bims-supasi Biomed News
on Sulfation pathways and signalling
Issue of 2022‒04‒10
twelve papers selected by
Jonathan Wolf Mueller
University of Birmingham

  1. Org Biomol Chem. 2022 Apr 07.
      Heparan sulfate (HS), a glycosaminoglycan related to heparin, is a linear polysaccharide, consisting of repeating disaccharide units. This compound is involved in multiple biological processes such as inflammation, coagulation, angiogenesis and viral infections. Our work focuses on the synthesis of simple HS analogs for the study of structure-activity relationships, with the aim of modulating these biological activities. Thioglycoside analogs, in which the interglycosidic oxygen is replaced by a sulfur atom, are very interesting compounds in terms of therapeutic applications. Indeed, the thioglycosidic bond leads to an improvement of their stability and can allow the inhibition of enzymes involved in physiological and pathological processes. In our previous work, we developed a synthetic sequence which led to a non-sulfated thiodisaccharide analog of HS. In this paper, we report our results of the development of a new synthetic method allowing access to the novel sulfated S-disaccharide, as well as to their oxygenated analogues (O-disaccharide and sulfated O-disaccharide). These 4 compounds were also tested for the inhibition of heparanase, an enzyme involved in biological processes like tumor growth and inflammation. The obtained IC50 values in the micromolar range showed the impact of the interglycosidic sulfur atom and the 6-sulfate group.
  2. Am J Physiol Cell Physiol. 2022 Apr 06.
      Aggrecan (Acan) and versican (Vcan) are large chondroitin sulfate proteoglycans of the extracellular matrix. They share the same structural domains at both N and C-termini. The N-terminal G1 domain binds hyaluronan (HA), forms an HA-rich matrix, and regulates HA-mediated signaling. The C-terminal G3 domain binds other extracellular matrix molecules and forms a supramolecular structure that stores TGFb and BMPs and regulates their signaling. EGF-like motifs in the G3 domain may directly act like an EGF ligand. Both Acan and Vcan are present in cartilage, intervertebral disc, brain, heart, and aorta. Their localizations are essentially reciprocal. This review describes their structural domains, expression patterns and functions, and regulation of their expression.
    Keywords:  aggrecan; hyaluronan; proteoglycan; versican
  3. Int J Nephrol Renovasc Dis. 2022 ;15 115-126
      Introduction: Indoxyl sulfate, a protein-bound uremic toxin, has been reported as an atherosclerosis and fibrosis accelerator. This study aimed to determine whether serum indoxyl sulfate is associated with cardiac abnormalities, cardiovascular events, and renal progression to dialysis in patients with chronic kidney disease (CKD).Methods: The prospective study enrolled 89 patients with CKD stage 3 to 5 patients. Serum biochemistry data and indoxyl sulfate were measured. All patients underwent echocardiographic examination. Global longitudinal strain (GLS) was calculated using two-dimensional speckle tracking. The clinical outcomes including cardiovascular event and dialysis initiation were recorded during a 2-year follow-up.
    Results: Patients were divided into 2 groups based on the median value of serum indoxyl sulfate (low and high indoxyl sulfate groups). Kaplan-Meier analysis revealed that patients with higher indoxyl sulfate (≥6.124 mg/L) were significantly associated with renal progression to dialysis (p < 0.001). There was no significant difference in cardiovascular events between 2 groups (p = 0.082). In addition, serum indoxyl sulfate level was independently associated with GLS (r = 0.62; p = 0.01). The risk of cardiovascular events was significantly higher in patients with impaired GLS (>-16%) (p = 0.015).
    Conclusion: Serum indoxyl sulfate level was a significant predictor for CKD progression to dialysis and was correlated with GLS, a speckle tracking echocardiography parameter representing early LV systolic dysfunction. Furthermore, GLS was associated with cardiovascular events in CKD patients. Serum indoxyl sulfate measurement may help to identify the high dialysis and cardiovascular risk CKD patients beyond traditional risk factors.
