bims-supasi Biomed News
on Sulfation pathways and signalling
Issue of 2023–07–16
eleven papers selected by
Jonathan Wolf Mueller, University of Birmingham
  1. Nuclear magnetic resonance-based structural elucidation of novel marine glycans and derived oligosaccharides.
  2. Chondroitin Sulfate Supplements for Osteoarthritis: A Critical Review.
  3. Expression of low-sulfated keratan sulfate in non-mucinous ovarian carcinoma.
  4. Quantification of orally administered chondroitin sulfate oligosaccharides in human plasma and urine.
  5. Quantification of chondroitin sulfate, hyaluronic acid and N-glycans in synovial fluid - A technical performance study.
  6. Enhanced tyrosine sulfation is associated with chronic kidney disease-related atherosclerosis.
  7. Fetal milieu-simulating hyaluronic acid-dopamine-chondroitin sulfate hydrogel promoting angiogenesis and hair regeneration for wound healing.
  8. Role of Chondroitin Sulfate Proteoglycan 5 in Steroid-Induced Cataract.
  9. Associations of DHEA(S) with negative and positive affect in people who smoke daily with elevated and low depression symptoms: A pilot laboratory study.
  10. Extraction of dermatan sulfate using ionic liquid-assisted enzymatic digestion: An efficient approach.
  11. Chondroitin sulfate functionalized palmitic acid and cysteine cografted-quaternized chitosan for CD44 and gut microbiota dual-targeted delivery of curcumin.
  1. Magn Reson Chem. 2023 Jul 13.
    Nuclear magnetic resonance-based structural elucidation of novel marine glycans and derived oligosaccharides.
    Rohini Dwivedi, Antim K Maurya, Hoda Ahmed, Marwa Farrag, Vitor H Pomin.
      Marine glycans of defined structures are unique representatives among all kinds of structurally complex glycans endowed with important biological actions. Besides their unique biological properties, these marine sugars also enable advanced structure-activity relationship (SAR) studies given their distinct and defined structures. However, the natural high molecular weights (MWs) of these marine polysaccharides, sometimes even bigger than 100 kDa, pose a problem in many biophysical and analytical studies. Hence, the preparation of low MW oligosaccharides becomes a strategy to overcome the problem. Regardless of the polymeric or oligomeric lengths of these molecules, structural elucidation is mandatory for SAR studies. For this, nuclear magnetic resonance (NMR) spectroscopy plays a pivotal role. Here, we revisit the NMR-based structural elucidation of a series of marine sulfated poly/oligosaccharides discovered in our laboratory within the last 2 years. This set of structures includes the α-glucan extracted from the bivalve Marcia hiantina; the two sulfated galactans extracted from the red alga Botryocladia occidentalis; the fucosylated chondroitin sulfate isolated from the sea cucumber Pentacta pygmaea; the oligosaccharides produced from the fucosylated chondroitin sulfates from this sea cucumber species and from another species, Holothuria floridana; and the sulfated fucan from this later species. Specific 1 H and 13 C chemical shifts, generated by various 1D and 2D homonuclear and heteronuclear NMR spectra, are exploited as the primary source of information in the structural elucidation of these marine glycans.
    Keywords:  13C; 1H; NMR; fucosylated chondroitin sulfate; glycosidic linkage; oligosaccharides; sulfated fucan; sulfated galactan; sulfation pattern; α-glucan
    DOI:  https://doi.org/10.1002/mrc.5377
  2. Cureus. 2023 Jun;15(6): e40192
    Chondroitin Sulfate Supplements for Osteoarthritis: A Critical Review.
    Rui Brito, Diogo Costa, Carina Dias, Patrícia Cruz, Paula Barros.
