bims-supasi Biomed News
on Sulfation pathways and signalling
Issue of 2024–12–22
thirteen papers selected by
Jonathan Wolf Mueller, University of Birmingham
  1. Synthesis of S-Glycoside Building Blocks as Mimetics of the Repeating d-GlcN-α-1,4-d-GlcA Heparan Sulfate Disaccharide.
  2. Inhibition of sulfated glycans on the binding of dengue virus envelope protein to heparin.
  3. Elucidating the Mechanism of Recognition and Binding of Heparin to Amyloid Fibrils of Serum Amyloid A.
  4. A Heparan Sulfate Mimetic RAFT Copolymer Inhibits SARS-CoV-2 Infection and Ameliorates Viral-Induced Inflammation.
  5. Shark chondroitin sulfate gold nanoparticles: A biocompatible apoptotic agent for osteosarcoma.
  6. Ameliorated delivery of Amphotericin B to Macrophages using Chondroitin Sulfate Surface-Modified Liposome Nanoparticles.
  7. Syndecan-1: a key player in health and disease.
  8. Whole exome sequencing reveals heparan sulfate proteoglycan 2 (HSPG2) as a potential causative gene for kidney stone disease in a Thai family.
  9. Structure and Biosynthetic Gene Cluster of Sulfated Capsular Polysaccharide from the Marine Bacterium Vibrio sp. KMM 8419.
  10. Steroid hormone concentrations in dried blood spots: A comparison between capillary and venous blood samples.
  11. Catalysts for sulfur: understanding the intricacies of enzymes orchestrating plant sulfur anabolism.
  12. Association of hormone profile with various respiratory disorders in sulfur mustard-chemical veterans.
  13. Differential Methylation of CYP11B1 in Girls with High DHEAS Levels and correlation with 11-Oxyandrogen levels: a pilot study.
  1. Molecules. 2024 Dec 09. pii: 5809. [Epub ahead of print]29(23):
    Synthesis of S-Glycoside Building Blocks as Mimetics of the Repeating d-GlcN-α-1,4-d-GlcA Heparan Sulfate Disaccharide.
    Conor O'Shea, Gavin J Miller.
      Heparan sulfate (HS), a sulfated linear carbohydrate that decorates the cell surface and extracellular matrix, is a key regulator of biological processes. Owing to the inherent structural complexity of HS, structure-to-function studies with its ligands are required, and materials to improve the understanding of such interactions are therefore of high importance. Herein, the synthesis of novel S-linked GlcN-α(1→4)-GlcA disaccharide building blocks is detailed. Initial attempts at constructing the desired disaccharide using d-GlcN donors and d-Glc/GlcA acceptors via an S-glycosylation failed. Reversing the reactivity polarity of the monosaccharide building blocks enabled successful SN2 coupling using α-d-GlcN thiohemiacetals and d-galactosyl triflates. Subsequent C6-oxidation furnished the desired S-linked GlcN-α(1→4)-GlcA disaccharide building blocks on a gram scale. Such disaccharides offer potential for incorporation into wider synthetic HS sequences to provide glycomimetic tools.
    Keywords:  S-glycoside; glycosylation; heparan sulfate; mimetic; substitution
    DOI:  https://doi.org/10.3390/molecules29235809
  2. Glycoconj J. 2024 Dec 16.
    Inhibition of sulfated glycans on the binding of dengue virus envelope protein to heparin.
    Jiyuan Yang, Payel Datta, Ke Xia, Vitor H Pomin, Chunyu Wang, Mingqiang Qiao, Robert J Linhardt, Jonathan S Dordick, Fuming Zhang.
      Dengue viruses (DENV) are transmitted to humans through mosquito bites and infect millions globally. DENV uses heparan sulfate (HS) for attachment and cell entry by binding the envelope protein to highly sulfated HS on target cells. Therefore, inhibiting the binding between DENV and HS could be a promising strategy for preventing DENV infection. In the current study, the interactions between DENV envelope protein (from Type 2 DENV) and heparin (a surrogate for HS) were analyzed using competition solution SPR. Results demonstrate that heparin binds to DENV envelope protein with high affinity (KD = 8.83 nM). Competitive Solution SPR assays using surface-immobilized heparin and a series of naturally-sourced and semi-synthetic sulfated glycans demonstrated significant inhibitory activity against the binding of DENV envelope proteins to heparin. This study of molecular interactions could provide insights into the development of therapeutics for DENV infection.
