bims-supasi Biomed News
on Sulfation pathways and signalling
Issue of 2022–10–09
eightteen papers selected by
Jonathan Wolf Mueller, University of Birmingham
  1. Glycosyltransferases EXTL2 and EXTL3 cellular balance dictates Heparan Sulfate biosynthesis and shapes gastric cancer cell motility and invasion.
  2. Interactions of marine sulfated glycans with antithrombin and platelet factor 4.
  3. Molecular insights into the self-assembly of hydrophobically modified chondroitin sulfate in aqueous media.
  4. Polymers Inspired by Heparin and Heparan Sulfate for Viral Targeting.
  5. Investigation of radical scavenging effects of acetaminophen, p-aminophenol and their O-sulfated conjugates.
  6. Biomaterials and Tissue Engineering Approaches using Glycosaminoglycans for Tissue Repair: Lessons Learned from the Native Extracellular Matrix.
  7. Expedient Synthesis of a Library of Heparan Sulfate-Like "Head-to-Tail" Linked Multimers for Structure and Activity Relationship Studies.
  8. Longitudinal evaluation of dehydroepiandrosterone (DHEA), its sulfated form and estradiol with cancer-related cognitive impairment in early-stage breast cancer patients receiving chemotherapy.
  9. Computationally guided conversion of the specificity of E-selectin to mimic that of Siglec-8.
  10. Engineering Pseudomonas aeruginosa arylsulfatase for hydrolysis of α-configured steroid sulfates.
  11. Glycan Modulation of Insulin-like Growth Factor-1 Receptor.
  12. Calcium dobesilate reduces SARS-CoV-2 entry into endothelial cells by inhibiting virus binding to heparan sulfate.
  13. Dehydroepiandrosterone supplementation results in varying tissue-specific levels of dihydrotestosterone in male mice.
  14. Changes in serum testosterone and adrenal androgen levels in transgender women with and without gonadectomy.
  15. Polypseudorotaxane hydrogel based on Tween 80 and α-cyclodextrin for sustained delivery of low molecular weight heparin.
  16. Sulfotransferases (SULTs), enzymatic and genetic variation in Carnivora: Limited sulfation capacity in pinnipeds.
  17. Sulfated Galactofucan from Sargassum Thunbergii Attenuates Atherosclerosis by Suppressing Inflammation Via the TLR4/MyD88/NF-κB Signaling Pathway.
  18. OAT, OATP, and MRP Drug Transporters and the Remote Sensing and Signaling Theory.
  1. J Biol Chem. 2022 Sep 28. pii: S0021-9258(22)00990-5. [Epub ahead of print] 102546
    Glycosyltransferases EXTL2 and EXTL3 cellular balance dictates Heparan Sulfate biosynthesis and shapes gastric cancer cell motility and invasion.
    Catarina Marques, Juliana Poças, Catarina Gomes, Isabel Faria-Ramos, Celso A Reis, Romain R Vivès, Ana Magalhães.
      Heparan Sulfate Proteoglycans (HSPGs) are abundant glycoconjugates in cells' glycocalyx and Extracellular Matrix (ECM). By acting as scaffolds for protein-protein interactions, HSPGs modulate extracellular ligand gradients, cell signaling networks, and cell-ECM crosstalk. Aberrant expression of HSPGs and enzymes involved in HSPG biosynthesis and processing has been reported in tumors, with impact in cancer cell behavior and tumor microenvironment properties. However, the roles of specific glycosyltransferases in the deregulated biosynthesis of HSPGs are not fully understood. In this study, we established glycoengineered gastric cancer cell models lacking either Exostosin Like glycosyltransferase 2 (EXTL2) or EXTL3, and revealed their regulatory roles in both Heparan Sulfate (HS) and Chondroitin Sulfate (CS) biosynthesis and structural features. We showed that EXTL3 is key for initiating the synthesis of HS chains in detriment of CS biosynthesis, intervening in the fine-tuned balance of the HS/CS ratio in cells, while EXTL2 functions as a negative regulator of HS biosynthesis, with impact over the glycoproteome of gastric cancer cells. We demonstrated that knock-out of EXTL2 enhanced HS levels along with concomitant upregulation of Syndecan-4, which is a major cell-surface carrier of HS. This aberrant HS expression profile promoted a more aggressive phenotype, characterized by higher cellular motility and invasion, and impaired activation of Ephrin type-A 4 cell surface receptor tyrosine kinase. Our findings uncover the biosynthetic roles of EXTL2 and EXTL3 in the regulation of cancer cell GAGosylation and proteoglycans expression, and unravel the functional consequences of aberrant HS/CS balance in cellular malignant features.