      Over the years, chondroitin sulfate (CS) has been used as a slow-acting drug for the treatment of osteoarthritis, for the reduction of pain and improvement of function, and for its disease-modifying properties by limiting cartilage volume loss and joint space narrowing progression. However, there have been inconsistencies in published trials regarding clinical efficacy, with reports of a lack of significant effects compared to placebo. The therapeutic effects of chondroitin sulfate may depend on many variables, such as the source of origin, purity, and contamination with by-products. Another source of confusion may be related to the fact that CS is commonly combined with glucosamine, which makes it challenging to isolate the specific contribution of chondroitin to the therapeutic outcome. This is aggravated by the fact that CS supplements, used in many countries, are not regulated, and labels wrongly claim high levels of purity. Many of these inferior CS products may have been used in clinical trials, which may have had limited but significant results. This has led to recent recommendations to opt for higher-purity pharmacologic-grade CS for the treatment of OA. This article aims to provide an up-to-date view of the current literature regarding the biological effects and efficacy of CS and discusses the quality of available chondroitin sulfate supplements and the current direction in CS investigation. This review concludes that pharmacologic-grade CS supplements may have clinically significant benefits when properly standardized; however, high-quality evidence from properly designed clinical trials is still needed to draw definitive conclusions about clinical efficacy in osteoarthritis.
    Keywords:  chondroitin sulfate; chondroprotection; joint health; osteoarthritis; supplementation
    DOI:  https://doi.org/10.7759/cureus.40192
  3. Glycobiology. 2023 Jul 13. pii: cwad056. [Epub ahead of print]
    Expression of low-sulfated keratan sulfate in non-mucinous ovarian carcinoma.
    Hitomi Hoshino, Ya-Ying Chen, Daisuke Inoue, Yoshio Yoshida, Kay-Hooi Khoo, Tomoya O Akama, Motohiro Kobayashi.
      Keratan sulfate glycosaminoglycan is composed of repeating N-acetyllactosamine (LacNAc) disaccharide units consisting of galactose (Gal) and N-acetylglucosamine (GlcNAc), both often 6-O-sulfated. Sulfate contents of keratan sulfate are heterogeneous depending upon the origins. In this study, keratan sulfate is classified as either highly sulfated (in which both GlcNAc and Gal residues are 6-O-sulfated) or low-sulfated (in which only GlcNAc residues are 6-O-sulfated). It is reported that highly sulfated keratan sulfate detected by the 5D4 monoclonal antibody is preferentially expressed in normal epithelial cells lining the female genital tract and in their neoplastic counterparts; however, expression of low-sulfated keratan sulfate in either has not been characterized. In the present study, we generated the 294-1B1 monoclonal antibody, which selectively recognizes low-sulfated keratan sulfate, and performed precise glycan analysis of sulfated glycans expressed on human serous ovarian carcinoma OVCAR-3 cells. We found that OVCAR-3 cells do not express highly sulfated keratan sulfate but rather express low-sulfated form, which was heterogeneous in 294-1B1 reactivity. Comparison of mass spectrometry spectra of sulfated glycans in 294-1B1-positive versus -negative OVCAR-3 cells indicated that the 294-1B1 epitope is likely at least two, and possibly three or more, tandem GlcNAc-6-O-sulfated LacNAc units. Then, using the 294-1B1 antibody, we performed quantitative immunohistochemical analysis of 40 specimens from patients with ovarian cancer, consisting of 10 each of serous, endometrioid, clear cell and mucinous carcinomas, and found that among them low-sulfated keratan sulfate was widely expressed in all but mucinous ovarian carcinoma.
    Keywords:  294-1B1 monoclonal antibody; Low-sulfated keratan sulfate; Mass spectrometry; Ovarian carcinoma
    DOI:  https://doi.org/10.1093/glycob/cwad056
  4. Glycobiology. 2023 Jul 13. pii: cwad054. [Epub ahead of print]
    Quantification of orally administered chondroitin sulfate oligosaccharides in human plasma and urine.
    Hiroko Mizuta, Shota Kawahara, Naonobu Tsutsumi, Nobuyuki Miyamoto.
