bims-supasi Biomed News
on Sulfation pathways and signalling
Issue of 2022‒06‒12
fourteen papers selected by
Jonathan Wolf Mueller
University of Birmingham

  1. Front Pharmacol. 2022 ;13 882304
      Objective: Osteoarthritis (OA) is a degenerative chronic disease that most often occurs in the knee joint. Studies have shown that some food supplements, such as curcumin and chondroitin sulfate, are effective in treating knee osteoarthritis (KOA) by exhibiting different protective effects. In this study, we further investigated the combined therapeutic effects of curcumin and chondroitin sulfate on cartilage injury in rats with arthritis. Methods: An experimental KOA model was induced by monosodium iodoacetate (MIA) in rats. All rats were randomly divided into five groups: Ctrl (control), model (saline), Cur (20 mg/kg curcumin in saline), CS (100 mg/kg chondroitin sulfate in saline), and CA (20 mg/kg curcumin and 100 mg/kg chondroitin sulfate in saline); drugs were given 2 weeks after MIA injection. The histomorphological changes of cartilage were observed by safranin fast green staining, H&E staining, and micro-CT scanning. Also, the levels of PGE2, TNF-α and IL-1β in the arthral fluid and serum were determined by the ELISA kits. The activities of SOD, CAT, COMP, MMP-3, and type II collagen were detected by biochemical kits. The expressions of TLR4, p-NF-κB, NF-κB, and COX-2 in cartilage were detected by Western blot. Results: Data show that serum levels of IL-1β (p < 0.05), SOD (p < 0.0001), and MMP-3 (p < 0.001) were downregulated significantly in the CA group when compared to those in the model group. Meanwhile, obvious repair of cartilage with higher contains collagen II (p < 0.0001) could be observed in the CA group than the ones in Cur or CS group. In addition, significant downregulation of the expression of p-p65/p65 (p < 0.05) was found in the CA group. Conclusion: Our findings showed that combined administration of curcumin and chondroitin sulfate could exert better repair for KOA in rat models. This may hold great promise for discovering potential drugs to treat KOA and may improve treatment options for it.
    Keywords:  NF-κB; chondroitin sulfate (CS); curcumin; inflammation; knee osteoarthritis (KOA)
  2. Int J Biol Macromol. 2022 Jun 03. pii: S0141-8130(22)01185-0. [Epub ahead of print]213 631-638
      Hydrogen sulfide (H2S) is a bioactive gas regulating insulin secretion and sensitivity, produced by sulfate-reducing bacteria in the gut. The present study investigated the effect of chondroitin sulfate (CS) treatment, which indirectly increased the H2S production on nonalcoholic fatty liver disease (NAFLD). A 7-week CS supplementation had beneficial effects on body weight gain, liver function, hepatic histology, and serum lipid levels. CS could ameliorate diet-induced insulin resistance and improve insulin sensitivity via the AKT pathway, and modulate gut microbiota composition, especially increased the abundance of Desulfovibrio and elevated levels of hydrogen sulfide (H2S). Collectively, these findings suggested that CS treatment was positively correlated with Desulfovibrio in the gut, and the metabolic H2S flowed into the liver via the gut-liver axis, thereby triggering the AKT signaling pathway and improving insulin resistance. Thus, CS-induced alterations in the gut microbiota seem a promising for ameliorating NAFLD.
    Keywords:  Chondroitin sulfate; Desulfovibrio; Gut-liver axis; Hydrogen sulfide; Insulin resistance; NAFLD
  3. Nat Commun. 2022 Jun 08. 13(1): 3314
      Heparan sulfate is a highly modified O-linked glycan that performs diverse physiological roles in animal tissues. Though quickly modified, it is initially synthesised as a polysaccharide of alternating β-D-glucuronosyl and N-acetyl-α-D-glucosaminyl residues by exostosins. These enzymes generally possess two glycosyltransferase domains (GT47 and GT64)-each thought to add one type of monosaccharide unit to the backbone. Although previous structures of murine exostosin-like 2 (EXTL2) provide insight into the GT64 domain, the rest of the bi-domain architecture is yet to be characterised; hence, how the two domains co-operate is unknown. Here, we report the structure of human exostosin-like 3 (EXTL3) in apo and UDP-bound forms. We explain the ineffectiveness of EXTL3's GT47 domain to transfer β-D-glucuronosyl units, and we observe that, in general, the bi-domain architecture would preclude a processive mechanism of backbone extension. We therefore propose that heparan sulfate backbone polymerisation occurs by a simple dissociative mechanism.
