bims-supasi 2022-12-25 papers

bims-supasi

Biomed News

on Sulfation pathways and signalling

Issue of 2022‒12‒25
thirteen papers selected by
Jonathan Wolf Mueller
University of Birmingham

The 3-O sulfation of heparan sulfate proteoglycans contributes to the cellular internalization of tau aggregates.
Heparan Sulfate Proteoglycans in Tauopathy.
Structural Characteristics of Heparin Binding to SARS-CoV-2 Spike Protein RBD of Omicron Sub-Lineages BA.2.12.1, BA.4 and BA.5.
Functions and specificity of bacterial carbohydrate sulfatases targeting host glycans.
Persisting neuropsychiatric symptoms, Alzheimer's disease, and cerebrospinal fluid cortisol and dehydroepiandrosterone sulfate.
Glucocorticoid Effects on Proteoglycans and Glycosaminoglycans.
Sulfotransferase 2B1b, Sterol Sulfonation, and Disease.
Pitfall in the analysis of the alcohol biomarkers ethyl glucuronide and ethyl sulfate by laboratory-caused contamination with disinfectants.
Targeting of bone morphogenetic protein complexes to heparin/heparan sulfate glycosaminoglycans in bioactive conformation.
Discovery of small-molecule protein stabilizers toward exogenous alpha-l-iduronidase to reduce the accumulated heparan sulfate in mucopolysaccharidosis type I cells.
Improving the In Vitro Removal of Indoxyl Sulfate and p-Cresyl Sulfate by Coating Diatomaceous Earth (DE) and Poly-vinyl-pyrrolidone-co-styrene (PVP-co-S) with Polydopamine.
Thrombin and Factor Xa Hydrolysis of Chromogenic Substrates in the Presence of Sulfated Derivatives of Galactomannan and Galactoglucomannan Natural Gels.
The Effects of Indoxyl Sulfate and Oxidative Stress on the Severity of Peripheral Nerve Dysfunction in Patients with Chronic Kidney Diseases.

BMC Mol Cell Biol. 2022 Dec 24. 23(1): 61

The 3-O sulfation of heparan sulfate proteoglycans contributes to the cellular internalization of tau aggregates.

Andreia Ferreira, Ines Royaux, Jian Liu, Zhangjie Wang, Guowei Su, Diederik Moechars, Nico Callewaert, Louis De Muynck.

  BACKGROUND: Considering the high correlation between the functional decline in Alzheimer's disease (AD) and the propagation of aggregated tau protein, many research efforts are focused on determining the underlying molecular mechanisms of tau spreading. Heparan sulfate proteoglycans (HSPGs) were reported to mediate cellular uptake of tau aggregates. Specifically, the heparan sulfates (HS) sulfation plays a critical role in the interaction of HSPGs with aggregated tau. HS can be N-/2-O/6-O- or 3-O-sulfated, some of which have been reported to take part in the interaction with tau aggregates. However, the role of the 3-O sulfation remains enigmatic.RESULTS: Here, we studied the contribution of HS 3-O sulfation in the binding and cellular uptake of tau aggregates. We observed reduced tau aggregates uptake in absence of 3-O sulfation or when outcompeting available cellular 3-O sulfated HS (3S-HS) with antithrombin III. The lack of HS3ST1-generated HS products in the HS3ST1-/- cells was further corroborated with an LC-MS/MS using 13C-labeled HS calibrants. Here, we showed that these functional changes can be explained by a higher affinity of aggregated tau to 3S-HS. When targeting tau aggregates with 3-O sulfation-containing HS, we observed an increase in inhibition of tau aggregates uptake.
CONCLUSIONS: These data indicate that HS 3-O sulfation plays a role in the binding of tau aggregates and, thus, contributes to their cellular uptake, highlighting a potential target value to modulate tau pathogenesis.

Keywords:  3-O sulfation; HS 3-O sulfotransferase 1; Heparan sulfates proteoglycans; Tau uptake; Tau-heparan sulfates interaction

DOI:  https://doi.org/10.1186/s12860-022-00462-1
Biomolecules. 2022 Nov 30. pii: 1792. [Epub ahead of print]12(12):

Heparan Sulfate Proteoglycans in Tauopathy.

Yanan Zhu, Lauren Gandy, Fuming Zhang, Jian Liu, Chunyu Wang, Laura J Blair, Robert J Linhardt, Lianchun Wang.