    Keywords:  Dengue virus; Heparin; Marine Sourced glycans; Sulfated glycans; Surface plasmon resonance
    DOI:  https://doi.org/10.1007/s10719-024-10172-9
  3. Biochemistry. 2024 Dec 17.
    Elucidating the Mechanism of Recognition and Binding of Heparin to Amyloid Fibrils of Serum Amyloid A.
    Conor B Abraham, Emily Lewkowicz, Olga Gursky, John E Straub.
      Amyloid diseases feature pathologic deposition of normally soluble proteins and peptides as insoluble fibrils in vital organs. Amyloid fibrils co-deposit with various nonfibrillar components including heparan sulfate (HS), a glycosaminoglycan that promotes amyloid formation in vitro for many unrelated proteins. HS-amyloid interactions have been proposed as a therapeutic target for inflammation-linked amyloidosis wherein N-terminal fragments of serum amyloid A (SAA) protein deposit in the kidney and liver. The structural basis for these interactions is unclear. Here, we exploit the high-resolution cryoelectron microscopy (cryo-EM) structures of ex vivo murine and human SAA fibrils in a computational study employing molecular docking, Brownian dynamics simulations, and molecular dynamics simulations to elucidate how heparin, a highly sulfated HS mimetic, recognizes and binds to amyloid protein fibrils. Our results demonstrate that negatively charged heparin chains bind to linear arrays of uncompensated positively charged basic residues along the spines of amyloid fibrils facilitated by electrostatic steering. The predicted heparin binding sites match the location of unidentified densities observed in cryo-EM maps of SAA amyloids, suggesting that these extra densities represent bound HS. Since HS is constitutively found in various amyloid deposits, our results suggest a common mechanism for HS-amyloid recognition and binding.
    DOI:  https://doi.org/10.1021/acs.biochem.4c00529
  4. Adv Sci (Weinh). 2024 Dec 16. e2411737
    A Heparan Sulfate Mimetic RAFT Copolymer Inhibits SARS-CoV-2 Infection and Ameliorates Viral-Induced Inflammation.
    Jiaxin Ling, Åke Lundkvist, Marco Guerrini, Vito Ferro, Jin-Ping Li, Jinlin Li.
      The high transmissibility and mutation ability of coronaviruses enable them to easily escape existing immune protection and also pose a challenge to existing antiviral drugs. Moreover, drugs only targeting viruses cannot always attenuate the "cytokine storm". Herein, a synthetic heparan sulfate (HS) mimetic, HMSA-06 is reported, that exhibited antiviral activities against both the SARS-CoV-2 prototype and Omicron strains by targeting viral entry and replication. Of particular note, HMSA-06 demonstrated more potent anti-SARS-CoV-2 effects than PG545 and Roneparstat. SARS-CoV-2 is reported to hijack autophagy to facilitate its replication, therefore boosting autophagy can attenuate SARS-CoV-2 infection. It is revealed that HMSA-06, but not a similar HS mimetic that failed to inhibit SARS-CoV-2, can upregulate cellular autophagy flux. In addition, HMSA-06 was found to robustly block the NLRP3-mediated inflammatory reaction in SARS-CoV-2 infected THP-1 derived macrophages as evidenced by a reduction in inflammasome formation and the subsequent decreased secretion of mature caspase-1 and IL-1β. The HMSA-06's inflammation inhibitory function is further confirmed using a LPS/ATP-stimulated THP-1 macrophage model. Altogether, this study has identified a promising HS mimetic to combat SARS-CoV-2-associated diseases by inhibiting viral infection and attenuating viral-induced inflammatory reaction, providing insights into the development of novel anti-coronavirus drugs in the future.
