bims-supasi 2024-10-13 papers

bims-supasi

Biomed News

on Sulfation pathways and signalling

Issue of 2024–10–13
twelve papers selected by
Jonathan Wolf Mueller, University of Birmingham

Immunogenic Sulfated l-Idose Homo Oligosaccharides Elicit Neutralizing Antibody against Native Heparan Sulfate with Biomarker and Therapeutic Possibilities.
Regulatory role of Heparan sulfate in leptin signaling.
Myeloid Deficiency of Heparan Sulfate 6-O-Endosulfatases Impairs Bone Marrow Hematopoiesis.
Resolving Sulfation Posttranslational Modifications on a Peptide Hormone using Nanopores.
Highly concentrated collagen/chondroitin sulfate scaffold with platelet-rich plasma promotes bone-exposed wound healing in porcine.
In laying hens, chronic heat stress-induced renal fibrosis is potentially promoted by indoxyl sulfate.
Synthesis of Low-Molecular-Weight Fucoidan Analogue and Its Inhibitory Activities against Heparanase and SARS-CoV-2 Infection.
Heparin treatment is associated with a delayed diagnosis of Alzheimer's dementia in electronic health records from two large United States health systems.
Tandem mass spectrometry-based assay for heparan-N-sulphatase in paediatric CSF: A potential pharmacodynamic biomarker for mucopolysaccharidosis type IIIA therapy.
Adipose tissue insulin resistance in young Japanese women is associated with metabolic abnormalities and dehydroepiandrosterone-sulfate.
VARIATIONS OF SERUM DEHYDROEPIANDROSTERONE-SULPHATE (DHEAS) LEVEL WITH PREGNANCY, FERTILITY, ABORTION, OVARIAN RESERVE AND ENDOTHELIAL FUNCTIONS.
Giantin mediates Golgi localization of Gal3-O-sulfotransferases and affects salivary mucin sulfation in Sjögren's disease patients.

J Med Chem. 2024 Oct 06.

Immunogenic Sulfated l-Idose Homo Oligosaccharides Elicit Neutralizing Antibody against Native Heparan Sulfate with Biomarker and Therapeutic Possibilities.

Sharath S Vishweshwara, Preeti Ravindra Bhoge, Saurabh Anand, Rakesh Raigawali, Ankita Chandra, Srinivas Vinod Saladi, Raghavendra Kikkeri.

Heparan sulfate (HS) is a non-immunogenic antigen, and developing antibodies against specific sulfated patterns in HS poses significant challenges. Herein, we employed an innovative immunization strategy that exploits the molecular mimicry of HS to generate antibodies against HS sequences. Mice were immunized with synthetic sulfated oligo-l-idose (ID49) that mimics optimum 67% of the conserved structure of HS ligands. This immunization of ID49@CRM197 with alum and Freund's adjuvant resulted in the production of robust IgG antibody responses targeting ID49 and cross-reactivity with the N-sulfated HS ligands compared to N-unsubstituted and N-acetate domain synthetic HS ligands. Such a pharmacological agent exhibited distinct staining of tissue sections and cell lines and induced complement-dependent cell cytotoxicity against SK-BR-3 cancer cells. Moreover, these antibodies inhibited heparin-mediated anticoagulation activity similar to that of protamine. These findings highlight the biomarker and possible therapeutic capability of the antibodies.

DOI: https://doi.org/10.1021/acs.jmedchem.4c01772
Cell Signal. 2024 Oct 07. pii: S0898-6568(24)00429-7. [Epub ahead of print] 111456

Regulatory role of Heparan sulfate in leptin signaling.

Naoko Nagai, Tatsumasa Shioiri, Sonoko Hatano, Nobuo Sugiura, Hideto Watanabe.

