bims-supasi Biomed News
on Sulfation pathways and signalling
Issue of 2024‒03‒17
ten papers selected by
Jonathan Wolf Mueller, University of Birmingham

  1. Acta Pharm Sin B. 2024 Mar;14(3): 1241-1256
      Sulfation is a crucial and prevalent conjugation reaction involved in cellular processes and mammalian physiology. 3'-Phosphoadenosine 5'-phosphosulfate (PAPS) synthase 2 (PAPSS2) is the primary enzyme to generate the universal sulfonate donor PAPS. The involvement of PAPSS2-mediated sulfation in adenomatous polyposis coli (APC) mutation-promoted colonic carcinogenesis has not been reported. Here, we showed that the expression of PAPSS2 was decreased in human colon tumors along with cancer stages, and the lower expression of PAPSS2 was correlated with poor prognosis in advanced colon cancer. Gut epithelial-specific heterozygous Apc deficient and Papss2-knockout (ApcΔgut-HetPapss2Δgut) mice were created, and the phenotypes were compared to the spontaneous intestinal tumorigenesis of ApcΔgut-Het mice. ApcΔgut-HetPapss2Δgut mice were more sensitive to gut tumorigenesis, which was mechanistically accounted for by the activation of Wnt/β-catenin signaling pathway due to the suppression of chondroitin sulfation and inhibition of the farnesoid X receptor (FXR)-transducin-like enhancer of split 3 (TLE3) gene regulatory axis. Chondroitin sulfate supplementation in ApcΔgut-HetPapss2Δgut mice alleviated intestinal tumorigenesis. In summary, we have uncovered the protective role of PAPSS2-mediated chondroitin sulfation and bile acids-FXR-TLE3 activation in the prevention of gut carcinogenesis via the antagonization of Wnt/β-catenin signaling. Chondroitin sulfate may be explored as a therapeutic agent for Papss2 deficiency-associated colonic carcinogenesis.
    Keywords:  APC; Bile acids; Chondroitin sulfate; Colon cancer; FXR; PAPSS2; Sulfation; Wnt/β-catenin
  2. mSphere. 2024 Mar 12. e0009424
      TcdB is an intracellular bacterial toxin indispensable to Clostridioides difficile infections. The ability to use chondroitin sulfate proteoglycan 4 (CSPG4) as a primary cell surface receptor is evolutionarily conserved by the two major variants of TcdB. As CSPG4 does not typically undergo receptor-mediated endocytosis, we sought to identify environmental factors that stabilize interactions between TcdB and CSPG4 to promote cell binding and entry into the cytosol. Using a series of TcdB receptor-binding mutants and cell lines with various receptor expression profiles, we discovered that extracellular Ca2+ promotes receptor-specific interactions with TcdB. Specifically, TcdB exhibits preferential binding to CSPG4 in the presence of Ca2+, with the absence of Ca2+ resulting in CSPG4-independent cell surface interactions. Furthermore, Ca2+ did not enhance TcdB binding to chondroitin sulfate (CS), the sole glycosaminoglycan of CSPG4. Instead, CS was found to impact the rate of cell entry by TcdB. Collectively, results from this study indicate that Ca2+ enhances cell binding by TcdB and CS interactions contribute to subsequent steps in cell entry.IMPORTANCE: Clostridioides difficile is a leading cause of antibiotic-associated gastrointestinal illness, and many disease pathologies are caused by the toxin TcdB. TcdB engages multiple cell surface receptors, with receptor tropisms differing among the variants of the toxin. Chondroitin sulfate proteoglycan 4 (CSPG4) is a critical receptor for multiple forms of TcdB, and insights into TcdB-CSPG4 interactions are applicable to many disease-causing strains of C. difficile. CSPG4 is modified by chondroitin sulfate (CS) and contains laminin-G repeats stabilized by Ca2+, yet the relative contributions of CS and Ca2+ to TcdB cytotoxicity have not been determined. This study demonstrates distinct roles in TcdB cell binding and cell entry for Ca2+ and CS, respectively. These effects are specific to CSPG4 and contribute to the activities of a prominent isoform of TcdB that utilizes this receptor. These findings advance an understanding of factors contributing to TcdB's mechanism of action and contribution to C. difficile disease.