  Tauopathies are a class of neurodegenerative diseases, including Alzheimer's disease, and are characterized by intraneuronal tau inclusion in the brain and the patient's cognitive decline with obscure pathogenesis. Heparan sulfate proteoglycans, a major type of extracellular matrix, have been believed to involve in tauopathies. The heparan sulfate proteoglycans co-deposit with tau in Alzheimer's patient brain, directly bind to tau and modulate tau secretion, internalization, and aggregation. This review summarizes the current understanding of the functions and the modulated molecular pathways of heparan sulfate proteoglycans in tauopathies, as well as the implication of dysregulated heparan sulfate proteoglycan expression in tau pathology and the potential of targeting heparan sulfate proteoglycan-tau interaction as a novel therapeutic option.

Keywords:  Alzheimer’s disease; heparan sulfate proteoglycan; tau; tauopathy

DOI:  https://doi.org/10.3390/biom12121792
Viruses. 2022 Dec 01. pii: 2696. [Epub ahead of print]14(12):

Structural Characteristics of Heparin Binding to SARS-CoV-2 Spike Protein RBD of Omicron Sub-Lineages BA.2.12.1, BA.4 and BA.5.

Deling Shi, Changkai Bu, Peng He, Yuefan Song, Jonathan S Dordick, Robert J Linhardt, Lianli Chi, Fuming Zhang.

  The now prevalent Omicron variant and its subvariants/sub-lineages have led to a significant increase in COVID-19 cases and raised serious concerns about increased risk of infectivity, immune evasion, and reinfection. Heparan sulfate (HS), located on the surface of host cells, plays an important role as a co-receptor for virus-host cell interaction. The ability of heparin and HS to compete for binding of the SARS-CoV-2 spike (S) protein to cell surface HS illustrates the therapeutic potential of agents targeting protein-glycan interactions. In the current study, phylogenetic tree of variants and mutations in S protein receptor-binding domain (RBD) of Omicron BA.2.12.1, BA.4 and BA.5 were described. The binding affinity of Omicron S protein RBD to heparin was further investigated by surface plasmon resonance (SPR). Solution competition studies on the inhibitory activity of heparin oligosaccharides and desulfated heparins at different sites on S protein RBD-heparin interactions revealed that different sub-lineages tend to bind heparin with different chain lengths and sulfation patterns. Furthermore, blind docking experiments showed the contribution of basic amino acid residues in RBD and sulfo groups and carboxyl groups on heparin to the interaction. Finally, pentosan polysulfate and mucopolysaccharide polysulfate were evaluated for inhibition on the interaction of heparin and S protein RBD of Omicron BA.2.12.1, BA.4/BA.5, and both showed much stronger inhibition than heparin.

Keywords:  Omicron; SARS-CoV-2; heparin; mucopolysaccharide polysulfate; pentosan polysulfate; spike protein RBD

DOI:  https://doi.org/10.3390/v14122696
Essays Biochem. 2022 Dec 23. pii: EBC20220120. [Epub ahead of print]

Functions and specificity of bacterial carbohydrate sulfatases targeting host glycans.

Ana S Luis, Edwin A Yates, Alan Cartmell.

  Sulfated host glycans (mucin O-glycans and glycosaminoglycans [GAGs]) are critical nutrient sources and colonisation factors for Bacteroidetes of the human gut microbiota (HGM); a complex ecosystem comprising essential microorganisms that coevolved with humans to serve important roles in pathogen protection, immune signalling, and host nutrition. Carbohydrate sulfatases are essential enzymes to access sulfated host glycans and are capable of exquisite regio- and stereo-selective substrate recognition. In these enzymes, the common recognition features of each subfamily are correlated with their genomic and environmental context. The exo-acting carbohydrate sulfatases are attractive drug targets amenable to small-molecule screening and subsequent engineering, and their high specificity will help elucidate the role of glycan sulfation in health and disease. Inhibition of carbohydrate sulfatases provides potential routes to control Bacteroidetes growth and to explore the influence of host glycan metabolism by Bacteroidetes on the HGM ecosystem. The roles of carbohydrate sulfatases from the HGM organism Bacteroides thetaiotaomicron and the soil isolated Pedobacter heparinus (P. heparinus) in sulfated host glycan metabolism are examined and contrasted, and the structural features underpinning glycan recognition and specificity explored.

