bims-supasi 2024-11-10 papers

bims-supasi

Biomed News

on Sulfation pathways and signalling

Issue of 2024–11–10
ten papers selected by
Jonathan Wolf Mueller, University of Birmingham

Synergistic defense: Quercetin and chondroitin sulfate combat bacterial trigger of rheumatoid arthritis, Proteus mirabilis through in-vitro and in-vivo mechanisms.
Preparation and structural characterization of a sulfated octasaccharide with heparin-like anticoagulant activity.
Enhancing BMP-2-mediated osteogenesis with a synthetic heparan sulfate mimetic.
Enhancing intrinsic TGF-β signaling via heparan sulfate glycosaminoglycan regulation to promote mesenchymal stem cell capabilities and chondrogenesis for cartilage repair.
The role of heparan sulfate in enhancing the chemotherapeutic response in triple-negative breast cancer.
Using chondroitin sulfate lithium hydrogel for diabetic bone regeneration via regulation of macrophage polarization.
Molecular dynamics simulation: Effect of sulfation on the structure of curdlan triple helix in aqueous solution.
Sulfated peptides: key players in plant development, growth, and stress responses.
Metabolomics reveals that sulfotransferase 1 may regulate colchicine-induced liver injury.
Bilirubin-Modified Chondroitin Sulfate-Mediated Multifunctional Liposomes Ameliorate Acute Kidney Injury by Inducing Mitophagy and Regulating Macrophage Polarization.

Microb Pathog. 2024 Oct 26. pii: S0882-4010(24)00553-9. [Epub ahead of print] 107086

Synergistic defense: Quercetin and chondroitin sulfate combat bacterial trigger of rheumatoid arthritis, Proteus mirabilis through in-vitro and in-vivo mechanisms.

P Snega Priya, Raghul Murugan, R Srileka, S P Ramya Ranjan Nayak, M Thirumal, Rajakrishnan Rajagopal, Mukesh Pasupuleti, Kathiravan Muthu Kumarodoss, Jesu Arockiaraj.

  Rheumatoid arthritis, a chronic autoimmune disorder characterized by joint inflammation, is thought to be exacerbated by bacterial infections, notably Proteus mirabilis. This study explores the combined effects of quercetin, a potent antioxidant and anti-inflammatory flavonoid, and chondroitin sulfate, known for its cartilage-protective properties, as a potential therapeutic approach. Molecular docking analyses revealed favourable interactions between these compounds and key pro-inflammatory cytokines IL-6 and TNF-α, suggesting their potential to disrupt inflammation-related signaling pathways. In vitro assays demonstrated that the quercetin- chondroitin sulfate combination (1:1 ratio) significantly inhibited oxidative stress and hemolysis, highlighting its enhanced anti-inflammatory and membrane-protective effects. The free radical scavenging assays further confirmed the antioxidant potential of this combination, which demonstrated strong radical scavenging activity. Antimicrobial assays showed notable antibacterial effects, with an increased inhibition zone against P. mirabilis when quercetin and chondroitin sulfate were combined, suggesting a synergistic antimicrobial action. In vivo, zebrafish subjected to bacterial stress showed improved survival rates with the quercetin and chondroitin sulfate combination treatment, along with enhanced mineralization and significant modulation of alkaline phosphatase (ALP) and tartrate-resistant acid phosphatase (TRAP) activities, indicating its protective role in maintaining joint health. Furthermore, gene expression analysis revealed a substantial reduction in pro-inflammatory markers, including TNF-α and IL-6, demonstrating the quercetin and chondroitin sulfate combination's ability to mitigate inflammation. Together, these findings suggest that the quercetin and chondroitin sulfate combination hold significant therapeutic potential in reducing oxidative stress, inflammation, and microbial-induced RA exacerbations.

Keywords:  Antibacterial activity; Chondroitin sulphate; Proteus mirabilis; Quercetin; Rheumatoid arthritis

DOI:  https://doi.org/10.1016/j.micpath.2024.107086
Carbohydr Polym. 2025 Jan 01. pii: S0144-8617(24)01008-7. [Epub ahead of print]347 122782

Preparation and structural characterization of a sulfated octasaccharide with heparin-like anticoagulant activity.

Ning Yu, Rui Fang, Zhao Ding, Xi Xu, Jianfa Zhang.

