bims-supasi Biomed News
on Sulfation pathways and signalling
Issue of 2023‒02‒12
thirteen papers selected by
Jonathan Wolf Mueller
University of Birmingham
  1. The heparan sulfate modification enzyme, Hs6st1, is essential for neuroectodermal patterning in Xenopus embryos.
  2. Chondroitin sulfate alleviates osteoporosis caused by calcium deficiency by regulating lipid metabolism.
  3. The Effects of Mechanical Load on Chondrogenic Responses of Bone Marrow Mesenchymal Stem Cells and Chondrocytes Encapsulated in Chondroitin Sulfate-Based Hydrogel.
  4. Evaluation of Local Application of Glucosamine Sulfate and Chondroitin Sulfate on Temporomandibular Joint Response and Alleviation of Pain and Tension During the Functional Treatment of Skeletal Class II Patients: A Randomized Control Clinical Trial.
  5. Hedgehog is relayed through dynamic heparan sulfate interactions to shape its gradient.
  6. Research Progress on Antiviral Activity of Heparin.
  7. Establishment and validation of a plasma oncofetal chondroitin sulfated proteoglycan for pan-cancer detection.
  8. Heparin is essential for optimal cell signaling by FGF21 and for regulation of βKlotho cellular stability.
  9. VT68.2: An Antibody to Chondroitin Sulfate Proteoglycan 4 (CSPG4) Displays Reactivity against a Tumor-Associated Carbohydrate Antigen.
  10. Chondroitin Sulphate/Dermatan Sulphate Proteoglycans: Potential Regulators of Corneal Stem/Progenitor Cell Phenotype In Vitro.
  11. In-vitro evaluation of immunomodulatory activity of sulphation-modified total ginsenosides derivative-3.
  12. Seaweed-Derived Sulfated Polysaccharides; The New Age Chemopreventives: A Comprehensive Review.
  13. Semi-Targeted Profiling of Bile Acids by High-Resolution Mass Spectrometry in a Rat Model of Drug-Induced Liver Injury.
  1. Dev Biol. 2023 Feb 03. pii: S0012-1606(23)00025-8. [Epub ahead of print]
    The heparan sulfate modification enzyme, Hs6st1, is essential for neuroectodermal patterning in Xenopus embryos.
    Takayoshi Yamamoto, Toki Kaneshima, Kohei Tsukano, Tatsuo Michiue.
      The nervous system has various types of cells derived from three neuroectodermal regions: neural plate (NP), neural crest (NC), and preplacodal ectoderm (PPE). Differentiation of these regions is regulated by various morphogens. However, regulatory mechanisms of morphogen distribution in neural patterning are still debated. In general, an extracellular component, heparan sulfate (HS), is essential to regulate morphogen gradients by modulating morphogen binding. The present study focused on an HS modification enzyme, heparan sulfate 6-O-sulfotransferase 1 (Hs6st1), which is highly expressed during the neurula stage in Xenopus. Our present in situ hybridization analysis revealed that Hs6st1 is expressed in the lateral sensorial layer of neuroectoderm. Overexpression of Hs6st1 expands Sox3 (NP marker gene) expression, and slightly dampens FoxD3 (NC marker) expression. Hs6st1 knockout using the CRISPR/Cas9 system also expands the neural plate region, followed by retinal malformation. These results imply that 6-O sulfation, mediated by Hs6st1, selectively regulates morphogen distribution required for neuroectodermal patterning. Among morphogens required for patterning, Fgf8a accumulates on Hs6st1-expressing cells, whereas a secreted BMP antagonist, Noggin, diffuses away from those cells. Thus, cell-autonomous 6-O sulfation of HS at the sensorial layer of neuroectoderm also affects neuroectodermal patterning in neighboring regions, including neural plate and neural crest, not only through accumulation, but also through dispersal of specific morphogens.
    Keywords:  Heparan sulfate; Morphogen; Neural crest; Neural plate; Neuroectodermal patterning; Xenopus
    DOI:  https://doi.org/10.1016/j.ydbio.2023.01.011
  2. Nutr Metab (Lond). 2023 Feb 06. 20(1): 6
    Chondroitin sulfate alleviates osteoporosis caused by calcium deficiency by regulating lipid metabolism.
    Tianshu Liu, Hai Yu, Shuai Wang, Huimin Li, Xinyiran Du, Xiaodong He.
