bims-supasi 2024-05-19 papers

bims-supasi

Biomed News

on Sulfation pathways and signalling

Issue of 2024–05–19
nine papers selected by
Jonathan Wolf Mueller, University of Birmingham

Assessing translational applicability of perineuronal net dysfunction in Alzheimer's disease across species.
Heparan sulfate proteoglycans: Mediators of cellular and molecular Alzheimer's disease pathogenic factors via tunnelling nanotubes?
Investigation of a chondroitin sulfate-based bioactive coating for neural interface applications.
Similar enzymatic functions in distinct bioluminescence systems: evolutionary recruitment of sulfotransferases in ostracod light organs.
Inhibitory effect of recombinant tyrosine‑sulfated madanin‑1, a thrombin inhibitor, on the behavior of MDA‑MB‑231 and SKOV3 cells in vitro.
Chondroitin sulfate proteoglycan 4: An attractive target for antibody-based immunotherapy.
Differential Solvent DEEP-STD NMR and MD Simulations Enable the Determinants of the Molecular Recognition of Heparin Oligosaccharides by Antithrombin to Be Disentangled.
Deciphering the triad of endothelial glycocalyx, von Willebrand Factor, and P-selectin in inflammation-induced coagulation.
Indoxyl sulfate aggravates podocyte damage through the TGF-β1/Smad/ROS signaling pathway.

Front Neurosci. 2024 ;18 1396101

Assessing translational applicability of perineuronal net dysfunction in Alzheimer's disease across species.

Aarun S Hendrickson, Kendra L Francis, Asmit Kumar, Jaden P Le, Jarrad M Scarlett, C Dirk Keene, David A Tovar, Kimberly M Alonge.

  In the context of aging and age-associated neurodegenerative disorders, the brain's extracellular matrix (ECM) serves as a critical regulator for neuronal health and cognitive function. Within the extracellular space, proteoglycans and their glycosaminoglycan attachments play essential roles in forming, stabilizing, and protecting neural circuits throughout neurodevelopment and adulthood. Recent studies in rodents reveal that chondroitin sulfate-glycosaminoglycan (CS-GAG) containing perineuronal nets (PNNs) exhibit both structural and compositional differences throughout the brain. While animal studies are illuminating, additional research is required to translate these interregional PNN/CS-GAG variations to human brain tissue. In this perspective article, we first investigate the translational potential for interregional CS-GAG variances across species as novel targets for region-specific therapeutic development. We specifically focus on the observation that alterations in brain PNN-associated CS-GAGs have been linked with the progression of Alzheimer's disease (AD) neuropathology in humans, but these changes have not been fully recapitulated in rodent models of this disease. A second highlight of this perspective article investigates whether AD-associated shifts in CS-GAGs in humans may be dependent on region-specific baseline differences in CS-GAG sulfation patterning. The current findings begin to disentangle the intricate relationships between the interregional differences in brain PNN/CS-GAG matrices across species, while emphasizing the need to better understand the close relationship between dementia and changes in brain CS-GAG sulfation patterns in patients with AD and related dementias.

Keywords:  Alzheimer’s disease; chondroitin sulfate; glycosmainoglycans; mass spectrometry; perineuronal nets; proteoglycans; translation

DOI:  https://doi.org/10.3389/fnins.2024.1396101
Mol Cell Neurosci. 2024 May 13. pii: S1044-7431(24)00021-6. [Epub ahead of print]129 103936

Heparan sulfate proteoglycans: Mediators of cellular and molecular Alzheimer's disease pathogenic factors via tunnelling nanotubes?

Duy L B Nguyen, Rachel K Okolicsanyi, Larisa M Haupt.

  Neurological disorders impact around one billion individuals globally (15 % approx.), with significant implications for disability and mortality with their impact in Australia currently amounts to 6.8 million deaths annually. Heparan sulfate proteoglycans (HSPGs) are complex extracellular molecules implicated in promoting Tau fibril formation resulting in Tau tangles, a hallmark of Alzheimer's disease (AD). HSPG-Tau protein interactions contribute to various AD stages via aggregation, toxicity, and clearance, largely via interactions with the glypican 1 and syndecan 3 core proteins. The tunnelling nanotubes (TNTs) pathway is emerging as a facilitator of intercellular molecule transport, including Tau and Amyloid β proteins, across extensive distances. While current TNT-associated evidence primarily stems from cancer models, their role in Tau propagation and its effects on recipient cells remain unclear. This review explores the interplay of TNTs, HSPGs, and AD-related factors and proposes that HSPGs influence TNT formation in neurodegenerative conditions such as AD.