  Heparins are sulfated polysaccharides with a heterogeneous mixture derived from animal tissues, subject to supply limitations and the risk of animal virus residues. Patients using heparin also face the risks of spontaneous bleeding and thrombocytopenia. Here we reported an efficient riclinoctaose-based approach for rapid chemical synthesis of a structurally defined heparin-like anticoagulant sulfated octasaccharide (SRO). We used sulfur trioxide-pyridine, sulfur trioxide-trimethylamine, and sulfur trioxide-triethylamine complexes as solvents for one-pot O-sulfation and determined the optimal conditions for synthesizing SRO. Sulfur trioxide-trimethylamine provided reasonable control over the degree of substitution between 1.85 and 1.88, revealing a single molecule with a theoretical molecular weight of 2952.96 g/mol. The structural features of the SRO were carried out by Fourier transform infrared spectroscopy and one- and two- dimensional 1H and 13C NMR analysis, revealing sulfation repeatedly present at the fixed positions of C-6/C-2/C-3 and reducing terminals. The anticoagulant activity of SRO was demonstrated by efficiently blocking coagulation in the blood of mice and human. SRO dose-dependently decreased ferric chloride-induced experimental thrombosis in mice. Like heparin, SRO specifically inhibits coagulation factor Xa, but significantly reduces the risk of bleeding compared to heparin. Therefore, we named it octaparin. These results support that octaparin is expected to replace animal-sourced heparin.

Keywords:  Anticoagulant effect; Riclinoctaose; Sulfated oligosaccharide; Sulfur trioxide-trimethylamine complexes

DOI:  https://doi.org/10.1016/j.carbpol.2024.122782
Biomater Adv. 2023 Oct 24. pii: S2772-9508(23)00394-1. [Epub ahead of print]155 213671

Enhancing BMP-2-mediated osteogenesis with a synthetic heparan sulfate mimetic.

Raymond A A Smith, Xiaoman Luo, Xiaohua Lu, Tuan Chun Tan, Bach Q Le, Olga V Zubkova, Peter C Tyler, Victor Nurcombe, Simon M Cool.

  Bone morphogenetic protein 2 (BMP-2) is an osteoinductive protein and a potent inducers of bone formation, playing an essential role during bone fracture repair. Heparan sulfate (HS), a highly charged and linear polysaccharide, is known to interact with and enhance BMP-2 bioactivity. Despite showing potential as a potent adjuvant of the endogenous bone healing response, commercially available HS is derived from animal sources which are less desirable when considering translation into the clinic. In the present study, we screen twenty glycomimetics against BMP-2 to determine if fully synthetic analogues of HS can enhance the bioactivity of BMP-2 in vitro and bone healing in vivo. We found that a four-armed dendrimer harboring oversulfated maltose residues could bind BMP-2 with high affinity, enhance BMP-2 bioactivity in vitro and enhance bone regeneration in vivo. These data suggest fully synthetic glycomimetics are viable alternatives to naturally derived HS and offer an attractive alternative for clinical translation.

Keywords:  BMP-2; Bone repair; Glycomimetic; Heparan sulfate; Osteogenesis

DOI:  https://doi.org/10.1016/j.bioadv.2023.213671
Int J Biol Macromol. 2024 Nov 04. pii: S0141-8130(24)08051-6. [Epub ahead of print] 137242

Enhancing intrinsic TGF-β signaling via heparan sulfate glycosaminoglycan regulation to promote mesenchymal stem cell capabilities and chondrogenesis for cartilage repair.

Pei-Hsuan Chung, Feng-Huei Lin, I-Hsuan Liu.