      The use of non-drug intervention for calcium deficiency has attracted attention in recent years. Although calcium carbonate is the preferred raw material for calcium supplementation, there are few reports on the mechanism of the combined action of chondroitin sulfate and calcium to alleviate osteoporosis from the perspective of gut microbiota and metabolomics. In this study, a rat model of osteoporosis was established by feeding a low-calcium diet. The intestinal microbiota abundance, fecal and plasma metabolite expression levels of rats fed a basal diet, a low-calcium diet, a low-calcium diet plus calcium carbonate, and a low-calcium diet plus chondroitin sulfate were compared. The results showed that compared with the low calcium group, the calcium content and bone mineral density of femur were significantly increased in the calcium carbonate and chondroitin sulfate groups. 16 S rRNA sequencing and metabolomics analysis showed that chondroitin sulfate intervention could reduce short-chain fatty acid synthesis of intestinal flora, slow down inflammatory response, inhibit osteoclast differentiation, promote calcium absorption and antioxidant mechanism, and alleviate osteoporosis in low-calcium feeding rats. Correlation analysis showed that the selected intestinal flora was significantly correlated with metabolites enriched in feces and plasma. This study provides scientific evidence of the potential impact of chondroitin sulfate as a dietary supplement for patients with osteoporosis.
    Keywords:  Chondroitin sulfate; Intestinal flora; Lipid metabolism; Metabolomics; Osteoporosis
    DOI:  https://doi.org/10.1186/s12986-023-00726-3
  3. Int J Mol Sci. 2023 Feb 02. pii: 2915. [Epub ahead of print]24(3):
    The Effects of Mechanical Load on Chondrogenic Responses of Bone Marrow Mesenchymal Stem Cells and Chondrocytes Encapsulated in Chondroitin Sulfate-Based Hydrogel.
    Ilona Uzieliene, Daiva Bironaite, Edvardas Bagdonas, Jolita Pachaleva, Arkadij Sobolev, Wei-Bor Tsai, Giedrius Kvederas, Eiva Bernotiene.
      Articular cartilage is vulnerable to mechanical overload and has limited ability to restore lesions, which leads to the development of chronic diseases such as osteoarthritis (OA). In this study, the chondrogenic responses of human bone marrow mesenchymal stem cells (BMMSCs) and OA cartilage-derived chondrocytes in 3D chondroitin sulfate-tyramine/gelatin (CS-Tyr)/Gel) hydrogels with or without experimental mechanical load have been investigated. Chondrocytes were smaller in size, had slower proliferation rate and higher level of intracellular calcium (iCa2+) compared to BMMSCs. Under 3D chondrogenic conditions in CS-Tyr/Gel with or without TGF-β3, chondrocytes more intensively secreted cartilage oligomeric matrix protein (COMP) and expressed collagen type II (COL2A1) and aggrecan (ACAN) genes but were more susceptible to mechanical load compared to BMMSCs. ICa2+ was more stably controlled in CS-Tyr/Gel/BMMSCs than in CS-Tyr/Gel/chondrocytes ones, through the expression of L-type channel subunit CaV1.2 (CACNA1C) and Serca2 pump (ATP2A2) genes, and their balance was kept more stable. Due to the lower susceptibility to mechanical load, BMMSCs in CS-Tyr/Gel hydrogel may have an advantage over chondrocytes in application for cartilage regeneration purposes. The mechanical overload related cartilage damage in vivo and the vague regenerative processes of OA chondrocytes might be associated to the inefficient control of iCa2+ regulating channels.
    Keywords:  bone marrow mesenchymal stem cells; cartilage explants; cartilage regeneration; chondrocytes; chondrogenic differentiation; chondroitin sulfate tyramine hydrogels; mechanical compression/load
    DOI:  https://doi.org/10.3390/ijms24032915
  4. Cureus. 2023 Feb;15(2): e34608
    Evaluation of Local Application of Glucosamine Sulfate and Chondroitin Sulfate on Temporomandibular Joint Response and Alleviation of Pain and Tension During the Functional Treatment of Skeletal Class II Patients: A Randomized Control Clinical Trial.
    Maria N Alhayek, Ahmad S Burhan, Mohammad Y Hajeer, Fehmieh R Nawaya, Ghaith F Sahtout.
