bims-supasi Biomed News
on Sulfation pathways and signalling
Issue of 2022‒10‒30
fifteen papers selected by
Jonathan Wolf Mueller
University of Birmingham

  1. Mar Drugs. 2022 Oct 21. pii: 653. [Epub ahead of print]20(10):
      Fucosylated chondroitin sulfate (FCS) from the sea cucumber Acaudina molpadioides (FCSAm) is the first one that was reported to be branched by disaccharide GalNAc-(α1,2)-Fuc3S4S (15%) and sulfated Fuc (85%). Here, four size-homogenous fractions, and seven oligosaccharides, were separated from its β-eliminative depolymerized products. Detailed NMR spectroscopic and MS analyses revealed the oligomers as hexa-, hepta-, octa-, and nonasaccharide, which further confirmed the precise structure of native FCSAm: it was composed of the CS-E-like backbone with a full content of sulfation at O-4 and O-6 of GalNAc in the disaccharide repeating unit, and the branches consisting of sulfated fucose (Fuc4S and Fuc2S4S) and heterodisaccharide [GalNAc-(α1,2)-Fuc3S4S]. Pharmacologically, FCSAm and its depolymerized derivatives, including fractions and oligosaccharides, showed potent neurite outgrowth-promoting activity in a chain length-dependent manner. A comparison of analyses among oligosaccharides revealed that the sulfate pattern of the Fuc branches, instead of the heterodisaccharide, could affect the promotion intensity. Fuc2S4S and the saccharide length endowed the neurite outgrowth stimulation activity most.
    Keywords:  disaccharide branch; fucosylated chondroitin sulfate; neurite outgrowth; oligosaccharide; sea cucumber; stimulation
  2. Int J Mol Sci. 2022 Oct 11. pii: 12082. [Epub ahead of print]23(20):
      β-cells in the islets of Langerhans of the pancreas secrete insulin in response to the glucose concentration in the blood. When these pancreatic β-cells are damaged, diabetes develops through glucose intolerance caused by insufficient insulin secretion. High molecular weight polysaccharides, such as heparin and heparan sulfate (HS) proteoglycans, and HS-degrading enzymes, such as heparinase, participate in the protection, maintenance, and enhancement of the functions of pancreatic islets and β-cells, and the demand for studies on glycobiology within the field of diabetes research has increased. This review introduces the roles of complex glycoconjugates containing high molecular weight polysaccharides and their degrading enzymes in pancreatic islets and β-cells, including those obtained in studies conducted by us earlier. In addition, from the perspective of glycobiology, this study proposes the possibility of application to diabetes medicine.
    Keywords:  core proteins; diabetes melitus; heparan sulfate proteoglycans; heparanase; insulin secretion; pancreatic islets and β-cells; signaling pathways; sulfotransferases
  3. Metabolites. 2022 Oct 04. pii: 941. [Epub ahead of print]12(10):
      The regulation of DHEA-sulfate by steroid sulfotransferase (SULT) and steryl-sulfatase (STS) enzymes is a vital process for the downstream formation of many steroid hormones. DHEA-sulfate is the most abundant steroid hormone in the human body; thus, DHEA-sulfate and its hydrolyzed form, DHEA, continue to be evaluated in numerous studies, given their importance to human health. Yet, a basic question of relevance to the reproductive-age female population-whether the two steroid hormones vary across the menstrual cycle-has not been addressed. We applied a validated, multi-step protocol, involving realignment and imputation of study data to early follicular, mid-late follicular, periovulatory, and early, mid-, and late luteal subphases of the menstrual cycle, and analyzed DHEA-sulfate and DHEA serum concentrations using ultraperformance liquid chromatography tandem mass spectrometry. DHEA-sulfate levels started to decrease in the early luteal, significantly dropped in the mid-luteal, and returned to basal levels by the late luteal subphase. DHEA, however, did not vary across the menstrual cycle. The present study deep-mapped trajectories of DHEA and DHEA-sulfate across the entire menstrual cycle, demonstrating a significant decrease in DHEA-sulfate in the mid-luteal subphase. These findings are relevant to the active area of research examining associations between DHEA-sulfate levels and various disease states.
