bims-supasi 2023-06-18 papers

bims-supasi

Biomed News

on Sulfation pathways and signalling

Issue of 2023–06–18
twelve papers selected by
Jonathan Wolf Mueller, University of Birmingham

Increased Cerebral Serum Amyloid A2 and Parameters of Oxidation in Arylsulfatase B (N-Acetylgalactosamine-4-Sulfatase)-Null Mice.
Nano-elemental selenium particle developed via supramolecular self-assembly of chondroitin sulfate A and Na2SeO3 to repair cartilage lesions.
The Sea Cucumber Thyonella gemmata Contains a Low Anticoagulant Sulfated Fucan with High Anti-SARS-CoV-2 Actions against Wild-Type and Delta Variants.
Glomerular endothelial glycocalyx-derived heparan sulfate inhibits glomerular leukocyte influx and attenuates experimental glomerulonephritis.
Sulfated Glycomimetic α-Helical Polypeptides for Antiviral Activity.
The αTSR Domain of Plasmodium Circumsporozoite Protein Bound Heparan Sulfates and Elicited High Titers of Sporozoite Binding Antibody After Displayed by Nanoparticles.
Effects of 2-year physical activity and dietary intervention on adrenarchal and pubertal development: the PANIC study.
Oral Delivery of Transformable Bilirubin Self-assembled System for Targeted Therapy of Colitis.
Sulfated carboxymethylcellulose mediated enhancement of Timp3 efficacy synergistically attenuates osteoarthritis through inhibition of NFκB and JNK.
Crosstalk between Circulating Tumor Cells and Plasma Proteins-Impact on Coagulation and Anticoagulation.
Chondroitin Sulfate Proteoglycans Revisited: Its Mechanism of Generation and Action for Spinal Cord Injury.
Structure Characterization, In Vitro Antioxidant and Anti-Tumor Activity of Sulfated Polysaccharide from Siraitia grosvenorii.

J Alzheimers Dis Rep. 2023 ;7(1): 527-534

Increased Cerebral Serum Amyloid A2 and Parameters of Oxidation in Arylsulfatase B (N-Acetylgalactosamine-4-Sulfatase)-Null Mice.

Sumit Bhattacharyya, Joanne K Tobacman.

   Background: Chondroitin sulfate and chondroitin sulfate proteoglycans have been associated with Alzheimer's disease (AD), and the impact of modified chondroitin sulfates is being investigated in several animal and cell-based models of AD. Published reports have shown the role of accumulation of chondroitin 4-sulfate and decline in Arylsulfatase B (ARSB; B-acetylgalactosamine-4-sulfatase) in other pathology, including nerve injury, traumatic brain injury, and spinal cord injury. However, the impact of ARSB deficiency on AD pathobiology has not been reported, although changes in ARSB were associated with AD in two prior reports. The enzyme ARSB removes 4-sulfate groups from the non-reducing end of chondroitin 4-sulfate and dermatan sulfate and is required for their degradation. When ARSB activity declines, these sulfated glycosaminoglycans accumulate, as in the inherited disorder Mucopolysaccharidosis VI.
Objective: Reports about chondroitin sulfate, chondroitin sulfate proteoglycans, and chondroitin sulfatases in AD were reviewed.
Methods: Measurements of SAA2, iNOS, lipid peroxidation, chondroitin sulfate proteoglycan 4 (CSPG4), and other parameters were performed in cortex and hippocampus from ARSB-null mice and controls by QRT-PCR, ELISA, and other standard assays.
Results: SAA2 mRNA expression and protein, CSPG4 mRNA, chondroitin 4-sulfate, and iNOS were increased significantly in ARSB-null mice. Measures of lipid peroxidation and redox state were significantly modified.
Conclusion: Findings indicate that decline in ARSB leads to changes in expression of parameters associated with AD in the hippocampus and cortex of the ARSB-deficient mouse. Further investigation of the impact of decline in ARSB on the development of AD may provide a new approach to prevent and treat AD.