    Keywords:  Clostridioides difficile; TcdB; calcium; chondroitin sulfate
  3. Nat Commun. 2024 Mar 09. 15(1): 1877
      Axonal growth cones mediate axonal guidance and growth regulation. We show that migrating neurons in mice possess a growth cone at the tip of their leading process, similar to that of axons, in terms of the cytoskeletal dynamics and functional responsivity through protein tyrosine phosphatase receptor type sigma (PTPσ). Migrating-neuron growth cones respond to chondroitin sulfate (CS) through PTPσ and collapse, which leads to inhibition of neuronal migration. In the presence of CS, the growth cones can revert to their extended morphology when their leading filopodia interact with heparan sulfate (HS), thus re-enabling neuronal migration. Implantation of an HS-containing biomaterial in the CS-rich injured cortex promotes the extension of the growth cone and improve the migration and regeneration of neurons, thereby enabling functional recovery. Thus, the growth cone of migrating neurons is responsive to extracellular environments and acts as a primary regulator of neuronal migration.
  4. Int J Mol Sci. 2024 Mar 04. pii: 2983. [Epub ahead of print]25(5):
      Sulfonation, primarily facilitated by sulfotransferases, plays a crucial role in the detoxification pathways of endogenous substances and xenobiotics, promoting metabolism and elimination. Traditionally, this bioconversion has been attributed to a family of human cytosolic sulfotransferases (hSULTs) known for their high sequence similarity and dependence on 3'-phosphoadenosine 5'-phosphosulfate (PAPS) as a sulfo donor. However, recent studies have revealed the presence of PAPS-dependent sulfotransferases within gut commensals, indicating that the gut microbiome may harbor a diverse array of sulfotransferase enzymes and contribute to detoxification processes via sulfation. In this study, we investigated the prevalence of sulfotransferases in members of the human gut microbiome. Interestingly, we stumbled upon PAPS-independent sulfotransferases, known as aryl-sulfate sulfotransferases (ASSTs). Our bioinformatics analyses revealed that members of the gut microbial genus Sutterella harbor multiple asst genes, possibly encoding multiple ASST enzymes within its members. Fluctuations in the microbes of the genus Sutterella have been associated with various health conditions. For this reason, we characterized 17 different ASSTs from Sutterella wadsworthensis 3_1_45B. Our findings reveal that SwASSTs share similarities with E. coli ASST but also exhibit significant structural variations and sequence diversity. These differences might drive potential functional diversification and likely reflect an evolutionary divergence from their PAPS-dependent counterparts.
    Keywords:  PAPS; Sutterella; aryl-sulfate sulfotransferases; detoxification; gut microbial enzymes; human gut microbiome; human sulfotransferases; sulfation; sulfotransferases
  5. Int J Biol Macromol. 2024 Mar 08. pii: S0141-8130(24)01513-7. [Epub ahead of print] 130709
      Versatile nanoplatform equipped with chemo-photodynamic therapeutic attributes play an important role in improving the effectiveness of tumor treatments. Herein, we developed multifunctional nanoparticles based on chondroitin sulfate A (CSA) for the targeted delivery of chlorin e6 (Ce6) and doxorubicin (DOX), in a combined chemo-photodynamic therapy against triple-negative breast cancer. CSA was chosen for its hydrophilic properties and its affinity to CD44 receptor-overexpressed tumor cells. The CSA-ss-Ce6 (CSSC) conjugate was synthesized utilizing a disulfide linker. Subsequently, DOX-loaded CSSC nanoparticles (CSSC-D) were fabricated, showcasing a nearly spherical shape with an average particle size of 267 nm. In the CSSC-D nanoparticles, the chemically attached Ce6 constituted 1.53 %, while the physically encapsulated DOX accounted for 8.11 %. Both CSSC-D and CSSC nanoparticles demonstrated a reduction-sensitive release of DOX or Ce6 in vitro. Under near-infrared (NIR) laser irradiation, CSSC-D showed the enhanced generation of reactive oxygen species (ROS), improving cytotoxic effects against triple-negative breast cancer 4T1 and MDA-MB-231 cells. Remarkably, the CSSC-D with NIR exhibited the most potent tumor growth inhibition in comparison to other groups in the 4T1-bearing Balb/c mice model. Overall, this CSSC-D nanoplatform shows significant promise as a powerful tool for a synergetic approach in chemo-photodynamic therapy in triple-negative breast cancer.