Keywords:  Alzheimer's disease; Aβ; Heparan sulfate proteoglycans; Neurological disorders; P-tau; Tau; Tunnelling nanotubes

DOI:  https://doi.org/10.1016/j.mcn.2024.103936
J Mater Chem B. 2024 May 15.

Investigation of a chondroitin sulfate-based bioactive coating for neural interface applications.

Vaishnavi Dhawan, Paige Nicole Martin, Xiaoming Hu, Xinyan Tracy Cui.

Invasive neural implants allow for high-resolution bidirectional communication with the nervous tissue and have demonstrated the ability to record neural activity, stimulate neurons, and sense neurochemical species with high spatial selectivity and resolution. However, upon implantation, they are exposed to a foreign body response which can disrupt the seamless integration of the device with the native tissue and lead to deterioration in device functionality for chronic implantation. Modifying the device surface by incorporating bioactive coatings has been a promising approach to camouflage the device and improve integration while maintaining device performance. In this work, we explored the novel application of a chondroitin sulfate (CS) based hydrophilic coating, with anti-fouling and neurite-growth promoting properties for neural recording electrodes. CS-coated samples exhibited significantly reduced protein-fouling in vitro which was maintained for up to 4-weeks. Cell culture studies revealed a significant increase in neurite attachment and outgrowth and a significant decrease in microglia attachment and activation for the CS group as compared to the control. After 1-week of in vivo implantation in the mouse cortex, the coated probes demonstrated significantly lower biofouling as compared to uncoated controls. Like the in vitro results, increased neuronal population (neuronal nuclei and neurofilament) and decreased microglial activation were observed. To assess the coating's effect on the recording performance of silicon microelectrodes, we implanted coated and uncoated electrodes in the mouse striatum for 1 week and performed impedance and recording measurements. We observed significantly lower impedance in the coated group, likely due to the increased wettability of the coated surface. The peak-to-peak amplitude and the noise floor levels were both lower in the CS group compared to the controls, which led to a comparable signal-to-noise ratio between the two groups. The overall single unit yield (% channels recording a single unit) was 74% for the CS and 67% for the control group on day 1. Taken together, this study demonstrates the effectiveness of the polysaccharide-based coating in reducing biofouling and improving biocompatibility for neural electrode devices.

DOI: https://doi.org/10.1039/d4tb00501e
Biol Lett. 2024 May;20(5): 20230585

Similar enzymatic functions in distinct bioluminescence systems: evolutionary recruitment of sulfotransferases in ostracod light organs.

Emily S Lau, Jessica A Goodheart, Nolan T Anderson, Vannie L Liu, Arnab Mukherjee, Todd H Oakley.

  Genes from ancient families are sometimes involved in the convergent evolutionary origins of similar traits, even across vast phylogenetic distances. Sulfotransferases are an ancient family of enzymes that transfer sulfate from a donor to a wide variety of substrates, including probable roles in some bioluminescence systems. Here, we demonstrate multiple sulfotransferases, highly expressed in light organs of the bioluminescent ostracod Vargula tsujii, transfer sulfate in vitro to the luciferin substrate, vargulin. We find luciferin sulfotransferases (LSTs) of ostracods are not orthologous to known LSTs of fireflies or sea pansies; animals with distinct and convergently evolved bioluminescence systems compared to ostracods. Therefore, distantly related sulfotransferases were independently recruited at least three times, leading to parallel evolution of luciferin metabolism in three highly diverged organisms. Reuse of homologous genes is surprising in these bioluminescence systems because the other components, including luciferins and luciferases, are completely distinct. Whether convergently evolved traits incorporate ancient genes with similar functions or instead use distinct, often newer, genes may be constrained by how many genetic solutions exist for a particular function. When fewer solutions exist, as in genetic sulfation of small molecules, evolution may be more constrained to use the same genes time and again.

Keywords:  bioluminescence; complex traits; convergent evolution; gene expression; parallel evolution; sulfotransferase

DOI:  https://doi.org/10.1098/rsbl.2023.0585
Mol Med Rep. 2024 Jul;pii: 114. [Epub ahead of print]30(1):

Inhibitory effect of recombinant tyrosine‑sulfated madanin‑1, a thrombin inhibitor, on the behavior of MDA‑MB‑231 and SKOV3 cells in vitro.