      OBJECTIVE:  This study was conducted to assess the effects of applying a gel of combined glucosamine sulfate and chondroitin sulfate on the temporomandibular joint (TMJ) area in patients with skeletal Class II malocclusion treated by removable functional appliances in terms of TMJ internal proportions, levels of pain, and tension.MATERIALS AND METHODS: The study included 36 patients aged 10-13 years with skeletal Class II malocclusion due to retrusion of the mandible characterized by: 4-8 degrees of the sagittal skeletal discrepancy (ANB) angle, 4-7 mm of overjet, 72-76 degrees of the sagittal mandibular positioning (SNB) angle, and a bone maturity stage located at pubertal growth spurt. Patients were distributed to the experimental group (Twin-Block appliance + Jointance® gel) or the control group (conventional treatment with the Twin-Block appliance). An allocation ratio of 1:1 was employed. Pre- and post-treatment digital lateral cephalometric radiograms were taken, and the TMJ joint spaces were measured using the Viewbox software (dHAL Software, Kifissia, Greece). The pain and discomfort levels were evaluated using a questionnaire with a four-point Likert scale at three assessment times.
    RESULTS:  The anterior and posterior glenoid and anterior condylar distances to the pterygoid vertical (PTV) reference plane significantly decreased after treatment (p<.001), and the anterior joint space decreased significantly (p<.001). In contrast, the superior distance of the condyle to the Frankfort horizontal reference plane increased significantly after treatment, and the same results were found for the posterior and superior joint spaces (p<.05). There were no significant differences between the two groups in the evaluated linear variables. No significant differences were found when comparing pain and tension levels between the two groups at each assessment time. A gradual decrease in pain and tension levels was observed between the three evaluation times in both groups.
    CONCLUSIONS:  A combination of glucosamine sulfate and chondroitin sulfate did not affect the temporomandibular joint spaces, pain, and tension levels in patients with skeletal Class II malocclusions treated by removable functional appliances.
    Keywords:  cephalometric analysis; chondroitin sulfate; functional treatment; glucosamine sulfate; pain; skeletal class ii; soft-tissue tension; tmj distances; twin-block
    DOI:  https://doi.org/10.7759/cureus.34608
  5. Nat Commun. 2023 Feb 10. 14(1): 758
    Hedgehog is relayed through dynamic heparan sulfate interactions to shape its gradient.
    Fabian Gude, Jurij Froese, Dominique Manikowski, Daniele Di Iorio, Jean-Noël Grad, Seraphine Wegner, Daniel Hoffmann, Melissa Kennedy, Ralf P Richter, Georg Steffes, Kay Grobe.
      Cellular differentiation is directly determined by concentration gradients of morphogens. As a central model for gradient formation during development, Hedgehog (Hh) morphogens spread away from their source to direct growth and pattern formation in Drosophila wing and eye discs. What is not known is how extracellular Hh spread is achieved and how it translates into precise gradients. Here we show that two separate binding areas located on opposite sides of the Hh molecule can interact directly and simultaneously with two heparan sulfate (HS) chains to temporarily cross-link the chains. Mutated Hh lacking one fully functional binding site still binds HS but shows reduced HS cross-linking. This, in turn, impairs Hhs ability to switch between both chains in vitro and results in striking Hh gradient hypomorphs in vivo. The speed and propensity of direct Hh switching between HS therefore shapes the Hh gradient, revealing a scalable design principle in morphogen-patterned tissues.
    DOI:  https://doi.org/10.1038/s41467-023-36450-y
  6. Curr Med Chem. 2023 Feb 03.
    Research Progress on Antiviral Activity of Heparin.
    Yi Wang, Yanqing Zhang, Ping Wang, Tianyuan Jing, Yanan Hu, Xiushan Chen.
      Heparin, as a glycosaminoglycan, is known for its anticoagulant and antithrombotic properties for several decades. Heparin is a life-saving drug and is widely used for anticoagulation in medical practice. In recent years, there have been extensive studies that heparin plays an important role in non-anticoagulant diseases, such as anti-inflammatory, anti-viral, anti-angiogenesis, anti-neoplastic, anti-metastatic effects, and so on. Clinical observation and in vitro experiments indicate that heparin displays a potential multi-target effect. In this brief review, we will summarize heparin and its derivative's recently studied progress for the treatment of various viral infections. The aim is to maximize the benefits of drugs through medically targeted development, to meet the unmet clinical needs of serious viral diseases.
