-caused G0/G1 cell cycle arrest. Although the mRNA levels of p53 were not considerably downregulated by cinchonidine in IS-treated HUVECs, the treatment of cinchonidine promoted the degradation of p53 and the cytoplasmic-nuclear shuttling of MDM2. Cinchonidine exhibited cell-protective effects against the IS-induced cell death, cellular senescence, and impairment of vasculogenic activity in HUVECs through the downregulation of p53 signaling pathway. Collectively, cinchonidine may be a potential cell-protective agent to rescue IS-induced endothelial cell damage.

Keywords:  Cinchonidine; Endothelial dysfunction; Indoxyl sulfate; MDM2; Renocardiac syndromes; p53

DOI:  https://doi.org/10.1016/j.lfs.2023.121477
Food Chem Toxicol. 2023 Feb 10. pii: S0278-6915(23)00066-2. [Epub ahead of print] 113664

Inhibition of human sulfotransferases (SULTs) by per- and polyfluoroalkyl substances (PFASs) and structure-activity relationship.

Yong-Zhe Liu, Kai Yang, Wei Zhang, Qian Zhang, Tong-Feng Liu, Tong Xu, Yang Li, Rui-Xue Ran, Kun Yang, Yun-Feng Cao, Zhong-Ze Fang.

  Per- and poly-fluoroalkyl substances (PFASs) are a family of highly fluorinated aliphatic substances widely used in industrial and commercial applications. This study aims to determine the inhibition of PFASs towards sulfotransferases (SULTs) activity, and trying to explain the toxicity mechanism of PFASs. In vitro recombinant SULTs-catalyzed sulfation of p-nitrophenol (PNP) was utilized as a probe reaction. The incubation system was consisted of PFASs, SULTs, PNP, 3'-phosphoadenosine-5'-phosphosulfate, MgCl2 and Tris-HCl buffer. Ultra-performance liquid chromatography was employed for analysis of the metabolites. All tested PFASs showed inhibition towards SULTs. The longer the carbon chain length of the PFASs terminated with -COOH, the higher is its capability of inhibiting SULT1A3. PFASs with -SO3H had a relatively higher ability to inhibit SULT1A3 activity than those with -COOH, -I and -OH. The inhibition kinetic parameter was 2.16 and 1.42 μM for PFOS-SULT1A1, PFTA-SULT1B1. In vitro in vivo extrapolation showed that the concentration of PFOS and PFTA in human matrices might be higher than the threshold for inducing inhibition of SULTs. Therefore, PFASs could interfere with the metabolic pathways catalyzed by SULTs in vivo. All these results will help to understand the toxicity of PFASs from the perspective of metabolism.

Keywords:  In vitro-in vivo extrapolation; Metabolic toxicity; Structure-inhibition relationships; Sulfotransferases inhibition; per- and poly-fluoroalkyl substances

DOI:  https://doi.org/10.1016/j.fct.2023.113664
Biophys J. 2023 Feb 10. pii: S0006-3495(22)02705-9. [Epub ahead of print]122(3S1): 319a

Directly mapping the O-sulfation sites within CCR2 via an engineered nanopore.

Hongyan Niu, Meng-Yin Li, Xue-Yuan Wu, Yi-Tao Long.

DOI: https://doi.org/10.1016/j.bpj.2022.11.1789
Pharmacol Rev. 2023 Feb 15. pii: PHARMREV-AR-2022-000684. [Epub ahead of print]

PHARMACOLOGY OF HEPARIN AND RELATED DRUGS: AN UPDATE.

John Hogwood, Barbara Mulloy, Rebecca Lever, Elaine Gray, Clive P Page.

  Heparin has been used extensively as an antithrombotic and anticoagulant for close to 100 years. This anticoagulant activity is attributed to the pentasaccharide sequence which potentiates the inhibitory action of antithrombin, a major inhibitor of the coagulation cascade. More recently it has been determined that heparin also has antithrombotic action through interference of the formation of neutrophil extracellular traps which have been determined to play a role in thrombosis. This demonstrated a well-known observation that heparin, given it is a highly negatively charged polysaccharide, interacts with a broad range of biomolecules demonstrating attenuating effect. Since our previous review, there has been an increased interest in these non-anticoagulant effects of heparin, with the beneficial role in patients infected with sars2-coronavirus a highly topical example. This article provides an update on our previous review with more recent developments and observations made for these novel uses of heparin and an overview of the development status of heparin-based drugs. Significance Statement This state of the art review covers recent developments in the use of heparin and heparin-like materials as anticoagulant, now including immuno-thrombosis observations, and as non-anticoagulant including a role in the treatment of sars-coronavirus and inflammatory conditions.

Keywords:  Anti-cancer agents; anti-inflammatory drugs; anticoagulants; drug development/discovery; heparin

DOI:  https://doi.org/10.1124/pharmrev.122.000684