    Keywords:  Cancer cell invasion; Chondroitin sulfate; Exostosin Like 2 glycosyltransferase; Exostosin Like 3 glycosyltransferase; Gastric cancer; Glycosaminoglycans; Heparan sulfate
    DOI:  https://doi.org/10.1016/j.jbc.2022.102546
  2. Front Mol Biosci. 2022 ;9 954752
    Interactions of marine sulfated glycans with antithrombin and platelet factor 4.
    Wenjing Zhang, Weihua Jin, Vitor H Pomin, Fuming Zhang, Robert J Linhardt.
      The molecular interactions of sulfated glycans, such as heparin, with antithrombin (AT) and platelet factor 4 (PF4) are essential for certain biological events such as anticoagulation and heparin induced thrombocytopenia (HIT). In this study, a library including 84 sulfated glycans (polymers and oligomers) extracted from marine algae along with several animal-originated polysaccharides were subjected to a structure-activity relationship (SAR) study regarding their specific molecular interactions with AT and PF4 using surface plasmon resonance. In this SAR study, multiple characteristics were considered including different algal species, different methods of extraction, molecular weight, monosaccharide composition, sulfate content and pattern and branching vs. linear chains. These factors were found to influence the binding affinity of the studied glycans with AT. Many polysaccharides showed stronger binding than the low molecular weight heparin (e.g., enoxaparin). Fourteen polysaccharides with strong AT-binding affinities were selected to further investigate their binding affinity with PF4. Eleven of these polysaccharides showed strong binding to PF4. It was observed that the types of monosaccharides, molecular weight and branching are not very essential particularly when these polysaccharides are oversulfated. The sulfation levels and sulfation patterns are, on the other hand, the primary contribution to strong AT and PF4 interaction.
    Keywords:  antithrombin; carbohydrate-protein interactions; heparin; platelet factor 4; sulfated glycans; surface plasmon resonance
    DOI:  https://doi.org/10.3389/fmolb.2022.954752
  3. Carbohydr Polym. 2022 Dec 01. pii: S0144-8617(22)00904-3. [Epub ahead of print]297 119999
    Molecular insights into the self-assembly of hydrophobically modified chondroitin sulfate in aqueous media.
    Agata Żak, Grzegorz Łazarski, Magdalena Wytrwal-Sarna, Dorota Jamróz, Magdalena Górniewicz, Aleksander Foryś, Barbara Trzebicka, Mariusz Kepczynski.
      Hydrophobically modified chondroitin sulfate (CS) is widely used in the preparation of nano-sized drug delivery systems. Herein, the behavior of amphiphilic CSs in aqueous media and the drug accumulation inside the formed micelle-like structures were studied using experimental methods and molecular dynamics simulations. In particular, we focused on the impact of the degree of substitution (DS) with hydrophobic groups and the presence of drug on the morphology of the nanostructures and their molecular organization. Our results show that with increasing DS, the morphology of the amphiphilic CS nanostructures changes from irregular, loosely packed nanogels to cylindrical micelles with a core-shell architecture. These structures can efficiently accumulate hydrophobic drugs. However, the drug molecules preferentially locate at the interface between the hydrophobic part and the hydrophilic corona formed by the CS chains. Our work provides detailed information that may be relevant to the development of amphiphilic polysaccharide-based drug delivery systems.
    Keywords:  Chondroitin sulfate; Chondroitin sulfate A (PubChem CID: 4368136); Curcumin; Curcumin (PubChem CID: 969516); Drug delivery; Molecular dynamics simulations; Octadecylamine (PubChem CID: 15793); Polymeric nanoparticles
    DOI:  https://doi.org/10.1016/j.carbpol.2022.119999
  4. Macromolecules. 2022 Sep 27. 55(18): 7957-7973
    Polymers Inspired by Heparin and Heparan Sulfate for Viral Targeting.
    Miriam Hoffmann, Nicole L Snyder, Laura Hartmann.