      Chondroitin sulfate (CS) has been widely administered orally to improve knee osteoarthritis (OA). CS also has various biological properties, such as anti-inflammatory, immunomodulatory, anti-oxidative, and anti-tumour activity. However, CS absorption in the digestive system and bioavailability remain controversial owing to its large molecular weight (MW). In this study, we aimed to evaluate the absorption of CS oligosaccharides (CSOS), depolymerized CS with low MW, in oral administration to humans. Four types of CS with varying MW [CS tetrasaccharide (MW. 980), CSOS-1 (MW. 1500), CSOS-2 (MW. 2800), and HMWCS (MW. 70,000)] were orally administered and quantified in plasma and urine. Exogenous CS (Exo-CS) in these samples was quantified using a high-performance liquid chromatography system equipped with a fluorescence detector. Quantitative changes of administered CS tetrasaccharide showed similar patterns in plasma and urine, therefore it was presumed that the amount of Exo-CS excreted in urine reflects its quantitative profile in blood. Considering urinary Exo-CS as a parameter of intestinal CS absorption, urinary contents of orally administered CS with varying MW were compared. Consequently, the amount of urinary Exo-CS in 24 hours after administration was higher in the CSOS group than that in the HMWCS group. Additionally, in the MW distribution, urinary Exo-CS after CSOS administration showed a lower content of CSOS with a higher MW than that observed before administration. In summary, our results demonstrated for the first time that lower MW of CS is more efficiently absorbed through the digestive tract in human, and the improvement of its bioavailability is expected.
    Keywords:  Chondroitin sulfate; Oligosaccharide; Oral administration; Plasma; Urine
    DOI:  https://doi.org/10.1093/glycob/cwad054
  5. Osteoarthr Cartil Open. 2023 Sep;5(3): 100380
    Quantification of chondroitin sulfate, hyaluronic acid and N-glycans in synovial fluid - A technical performance study.
    Elin Andersson, Emil Tykesson, L Stefan Lohmander, Niclas G Karlsson, Chunsheng Jin, Ekaterina Mirgorodskaya, Per Swärd, André Struglics.
       Objective: To validate a quantitative high performance liquid chromatography (HPLC) assay for chondroitin sulfate (CS) and hyaluronic acid (HA) in synovial fluid, and to analyze glycan-patterns in patient samples.
    Design: Synovial fluid from osteoarthritis (OA, n ​= ​25) and knee-injury (n ​= ​13) patients, a synovial fluid pool (SF-control) and purified aggrecan, were chondroitinase digested and together with CS- and HA-standards fluorophore labelled prior to quantitative HPLC analysis. N-glycan profiles of synovial fluid and aggrecan were assessed by mass spectrometry.
    Results: Unsaturated uronic acid and sulfated-N-acetylgalactosamine (ΔUA-GalNAc4S and ΔUA-GalNAc6S) contributed to 95% of the total CS-signal in the SF-control sample. For HA and the CS variants in SF-control the intra- and inter-experiment coefficient of variation was between 3-12% and 11-19%, respectively; tenfold dilution gave recoveries between 74 and 122%, and biofluid stability test (room temperature storage and freeze-thaw cycles) showed recoveries between 81 and 140%. Synovial fluid concentrations of the CS variants ΔUA-GalNAc6S and ΔUA2S-GalNAc6S were three times higher in the recent injury group compared to the OA group, while HA was four times lower. Sixty-one different N-glycans were detected in the synovial fluid samples, but there were no differences in levels of N-glycan classes between patient groups. The CS-profile (levels of ΔUA-GalNAc4S and ΔUA-GalNAc6S) in synovial fluid resembled that of purified aggrecan from corresponding samples; the contribution to the N-glycan profile in synovial fluid from aggrecan was low.
    Conclusions: The HPLC-assay is suitable for analyzing CS variants and HA in synovial fluid samples, and the GAG-pattern differs between OA and recently knee injured subjects.
    Keywords:  Chondroitin sulfate; HPLC; Mass spectrometry; N-Glycan; Synovial fluid
    DOI:  https://doi.org/10.1016/j.ocarto.2023.100380
  6. BMC Biol. 2023 07 10. 21(1): 151
    Enhanced tyrosine sulfation is associated with chronic kidney disease-related atherosclerosis.