  4. ACS Chem Biol. 2022 Jun 04.
      Diabetes is a chronic disease in which the levels of blood glucose are too high because the body does not effectively produce insulin to meet its needs or is resistant to insulin. β Cells in human pancreatic islets produce insulin, which signals glucogen production by the liver and causes muscles and fat to uptake glucose. Progressive loss of insulin-producing β cells is the main cause of both type 1 and type 2 diabetes. Heparan sulfate (HS) is a ubiquitous polysaccharide found at the cell surface and in the extracellular matrix (ECM) of a variety of tissues. HS binds to and assembles proteins in ECM, thus playing important roles in the integrity of ECM (particularly basement membrane), barrier function, and ECM-cell interactions. Islet HS is highly expressed by the pancreatic β cells and critical for the survival of β cells. Heparanase is an endoglycosidase and cleaves islet HS in the pancreas, resulting in β-cell death and oxidative stress. Heparanase could also accelerate β-cell death by promoting cytokine release from ECM and secretion by activated inflammatory and endothelial cells. We demonstrate that HS-mimicking glycopolymer, a potent heparanase inhibitor, improves the survival of cultured mouse pancreatic β cells and protects HS contents under the challenge of heparanase in human pancreatic islets. Moreover, this HS-mimicking glycopolymer reduces the expression levels of cytokines (IL8, IL1β, and TNFα) and the gene encoding Toll-like Receptor 2 (TLR2) in human pancreatic islets.
  5. Int J Mol Sci. 2022 May 26. pii: 6003. [Epub ahead of print]23(11):
      The extracellular matrix (ECM) has long been regarded as a packing material; supporting cells within the tissue and providing tensile strength and protection from mechanical stress. There is little surprise when one considers the dynamic nature of many of the individual proteins that contribute to the ECM, that we are beginning to appreciate a more nuanced role for the ECM in tissue homeostasis and disease. Articular cartilage is adapted to be able to perceive and respond to mechanical load. Indeed, physiological loads are essential to maintain cartilage thickness in a healthy joint and excessive mechanical stress is associated with the breakdown of the matrix that is seen in osteoarthritis (OA). Although the trigger by which increased mechanical stress drives catabolic pathways remains unknown, one mechanism by which cartilage responds to increased compressive load is by the release of growth factors that are sequestered in the pericellular matrix. These are heparan sulfate-bound growth factors that appear to be largely chondroprotective and displaced by an aggrecan-dependent sodium flux. Emerging evidence suggests that the released growth factors act in a coordinated fashion to drive cartilage repair. Thus, we are beginning to appreciate that the ECM is the key mechano-sensor and mechano-effector in cartilage, responsible for directing subsequent cellular events of relevance to joint health and disease.
    Keywords:  articular cartilage; extracellular matrix; growth factors; heparan sulfate; mechanotransduction; osteoarthritis; pericellular matrix; perlecan
  6. Respir Res. 2022 Jun 08. 23(1): 149
      BACKGROUND: Dehydroepiandrosterone (DHEA) is a precursor sex hormone with antifibrotic properties. The aims of this study were to investigate antifibrotic mechanisms of DHEA, and to determine the relationship between DHEA-sulfate (DHEAS) plasma levels, disease severity and survival in patients with fibrotic interstitial lung diseases (ILDs).METHODS: Human precision cut lung slices (PCLS) and normal human lung fibroblasts were treated with DHEA and/or transforming growth factor (TGF)-β1 before analysis of pro-fibrotic genes and signal proteins. Cell proliferation, cytotoxicity, cell cycle and glucose-6-phosphate dehydrogenase (G6PD) activity were assessed. DHEAS plasma levels were correlated with pulmonary function, the composite physiologic index (CPI), and time to death or lung transplantation in a derivation cohort of 31 men with idiopathic pulmonary fibrosis (IPF) and in an independent validation cohort of 238 men and women with fibrotic ILDs.
