bims-supasi 2025-02-02 papers

bims-supasi

Biomed News

on Sulfation pathways and signalling

Issue of 2025–02–02
ten papers selected by
Jonathan Wolf Mueller, University of Birmingham

Porcine-Derived Chondroitin Sulfate Sodium Alleviates Osteoarthritis in HTB-94 Cells and MIA-Induced SD Rat Models.
Divergent Chemoenzymatic Synthesis of Sulfated Ganglio-Oligosaccharides for Probing Ligand Requirements of Glycan Binding Proteins.
Fabrication and characterization of teriflunomide-loaded chondroitin sulfate hybridized zein nanoparticles for the management of triple negative breast cancer.
Development and Characterization of Lyophilized Chondroitin Sulfate-Loaded Solid Lipid Nanoparticles: Encapsulation Efficiency and Stability.
A Network Pharmacology Study and Experimental Validation to Identify the Potential Mechanism of Heparan Sulfate on Alzheimer's Disease-Related Neuroinflammation.
Chondroitin Sulphate-Chitosan Based Nanogels Loaded with Naringenin-β-Cyclodextrin Complex as Potential Tool for the Treatment of Diabetic Retinopathy: A Formulation Study.
Mechanistic studies of chondroitin sulfate/dermatan sulfate isolated from freshwater fish discards on osteogenesis in MC3T3-E1 cells.
Chondroitin sulfate-based dissolvable microneedles loaded with NIR-II photothermal and natural anticancer agents for synergistic melanoma therapy.
Tuning of sulfur flows and sulfur seed metabolism in oilseed rape facing sulfate limited conditions.
Progesterone sulfates are enterohepatically recycled and stimulate G protein-coupled bile acid receptor 1-mediated gut hormone release.

Int J Mol Sci. 2025 Jan 09. pii: 521. [Epub ahead of print]26(2):

Porcine-Derived Chondroitin Sulfate Sodium Alleviates Osteoarthritis in HTB-94 Cells and MIA-Induced SD Rat Models.

Hyelim Kim, Jinhee Kim, Seong-Hoo Park, Jinhak Kim, Yuri Gwon, Minhee Lee, Soo-Jeung Park.

  Osteoarthritis (OA) is a chronic disease characterized by cartilage degradation, leading to bone friction, inflammation, stiffness, pain, and reduced mobility. This study investigates the therapeutic effects of porcine-derived chondroitin sulfate sodium (CS) on OA symptoms at both cellular and animal levels. In vitro study, HTB-94 chondrocytes were treated with inflammatory stimuli and CS (10, 50, 100, and 200 μg/mL) to assess the release of inflammatory mediators and the expression of genes and proteins related to cartilage synthesis and degradation. In vivo study, an MIA-induced OA rat model was used, and CS (62, 124, and 248 mg/kg b.w.) was orally administered for 4 weeks. Key parameters, such as exercise capacity, micro-CT, histological evaluation of joint tissues, serum inflammatory markers, and the expression of mRNA and proteins (inflammatory, cartilage synthesis and degradation, and apoptosis markers), were analyzed. Porcine-derived CS significantly reduced PGE2, NO, and extracellular matrix degradation marker (COMP and CTX-II) levels and increased the expression of cartilage synthesis-related genes and proteins in both HTB-94 cells and the MIA-induced rats. Additionally, CS modulated cartilage degradation pathways and notably inhibited apoptosis in vivo. The effects of porcine CS were comparable to the NSAID ibuprofen, demonstrating its potential as an anti-inflammatory and chondroprotective agent for OA management and dietary supplementation.

Keywords:  HTB-94; MIA; apoptosis; chondroitin; inflammation; joint cartilage; osteoarthritis

DOI:  https://doi.org/10.3390/ijms26020521
Angew Chem Int Ed Engl. 2025 Jan 31. e202415521

Divergent Chemoenzymatic Synthesis of Sulfated Ganglio-Oligosaccharides for Probing Ligand Requirements of Glycan Binding Proteins.

Mehman I Bunyatov, Margreet A Wolfert, Geert-Jan Boons.