Keywords:  Carbohydrate sulfatases; Human gut microbiota; Mucin; glycosaminoglycans; structural biology

DOI:  https://doi.org/10.1042/EBC20220120
Alzheimers Res Ther. 2022 Dec 19. 14(1): 190

Persisting neuropsychiatric symptoms, Alzheimer's disease, and cerebrospinal fluid cortisol and dehydroepiandrosterone sulfate.

Sami Ouanes, Miriam Rabl, Christopher Clark, Clemens Kirschbaum, Julius Popp.

  INTRODUCTION: Neuropsychiatric symptoms are important treatment targets in the management of dementia and can be present at very early clinical stages of neurodegenerative diseases. Increased cortisol has been reported in Alzheimer's disease (AD) and has been associated with faster cognitive decline. Elevated cortisol output has been observed in relation to perceived stress, depression, and anxiety. Dehydroepiandrosterone sulfate (DHEAS) has known anti-glucocorticoid effects and may counter the effects of cortisol.OBJECTIVES: We aimed to examine whether CSF cortisol and DHEAS levels were associated with (1) neuropsychiatric symptoms at baseline, (2) changes in neuropsychiatric symptoms over 3 years, and (3) whether these associations were related to or independent of AD pathology.
METHODS: One hundred and eighteen participants on a prospective study in a memory clinic setting, including patients with cognitive impairment (n = 78), i.e., mild cognitive impairment or mild dementia, and volunteers with normal cognition (n = 40), were included. Neuropsychiatric symptoms were assessed using the Neuropsychiatric Inventory Questionnaire (NPI-Q). CSF cortisol and DHEAS, as well as CSF AD biomarkers, were obtained at baseline. Neuropsychiatric symptoms were re-assessed at follow-up visits 18 and 36 months from baseline. We constructed linear regression models to examine the links between baseline neuropsychiatric symptoms, the presence of AD pathology as indicated by CSF biomarkers, and CSF cortisol and DHEAS. We used repeated-measures mixed ANCOVA models to examine the associations between the neuropsychiatric symptoms' changes over time, baseline CSF cortisol and DHEAS, and AD pathology.
RESULTS: Higher CSF cortisol was associated with higher NPI-Q severity scores at baseline after controlling for covariates including AD pathology status (B = 0.085 [0.027; 0.144], p = 0.027; r = 0.277). In particular, higher CSF cortisol was associated with higher baseline scores of depression/dysphoria, anxiety, and apathy/indifference. Elevated CSF cortisol was also associated with more marked increase in NPI-Q scores over time regardless of AD status (p = 0.036, η2 = 0.207), but this association was no longer significant after controlling for BMI and the use of psychotropic medications. CSF DHEAS was associated neither with NPI-Q scores at baseline nor with their change over time. Cortisol did not mediate the association between baseline NPI-Q and changes in clinical dementia rating sum of boxes over 36 months.
CONCLUSION: Higher CSF cortisol may reflect or contribute to more severe neuropsychiatric symptoms at baseline, as well as more pronounced worsening over 3 years, independently of the presence of AD pathology. Our findings also suggest that interventions targeting the HPA axis may be helpful to treat neuropsychiatric symptoms in patients with dementia.

Keywords:  Alzheimer’s disease; Behavioral and psychological symptoms of dementia; Biomarkers; Cerebrospinal fluid; Cortisol; Dehydroepiandrosterone sulfate; Neuropsychiatric symptoms

DOI:  https://doi.org/10.1186/s13195-022-01139-9
Int J Mol Sci. 2022 Dec 10. pii: 15678. [Epub ahead of print]23(24):

Glucocorticoid Effects on Proteoglycans and Glycosaminoglycans.

Anastasia V Strokotova, Elvira V Grigorieva.

  Glucocorticoids are steroid hormones that play diverse roles in numerous normal and pathological processes. They are actively used to treat a wide variety of diseases, including neurodegenerative and inflammatory diseases, cancers, and COVID-19, among others. However, the long-term use of glucocorticoids is associated with numerous side effects. Molecular mechanisms of these negative side effects are not completely understood. Recently, arguments have been made that one such mechanisms may be related to the influence of glucocorticoids on O-glycosylated components of the cell surface and extracellular matrix, in particular on proteoglycans and glycosaminoglycans. The potential toxic effects of glucocorticoids on these glycosylated macromolecules are particularly meaningful for brain physiology because proteoglycans/glycosaminoglycans are the main extracellular components of brain tissue. Here, we aim to review the known effects of glucocorticoids on proteoglycan expression and glycosaminoglycan content in different tissues, with a specific focus on the brain.