  Leptin, a hormone mainly secreted by adipocytes, has attracted significant attention since its discovery in 1994. Initially known for its role in appetite suppression and energy regulation, leptin is now recognized for its influence on various physiological processes, including immune response, bone formation, and reproduction. It exerts its effects by binding to receptors and initiating an intracellular signaling cascade. Heparan sulfate (HS) is known to regulate the intracellular signaling of various ligands. HS is present as the glycan portion of HSPGs on cell surfaces and in intercellular spaces, with diverse structures due to extensive sulfation and epimerization. Although HS chains on HSPGs are involved in many physiological processes, the detailed effects of HS chains on leptin signaling are not well understood. This study examined the role of HS chains on HSPGs in leptin signaling using Neuro2A cells expressing the full-length leptin receptor (LepR). We showed that cell surface HS was essential for efficient leptin signaling. Enzymatic degradation of HS significantly reduced leptin-induced phosphorylation of downstream molecules, such as signal transducer and activator of transcription 3 and p44/p42 Mitogen-activated protein kinase. In addition, HS regulated LepR expression and internalization, as treatment with HS-degrading enzymes decreased cell surface LepR. HS was also found to exhibit a weak interaction with LepR. Enzymatic removal of HS enhanced the interaction between LepR and low-density lipoprotein receptor-related protein 1, suggesting that HS negatively regulates this interaction. In conclusion, HS plays a significant role in modulating LepR availability on the cell surface, thereby influencing leptin signaling. These findings provide new insights into the complex regulation of leptin signaling and highlight potential therapeutic targets for metabolic disorders and obesity.

Keywords:  Endocytosis; Heparan sulfate; Leptin receptor; Leptin signaling; Low-density lipoprotein receptor-related protein 1

DOI:  https://doi.org/10.1016/j.cellsig.2024.111456
Matrix Biol. 2024 Oct 03. pii: S0945-053X(24)00123-9. [Epub ahead of print]

Myeloid Deficiency of Heparan Sulfate 6-O-Endosulfatases Impairs Bone Marrow Hematopoiesis.

Anna K Whitehead, Zhangjie Wang, Rebecca-Joe Boustany, Romain R Vivès, Eric Lazartigues, Jian Liu, Robert W Siggins, Xinping Yue.

  The heparan sulfate (HS) 6-O-endosulfatases or the Sulfs (Sulf1 and Sulf2) are the only known enzymes that can modify HS sulfation status extracellularly and have been shown to regulate diverse biological processes. The role of the Sulfs in bone marrow (BM) hematopoiesis is not known. In this study, we generated a novel mouse line with myeloid-specific deletion of the Sulfs by crossing Sulf1/2 double floxed mice with the LysM-cre line. The LysM-Sulf knockout (KO) male mice exhibited age-dependent expansion of hematopoietic stem cells and the granulocyte-monocyte lineages in the BM, whereas common lymphoid progenitors and B lymphocyte populations were significantly reduced. Although megakaryocytic and erythroid progenitors were not reduced in the BM, the LysM-Sulf KO males suffered age-dependent reduction of red blood cells (RBCs) and platelets in the peripheral blood, suggesting that the production of RBCs and platelets was arrested at later stages. In addition, LysM-Sulf KO males displayed progressive splenomegaly with extramedullary hematopoiesis. Compared to males, LysM-Sulf KO females exhibited a much-reduced phenotype, and ovariectomy had little effect. Mechanistically, reduced TGF-β/Smad2 but enhanced p53/p21 signaling were observed in male but not female LysM-Sulf KO mice. Finally, HS disaccharide analysis via LC-MS/MS revealed increased HS 6-O-sulfation in the BM from both male and female LysM-Sulf KO mice, however, the distribution of 6-O-sulfated motifs were different between the sexes with compensatory increase in Sulf1 expression observed only in LysM-Sulf KO females. In conclusion, our study reveals that myeloid deficiency of the Sulfs leads to multilineage abnormalities in BM hematopoiesis in an age- and sex-dependent manner.

Keywords:  Sulf1; Sulf2; bone marrow; hematopoiesis; heparan sulfate

DOI:  https://doi.org/10.1016/j.matbio.2024.10.002
ACS Nano. 2024 Oct 10.

Resolving Sulfation Posttranslational Modifications on a Peptide Hormone using Nanopores.