      Heparin (HP) and heparan sulfate (HS) are linear, anionically charged polysaccharides well-known for their diverse biological activities. While HP is generally localized in mast cells and in connective tissues, HS is part of the glycocalyx and involved in the attachment of viruses to host cells, constituting the first step of an infection. HP and HS also exhibit antiviral activity by blocking viral receptors, thereby inhibiting viruses from engaging with host cells. Inspired by their structural features, such as their high molecular weight and polyanionic character, various synthetic polymers mimicking HP/HS have been developed and used as model systems to study bioactivity, as well as for therapeutic applications. This Perspective provides an overview of the roles of HP/HS in viral engagement, and examines historical and recent approaches toward oligo-/polysaccharide, glycopolymer, and anionic polymer HP/HS mimetics. An overview of current applications and future prospects of these molecules is provided, demonstrating their potential in addressing current and future epidemics and pandemics.
    DOI:  https://doi.org/10.1021/acs.macromol.2c00675
  5. J Toxicol Sci. 2022 ;47(10): 421-428
    Investigation of radical scavenging effects of acetaminophen, p-aminophenol and their O-sulfated conjugates.
    Chihiro Morita, Yuki Tokunaga, Yuto Ueda, Masateru Ono, Hideki Kinoshita, Katsuhisa Kurogi, Yoichi Sakakibara, Masahito Suiko, Ming-Cheh Liu, Shin Yasuda.
      Acetaminophen (APAP) and p-aminophenol (p-AP) are the analogous simple phenolic compounds that undergo sulfate conjugation (sulfation) by cytosolic sulfotransferases. Sulfation is generally thought to lead to the inactivation and disposal of endogenous as well as xenobiotic compounds. This study aimed to investigate the antioxidative effects of O-sulfated form of APAP and p-AP, i.e., APAPS and p-APS, in comparison with their unsulfated counterparts. Using a 1,1-diphenyl-2-picrylhydrazyl radical scavenging assay, the antioxidant capacity of APAPS was shown to be approximately 126-times lower than that of APAP. In contrast, p-APS displayed comparable activity as unsulfated p-AP. Similar trends concerning the suppressive effects of these chemicals on cellular O2- radical generation were found using an activated granulocytic neutrophil cell model. Collectively, these results indicated that, depending on the presence of an additional "active site", sulfation may not always decrease the antioxidant activities of phenolic compounds.
    Keywords:  Acetaminophen; Aminophenol; Antioxidant activity; Free radical; Sulfate
    DOI:  https://doi.org/10.2131/jts.47.421
  6. Acta Biomater. 2022 Sep 28. pii: S1742-7061(22)00636-5. [Epub ahead of print]
    Biomaterials and Tissue Engineering Approaches using Glycosaminoglycans for Tissue Repair: Lessons Learned from the Native Extracellular Matrix.
    Roseline Menezes, Richard Vincent, Laura Osorno, Phillip Hu, Treena Livingston Arinzeh.
      Glycosaminoglycans (GAGs) are an important component of the extracellular matrix as they influence cell behavior and have been sought for tissue regeneration, biomaterials, and drug delivery applications. GAGs are known to interact with growth factors and other bioactive molecules and impact tissue mechanics. This review will provide an overview of native GAGs, their structure, and properties, specifically their interaction with proteins, their effect on cell behavior, and their mechanical role in the ECM. GAGs' function in the extracellular environment is still being understood however, promising studies have led to the development of medical devices and therapies. Native GAGs, including hyaluronic acid, chondroitin sulfate, and heparin, have been widely explored in tissue engineering and biomaterial approaches for tissue repair or replacement. This review will focus on orthopaedic and wound healing applications. The use of GAGs in these applications have had significant advances leading to clinical use. Promising studies using GAG mimetics and future directions will also be discussed. STATEMENT OF SIGNIFICANCE: Glycosaminoglycans (GAGs) are an important component of the native extracellular matrix and have shown promise in medical devices and therapies. This review emphasizes the structure and properties of native GAGs, their role in the ECM providing biochemical and mechanical cues that influence cell behavior, and their use in tissue regeneration and biomaterial approaches for orthopaedic and wound healing applications.
    Keywords:  Biomaterials; Extracellular Matrix; Glycosaminoglycans; Scaffolds; Tissue Engineering
    DOI:  https://doi.org/10.1016/j.actbio.2022.09.064
  7. Angew Chem Int Ed Engl. 2022 Oct 05.
    Expedient Synthesis of a Library of Heparan Sulfate-Like "Head-to-Tail" Linked Multimers for Structure and Activity Relationship Studies.
    Jicheng Zhang, Li Liang, Weizhun Yang, Sherif Ramadan, Kedar Baryal, Chang-Xin Huo, Jamie Bernard, Jian Liu, Linda Hsieh-Wilson, Fuming Zhang, Robert Linhardt, Xuefei Huang.