Keywords:  brain; chondroitin sulfate; extracellular matrix; glucocorticoid; glycosaminoglycan; heparan sulfate; proteoglycan; tumor microenvironment

DOI:  https://doi.org/10.3390/ijms232415678
Pharmacol Rev. 2022 Dec 22. pii: PHARMREV-AR-2022-000679. [Epub ahead of print]

Sulfotransferase 2B1b, Sterol Sulfonation, and Disease.

Ian Cook, Thomas S Leyh.

  The primary function of human sulfotransferase 2B1b (SULT2B1b) is to sulfonate cholesterol and closely related sterols. SULT2B1b sterols perform a number of essential cellular functions. Many are signaling molecules whose activities are redefined by sulfonation - allosteric properties are switched "on" or "off," agonists are transformed into antagonists, and vice versa. Sterol sulfonation is tightly coupled to cholesterol homeostasis and sulfonation imbalances are causally linked to cholesterol related diseases including certain cancers, Alzheimer's disease and recessive X‑linked ichthyosis - an orphan skin disease. Numerous studies link SULT2B1b activity to disease-relevant molecular processes. Here, these multifaceted processes are integrated into metabolic maps that highlight their interdependence and how their actions are regulated and coordinated by SULT2B1b oxysterol sulfonation. The maps help explain why SULT2B1b inhibition arrests the growth of certain cancers, and make the novel prediction that SULT2B1b inhibition will suppress production of amyloid beta (Ab) plaques and tau fibrils while simultaneously stimulating Ab plaque phagocytosis. SULT2B1b harbors a sterol-selective allosteric site whose structure is discussed as a template for creating inhibitors to regulate SULT2B1b and its associated biology. Significance Statement Human sulfotransferase 2B1b (SULT2B1b) produces sterol-sulfate signaling molecules that maintain the homeostasis of otherwise pro-disease processes in cancer, Alzheimer's disease and X-linked ichthyosis - an orphan skin disease. The functions of sterol sulfates in each disease are considered and codified into metabolic maps that explain the interdependencies of the sterol-regulated networks and their coordinate regulation by SULT2B1b. The structure of the SULT2B1b sterol-sensing allosteric site is discussed as a means of controlling sterol sulfate biology.

Keywords:  Alzheimer's Disease; SULT; Skin; Sulfotranserase; cancer

DOI:  https://doi.org/10.1124/pharmrev.122.000679
Clin Chem Lab Med. 2022 Dec 26.

Pitfall in the analysis of the alcohol biomarkers ethyl glucuronide and ethyl sulfate by laboratory-caused contamination with disinfectants.

Katharina Habler, Michael Paal, Felix Lucian Happich, Michael Vogeser.



Keywords:  alcohol marker; disinfectant; ethyl glucuronide; ethyl sulfate; mecetronium ethyl sulfate

DOI:  https://doi.org/10.1515/cclm-2022-1141
FASEB J. 2023 Jan;37(1): e22717

Targeting of bone morphogenetic protein complexes to heparin/heparan sulfate glycosaminoglycans in bioactive conformation.

Chara E S Spanou, Alexander P Wohl, Sandra Doherr, Annkatrin Correns, Niklas Sonntag, Steffen Lütke, Matthias Mörgelin, Thomas Imhof, Jan M Gebauer, Ulrich Baumann, Kay Grobe, Manuel Koch, Gerhard Sengle.

  Bone morphogenetic proteins (BMP) are powerful regulators of cellular processes such as proliferation, differentiation, and apoptosis. However, the specific molecular requirements controlling the bioavailability of BMPs in the extracellular matrix (ECM) are not yet fully understood. Our previous work showed that BMPs are targeted to the ECM as growth factor-prodomain (GF-PD) complexes (CPLXs) via specific interactions of their PDs. We showed that BMP-7 PD binding to the extracellular microfibril component fibrillin-1 renders the CPLXs from an open, bioactive V-shape into a closed, latent ring shape. Here, we show that specific PD interactions with heparin/heparan sulfate glycosaminoglycans (GAGs) allow to target and spatially concentrate BMP-7 and BMP-9 CPLXs in bioactive V-shape conformation. However, targeting to GAGs may be BMP specific, since BMP-10 GF and CPLX do not interact with heparin. Bioactivity assays on solid phase in combination with interaction studies showed that the BMP-7 PD protects the BMP-7 GF from inactivation by heparin. By using transmission electron microscopy, molecular docking, and site-directed mutagenesis, we determined the BMP-7 PD-binding site for heparin. Further, fine-mapping of the fibrillin-1-binding site within the BMP-7 PD and molecular modeling showed that both binding sites are mutually exclusive in the open V- versus closed ring-shape conformation. Together, our data suggest that targeting exquisite BMP PD-binding sites by extracellular protein and GAG scaffolds integrates BMP GF bioavailability in a contextual manner in development, postnatal life, and connective tissue disease.

