bims-supasi Biomed News
on Sulfation pathways and signalling
Issue of 2022‒10‒02
twelve papers selected by
Jonathan Wolf Mueller
University of Birmingham

  1. Matrix Biol Plus. 2022 Dec;16 100121
      The glycocalyx attached to the apical surface of vascular endothelial cells is a rich network of proteoglycans, glycosaminoglycans, and glycoproteins with instrumental roles in vascular homeostasis. Given their molecular complexity and ability to interact with the intra- and extracellular environment, heparan sulfate proteoglycans uniquely contribute to the glycocalyx's role in regulating endothelial permeability, mechanosignaling, and ligand recognition by cognate cell surface receptors. Much attention has recently been devoted to the enzymatic shedding of heparan sulfate proteoglycans from the endothelial glycocalyx and its impact on vascular function. However, other molecular modifications to heparan sulfate proteoglycans are possible and may have equal or complementary clinical significance. In this narrative review, we focus on putative mechanisms driving non-proteolytic changes in heparan sulfate proteoglycan expression and alterations in the sulfation of heparan sulfate side chains within the endothelial glycocalyx. We then discuss how these specific changes to the endothelial glycocalyx impact endothelial cell function and highlight therapeutic strategies to target or potentially reverse these pathologic changes.
    Keywords:  ACE2, Angiotensin-converting enzyme 2; CLP, cecal ligation and puncture; COVID-19, Coronavirus disease 2019; EXT, Exostosin; EXTL, Exostosin-like glycosyltransferase; FFP, Fresh frozen plasma; FGF, Fibroblast growth factor; FGFR1, Fibroblast growth factor receptor 1; GAG, Glycosaminoglycan; GPC, Glypican; Gal, Galactose; GlcA, Glucuronic acid; GlcNAc, N-actetyl glucosamine; Glycocalyx; HLMVEC, Human lung microvascular endothelial cell; HS, Heparan sulfate; HS2ST, Heparan sulfate 2-O-sulfotransferase; HS3ST, Heparan sulfate 3-O-sulfotransferase; HS6ST, Heparan sulfate 6-O-sulfotransferase; HSPG, Heparan sulfate proteoglycan; HUVEC, Human umbilical vein endothelial cell; Heparan sulfate proteoglycan; LPS, lipopolysaccharide; NDST, N-deacetylase/N-sulfotransferase; SARS-CoV-2, Severe acute respiratory syndrome coronavirus 2; SDC, Syndecan; Sulf, Endosulfatase; Sulfation; Synthesis; TNFα, Tumor necrosis factor alpha; UA, Hexuronic acid; VEGF, Vascular endothelial growth factor; Vascular endothelium; XYLT, Xylosyltransferase; Xyl, Xylose; eGCX, Endothelial glycocalyx; eNOS, Endothelial nitric oxide synthase
  2. Angew Chem Int Ed Engl. 2022 Sep 29.
      Heparan sulfate (HS) has multifaceted biological activities. To date, no libraries of HS oligosaccharides bearing systemically varied sulfation structures are available yet due to the challenges in synthesizing a large number of HS oligosaccharides. To overcome the obstacles and expedite the synthesis, a divergent approach was designed, where 64 HS tetrasaccharides covering all the possible structures of 2- O , 6- O and N - sulfations with the glucosamine-glucuronic acid-glucosamine-iduronic acid backbone were successfully produced from a single strategically protected tetrasaccharide intermediate. This extensive library helped identify the structural requirements for HS sequences to have strong fibroblast growth factor-2 binding but weak affinity with platelet factor-4. This can provide a strategy to separate out these two interactions to obtain new HS based potential therapeutics without the dangerous adverse effect of heparin-induced thrombocytopenia .
    Keywords:  Heparan Sulfate; biological activity; carbohydrates; library synthesis; oligosaccharides