    Keywords:  Antiviral; Heparan sulfate; Heparin; Heparin mimic; Mechanism; Virus
    DOI:  https://doi.org/10.2174/0929867330666230203124032
  7. Nat Commun. 2023 Feb 06. 14(1): 645
    Establishment and validation of a plasma oncofetal chondroitin sulfated proteoglycan for pan-cancer detection.
    Pei-Fen Zhang, Zi-Yi Wu, Wen-Bin Zhang, Yong-Qiao He, Kexin Chen, Tong-Min Wang, Haixin Li, Hong Zheng, Dan-Hua Li, Da-Wei Yang, Ting Zhou, Chang-Mi Deng, Ying Liao, Wen-Qiong Xue, Lian-Jing Cao, Xi-Zhao Li, Jiang-Bo Zhang, Si-Qi Dong, Fang Wang, Mei-Qi Zheng, Wen-Li Zhang, Jianbing Mu, Wei-Hua Jia.
      Various biomarkers targeting cell-free DNA (cfDNA) and circulating proteins have been tested for pan-cancer detection. Oncofetal chondroitin sulfate (ofCS), which distinctively modifies proteoglycans (PGs) of most cancer cells and binds specifically to the recombinant Plasmodium falciparum VAR2CSA proteins (rVAR2), is explored for its potential as a plasma biomarker in pan-cancer detection. To quantitate the plasma ofCS/ofCSPGs, we optimized an ELISA using different capture/detection pairs (rVAR2/anti-CD44, -SDC1, and -CSPG4) in a case-control study with six cancer types. We show that the plasma levels of ofCS/ofCSPGs are significantly higher in cancer patients (P values, 1.2 × 10-2 to 4.4 × 10-10). Validation studies are performed with two independent cohorts covering 11 malignant tumors. The individuals in the top decile of ofCS-CD44 have more than 27-fold cancer risk (OR = 27.8, 95%CI = 18.8-41.4, P = 2.72 × 10-62) compared with the lowest 20%. Moreover, the elevated plasma ofCS-CD44 could be detected at the early stage of pan-cancer with strong dose-dependent odds risk prediction.
    DOI:  https://doi.org/10.1038/s41467-023-36374-7
  8. Proc Natl Acad Sci U S A. 2023 Feb 14. 120(7): e2219128120
    Heparin is essential for optimal cell signaling by FGF21 and for regulation of βKlotho cellular stability.
    Seong J An, Jyotidarsini Mohanty, Francisco Tome, Yoshihisa Suzuki, Irit Lax, Joseph Schlessinger.
      While important insights were gained about how FGF21 and other endocrine fibroblast growth factors (FGFs) bind to Klotho proteins, the exact mechanism of Klotho/FGF receptor assembly that drives receptor dimerization and activation has not been elucidated. The prevailing dogma is that Klotho proteins substitute for the loss of heparan sulfate proteoglycan (HSPG) binding to endocrine FGFs by high-affinity binding of endocrine FGF molecules to Klotho receptors. To explore a potential role of HSPG in FGF21 signaling, we have analyzed the dynamic properties of FGF21-induced FGF21-βKlotho-FGFR1c complexes on the surface of living wild-type (WT) or HSPG-deficient Chinese hamster ovary (CHO) cells by employing quantitative single-molecule fluorescence imaging analyses. Moreover, detailed analyses of FGF21 and FGF1 stimulation of cellular signaling pathways activated in WT or in HSPG-deficient CHO cells are also analyzed and compared. These experiments demonstrate that heparin is required for the formation of FGF21-βKlotho-FGFR1c complexes on the cell membrane and that binding of heparin or HSPG to FGFR1c is essential for optimal FGF21 stimulation of FGFR1c activation, mitogen-activated protein kinase responses, and intracellular Ca2+ release. It is also shown that FGF1 binding stimulates assembly of βKlotho and FGFR1c on cell membranes, resulting in endocytosis and degradation of βKlotho. We conclude that heparin or HSPG is essential for FGF21 signaling and for regulation of βKlotho cellular stability by acting as a coligand of FGFR1c.
    Keywords:  cell signaling; endocrine FGFs; phosphorylation; proteoglycans
    DOI:  https://doi.org/10.1073/pnas.2219128120
  9. Int J Mol Sci. 2023 Jan 28. pii: 2506. [Epub ahead of print]24(3):
    VT68.2: An Antibody to Chondroitin Sulfate Proteoglycan 4 (CSPG4) Displays Reactivity against a Tumor-Associated Carbohydrate Antigen.