    Keywords:  NLRP3; SARS‐CoV‐2; coronavirus; heparan sulfate mimetics; poly(SS‐co‐AA)
    DOI:  https://doi.org/10.1002/advs.202411737
  5. Int J Biol Macromol. 2024 Dec 15. pii: S0141-8130(24)09604-1. [Epub ahead of print] 138793
    Shark chondroitin sulfate gold nanoparticles: A biocompatible apoptotic agent for osteosarcoma.
    Sekar Vijayakumar, Zaira I González-Sánchez, Mohammed Amanullah, Jegatheeswaran Sonamuthu, Mangaiyarkarasi Rajkumar, Mani Divya, Esteban F Durán-Lara, Mingchun Li.
      Osteosarcoma is a highly aggressive tumor that originates in the bone and often infiltrates nearby bone cells. It is the most prevalent type of primary bone cancer among the various bone malignancies. Traditional cancer treatment methods such as surgery, chemotherapy, immunotherapy, and radiotherapy have had restricted success. However, the integration of nanotechnology into cancer research has led to notable progress. One promising area is the use of marine-derived polysaccharide-based nano formulations for treating various human diseases, including cancer. This study presents a straightforward method for synthesizing biocompatible gold nanoparticles (AuNPs), utilizing sodium borohydride as a reducing agent and a cost-effective, water-soluble chondroitin sulfate (CS) derived from shark cartilage as a stabilizing agent. The synthesized CS-Au NPs appeared purple and were mainly spherical, with 40.768 nm of average size. Cytotoxicity assays (MTT) indicated that CS-Au NPs significantly reduced the viability of human osteosarcoma cells (MG63) at 100 μg/mL, while it showed no cytotoxic effects on mouse embryonic fibroblast cells (NIH3T3) at the same concentration. The observed toxicity of the CS-Au NPs was linked to a rise in the production of reactive oxygen species (ROS) within damaged mitochondria. ROS generation and changes in mitochondrial membrane potential were detected in MG63 cells treated with CS-Au NPs. Furthermore, apoptotic analysis through ethidium bromide dual staining and flow cytometry demonstrated that CS-Au NPs at higher concentrations significantly increased the amount of apoptotic cells, as demonstrated by acridine orange/ethidium bromide staining. Flow cytometry also confirmed that CS-Au NPs activated the apoptotic pathway in MG63 cells.
    Keywords:  Chondroitin sulphate; Cytotoxicity; Flow cytometry; Gold nanoparticles; Osteosarcoma; ROS
    DOI:  https://doi.org/10.1016/j.ijbiomac.2024.138793
  6. Drug Dev Ind Pharm. 2024 Dec 16. 1-17
    Ameliorated delivery of Amphotericin B to Macrophages using Chondroitin Sulfate Surface-Modified Liposome Nanoparticles.
    Marium Azim, Saeed A Khan, Nashwa Osman, Sajid K Sadozai, Iftikhar Khan.
       BACKGROUND: The neglected tropical disease leishmaniasis has significant adverse effects from current treatments and limited therapeutic options are currently available.
    OBJECTIVE: The aim of this study was to develop a surface-modified nano-liposomal drug delivery system, anchored with chondroitin sulfate (CS), to effectively transport Amphotericin B (AmB) to macrophages.
    METHODS: Conventional liposome formulations (CL-F) and CS-coated surface-modified liposome formulations (CS-SML-F) were formulated by the thin film hydration method and characterized for particle size, polydispersity index (PDI), zeta potential and entrapment efficiency with long-term stability. In-vitro drug release using simulation medium, deformability index (DI) by using a polycarbonate membrane, and cell uptake studies among murine macrophages via flow cytometry were analyzed. Scanning and transmission electron microscopy were used to study the surface morphology and shape of the particles.