    Daopeng Dai, Zhengbin Zhu, Hui Han, Tian Xu, Shuo Feng, Wenli Zhang, Fenghua Ding, Ruiyan Zhang, Jinzhou Zhu.
       BACKGROUND: Chronic kidney disease (CKD) accelerates atherosclerosis, but the mechanisms remain unclear. Tyrosine sulfation has been recognized as a key post-translational modification (PTM) in regulation of various cellular processes, and the sulfated adhesion molecules and chemokine receptors have been shown to participate in the pathogenesis of atherosclerosis via enhancement of monocyte/macrophage function. The levels of inorganic sulfate, the essential substrate for the sulfation reaction, are dramatically increased in patients with CKD, which indicates a change of sulfation status in CKD patients. Thus, in the present study, we detected the sulfation status in CKD patients and probed into the impact of sulfation on CKD-related atherosclerosis by targeting tyrosine sulfation function.
    RESULTS: PBMCs from individuals with CKD showed higher amounts of total sulfotyrosine and tyrosylprotein sulfotransferase (TPST) type 1 and 2 protein levels. The plasma level of O-sulfotyrosine, the metabolic end product of tyrosine sulfation, increased significantly in CKD patients. Statistically, O-sulfotyrosine and the coronary atherosclerosis severity SYNTAX score positively correlated. Mechanically, more sulfate-positive nucleated cells in peripheral blood and more abundant infiltration of sulfated macrophages in deteriorated vascular plaques in CKD ApoE null mice were noted. Knockout of TPST1 and TPST2 decreased atherosclerosis and peritoneal macrophage adherence and migration in CKD condition. The sulfation of the chemokine receptors, CCR2 and CCR5, was increased in PBMCs from CKD patients.
    CONCLUSIONS: CKD is associated with increased sulfation status. Increased sulfation contributes to monocyte/macrophage activation and might be involved in CKD-related atherosclerosis. Inhibition of sulfation may suppress CKD-related atherosclerosis and is worthy of further study.
    Keywords:  Atherosclerosis; Chronic kidney disease; Tyrosine sulfation
    DOI:  https://doi.org/10.1186/s12915-023-01641-y
  7. Int J Biol Macromol. 2023 Jul 07. pii: S0141-8130(23)02633-8. [Epub ahead of print] 125739
    Fetal milieu-simulating hyaluronic acid-dopamine-chondroitin sulfate hydrogel promoting angiogenesis and hair regeneration for wound healing.
    Hehui Rong, Yating Dong, Junke Zhao, Xuefei Zhang, Shuxuan Li, Yingying Sun, Tianli Lu, Shihui Yu, Haiyan Hu.
      Wound regeneration with complete functions and skin appendages is still challenging in wound dressing application. Inspired by the efficient wound healing in the fetal environment, we developed a fetal milieu-mimicking hydrogel for accelerating wound healing simultaneously with hair follicle regeneration. To mimic the fetal extracellular matrix (ECM), which contains high content of glycosaminoglycans, hyaluronic acid (HA) and chondroitin sulfate (CS) were selected to fabricate hydrogels. Meanwhile, dopamine (DA) modification endowed hydrogels with satisfactory mechanical properties and multi-functions. The hydrogel encapsulated atorvastatin (ATV) and zinc citrate (ZnCit), namely HA-DA-CS/Zn-ATV, exhibited tissue adhesion, self-healing capacity, good biocompatibility, excellent anti-oxidant ability, high exudate absorption, and hemostasis property. In vitro results revealed that hydrogels exerted significant angiogenesis and hair follicle regeneration efficacy. In vivo results confirmed that hydrogels significantly promoted wound healing, and the closure ratio reached over 94 % after 14 days of hydrogels-treatment. The regenerated skin exhibited a complete epidermis, dense and ordered collagen. Furthermore, the number of neovessels and hair follicles in the HA-DA-CS/Zn-ATV group were 1.57- and 3.05-fold higher than those of the HA-DA-CS group. Thus, HA-DA-CS/Zn-ATV serves as multifunctional hydrogels for simulating the fetal milieu and achieving efficient skin reconstruction with hair follicle regrowth, exhibiting potential in clinical wound healing.