      Heparan sulfate (HS) plays important roles in many biological processes. The inherent complexity of naturally existing HS has severely hindered the thorough understanding of their structure-activity relationship. To facilitate biological studies, a new strategy has been developed to synthesize a HS-like pseudo-hexasaccharide library, where HS disaccharides were linked in a "head-to-tail" fashion from the reducing end of a disaccharide module to the non-reducing end of a neighboring module. Combinatorial syntheses of 27 HS-like pseudo-hexasaccharides were achieved. This new class of compounds bound with fibroblast growth factor 2 (FGF-2) with similar structure-activity trends as HS oligosaccharides bearing native glycosyl linkages. The ease of synthesis and the ability to mirror natural HS activity trends suggest that the new head-to-tail linked pseudo-oligosaccharides could be an exciting tool to facilitate the understanding of HS biology.
    Keywords:  heparan sulfate; library synthesis; mimetic design; structure and activity relationship
    DOI:  https://doi.org/10.1002/anie.202209730
  8. Sci Rep. 2022 Oct 03. 12(1): 16552
    Longitudinal evaluation of dehydroepiandrosterone (DHEA), its sulfated form and estradiol with cancer-related cognitive impairment in early-stage breast cancer patients receiving chemotherapy.
    Yi Long Toh, Chia Jie Tan, Ning Yi Yap, Ritesh Parajuli, Aik Jiang Lau, Alexandre Chan.
      The purpose of this study is to elucidate how patient-reported cognitive symptoms manifest from variations in hormone levels or precursors such as dehydroepiandrosterone (DHEA) and its sulfated form [collectively termed as DHEA(S)] and to investigate their association in breast cancer survivors. Levels of estradiol and DHEA(S) were compared between early-stage breast cancer patients with and without cancer-related cognitive impairment (CRCI) during adjuvant chemotherapy. Data were analyzed from 242 patients (mean age ± SD = 50.8 ± 9.2 years) who had completed FACT-Cog v.3.0, blood draws and questionnaires. Regression model was used to fit the magnitude of change in each respective biomarker levels against overall cognitive impairment status while adjusting for clinically important covariates. There was reduction in mean plasma levels of estradiol and DHEAS during and towards the end of chemotherapy (p-values < 0.001). Compared to non-impaired patients, smaller magnitude of decline was observed in DHEA(S) levels in patients reporting CRCI, with significant association between decline in DHEAS levels and acute onset of CRCI at 6 weeks from baseline (adjusted β of 0.40, p-value of 0.02). In contrast, patients reporting CRCI showed greater magnitude of decline in estradiol compared to non-impaired patients, although this was not found to be statistically significant. There was an association between magnitude of change in biomarker levels with self-reported CRCI which suggests that the hormonal pathway related to DHEAS may be implicated in acute CRCI for breast cancer survivors. Our findings help to improve biological understanding of the pathway from which DHEAS may correlate with cognitive dysfunction and its impact on cancer survivors.
    DOI:  https://doi.org/10.1038/s41598-022-20420-3
  9. Proc Natl Acad Sci U S A. 2022 Oct 11. 119(41): e2117743119
    Computationally guided conversion of the specificity of E-selectin to mimic that of Siglec-8.
    Xiaocong Wang, Melinda S Hanes, Richard D Cummings, Robert J Woods.
      Sulfated glycans have been found to be associated with various diseases and therefore have significant potential in molecular pathology as biomarkers. Although lectins are useful reagents for detecting glycans, there is a paucity of sulfate-recognizing lectins, and those that exist, such as from Maackia amurensis, display mixed specificities. Recombinant lectin engineering offers an emerging tool for creating novel glycan recognition by altering and/or enhancing endogenous specificities. The present study demonstrated the use of computational approaches in the engineering of a mutated form of E-selectin that displayed highly specific recognition of 6'-sulfo-sialyl Lewis X (6'-sulfo-sLex), with negligible binding to its endogenous nonsulfated ligand, sLex. This new specificity mimics that of the unrelated protein Siglec-8, for which 6'-sulfo-sLex is its preferred ligand. Molecular dynamics simulations and energy calculations predicted that two point mutations (E92A/E107A) would be required to stabilize binding to the sulfated oligosaccharide with E-selectin. In addition to eliminating putative repulsions between the negatively charged side chains and the sulfate moiety, the mutations also abolished favorable interactions with the endogenous ligand. Glycan microarray screening of the recombinantly expressed proteins confirmed the predicted specificity change but also identified the introduction of unexpected affinity for the unfucosylated form of 6'-sulfo-sLex (6'-sulfo-sLacNAc). Three key requirements were demonstrated in this case for engineering specificity for sulfated oligosaccharide: 1) removal of unfavorable interactions with the 6'-sulfate, 2) introduction of favorable interactions for the sulfate, and 3) removal of favorable interactions with the endogenous ligand.