    RESULTS: Optimized conventional liposome CL-F6, CL-F9 and surface-modified liposomes CS-SML-F6 and CS-SML-F9 exhibited particle size diameters around 280 nm with a PDI of approximately 0.3 over six months of storage at 5 °C, maintaining stable surface charge (circa -30 mV). Sustained drug release peaked between 4 and 12 hours and surface morphology showed a uniform distribution of spherical liposome particles. Cell uptake measured by flow cytometry showed the highest rate of macrophage targeting by the CS-SML-Fs.
    CONCLUSION: These findings have demonstrated that CS surface-modification has enhanced nanoparticle targeting to macrophage binding sites, particularly the cysteine-rich domain, potentially advancing macrophage-targeted drug delivery systems.
    Keywords:  Amphotericin B; Leishmania tropica; Leishmaniasis; Liposome; Macrophages; Surface-modification
    DOI:  https://doi.org/10.1080/03639045.2024.2443007
  7. Immunogenetics. 2024 Dec 17. 77(1): 9
    Syndecan-1: a key player in health and disease.
    Lara Diab, Sahar Al Kattar, Naim Oueini, Jihad Hawi, Antoine Chrabieh, Laura Dosh, Rosalyn Jurjus, Angelo Leone, Abdo Jurjus.
      Syndecan-1 (SDC-1) is a transmembrane protein localized on the basolateral surface of epithelial cells, encompassing a core protein with heparin sulfate and chondroitin sulfate glycosaminoglycan side chains. SDC-1 is involved in a panoply of cellular mechanisms including cell-to-cell adhesion, extracellular matrix interactions, cell cycle modulation, and lipid clearance. Alterations in the expression and function of SDC-1 are implicated in numerous disease entities, making it an attractive diagnostic and therapeutic target. However, despite its broad involvement in several disease processes, the underlying mechanism contributing to its diverse functions, pathogenesis, and therapeutic uses remains underexplored. Therefore, this review examines the role of SDC-1 in health and disease, focusing on liver pathologies, inflammatory diseases, infectious diseases, and cancer, and sheds light on SDC-1-based therapeutic approaches. Moreover, it delves into the mechanisms through which SDC-1 contributes to these diseases, emphasizing cell-type specific mechanisms. By comprehensively summarizing the significance of SDC-1, its association with several diseases, and its underlying mechanisms of action, the findings of this review could inform future research directions toward the development of targeted therapies and early diagnosis for a multitude of disease entities.
    Keywords:  Cancer; Infectious disease; Inflammation; Liver disease; Syndecan-1; Therapy
    DOI:  https://doi.org/10.1007/s00251-024-01366-4
  8. Urolithiasis. 2024 Dec 16. 53(1): 7
    Whole exome sequencing reveals heparan sulfate proteoglycan 2 (HSPG2) as a potential causative gene for kidney stone disease in a Thai family.
    Oranud Praditsap, Nawara Faiza Ahsan, Choochai Nettuwakul, Nunghathai Sawasdee, Suchai Sritippayawan, Pa-Thai Yenchitsomanus, Nanyawan Rungroj.
      Kidney stone disease (KSD) is a prevalent and complex condition, with an incidence of 85 cases per 100,000 individuals in Thailand. Notably, over 40% of cases are concentrated in the northeastern region, indicating a potential genetic influence, which is supported by genetic mutations reported in several families by our research group. Despite this, the genetic basis of KSD remains largely unknown for many Thai families. This study aimed to identify the genetic mutation responsible for KSD in a specific Thai family, the UBRS131 family, which includes four affected individuals. Whole exome sequencing was performed, and variant filtering using the VarCards2 program identified 10 potentially causative mutations across 9 genes. These mutations were subjected to segregation analysis among family members and screened in 180 control and 179 case samples using real-time PCR-HRM or PCR-RFLP techniques. Prioritization of these variants using GeneDistiller identified the p.Asp775Glu mutation in the heparan sulfate proteoglycan 2 (HSPG2) gene as the likely causative mutation for KSD in this family. The Asp775 residue is highly conserved across vertebrates, and structural analysis suggests that the Glu775 substitution may disrupt the formation of two crucial hydrogen bonds, potentially altering the mutant protein's configuration. Immunohistochemistry confirmed the presence of perlecan (HSPG2 protein) in the proximal tubules in nephrons. These findings highlight the significant role of the HSPG2 gene in familial KSD within this study family.