    RESULTS: DHEA decreased the expression of pro-fibrotic markers in-vitro and ex-vivo. There was no cytotoxic effect for the applied concentrations, but DHEA interfered in proliferation by modulating the cell cycle through reduction of G6PD activity. In men with IPF (derivation cohort) DHEAS plasma levels in the lowest quartile were associated with poor lung function and higher CPI (adjusted OR 1.15 [95% CI 1.03-1.38], p = 0.04), which was confirmed in the fibrotic ILD validation cohort (adjusted OR 1.03 [95% CI 1.00-1.06], p = 0.01). In both cohorts the risk of early mortality was higher in patients with low DHEAS levels, after accounting for potential confounding by age in men with IPF (HR 3.84, 95% CI 1.25-11.7, p = 0.02), and for age, sex, IPF diagnosis and prednisone treatment in men and women with fibrotic ILDs (HR 3.17, 95% CI 1.35-7.44, p = 0.008).
    CONCLUSIONS: DHEA reduces lung fibrosis and cell proliferation by inducing cell cycle arrest and inhibition of G6PD activity. The association between low DHEAS levels and disease severity suggests a potential prognostic and therapeutic role of DHEAS in fibrotic ILD.
  7. Life Sci. 2022 Jun 06. pii: S0024-3205(22)00394-0. [Epub ahead of print] 120694
      AIMS: Acetaminophen (APAP) is a relatively safe analgesic drug, but overdosing can cause acute liver failure. Ingested APAP is detoxified by metabolic conversion through conjugation reactions with glucuronate, sulfate, or glutathione (GSH). The consumption of GSH through conjugation as well as mitochondrial dysfunction is considered to be responsible for the increased susceptibility to APAP-induced hepatotoxicity. Compared to wild-type (WT) mice, Akr1a-knockout (KO) mice are vulnerable to developing hepatotoxicity due to the fact that ascorbate synthesis is attenuated. We used such KO mice to investigate how these conjugation reactions are involved in the hepatotoxicity caused by an overdose of APAP under ascorbate-deficient conditions.MAIN METHODS: APAP (400 mg/kg) was intraperitoneally administered to WT mice and KO mice. In addition to histological and blood biochemical analyses, metabolites in the liver, blood plasma, and urine were measured at several time points by liquid chromatography-mass spectrometry.
    KEY FINDINGS: Liver damage occurred earlier in the KO mice than in the WT mice. The levels of APAP-Cys, a final metabolite of GSH-conjugated APAP, as well as glucuronidated APAP and sulfated APAP were all higher in the KO mice compared to the WT mice. Treatment of the APAP-administered KO mice with N-acetylcysteine or supplementation of ascorbate suppressed the conjugation reactions at 6 h after APAP had been administrated, which mitigated the degree of liver damage.
    SIGNIFICANCE: An ascorbate deficiency coordinately stimulates conjugation reactions of APAP, which, combined with the mitochondrial damage caused by APAP metabolites, collectively results in the aggravation of the acute liver failure.