    Keywords:  GLYCAM; glycan microarray screening; lectin engineering; rational protein design; sulfated oligosaccharide
    DOI:  https://doi.org/10.1073/pnas.2117743119
  10. Protein Eng Des Sel. 2022 Oct 03. pii: gzac007. [Epub ahead of print]
    Engineering Pseudomonas aeruginosa arylsulfatase for hydrolysis of α-configured steroid sulfates.
    Bradley J Stevenson, Andy Pranata, Malcolm D McLeod.
      Steroid sulfate esters are important metabolites for anti-doping efforts in sports, pathology, and research. Analysis of these metabolites is facilitated by hydrolysis using either acid or enzymatic catalysis. Although enzymatic hydrolysis is preferred for operating at neutral pH, no known enzyme is capable of hydrolyzing all steroid sulfate metabolites. Pseudomonas aeruginosa arylsulfatase (PaS) is ideal for the hydrolysis of β-configured steroid sulfates but like other known class I sulfatases it is inefficient at hydrolyzing α-configured steroid sulfates. We have used directed evolution with liquid chromatography mass spectrometry screening to find variants capable of hydrolyzing an α-configured steroid sulfate: etiocholanolone sulfate (ECS). After targeting two regions of PaS, four residues were identified and optimized to yield a final variant with a total of seven mutations (DRN-PaS) capable of hydrolyzing ECS approximately 80-times faster than the best PaS variant previously available. This DRN-PaS also shows improved activity for other α-configured steroid sulfates. Simultaneous mutagenesis was essential to obtain DRN-PaS due to complementarity between targeted residues.
    DOI:  https://doi.org/10.1093/protein/gzac007
  11. Angew Chem Int Ed Engl. 2022 Oct 07.
    Glycan Modulation of Insulin-like Growth Factor-1 Receptor.
    Rio S Boothello, Nehru Viji Sankaranarayanan, Jyothi C Sistla, Balaji Nagarajan, Chetna Sharon, John E Chittum, Rabiya Y Niyaz, Swarnali Roy, Aditi Nandi, Connor P O'Hara, Rahaman Navaz Gangji, Daniel K Afosah, Ravikumar Ongolu, Bhaumik B Patel, Umesh R Desai.
      The insulin-like growth factor-1 receptor (IGF-1R) is a receptor tyrosine kinase (RTK) that plays critical roles in cancer. Microarray, computational, thermodynamic, and cellular imaging studies reveal that activation of IGF-1R by its cognate ligand IGF-1 is inhibited by shorter, soluble heparan sulfate (HS) sequences (e.g., HS06), whereas longer polymeric chains do not inhibit the RTK, a phenomenon directly opposed to the traditional relationship known for GAG-protein systems. The inhibition arises from smaller oligosaccharides binding in a unique pocket in the IGF-1R ectodomain, which competes with the natural cognate ligand IGF1. This work presents a highly interesting observation on preferential and competing inhibition of IGF-1R by smaller sequences, whereas polysaccharides are devoid of this function. These insights will be of major value to glycobiologists and anti-cancer drug discoverers.
    Keywords:  Drug Discovery; Glycosaminoglycans; Growth factors; Receptor Tyrosine Kinases; heparan sulfate
    DOI:  https://doi.org/10.1002/anie.202211320
  12. Sci Rep. 2022 Oct 07. 12(1): 16878
    Calcium dobesilate reduces SARS-CoV-2 entry into endothelial cells by inhibiting virus binding to heparan sulfate.
    Yulia Kiyan, Anna Schultalbers, Ekaterina Chernobrivaia, Sergey Tkachuk, Song Rong, Nelli Shushakova, Hermann Haller.