  Osteoarthritis burdens patients due to the limited regenerative capacity of chondrocytes. Traditional cartilage repair often falls short, necessitating innovative approaches. Mesenchymal stem cells (MSCs) show promise for regeneration. Heparan sulfate glycosaminoglycans (HS-GAGs) regulate cellular functions, making them a target for cartilage repair. This study highlights how Heparinase III (HepIII) cleaves intact HS-GAGs in bone marrow-derived MSCs (BM-MSCs), enhancing their capabilities and specifically promoting chondrogenesis. HepIII-treated BM-MSCs cultured in a hanging drop device for three days, significantly increased cell number and aggregation into a cell sphere with early chondrogenesis. HepIII promoted BM-MSCs toward chondrogenesis, increasing type II collagen, intact HS-GAGs, and sulfated GAG content, while upregulating chondrogenic and heparan sulfate proteoglycan genes. Treatment with the TGF-β inhibitor (SB-431542) in HepIII-treated BM-MSCs demonstrated enhanced intrinsic transforming growth factor-β (TGF-β) signaling and fibronectin expression. This approach also boosted BM-MSC self-renewal, immunosuppressive potential, and modified acetylated histone signatures, offering a cost-effective strategy for cartilage repair by addressing inflammation, metabolic changes, and the high costs of traditional TGF-β methods. From the results, HepIII-treated BM-MSCs show potential for use in combination with other biopolymers as injectable gels to improve cartilage repair in osteoarthritis patients in the near future.

Keywords:  BM-MSC; Chondrogenesis; HS-GAG; Heparinase III enzyme; Immunosuppressive potential; Intrinsic TGF-β signaling; Self-renewal activity

DOI:  https://doi.org/10.1016/j.ijbiomac.2024.137242
Breast Cancer Res. 2024 Nov 06. 26(1): 153

The role of heparan sulfate in enhancing the chemotherapeutic response in triple-negative breast cancer.

Jasmine M Manouchehri, Jharna Datta, Lynn M Marcho, Jesse J Reardon, Daniel Stover, Robert Wesolowski, Uma Borate, Ting-Yuan David Cheng, Patrick M Schnell, Bhuvaneswari Ramaswamy, Gina M Sizemore, Mark P Rubinstein, Mathew A Cherian.

   BACKGROUND: Breast cancer, one of the most common forms of cancer, is associated with the highest cancer-related mortality among women worldwide. In comparison to other types of breast cancer, patients diagnosed with the triple-negative breast cancer (TNBC) subtype have the worst outcome because current therapies do not produce long-lasting responses. Hence, innovative therapies that produce persisting responses are a critical need. We previously discovered that hyperactivating purinergic receptors (P2RXs) by increasing extracellular adenosine triphosphate (eATP) concentrations enhances TNBC cell lines' response to chemotherapy. Heparan sulfate inhibits multiple extracellular ATPases, so it is a molecule of interest in this regard. In turn, heparanase degrades polysulfated polysaccharide heparan sulfate. Importantly, previous work suggests that breast cancer and other cancers express heparanase at high levels. Hence, as heparan sulfate can inhibit extracellular ATPases to facilitate eATP accumulation, it may intensify responses to chemotherapy. We postulated that heparanase inhibitors would exacerbate chemotherapy-induced decreases in TNBC cell viability by increasing heparan sulfate in the cellular microenvironment and hence, augmenting eATP.
METHODS: We treated TNBC cell lines MDA-MB 231, Hs 578t, and MDA-MB 468 and non-tumorigenic immortal mammary epithelial MCF-10A cells with paclitaxel (cytotoxic chemotherapeutic) with or without the heparanase inhibitor OGT 2115 and/or supplemental heparan sulfate. We evaluated cell viability and the release of eATP. Also, we compared the expression of heparanase protein in cell lines and tissues by immunoblot and immunohistochemistry, respectively. In addition, we examined breast-cancer-initiating cell populations using tumorsphere formation efficiency assays on treated cells.
RESULTS: We found that combining heparanase inhibitor OGT 2115 with chemotherapy decreased TNBC cell viability and tumorsphere formation through increases in eATP and activation of purinergic receptors as compared to TNBC cells treated with single-agent paclitaxel.
CONCLUSION: Our data shows that by preventing heparan sulfate breakdown, heparanase inhibitors make TNBC cells more susceptible to chemotherapy by enhancing eATP concentrations.

Keywords:  ATP; Breast cancer; Chemotherapy; Heparan sulfate; Heparanase; Purinergic signaling

DOI:  https://doi.org/10.1186/s13058-024-01906-6
Carbohydr Polym. 2025 Jan 01. pii: S0144-8617(24)01013-0. [Epub ahead of print]347 122787

Using chondroitin sulfate lithium hydrogel for diabetic bone regeneration via regulation of macrophage polarization.

Chenci Xu, Weiqi Li, Jing Mao, Ziyang Liu, An Lao, Lixia Mao, Anqi Gu, Jiaqing Wu, Aili Shen, Kaili Lin, Jiaqiang Liu.