Keywords:  ELISA-style bioactivity assay; bone morphogenetic protein; complex; growth factor; heparan sulfate; heparan sulfate proteoglycans; heparin; heparin affinity chromatography; molecular modeling; negative-staining transmission electron microscopy; prodomain; surface plasmon resonance; vascular endothelial growth factor

DOI:  https://doi.org/10.1096/fj.202200904R
Eur J Med Chem. 2022 Dec 09. pii: S0223-5234(22)00907-2. [Epub ahead of print]247 115005

Discovery of small-molecule protein stabilizers toward exogenous alpha-l-iduronidase to reduce the accumulated heparan sulfate in mucopolysaccharidosis type I cells.

Hung-Yi Lin, Shih-Ying Chang, Hsuan-Hsuan Teng, Hsi-Ju Wu, Huang-Yi Li, Chia-Chun Cheng, Chih-Kuang Chuang, Hsiang-Yu Lin, Shuan-Pei Lin, Wei-Chieh Cheng.

Synthesis of a series of l-iduronic acid (IdoA)- and imino-IdoA-typed C-glycosides for modulating α-l-iduronidase (IDUA) activity is described. In an enzyme inhibition study, IdoA-typed C-glycosides were more potent than imino-IdoA analogs, with the most potent IdoA-typed C-glycoside 27c showing an IC50 value of 1 μM. On the other hand, co-treatment of 12 with rh-α-IDUA in mucopolysaccharidosis type I (MPS I) fibroblasts exhibited a nearly 3-fold increase of the IDUA activity, resulting in a clear reduction of the accumulated heparan sulfate (HS) compared to the exogenous enzyme treatment alone. This is the first report of small molecules facilitating IDUA stabilization, enhancing enzyme activity, and reducing accumulated HS in MPS I cell-based assays, which reveals that small molecules as rh-α-IDUA stabilizers to improve enzyme replacement therapy (ERT) efficacy toward MPS I is feasible and promising.

DOI: https://doi.org/10.1016/j.ejmech.2022.115005
Toxins (Basel). 2022 Dec 08. pii: 864. [Epub ahead of print]14(12):

Improving the In Vitro Removal of Indoxyl Sulfate and p-Cresyl Sulfate by Coating Diatomaceous Earth (DE) and Poly-vinyl-pyrrolidone-co-styrene (PVP-co-S) with Polydopamine.

Stefania Roberta Cicco, Maria Michela Giangregorio, Maria Teresa Rocchetti, Ighli di Bari, Claudio Mastropaolo, Rossella Labarile, Roberta Ragni, Loreto Gesualdo, Gianluca Maria Farinola, Danilo Vona.

  Polydopamine (PDA) is a synthetic eumelanin polymer mimicking the biopolymer secreted by mussels to attach to surfaces with a high binding strength. It exhibits unique adhesive properties and has recently attracted considerable interest as a multifunctional thin film coating. In this study, we demonstrate that a PDA coating on silica- and polymer-based materials improves the entrapment and retention of uremic toxins produced in specific diseases. The low-cost natural nanotextured fossil diatomaceous earth (DE), an abundant source of mesoporous silica, and polyvinylpyrrolidone-co-Styrene (PVP-co-S), a commercial absorbent comprising polymeric particles, were easily coated with a PDA layer by oxidative polymerization of dopamine at mild basic aqueous conditions. An in-depth chemical-physical investigation of both the resulting PDA-coated materials was performed by SEM, AFM, UV-visible, Raman spectroscopy and spectroscopic ellipsometry. Finally, the obtained hybrid systems were successfully tested for the removal of two uremic toxins (indoxyl sulfate and p-cresyl sulfate) directly from patients' sera.