Xiuqi Chen, Jasper W van de Sande, Justas Ritmejeris, Chenyu Wen, Henry Brinkerhoff, Andrew H Laszlo, Bauke Albada, Cees Dekker.

  Peptide hormones are decorated with post-translational modifications (PTMs) that are crucial for receptor recognition. Tyrosine sulfation on plant peptide hormones is, for example, essential for plant growth and development. Measuring the occurrence and position of sulfotyrosine is, however, compromised by major technical challenges during isolation and detection. Nanopores can sensitively detect protein PTMs at the single-molecule level. By translocating PTM variants of the plant pentapeptide hormone phytosulfokine (PSK) through a nanopore, we here demonstrate the accurate identification of sulfation and phosphorylation on the two tyrosine residues of PSK. Sulfation can be clearly detected and distinguished (>90%) from phosphorylation on the same residue. Moreover, the presence or absence of PTMs on the two close-by tyrosine residues can be accurately determined (>96% accuracy). Our findings demonstrate the extraordinary sensitivity of nanopore protein measurements, providing a powerful tool for identifying position-specific sulfation on peptide hormones and promising wider applications to identify protein PTMs.

Keywords:  nanopore; peptide fingerprinting; plant peptide hormone; post-translational modifications; single-molecule technique

DOI:  https://doi.org/10.1021/acsnano.4c09872
Front Bioeng Biotechnol. 2024 ;12 1441053

Highly concentrated collagen/chondroitin sulfate scaffold with platelet-rich plasma promotes bone-exposed wound healing in porcine.

Zhihao Li, Qian Li, Akhlaq Ahmad, Zhongjie Yue, Hongxia Wang, Guofeng Wu.

  In the case of wounds with exposed bone, it is essential to provide not only scaffolds with sufficient mechanical strength for protection, but also environments that are conducive to the regeneration of tissues and blood vessels. Despite the excellent biocompatibility and biodegradability of collagen and chondroitin sulfate, they display poor mechanical strength and rapid degradation rates. In contrast to previous methodologies that augmented the mechanical properties of biomaterials through the incorporation of additional substances, this investigation exclusively enhanced the mechanical strength of collagen/chondroitin sulfate scaffolds by modulating collagen concentrations. Furthermore, platelet-rich plasma (PRP) was employed to establish optimal conditions for vascular and tissue regeneration at the wound site. High-concentration collagen/chondroitin sulfate (H C-S) scaffolds were synthesized using high-speed centrifugation and combined with PRP, and their effects on endothelial cell proliferation were assessed. A porcine model of bone-exposed wounds was developed to investigate the healing effects and mechanisms. The experimental results indicated that scaffolds with increased collagen concentration significantly enhanced both tensile and compressive moduli. The combination of H C-S scaffolds with PRP markedly promoted endothelial cell proliferation. In vivo experiments demonstrated that this combination significantly accelerated the healing of porcine bone-exposed wounds and promoted vascular regeneration. This represents a promising strategy for promoting tissue regeneration that is worthy of further exploration and clinical application.

Keywords:  bone-exposed wounds; high concentration collagen; mechanical strength; platelet-rich plasma; vascular regeneration

DOI:  https://doi.org/10.3389/fbioe.2024.1441053
Sci Rep. 2024 10 05. 14(1): 23213

In laying hens, chronic heat stress-induced renal fibrosis is potentially promoted by indoxyl sulfate.

Fumika Nanto-Hara, Haruhiko Ohtsu.