  3. Pflugers Arch. 2022 Oct 01.
      The protein-bound uremic toxin indoxyl sulfate has negative effects on a variety of physiological activities including vascular function. Uridine adenosine tetraphosphate (Up4A), a new dinucleotide molecule affects vascular function including induction of vasocontraction, and aberrant responsiveness to Up4A is evident in arteries from disorders such as hypertension and diabetes. The link between indoxyl sulfate and the Up4A-mediated response is, however, unknown. We used Wistar rat's renal arteries to see if indoxyl sulfate will affect Up4A-mediated vascular contraction. In renal arteries of indoxyl sulfate, the contractile response generated by Up4A was dramatically reduced compared to the non-treated control group. Indoxyl sulfate increased endothelin-1-induced contraction but had no effect on phenylephrine, thromboxane analog, or isotonic K+-induced renal arterial contractions. UTP, ATP, UDP, and ADP-produced contractions were reduced by indoxyl sulfate. CH223191, an aryl hydrocarbon receptor (AhR) antagonist, did not reverse Up4A, and UTP contraction decreases caused by indoxyl sulfate. The ectonucleotidase inhibitor ARL67156 prevents indoxyl sulfate from reducing Up4A- and UTP-mediated contractions. In conclusion, we discovered for the first time that indoxyl sulfate inhibits Up4A-mediated contraction in the renal artery, possibly through activating ectonucleotidase but not AhR. Indoxyl sulfate is thought to play a function in the pathophysiology of purinergic signaling.
    Keywords:  Contraction; Indoxyl sulfate; Purinoceptor ligand; Renal artery; Up4A
  4. Food Funct. 2022 Sep 26.
      Extensive phase II metabolic reactions (i.e., glucuronidation and sulfation) have resulted in low bioavailability and decreased biological effects of curcumin and quercetin. Compared to glucuronidation, information on the sulfation disposition of curcumin and quercetin is limited. In this study, we identified that BCRP and MRP4 played a critical role in the cellular excretion of curcumin-O-sulfate (C-O-S) and quercetin-O-sulfate (Q-O-S) by integrating chemical inhibition with transporter knock-down experiments. Inhibited excretion of sulfate (C-O-S and Q-O-S) caused significant reductions in cellular O-sulfation of curcumin (a maximal 74.4% reduction) and quercetin (a maximal 76.9% reduction), revealing a strong interplay of sulfation with efflux transport. It was further identified that arylsulfatase B (ARSB) played a crucial role in the regulation of cellular O-sulfation by transporters. ARSB overexpression significantly enhanced the reduction effect of MK-571 on the cellular O-sulfation (fmet) of the model compound (38.8% reduction for curcumin and 44.2% reduction for quercetin). On the contrary, ARSB knockdown could reverse the effect of MK-571 on the O-sulfation disposition of the model compound (29.7% increase for curcumin and 47.3% increase for quercetin). Taken together, ARSB has been proven to be involved in cellular O-sulfation, accounting for transporter-dependent O-sulfation of curcumin and quercetin. A better understanding of the interplay beneath metabolism and transport will contribute to the exact prediction of in vivo drug disposition and drug-drug interactions.
  5. J Gene Med. 2022 Sep 30. e3451
      BACKGROUND: The abnormal modification of chondroitin sulfate is one of the leading causes of disease, including cancer progression. During chondroitin sulfate biosynthesis, the CHST11 enzyme plays a vital role in its modification, but its role in cancer is not fully understood. Therefore, understanding the relationship between CHST11 and pulmonary-related diseases through clinically relevant information may be useful for diagnosis or treatment.METHODS: A variety of pulmonary fibrosis clinical gene expression omnibus (GEO) datasets were used to assess the association between CHST11-related manifestations and fibrosis. Multiple lung cancer-related databases, including The Cancer Genome Atlas (TCGA), GEO datasets, UCSC Xena, GEPIA2, Cbioportal and Ingenuity Pathway Analysis, have been used to evaluate the clinical correlation between CHST11 and lung cancer and potential molecular mechanisms. For drug repurposing prediction, the molecules that correlated with CHST11 were subjected to the LINCS L1000 algorithm. A variety of in vitro assays were performed to evaluate the in-silico models, including RNA and protein expression, proliferation, migration, and invasion.
    RESULTS: Clinical analyses indicate that the levels of CHST11 are significantly elevated in cases of pulmonary-related diseases, including fibrosis and lung cancer. According to multiple lung cancer cohorts, CHST11 is the only member of the carbohydrate sulfotransferase family associated with overall survival for lung adenocarcinomas (LUAD), and it is highly related to smoking-induced lung cancer patients. Based on the results of in vitro experiments, CHST11 expression contributes to tumor malignancy and promotes multiple fibrotic activators. Correlation-based-ingenuity pathway analysis (IPA) indicated that CHST11-related molecules contributed to pulmonary fibrosis or LUAD via similar upstream stimulators. Based on known molecular regulatory relationships, CHST11 has been associated with the regulation of TGF-β and INFγ as important molecules contributing to fibrosis and cancer progression. Interestingly, WordCloud analysis revealed that CHST11-related molecules are involved in regulation primarily by integrin signaling, and these relationships were consistently reflected in the analysis of cell lines and the clinical correlation. A CHST11 signature-based drug repurposing analysis demonstrated that the CHST11/integrin axis could be targeted by AG-1478 (Tyrphostin AG 1478), brefeldin A, geldanamycin and importazole.