Keywords:  Alzheimer’s disease; N-acetylgalactosamine-4-sulfatase; SAA; arylsulfatase B; chondroitin sulfate; glycosaminoglycan; iNOS; lipid peroxidation; thiol

DOI:  https://doi.org/10.3233/ADR-230028
Carbohydr Polym. 2023 Sep 15. pii: S0144-8617(23)00512-X. [Epub ahead of print]316 121047

Nano-elemental selenium particle developed via supramolecular self-assembly of chondroitin sulfate A and Na2SeO3 to repair cartilage lesions.

Jing Han, Huan Deng, Yang Li, Lichun Qiao, Hongrui Jia, Lan Zhang, Linghang Wang, Chengjuan Qu.

  Cartilage repair is a significant clinical issue due to its restricted ability to regenerate and self-heal after cartilage lesions or degenerative disease. Herein, a nano-elemental selenium particle (chondroitin sulfate A‑selenium nanoparticle, CSA-SeNP) is developed by the supramolecular self-assembly of Na2SeO3 and negatively charged chondroitin sulfate A (CSA) via electrostatic interactions or hydrogen bonds followed by in-situ reducing of l-ascorbic acid for cartilage lesions repair. The constructed micelle exhibits a hydrodynamic particle size of 171.50 ± 2.40 nm and an exceptionally high selenium loading capacity (9.05 ± 0.03 %) and can promote chondrocyte proliferation, increase cartilage thickness, and improve the ultrastructure of chondrocytes and organelles. It mainly enhances the sulfation modification of chondroitin sulfate by up-regulating the expression of chondroitin sulfate 4-O sulfotransferase-1, -2, -3, which in turn promotes the expression of aggrecan to repair articular and epiphyseal-plate cartilage lesions. The micelles combine the bio-activity of CSA with selenium nanoparticles (SeNPs), which are less toxic than Na2SeO3, and low doses of CSA-SeNP are even superior to inorganic selenium in repairing cartilage lesions in rats. Thus, the developed CSA-SeNP is anticipated to be a promising selenium supplementation preparation in clinical application to address the difficulty of healing cartilage lesions with outstanding repair effects.

Keywords:  Aggrecan; Cartilage repair; Chondroitin sulfate 4-O sulfotransferase; Chondroitin sulfate A; Nano-elemental selenium particle

DOI:  https://doi.org/10.1016/j.carbpol.2023.121047
J Nat Prod. 2023 Jun 12.

The Sea Cucumber Thyonella gemmata Contains a Low Anticoagulant Sulfated Fucan with High Anti-SARS-CoV-2 Actions against Wild-Type and Delta Variants.

Rohini Dwivedi, Marwa Farrag, Poonam Sharma, Deling Shi, Anter A Shami, Sandeep K Misra, Priya Ray, Jayanti Shukla, Fuming Zhang, Robert J Linhardt, Joshua S Sharp, Ritesh Tandon, Vitor H Pomin.

In this work, we isolated two new sulfated glycans from the body wall of the sea cucumber Thyonella gemmata: one fucosylated chondroitin sulfate (TgFucCS) (17.5 ± 3.5% kDa) and one sulfated fucan (TgSF) (383.3 ± 2.1% kDa). NMR results showed the TgFucCS backbone composed of [→3)-β-N-acetylgalactosamine-(1→4)-β-glucuronic acid-(1→] with 70% 4-sulfated and 30% 4,6-disulfated GalNAc units and one-third of the GlcA units decorated at the C3 position with branching α-fucose (Fuc) units either 4-sulfated (65%) or 2,4-disulfated (35%) and the TgSF structure composed of a tetrasaccharide repeating unit of [→3)-α-Fuc2,4S-(1→2)-α-Fuc4S-(1→3)-α-Fuc2S-(1→3)-α-Fuc2S-(1→]n. Inhibitory properties of TgFucCS and TgSF were investigated using SARS-CoV-2 pseudovirus coated with S-proteins of the wild-type (Wuhan-Hu-1) or the delta (B.1.617.2) strains and in four different anticoagulant assays, comparatively with unfractionated heparin. Molecular binding to coagulation (co)-factors and S-proteins was investigated by competitive surface plasmon resonance spectroscopy. Among the two sulfated glycans tested, TgSF showed significant anti-SARS-CoV-2 activity against both strains together with low anticoagulant properties, indicating a good candidate for future studies in drug development.