  Indoxyl sulfate (IS), a uremic toxin, is a harmful factor that damages kidneys. Chronic heat stress in laying hens causes renal injury; however, whether IS accumulation is involved in this injury remains unknown. We selected 20 Boris brown laying hens (27 weeks old) and randomly assigned them to two groups (n = 10), one group was exposed to chronic heat stress (32 °C for 4 weeks), whereas the other was maintained at 24 °C. Chronic heat exposure significantly increased plasma and renal IS concentrations (P < 0.05). Exposure to heat also increased renal expression of the aryl hydrocarbon receptor (AhR) and its target genes (CYP1A4 and CYP1B1). Furthermore, chronic heat exposure tended to increase the 2-thiobarbituric acid reactive substances content (P = 0.08) and significantly decreased the antioxidant capacity in the kidney, while increasing the transcription levels of nuclear factor κB and fibrosis-related genes (COLA1A1, αSMA, TGF-β, Smad3, and VCAM-1) and the area of renal fibrosis. Our results indicate that chronic heat exposure induces systemic and renal IS accumulation in laying hens. This accumulated IS may activate the AhR pathway and chronically disrupt the oxidative stress status and antioxidant activity, thus promoting renal fibrosis and dysfunction in laying hens.

Keywords:  Fibrosis; Heat stress; Indoxyl sulfate; Kidney; Laying hens; Uremic toxins

DOI:  https://doi.org/10.1038/s41598-024-75066-0
Angew Chem Int Ed Engl. 2024 Oct 07. e202411760

Synthesis of Low-Molecular-Weight Fucoidan Analogue and Its Inhibitory Activities against Heparanase and SARS-CoV-2 Infection.

Aoi Sugimoto, Tatsuki Koike, Yuya Kuboki, Sumika Komaba, Shuhei Kosono, Maniyamma Aswathy, Itsuki Anzai, Tokiko Watanabe, Kazunobu Toshima, Daisuke Takahashi.

  Heparan sulfate (HS) is ubiquitous on cell surfaces and is used as a receptor by many viruses including SARS-CoV-2. However, increased activity of the inflammatory enzyme heparanase (HPSE), which hydrolyses HS, in patients with COVID-19 not only increases the severity of symptoms but also may facilitate the spread of the virus by degrading HS on the cell surface. Therefore, synthetic HPSE blockades, which can bind to SARS-CoV-2 spike protein (SARS-CoV-2-S) and inhibit viral entry, have attracted much attention. This study investigated the development of a new dual-targeting antiviral agent against HPSE and SARS-CoV-2-S using fucoidan as a structural motif. It was found that all-sulfated fucoidan derivative 10, which exhibited the highest binding affinity to SARS-CoV-2-S among 13 derivatives, also showed the highest inhibitory activity against HPSE. Based on this, a newly designed and synthesized fucoidan analogue 16, in which the octyl group of 10 was changed to a cholestanyl group, was found to show higher activity than 10 but did not inhibit factor Xa associated with undesired anticoagulant effects. The binding affinity of 16 to SARS-CoV-2-S was significantly increased approximately 400-fold over that of 10. Furthermore, 16 effectively inhibited infection by the SARS-CoV-2 Wuhan strain and two Omicron subvariants.

Keywords:  SARS-CoV-2; antivirals; fucoidan; heparanase; spike protein

DOI:  https://doi.org/10.1002/anie.202411760
Mol Psychiatry. 2024 Oct 08.

Heparin treatment is associated with a delayed diagnosis of Alzheimer's dementia in electronic health records from two large United States health systems.

Benjamin Readhead, Eyal Klang, Undina Gisladottir, Maxence Vandromme, Li Li, Yakeel T Quiroz, Joseph F Arboleda-Velasquez, Joel T Dudley, Nicholas P Tatonetti, Benjamin S Glicksberg, Eric M Reiman.

Recent studies suggest that heparan sulfate proteoglycans (HSPG) contribute to the predisposition to, protection from, and potential treatment and prevention of Alzheimer's disease (AD). Here, we used electronic health records (EHR) from two different health systems to examine whether heparin therapy was associated with a delayed diagnosis of AD dementia. Longitudinal EHR data from 15,183 patients from the Mount Sinai Health System (MSHS) and 6207 patients from Columbia University Medical Center (CUMC) were used in separate survival analyses to compare those who did or did not receive heparin therapy, had a least 5 years of observation, were at least 65 years old by their last visit, and had subsequent diagnostic code or drug treatment evidence of possible AD dementia. Analyses controlled for age, sex, comorbidities, follow-up duration and number of inpatient visits. Heparin therapy was associated with significant delays in age of clinical diagnosis of AD dementia, including +1.0 years in the MSMS cohort (P < 0.001) and +1.0 years in the CUMC cohort (P < 0.001). While additional studies are needed, this study supports the potential roles of heparin-like drugs and HSPGs in the protection from and prevention of AD dementia.