    CONCLUSIONS: This study provides the first demonstration that CHST11 may be used as a biomarker for pulmonary fibrosis or lung cancer, and the levels of CHST11 were increased by TGF-β and INFγ. The molecular simulation analyses demonstrate that the CHST11/integrin axis is a potential therapeutic target for treating lung cancer.
    Keywords:  Bioinformatics; carbohydrate sulfotransferase 11; lung cancer; pulmonary fibrosis
  6. J Pak Med Assoc. 2022 Jul;72(7): 1272-1277
      OBJECTIVE: To determine the added benefits of short-term glucosamine and chondroitin sulfate supplementation in combination with manual therapy and resistance exercise training in the management of knee osteoarthritis.METHODS: A parallel-design, double-blind randomised controlled trial was conducted from January to September 2020 at the Foundation University Institute of Rehabilitation Sciences and Fauji Foundation Hospital, Rawalpindi, Pakistan, and comprised of knee osteoarthritis patients of either gender having radiological evidence of grade III or less on Kellgren classification. The subjects were randomly allocated to active comparator group A and experimental group B. Both the groups received manual therapy and resistance exercise training, while group B additionally received glucosamine and chondroitin sulfate supplementation for 4 weeks. Study outcomes included pain, function, quality of life, range of motion, strength, fall risk, skeletal muscle mass, visceral fat area, body fat, intracellular water ratio, and segmental lean and fat mass. Data was analysed using SPSS 21.
    RESULTS: Of the 24 subjects, there were 12(50%) in each of the two groups. Each groups had 9(75%) males and 3(25%) females. In terms knee osteoarthritis grade, there was no significant difference between the groups (p=1.00). No significant differences were observed in any of the outcome measures neither at 2 weeks, nor at 4 weeks post-intervention between the groups (p>0.05) except for percentage change in segmental lean mass of the right leg at 2nd week and of the left leg at 4th week (p<0.05).
    CONCLUSIONS: Manual therapy and resistance exercise training are effective in the management of knee osteoarthritis, however, glucosamine and chondroitin sulfate supplementation for 4 weeks showed no additional benefits.
    Clinical Trial Number: NCT04654871.
    Keywords:  Chondroitin sulfate, Glucosamine, Knee osteoarthritis, Physiotherapy, Resistance exercise, Manual therapy
  7. Endocr J. 2022 Sep 29.
      Adrenal incidentaloma is a clinically unapparent adrenal mass more than one cm in diameter detected during imaging performed not for adrenal disease. A 34-year-old man was evaluated for AI with a diameter of 3.5 cm in the left adrenal. He was obese with body mass index of 33,9. Blood pressure was 110-120/90 mmHg. The general laboratory tests were unremarkable. An adrenal hormone screening set revealed that ACTH was 6.9 pg/mL, cortisol 14.9 μg/dL, renin activity 0.9 ng/mL/h, aldosterone 79.4 pg/mL, dehydroepiandrosterone-sulfate (DHEA-S) measured on two occasions 5,217 ng/mL and 6,477 ng/mL (gender- and age-adjusted reference values, 1,060-4,640 ng/mL). The levels of metanephrine and normetanephrine were normal. The tumor was thought to produce solely DHEA-S. The excised left adrenal tissue contained a tumor with a diameter of 26 mm and neighboring adrenal tissue. The tumor consisted mostly of acidophil cells without necrosis, capsular or vascular invasion, and mitosis. Immunohistochemical study revealed followings: the cells of the tumors were stained positive for 3β-hydroxysteroid dehydrogenase, and 17α-hydroxylase, and 11β-hydroxylase, weakly positive for DHEA sulphotransferase, and negative for aldosterone synthetase. The atrophy of neighboring tissue was presumably caused by excess cortisol production. Four months after surgery, the cortisol level was 11.2 μg/dL and DHEA-S level 1,462 ng/mL. The tumor is considered to be a cortisol-producing adenoma with modestly excessive DHEA-S production rather than isolated DHEA-S-producing adenoma. Immunohistochemical study of steroidogenic enzymes is a valuable addition to blood hormone measurement to clarify steroid production profile.