DOI: https://doi.org/10.1021/acs.jnatprod.3c00151
Front Mol Biosci. 2023 ;10 1177560

Glomerular endothelial glycocalyx-derived heparan sulfate inhibits glomerular leukocyte influx and attenuates experimental glomerulonephritis.

Marissa L Maciej-Hulme, Jasper J Van Gemst, Patience Sanderson, Angelique L W M M Rops, Jo H Berden, Bart Smeets, I Jonathan Amster, Ton J Rabelink, Johan Van Der Vlag.

  Proliferative forms of glomerulonephritis are characterized by the influx of leukocytes, albuminuria, and loss of kidney function. The glomerular endothelial glycocalyx is a thick carbohydrate layer that covers the endothelium and is comprised of heparan sulfate (HS), which plays a pivotal role in glomerular inflammation by facilitating endothelial-leukocyte trafficking. We hypothesize that the exogenous glomerular glycocalyx may reduce the glomerular influx of inflammatory cells during glomerulonephritis. Indeed, administration of mouse glomerular endothelial cell (mGEnC)-derived glycocalyx constituents, or the low-molecular-weight heparin enoxaparin, reduced proteinuria in mice with experimental glomerulonephritis. Glomerular influx of granulocytes and macrophages, as well as glomerular fibrin deposition, was reduced by the administration of mGEnC-derived glycocalyx constituents, thereby explaining the improved clinical outcome. HSglx also inhibited granulocyte adhesion to human glomerular endothelial cells in vitro. Notably, a specific HSglx fraction inhibited both CD11b and L-selectin binding to activated mGEnCs. Mass spectrometry analysis of this specific fraction revealed six HS oligosaccharides, ranging from tetra- to hexasaccharides with 2-7 sulfates. In summary, we demonstrate that exogenous HSglx reduces albuminuria during glomerulonephritis, which is possibly mediated via multiple mechanisms. Our results justify the further development of structurally defined HS-based therapeutics for patients with (acute) inflammatory glomerular diseases, which may be applicable to non-renal inflammatory diseases as well.

Keywords:  glomerular endothelial cell; glomerulonephritis; glycocalyx; heparan sulfate; inflammation; leukocyte

DOI:  https://doi.org/10.3389/fmolb.2023.1177560
Biomacromolecules. 2023 Jun 14.

Sulfated Glycomimetic α-Helical Polypeptides for Antiviral Activity.

Xiang Xu, Ruimin Liang, Yubin Zheng, Ye Qiu, Nan Zheng.

In this work, we developed a library of sulfated glycomimetic polypeptides with a high sulfated degree (up to 99%) via a click reaction and sulfation modification, enabling control over the helicity, molecular weight, rigidity, and side-chain structure. Their potentials as the inhibitors of SARS-CoV-2 and common enterovirus were investigated, and the structure-activity relationship was explored in detail. The in vitro results revealed the crucial role of α-helical conformation and sulfated sugar since all the sulfated glycopolypeptides exhibited outperformed activity in suppressing SARS-CoV-2 infection with the inhibition efficiency up to 85%. Other structural properties, including the rigid chain structure and a moderate molecular weight, also contributed to blocking the viral entry into host cells. Among the sulfated glycopolypeptides, L60-SG-POB showed the highest inhibition efficiency with an IC50 of 0.71 μg/mL. Furthermore, these optimized sulfated glycopolypeptides were also capable of preventing enterovirus infection with the inhibition efficiency of up to 86%. This work opens new avenues for the development of synthetic polypeptides bearing sulfated sugars against SARS-CoV-2 and other viruses.

DOI: https://doi.org/10.1021/acs.biomac.3c00184
Int J Nanomedicine. 2023 ;18 3087-3107

The αTSR Domain of Plasmodium Circumsporozoite Protein Bound Heparan Sulfates and Elicited High Titers of Sporozoite Binding Antibody After Displayed by Nanoparticles.

Ming Xia, Frank Vago, Ling Han, Pengwei Huang, Linh Nguyen, Geert-Jan Boons, John S Klassen, Wen Jiang, Ming Tan.

