bims-supasi Biomed News
on Sulfation pathways and signalling
Issue of 2023–12–17
twelve papers selected by
Jonathan Wolf Mueller, University of Birmingham
  1. Low serum dehydroepiandrosterone is associated with diabetic dyslipidemia risk in males with type 2 diabetes.
  2. Sulfated polysaccharides of Laetiporus sulphureus fruiting bodies exhibit anti-breast cancer activity through cell cycle arrest, apoptosis induction, and inhibiting cell migration.
  3. Modified minimal-size fragments of heparan sulfate as inhibitors of endosulfatase-2 (Sulf-2).
  4. Differential heparan sulfate-dependency of the Drosophila glypicans.
  5. B3GALT6 promotes dormant breast cancer cell survival and recurrence by enabling heparan sulfate-mediated FGF signaling.
  6. High gastrointestinal digestive stability endows chondroitin sulfate-soluble undenatured type II collagen complex with high activity: Improvement of osteoarthritis in rats.
  7. Asperulosidic Acid Ameliorates Renal Interstitial Fibrosis via Removing Indoxyl Sulfate by Up-Regulating Organic Anion Transporters in a Unilateral Ureteral Obstruction Mice Model.
  8. NMR Structural Study of Syndecan-4 Transmembrane Domain with Cytoplasmic Region.
  9. Role of Conformational Dynamics of Sulfotransferases SULT1A1 and SULT1A3 in Substrate Specificity.
  10. Genetically predicted serum testosterone and risk of gynecological disorders: a Mendelian randomization study.
  11. Structural Analysis and Novel Mechanism of Enteromorpha prolifera Sulfated Polysaccharide in Preventing Type 2 Diabetes Mellitus.
  12. Bone Phenotype is Always Present; Androgen Excess is Less Frequently Seen in PAPSS2 Deficiency.
  1. Front Endocrinol (Lausanne). 2023 ;14 1272797
    Low serum dehydroepiandrosterone is associated with diabetic dyslipidemia risk in males with type 2 diabetes.
    Shanshan Chen, Shuo Li, Xinxin Zhang, Yuxin Fan, Ming Liu.
       Objective: Sex steroid hormones are associated with the advancement of metabolic diseases such as dyslipidemia. This cross-sectional study aimed to investigate the relationship between dehydroepiandrosterone, dehydroepiandrosterone sulfate, androstenedione, and testosterone levels and the risk of dyslipidemia in people with type 2 diabetes mellitus.
    Materials and Methods: The analysis included 1,927 patients with type 2 diabetes mellitus. Serum dehydroepiandrosterone, dehydroepiandrosterone sulfate, androstenedione, and testosterone levels were determined using lipid chromatography-tandem mass spectrometry. Multivariable analyses were performed to investigate the association between the variables and dyslipidemia.
    Results: The multivariable-adjusted odds ratio (OR) and 95% confidence interval (CI) of dyslipidemia across DHEA tertiles were 0.39 and 0.24-0.64, respectively (p trend = 0.001). This relationship was still maintained when analyzed as a continuous variable (odds ratio, 0.96; 95% confidence interval, 0.92-0.99; P < 0.01). However, in males with type 2 diabetes mellitus, no significant correlations were found between rising levels of dehydroepiandrosterone sulfate, androstenedione, and total testosterone and the risk of dyslipidemia (all P > 0.05). Furthermore, there was no significant association between androgen precursors and total testosterone with regard to the risk of developing dyslipidemia (all P > 0.05).
    Conclusions: Serum dehydroepiandrosterone levels were substantially and adversely correlated with dyslipidemia in adult men with T2DM. These results indicated that dehydroepiandrosterone may have an essential role in the development of dyslipidemia. More prospective research is required to validate this link.
    Keywords:  androgen; dehydroepiandrosterone; dehydroepiandrosterone sulfate; diabetes mellitus; dyslipidemia; type 2
    DOI:  https://doi.org/10.3389/fendo.2023.1272797
  2. J Ethnopharmacol. 2023 Dec 06. pii: S0378-8741(23)01416-2. [Epub ahead of print]321 117546
    Sulfated polysaccharides of Laetiporus sulphureus fruiting bodies exhibit anti-breast cancer activity through cell cycle arrest, apoptosis induction, and inhibiting cell migration.