    Keywords:  Adrenal incidentaloma; Dehydroepiandrosterone-sulphate; Immunohistochemical staining
  8. Clin Genet. 2022 Sep 29.
      Sulfate is the fourth most abundant anion in human plasma but is not measured in clinical practice and little is known about the consequences of sulfate deficiency. Nevertheless, sulfation plays an essential role in the modulation of numerous compounds, including proteoglycans and steroids. We report the first patient with a homozygous loss-of-function variant in the SLC13A1 gene, encoding a renal and intestinal sulfate transporter which is essential for maintaining plasma sulfate levels. The homozygous (Arg12Ter) variant in SLC13A1 was found by exome sequencing performed in a patient with unexplained skeletal dysplasia. The main clinical features were enlargement of joints and spondylo-epi-metaphyseal radiological abnormalities in early childhood which improved with age. In addition, autistic features were noted. We found profound hyposulfatemia due to complete loss of renal sulfate reabsorption. Cholesterol sulfate was reduced. Intravenous N-acetylcysteine administration temporarily restored plasma sulfate levels. We conclude that loss of the SLC13A1 gene leads to profound hypersulfaturia and hyposulfatemia which is mainly associated with abnormal skeletal development, possibly predisposing to degenerative bone and joint disease. The diagnosis might be easily missed and more frequent.
    Keywords:  acetylcysteine; autistic disorder; cholesterol; chondroitin; joint diseases; proteoglycans; skeletal dysplasia; sulfation
  9. Biomed Mater. 2022 Sep 28.
      Wound healing of skin defects is complex. For the treatment of large and deep wounds, it is a good alternative to accept artificial dermis grafting at the first stage surgery, and autologous split-thickness skin grafting 2~3 weeks later at the second stage surgery. In addition, the effectiveness of numerous cytokines such as fibroblast growth factor (FGF) on wounds healing has been widely researched. The traditional view is that direct external application or in vivo injection of exogenous FGFs may not achieve the desired therapeutic effect as the effective concentration cannot be maintained for a long time. Therefore, some researchers have tried to integrate various cytokines into skin substitutes for combined application. However, we believe that considering the current situation, it is still difficult to achieve mass production of these types of artificial dermis. Here, we manufactured a collagen-chondroitin sulfate (CS) scaffold material by imitating the marketed artificial dermis materials. Then, we combined it with recombinant human acidic fibroblast growth factor (rh-aFGF) in a single full dose during the first-stage artificial dermis transplantation, which is simple and completely feasible but always controversial in the current clinical work, to explore whether this combinatorial therapy could serve as an efficient way wound healing in the Balb/c-nu mice full-thickness skin defect model.
    Keywords:  artificial dermis; collagen-chondroitin sulfate scaffold; fibroblast growth factor; full thickness skin defects
  10. J Steroid Biochem Mol Biol. 2022 Sep 21. pii: S0960-0760(22)00133-9. [Epub ahead of print]225 106182
      Xian-Ling-Gu-Bao capsule (XLGB) is a widely prescribed traditional Chinese medicine used for the treatment of osteoporosis. However, it significantly elevates levels of serum estrogens. Here we aimed to assess the dominant contributors of sulfotransferase (SULT) enzymes to the sulfation of estrogens and identify the effective inhibitors of this pathway in XLGB. First, estrone, 17β-estradiol, and estriol underwent sulfation in human liver S9 extracts. Phenotyping reactions and enzyme kinetics assays revealed that SULT1A1, 1A2, 1A3, 1C4, 1E1, and 2A1 all participated in estrogen sulfation, with SULT1E1 and 1A1 as the most important contributors. The incubation system for these two active enzymes were optimized with Tris-HCl buffer, DL-Dithiothreitol (DTT), MgCl2, adenosine 3'-phosphate 5'-phosphosulfate (PAPS), protein concentration, and incubation time. Then, 29 compounds in XLGB were selected to investigate their inhibitory effects and mechanisms against SULT1E1 and 1A1 through kinetic modelling. Moreover, in silico molecular docking was used to validate the obtained results. And finally, the prenylated flavonoids (isobavachin, neobavaisoflavone, etc.) from Psoralea corylifolia L., prenylated flavanols (icariside II) from Epimedium brevicornu Maxim., tanshinones (dihydrotanshinone, tanshinone II-A,) from Salvia miltiorrhiza Bge., and others (corylifol A, corylin) were identified as the most potent inhibitors of estrogen sulfation. Taken together, these findings provide insights into the understanding regioselectivity of estrogen sulfation and identify the effective components of XLGB responsible for the promotion of estrogen levels.