    Keywords:  DHEA; DHEA-sulfate; STS; SULT; dehydroepiandrosterone-sulfate; follicular; luteal; menstrual cycle; steroid sulfotransferase; steryl-sulfatase
  4. Polymers (Basel). 2022 Oct 14. pii: 4324. [Epub ahead of print]14(20):
      Polyelectrolyte microgels derived from natural sources such as chondroitin sulfate (CS) possess considerable interest as therapeutic carriers because of their ionic nature and controllable degradation capability in line with the extent of the used crosslinker for long-term drug delivery applications. In this study, chemically crosslinked CS microgels were synthesized in a single step and treated with an ammonia solution to attain polyelectrolyte CS-[NH4]+ microgels via a cation exchange reaction. The spherical and non-porous CS microgels were injectable and in the size range of a few hundred nanometers to tens of micrometers. The average size distribution of the CS microgels and their polyelectrolyte forms were not significantly affected by medium pH. It was determined that the -34 ± 4 mV zeta potential of the CS microgels was changed to -23 ± 3 mV for CS- [NH4]+ microgels with pH 7 medium. No important toxicity was determined on L929 fibroblast cells, with 76 ± 1% viability in the presence of 1000 μg/mL concentration of CS-[NH4]+ microgels. Furthermore, these microgels were used as a drug carrier material for rosmarinic acid (RA) active agent. The RA-loading capacity was about 2.5-fold increased for CS-[R]+ microgels with 32.4 ± 5.1 μg/mg RA loading, and 23% of the loaded RA was sustainably release for a long-term period within 150 h in comparison to CS microgels. Moreover, RA-loaded CS-[R]+ microgels exhibited great antioxidant activity, with 0.45 ± 0.02 μmol/g Trolox equivalent antioxidant capacity in comparison to no antioxidant properties for bare CS particles.
    Keywords:  antioxidant; biocompatible; chondroitin sulfate (CS); polyelectrolyte microgels; rosmarinic acid
  5. Bioengineering (Basel). 2022 Oct 18. pii: 566. [Epub ahead of print]9(10):
      Since chronically inflamed periodontal tissue exhibits extracellular matrix (ECM) degradation, the possible alternative to standard periodontitis treatment is to restore ECM by supplementing its components, including heparan sulfate glycosaminoglycan (HS GAG). Supplementation of the degraded ECM with synthetic derivatives of HS GAGs has been shown to be effective for periodontal tissue regeneration in experimental animal models of periodontitis. However, the potential of HS GAG supplementation for the treatment of periodontal disease in humans is still unknown. Here, we used a statistical model to investigate the role of HS GAG on inflammatory infiltrate formation and alveolar bone resorption in humans with severe periodontitis. The model was based on data from immunofluorescence staining (IF) of human gingiva samples, and reconstruction of a subset of HS GAG -related proteins from STRING reactome database. According to predictions, increased expression of native HS GAG might stabilize the accumulation of gingival inflammatory infiltrate (represented by the general inflammatory cell marker CD45) and alveolar bone resorption (represented by Receptor Activator of Nuclear ΚΒ ligand (RANKL) and osteoprotegerin (OPG) ratio) but could not restore them to healthy tissue levels. Therefore, supplementation of native HS GAG may be of limited benefits for the treatment of sever periodontitis in humans.