    Keywords:  Acetaminophen; Acute liver failure; Ascorbate; Glucuronate conjugation
  8. Endocr J. 2022 Jun 09.
      Sulfonation is an important step in the metabolism of dopamine, estrogens, dehydroepiandrosterone, as well as thyroid hormones. However, the regulation of cytosolic sulfotransferases in the thyroid is not well understood. In a DNA microarray analysis of rat thyroid FRTL-5 cells, we found that the mRNA expression of 10 of 48 sulfotransferases was significantly altered by thyroid stimulating hormone (TSH), with that of sulfotransferase family 1A member 1 (SULT1A1) being the most significantly affected. Real-time PCR and Western blot analyses revealed that TSH, forskolin and dibutyryl cyclic AMP significantly suppressed SULT1A1 mRNA and protein levels in a time- and concentration-dependent manner. Moreover, immunofluorescence staining of FRTL-5 cells showed that SULT1A1 is localized in the perinuclear area in the absence of TSH but is spread throughout the cytoplasm with reduced fluorescence intensity in the presence of TSH. Sulfotransferase activity in FRTL-5 cells, measured using 3'-phosphoadenosine-5'-phosphosulfate as a donner and p-nitrophenol as an acceptor substrate, was significantly reduced by TSH. These findings suggest that the expression and activity of SULT1A1 are modulated by TSH in thyrocytes.
    Keywords:  FRTL-5; Sulfotransferase; Sulfotransferase family 1A member 1 (SULT1A1); Thyroid; Thyroid stimulating hormone
  9. Mol Ther Methods Clin Dev. 2022 Jun 09. 25 534-544
      Deposition of heparan sulfate (HS) in the brain of patients with mucopolysaccharidosis II (MPS II) is believed to be the leading cause of neurodegeneration, resulting in several neurological signs and symptoms, including neurocognitive impairment. We recently showed that pabinafusp alfa, a blood-brain-barrier-penetrating fusion protein consisting of iduronate-2-sulfatase and anti-human transferrin receptor antibody, stabilized learning ability by preventing the deposition of HS in the CNS of MPS II mice. We further examined the dose-dependent effect of pabinafusp alfa on neurological function in relation to its HS-reducing efficacy in a mouse model of MPS II. Long-term intravenous treatment with low (0.1 mg/kg), middle (0.5 mg/kg), and high (2.0 mg/kg) doses of the drug dose-dependently decreased HS concentration in the brain and cerebrospinal fluid (CSF). A comparable dose-dependent effect in the prevention of neuronal damage in the CNS, and dose-dependent improvements in neurobehavioral performance tests, such as gait analysis, pole test, Y maze, and Morris water maze, were also observed. Notably, the water maze test performance was inversely correlated with the HS levels in the brain and CSF. This study provides nonclinical evidence substantiating a quantitative dose-dependent relationship between HS reduction in the CNS and neurological improvements in MPS II.
    Keywords:  biomarker; blood-brain barrier; enzyme-replacement therapy; heparan sulfate; lysosomal storage disease; mucopolysaccharidosis II
  10. Int J Mol Sci. 2022 May 31. pii: 6203. [Epub ahead of print]23(11):
      Sulfur (S) is an essential mineral nutrient required for plant growth and development. Plants usually face temporal and spatial variation in sulfur availability, including the heterogeneous sulfate content in soils. As sessile organisms, plants have evolved sophisticated mechanisms to modify their gene expression and physiological processes in order to optimize S acquisition and usage. Such plasticity relies on a complicated network to locally sense S availability and systemically respond to S status, which remains poorly understood. Here, we took advantage of a split-root system and performed transcriptome-wide gene expression analysis on rice plants in S deficiency followed by sulfate resupply. S deficiency altered the expressions of 6749 and 1589 genes in roots and shoots, respectively, accounting for 18.07% and 4.28% of total transcripts detected. Homogeneous sulfate resupply in both split-root halves recovered the expression of 27.06% of S-deficiency-responsive genes in shoots, while 20.76% of S-deficiency-responsive genes were recovered by heterogeneous sulfate resupply with only one split-root half being resupplied with sulfate. The local sulfate resupply response genes with expressions only recovered in the split-root half resupplied with sulfate but not in the other half remained in S deficiency were identified in roots, which were mainly enriched in cellular amino acid metabolic process and root growth and development. Several systemic response genes were also identified in roots, whose expressions remained unchanged in the split-root half resupplied with sulfate but were recovered in the other split-root half without sulfate resupply. The systemic response genes were mainly related to calcium signaling and auxin and ABA signaling. In addition, a large number of S-deficiency-responsive genes exhibited simultaneous local and systemic responses to sulfate resupply, such as the sulfate transporter gene OsSULTR1;1 and the O-acetylserine (thiol) lyase gene, highlighting the existence of a systemic regulation of sulfate uptake and assimilation in S deficiency plants followed by sulfate resupply. Our studies provided a comprehensive transcriptome-wide picture of a local and systemic response to heterogeneous sulfate resupply, which will facilitate an understanding of the systemic regulation of S homeostasis in rice.