      Recent reports demonstrate that SARS-CoV-2 utilizes cell surface heparan sulfate as an attachment factor to facilitate the initial interaction with host cells. Heparan sulfate interacts with the receptor binding domain of SARS-CoV-2 spike glycoprotein, and blocking this interaction can decrease cell infection. We and others reported recently that the family of compounds of 2,5-dihydroxyphenylic acid interferes with the binding of the positively charged groove in growth factor molecules to negatively charged cell surface heparan sulfate. We hypothesized that Calcium Dobesilate (CaD)-calcium salt of 2,5-dihydroxyphenylic acid-may also interfere with the binding of SARS-CoV-2 spike protein to heparan sulfate. Using lentiviral SARS-CoV-2 spike protein pseudotyped particles we show that CaD could significantly reduce pseudovirus uptake into endothelial cells. On the contrary, CaD did not affect cell infection with VSVG-expressing lentivirus. CaD could also prevent retention of SARS-CoV-2 spike protein in ex vivo perfused mouse kidney. Using microfluidic culture of endothelial cells under flow, we show that CaD prevents spike protein interaction with heparan sulfate glycocalyx. Since CaD has no adverse side effects and is approved in humans for other medical indications, our findings can rapidly translate into clinical studies.
    DOI:  https://doi.org/10.1038/s41598-022-20973-3
  13. Endocrinology. 2022 Oct 06. pii: bqac163. [Epub ahead of print]
    Dehydroepiandrosterone supplementation results in varying tissue-specific levels of dihydrotestosterone in male mice.
    Hannah Colldén, Maria E Nilsson, Anna Karin Norlén, Andreas Landin, Sara H Windahl, Jianyao Wu, Karin Horkeby, Marie K Lagerquist, Henrik Ryberg, Matti Poutanen, Liesbeth Vandenput, Claes Ohlsson.
      Dehydroepiandrosterone (DHEA), an adrenal androgen precursor, can be metabolized in target tissues into active sex steroids. It has been proposed that DHEA supplementation might result in restoration of physiological local sex steroid levels, but knowledge on the effect of DHEA treatment on local sex steroid levels in multiple tissues is lacking. To determine the effects of DHEA on tissue-specific levels of sex steroids, we treated orchiectomized (ORX) male mice with DHEA for three weeks and compared them with vehicle-treated ORX mice and gonadal intact mice. Intra-tissue levels of sex steroids were analyzed in reproductive organs (seminal vesicles, prostate, m. levator ani), major body compartments (white adipose tissue, skeletal muscle, and brain), adrenals, liver and serum using a sensitive and validated gas chromatography-mass spectrometry method. DHEA treatment restored levels of both testosterone (T) and dihydrotestosterone (DHT) to approximately physiological levels in male reproductive organs. In contrast, this treatment did not increase DHT levels in skeletal muscle or brain. In the liver, DHEA treatment substantially increased levels of T (at least four-fold) and DHT (+ 536%, p < 0.01) compared with vehicle-treated ORX mice. In conclusion, we provide a comprehensive map of the effect of DHEA treatment on intra-tissue sex steroid levels in ORX mice with a restoration of physiological levels of androgens in male reproductive organs while DHT levels were not restored in the skeletal muscle or brain. This, and the unexpected supraphysiological androgen levels in the liver, may be a cause for concern considering the uncontrolled use of DHEA.
    Keywords:  androgens; dehydroepiandrosterone; dihydrotestosterone; intracrinology; mice; reproductive organs
    DOI:  https://doi.org/10.1210/endocr/bqac163
  14. J Clin Endocrinol Metab. 2022 Oct 06. pii: dgac576. [Epub ahead of print]
    Changes in serum testosterone and adrenal androgen levels in transgender women with and without gonadectomy.
    Sarah Collet, Noor Gieles, Chantal M Wiepjes, Annemieke C Heijboer, Tim Reyns, Tom Fiers, Bruno Lapauw, Martin den Heijer, Guy T'Sjoen.
       BACKGROUND: Initiating feminizing gender-affirming hormone therapy (GAHT) in transgender women causes a steep decline in serum testosterone. It is unknown if testosterone concentrations change further and whether adrenal androgen levels change during feminizing GAHT and after gonadectomy. This limits clinical decision making in transgender women with symptoms attributed to GAHT or gonadectomy.
    METHODS: Transgender women (n = 275) initiating estradiol and cyproterone acetate (CPA) were included at baseline, and had follow-up visits after 3, 12 months, and 2-4 years. During follow-up, 49.5% of transgender women underwent a gonadectomy. Total testosterone (TT), dehydroepiandrosterone (DHEA), dehydroepiandrosteronesulfate (DHEAS) and androstenedione (A4) were measured using LC-MS/MS.
