bims-supasi Biomed News
on Sulfation pathways and signalling
Issue of 2023‒07‒02
twelve papers selected by
Jonathan Wolf Mueller
University of Birmingham

  1. Int J Mol Sci. 2023 Jun 16. pii: 10243. [Epub ahead of print]24(12):
      Glioblastoma (GB) is an aggressive cancer with a high probability of recurrence, despite active chemoradiotherapy with temozolomide (TMZ) and dexamethasone (DXM). These systemic drugs affect the glycosylated components of brain tissue involved in GB development; however, their effects on heparan sulfate (HS) remain unknown. Here, we used an animal model of GB relapse in which SCID mice first received TMZ and/or DXM (simulating postoperative treatment) with a subsequent inoculation of U87 human GB cells. Control, peritumor and U87 xenograft tissues were investigated for HS content, HS biosynthetic system and glucocorticoid receptor (GR, Nr3c1). In normal and peritumor brain tissues, TMZ/DXM administration decreased HS content (5-6-fold) but did not affect HS biosynthetic system or GR expression. However, the xenograft GB tumors grown in the pre-treated animals demonstrated a number of molecular changes, despite the fact that they were not directly exposed to TMZ/DXM. The tumors from DXM pre-treated animals possessed decreased HS content (1.5-2-fold), the inhibition of HS biosynthetic system mainly due to the -3-3.5-fold down-regulation of N-deacetylase/N-sulfotransferases (Ndst1 and Ndst2) and sulfatase 2 (Sulf2) expression and a tendency toward a decreased expression of the GRalpha but not the GRbeta isoform. The GRalpha expression levels in tumors from DXM or TMZ pre-treated mice were positively correlated with the expression of a number of HS biosynthesis-involved genes (Ext1/2, Ndst1/2, Glce, Hs2st1, Hs6st1/2), unlike tumors that have grown in intact SCID mice. The obtained data show that DXM affects HS content in mouse brain tissues, and GB xenografts grown in DXM pre-treated animals demonstrate attenuated HS biosynthesis and decreased HS content.
    Keywords:  dexamethasone; expression; glioblastoma; glucocorticoid receptor; glycosaminoglycan; heparan sulfate; heparan sulfate biosynthesis; temozolomide
  2. Int J Mol Sci. 2023 Jun 08. pii: 9926. [Epub ahead of print]24(12):
      The sodium-dependent organic anion transporter (SOAT, gene symbol SLC10A6) specifically transports 3'- and 17'-monosulfated steroid hormones, such as estrone sulfate and dehydroepiandrosterone sulfate, into specific target cells. These biologically inactive sulfo-conjugated steroids occur in high concentrations in the blood circulation and serve as precursors for the intracrine formation of active estrogens and androgens that contribute to the overall regulation of steroids in many peripheral tissues. Although SOAT expression has been detected in several hormone-responsive peripheral tissues, its quantitative contribution to steroid sulfate uptake in different organs is still not completely clear. Given this fact, the present review provides a comprehensive overview of the current knowledge about the SOAT by summarizing all experimental findings obtained since its first cloning in 2004 and by processing SOAT/SLC10A6-related data from genome-wide protein and mRNA expression databases. In conclusion, despite a significantly increased understanding of the function and physiological significance of the SOAT over the past 20 years, further studies are needed to finally establish it as a potential drug target for endocrine-based therapy of steroid-responsive diseases such as hormone-dependent breast cancer.
    Keywords:  SLC10A6; SOAT; breast cancer; inhibitor; sulfated steroids; transport
  3. Carbohydr Polym. 2023 Oct 01. pii: S0144-8617(23)00545-3. [Epub ahead of print]317 121080
      Fucan sulfate (FS) from sea cucumber shows intriguing structure and extensive activities. Here, three homogeneous FS (BaFSI - III) were obtained from Bohadschia argus, followed with physicochemical properties analyses including monosaccharide composition, molecular weight, and sulfate content. BaFSI was proposed to carry a unique distribution pattern of sulfate groups as a novel sequence composed of domain A and domain B that formed by different FucS residues, markedly differing from FS reported before, according to the analyses of 12 oligosaccharides and a representative residual saccharide chain. BaFSII possessed a highly regular structure {4-L-Fuc3S-α1,}n according to its peroxide depolymerized product. BaFSIII was confirmed as a FS mixture bearing similar structural characteristics with BaFSI and BaFSII by means of mild acid hydrolysis and oligosaccharide analysis. Bioactivity assays showed that BaFSI and BaFSII could potently inhibit P-selectin binding to PSGL-1 and HL-60 cells. Structure-activity relationship analysis showed that molecular weight and sulfation pattern were the essential factors for the potent inhibition. Meanwhile, an acid hydrolysate of BaFSII with a molecular weight about 15 kDa exhibited a comparable inhibition with the native BaFSII. Given the potent activity and highly regular structure of BaFSII, it shows great potential for development as a P-selectin inhibitor.