Guk Heui Jo, Sun Ah Jung, Tae Hoon Roh, Jin Sook Yoon, Joon H Lee.

  Thrombin, which plays a crucial role in hemostasis, is also implicated in cancer progression. In the present study, the effects of the thrombin‑targeting recombinant tyrosine‑sulfated madanin‑1 on cancer cell behavior and signaling pathways compared with madanin‑1 wild‑type (WT) were investigated. Recombinant madanin‑1 2 sulfation (madanin‑1 2S) and madanin‑1 WT proteins were generated using Escherichia coli. SKOV3 and MDA‑MB‑231 cells were treated with purified recombinant proteins with or without thrombin stimulation. Migration and invasion of cells were analyzed by wound healing assay and Transwell assay, respectively. Thrombin markedly increased cell migration and invasion in both SKOV3 and MDA‑MB‑231 cells, which were significantly suppressed by madanin‑1 2S (P<0.05). Madanin‑1 2S also significantly suppressed thrombin‑induced expression of phosphorylated (p)‑Akt and p‑extracellular signal‑regulated kinase in both cell lines (P<0.05), whereas madanin‑1 WT had no effect on the expression levels of these proteins in MDA‑MB‑231 cells. Furthermore, madanin‑1 2S significantly reversed the effects of thrombin on E‑cadherin, N‑cadherin and vimentin expression in MDA‑MB‑231 cells (P<0.05), whereas madanin‑1 WT did not show any effect. In conclusion, madanin‑1 2S suppressed the migration and invasion of cancer cells more effectively than madanin‑1 WT. It is hypothesized that inhibiting thrombin via the sulfated form of madanin‑1 may be a potential candidate for enhanced cancer therapy; however, further in vivo validation is required.

Keywords:  cancer; epithelial‑mesenchymal transition; invasion; madanin‑1; migration; thrombin; tyrosine sulfation

DOI:  https://doi.org/10.3892/mmr.2024.13238
Proc Jpn Acad Ser B Phys Biol Sci. 2024 ;100(5): 293-308

Chondroitin sulfate proteoglycan 4: An attractive target for antibody-based immunotherapy.

Tomohiro Kurokawa, Kohzoh Imai.

  Multifunctional molecules involved in tumor progression and metastasis have been identified as valuable targets for immunotherapy. Among these, chondroitin sulfate proteoglycan 4 (CSPG4), a significant tumor cell membrane-bound proteoglycan, has emerged as a promising target, especially in light of advances in chimeric antigen receptor (CAR) T-cell therapy. The profound bioactivity of CSPG4 and its role in pivotal processes such as tumor proliferation, migration, and neoangiogenesis underline its therapeutic potential. We reviewed the molecular intricacies of CSPG4, its functional attributes within tumor cells, and the latest clinical-translational advances targeting it. Strategies such as blocking monoclonal antibodies, conjugate therapies, bispecific antibodies, small-molecule inhibitors, CAR T-cell therapies, trispecific killer engagers, and ribonucleic acid vaccines against CSPG4 were assessed. CSPG4 overexpression in diverse tumors and its correlation with adverse prognostic outcomes emphasize its significance in cancer biology. These findings suggest that targeting CSPG4 offers a promising avenue for future cancer therapy, with potential synergistic effects when combined with existing treatments.

Keywords:  antibodies; cancer; chondroitin sulfate proteoglycan 4; immunotherapy; targeted therapy; tumor progression

DOI:  https://doi.org/10.2183/pjab.100.019
Int J Mol Sci. 2024 Apr 25. pii: 4669. [Epub ahead of print]25(9):

Differential Solvent DEEP-STD NMR and MD Simulations Enable the Determinants of the Molecular Recognition of Heparin Oligosaccharides by Antithrombin to Be Disentangled.

Michela Parafioriti, Stefano Elli, Juan C Muñoz-García, Jonathan Ramírez-Cárdenas, Edwin A Yates, Jesús Angulo, Marco Guerrini.