    Keywords:  rice; split-root system; sulfur; systemic signaling; transcriptome
  11. Clin Exp Optom. 2022 Jun 09. 1-5
      CLINICAL RELEVANCE: There is growing evidence for the involvement of sex hormones in the pathogenesis of keratoconus.BACKGROUND: This study aimed to evaluate serum androgen and prolactin levels in patients suffering from keratoconus.
    METHODS: One hundred and two subjects were enrolled in the keratoconus (76 patients) and control (26 subjects) groups in a cross-sectional survey. Topographic evaluation of the cornea was undertaken for all enrolled participants. Serum testosterone, dehydroepiandrosterone sulphate (DHEAS), prolactin (PRL), luteinising hormone (LH), and follicle-stimulating hormone (FSH) were measured in all subjects.
    RESULTS: There was no significant difference in demographic characteristics between the study groups. Significantly higher mean serum levels of DHEAS (3.71 ± 2.23 vs. 2.53 ± 1.77 µg/mL; P = 0.009) and T (6.18 ± 3.80 vs. 1.57 ± 1.76 ng/mL; P < 0.001) were observed in men with keratoconus compared to controls. In females, there were also higher mean levels of DHEAS (2.40 ± 1.57 vs. 2.18 ± 0.72 µg/mL; P = 0.355) and T (0.78 ± 0.96 vs. 0.32 ± 0.13 ng/mL; P < 0.001) in patients with keratoconus but only T level reached the statistically significant level of difference. Also, the mean serum PRL level was significantly higher in women with keratoconus compared to control (13.33 ± 17.85 vs. 4.63 ± 3.10 ng/mL; P < 0.001). There was no significant difference between serum FSH and LH levels between study groups.
    CONCLUSION: In patients with keratoconus, serum PRL in females and serum androgen levels in both genders are elevated.
    Keywords:  Androgens; Cornea; Dehydroepiandrosterone sulfate; Keratoconus; Prolactin; Sex hormones; Testosterone
  12. Cancers (Basel). 2022 May 24. pii: 2583. [Epub ahead of print]14(11):
      Ovarian cancer (OC) is highly lethal and heterogeneous. Several hormones are involved in OC etiology including estrogens; however, their role in OC is not completely understood. Here, we performed targeted transcriptomics and estrogen metabolism analyses in high-grade serous OC (HGSOC), OVSAHO, Kuramochi, COV632, and immortalized normal ovarian epithelial HIO-80 cells. We compared these data with public transcriptome and proteome data for the HGSOC tissues. In all model systems, high steroid sulfatase expression and weak/undetected aromatase (CYP19A1) expression indicated the formation of estrogens from the precursor estrone-sulfate (E1-S). In OC cells, the metabolism of E1-S to estradiol was the highest in OVSAHO, followed by Kuramochi and COV362 cells, and decreased with increasing chemoresistance. In addition, higher HSD17B14 and CYP1A2 expressions were observed in highly chemoresistant COV362 cells and platinum-resistant tissues compared to those in HIO-80 cells and platinum-sensitive tissues. The HGSOC cell models differed in HSD17B10, CYP1B1, and NQO1 expression. Proteomic data also showed different levels of HSD17B10, CYP1B1, NQO1, and SULT1E1 between the four HGSOC subtypes. These results suggest that different HGSOC subtypes form different levels of estrogens and their metabolites and that the estrogen-biosynthesis-associated targets should be further studied for the development of personalized treatment.