  Bone regeneration in a diabetic environment remains a clinical challenge because of the proinflammatory microenvironment and malfunction of osteogenesis. Traditional therapy for bone defects doesn't work out in diabetes. Therefore, we introduced lithium (Li) into chondroitin sulfate (CS) and developed a crosslinked hydrogel composed of gelatin methacryloyl (GelMA) and chondroitin sulfate lithium (CS-Li) which could release Li in a sustained manner. This crosslinked hydrogel has a porous microstructure, excellent biocompatibility, and osteogenesis properties. With the synergetic effects of CS and Li, this crosslinked hydrogel regulates macrophage polarization to anti-inflammatory phenotype in the high glucose microenvironment and alleviates the inhibition of angiogenesis and osteogenesis caused by diabetes both in vitro and in vivo. The relationship between macrophage polarization and the promotion of angiogenesis and osteogenesis in diabetic microenvironments may be attributed to the activation of Glycogen synthase kinase-3β/β-catenin pathways. Overall, significant results in this study present that CS-Li was a potential therapy for bone defects in diabetic patients.

Keywords:  Chondroitin sulfate; Diabetic bone regeneration; Lithium; Macrophages polarization; Osteoimmunomodulation

DOI:  https://doi.org/10.1016/j.carbpol.2024.122787
Int J Biol Macromol. 2024 Nov 04. pii: S0141-8130(24)07928-5. [Epub ahead of print] 137119

Molecular dynamics simulation: Effect of sulfation on the structure of curdlan triple helix in aqueous solution.

Yufu Gao, Xuan Feng, Ran Zhang, Jie Xiao, Qingrong Huang, Jiawei Li, Tongfei Shi.

  In this work, by using molecular dynamics simulations, we elucidate the effect of sulfation substitution on the stability of the curdlan triple helix structure. The simulation results indicate that the stability of the triple helix structure is significantly influenced by the sites of sulfation substitution. The substitution at the O2 site directly disrupts the hydrogen bonding network between the triple helix chains, significantly destroying the triple helix conformation. When substitutions occur at both the O4 and O6 sites simultaneously (O4,6), the electrostatic repulsion between numerous sulfate groups introduces considerable energy perturbation to the triple helix, leading to alterations in the glucan chain conformation and consequent destabilization of the triple helix structure. Meanwhile, we find that even if the sulfation substitution is performed at the same substitution sites, the difference in the degree of substitution also has an impact on the triple helix stability. The resistance of the triple helix to sulfation substitution at O2 is weak, and low degree of substitution can lead to the unwinding of the triple helix. However, it demonstrates higher resistance to substitution at O4,6 where only higher degree of substitution results in triple helix destabilization.

Keywords:  Conformation; Curdlan; Molecular dynamics; Sulfation; Triple helix

DOI:  https://doi.org/10.1016/j.ijbiomac.2024.137119
Front Plant Sci. 2024 ;15 1474111

Sulfated peptides: key players in plant development, growth, and stress responses.

Penghong Zhang, Jiangzhe Zhao, Wei Zhang, Yongfeng Guo, Kewei Zhang.

  Peptide hormones regulate plant development, growth, and stress responses. Sulfated peptides represent a class of proteins that undergo posttranslational modification by tyrosylprotein sulfotransferase (TPST), followed by specific enzymatic cleavage to generate mature peptides. This process contributes to the formation of various bioactive peptides, including PSKs (PHYTOSULFOKINEs), PSYs (PLANT PEPTIDE CONTAINING SULFATED TYROSINE), CIFs (CASPARIAN STRIP INTEGRITY FACTOR), and RGFs (ROOT MERISTEM GROWTH FACTOR). In the past three decades, significant progress has been made in understanding the molecular mechanisms of sulfated peptides that regulate plant development, growth, and stress responses. In this review, we explore the sequence properties of precursors, posttranslational modifications, peptide receptors, and signal transduction pathways of the sulfated peptides, analyzing their functions in plants. The cross-talk between PSK/RGF peptides and other phytohormones, such as brassinosteroids, auxin, salicylic acid, abscisic acid, gibberellins, ethylene, and jasmonic acid, is also described. The significance of sulfated peptides in crops and their potential application for enhancing crop productivity are discussed, along with future research directions in the study of sulfated peptides.