    Chia-I Jen, Mei-Kuang Lu, Ming-Nan Lai, Lean-Teik Ng.
       ETHNOPHARMACOLOGICAL RELEVANCE: Laetiporus sulphureus has long been used as an edible and medicinal mushroom in Asia, America, and Europe. Its fruiting bodies are widely used in folk medicine for treating cancer, gastric diseases, cough, and rheumatism. Polysaccharides are an important bioactive component of mushrooms. In nature, sulfated polysaccharides have never been reported in mushrooms. Furthermore, there is no information on differences in physicochemical properties and anti-breast cancer activities between polysaccharides (PS) and sulfated polysaccharides (SPS) of L. sulphureus.
    AIM OF THE STUDY: This study aimed to investigate the physicochemical properties of PS and SPS isolated from fruiting bodies of L. sulphureus and examine their anti-proliferative effects and mechanism(s) of action on MDA-MB-231 breast cancer cells.
    METHODS: Polysaccharides (PS) were isolated using hot water and ethanol precipitation methods. Sulfated polysaccharides (SPS) were isolated by the papain-assisted hydrolysis method. Physicochemical properties comprising sugar, protein, uronic acid, and sulfate contents, and molecular weight, monosaccharide composition, and structural conformation were analyzed on PS and SPS. In the anti-cancer study, a triple-negative breast cancer cell line (MDA-MB-231) and a normal human mammary epithelial cell line (H184B5F5/M10) were used to evaluate the anti-proliferative activity of PS and SPS, and their mechanism(s) of action.
    RESULTS: The results showed that SPS, which had higher sulfate and protein contents and diversified monosaccharide composition, exhibited more potent anti-proliferative activity against MDA-MB-231 cells than PS. Furthermore, it had a selective cytotoxic effect on breast cancer cells but not the normal cells. SPS induced cell cycle arrest at G0/G1 phase via down-regulating CDK4 and cyclin D1 and up-regulating p21 protein expression. Breast cancer cell apoptosis was not observed until 72 h after SPS treatment. In addition, SPS also markedly inhibited breast cancer cell migration.
    CONCLUSION: This study demonstrates that SPS exhibited selective cytotoxicity and was more potent than PS in inhibiting MDA-MB-231 cell proliferation. The contents of sulfate and protein, and monosaccharide composition could be the main factors affecting the anti-breast cancer activity of L. sulphureus SPS.
    Keywords:  Breast cancer cells; Cell cycle arrest; Laetiporus sulphureus; Physicochemical properties; Sulfated polysaccharides
    DOI:  https://doi.org/10.1016/j.jep.2023.117546
  3. Chem Commun (Camb). 2023 Dec 12.
    Modified minimal-size fragments of heparan sulfate as inhibitors of endosulfatase-2 (Sulf-2).
    Alice Kennett, Sven Epple, Gabriella van der Valk, Irene Georgiou, Evelyne Gout, Romain R Vivès, Angela J Russell.
      Sulf-2 has been identified as a putative target for anticancer therapies. Here we report the design and synthesis of sulfated disaccharide inhibitors based on IdoA(2S)-GlcNS(6S). Trisulfated disaccharide inhibitor IdoA(2S)-GlcNS(6Sulfamate) demonstrated potent Sulf-2 inhibition. The IC50 value was determined to be 39.8 μM ± 18.3, which is comparable to a tetrasaccharide inhibitor of HSulf-1 reported in the literature. We propose that the disaccharide IdoA(2S)-GlcNS(6S) is the shortest fragment size required for effective inhibition of the Sulfs.
    DOI:  https://doi.org/10.1039/d3cc02565a
  4. J Biol Chem. 2023 Dec 08. pii: S0021-9258(23)02572-3. [Epub ahead of print] 105544
    Differential heparan sulfate-dependency of the Drosophila glypicans.
    Eriko Nakato, Keisuke Kamimura, Collin Knudsen, Suzuka Masutani, Masahiko Takemura, Yoshiki Hayashi, Takuya Akiyama, Hiroshi Nakato.