    Keywords:  Angiogenesis; Extracellular matrix; Fetal milieu; Hair regeneration; Multifunctional hydrogel; Wound healing
    DOI:  https://doi.org/10.1016/j.ijbiomac.2023.125739
  8. Cells. 2023 Jun 23. pii: 1705. [Epub ahead of print]12(13):
    Role of Chondroitin Sulfate Proteoglycan 5 in Steroid-Induced Cataract.
    Woong-Sun Yoo, Hyemin Seong, Chieun Song, Mee-Young Choi, Bina Lee, Youngsub Eom, Hae-Jin Kim, Seung Pil Yun, Seong-Jae Kim.
      Steroid-induced cataracts (SIC) are defined as cataracts associated with the administration of corticosteroids. Long-term glucocorticoid treatment for inflammatory diseases reportedly increases the risk of SIC, and steroids can induce cataracts by disrupting ocular growth factor balance or homeostasis. In this study, we verified the effect of chondroitin sulfate proteoglycan 5 (CSPG5) using dexamethasone (dexa)-treated human lens epithelial (HLE-B3) cells and the lens epithelium from the anterior capsule of SIC patients obtained during cataract surgery. CSPG5 expression increased in the lens epithelium of SIC patients. The downregulation of CSPG5 suppressed the dexa-induced epithelial-mesenchymal transition (EMT)-related protein expression and motility in HLE-B3 cells. The disruption of the transcription factors EZH2 and B-Myb downregulated CSPG5, dexa-induced fibronectin expression, and cell migration in HLE-B3 cells, reaffirming that CSPG5 expression regulates EMT in lens epithelial cells. Taken together, these results indicate that the steroid-induced effects on lens epithelial cells are mediated via alterations in CSPG5 expression. Therefore, our study emphasizes the potential of CSPG5 as a therapeutic target for the prevention and treatment of SIC.
    Keywords:  EGF-like domain; epithelial–mesenchymal transition; glucocorticoid treatment; lens epithelial cells; steroid-induced
    DOI:  https://doi.org/10.3390/cells12131705
  9. Addict Behav. 2023 Jul 04. pii: S0306-4603(23)00196-X. [Epub ahead of print]146 107801
    Associations of DHEA(S) with negative and positive affect in people who smoke daily with elevated and low depression symptoms: A pilot laboratory study.
    Raina D Pang, Chyna J Tucker, Casey R Guillot, Britni Belcher, Matthew G Kirkpatrick.
       BACKGROUND: Individuals with depression symptoms have a harder time quitting smoking. High negative affect and low positive affect are core depression symptoms and arise following cigarette abstinence. Investigating associations of biological markers with negative and positive affect may provide valuable information about factors relevant to smoking cessation in individuals with elevated depression symptoms.
    METHODS: Depression symptoms were measured at a baseline session. Participants then completed two counterbalanced experimental sessions (non-abstinent, abstinent) and completed measures of positive and negative affect, and provided saliva samples. Saliva samples were assayed at the Salimetrics' SalivaLab (Carlsbad, CA) using the Salimetrics Salivary Dehydroepiandrosterone (DHEA) Assay Kit (Cat. No. 1-1202) and Dehydroepiandrosterone-sulfate (DHEA-S) Assay Kit (Cat. No. 1-1252).
    RESULTS: There were no main or interactive associations of DHEA with negative affect. However, there were significant DHEAS × experimental session and DHEAS × experimental session × depression symptom level interactions with negative affect. In the high depression symptom group, DHEAS positively associated with negative affect during the non-abstinent experimental session, but DHEAS negatively associated with negative affect during the abstinent experimental session. There were no associations of DHEA or DHEAS with positive affect.
    CONCLUSION: This study found that DHEAS negatively associated with negative affect during cigarette abstinence in individuals with elevated depression symptoms. This is important as high negative affect during cigarette abstinence may result in a return to smoking.