    Keywords:  heparan sulfate glycosaminoglycan; immunofluorescence; inflammation; periodontitis; statistical modeling
  6. Cells. 2022 Oct 12. pii: 3198. [Epub ahead of print]11(20):
      Cardiovascular disease (CVD) is the leading cause of death and disability worldwide, and its management places a huge burden on healthcare systems through hospitalisation and treatment. Atherosclerosis is a chronic inflammatory disease of the arterial wall resulting in the formation of lipid-rich, fibrotic plaques under the subendothelium and is a key contributor to the development of CVD. As such, a detailed understanding of the mechanisms involved in the development of atherosclerosis is urgently required for more effective disease treatment and prevention strategies. Heparanase is the only mammalian enzyme known to cleave heparan sulfate of heparan sulfate proteoglycans, which is a key component of the extracellular matrix and basement membrane. By cleaving heparan sulfate, heparanase contributes to the regulation of numerous physiological and pathological processes such as wound healing, inflammation, tumour angiogenesis, and cell migration. Recent evidence suggests a multifactorial role for heparanase in atherosclerosis by promoting underlying inflammatory processes giving rise to plaque formation, as well as regulating lesion stability. This review provides an up-to-date overview of the role of heparanase in physiological and pathological processes with a focus on the emerging role of the enzyme in atherosclerosis.
    Keywords:  atherosclerosis; extracellular matrix (ECM); heparan sulfate; heparanase; immune cells; inflammation
  7. Viruses. 2022 Sep 30. pii: 2156. [Epub ahead of print]14(10):
      Herpes Simplex Virus 1 (HSV-1) is a neurotropic human virus that belongs to the Alphaherpesvirinae subfamily of Herpesviridae. Establishment of its productive infection and progression of disease pathologies depend largely on successful release of virions from the virus-producing cells. HSV-1 is known to exploit many host factors for its release. Recent studies have shown that heparanase (HPSE) is one such host enzyme that is recruited for this purpose. It is an endoglycosidase that cleaves heparan sulfate (HS) from the surface of infected cells. HS is a virus attachment coreceptor that is commonly found on cell surfaces as HS proteoglycans e.g., syndecan-1 (SDC-1). The current model suggests that HSV-1 during the late stage of infection upregulates HPSE, which in turn enhances viral release by removing the virus-trapping HS moieties. In addition to its role in directly enabling viral release, HPSE accelerates the shedding of HS-containing ectodomains of SDC-1, which enhances HSV-1 release via a similar mechanism by upregulating CREB3 and COPII proteins. This review outlines the role of HPSE and SDC-1 as newly assigned host factors that facilitate HSV-1 release during a lytic infection cycle.
    Keywords:  CREB3; HSV-1; MMPs; heparan sulfate; heparanase; syndecan-1; viral release
  8. Cureus. 2022 Sep;14(9): e29248
      Hydrogels are thought of as unique polymers utilized to build new materials, and two key factors that impact their features are their hydrophilicity and the degree of cross-linking of the polymer chains. An injectable hydrogel is based on the hypothesis that certain biomaterials can be injected into the body as a liquid and progressively solidify there. The scientific research community was intrigued and interested by its discovery. The hydrophilic polymers that are used to make hydrogels can typically be split into two groups: natural polymers derived from tissues or other sources of natural materials, and synthetic polymers produced by combining principles from organic chemistry and molecular engineering. A variety of organic and synthetic biomaterials, such as chitosan, collagen or gelatin, alginate, hyaluronic acid, heparin, chondroitin sulfate, polyethylene glycol, and polyvinyl alcohol, are used to generate injectable hydrogels. A promising biomaterial for the therapeutic injection of cells and bioactive chemicals for tissue regeneration in both dentistry and medicine, injectable hydrogels have recently attracted attention. Since injectable scaffolds can be implanted with less invasive surgery, their application is seen as a viable strategy in the regeneration of craniofacial tissue. Treatment for periodontitis that effectively promotes periodontal regeneration involves injecting a hydrogel that contains medications with simultaneous anti-inflammatory and tissue-regenerating capabilities. The advantages of injectable hydrogel for tissue engineering are enhanced by the capability of three-dimensional encapsulation. A material's injectability can be attributed to a variety of mechanisms. The hydrogels work well to reduce inflammation and promote periodontal tissue regeneration.