    Keywords:  Bohadschia argus; Fucan sulfate; Mild acid hydrolysis; Oligosaccharides; P-selectin inhibition; Peroxide depolymerization
  4. J Clin Med. 2023 Jun 13. pii: 4027. [Epub ahead of print]12(12):
      The adrenal steroid hormones, cortisol and dehydroepiandrosterone sulfate (DHEAS), are associated with the immune system in opposite actions. This study aimed to investigate the relationship between cortisol and DHEAS serum concentrations, their ratio (CDR), and natural killer cell activity (NKA). This cross-sectional study included 2275 subjects without current infection or inflammation in the final analyses. NKA was estimated by measuring the amount of interferon-gamma (IFN-γ) released by activated natural killer cells; low NKA was defined as IFN-γ level < 500 pg/mL. Cortisol, DHEAS levels, and CDRs were categorized by quartiles in men, premenopausal women, and postmenopausal women. Compared with the lowest quartile as reference, the adjusted odd ratios (ORs) and 95% confidence intervals (CIs) for low NKA of the highest cortisol and CDR group were 1.66 (1.09-2.51) and 1.68 (1.11-2.55) in men, 1.58 (1.07-2.33) and 2.33 (1.58-3.46) in premenopausal women, and 2.23 (1.28-3.87) and 1.85 (1.07-3.21) in postmenopausal women. Only in premenopausal women, the highest DHEAS group showed significantly lower risk of low NKA (OR: 0.51, 95% CI: 0.35-0.76). HPA axis activation indicated as high cortisol level, CDR was significantly associated with low NKA, while high DHEAS levels were inversely associated with low NKA in premenopausal women.
    Keywords:  cortisol; dehydroepiandrosterone sulfate; immunity; natural killer cell; natural killer cell activity
  5. Cell Rep. 2023 Jun 27. pii: S2211-1247(23)00725-8. [Epub ahead of print]42(7): 112714
      Neurexin synaptic organizing proteins are central to a genetic risk pathway in neuropsychiatric disorders. Neurexins also exemplify molecular diversity in the brain, with over a thousand alternatively spliced forms and further structural heterogeneity contributed by heparan sulfate glycan modification. Yet, interactions between these modes of post-transcriptional and post-translational modification have not been studied. We reveal that these regulatory modes converge on neurexin-1 splice site 5 (S5): the S5 insert increases the number of heparan sulfate chains. This is associated with reduced neurexin-1 protein level and reduced glutamatergic neurotransmitter release. Exclusion of neurexin-1 S5 in mice boosts neurotransmission without altering the AMPA/NMDA ratio and shifts communication and repetitive behavior away from phenotypes associated with autism spectrum disorders. Thus, neurexin-1 S5 acts as a synaptic rheostat to impact behavior through the intersection of RNA processing and glycobiology. These findings position NRXN1 S5 as a potential therapeutic target to restore function in neuropsychiatric disorders.