   Introduction: Malaria is a devastating infectious illness caused by protozoan Plasmodium parasites. The circumsporozoite protein (CSP) on Plasmodium sporozoites binds heparan sulfate proteoglycan (HSPG) receptors for liver invasion, a critical step for prophylactic and therapeutic interventions.
Methods: In this study, we characterized the αTSR domain that covers region III and the thrombospondin type-I repeat (TSR) of the CSP using various biochemical, glycobiological, bioengineering, and immunological approaches.
Results: We found for the first time that the αTSR bound heparan sulfate (HS) glycans through support by a fused protein, indicating that the αTSR is a key functional domain and thus a vaccine target. When the αTSR was fused to the S domain of norovirus VP1, the fusion protein self-assembled into uniform S60-αTSR nanoparticles. Three-dimensional structure reconstruction revealed that each nanoparticle consists of an S60 nanoparticle core and 60 surface displayed αTSR antigens. The nanoparticle displayed αTSRs retained the binding function to HS glycans, indicating that they maintained authentic conformations. Both tagged and tag-free S60-αTSR nanoparticles were produced via the Escherichia coli system at high yield by scalable approaches. They are highly immunogenic in mice, eliciting high titers of αTSR-specific antibody that bound specifically to the CSPs of Plasmodium falciparum sporozoites at high titer.
Discussion and Conclusion: Our data demonstrated that the αTSR is an important functional domain of the CSP. The S60-αTSR nanoparticle displaying multiple αTSR antigens is a promising vaccine candidate potentially against attachment and infection of Plasmodium parasites.

Keywords:  Plasmodium; S60 nanoparticle; malaria; malaria vaccine; norovirus; receptor binding domain; αTSR domain

DOI:  https://doi.org/10.2147/IJN.S406314
J Clin Endocrinol Metab. 2023 Jun 17. pii: dgad367. [Epub ahead of print]

Effects of 2-year physical activity and dietary intervention on adrenarchal and pubertal development: the PANIC study.

Jani Liimatta, Christa E Flück, Aino Mäntyselkä, Merja R Häkkinen, Seppo Auriola, Raimo Voutilainen, Jarmo Jääskeläinen, Timo A Lakka.

   CONTEXT: Childhood overweight has been linked to earlier development of adrenarche and puberty, but it remains unknown if lifestyle interventions influence sexual maturation in general populations.
OBJECTIVE: To investigate if a 2-year lifestyle intervention influences circulating androgen concentrations and sexual maturation in a general population of children.
DESIGN AND PARTICIPANTS: A 2-year intervention study in which 421 prepubertal and mostly normal-weight 6-9-year-old children were allocated either to a lifestyle intervention group (119 girls, 132 boys) or a control group (84 girls, 86 boys).
INTERVENTION: A 2-year physical activity and dietary intervention.
MAIN OUTCOME MEASURES: Serum dehydroepiandrosterone, dehydroepiandrosterone sulfate, androstenedione, and testosterone concentrations, and clinical adrenarchal and pubertal signs.
RESULTS: The intervention and control groups had no differences in body size and composition, clinical signs of androgen action, and serum androgens at baseline. The intervention attenuated the increase of dehydroepiandrosterone (p = 0.032), dehydroepiandrosterone sulfate (p = 0.001), androstenedione (p = 0.003), and testosterone (p = 0.007) and delayed pubarche (p = 0.038) in boys but it only attenuated the increase of dehydroepiandrosterone (p = 0.013) and dehydroepiandrosterone sulfate (p = 0.003) in girls. These effects of lifestyle intervention on androgens and the development of pubarche were independent of changes in body size and composition but the effects of intervention on androgens were partly explained by changes in fasting serum insulin.
CONCLUSIONS: A combined physical activity and dietary intervention attenuates the increase of serum androgen concentrations and sexual maturation in a general population of prepubertal and mostly normal-weight children, independently of changes in body size and composition.

Keywords:  Adrenarche; DHEAS; Diet; Lifestyle Intervention; Physical Activity; Puberty

DOI:  https://doi.org/10.1210/clinem/dgad367
Adv Healthc Mater. 2023 Jun 15. e2300946

Oral Delivery of Transformable Bilirubin Self-assembled System for Targeted Therapy of Colitis.

Zhejie Chen, Yi Chen, Wei Hao, Mingju Shui, Jinming Zhang, Hefeng Zhou, Chen Zhang, Yitao Wang, Shengpeng Wang.