Keywords:  bioremoval; chemical functionalization; diatomaceous earth; polydopamine; polyvinylpyrrolidone-co-styrene; uremic toxins

DOI:  https://doi.org/10.3390/toxins14120864
Pharmaceutics. 2022 Dec 01. pii: 2678. [Epub ahead of print]14(12):

Thrombin and Factor Xa Hydrolysis of Chromogenic Substrates in the Presence of Sulfated Derivatives of Galactomannan and Galactoglucomannan Natural Gels.

Natalia N Drozd, Svetlana A Kuznetsova, Yuriy N Malyar, Aleksandr S Kazachenko, Valentina S Borovkova, Yarosvala D Berezhnaya.

  Polysaccharides are important structural components of all plant species. Gel-like polysaccharides have found wide application in various fields, including medicine, construction, and the food industry. In the present work, galactomannan and galactoglucomannan gel-like polysaccharides were modified with sulfate groups and their anticoagulant activity was studied. Sulfation with chlorosulfonic acid in pyridine and with sulfamic acid in pyridine and a sulfamic acid-urea deep eutectic solvent were used as synthesis routes. The resulting gel-like polysaccharide sulfates were studied by elemental analysis, Fourier-transform infrared spectroscopy, and gel permeation chromatography. It was established that the anticoagulant effect of sulfated galactoglucomannan (SGGM) and galactomannan (SGM-1 and SGM-2) is related to an independent antithrombin-independent decrease in the amidolytic activity of thrombin and factor Xa. It is shown that the inhibitory activity of SGGM and SGM-2 against the collagen-induced platelet aggregation can be an additional factor in selecting compounds that are most promising for modifying polymer surfaces to ensure resistance to blood clotting.

Keywords:  chromogenic substrate; factor Xa; galactoglucomannan sulfate; galactomannan sulfate; platelet aggregation; thrombin

DOI:  https://doi.org/10.3390/pharmaceutics14122678
Antioxidants (Basel). 2022 Nov 28. pii: 2350. [Epub ahead of print]11(12):

The Effects of Indoxyl Sulfate and Oxidative Stress on the Severity of Peripheral Nerve Dysfunction in Patients with Chronic Kidney Diseases.

Yun-Ru Lai, Ben-Chung Cheng, Chia-Ni Lin, Wen-Chan Chiu, Ting-Yin Lin, Hui-Ching Chiang, Chun-En Aurea Kuo, Chih-Cheng Huang, Cheng-Hsien Lu.

  Pieces of evidence support the view that the accumulation of uremic toxins enhances oxidative stress and downstream regulation of signaling pathways, contributing to both endothelial microangiography and cell dysfunction. This study is to address the impact of protein-binding uremic toxins on the severity of peripheral nerve function in patients with chronic kidney disease (CKD). Fifty-four patients with CKD were included in the Toronto Clinical Neuropathy Score (TCNS), nerve conduction study (NCS), and laboratory studies including protein-binding uremic toxin (indoxyl sulfate [IS] and p-cresyl sulfate [PCS]), oxidative stress (Thiol and thiobarbituric acid reacting substances [TBARS]), and endothelial dysfunction (serum intercellular adhesion molecule 1 [sICAM-1] and serum vascular adhesion molecule 1 [sVCAM-1]) at enrollment. We used composite amplitude scores (CAS) to analyze the severity of nerve conductions on peripheral nerve function. TCNS and CAS were higher in the diabetic CKD group (p = 0.02 and 0.01, respectively). The NCS revealed the compound muscle action potential of ulnar and peroneal nerves and the sensory nerve action potential of ulnar and sural nerves (p = 0.004, p = 0.004, p = 0.004, and p = 0.001, respectively), which was found to be significantly low in the diabetic group. CAS was significantly correlated with age (r = 0.27, p = 0.04), urine albumin-creatinine ratio (UACR) (r = 0.29, p = 0.046), free-form IS (r = 0.39, p = 0.009), sICAM-1 (r = 0.31, p = 0.02), sVCAM-1 (r = 0.44, p < 0.0001), TBARS (r = 0.35, p = 0.002), and thiols (r = -0.28, p = 0.045). Linear regression revealed that only TBARS and free-form IS were strongly associated with CAS. The mediation analysis shows that the sVCAM-1 level serves as the mediator between higher IS and higher CAS. IS and oxidative stress contribute to the severity of peripheral nerve dysfunction in patients with CKD, and chronic glycemic impairment can worsen the conditions.

Keywords:  chronic kidney disease; indoxyl sulfate; oxidative stress; protein-binding uremic toxin; severity of peripheral nerve dysfunction

DOI:  https://doi.org/10.3390/antiox11122350