      Heparan sulfate proteoglycans (HSPGs) are composed of a core-protein and glycosaminoglycan (GAG) chains and serve as co-receptors for many growth factors and morphogens. To understand the molecular mechanisms by which HSPGs regulate morphogen gradient formation and signaling, it is important to determine the relative contributions of the carbohydrate and protein moieties to the PG function. To address this question, we generated ΔGAG alleles for dally and dally-like protein (dlp), two Drosophila HSPGs of the glypican family, in which all GAG-attachment Serine residues are substituted to Alanine residues using CRISPR/Cas9 mutagenesis. In these alleles, the glypican core-proteins are expressed from the endogenous loci with no GAG modification. Analyses of the dallyΔGAG allele defined Dally functions that do not require HS chains and that need both core-protein and HS chains. We found a new, dallyΔGAG-specific phenotype, the formation of a posterior ectopic vein, which we have never seen in the null mutants. Unlike dallyΔGAG, dlpΔGAG mutants do not show most of the dlp null mutant phenotypes, suggesting that HS chains are dispensable for these dlp functions. As an exception, HS is essentially required for Dlp's activity at the neuromuscular junction. Thus, Drosophila glypicans show strikingly different levels of HS-dependency. The ΔGAG mutant alleles of the glypicans serve as new molecular genetic toolsets highly useful to address important biological questions, such as molecular mechanisms of morphogen gradient formation.
    DOI:  https://doi.org/10.1016/j.jbc.2023.105544
  5. Cancer Cell. 2023 Dec 01. pii: S1535-6108(23)00399-9. [Epub ahead of print]
    B3GALT6 promotes dormant breast cancer cell survival and recurrence by enabling heparan sulfate-mediated FGF signaling.
    Amulya Sreekumar, Michelle Lu, Biswa Choudhury, Tien-Chi Pan, Dhruv K Pant, Matthew R Lawrence-Paul, Christopher J Sterner, George K Belka, Takashi Toriumi, Brian A Benz, Matias Escobar-Aguirre, Francesco E Marino, Jeffrey D Esko, Lewis A Chodosh.
      Breast cancer mortality results from incurable recurrences thought to be seeded by dormant, therapy-refractory residual tumor cells (RTCs). Understanding the mechanisms enabling RTC survival is therefore essential for improving patient outcomes. Here, we derive a dormancy-associated RTC signature that mirrors the transcriptional response to neoadjuvant therapy in patients and is enriched for extracellular matrix-related pathways. In vivo CRISPR-Cas9 screening of dormancy-associated candidate genes identifies the galactosyltransferase B3GALT6 as a functional regulator of RTC fitness. B3GALT6 is required for glycosaminoglycan (GAG) linkage to proteins to generate proteoglycans, and its germline loss of function in patients causes skeletal dysplasias. We find that B3GALT6-mediated biosynthesis of heparan sulfate GAGs predicts poor patient outcomes and promotes tumor recurrence by enhancing dormant RTC survival in multiple contexts, and does so via a B3GALT6-heparan sulfate/HS6ST1-heparan 6-O-sulfation/FGF1-FGFR2 signaling axis. These findings implicate B3GALT6 in cancer and nominate FGFR2 inhibition as a promising approach to eradicate dormant RTCs and prevent recurrence.
    Keywords:  6-O-sulfation; B3GALT6; FGFR2; HS6ST1; breast cancer; dormancy; glycans; glycosaminoglycans; heparan sulfate; proteoglycans
    DOI:  https://doi.org/10.1016/j.ccell.2023.11.008
  6. Int J Biol Macromol. 2023 Dec 07. pii: S0141-8130(23)05529-0. [Epub ahead of print] 128630
    High gastrointestinal digestive stability endows chondroitin sulfate-soluble undenatured type II collagen complex with high activity: Improvement of osteoarthritis in rats.
    Rong Xu, Lin Zheng, Mingtao Huang, Mouming Zhao.