  Ulcerative colitis (UC) is a high incidence disease worldwide and clinically presents as relapsing and incurable inflammation of the colon. Bilirubin (BR), a natural antioxidant with significant anti-colitic effects, has been utilized in preclinical studies as an intestinal disease therapy. Due to their water-insolubility, the design of BR-based agents usually involves complicated chemosynthetic processes, introducing various uncertainties in BR development. After screening numerous materials, we identified that chondroitin sulfate can efficiently mediate the construction of BR self-assembled nanomedicine (BSNM) via intermolecular hydrogen bonds between dense sulfate and carboxyl of chondroitin sulfate and imino groups of BR. BSNM exhibits pH sensitivity and reactive oxygen species responsiveness, enabling targeted delivery to the colon. After oral administration, BSNM significantly inhibits colonic fibrosis and apoptosis of colon and goblet cells; it also reduces the expression of inflammatory cytokines. Moreover, BSNM maintains the normal level of zonula occludens-1 (ZO-1) and occludin to sustain the integrity of intestinal barrier, regulates the macrophage polarization from M1 to M2 type, and promotes the ecological recovery of intestinal flora. Collectively, our work provides a colon-targeted and transformable BSNM that is simple to prepare and is useful as an efficient targeted UC therapy. This article is protected by copyright. All rights reserved.

Keywords:  Bilirubin; chondroitin sulfate; intermolecular hydrogen bond; self-assembled; ulcerative colitis

DOI:  https://doi.org/10.1002/adhm.202300946
Carbohydr Polym. 2023 Sep 15. pii: S0144-8617(23)00526-X. [Epub ahead of print]316 121061

Sulfated carboxymethylcellulose mediated enhancement of Timp3 efficacy synergistically attenuates osteoarthritis through inhibition of NFκB and JNK.

Arijit Bhattacharjee, Nihal Singh, Praganesh Kumar, Dhirendra S Katti.

  Osteoarthritis (OA) is a prevalent degenerative joint condition with no effective disease modifying treatments. In this study, we aimed to address multiple OA hallmarks using a combination of pro-chondrogenic sulfated carboxymethylcellulose (sCMC) and anti-catabolic tissue inhibitor of metalloproteases 3 (Timp3) in relevant disease systems. Firstly, we chemically sulfated carboxymethylcellulose to impart a negative charge and improve the stability of cationic Timp3. The modified sCMC exhibited a molecular weight of 10 kDa and a degree of sulfation of ∼10 %. We further demonstrated that sulfation of CMC confers pro-chondrogenic characteristics. Subsequently, we demonstrated that the combination of sCMC and Timp3 effectively reduced key OA hallmarks, such as matrix degradation, inflammation, and protease expression, in a goat ex vivo OA model compared to individual treatments. We further demonstrated that the anti-OA effect of sCMC and Timp3 is mediated through the suppression of NFκB and JNK activation. To validate the clinical potential and mechanism of action, we conducted experiments on human OA explants. The combination treatment synergistically reduced the expression of MMP13 and NFκB in human OA explants. Overall, sCMC-mediated enhancement of Timp3 efficacy synergistically reduced OA-like traits and demonstrates the potential for OA amelioration.

Keywords:  Combination therapy; Disease modifying OA drugs; Goat ex vivo OA model; Human OA cartilage; Sulfated carboxymethylcellulose; Tissue inhibitor of metalloproteases 3

DOI:  https://doi.org/10.1016/j.carbpol.2023.121061
Cancers (Basel). 2023 Jun 01. pii: 3025. [Epub ahead of print]15(11):

Crosstalk between Circulating Tumor Cells and Plasma Proteins-Impact on Coagulation and Anticoagulation.

Yuanyuan Wang, Stefan W Schneider, Christian Gorzelanny.