  Sulfoglycolipids are an important class of acidic glycosphingolipids implicated in a multitude of biological processes. Little is known about the interactome of sulfated gangliosides, and it is not well understood how a possible interplay between sialylation and sulfation influences molecular recognition. We describe a chemoenzymatic strategy that readily provided a panel of twenty-one sulfated and sialylated ganglio-oligosaccharides. It is based on the chemical synthesis of a core tetra- and pentasaccharide that are equipped with the orthogonal protecting groups allyloxycarbonate, levulinate ester and t-butyldimethylsilyl ether. Selective removal of one or more protecting groups followed by sulfation of the resulting alcohol(s) and deprotecting gave several ganglio-oligosaccharides. Compound lacking an internal sialic acid could be prepared by exposing several derivatives to a sialidase. Compounds having an unmodified terminal galactoside could enzymatically be sialylated to give hybrid structures, which could be further extended to provide 2,8-sialosides. The synthetic glycans were printed as a microarray which was used to examine ligand requirements of a series of glycan-binding proteins including antibodies, toxins, galectins and siglecs. It was found that sulfation regulates protein binding in complex manners and in general sulfation and sialylation of C-3 of the terminal Gal influences protein binding in different ways.

Keywords:  Carbohydrates; Enzyme catalysis; gangliosides; glycosylation; sulfates

DOI:  https://doi.org/10.1002/anie.202415521
Int J Biol Macromol. 2025 Jan 24. pii: S0141-8130(25)00865-7. [Epub ahead of print]300 140316

Fabrication and characterization of teriflunomide-loaded chondroitin sulfate hybridized zein nanoparticles for the management of triple negative breast cancer.

Naveen Rajana, Lakshmi Tulasi Naraharisetti, Nalla Usha Kumari, Ravindra Vasave, Sri Pada Datta Chigurupati, Anamika Sharma, Chandraiah Godugu, Neelesh Kumar Mehra.

  The objective of this work was to explore the Teriflunomide (TFM) -loaded chondroitin sulfate hybridized zein nanoparticles (TZCNPs) for the treatment of triple-negative breast cancer (TNBC). The particle size, PDI and %EE of optimized TZCNPs was found 208.7 ± 7.26 nm,0.173 ± 0.004, and 80.18 ± 1.03 %, respectively. TZCNPs demonstrate a 7-10 folds increase in cytotoxicity against free TFM in MDA-MB-231 cells and a 4-6 folds increase in MCF-7 cells, respectively. CD44 receptor blocking resulted in a 3.4-fold reduction in anti-cancer efficacy and a 1.7-fold decrease in cellular uptake of TZCNPs in MDA-MB-231 cells, significantly/strongly indicating the critical role of the CD44-mediated uptake mechanism. TZCNPs displayed enhanced apoptosis, mitochondrial depolarization, ROS generation, cell invasion inhibition, and inhibited colony formation compared to free TFM in MDA-MB-231 cells. TZCNPs exhibited approximately 6.8-fold enhanced cytotoxicity and a 1.66-fold decrease in spheroid volume in a multicellular tumor spheroid model of MDA-MB-231 cells compared to free TFM. TZCNPs also exhibited greater disintegration of spheroids and more dead cells (live/dead staining). In pharmacokinetic studies, TZCNPs displayed reduced CL and enhanced the AUC, MRT, and t ½ by 3.64-fold, 2.17-fold, 1.83-fold, and 1.73-fold than the free TFM suspension. An acute toxicity study revealed a good safety profile of TZCNPs, which could be a potential treatment option for TNBC.

Keywords:  Chondroitin sulfate; Multicellular Tumor Spheroid (MCTS) model; TNBC; Teriflunomide; Zein

DOI:  https://doi.org/10.1016/j.ijbiomac.2025.140316
Pharmaceutics. 2025 Jan 10. pii: 86. [Epub ahead of print]17(1):

Development and Characterization of Lyophilized Chondroitin Sulfate-Loaded Solid Lipid Nanoparticles: Encapsulation Efficiency and Stability.

Marta E Bustos Araya, Anna Nardi Ricart, Ana C Calpena Campmany, Rafel Prohens, Montserrat Miñarro Carmona.

  This study explores the development and characterization of lyophilized chondroitin sulfate (CHON)-loaded solid lipid nanoparticles (SLN) as an innovative platform for advanced drug delivery. Background/Objectives: Solid lipid nanoparticles are increasingly recognized for their biocompatibility, their ability to encapsulate diverse compounds, their capacity to enhance drug stability, their bioavailability, and their therapeutic efficacy. Methods: CHON, a naturally occurring glycosaminoglycan with anti-inflammatory and regenerative properties, was integrated into SLN formulations using the hot microemulsion technique. Two formulations (SLN-1 and SLN-2) were produced and optimized by evaluating critical physicochemical properties such as particle size, zeta potential, encapsulation efficiency (EE%), and stability. The lyophilization process, with the addition of various cryoprotectants, revealed trehalose to be the most effective agent in maintaining nanoparticle integrity and functional properties. Results: Morphological analyses using transmission electron microscopy (TEM) and atomic force microscopy (AFM) confirmed the dimensions of the nanoscales and their structural uniformity. Differential scanning calorimetry (DSC) and X-ray diffraction (XRD) revealed minimal excipient interaction with CHON, ensuring formulation stability. Stability studies under different environmental conditions highlighted that SLN-2 is the most stable formulation, maintaining superior encapsulation efficiency (≥88%) and particle size consistency over time. Conclusions: These findings underscore the potential of CHON-loaded SLNs as promising candidates for targeted, sustained-release therapies in the treatment of inflammatory and degenerative diseases.