    Keywords:  3d bioprinting; chitosan; choindritin sulfate (cs); col; ecm; gel; ha; hydrogel; poly-vinyl; polymer
  9. Gels. 2022 Sep 28. pii: 620. [Epub ahead of print]8(10):
      The physicochemical properties and microstructure of hybrid hydrogels prepared using sodium alginate (SA) and chondroitin sulfate (CS) extracted from two animal sources were investigated. SA-based hybrid hydrogels were prepared by mixing chicken- and bovine-derived CS (CCS and BCS, respectively) with SA at 1/3 and 2/3 (w/w) ratios. The results indicated that the evaporation water loss rate of the hybrid hydrogels increased significantly upon the addition of CS, whereas CCS/SA (2/3) easily absorbed moisture from the environment. The thermal stability of the BCS/SA (1/3) hybrid hydrogel was higher than that of CCS/SA (1/3) hybrid hydrogel, whereas the hardness and adhesiveness of the CCS/SA (1/3) hybrid hydrogel were lower and higher, respectively, than those of the BCS/SA (1/3) hybrid hydrogel. Low-field nuclear magnetic resonance experiments demonstrated that the immobilized water content of the CCS/SA (1/3) hybrid hydrogel was higher than that of the BCS/SA (1/3) hybrid hydrogel. FTIR showed that S=O characteristic absorption peak intensity of BCS/SA (2/3) was obviously higher, suggesting that BCS possessed more sulfuric acid groups than CCS. SEM showed that the hybrid hydrogels containing CCS have more compact porous microstructure and better interfacial compatibility compared to BCS.
    Keywords:  characterization; chondroitin sulfate; hybrid; hydrogel; sodium alginate
  10. J Dent Res. 2022 Oct 24. 220345221130682
      Dental pulp stem cells (DPSCs) can differentiate into vascular endothelial cells and display sprouting ability. During this process, DPSC responses to the extracellular microenvironment and cell-extracellular matrix interactions are critical in regulating their ultimate cell fate. Heparan sulfate (HS) glycosaminoglycan, a major component of extracellular matrix, plays important roles in various biological cell activities by interacting with growth factors and relative receptors. However, the regulatory function of HS on vasculogenesis of mesenchymal stem cells remains unclear. The objective of this study was to investigate the role of HS in endothelial differentiation and vasculogenesis of DPSCs. Our results show that an HS antagonist suppressed the proliferation and sprouting ability of DPSCs undergoing endothelial differentiation. Furthermore, expression of proangiogenic markers significantly declined with increasing dosages of the HS antagonist; in contrast, expression of stemness marker increased. Silencing of exostosin 1 (EXT1), a crucial glycosyltransferase for HS biosynthesis, in DPSCs using a short hairpin RNA significantly altered their gene expression profile. In addition, EXT1-silenced DPSCs expressed lower levels of endothelial differentiation markers and displayed a reduced vascular formation capacity compared with control DPSCs transduced with scrambled sequences. The sprouting ability of EXT1-silenced DPSCs was rescued by the addition of exogenous HS in vitro. Next, we subcutaneously transplanted biodegradable scaffolds seeded with EXT1-silenced or control DPSCs into immunodeficient mice. Lumen-like structures positive for human CD31 and von Willebrand factor were formed by green fluorescent protein-transduced DPSCs. Numbers of blood-containing vessels were significantly lower in scaffolds loaded with EXT1-silenced DPSCs than specimens implanted with control DPSCs. Collectively, our findings unveil the crucial role of HS on endothelial differentiation and vasculogenesis of DPSCs, opening new perspectives for the application of HS to tissue engineering and dental pulp regeneration.