DOI: https://doi.org/10.1038/s41380-024-02757-5
Clin Chim Acta. 2024 Oct 03. pii: S0009-8981(24)02240-X. [Epub ahead of print] 119987

Tandem mass spectrometry-based assay for heparan-N-sulphatase in paediatric CSF: A potential pharmacodynamic biomarker for mucopolysaccharidosis type IIIA therapy.

Roberto Speziale, Michaël Hocquemiller, Xin Mei, Danilo Fabbrini, Savina Malancona, Karen Aiach, Ralph Laufer, Laura Orsatti.

  Mucopolysaccharidosis type IIIA is a lysosomal storage disorder caused by mutations in the gene coding for heparan-N-sulphatase, a crucial enzyme in the degradation of heparan sulfate. In mucopolysaccharidosis type IIIA, heparan sulfate accumulates in the lysosomes, predominantly affecting the central nervous system. It is the most common and most severe form of mucopolysaccharidosis type III, with onset typically before the age of ten years. There is an ongoing effort to develop therapies that aim at restoring enzyme function in the brain. This study introduces a novel tandem mass spectrometry method for assessing heparan-N-sulphatase activity in pediatric cerebrospinal fluid from healthy and disease individuals. Analysis of cerebrospinal fluid samples revealed marked differences in enzyme activity, with mucopolysaccharidosis type IIIA individuals exhibiting significantly reduced levels. This new method could serve as a valuable tool for evaluating the efficacy of future therapeutic interventions targeting sulphatase activity restoration in the brain.

Keywords:  Cerebrospinal fluid; Heparan sulfate; High pressure liquid chromatography; Mucopolysaccharidosis type IIIA; SGSH activity assay; Tandem mass spectrometry

DOI:  https://doi.org/10.1016/j.cca.2024.119987
Front Endocrinol (Lausanne). 2024 ;15 1390778

Adipose tissue insulin resistance in young Japanese women is associated with metabolic abnormalities and dehydroepiandrosterone-sulfate.

Motonori Sato, Yoshifumi Tamura, Hideyoshi Kaga, Nozomu Yamasaki, Satoshi Kadowaki, Daisuke Sugimoto, Takashi Nakagata, Yuki Someya, Yuya Nishida, Ryuzo Kawamori, Hirotaka Watada.

   Objective: The proportion of young Japanese women who are underweight is exceptionally high. We previously showed that the prevalence of impaired glucose tolerance (IGT) was high in underweight young Japanese women, and that IGT was characterized by high free fatty acid levels and adipose tissue insulin resistance (ATIR). As the next step, this study aimed to explore factors associated with elevated ATIR in this population.
Participants: Ninety-eight young, healthy, underweight women participated in this study.
Design: To investigate the relationship between ATIR and metabolic parameters, participants were divided into three groups (Low, Medium, and High) according to ATIR level. Body composition examination, oral glucose tolerance testing, and blood biochemical analysis were performed; Adipo-IR and the Matsuda index were used as indices of ATIR and systemic insulin sensitivity, respectively.
Results: Participants in the High ATIR group had the highest prevalence of IGT (25%), and significantly higher body fat percentage, whole-body insulin resistance, and levels of insulin-like growth factor-1 and dehydroepiandrosterone sulfate (DHEA-S) than the other two groups. They were also significantly younger and had higher systolic blood pressure than the Low ATIR group. Multiple regression analysis showed that DHEA-S, which is known to enhance lipolysis in adipose tissue, was an independent correlate of ATIR.
Conclusions: Underweight Japanese women with high ATIR had impaired metabolism, a higher prevalence of IGT, higher systemic insulin resistance, and higher systolic blood pressure. DHEA-S was a determinant of high ATIR levels.