Keywords:  chondroitin sulfate; encapsulation efficiency; lyophilization; solid lipid nanoparticles; stability studies

DOI:  https://doi.org/10.3390/pharmaceutics17010086
Biomedicines. 2025 Jan 05. pii: 103. [Epub ahead of print]13(1):

A Network Pharmacology Study and Experimental Validation to Identify the Potential Mechanism of Heparan Sulfate on Alzheimer's Disease-Related Neuroinflammation.

Dong-Uk Kim, Bitna Kweon, Jinyoung Oh, Yebin Lim, Gyeongran Noh, Jihyun Yu, Hyang-Rin Kang, Tackmin Kwon, Kwang Youll Lee, Gi-Sang Bae.

   BACKGROUND/OBJECTIVES: Heparan sulfate (HS) is a polysaccharide that is found on the surface of cells and has various biological functions in the body.
METHODS: The purpose of this study was to predict the pharmacological effects and molecular mechanisms of HS on Alzheimer's disease (AD) and neuroinflammation (NI) through a network pharmacology analysis and to experimentally verify them.
RESULTS: We performed functional enrichment analysis of common genes between HS target genes and AD-NI gene sets and obtained items such as the "Cytokine-Mediated Signaling Pathway", "Positive Regulation Of MAPK Cascade", and "MAPK signaling pathway". To confirm the predicted results, the anti-inflammatory effect of HS was investigated using lipopolysaccharide (LPS)-stimulated BV2 microglia cells. HS inhibited the production of nittic oxide, interleukin (IL)-6, and tumor necrosis factor-α in LPS-stimulated BV2 cells, but not IL-1β. In addition, HS inactivated P38 in the MAPK signaling pathway.
CONCLUSIONS: These findings suggest the potential for HS to become a new treatment for AD and NI.

Keywords:  Alzheimer’s disease; BV2; heparan sulfate; network pharmacology; neuroinflammation

DOI:  https://doi.org/10.3390/biomedicines13010103
Int J Nanomedicine. 2025 ;20 907-932

Chondroitin Sulphate-Chitosan Based Nanogels Loaded with Naringenin-β-Cyclodextrin Complex as Potential Tool for the Treatment of Diabetic Retinopathy: A Formulation Study.

Gaia Zucca, Barbara Vigani, Caterina Valentino, Marco Ruggeri, Nicoletta Marchesi, Alessia Pascale, Giulia Giovilli, Lorenzo Malavasi, Giuseppina Sandri, Silvia Rossi.

   Purpose: The main purpose of the study was the formulation development of nanogels (NHs) composed of chondroitin sulfate (CS) and low molecular weight chitosan (lCH), loaded with a naringenin-β-cyclodextrin complex (NAR/β-CD), as a potential treatment for early-stage diabetic retinopathy.
Methods: Different formulations of NHs were prepared by varying polymer concentration, lCH ratio, and pH and, then, characterized for particle size, zeta potential, particle concentration (particles/mL) and morphology. Cytotoxicity and internalization were assessed in vitro using Human Umbilical Vein Endothelial Cells (HUVEC). The NAR/β-CD complex was prepared and evaluated for morphology, complexation efficiency, and solubility. Finally, the most promising NH prototype was loaded with NAR/β-CD (NH@NAR/β-CD) and further characterized for encapsulation efficiency, loading capacity, opacity and cytotoxicity on HUVEC; in vitro release test and DPPH assay were performed to investigate NH capability to sustain NAR release and NH@NAR/β-CD antioxidant properties, respectively.
Results: NH properties were influenced by polymer concentration, lCH ratio, and pH. N3 (0.5 mg/mL; lCH=1.5:1; pH = 5) and N9 (0.5 mg/mL; lCH=1:1; pH = 5) showed optimal characteristics, including small size (<350 nm) and positive zeta potential, facilitating cellular uptake. The NAR/β-CD complex showed 71% complexation efficiency and enhanced NAR solubility. Since characterized by superior properties and better in vitro biocompatibility, N3 was loaded with NAR/β-CD. N3@NAR/β-CD capability to sustain in vitro NAR release, radical scavenging activity and in vitro biocompatibility were finally demonstrated.
Conclusion: The physico-chemical properties of N3@NAR/β-CD were responsible for their cell uptake, suggesting their potential to target retinal endothelial cells. The high NAR/β-CD complexation efficiency and the sustained NAR release over 72 hours could guarantee the maintenance of an effective drug concentration at the damage site while reducing the injection number. Further studies about the safety and the effectiveness of the intravitreal injection of NHs@NAR/β-CD will be performed on a diabetic animal model.