    Keywords:  cell differentiation; endothelial cells; extracellular matrix; gene silencing; glycosaminoglycans; mesenchymal stem cells
  11. Gels. 2022 Oct 20. pii: 676. [Epub ahead of print]8(10):
      Hydrogels can provide instant relief to pain and facilitate the fast recovery of wounds. Currently, the incorporation of medicinal herbs/plants in polymer matrix is being investigated due to their anti-bacterial and wound healing properties. Herein, we investigated the novel combination of chitosan (CS) and chondroitin sulfate (CHI) to synthesize hydrogels through freeze gelation process and enriched it with garlic (Gar) by soaking the hydrogels in garlic juice for faster wound healing and resistance to microbial growth at the wound surface. The synthesized hydrogels were characterized via Fourier-transform infrared spectroscopy (FTIR), which confirmed the presence of relevant functional groups. The scanning electron microscopy (SEM) images exhibited the porous structure of the hydrogels, which is useful for the sustained release of Gar from the hydrogels. The synthesized hydrogels showed significant inhibition zones against Escherichia coli (E. coli) and Staphylococcus aureus (S. aureus). Furthermore, cell culture studies confirmed the cyto-compatibility of the synthesized hydrogels. Thus, the novel hydrogels presented in this study can offer an antibacterial effect during wound healing and promote tissue regeneration.
    Keywords:  alicin; antibacterial; drug release; garlic; hydrogels; polymers; regeneration
  12. Cells. 2022 Oct 17. pii: 3255. [Epub ahead of print]11(20):
      It is well known that a subgroup of women with PCOS present an excessive adrenal androgen production, generally associated with ovarian hyperandrogenism. In the past, it has been impossible to correlate adrenal hyperandrogenism to any clinical or hormonal pattern of PCOS. However, adrenal androgens are strictly dependent on age and their blood values reduce by 40% in patients moving from their twenties to thirties. Due to this, serum DHEAS values are strongly influenced by the age distribution of studied populations. To avoid this bias, in this study we retrospectively analyzed the clinical and hormonal data of PCOS women in their twenties (age between 20 and 29 years). Data of 648 young hyperandrogenic women with PCOS were evaluated. Serum DHEAS was increased in a third (33%) of studied patients and was associated with higher values of testosterone (T) and androstenedione (A). In each phenotype, patients with high DHEAS had higher values of T and A than patients with normal DHEAS of the same phenotype. Therefore, a DHEAS increase is generally part of a generalized higher androgen production in a subgroup of PCOS patients, independently of the finding of anovulatory or ovulatory cycles or of polycystic or normal ovaries. However, our study showed some important differences between PCOS phenotypes. A lower prevalence of increased DHEAS in A phenotype PCOS patients who generally have the highest androgen levels, versus non-classic (B or C) PCOS phenotypes, was observed. It was also found that patients with A phenotype PCOS present significantly lower BMI and serum insulin than patients with normal DHEAS of the same phenotype while, in patients with the B or C phenotype, the opposite occurs. We conclude that adrenal hyperandrogenism is more common in patients with non-classic (B and C) phenotypes of PCOS and is generally part of a generalized higher production of androgens in a subgroup of PCOS patients. However, other factors may increase the adrenal androgen production and influence the clinical expression of the syndrome. More studies in large, selected for age, populations of PCOS women with different phenotypes are needed.
    Keywords:  DHEAS; PCOS; PCOS phenotypes; adrenal androgens; adrenal hyperandrogenism in PCOS
  13. Ren Fail. 2022 Dec;44(1): 1791-1800
      BACKGROUND: The impact of p-cresyl sulfate (PCS) and indoxyl sulfate (IS) on the prognosis of patients with uremia remains controversial. We performed a prospective study on peritoneal dialysis (PD) to investigate the relationship between PCS or IS levels with clinical outcomes.METHODS: This prospective cohort study investigated the association of serum PCS and IS with clinical outcomes in patients undertaking PD. We performed a correlations analysis to explore the influencing factors of PCS an IS. Meta-analysis was conducted to objectively evaluate the prognostic effects of PCS and IS on different stages of CKD patients.