    Keywords:  CP: Neuroscience; alternative splicing; grooming; heparan sulfate; heparan sulfate valency; neurexin; neurotransmission; synaptic adhesion molecule; synaptic organizing protein; synaptogenesis; ultrasonic vocalizaton
  6. Vet Sci. 2023 May 25. pii: 373. [Epub ahead of print]10(6):
      Testicular ultrasonography and steroid concentrations (cortisol, dehydroepiandrosterone sulfate (DHEA-S), cortisol/DHEA-S ratio, testosterone) in hair were examined for their utility in the bull breeding soundness evaluation (BBSE). Beef and dairy bulls (n = 16; 2.7 ± 0.4 years old; body condition score 3.2 ± 0.1) of five breeds were maintained under the same conditions at an accredited semen collection center. Bulls underwent routine semen collection twice weekly for 12 weeks and semen was processed and cryopreserved. Ultrasonography and hair sampling were undertaken at the last semen collection. Bulls with homogeneous testicular parenchyma (n = 8) had a higher (p < 0.05) percentage of motile sperm post-thawing compared with bulls with heterogeneous parenchyma (n = 8). There were no differences (p > 0.05) in the hair concentrations of cortisol, DHEA-S, and testosterone between bulls with homogeneous and heterogeneous parenchyma. In bulls with homogeneous parenchyma, hair DHEA-S concentration was positively correlated with percentage motile sperm (R2 = 0.76), progressively motile sperm (R2 = 0.70), and motility yield (R2 = 0.71). The findings indicate that the integration of testicular ultrasonography and hair DHEA-S status in the BBSE could provide a more comprehensive assessment of indicative fertility in bulls. Additionally, ultrasonography can be used in the BBSE when the evaluation of semen parameters is not available.
    Keywords:  bull; hair steroids; semen; testicular ultrasonography
  7. Genes (Basel). 2023 06 13. pii: 1257. [Epub ahead of print]14(6):
      Chronic kidney disease (CKD) induces several systemic effects, including the accumulation and production of uremic toxins responsible for the activation of various harmful processes. Gut dysbiosis has been widely described in CKD patients, even in the early stages of the disease. The abundant discharge of urea and other waste substances into the gut favors the selection of an altered intestinal microbiota in CKD patients. The prevalence of bacteria with fermentative activity leads to the release and accumulation in the gut and in the blood of several substances, such as p-Cresol (p-C), Indoxyl Sulfate (IS) and p-Cresyl Sulfate (p-CS). Since these metabolites are normally eliminated in the urine, they tend to accumulate in the blood of CKD patients proportionally to renal impairment. P-CS, IS and p-C play a fundamental role in the activation of various pro-tumorigenic processes, such as chronic systemic inflammation, the increase in the production of free radicals and immune dysfunction. An up to two-fold increase in the incidence of colon cancer development in CKD has been reported in several studies, although the pathogenic mechanisms explaining this compelling association have not yet been described. Based on our literature review, it appears likely the hypothesis of a role of p-C, IS and p-CS in colon cancer development and progression in CKD patients.
    Keywords:  chronic renal failure; colon cancer; dysbiosis; indoxyl sulfate; p-cresol; p-cresyl sulfate; uremic toxins
  8. Elife. 2023 06 27. pii: RP88273. [Epub ahead of print]12
      Heparan sulfate proteoglycans (HSPGs) form essential components of the extracellular matrix (ECM) and basement membrane (BM) and have both structural and signaling roles. Perlecan is a secreted ECM-localized HSPG that contributes to tissue integrity and cell-cell communication. Although a core component of the ECM, the role of Perlecan in neuronal structure and function is less understood. Here, we identify a role for Drosophila Perlecan in the maintenance of larval motoneuron axonal and synaptic stability. Loss of Perlecan causes alterations in the axonal cytoskeleton, followed by axonal breakage and synaptic retraction of neuromuscular junctions. These phenotypes are not prevented by blocking Wallerian degeneration and are independent of Perlecan's role in Wingless signaling. Expression of Perlecan solely in motoneurons cannot rescue synaptic retraction phenotypes. Similarly, removing Perlecan specifically from neurons, glia, or muscle does not cause synaptic retraction, indicating the protein is secreted from multiple cell types and functions non-cell autonomously. Within the peripheral nervous system, Perlecan predominantly localizes to the neural lamella, a specialized ECM surrounding nerve bundles. Indeed, the neural lamella is disrupted in the absence of Perlecan, with axons occasionally exiting their usual boundary in the nerve bundle. In addition, entire nerve bundles degenerate in a temporally coordinated manner across individual hemi-segments throughout larval development. These observations indicate disruption of neural lamella ECM function triggers axonal destabilization and synaptic retraction of motoneurons, revealing a role for Perlecan in axonal and synaptic integrity during nervous system development.