Keywords:  adipose tissue insulin resistance; dehydroepiandrosterone-sulfate; impaired glucose tolerance; metabolic abnormality; underweight young women

DOI:  https://doi.org/10.3389/fendo.2024.1390778
Acta Endocrinol (Buchar). 2024 Jan-Mar;20(1):20(1): 51-58

VARIATIONS OF SERUM DEHYDROEPIANDROSTERONE-SULPHATE (DHEAS) LEVEL WITH PREGNANCY, FERTILITY, ABORTION, OVARIAN RESERVE AND ENDOTHELIAL FUNCTIONS.

H Düğeroğlu, N Özer, M Öztürk.

   Objectives: It was aimed to evaluate the relationship of Dehydroepiandrosterone-sulphate(DHEAS) level with pregnancy, fertility, abortion, ovarian reserve and endothelial functions.
Patients and Method: Ninety-six fertile women aged 20-35 years whose DHEAS levels were measured and 28 women aged 40-55 years with oligomenorrhea-amenorrhea were included in the study.The DHEAS values of the patients,which were measured at least 12 months apart,were recorded.
Results: The first measured mean DHEAS level was 208.34±119.7ug/dL and the last measured mean DHEAS level was 187.5±101.7ug/dL. Among 28 patients with oligomenorrhea-amenorrhea, the levels of DHEAS increased in 10 patients and decreased in 18 patients. Although the annual decrease in DHEAS levels was greater in those who had pregnancy than in those who had not given birth, the difference was not statistically significant (p=0.085). Although the initial DHEAS level in 5 patients who had an abortion was higher than in those who did not have an abortion, the difference was not statistically significant (p=0.427). The increase in systolic blood pressure was statistically significant in patients with decreased DHEAS levels (p=0.03). While the mean DHEAS level was 85.3±47.3ug/dL in menopausal patients, the DHEAS level was 82.1±49.2ug/dL in non-menopausal patients (p=0.435).
Conclusion: The age at which the DHEAS level reaches its peak level shows individual differences. While pregnancy slows down the decrease in DHEAS levels,abortion accelerates the decrease in DHEAS levels. A decrease in serum DHEAS levels can increase systolic blood pressure.

Keywords:  Dehydroepiandrosterone-sulphate; abortion menopause; fertility; hypertension; pregnancy

DOI:  https://doi.org/10.4183/aeb.2024.51
JCI Insight. 2024 Oct 10. pii: e171585. [Epub ahead of print]

Giantin mediates Golgi localization of Gal3-O-sulfotransferases and affects salivary mucin sulfation in Sjögren's disease patients.

Matilde Nuñez, Patricia Carvajal, Sergio Aguilera, María-José Barrera, Soledad Matus, Alicia Couto, Malena Landoni, Gaelle Boncompain, Sergio González, Claudio Molina, Karina Pino, Sebastián Indo, Lourdes Figueroa, María-Julieta González, Isabel Castro.

  Sjögren's disease is a chronic autoimmune disease characterized by symptoms of oral and ocular dryness and extra-glandular manifestations. Mouth dryness is not only due to reduced saliva volume but also to alterations in the quality of salivary mucins in these patients. Mucins play a leading role in mucosa hydration and protection, where sulfated and sialylated oligosaccharides retain water molecules at the epithelial surface. The correct localization of glycosyltransferases and sulfotransferases within the Golgi apparatus determines adequate O-glycosylation and sulfation of mucins, which depends on specific golgins that tether enzyme-bearing vesicles. Here, we show that a golgin called Giantin is mislocalized in salivary glands from patients with Sjögren's disease and forms protein complexes with Gal3-O-sulfotransferases (Gal3STs), which change their localization in Giantin knockout and knockdown cells. Our results suggest that Giantin could tether Gal3ST-bearing vesicles and that its altered localization could affect Gal3ST activity, explaining the decreased sulfation of MUC5B observed in salivary glands from patients with Sjögren's disease.

Keywords:  Autoimmune diseases; Autoimmunity; Cell biology; Glycobiology; Protein traffic

DOI:  https://doi.org/10.1172/jci.insight.171585