    Keywords:  cardiovascular events; chronic kidney disease; echocardiographic parameters; indoxyl sulfate; renal outcomes
  4. Aging Dis. 2022 Apr;13(2): 423-432
      The biological significance of dehydroepiandrosterone (DHEA) which, in the form of its sulfated ester is the most abundant steroid hormone in human plasma, is an enigma. Over the past years, numerous investigators have reported preclinical findings that DHEA has preventive and therapeutic efficacy in treating major age-associated diseases, including cancer, atherosclerosis, diabetes, obesity, as well as ameliorating the deleterious effects of excess cortisol exposure. Epidemiological studies have also found that low DHEA(S) levels predict an increased all-cause mortality. However, clinical trials, in which oral doses of DHEA at 50 mg-100 mg have been administered to elderly individuals for up to two years, have produced no clear evidence of benefit in parameters such as body composition, peak volume of oxygen consumption, muscle strength, or insulin sensitivity. I discuss why clinical trials, which use doses of DHEA in the 100 mg range, which are the human equivalent of about 1/20th the doses used in animal studies, are an inadequate test of DHEA's therapeutic potential. I also discuss three mechanisms of DHEA action that very likely contribute to its biological effects in animal studies. Lastly, I describe the development of a DHEA analog which lacks DHEA's androgenic and estrogenic action and that demonstrates enhanced potency and is currently in clinical trials. The use of such analogs may provide a better understanding of DHEA's potential therapeutic utility.
    Keywords:  Cortisol; DHEA; G6PD; NADPH; NOX
  5. Pediatr Int. 2022 Jan;64(1): e15116
    Keywords:  cartilage; chondroitin sulfate proteoglycans; dwarfism; extracellular matrix; mutation
  6. Am J Physiol Cell Physiol. 2022 Apr 06.
      Glycosaminoglycans (GAGs) are an important component of the tumor microenvironment (TME). GAGs can interact with a variety of binding partners and thereby influence cancer progression on multiple levels. GAGs can modulate growth factor and chemokine signaling, invasion and metastasis formation. Moreover, GAGs are able to change the physical property of the extracellular matrix (ECM). Abnormalities in GAG abundance and structure (e.g., sulfation patterns and molecular weight) are found across various cancer types and show biomarker potential. Targeting GAGs, as well as the usage of GAGs and their mimetics, are promising approaches to interfere with cancer progression. In addition, GAGs can be used as drug and cytokine carriers to induce an anti-tumor response. In this review, we summarize the role of GAGs in cancer and the potential use of GAGs and GAG derivatives to target cancer.
    Keywords:  cancer therapy; heparin; hyaluronidase; nanoparticles; proteoglycans
  7. Kidney360. 2020 Dec 31. 1(12): 1398-1406
      Background: Cognitive functions are altered in patients with CKD. However, it is suggested that cognitive functions improve after kidney transplantation, at least partially. A possible cause for this improvement could be the reduction of uremic retention solutes after transplantation. This study assessed the association between the changes in uremic toxin concentration with the changes in cognitive function in patients after kidney transplantation.Methods: Ten recipients of kidney transplants were compared with 18 controls (nine patients on hemodialysis, and nine patients with CKD stage 4 or 5 [eGFR <30 ml/min per 1.73 m2] who were not on dialysis). An extensive neuropsychological assessment, covering the five major cognitive domains (i.e., memory, attention and concentration, information processing speed, abstract reasoning, and executive function), was done before transplantation, at 1 week post-transplant, and 3 months after transplantation. Similarly, assessments of the 18 matched, control patients were performed longitudinally over a period of 3-5 months. Concentrations of 16 uremic retention solutes (indoxyl glucuronide, p-cresyl glucuronide, phenylglucuronide, 3-carboxy-4-methyl-5-propyl-2-furanpropanoic acid, indoxyl sulfate, p-cresyl sulfate, hippuric acid, phenyl sulfate, kynurenine, tryptophan, kynurenic acid, tyrosine, indole-3-acetic acid, phenylalanine, trimethylamine N-oxide, and phenylacetylglutamine) were measured in serum samples collected at the time of the neuropsychological assessments.
    Results: A significant improvement in cognitive function was only found in the processing-speed domain, and this was observed in both patients who received a transplant and patients with CKD. No significant differences between patients who received a transplant and the control groups were seen in the other cognitive domains. As expected, the serum concentration of most uremic toxins decreased significantly within 1 week after kidney transplantation.
    Conclusions: There was no significant improvement in cognitive function that could be specifically related to kidney transplantation in the first 3 months after the procedure. These data do not support the notion that uremic toxins exert an immediate effect on cognitive function.