  The interaction of heparin with antithrombin (AT) involves a specific sequence corresponding to the pentasaccharide GlcNAc/NS6S-GlcA-GlcNS3S6S-IdoA2S-GlcNS6S (AGA*IA). Recent studies have revealed that two AGA*IA-containing hexasaccharides, which differ in the sulfation degree of the iduronic acid unit, exhibit similar binding to AT, albeit with different affinities. However, the lack of experimental data concerning the molecular contacts between these ligands and the amino acids within the protein-binding site prevents a detailed description of the complexes. Differential epitope mapping (DEEP)-STD NMR, in combination with MD simulations, enables the experimental observation and comparison of two heparin pentasaccharides interacting with AT, revealing slightly different bound orientations and distinct affinities of both glycans for AT. We demonstrate the effectiveness of the differential solvent DEEP-STD NMR approach in determining the presence of polar residues in the recognition sites of glycosaminoglycan-binding proteins.

Keywords:  DEEP-STD NMR; MD simulations; STD NMR; glycosaminoglycan–protein interactions; ligand-based NMR; molecular recognition; radial distribution function

DOI:  https://doi.org/10.3390/ijms25094669
Front Cell Dev Biol. 2024 ;12 1372355

Deciphering the triad of endothelial glycocalyx, von Willebrand Factor, and P-selectin in inflammation-induced coagulation.

Guinevere Ferreira, Alexandra Taylor, Solomon A Mensah.

  This review examines the endothelial glycocalyx's role in inflammation and explores its involvement in coagulation. The glycocalyx, composed of proteins and glycosaminoglycans, interacts with von Willebrand Factor and could play a crucial role in anchoring it to the endothelium. In inflammatory conditions, glycocalyx degradation may leave P-selectin as the only attachment point for von Willebrand Factor, potentially leading to uncontrolled release of ultralong von Willebrand Factor in the bulk flow in a shear stress-dependent manner. Identifying specific glycocalyx glycosaminoglycan interactions with von Willebrand Factor and P-selectin can offer insights into unexplored coagulation mechanisms.

Keywords:  P-selectin; coagulation; endothelial glycocalyx; heparan sulfate; von Willebrand Factor

DOI:  https://doi.org/10.3389/fcell.2024.1372355
Kidney Blood Press Res. 2024 May 10.

Indoxyl sulfate aggravates podocyte damage through the TGF-β1/Smad/ROS signaling pathway.

Miao Jia, Lihua Lin, Kang Xun, Damei Li, Weijiang Wu, Shaobo Sun, Hong Qiu, Donghua Jin.

INTRODUCTION: Hyperglycaemia induces the production of a large quantity of reactive oxygen species (ROS) and activates the transforming growth factor β1(TGF-β1)/Smad signalling pathway, which is the main initiating factor in the formation of diabetic nephropathy. Indoxyl sulfate (IS) is a protein-binding gut-derived uraemic toxin that localizes to podocytes, induces oxidative stress and inflames podocytes. The involvement of podocyte damage in diabetic nephropathy through the TGF-β1/) signalling pathway is still unclear.
METHODS: In this study, we cultured differentiated rat podocytes in vitro and measured the expression levels of nephrin, synaptopodin, CD2AP, SRGAP2a and α-SMA by quantitative real-time PCR (qRT‒PCR) and western blotting after siRNA-mediated TGF-β1 silencing, TGF-β1 overexpression and the presence of the ROS inhibitor acetylcysteine. We detected the expression levels of nephrin, synaptopodin, CD2AP, SRGAP2a, SRGAP2a in the Smad2/3, phosphorylated-Smad2/3 (p-Smad2/3), Smad7, NADPH oxidase 4 (NOX4), and ROS levels under high glucose (HG) and IS conditions.
RESULTS: The results indicated that nephrin, synaptopodin, CD2AP and SRGAP2a expressions were significantly upregulated and α-SMA expression was significantly downregulated in the presence of HG under siRNA-mediated TGF-β1 silencing or after the addition of acetylcysteine. However, in the presence of HG, the expressions of nephrin, synaptopodin, CD2AP and SRGAP2a were significantly downregulated, and the expression of α-SMA was significantly upregulated with the overexpression of TGF-β1. IS supplementation under HG conditions further significantly reduced the expressions of nephrin, synaptopodin, CD2AP and SRGAP2a; altered the expressions of Smad2/3, p-Smad2/3, Smad7 and NOX4; and increased ROS production in podocytes.
CONCLUSIONS: This study suggests that IS may modulate the expression of nephrin, synaptopodin, CD2AP and SRGAP2a by regulating the ROS and TGF-β1/Smad signalling pathways, providing new theoretical support for the treatment of diabetic nephropathy.

DOI: https://doi.org/10.1159/000538858