Keywords:  antioxidant properties; cellular uptake; inclusion complex; intravitreal administration; polyelectrolyte complexation

DOI:  https://doi.org/10.2147/IJN.S488507
Glycoconj J. 2025 Jan 30.

Mechanistic studies of chondroitin sulfate/dermatan sulfate isolated from freshwater fish discards on osteogenesis in MC3T3-E1 cells.

Chandra Gavva, Kunal Sharan, Nandini Chilkunda.

  Glycosaminoglycans (GAGs) are essential bone extracellular matrix molecules that regulate osteoblast differentiation. Numerous studies have explored endogenous and exogenous GAG osteoanabolic activities using appropriate in vitro and in vivo models. However, GAGs' underlying the mechanism of action and structure-function relationships need to be elucidated in detail. Earlier, we showed that exogenous GAG can bring about osteogenesis in pre-osteoblast cells. In the present study, we have elucidated the mechanism of action of exogenous GAGs, especially of the chondroitin sulfate/dermatan sulfate (CS/DS) class on osteogenesis. GAGs were immobilized, and osteoblast differentiation was evaluated in MC3T3-E1 cells. Results indicated that GAGs supported osteoblast differentiation by promoting collagen production, extracellular matrix formation, and subsequent mineralization. We elucidated the mechanisms underlying these effects by assessing the key signaling molecules involved in osteogenesis in response to exogenous CS/DS with/without BMP2. CS/DS alone significantly increased pERK1/2 and ATF4 expression levels differentially in a time-dependent manner without significant effects on BMP2, RUNX2, and pSMAD5 protein expression. On the other hand, CS/DS, in the presence of BMP2, differentially increased BMP2, pSMAD5, pERK1/2, RUNX2, and ATF4 expression levels at various time points. Collectively, these results strongly suggest that CS/DS can promote osteogenesis, and in the presence of BMP2, it could promote SMAD-mediated ERK-dependent osteogenesis.

Keywords:  BMP2; Chondroitin sulfate/dermatan sulfate; Glycosaminoglycans; MC3T3-E1 cells; Osteogenesis

DOI:  https://doi.org/10.1007/s10719-025-10178-x
Int J Biol Macromol. 2025 Jan 22. pii: S0141-8130(25)00772-X. [Epub ahead of print]300 140223

Chondroitin sulfate-based dissolvable microneedles loaded with NIR-II photothermal and natural anticancer agents for synergistic melanoma therapy.

Yushan Li, Zhaoyi Ye, Huiling Ye, Wanting Liang, Zhenxing Pan, Guining Cao, Yaoxun Zeng, Jiapeng Dong, Zhili Ran, Junze Tang, Xinyi Li, Xin Cheng, Yan He, Wen Yan, Xujie Liu.

  Melanoma is characterized by its aggressiveness, high metastatic potential, and numerous mutations, which limit the effectiveness of current treatments. To address this issue, we developed a dissolvable microneedle (MN) system composed of poly(2-ethyl-2-oxazoline) (PEtOz) and chondroitin sulfate (CS). This MN system was loaded with liposomes containing both a NIR-II photothermal small molecule (IRLy) and the natural anticancer agent Gambogic acid (GA), forming Lip(IRLy + GA) MNs. The integration of the dissolvable microneedle with drug-loaded liposomes aligns with the mechanical properties and skin penetration efficiency required for effective drug delivery. It enables minimally invasive, painless, and precise administration of IRLy and GA. Under NIR-II 1064 nm laser irradiation, Lip(IRLy + GA) effectively inhibited melanoma by disrupting blood vessels, inducing apoptosis, and altering mitochondrial membrane potential. In a subcutaneous melanoma (A375) model in nude mice, the combination of Lip(IRLy + GA) and laser treatment demonstrated a synergistic effect, enhancing both photothermal and chemotherapeutic outcomes. This research presents a promising strategy that combines NIR-II photothermal agents with natural chemotherapeutic drugs and highlights the potential of microneedles in combination therapies for superficial skin cancers like melanoma.