    Keywords:  COV362; HIO-80; Kuramochi; OVSAHO; differentiated; high-grade serous ovarian carcinoma; immunoreactive; mesenchymal subtype; ovarian cancer; proliferative
  13. Neuroscience. 2022 Jun 04. pii: S0306-4522(22)00287-1. [Epub ahead of print]
      Estrogen replacement has been repeatedly shown to enhance memory and increase dendritic spine density in the hippocampus and prefrontal cortex of ovariectomized (OVX) female rats. Given the potential deleterious effects of chronic estrogen administration, the present study assessed cognitive function using recognition memory tasks and measured dendritic spine density in the CA1 region of the hippocampus and medial prefrontal cortex after subchronic androgen replacement to adult OVX female rats. All androgens enhanced recognition memory in OVX rats, but object placement (OP) and object recognition (OR) results differed. Only testosterone enhanced OR. Testosterone had no effect on OP while dehydroepiandrosterone (DHEA), dihydrotestosterone (DHT) and androstenedione (AD) enhanced OP. Dendritic spine density was increased by both TP and DHEA in both brain areas (DHT and AD were not tested). Lastly, we used the aromatase inhibitor, letrozole, to discriminate between potential androgenic and estrogenic effects of androgens on behavior. Letrozole alone did not alter recognition memory in OVX rats and did not block the effects of either TP or DHEA on recognition memory suggesting that effects were mediated via androgenic mechanisms. The present results expand previous information on gonadal hormone actions and show that, in addition to estrogens, androgens also improve memory and increase spine density in brains of OVX female rats. While requiring further investigation, these observations provide a basis for therapeutic interventions in the treatment of menopausal, age or disease related memory loss.
    Keywords:  Androgens; Dendritic spines; Hippocampus; Memory; Neural plasticity; Prefrontal cortex; Testosterone
  14. Acta Biomater. 2022 Jun 01. pii: S1742-7061(22)00325-7. [Epub ahead of print]
      Biomaterials capable of generating growth factor gradients have shown success in guiding tissue regeneration, as growth factor gradients are a physiologic driver of cell migration. Of particular importance, a focus on promoting endothelial cell migration is vital to angiogenesis and new tissue formation. Microporous Annealed Particle (MAP) scaffolds represent a unique niche in the field of regenerative biomaterials research as an injectable biomaterial with an open porosity that allows cells to freely migrate independent of material degradation. Recently, we have used the MAP platform to heterogeneously include spatially isolated heparin-modified microgels (heparin microislands) which can sequester growth factors and guide cell migration. In in vitro sprouting angiogenesis assays, we observed a parabolic relationship between the percentage of heparin microislands and cell migration, where 10% heparin microislands had more endothelial cell migration compared to 1% and 100%. Due to the low number of heparin microisland ratios tested, we hypothesize the spacing between microgels can be further optimized. Rather than use purely empirical methods, which are both expensive and time intensive, we believe this challenge represents an opportunity to use computational modeling. Here we present the first agent-based model of a MAP scaffold to optimize the ratio of heparin microislands. Specifically, we develop a two-dimensional model in Hybrid Automata Library (HAL) of endothelial cell migration within the unique MAP scaffold geometry. Finally, we present how our model can accurately predict cell migration trends in vitro, and these studies provide insight on how computational modeling can be used to design particle-based biomaterials. STATEMENT OF SIGNIFICANCE: : While the combination of experimental and computational approaches is increasingly being used to gain a better understanding of cellular processes, their combination in biomaterials development has been relatively limited. Heparin microislands are spatially isolated heparin microgels; when located within a microporous annealed particle (MAP) scaffold, they can sequester and release growth factors. Importantly, we present the first agent-based model of MAP scaffolds to optimize the ratio of heparin microislands within the scaffold to promote endothelial cell migration. We demonstrate this model can accurately predict trends in vitro, thus opening a new avenue of research to aid in the design of MAP scaffolds.
    Keywords:  agent-based modeling; angiogenesis; heparin microislands; porous hydrogels