Keywords:  environmental signals; immunity; phytohormone; plant growth and development; stress response; sulfated peptide

DOI:  https://doi.org/10.3389/fpls.2024.1474111
Chem Biol Interact. 2023 Oct 28. pii: S0009-2797(23)00443-X. [Epub ahead of print] 110776

Metabolomics reveals that sulfotransferase 1 may regulate colchicine-induced liver injury.

Ruoyue Huang, Chunyan Wang, Zhanxuan E Wu, Qi Zhao, Jingyi Duan, Wen Huang, Yan Cheng, Beiwei Zhu, Fei Li.

  Colchicine is widely used to treat gouty arthritis for years. Previous studies showed that colchicine overdose can cause liver damage, yet the mechanism underlying its hepatotoxicity remains unclear. In this study, hepatotoxicity of colchicine was investigated in vivo. Metabolomic analysis of colchicine metabolites and endogenous metabolites was performed using Ultra High Performance Liquid Chromatography (UHPLC) - mass spectrometry (MS). Seventeen metabolites of colchicine were identified, including 3 novel sulfated metabolites. Meanwhile, endogenous sulfated metabolites were found to be decreased by colchicine. Colchicine might regulate sulfotransferase 1 (SULT1) through perixisome proliferation-activated receptor ɑ (PPARα), and inhibition of SULT1 reduced the levels of sulfated metabolites of colchicine. Inhibition of SULT1 aggravated colchicine-induced liver injury, whereas activation of SULT1 attenuated its liver injury. The supplementation of endogenous sulfated metabolites indoxyl sulfate (IS) or p-cresol sulfate (PCS) alleviated colchicine-induced liver injury through modulation of the CASPASE-1-gasdermin D (GSDMD) pathway. These results indicated that colchicine might cause hepatotoxicity through inhibition of SULT1and decreased production of bioactive sulfated endogenous metabolites IS and PCS. Our results provided evidence for potential therapeutic targets and agents to prevent liver injury caused by colchicine. Targeting the SULT1 enzyme and administration of IS and PCS may be useful in alleviating colchicine hepatotoxicity.

Keywords:  Colchicine; Liver injury; Mass spectrometry; Metabolomics analysis; Sulfotransferase

DOI:  https://doi.org/10.1016/j.cbi.2023.110776
ACS Appl Mater Interfaces. 2024 Nov 04.

Bilirubin-Modified Chondroitin Sulfate-Mediated Multifunctional Liposomes Ameliorate Acute Kidney Injury by Inducing Mitophagy and Regulating Macrophage Polarization.

Ziqi Shen, Xiaohua Wang, Li Lu, Runkong Wang, Danni Hu, Ziyan Fan, Liyang Zhu, Ruixue Zhong, Mingquan Wu, Xu Zhou, Xi Cao.

  Acute kidney injury (AKI) is a dynamic process associated with inflammation, oxidative stress, and lipid peroxidation, in which mitochondrial mitophagy and macrophage polarization play a critical role in the pathophysiology. Based on the expression of the CD44 receptor on renal tubular epithelial cells (RTECs) and activated M1 macrophages being abnormally increased, accompanied by up-regulation of reactive oxygen species (ROS) during AKI, the conjugates of bilirubin (BR), an endogenous antioxidant which has the property of anti-inflammation, and chondroitin sulfate (CS) with CD44-targeting property could be a promising therapeutic carrier. In this study, we develop a CD44-targeted/ROS-responsive CS-BR-mediated multifunctional liposome loading celastrol (CS-BR@CLT) for the targeted therapy of AKI. CS-BR@CLT is shown to selectively accumulate in AKI mouse kidneys via targeting of CD44 receptors. Treatment with CS-BR@CLT significantly ameliorates acute kidney injury caused by ischemia-reperfusion and protects renal function. Mechanistically, CS-BR@CLT inhibits apoptosis, protects mitochondria, promotes autophagy, regulates macrophage polarization, and alleviates interstitial inflammation. Overall, our study demonstrates that CS-BR@CLT could be a promising strategy to ameliorate acute kidney injury.

Keywords:  acute kidney injury; autophagy; bilirubin; chondroitin sulfate; macrophage polarization

DOI:  https://doi.org/10.1021/acsami.4c14169