  Cancer metastasis is a complex process. After their intravasation into the circulation, the cancer cells are exposed to a harsh environment of physical and biochemical hazards. Whether circulating tumor cells (CTCs) survive and escape from blood flow defines their ability to metastasize. CTCs sense their environment with surface-exposed receptors. The recognition of corresponding ligands, e.g., fibrinogen, by integrins can induce intracellular signaling processes driving CTCs' survival. Other receptors, such as tissue factor (TF), enable CTCs to induce coagulation. Cancer-associated thrombosis (CAT) is adversely connected to patients' outcome. However, cancer cells have also the ability to inhibit coagulation, e.g., through expressing thrombomodulin (TM) or heparan sulfate (HS), an activator of antithrombin (AT). To that extent, individual CTCs can interact with plasma proteins, and whether these interactions are connected to metastasis or clinical symptoms such as CAT is largely unknown. In the present review, we discuss the biological and clinical relevance of cancer-cell-expressed surface molecules and their interaction with plasma proteins. We aim to encourage future research to expand our knowledge of the CTC interactome, as this may not only yield new molecular markers improving liquid-biopsy-based diagnostics but also additional targets for better cancer therapies.

Keywords:  cancer-associated thrombosis; circulating cancer cell; coagulation; heparan sulfate; plasma protein

DOI:  https://doi.org/10.3390/cancers15113025
Aging Dis. 2023 Jun 04.

Chondroitin Sulfate Proteoglycans Revisited: Its Mechanism of Generation and Action for Spinal Cord Injury.

Rui Yang, Ying Zhang, Jianning Kang, Ce Zhang, Bin Ning.

Reactive astrocytes (RAs) produce chondroitin sulfate proteoglycans (CSPGs) in large quantities after spinal cord injury (SCI) and inhibit axon regeneration through the Rho-associated protein kinase (ROCK) pathway. However, the mechanism of producing CSPGs by RAs and their roles in other aspects are often overlooked. In recent years, novel generation mechanisms and functions of CSPGs have gradually emerged. Extracellular traps (ETs), a new recently discovered phenomenon in SCI, can promote secondary injury. ETs are released by neutrophils and microglia, which activate astrocytes to produce CSPGs after SCI. CSPGs inhibit axon regeneration and play an important role in regulating inflammation as well as cell migration and differentiation; some of these regulations are beneficial. The current review summarized the process of ET-activated RAs to generate CSPGs at the cellular signaling pathway level. Moreover, the roles of CSPGs in inhibiting axon regeneration, regulating inflammation, and regulating cell migration and differentiation were discussed. Finally, based on the above process, novel potential therapeutic targets were proposed to eliminate the adverse effects of CSPGs.

DOI: https://doi.org/10.14336/AD.2023.0512
Foods. 2023 May 25. pii: 2133. [Epub ahead of print]12(11):

Structure Characterization, In Vitro Antioxidant and Anti-Tumor Activity of Sulfated Polysaccharide from Siraitia grosvenorii.

Pin Gong, Mengrao Wang, Yuxi Guo, Hui Long, Zhineng Wang, Dandan Cui, Wenbo Yao, Wenjuan Yang, Fuxin Chen, Jianwu Xie.

  From Siraitia grosvenorii, a natural polysaccharide named SGP-1 was discovered, and its purity was determined to be 96.83%. Its structure is a glucan with 4-, 6- and 4,6-linked glucose units. In this paper, the sulfated derivative S-SGP of SGP-1 was prepared by the chlorosulfonic acid method. The sulfated derivatives were analyzed by Fourier transform infrared spectroscopy (FT-IR), gel permeation chromatography (GPC), and scanning electron microscopy (SEM). The degree of substitution (DS) of the polysaccharide is 0.62, and the weight average molecular weight (Mw) is 1.34 × 104 Da. While retaining the morphological characteristics of polysaccharides, S-SGP appeared a large number of spherical structures and strong intermolecular forces. The in vitro activity study of S-SGP showed that the sulfated derivatives had the ability to scavenge DPPH radicals, hydroxyl radicals and superoxide anions, and the scavenging power tended to increase with the increase in polysaccharide concentration. It can inhibit the growth of human hepatoma cells (HepG2), human breast cancer cells (MDA-MB-231) and human non-small cell lung cancer cells (A549) in vitro. In addition, the treatment of A549 cells with sulfuric acid derivatives can decrease the mitochondrial membrane potential, induce apoptosis, and alter the expression of apoptosis-related mRNA and protein.

Keywords:  Siraitia grosvenorii polysaccharides; anti-tumor; sulfated modifications

DOI:  https://doi.org/10.3390/foods12112133