    Keywords:  biological toxins; cognition; kidney transplantation; transplantation
  8. Nutr Res Pract. 2022 Apr;16(2): 147-160
      BACKGROUND/OBJECTIVES: Patients with chronic kidney disease (CKD) have a high concentration of uremic toxins in their blood and often experience muscle atrophy. Indoxyl sulfate (IS) is a uremic toxin produced by tryptophan metabolism. Although an elevated IS level may induce muscle dysfunction, the effect of IS on physiological concentration has not been elucidated. Additionally, the effects of ursolic acid (UA) on muscle hypertrophy have been reported in healthy models; however, it is unclear whether UA ameliorates muscle dysfunction associated with chronic diseases, such as CKD. Thus, this study aimed to investigate whether UA can improve the IS-induced impairment of mitochondrial biogenesis.MATERIALS/METHODS: C2C12 cells were incubated with or without IS (0.1 mM) and UA (1 or 2 µM) to elucidate the physiological effect of UA on CKD-related mitochondrial dysfunction and its related mechanisms using real-time reverse transcription-polymerase chain reaction, western blotting and enzyme-linked immunosorbent assay.
    RESULTS: IS suppressed the expression of differentiation marker genes without decreasing cell viability. IS decreased the mitochondrial DNA copy number and ATP levels by downregulating the genes pertaining to mitochondrial biogenesis (Ppargc1a, Nrf1, Tfam, Sirt1, and Mef2c), fusion (Mfn1 and Mfn2), oxidative phosphorylation (Cycs and Atp5b), and fatty acid oxidation (Pdk4, Acadm, Cpt1b, and Cd36). Furthermore, IS increased the intracellular mRNA and secretory protein levels of interleukin (IL)-6. Finally, UA ameliorated the IS-induced impairment in C2C12 cells.
    CONCLUSIONS: Our results indicated that UA improves the IS-induced impairment of mitochondrial biogenesis by affecting differentiation, ATP levels, and IL-6 secretion in C2C12 cells. Therefore, UA could be a novel therapeutic agent for CKD-induced muscle dysfunction.
    Keywords:  Chronic kidney disease; indoxyl sulfate; mitochondrial biogenesis; ursolic acid
  9. Biol Pharm Bull. 2022 ;45(4): 508-516
      Domestic pigs are attractive as an animal model for humans because of their anatomical and physiological similarities to humans. In this study, sex, organ, and breed differences in the mRNA expression of drug transporters such as breast cancer resistance protein (BCRP), multidrug resistance protein 1 (MDR1), multidrug resistance associated protein 2 (MRP2), organic anion porting polypeptide 1B3 (OATP1B3), organic anion transporters (OAT1, OAT2, and OAT3), and organic cation transporters (OCT1 and OCT2) were examined by RT-PCR in the liver and kidney of 5-month-old Meishan and Landrace pigs. No sex differences in the amount of BCRP mRNA were observed in both breeds. In Meishan pigs, sex differences (male < female) in the mRNA amounts of MDR1, OATP1B3, and OCT1 were observed in the liver. Similarly, sex differences in the mRNA amounts of MRP2, OAT1, OAT2, OAT3, and OCT2 were observed in the kidney of Meishan pigs: male > female for MRP2, OAT3, and OCT2, and male < female for OAT1 and OAT2. However, no such sex differences were observed in Landrace pigs. In addition, regardless of breed, hepatic OAT1, OAT3, and OCT2 mRNAs and renal OATP1B3 mRNA were not detected. Thus, organ and breed differences in the expression of drug transporters suggest the existence of genetically controlled organ-selective factors. Furthermore, additional experiments in castrated and/or testosterone propionate-treated pigs strongly suggested that sex and breed differences in the gene expression of drug transporters, especially hepatic OCT1 and renal OAT1, were primarily due to the difference in serum testosterone concentration.
    Keywords:  breed difference; drug transporter; pig; sex difference; testosterone; tissue difference
  10. Water Environ Res. 2022 Mar 13. 94(4): e10704
      Arylsulfatase and β-glucuronidase are two important enzymes in wastewater and surface water, which play important roles on cleavage of sulfate/glucuronide estrogens. In this work, a high-performance liquid chromatography (HPLC)-based new method was firstly established for arylsulfatase/β-glucuronidase with determination of p-nitrophenyl sulfate (pNPS)/p-nitrophenyl-β-D-glucuronide (pNPG). The limits of detections (LODs) of the developed method for pNPS and pNPG were 0.164 and 0.098 μM, respectively. Intraday and interday reproducibility expressed as relative standard deviation (RSD) values of retention times and peak areas was 0.39%-3.68% and 0.23%-4.74%, respectively. The respective recovery efficiencies of this HPLC-based method spiking at three different concentrations for p-nitrophenol (pNP), pNPS, and pNPG in activated sludge were 76.5%-88.1%, 79.2%-93.1%, and 84.2%-96.1%, with RSD below 3.9%. The HPLC-based method was finally applied to estimate the enzyme activity of arylsulfatase/β-glucuronidase in one activated sludge system and along which the classical spectrophotometric method was also evaluated. Compared with the classic spectrophotometric analytical method, the HPLC-based new method could simultaneously measure arylsulfatase/β-glucuronidase one time, which was convenient and time-saving. Moreover, the developed method could effectively avoid possible underestimation that the spectrophotometric method might encounter. PRACTITIONER POINTS: A new HPLC-based method for activity estimation of arylsulfatase and β-glucuronidase was developed. The HPLC-based method can simultaneously estimate enzyme activity of both arylsulfatase and β-glucuronidase. The HPLC-based method can avoid possible underestimation that spectrophotometric method may encounter.