    Keywords:  Chondroitin sulfate; Controlled release; Nanoparticles; Targeted drug delivery; Tumor therapy
  6. PNAS Nexus. 2024 Mar;3(3): pgae097
      Cytosolic sulfotransferases (SULTs) are cytosolic enzymes that catalyze the transfer of sulfonate group to key endogenous compounds, altering the physiological functions of their substrates. SULT enzymes catalyze the O-sulfonation of hydroxy groups or N-sulfonation of amino groups of substrate compounds. In this study, we report the discovery of C-sulfonation of α,β-unsaturated carbonyl groups mediated by a new SULT enzyme, SULT7A1, and human SULT1C4. Enzymatic assays revealed that SULT7A1 is capable of transferring the sulfonate group from 3'-phosphoadenosine 5'-phosphosulfate to the α-carbon of α,β-unsaturated carbonyl-containing compounds, including cyclopentenone prostaglandins as representative endogenous substrates. Structural analyses of SULT7A1 suggest that the C-sulfonation reaction is catalyzed by a novel mechanism mediated by His and Cys residues in the active site. Ligand-activity assays demonstrated that sulfonated 15-deoxy prostaglandin J2 exhibits antagonist activity against the prostaglandin receptor EP2 and the prostacyclin receptor IP. Modification of α,β-unsaturated carbonyl groups via the new prostaglandin-sulfonating enzyme, SULT7A1, may regulate the physiological function of prostaglandins in the gut. Discovery of C-sulfonation of α,β-unsaturated carbonyl groups will broaden the spectrum of potential substrates and physiological functions of SULTs.
    Keywords:  SULT; prostaglandin; sulfonation; sulfotransferase; α,β-unsaturated carbonyl
  7. Endocrine. 2024 Mar 09.
      PURPOSE: Measurement of cortisol concentrations is method dependent. The study aimed to establish assay-specific cut-off limits for cortisol after adrenocorticotropic hormone (ACTH) stimulation, comparing Roche Elecsys Cortisol II immunoassay to liquid chromatography-mass spectrometry (LC-MS/MS), and to assess the impact of patient characteristics, estrogen containing oral contraceptives as well as relation to other adrenocortical steroid hormone dynamics.METHODS: One hundred healthy participants underwent a 250 μg ACTH-test, with plasma samples analyzed using ElecsysCortI, ElecsysCortII, and LC-MS/MS. Cortisone, corticosterone, 17-OH-progesterone, dehydroepiandrosterone sulfate (DHEAS), androstenedione, and testosterone were additionally analyzed with LC-MS/MS. Cut-off limit for a normal cortisol response to the ACTH-test was defined as: 2.5th percentile-1.96 × SE.
    RESULTS: ElecsysCort II measured cortisol concentrations 21% (95% CI: 19-22%) lower than ElecsysCort I. Cut-off limits for cortisol 30 and 60 min after ACTH were 426 and 485 nmol/L (ElecsysCort II) and 411 and 470 nmol/L (LC-MS/MS). Cut-offs were unaffected by gender, or body-composition. The ACTH-test resulted in significantly increased adrenocortical steroid hormones, except for decreased cortisone concentrations (both sexes), and decreased testosterone in men (1.9 nmol/L, 95% CI: 1.3-2.5). Testosterone was increased in women (0.07 nmol/L, 95% CI: 0.02-0.13).
    CONCLUSION: ElecsysCort II has high analytical performance and yields significantly lower cortisol concentrations than prior polyclonal immunoassays. This clinically relevant difference underscores the necessity for revised cut-off limits for improved diagnostic precision. Suggested 30-minute cortisol cutoff limits are 411 nmol/L (LC-MS/MS) and 426 nmol/L (ElecsysCort II). Adrenocortical steroids increased upon ACTH stimulation, except for cortisone in both sexes and testosterone in men, both of which decreased.