    RESULTS: A total of 127 patients were enrolled consecutively and followed with an average period of 51.3 months. Multivariate Cox regression showed that serum total PCS not only contributed to the occurrence of PD failure event (HR: 1.05, 95% CI = 1.02 to 1.07, p < 0.001), but also increased the risk of cardiovascular event (HR: 1.08, 95% CI = 1.04 to 1.13, p < 0.001) and PD-associated peritonitis (HR: 1.04, 95% CI = 1.02 to 1.08, p = 0.001). Dividing the total PCS level by 18.99 mg/L, which was calculated from the best cutoff value of the ROC curve, patients with total PCS higher than 18.99 mg/L had worse prognosis. Meta-analysis confirmed its value in cardiovascular event in PD.
    CONCLUSION: The serum total PCS concentration was a detrimental factor for higher PD failure event, cardiovascular event, and PD-associated peritonitis. It could be used as an innovative marker in predicting poor clinical outcome in PD.
    Keywords:  cardiovascular disease; p-Cresyl sulfate; peritoneal dialysis; peritoneal dialysis failure; peritoneal dialysis-associated peritonitis
  14. Toxins (Basel). 2022 Sep 23. pii: 660. [Epub ahead of print]14(10):
      Serum myostatin and indoxyl sulfate (IS) levels increase with kidney function decline and may function as uremic toxins in chronic kidney disease (CKD)-related sarcopenia. Herein, we analyzed the association between serum myostatin and IS levels and sarcopenia in patients with CKD, by performing a post hoc analysis of baseline data extracted from the RECOVERY study ( NCT03788252) of 150 patients with CKD. We stratified patients into two groups according to the median value of myostatin (cutoff 4.5 ng/mL) and IS levels (cutoff 0.365 mg/dL). The proportion of patients with sarcopenia was higher in those with high IS levels but lower in those with high myostatin levels. The skeletal muscle mass index (SMI) and handgrip strength (HGS) were significantly lower in patients with high IS levels but significantly higher in patients with high myostatin levels. IS levels showed a negative correlation with glomerular filtration rate (GFR), SMI, and HGS. However, myostatin levels were positively correlated with SMI and HGS, but not with GFR. Sarcopenia was independently associated with age and IS level after adjustment. Increased levels of serum total IS might play a role in sarcopenia, while increased levels of serum myostatin are associated with muscle mass in patients with CKD.
    Keywords:  chronic kidney disease; indoxyl sulfate; myostatin; sarcopenia
  15. Biology (Basel). 2022 Oct 08. pii: 1476. [Epub ahead of print]11(10):
      In the present study, a culture of Chaetoceros muelleri, a cosmopolitan planktonic diatom microalga present in the Sea of Cortez, was established under controlled laboratory conditions. A sulfated polysaccharide (CMSP) extraction was carried out from the biomass obtained, resulting in a yield of 2.2% (w/w of dry biomass). The CMSP sample was analyzed by Fourier transform infrared spectroscopy, showing bands ranging from 3405 to 590 cm-1 and a sulfate substitution degree of 0.10. Scanning electron microscopy with elemental analysis revealed that the CMSP particles are irregularly shaped with non-acute angles and contain sulfur. High-performance liquid chromatography coupled to a dynamic light-scattering detector yielded molecular weight (Mw), polydispersity index (PDI), intrinsic viscosity [η], and hydrodynamic radius (Rh) values of 4.13 kDa, 2.0, 4.68 mL/g, and 1.3 nm, respectively, for the CMSP. This polysaccharide did not present cytotoxicity in CCD-841 colon cells. The antioxidant activity and the glycemic index of the CMSP were 23% and 49, respectively, which gives this molecule an added value by keeping low glycemic levels and exerting antioxidant activity simultaneously.
    Keywords:  bioactivity; microalgae; microstructure; molecular conformation; sulfated polysaccharides