    Keywords:  HPLC; activated sludge; arylsulfatase; p-nitrophenol; β-glucuronidase
  11. Toxicology. 2022 Apr 05. pii: S0300-483X(22)00087-7. [Epub ahead of print] 153175
      Bisphenol compounds (BPs) are ubiquitously existing pollutants. Recent evidence shows that they may be activated by human CYP1A1 for clastogenic effects; however, factors that influence/mediate CYP1A1-activated 4,4'-(hexafluoroisopropylidene)diphenol (BPAF) toxicity, particularly the aryl hydrocarbon receptor (AhR), sulfotransferase (SULT) 1A1 [known to conjugate 2,2-bis(4-hydroxyphenol)-propane (BPA)] and reactive oxygen species (ROS), remain unclear. In this study, a human hepatoma (HepG2) cell line was genetically engineered for the expression of human CYP1A1 and SULT1A1, producing HepG2-hCYP1A1 and HepG2-hSULT1A1, respectively. They were used in the micronucleus test and γ-H2AX analysis (Western blot) (indicating double-strand DNA breaks) with BPAF; the role of AhR in mediating BPAF toxicity was investigated by coexposure of AhR modulators in HepG2 and its derivative C3A (with no genetic modifications but enhanced CYP expression). The results indicated induction of micronuclei by BPAF (≥ 2.5µM, for 2-cell cycle) in HepG2-hCYP1A1 and C3A, while inactive in HepG2 and HepG2-hSULT1A1; however, BPAF induced micronuclei in HepG2 pretreated with 3,3',4,4',5-pentachlorobiphenyl (PCB126, AhR activator), and BAY-218 (AhR inhibitor) blocked the effect of BPAF in C3A. In HepG2-hCYP1A1 BPAF selectively induced centromere-free micronuclei (immunofluorescent assay) and double-strand DNA breaks. In HepG2 cells receiving conditional medium from BPAF-HepG2-hCYP1A1 incubation micronuclei were formed, while negative in HepG2-hSULT1A1. Finally, the intracellular levels of ROS, superoxide dismutase and reduced glutathione in C3A and HepG2-hCYP1A1 exposed to BPAF were all moderately increased, while unchanged in HepG2 cells. In conclusion, like other BPs BPAF is activated by human CYP1A1 for potent clastogenicity, and this effect is enhanced by AhR while alleviated by SULT1A1.
    Keywords:  Aryl hydrocarbon receptor (AhR); Bisphenol AF; CYP1A1; Centromere protein B; Micronuclei; Sulfotransferase
  12. Crit Rev Food Sci Nutr. 2022 Apr 05. 1-23
      Sulfur is essential for the health of plants and is an indispensable dietary component for human health and disease prevention. Its incorporation into our food supply is heavily reliant upon the uptake of sulfur into plant tissue and our subsequent intake. Dietary requirements for sulfur are largely calculated based upon requirements for the sulfur-containing amino acids (SAA), cysteine and methionine, to meet the demands for synthesis of proteins, enzymes, co-enzymes, vitamins, and hormones. SAA are found in abundance in animal sources and are relatively low in plants. However, some plants, particularly cruciferous and allium vegetables, produce many protective sulfur-containing secondary metabolites, such as glucosinolates and cysteine sulfoxides. The variety and quantity of these sulfur-containing metabolites are extensive and their effects on human health are wide-reaching. Many benefits appear to be related to sulfur's role in redox biochemistry, protecting against uncontrolled oxidative stress and inflammation; features consistent within cardiometabolic dysfunction and many chronic metabolic diseases of aging. This narrative explores the origins and importance of sulfur, its incorporation into our food supply and dietary sources. It also explores the overarching potential of sulfur for human health, particularly around the amelioration of oxidative stress and chronic inflammation, and subsequent chronic disease prevention.
    Keywords:  Sulfur-containing secondary metabolites; allium vegetables; cardiometabolic; cruciferous vegetables; cysteine sulfoxides; glucosinolates