    Keywords:  Adrenal insufficiency; Adrenocorticotropic hormone test; Cortisol; Immunoassay; LC-MS/MS; Steroids
  8. Int J Pharm X. 2024 Jun;7 100235
      In this study, we developed self-assembling nanoparticles (LCPs) able to trigger the release of Chlorambucil (Chl) and Doxorubicin (DOX) to MDA-MB-231 cells by exploiting the enzyme and redox signals. The DOX loaded LCPs was prepared by the self-assembly of two chondroitin sulphate (CS) derivatives, obtained by the covalent conjugation of Lipoic Acid (LA) and Chlorambucil (Chl) to the CS backbone. After the physic-chemical characterization of the conjugates by FT-IR, 1H NMR, and determination of the critical aggregation concentration, spherical nanoparticles with mean hydrodynamic diameter of 45 nm (P.D.I. 0.24) and Z-potential of - 44 mV were obtained by water addition/solvent evaporation method. In vitro experiments for the release of Chl and DOX were performed in healthy and cancer cells, using a cell culture media to maintain the physiological intracellular conditions (pH 7.4) (and concentration of esterase and GSH. The results allowed the selective release of the payloads to be detected: Chl release of 0 and 41% were obtained after 2 h incubation in normal and in cancer cells respectively, while values of 35 (in healthy cells) and 60% (in cancer cells) were recorded for DOX release after 96 h. Finally, viability studies proved the ability of the newly proposed nanosystem to enhance the cytotoxic activity of the two drugs against cancer cells.
    Keywords:  Co-delivery; Prodrugs; Self-assembling nanoparticles; Stimuli-responsive release
  9. Polymers (Basel). 2024 Mar 06. pii: 720. [Epub ahead of print]16(5):
      This study involved the creation of highly porous PLA scaffolds through the porogen/leaching method, utilizing polyethylene glycol as a porogen with a 75% mass ratio. The outcome achieved a highly interconnected porous structure with a thickness of 25 μm. To activate the scaffold's surface and improve its hydrophilicity, radiofrequency (RF) air plasma treatment was employed. Subsequently, furcellaran subjected to sulfation or carboxymethylation was deposited onto the RF plasma treated surfaces with the intention of improving bioactivity. Surface roughness and water wettability experienced enhancement following the surface modification. The incorporation of sulfate/carboxymethyl group (DS = 0.8; 0.3, respectively) is confirmed by elemental analysis and FT-IR. Successful functionalization of PLA scaffolds was validated by SEM and XPS analysis, showing changes in topography and increases in characteristic elements (N, S, Na) for sulfated (SF) and carboxymethylated (CMF). Cytocompatibility was evaluated by using mouse embryonic fibroblast cells (NIH/3T3).
    Keywords:  PLA; carboxymethylation; furcellaran; plasma treatment; scaffolds; seaweed polysaccharide; sulfation
  10. Int J Biol Macromol. 2024 Mar 09. pii: S0141-8130(24)01547-2. [Epub ahead of print]264(Pt 2): 130743
      Heparin, a member of the glycosaminoglycan family, is renowned as the most negatively charged biomolecule discovered within the realm of human biology. This polysaccharide serves a vital role as a regulator for various proteins, cells, and tissues within the human body, positioning itself as a pivotal macromolecule of significance. The domain of biology has witnessed substantial interest in the intricate design of heparin and its derivatives, particularly focusing on heparin-based polymers and hydrogels. This intrigue spans a wide spectrum of applications, encompassing diverse areas such as protein adsorption, anticoagulant properties, controlled drug release, development of implants, stent innovation, enhancement of blood compatibility, acceleration of wound healing, and pioneering strides in tissue engineering. This comprehensive overview delves into a multitude of developed heparin conjugates, employing various methods, and explores their functions in both the biomedicine and electronics fields. The efficacy of materials derived from heparin is also thoroughly investigated, encompassing considerations such as thrombogenicity, drug release kinetics, affinity for growth factors (GFs), biocompatibility, and electrochemical analyses. We firmly believe that by redirecting focus towards research and advancements in heparin-related polymers/hydrogels, this study will ignite further research and accelerate potential breakthroughs in this promising and evolving field of discovery.
    Keywords:  Biomedical; Heparin; Heparin-based polymers/hydrogels; Immobilization of heparin