    RESULTS: After three months of GAHT, mean TT, cFT and A4 decreased by 18.4 nmol/L (95%CI -19.4, -17.4, p < 0.001) i.e. -97.1%, 383 pmol/L (95%CI -405, -362, p < 0.001) i.e. -98.3% and 1.2 nmol/L (95%CI -1.4, -1.0, p < 0.001) i.e. -36.5% respectively, and remained stable thereafter. DHEA and DHEAS decreased by 7.4 nmol/L (95%CI -9.7, -5.1) i.e -28.0% and 1.8 µmol/L (95%CI -2.2, -1.4) i.e. -20.1%, respectively, after one year and did not change thereafter. After gonadectomy, CPA therapy is stopped, which induced no further change in TT, cFT, DHEA, DHEAS and A4 compared those who did not undergo gonadectomy.
    CONCLUSIONS: Our findings confirm that after an initial drop, testosterone levels in transgender women remain stable. Adrenal androgens decrease in the first year of CPA and estrogen supplementation and remain unchanged after gonadectomy. Androgens did not change after gonadectomy and cessation of CPA. Correlates with clinical symptoms remain to be elucidated.
    DOI:  https://doi.org/10.1210/clinem/dgac576
  15. Carbohydr Polym. 2022 Dec 01. pii: S0144-8617(22)00907-9. [Epub ahead of print]297 120002
    Polypseudorotaxane hydrogel based on Tween 80 and α-cyclodextrin for sustained delivery of low molecular weight heparin.
    Bo Tang, Xuewen Yang, Aiwen Zhang, Qiuxiang Wang, Lei Fan, Guihua Fang.
      Low molecular weight heparin (LMWH), an anionic polysaccharide, has been widely used as a clinical anticoagulant. However, repeated subcutaneous injection is sometimes required due to its short half-life. To reduce the dosing frequency, the injectable polypseudorotaxane hydrogel was fabricated by inclusion complexation formation between Tween 80 and α-Cyclodextrin (αCD) for sustained release of LMWH. The physicochemical properties of such hydrogel were characterized by SEM, XRD, DSC, and FTIR. This hydrogel showed shear-thinning and thixotropic behavior and was easily injected through standard syringe needles. The gelation time, mechanical strength, shear viscosity, in vitro drug release rate, in vitro hydrogel dissolution rate, and in vivo hydrogel retention could be tuned by αCD concentration in the hydrogel. In vivo safety evaluation indicated that the polypseudorotaxane hydrogel was biocompatible. Most importantly, this polypseudorotaxane hydrogel could sustain release of LMWH after subcutaneous injection.
    Keywords:  Low molecular weight heparin; Polypseudorotaxane hydrogel; Sustained release; Tween 80; α-Cyclodextrin
    DOI:  https://doi.org/10.1016/j.carbpol.2022.120002
  16. Comp Biochem Physiol C Toxicol Pharmacol. 2022 Sep 28. pii: S1532-0456(22)00211-3. [Epub ahead of print] 109476
    Sulfotransferases (SULTs), enzymatic and genetic variation in Carnivora: Limited sulfation capacity in pinnipeds.
    Mitsuki Kondo, Yoshinori Ikenaka, Shouta M M Nakayama, Yusuke K Kawai, Hazuki Mizukawa, Yoko Mitani, Kei Nomyama, Shinsuke Tanabe, Mayumi Ishizuka.
      Wild carnivorans are one of the most important species due to their high positions in the food chain. They are also highly affected by numerous environmental contaminants through bioaccumulation and biomagnification. Xenobiotic metabolism is a significant chemical defense system from xenobiotics because it degrades the activity of a wide range of chemicals, generally into less active forms, resulting in their deactivation. Sulfotransferases (SULTs) are one of the most important xenobiotic metabolic enzymes, which catalyze the sulfonation of a variety of endogenous and exogenous chemicals, such as hormones, neurotransmitters, and a wide range of xenobiotic compounds. Although SULTs are of such high importance, little research has focused on these enzymes in wild carnivorans. In this study, we clarified the genetic properties of SULTs in a wide range of mammals, focusing on carnivorans, using in silico genetic analyses. We found genetic deficiencies of SULT1E1 and SULT1D1 isoforms in all pinnipeds analyzed and nonsense mutations in SULT1Cs in several carnivorans including pinnipeds. We further investigated the enzymatic activity of SULT1E1 in vitro using liver cytosols from pinnipeds. Using a SULT1E1 probe substrate, we found highly limited estradiol sulfonation in pinnipeds, whereas other mammals had relatively high sulfation. These results suggest that pinnipeds have severely or completely absent SULT1E1 activity, which importantly catalyzes the metabolism of estrogens, drugs, and environmental toxins. This further implies a high susceptibility to a wide range of xenobiotics in these carnivorans, which are constantly exposed to environmental chemicals throughout their lifetime.