      Previously, we prepared a chondroitin sulfate-soluble undenatured type II collagen complex (CS-SC II) with low salt content. This paper further explored the differences between CS-SC II and SC II in terms of gastrointestinal digestive characteristics and osteoarthritis (OA) improvement. In vitro and in vivo experiments showed that the gastric digestive stability of CS-SC II was high under both pH 2.0 and pH 3.0, the α1 chain and triple helix structure of type II collagen retained >60 %. However, SC II had high gastric digestive stability only under pH 3.0. Furthermore, intestinal digestion had little effect on α1 chains of CS-SC II and SC II, and distribution experiments showed that they might exert their biological activities in the intestine. CS-SC II had obvious improvement in OA rats at 1.0 mg/kg/d, that is, the joint swelling was significantly reduced and the weight-bearing ratio of the right hind limb was increased to 49 %, which was close to that of 4.0 mg/kg/d SC II. The wear of articular cartilage, Mankin and OARSI scores of rats in CS-SC II group were significantly reduced. The effects of low-dose CS-SC II on the proportion of regulatory T cells (Treg), mRNA expression of OA key biomarkers (Il6, Ccl7, MMP-3 and MMP13) and signaling pathway genes (NF-κB, AKT or AMPKα) were comparable to those of high-dose SC II. These results showed that CS-SC II might have greater potential to improve OA at a lower dose than SC II due to its high gastrointestinal digestive stability at a wide range of pH conditions.
    Keywords:  Chondroitin sulfate-soluble undenatured type II collagen complex; Gastrointestinal digestive stability; Osteoarthritis
    DOI:  https://doi.org/10.1016/j.ijbiomac.2023.128630
  7. Molecules. 2023 Nov 21. pii: 7690. [Epub ahead of print]28(23):
    Asperulosidic Acid Ameliorates Renal Interstitial Fibrosis via Removing Indoxyl Sulfate by Up-Regulating Organic Anion Transporters in a Unilateral Ureteral Obstruction Mice Model.
    Jing Wang, Birui Shi, Yueqing Pan, Zhuan Yang, Wei Zou, Menghua Liu.
      Asperulosidic acid is a bioactive iridoid isolated from Hedyotis diffusa Willd. with anti-inflammatory and renal protective effects. However, its mechanism on renal interstitial fibrosis has not been elucidated yet. The present study aims to explore whether asperulosidic acid could retard renal fibrosis by reducing the circulating indoxyl sulfate (IS), which is a uremic toxin and accelerates chronic kidney disease progression by inducing renal fibrosis. In this paper, a unilateral ureteral obstruction (UUO) model of Balb/C mice was established. After the mice were orally administered with asperulosidic acid (14 and 28 mg/kg) for two weeks, blood, liver and kidney were collected for biochemical, histological, qPCR and Western blot analyses. Asperulosidic acid administration markedly reduced the serum IS level and significantly alleviated the histological changes in glomerular sclerosis and renal interstitial fibrosis. It is noteworthy that the mRNA and protein levels of the organic anion transporter 1 (OAT1), OAT3 and hepatocyte nuclear factor 1α (HNF1α) in the kidney were significantly increased, while the mRNA expressions of cytochrome P450 2e1 (Cyp2e1) and sulfotransferase 1a1 (Sult1a1) in the liver were not altered after asperulosidic acid administration. These results reveal that asperulosidic acid could accelerate the renal excretion of IS by up-regulating OATs via HNF1α in UUO mice, thereby alleviating renal fibrosis, but did not significantly affect its production in the liver, which might provide important information for the development of asperulosidic acid.
    Keywords:  OATs; asperulosidic acid; chronic kidney disease; indoxyl sulfate; renal interstitial fibrosis
    DOI:  https://doi.org/10.3390/molecules28237690
  8. Molecules. 2023 Nov 29. pii: 7855. [Epub ahead of print]28(23):
    NMR Structural Study of Syndecan-4 Transmembrane Domain with Cytoplasmic Region.
    Minseon Kim, Yongae Kim.