    Keywords:   HSPG2 ; Heparan sulfate proteoglycan 2 ; Kidney stone disease; Whole exome sequencing
    DOI:  https://doi.org/10.1007/s00240-024-01674-0
  9. Int J Mol Sci. 2024 Dec 01. pii: 12927. [Epub ahead of print]25(23):
    Structure and Biosynthetic Gene Cluster of Sulfated Capsular Polysaccharide from the Marine Bacterium Vibrio sp. KMM 8419.
    Maxim S Kokoulin, Yulia V Savicheva, Nadezhda Y Otstavnykh, Valeria V Kurilenko, Dmitry A Meleshko, Marina P Isaeva.
      Vibrio sp. KMM 8419 (=CB1-14) is a Gram-negative bacterium isolated from a food-net mucus sample of marine polychaete Chaetopterus cautus collected in the Sea of Japan. Here, we report the structure and biosynthetic gene cluster of the capsular polysaccharide (CPS) from strain KMM 8419. The CPS was isolated and studied by one- and two-dimensional 1H and 13C nuclear magnetic resonance (NMR) spectroscopy. The molecular weight of the CPS was about 254 kDa. The CPS consisted of disaccharide repeating units of D-glucose and sulfated and acetylated L-rhamnose established as →2)-α-L-Rhap3S4Ac-(1→6)-α-D-Glcp-(1→. To identify the genes responsible for CPS biosynthesis, whole-genome sequencing of KMM 8419 was carried out. Based on the genome annotations together with the Interproscan, UniProt and AntiSMASH results, a CPS-related gene cluster of 80 genes was found on chromosome 1. This cluster contained sets of genes encoding for the nucleotide sugar biosynthesis (UDP-Glc and dTDP-Rha), assembly (glycosyltransferases (GT)), transport (ABC transporter) and sulfation (PAPS biosynthesis and sulfotransferases) of the sulfated CPS. A hypothetical model for the assembly and transportation of the sulfated CPS was also proposed. In addition, this locus included genes for O-antigen biosynthesis. Further studies of biological activity, the structure-activity relationship in the new sulfated polysaccharide and its biosynthesis are necessary for the development of potent anticancer agents or drug delivery systems.
    Keywords:  NMR; Vibrio sp. KMM 8419; biosynthetic gene cluster; genome; marine bacteria; sulfated capsular polysaccharide
    DOI:  https://doi.org/10.3390/ijms252312927
  10. Clin Chim Acta. 2024 Dec 17. pii: S0009-8981(24)02352-0. [Epub ahead of print] 120099
    Steroid hormone concentrations in dried blood spots: A comparison between capillary and venous blood samples.
    Anouk Olthof, Vera H de Kleijne, Anita Boelen, Annemieke C Heijboer.
       BACKGROUND: An important aspect of the shift towards dried blood spots (DBS) as a sample matrix for laboratory measurements, is the availability of robust liquid chromatography-tandem mass spectrometry (LC-MS/MS) methods that can reliably quantify analyte concentrations in DBS. The development and validation of these LC-MS/MS methods, however, concerns an extensive process, for which large amounts of DBS samples are required. DBS are usually obtained from capillary blood samples, but they can also be prepared from venous (residual) blood samples, which are widely available in clinical laboratories. Therefore, we aimed to determine whether DBS prepared from (residual) venous blood samples, collected in EDTA blood tubes, can be used for future development and validation of LC-MS/MS methods to quantify steroid hormones in DBS.
    METHODS: Capillary DBS and venous blood samples (EDTA tube and tube without additives) were collected from twenty healthy volunteers (12F/8M). From both venous blood samples, DBS were prepared volumetrically. Samples were analyzed using in-house developed LC-MS/MS methods for testosterone, androstenedione, 17-hydroxyprogesterone (17-OHP), cortisol, cortisone, corticosterone, and for dehydroepiandrosterone sulfate (DHEA-S).