    Keywords:  Estrogens; Inhibitory effects; Molecular docking; Sulfotransferase enzymes; Xian-Ling-Gu-Bao capsule
  11. Psychoneuroendocrinology. 2022 Sep 08. pii: S0306-4530(22)00264-5. [Epub ahead of print]146 105923
      Attention deficit hyperactivity disorder (ADHD) has increasing evidence for the role of neurohormones in its etiopathogenesis. It has been suggested that the effects of neurosteroids on the brain in the early developmental period may predispose to neurodevelopmental pathologies. In our study, we examined serum dehydroepiandrosterone (DHEA), dehydroepiandrosterone sulfate (DHEA-S), and allopregnanolone levels in children with ADHD and whether these neurosteroids differ in the presence of specific learning disorder (SLD) and oppositional defiant disorder (ODD) comorbidities (ADHD+SLD and ADHD+ODD). We also investigated the relationship between neurosteroid levels and the severity of ADHD symptoms. Thirty-five prepubertal children with ADHD and 33 prepubertal healthy children, all aged 6-10 years, were included in this study. The severity of ADHD symptoms was assessed with the parent-rated and teacher-rated Turgay DSM-IV Disruptive Behavior Disorders Rating Scale (T-DSM-IV-S). Serum allopregnanolone levels were significantly lower in the ADHD group compared to healthy controls. When analyzed according to comorbidity status, serum allopregnanolone levels were lower in ADHD+SLD and ADHD+ODD groups compared to healthy controls. However, when compared to healthy children, serum DHEA and DHEA-S levels in children with ADHD were not significantly different. Serum allopregnanolone levels were negatively associated with teacher-rated T-DSM-IV-S hyperactivity/impulsivity scores for all participants only. These findings suggest that allopregnanolone may play a role in the pathophysiology of ADHD, especially in the presence of ODD and SLD comorbidities.
    Keywords:  ADHD; Allopregnanolone; DHEA; Neurosteroid; Oppositional defiant disorder; Specific learning disorder
  12. Domest Anim Endocrinol. 2022 Aug 31. pii: S0739-7240(22)00055-8. [Epub ahead of print]82 106764
      Sepsis is a major cause of morbidity and mortality in neonatal foals. Relative adrenal insufficiency (RAI), defined as an inadequate cortisol response to stress, has been associated with sepsis, prematurity, and poor outcome in newborn foals. In addition to cortisol, the adrenal gland synthesizes several biologically important steroids and steroid precursors, including aldosterone, androgens, and progestogens. However, concentration of these hormones during hospitalization and their association with the severity of disease and mortality in critically ill foals have not been completely evaluated. We hypothesized, that in addition to cortisol and aldosterone, concentration of steroid precursors (progestogens and androgens) will be altered in critically ill foals. We also proposed that septic foals will have higher concentrations of steroid precursors than healthy foals, and steroid concentrations will be persistently increased during hospitalization in non-surviving septic and premature foals. Foals <4 days of age were categorized as healthy, septic, sick non-septic, and premature based on physical exam, medical history, and laboratory data. Blood samples were collected on admission (0 h), 24 h, and 72 h after admission. Concentrations of steroids and ACTH were measured by immunoassays. The area under the curve over 72 h (AUC0-72h) of hospitalization was calculated for each hormone. Serum cortisol, aldosterone, progesterone, pregnenolone, dehydroepiandrosterone sulfate (DHEAS), and 17 α-hydroxyprogesterone concentrations were higher in septic and premature foals compared to healthy foals at 0 h and throughout 72 h of hospitalization (P < 0.05). Plasma ACTH concentrations were higher in septic and premature foals on admission compared to healthy controls (P < 0.05). The progesterone (AUC0-72h) cut-off value above which non-survival could be reliably predicted in hospitalized foals was 1,085 ng/mL/h, with 82% sensitivity and 77% specificity. Critically ill neonatal foals had an appropriate response to stress characterized by increased concentrations of cortisol and steroid precursors on admission. A rapid decline in steroid concentration was observed in healthy foals. However, persistently elevated progestogen and androgen concentrations were associated with a lack of improvement in the course of disease and poor outcome.
    Keywords:  Equine neonates; Hypothalamic-pituitary-adrenal axis; Neurosteroids; Relative adrenal insufficiency; Sepsis