Keywords:  Chemotherapy; Chondroitin sulfate; Melanoma; Microneedle; Photothermal therapy

DOI:  https://doi.org/10.1016/j.ijbiomac.2025.140223
J Exp Bot. 2025 Jan 27. pii: eraf028. [Epub ahead of print]

Tuning of sulfur flows and sulfur seed metabolism in oilseed rape facing sulfate limited conditions.

Philippe D'Hooghe, Stanislav Kopriva, Jean-Christophe Avice, Jacques Trouverie.

  The response of oilseed rape to sulfur (S) restriction usually consists of increasing the components of S utilization efficiency (absorption, assimilation and remobilization) to provide S to seeds. However, source-sink relationships and S management in developing seeds under sulfate restriction are poorly understood. To address this, impacts of sulfate restrictions applied at "visible bud" or "start of pod filling" stages were studied with two genotypes (Aviso, Capitol) showing similar seed yield but higher seed weight and lower number of seeds per plant for Capitol under non-limited conditions. S flows at the whole plant level (using 34S-sulfate labelling) and S metabolism changes (S-compounds, ATP sulfurylase and adenosine 5'phosphosulfate reductase (APR) activities) were followed during seed development. Seed yield, protein quality and accumulation of S metabolites were affected by sulfate restriction less and later in Aviso than in Capitol. This is related to higher S uptake and stronger remobilization of S from vegetative organs to seeds during early seed development in response to sulfate restriction. A higher seed APR activity was observed for Capitol in response to sulfate limitation, suggesting that APR is not limiting for sulfate assimilation and that seed S metabolism is principally devoted to S-amino acids and protein synthesis.

Keywords:   Brassica napus ; APR; fluxes; protein quality; seed development; seed metabolism; source-sink relationships; sulfate limitation; sulfur assimilation; sulfur/nitrogen interactions

DOI:  https://doi.org/10.1093/jxb/eraf028
Am J Physiol Gastrointest Liver Physiol. 2025 Jan 31.

Progesterone sulfates are enterohepatically recycled and stimulate G protein-coupled bile acid receptor 1-mediated gut hormone release.

Alice L Mitchell, Iain R Tough, Hei Man Fan, Anita Lovgren-Sandblom, Caroline Ovadia, Jenny Chambers, Patricia Fonseca Pedro, Anastasia Tsakmaki, Gavin A Bewick, Hanns-Ulrich Marschall, Helen M Cox, Catherine Williamson.

  Sulfated progesterone metabolites (PMxS) increase during gestation and are raised further in intrahepatic cholestasis of pregnancy (ICP), a disorder characterised by pruritus and elevated serum bile acids. PMxS interact with bile acid receptor G protein-coupled bile acid receptor 1 (GPBAR1) to cause itch. We investigated whether PMxS could undergo enterohepatic recycling and stimulate intestinal GPBAR1-mediated release of gut hormones glucagon-like peptide-1 (GLP-1) and peptide YY (PYY). PMxS were quantified in pre-/postprandial serum samples (n=21) and feces (n=18) by ultra-performance liquid chromatography-tandem mass spectrometry in prospectively recruited third trimester of pregnancy outpatients with uncomplicated pregnancy or ICP. Ussing chambers were used to evaluate colonic ion secretion changes (ΔIsc) in wildtype, GPBAR1-/-, and PYY-/- mice by PMxS metabolites, PM3S and PM5S, and in wildtype mice with or without apical sodium bile acid transporter (ASBT) inhibition (n=6/condition). PM3S/PM5S stimulation of GLP-1 release from wildtype and GPBAR1-/- murine crypts and human colonoids was measured by ELISA (n=3). Serum PMxS increase postprandially in women with ICP but are unaltered in uncomplicated pregnancies. PMxS are present in feces. Apical and basolateral PM3S and PM5S stimulated PYY-mediated -ΔIsc in wildtype (p<0.01) but not GPBAR1-/- or PYY-/- colons. PM3S and PM5S caused GLP-1 secretion in murine crypts and human colonoids (p<0.001). ASBT inhibition blunted -ΔIsc by 68% after apical PM3S and PM5S addition (p<0.001). Serum PMxS, elevated in women with ICP and particularly postprandially, can undergo ASBT-mediated intestinal reuptake and activate GPBAR1 to stimulate gut hormone release. PMxS may therefore augment GPBAR1-mediated metabolic responses during pregnancy.

Keywords:  enterohepatic recycling; gut hormones; intrahepatic cholestasis of pregnancy; prandial; progesterone sulfate metabolites

DOI:  https://doi.org/10.1152/ajpgi.00211.2024