    RESULTS: DBS made from venous blood collected in EDTA tubes compared with capillary blood showed a correlation coefficient of ≥ 0.89 for all steroid hormones except corticosterone (0.67). DBS made from venous blood collected in tubes without additives showed a strong correlation with both DBS made from venous blood collected in EDTA tubes (≥0.97 for all steroid hormones) and capillary DBS (>0.90) except corticosterone (0.64).
    CONCLUSION: DBS prepared from (residual) venous blood collected in EDTA blood tubes can be used for future development and validation of LC-MS/MS methods to quantify steroid hormones, except for corticosterone, in capillary DBS.
    Keywords:  Androgens; Corticosteroids; DBS; Dried blood spots; LC-MS/MS; Sample matrices
    DOI:  https://doi.org/10.1016/j.cca.2024.120099
  11. Planta. 2024 Dec 17. 261(1): 16
    Catalysts for sulfur: understanding the intricacies of enzymes orchestrating plant sulfur anabolism.
    Ziyue Xu, Dun Liu, Jiadong Zhu, Jiayi Zhao, Shenghai Shen, Yueduo Wang, Pei Yu.
       MAIN CONCLUSION: This review highlights the sulfur transporters, key enzymes and their encoding genes involved in plant sulfur anabolism, focusing on their occurrence, chemistry, location, function, and regulation within sulfur assimilation pathways. Sulfur, a vital element for plant life, plays diverse roles in metabolism and stress response. This review provides a comprehensive overview of the sulfur assimilation pathway in plants, highlighting the intricate network of enzymes and their regulatory mechanisms. The primary focus is on the key enzymes involved: ATP sulfurylase (ATPS), APS reductase (APR), sulfite reductase (SiR), serine acetyltransferase (SAT), and O-acetylserine(thiol)lyase (OAS-TL). ATPS initiates the process by activating sulfate to form APS, which is then reduced to sulfite by APR. SiR further reduces sulfite to sulfide, a crucial step that requires significant energy. The cysteine synthase complex (CSC), formed by SAT and OAS-TL, facilitates the synthesis of cysteine, thereby integrating serine metabolism with sulfur assimilation. The alternative sulfation pathway, catalyzed by APS kinase and sulfotransferases, is explored for its role in synthesizing essential secondary metabolites. This review also delves into the regulatory mechanism of these enzymes such as environmental stresses, sulfate availability, phytohormones, as well as translational and post-translational regulations. Understanding the key transporters and enzymes in sulfur assimilation pathways and their corresponding regulation mechanisms can help researchers grasp the importance of sulfur anabolism for the life cycle of plants, clarify how these enzymes and their regulatory processes are integrated to balance plant life systems in response to changes in both external conditions and intrinsic signals.
    Keywords:  Cellular location; Enzymatic function; Key enzymes; Regulation; Sulfur; Sulfur assimilation pathway
    DOI:  https://doi.org/10.1007/s00425-024-04594-w
  12. Int Immunopharmacol. 2024 Dec 16. pii: S1567-5769(24)02369-5. [Epub ahead of print]146 113847
    Association of hormone profile with various respiratory disorders in sulfur mustard-chemical veterans.
    Nayere Askari, Leila Nasiri, Hossein Hassanpour, Mohammad-Reza Vaez-Mahdavi, Sussan Kaboudanian Ardestani, Mohammad-Reza Soroush, Shahryar Poorfarzam, Davood Jamali, Mahdieh Taghvaei, Tooba Ghazanfari.
       BACKGROUNDS: Chronic respiratory complications such as asthma, bronchiolitis obliterans, and chronic bronchitis are prevalent among individuals exposed to sulfur mustard (SM). This study investigates the hormonal changes associated with SM-induced respiratory disorders.
    METHODS: A cross-sectional analysis was conducted involving 276 male participants exposed to SM during the Iraq-Iran war and 64 healthy controls. Serum levels of various hormones were measured.