    Keywords:  D. melanogaster; axonal degeneration; collagen; cytoskeleton; extracellular matrix; neuroscience; synapse retraction
  9. World J Orthop. 2023 Jun 18. 14(6): 443-457
      BACKGROUND: Oral treatment of glucosamine (GA) combined with chondroitin sulfate (CS) was reportedly effective for pain relief and function improvement in osteoarthritis patients with moderate to severe knee pain in clinical trials. While the effectiveness of GA and CS on both clinical and radiological findings has been demonstrated, only a few high-quality trials exist. Therefore, controversy regarding their effectiveness in real-world clinical practice remains.AIM: To investigate the impact of GA + CS on clinical outcomes of patients with knee and hip osteoarthritis in routine clinical practice.
    METHODS: A multicenter prospective observational cohort study included 1102 patients of both genders with knee or hip osteoarthritis (Kellgren & Lawrence grades I-III) in 51 clinical centers in the Russian Federation from November 20, 2017, to March 20, 2020, who had started to receive oral capsules of glucosamine hydrochloride 500 mg and CS 400 mg according to the approved patient information leaflet starting from 3 capsules daily for 3 wk, followed by a reduced dosage of 2 capsules daily before study inclusion (minimal recommended treatment duration is 3-6 mo). Changes in subscale scores [Pain, Symptoms, Function, and Quality of Life (QOL)] of the Knee Injury and Osteoarthritis Outcome Score (KOOS)/Hip Disability and Osteoarthritis Outcome Score (HOOS) questionnaires during the observational period (up to 54-64 wk with a total of 4 visits). Patients' treatment satisfaction, data on the combined oral use of glucosamine hydrochloride and CS, concomitant use of non-steroidal anti-inflammatory drugs (NSAIDs), and adverse events (AEs) were also evaluated.
    RESULTS: A total of 1102 patients with knee and hip osteoarthritis were included in the study. The mean patient age was 60.4 years, most patients were women (87.8%), and their average body mass index was 29.49 kg/m2. All subscale scores (Pain, Symptoms, Function, and QOL) of the KOOS and HOOS demonstrated clinically and statistically significant improvements. In patients with knee osteoarthritis, the mean score increases from baseline to the end of Week 64 were 22.87, 20.78, 16.60, and 24.87 on Pain, Symptoms, Physical Function (KOOS-PS), and QOL subscales (P < 0.001 for all), respectively. In patients with hip osteoarthritis, the mean score increases were 22.81, 19.93, 18.77, and 22.71 on Pain, Symptoms, Physical Function (HOOS-PS), and QOL subscales (P < 0.001 for all), respectively. The number of patients using any NSAIDs decreased from 43.1% to 13.5% (P < 0.001) at the end of the observation period. Treatment-related AEs occurred in 2.8% of the patients and mainly included gastrointestinal disorders [25 AEs in 24 (2.2%) patients]. Most patients (78.1%) were satisfied with the treatment.
    CONCLUSION: Long-term oral GA + CS was associated with decreased pain, reduced concomitant NSAID therapy, improved joint function and QOL in patients with knee and hip osteoarthritis in routine clinical practice.
    Keywords:  Chondroitin sulfate; Glucosamine; Hip disability and osteoarthritis outcome score; Hip osteoarthritis; Knee injury and osteoarthritis outcome score; Knee osteoarthritis
  10. J Clin Endocrinol Metab. 2023 Jun 12. pii: dgad351. [Epub ahead of print]
      CONTEXT: Epidemiological as well as preclinical data support cardiovascular, mainly protective, effects of sex steroids in men, but the mechanisms underlying the cardiovascular actions of sex steroids are poorly understood. Vascular calcification parallels the development of atherosclerosis, but is increasingly recognized as a diversified, highly regulated process, which itself may have pathophysiological importance for clinical cardiovascular events.OBJECTIVE: To investigate the association between serum sex steroids and coronary artery calcification (CAC) in elderly men.
    DESIGN, SETTING AND PARTICIPANTS: We used gas chromatography-tandem mass spectrometry to analyze a comprehensive sex steroid profile, including levels of dehydroepiandrosterone (DHEA), androstenedione, estrone, testosterone, estradiol and dihydrotestosterone, in men from the population-based AGES-Reykjavik study (n=1287, mean 76 years). Further, sex hormone-binding globulin (SHBG) was assayed and bioavailable hormone levels calculated. CAC score was determined by computed tomography.