      Syndecan-4 (SDC4) consists of transmembrane heparan sulfate proteoglycan (HSPG) belonging to the syndecan family. It is present in most cell types of Mammalia. Its structure contains a heparan-sulfate-modified extracellular domain, a single transmembrane domain, and a short C-terminal cytoplasmic domain. Regarding the overall cellular function of SDC4, other cells or ligands can bind to its ecto-domain. In addition, 4,5-bisphosphate phosphatidylinositol (PIP2) or protein kinase Cα can bind to its cyto-domain to activate downstream signaling pathways. To understand the signal transduction mechanism of syndecan, it is important to know the interactions between their actual structure and function in vivo. Therefore, it is important to identify the structure of SDC4 to understand the ligand binding behavior of SDC4. In this study, expression and purification were performed to reveal structures of the short ecto-domain, the transmembrane domain, and the cytoplasmic domain of Syd4-eTC (SDC4). Solution-state NMR spectroscopy and solid-state NMR spectroscopy were used to study the structure of Syd4-eTC in membrane environments and to demonstrate the interaction between Syd4-eTC and PIP2.
    Keywords:  PIP2; Syd4-eTC; solid-state NMR; syndecan-4; transmembrane protein
    DOI:  https://doi.org/10.3390/molecules28237855
  9. Int J Mol Sci. 2023 Nov 29. pii: 16900. [Epub ahead of print]24(23):
    Role of Conformational Dynamics of Sulfotransferases SULT1A1 and SULT1A3 in Substrate Specificity.
    Daniel Toth, Balint Dudas, Maria A Miteva, Erika Balog.
      Sulfotransferases (SULTs) are phase II metabolizing enzymes catalyzing the sulfoconjugation from the co-factor 3'-Phosphoadenosine 5'-Phosphosulfate (PAPS) to a wide variety of endogenous compounds, drugs and natural products. Although SULT1A1 and SULT1A3 share 93% identity, SULT1A1, the most abundant SULT isoform in humans, exhibits a broad substrate range with specificity for small phenolic compounds, while SULT1A3 displays a high affinity toward monoamine neurotransmitters like dopamine. To elucidate the factors determining the substrate specificity of the SULT1 isoenzymes, we studied the dynamic behavior and structural specificities of SULT1A1 and SULT1A3 by using molecular dynamics (MD) simulations and ensemble docking of common and specific substrates of the two isoforms. Our results demonstrated that while SULT1A1 exhibits a relatively rigid structure by showing lower conformational flexibility except for the lip (loop L1), the loop L2 and the cap (L3) of SULT1A3 are extremely flexible. We identified protein residues strongly involved in the recognition of different substrates for the two isoforms. Our analyses indicated that being more specific and highly flexible, the structure of SULT1A3 has particularities in the binding site, which are crucial for its substrate selectivity.
    Keywords:  SULTs selectivity; docking; drug–drug interactions; molecular dynamics; sulfotransferase
    DOI:  https://doi.org/10.3390/ijms242316900
  10. Front Endocrinol (Lausanne). 2023 ;14 1161356
    Genetically predicted serum testosterone and risk of gynecological disorders: a Mendelian randomization study.
    Benzheng Zhao, Zhenpeng Wang, Dongzhen Liu, Songling Zhang.
       Background: Testosterone plays a key role in women, but the associations of serum testosterone level with gynecological disorders risk are inconclusive in observational studies.
    Methods: We leveraged public genome-wide association studies to analyze the effects of four testosterone related exposure factors on nine gynecological diseases. Causal estimates were calculated by inverse variance-weighted (IVW), MR-Egger and weighted median methods. The heterogeneity test was performed on the obtained data through Cochrane's Q value, and the horizontal pleiotropy test was performed on the data through MR-Egger intercept and MR-PRESSO methods. "mRnd" online analysis tool was used to evaluate the statistical power of MR estimates.
    Results: The results showed that total testosterone and bioavailable testosterone were protective factors for ovarian cancer (odds ratio (OR) = 0.885, P = 0.012; OR = 0.871, P = 0.005) and endometriosis (OR = 0.805, P = 0.020; OR = 0.842, P = 0.028) but were risk factors for endometrial cancer (OR = 1.549, P < 0.001; OR = 1.499, P < 0.001) and polycystic ovary syndrome (PCOS) (OR = 1.606, P = 0.019; OR = 1.637, P = 0.017). dehydroepiandrosterone sulfate (DHEAS) is a protective factor against endometriosis (OR = 0.840, P = 0.016) and premature ovarian failure (POF) (OR = 0.461, P = 0.046) and a risk factor for endometrial cancer (OR= 1.788, P < 0.001) and PCOS (OR= 1.970, P = 0.014). sex hormone-binding globulin (SHBG) is a protective factor against endometrial cancer (OR = 0.823, P < 0.001) and PCOS (OR = 0.715, P = 0.031).