    Keywords:  Cigarette smoking; DHEA(S); Depression symptoms; Negative affect; People who smoke; Positive affect
    DOI:  https://doi.org/10.1016/j.addbeh.2023.107801
  10. Carbohydr Res. 2023 Jul 10. pii: S0008-6215(23)00159-3. [Epub ahead of print]531 108897
    Extraction of dermatan sulfate using ionic liquid-assisted enzymatic digestion: An efficient approach.
    Aafiya Tarannum, Sangeeta Ballav, Jonnalagadda Raghava Rao, Nishter Nishad Fathima.
      Dermatan sulfate is one of the major glycosaminoglycan (GAG) present in the animal hides, which is a waste/byproduct from meat industry. Efficient utilization of these meat industry wastes is garnering attention because these wastes render a possibility for their conversion into useful products. With the increased concerns over health, various initiatives have been developed to permit more efficient utilization of these by-products and thereby directly impacting environmental sustainability. Herein, we demonstrate for the first time an efficient and environmentally safe ionic liquid-assisted enzymatic process for the extraction of dermatan sulfate from buffalo hides. Dermatan sulfate has been extracted, separated, and purified from the GAG mixture using IL-assisted enzymatic digestions and chromatographic separations. NMR, FT-IR, and ESI-MS measurements showed typical characteristic peaks for dermatan sulfate. The advantages of this eco-friendly process adopted include i) use of fewer chemicals, ii) elimination of harsh chemicals, iii) elimination of various steps and sub-steps, iv) reduction in process time (12 h), and v) increase in extraction yield by 75% when compared to conventional enzymatic process (57%). Thus, the use of ionic liquids alongside enzymes will serve as an efficient methodology for the futuristic development of these derived GAGs for their potential applications.
    Keywords:  Dermatan sulfate; Enzymes; Extraction; Glycosaminoglycans; Hides; Ionic liquid
    DOI:  https://doi.org/10.1016/j.carres.2023.108897
  11. Mater Today Bio. 2023 Jun;20 100617
    Chondroitin sulfate functionalized palmitic acid and cysteine cografted-quaternized chitosan for CD44 and gut microbiota dual-targeted delivery of curcumin.
    Yinzhuo Xie, Wei Xu, Zheng Jin, Kai Zhao.
      Curcumin (CUR) has a regulatory effect on the gut microbiota (GM), and its significant anti-inflammatory properties make it a research hotspot for inflammatory bowel disease (IBD) treatment. However, the low bioavailability and poor pharmacokinetic properties of CUR limit its practical application. Herein, CD44 and GM dual-targeted nanoparticles (NPs) loaded with CUR (CUR@Chs-PNC NPs) were derived from a quaternized chitosan and surface functionalization with chondroitin sulfate (Chs). The generated CUR@Chs-PNC NPs had an ideal average particle size (238.9 ​nm), a uniform size distribution, and a positive surface charge (+41.93 ​mV). Strikingly, the CUR@Chs-PNC NPs had a good sustained-release effect in a simulated gastrointestinal environment and exhibited the full drug release when in a simulated colon environment. Moreover, Chs functionalization endowed the NPs with a notable CD44-targeted drug delivery ability and thereby enhanced the CUR content in the plasma of SD rats. The biodistribution of the CUR@Chs-PNC NPs in vivo indicated that the NPs could prolong the intestinal residence time, thereby promoting the interaction between CUR and GM. Most importantly, in a DSS-induced colitis mouse model, the CUR@Chs-PNC NPs decreased the disease activity index, improved the oxidative stress and inflammation condition, promoted the production of short-chain fatty acids (SCFAs), regulated immune cells, and maintained intestinal microbiome homeostasis. This study demonstrates that CUR@Chs-PNC NPs, which exhibit excellent biocompatibility and biodegradability, on-demand drug release property, and CD44 and GM dual-targeted capacities, have the potential for further application in the treatment of colitis.
    Keywords:  CD44 glycoprotein; Curcumin; Gut microbiota; Inflammatory bowel disease; Mucoadhesive nanoparticles; Targeted delivery
    DOI:  https://doi.org/10.1016/j.mtbio.2023.100617
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