    MAIN OUTCOME MEASURES: Cross-sectional associations between dehydroepiandrosterone, androstenedione, estrone, testosterone, dihydrotestosterone, and estradiol and quintiles of CAC.
    RESULTS: Serum levels of DHEA, androstenedione, testosterone, dihydrotestosterone and bioavailable testosterone showed significant inverse associations with CAC, while estrone, estradiol, bioavailable estradiol and SHBG did not. DHEA, testosterone and bioavailable testosterone remained associated with CAC after adjustment for traditional cardiovascular risk factors. In addition, our results support partially independent associations between adrenal-derived DHEA and testes-derived testosterone and CAC.
    CONCLUSIONS: Serum levels of DHEA and testosterone are inversely associated with CAC in elderly men, partially independently from each other. These results raise the question whether androgens from both the adrenals and the testes may contribute to male cardiovascular health.
    Keywords:  atherosclerosis; coronary artery calcification; men; sex steroids
  11. J Steroid Biochem Mol Biol. 2023 Jun 28. pii: S0960-0760(23)00114-0. [Epub ahead of print] 106359
      Estetrol (E4) has emerged as a novel and highly promising estrogen for therapeutic use. E4 is a weak natural estrogen produced only in pregnancy. Because of its novelty, there is considerable interest by clinicians in how it is produced in pregnancy. Although the fetal liver plays a key role in its production, the placenta is also involved. A current view is that estradiol (E2) formed in the placenta enters the fetal compartment and is then rapidly sulfated. E2 sulfate then undergoes 15α-/16α-hydroxylation in the fetal liver thereby forming E4 sulfate (phenolic pathway). However, another pathway involving 15α,16α-dihydroxy-DHEAS formed in the fetal liver and converted to E4 in the placenta also plays a significant role (neutral pathway). It is not known which pathway predominates, but both pathways appear to be important in E4 biosynthesis. In this commentary, we summarize the well-established pathways in the formation of estrogens in the nonpregnant and pregnant female. We then review what is known about the biosynthesis of E4 and describe the 2 proposed pathways involving the fetus and placenta.
    Keywords:  estetrol; estrogens; fetus; placenta; pregnancy
  12. Pharmaceutics. 2023 Jun 05. pii: 1662. [Epub ahead of print]15(6):
      Hydrogels based on natural polysaccharides can have unique properties and be tailored for several applications, which may be mainly limited by the fragile structure and weak mechanical properties of this type of system. We successfully prepared cryogels made of newly synthesized kefiran exopolysaccharide-chondroitin sulfate (CS) conjugate via carbodiimide-mediated coupling to overcome these drawbacks. The freeze-thawing procedure of cryogel preparation followed by lyophilization is a promising route to fabricate polymer-based scaffolds with countless and valuable biomedical applications. The novel graft macromolecular compound (kefiran-CS conjugate) was characterized through 1H-NMR and FTIR spectroscopy-which confirmed the structure of the conjugate, differential scanning calorimetry (DSC) and thermogravimetric analysis (TGA)-which mirrored good thermal stability (degradation temperature of about 215 °C) and, finally, gel permeation chromatography-size exclusion chromatography (GPC-SEC)-which proved an increased molecular weight due to chemical coupling of kefiran with CS. At the same time, the corresponding cryogels physically crosslinked after the freeze-thawing procedure were investigated by scanning electron microscopy (SEM), Micro-CT, and dynamic rheology. The results revealed a prevalent contribution of elastic/storage component to the viscoelastic behavior of cryogels in swollen state, a micromorphology with micrometer-sized open pores fully interconnected, and high porosity (ca. 90%) observed for freeze-dried cryogels. Furthermore, the metabolic activity and proliferation of human adipose stem cells (hASCs), when cultured onto the developed kefiran-CS cryogel, was maintained at a satisfactory level over 72 h. Based on the results obtained, it can be inferred that the newly freeze-dried kefiran-CS cryogels possess a host of unique properties that render them highly suitable for use in tissue engineering, regenerative medicine, drug delivery, and other biomedical applications where robust mechanical properties and biocompatibility are crucial.
    Keywords:  biomedical device; carbodiimide-mediated coupling; characterization; chondroitin sulfate; cryogelation technique; kefiran; scaffold