    Keywords:  Genome database; In silico analysis; Phase II metabolism; Wildlife; Xenobiotic metabolism
    DOI:  https://doi.org/10.1016/j.cbpc.2022.109476
  17. Cardiovasc Drugs Ther. 2022 Oct 04.
    Sulfated Galactofucan from Sargassum Thunbergii Attenuates Atherosclerosis by Suppressing Inflammation Via the TLR4/MyD88/NF-κB Signaling Pathway.
    Kefu Zhu, Xihao Wang, Yingzheng Weng, Genxiang Mao, Yizhong Bao, Jiangjie Lou, Shaoze Wu, Weihua Jin, Lijiang Tang.
       PURPOSE: Sulfated galactofucan (SWZ-4), which was extracted from Sargassum thunbergii, has recently been reported to show anti-inflammatory and anticancer properties. The present study aimed to evaluate whether SWZ-4 attenuates atherosclerosis in apolipoprotein E-knockout (ApoE-KO) mice by suppressing the inflammatory response through the TLR4/MyD88/NF-κB signaling pathway.
    METHODS: Male ApoE-KO mice were fed with a high-fat diet for 16 weeks and intraperitoneally injected with SWZ-4. RAW246.7 cells were treated with lipopolysaccharide (LPS) and SWZ-4. Atherosclerotic lesions were measured by Sudan IV and oil red O staining. Serum lipid profiles, inflammatory cytokines, and mRNA and protein expression levels were evaluated.
    RESULTS: SWZ-4 decreased serum TNF-α, IL-6 and IL-1 levels, but did not reduce blood lipid profiles. SWZ-4 downregulated the mRNA and protein expression of TLR4 and MyD88, reduced the phosphorylation of p65, and attenuated atherosclerosis in the ApoE-KO mice (p < 0.01). In LPS-stimulated RAW 264.7 cells, SWZ-4 inhibited proinflammatory cytokine production and the mRNA expression of TLR4, MyD88, and p65 and reduced the protein expression of TLR4 and MyD88 and the phosphorylation of p65 (p < 0.01).
    CONCLUSION: These results suggest that SWZ-4 may exert an anti-inflammatory effect on ApoE-KO atherosclerotic mice by inhibiting the TLR4/MyD88/NF-κB signaling pathway in macrophages and therefore may be a treatment for atherosclerosis.
    Keywords:  Anti-inflammatory; Atherosclerosis; Plant extracts; Sargassum; TLR4-MyD88-NF-κB
    DOI:  https://doi.org/10.1007/s10557-022-07383-3
  18. Annu Rev Pharmacol Toxicol. 2022 Oct 07.
    OAT, OATP, and MRP Drug Transporters and the Remote Sensing and Signaling Theory.
    Sanjay K Nigam, Jeffry C Granados.
      The coordinated movement of organic anions (e.g., drugs, metabolites, signaling molecules, nutrients, antioxidants, gut microbiome products) between tissues and body fluids depends, in large part, on organic anion transporters (OATs) [solute carrier 22 (SLC22)], organic anion transporting polypeptides (OATPs) [solute carrier organic (SLCO)], and multidrug resistance proteins (MRPs) [ATP-binding cassette, subfamily C (ABCC)]. Depending on the range of substrates, transporters in these families can be considered multispecific, oligospecific, or (relatively) monospecific. Systems biology analyses of these transporters in the context of expression patterns reveal they are hubs in networks involved in interorgan and interorganismal communication. The remote sensing and signaling theory explains how the coordinated functions of drug transporters, drug-metabolizing enzymes, and regulatory proteins play a role in optimizing systemic and local levels of important endogenous small molecules. We focus on the role of OATs, OATPs, and MRPs in endogenous metabolism and how their substrates (e.g., bile acids, short chain fatty acids, urate, uremic toxins) mediate interorgan and interorganismal communication and help maintain and restore homeostasis in healthy and disease states. Expected final online publication date for the Annual Review of Pharmacology and Toxicology, Volume 63 is January 2023. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.
    DOI:  https://doi.org/10.1146/annurev-pharmtox-030322-084058
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