    Conclusion: Our analysis suggested causal associations between serum testosterone level and ovarian cancer, endometrial cancer, endometriosis, PCOS, POF.
    Keywords:  Mendelian randomization; causal inference; gynecological disorders; serum testosterone; sex hormone-binding globulin
    DOI:  https://doi.org/10.3389/fendo.2023.1161356
  11. Plant Foods Hum Nutr. 2023 Dec 12.
    Structural Analysis and Novel Mechanism of Enteromorpha prolifera Sulfated Polysaccharide in Preventing Type 2 Diabetes Mellitus.
    Dai Lin, Nan Zhang, Siyi Wu, Shuting Wang, Fang Huang, Yong Lin, Aili Zhao, Fuchuan Guo, Qiaorong Gan, Wenxiang Wang.
      A water-soluble polysaccharide (EP) was purified from edible algae Enteromorpha prolifera. Gel permeation chromatography (GPC), ion chromatography (IC), and fourier transform infrared (FT-IR) were performed to characterize its structure. EP was defined as a low molecular weight (6625 Da) composed of rhamnose, glucose, glucuronic acid, xylose, galactose, arabinose, and mannose. Moreover, it was a sulfated polysaccharide with a degree of substitution (DS) of 1.48. Then, the high-fat diet/streptozotocin (HFD/STZ) induced diabetic mouse model was established to support evidence for a novel hypoglycemic mechanism. Results showed that blood glucose (47.32%), liver index (7.65%), epididymal fat index (16.86%), serum total cholesterol (26.78%) and triglyceride (37.61%) in the high-dose EP (HEP) group were significantly lower than those in the HFD group. Noticeably, the content of liver glycogen in the HEP group was significantly higher (62.62%) than that in the HFD group, indicating the promotion of glycogen synthesis. These beneficial effects were attributed to significantly increased protein kinase B (AKT) phosphorylation and its downstream signaling response. Further studies showed that diabetic mice exhibited excessive O-GlcNAcylation level and high expression of O-linked β-D-N-acetylglucosamine transferase (OGT), which were decreased by 62.21 and 30.43% in the HEP group. This result suggested that EP had a similar effect to OGT inhibitors, which restored AKT phosphorylation and prevented pathoglycemia. This work reveals a novel hypoglycemic mechanism of EP, providing a theoretical basis for further studies on its pharmacological properties in improvement of T2DM.
    Keywords:  Edible algae; Hepatic glycogen; OGT, AKT; Pathoglycemia; Sulfated polysaccharide
    DOI:  https://doi.org/10.1007/s11130-023-01129-8
  12. J Clin Res Pediatr Endocrinol. 2023 Dec 12.
    Bone Phenotype is Always Present; Androgen Excess is Less Frequently Seen in PAPSS2 Deficiency.
    Didem Helvacioglu, Tulay Guran.
      3'-Phosphoadenosine 5'-phosphosulfate synthase 2 (PAPSS2) deficiency is a rare disorder due to biallelic pathogenic variants in the PAPSS2 gene. This disorder was first described in 1998 by Ahmad M, et al. and Faiyaz ul Haque M et al.. So far 79 patients with PAPSS2 deficiency were reported in the literature. The main reported features of these patients are related to bone abnormalities and clinical/biochemical androgen excess. Disproportionate short stature and symptoms associated with spondylar skeletal dysplasia are the most common clinical features that require clinical attention. Androgen excess has been described much less commonly. This review summarises the clinical, molecular, and biochemical features of patients with PAPSS2 deficiency published so far.
    Keywords:  DHEAS; PAPSS2; SEMD; androgen excess; brachyolmia; sulfation
    DOI:  https://doi.org/10.4274/jcrpe.galenos.2023.2023-12-10
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