    RESULTS: Testosterone, dehydroepiandrosterone sulfate (DHEA-S), luteinizing hormone (LH), DHEA-S/cortisol ratio, and DHEA-S/prolactin ratio were decreased in the SM-exposed group compared to the control group while prolactin level and prolactin/cortisol ratio were increased (P < 0.05). The prolactin was increased in bronchiolitis obliterans, chronic bronchitis, and asthma compared to the control group while DHEA-S and DHEA-S/prolactin ratio were decreased in those disorders (P < 0.05). The testosterone was only decreased in asthma, and DHEA-S/cortisol ratio was only decreased in bronchiolitis obliterans and chronic bronchitis compared to control and other disorders (P < 0.05). The principle component analysis showed that the DHEA-S/cortisol and testosterone/cortisol ratios had the most contributing to interpatient variation in total SM-exposed patients in the principle component 1 (PC1). In patients with asthma and bronchiolitis obliterans, prolactin/cortisol and testosterone/cortisol ratios had the most contributing in PC1 while in patients with chronic bronchitis, the DHEA-S/cortisol and testosterone/cortisol ratios had the most contributing.
    CONCLUSION: Hormones including testosterone, prolactin, and DHEA-S or their ratios (DHEA-S/cortisol and DHEA-S/prolactin ratios) had the most alterations as delayed effects of sulfur mustard. Also, DHEA-S/cortisol, DHEA-S/prolactin, testosterone/cortisol, and prolactin/cortisol had the most contributing in changes of hormone profile for SM-induced pulmonary disorders. These data may suggest the best parameters for evaluating of hormone profile of SM-exposed people.
    Keywords:  Asthma; Bronchiolitis obliterans; Chronic bronchitis; Hormone profile; Sulfur mustard
    DOI:  https://doi.org/10.1016/j.intimp.2024.113847
  13. Horm Res Paediatr. 2024 Dec 13. 1-17
    Differential Methylation of CYP11B1 in Girls with High DHEAS Levels and correlation with 11-Oxyandrogen levels: a pilot study.
    Fernando Rodríguez, Diana Ponce, José Patricio Miranda, José L Santos, Gordon B Cutler, Ana Pereira, Esteban Barnafi, Germán Iñiguez, Verónica Mericq.
       INTRODUCTION: Premature adrenarche in girls is defined biochemically by an increase in adrenal androgen (DHEAS) levels above the age-specific reference range before age 8 years. Recently, increased levels of 11-oxyandrogens have also been reported in girls with premature adrenarche. Epigenetic modifications, specifically CpG methylation, may affect gene expression and/or activity of steroidogenic enzymes during developmental changes in adrenal androgen secretion.
    OBJECTIVE: To determine whether circulating 11-oxyandrogen levels in post-menarcheal girls are associated with methylation status of genes involved in 11-oxyandrogen steroidogenesis.
    METHODS: Ninety-seven healthy girls followed since the age of 3 years were classified, according to DHEAS serum concentration at age 6-7 years, as normal DHEAS (<42μg/dL [75th percentile for population]) or high DHEAS (≥42μg/dL). At Tanner stage 2, methylation status of CpG sites located in CYP11B1 and HSD11B2 genes were analyzed in genomic DNA from peripheral blood leukocytes by Melting Curve Analysis Methylation assay. Eleven-oxyandrogen concentrations were assessed at four years post menarche.
    RESULTS: Significantly lower methylation levels were detected in the CYP11B1 gene in girls with high versus normal serum DHEAS levels, with no differences found in HSD11B2 gene. Additionally, CYP11B1 methylation status correlated inversely with 11β-hydroxy-androstenedione and 11-ketotestosterone levels. Furthermore, CYP11B1 methylation in the full cohort correlated inversely with insulin concentration at Tanner 1 and with BMI at Tanner stage 1 and 2.
    CONCLUSION: This pilot study proposes the hypothesis that a lower methylation of CYP11B1 may be a mechanism contributing to increased concentrations of 11-oxyandrogens in premature adrenarche and its associated metabolic risk.
    DOI:  https://doi.org/10.1159/000542963
This page is being maintained by Thomas Krichel. It was last updated on 2024‒12‒22 at 11:17.