    Bernice Nounamo, Fariba Jousheghany, Eric Robb Siegel, Steven R Post, Thomas Kelly, Soldano Ferrone, Thomas Kieber-Emmons, Behjatolah Monzavi-Karbassi.
      The anti-CSPG4 monoclonal antibodies (mAbs) have shown anti-tumor activity and therapeutic potential for treating breast cancer. In addition, CSPG4 is a dominant tumor-associated antigen that is also involved in normal-tissue development in humans. Therefore, the potential for off-tumor activity remains a serious concern when targeting CSPG4 therapeutically. Previous work suggested that glycans contribute to the binding of specific anti-CSPG4 antibodies to tumor cells, but the specificity and importance of this contribution are unknown. In this study, the reactivity of anti-CSPG4 mAbs was characterized with a peptide mimetic of carbohydrate antigens expressed in breast cancer. ELISA, flow cytometry, and microarray assays were used to screen mAbs for their ability to bind to carbohydrate-mimicking peptides (CMPs), cancer cells, and glycans. The mAb VT68.2 displayed a distinctly strong binding to a CMP (P10s) and bound to triple-negative breast cancer cells. In addition, VT68.2 showed a higher affinity for N-linked glycans that contain terminal fucose and fucosylated lactosamines. The functional assays demonstrated that VT68.2 inhibited cancer cell migration. These results define the glycoform reactivity of an anti-CSPG4 antibody and may lead to the development of less toxic therapeutic approaches that target tumor-specific glyco-peptides.
    Keywords:  CSPG4; TACAs; breast cancer; carbohydrate-mimicking peptide
    DOI:  https://doi.org/10.3390/ijms24032506
  10. Int J Mol Sci. 2023 Jan 20. pii: 2095. [Epub ahead of print]24(3):
    Chondroitin Sulphate/Dermatan Sulphate Proteoglycans: Potential Regulators of Corneal Stem/Progenitor Cell Phenotype In Vitro.
    Kiranjit K Bains, Sean Ashworth, Elena Koudouna, Robert D Young, Clare E Hughes, Andrew J Quantock.
      Chondroitin sulphate (CS) proteoglycans with variable sulphation-motifs along their glycosaminoglycan (GAG) chains are closely associated with the stem cell niche of articular cartilage, where they are believed to influence the characteristics of the resident stem cells. Here, we investigated the immunohistochemical distribution of hybrid CS/dermatan sulphate (DS) GAGs in the periphery of the adult chicken cornea, which is the location of the cornea's stem cell niche in a number of species, using a monoclonal antibody, 6C3, that recognises a sulphation motif-specific CS/DS GAG epitope. This revealed positive labelling that was restricted to the subepithelial corneal stroma, as well as nearby bony structures within the sclera, called ossicles. When cultivated on cell culture dishes coated with 6C3-rich CS/DS, corneal stromal cells (keratocytes) that had been isolated from embryonic chicken corneas formed circular colonies, which took several days to reach confluency. A flow cytometric analysis of these keratocytes revealed changes in their expression levels of the indicative stem cell markers, Connexin 43 (Cx43), Paired Box 6 (PAX6), B-lymphoma Moloney murine leukemia virus insertion region-1 (Bmi-1), and C-X-C Chemokine Receptor 4 (CXCR4) suggestive of a less-differentiated phenotype compared with expression levels in cells not exposed to CS/DS. These findings support the view that CS/DS promotes the retention of a stem cell phenotype in corneal cells, much as it has been proposed to do in other connective tissues.
    Keywords:  chondroitin sulphate; cornea; dermatan sulphate; glycosaminoglycans; keratocytes; stem cell niche
    DOI:  https://doi.org/10.3390/ijms24032095
  11. Front Vet Sci. 2023 ;10 1068315
    In-vitro evaluation of immunomodulatory activity of sulphation-modified total ginsenosides derivative-3.
    Zhiting Guo, Ling Wang, Shahbaz Ul Haq, Lu Wang, Wenzhu Guo, Yongjiang Luo, Nabeel Ijaz.
      Background: Ginseng has been used in biomedicine to prevent and treat decreased physical and mental capacities. Total ginsenosides (TG) from ginseng root which have antitumor and immune-enhancing properties, are the principal active components of Panax ginseng, while the sulphation-modified TG derivative-3 (SMTG-d3) was expected to enhance the anticancer activity in conventional medicinal treatments.Methods: The chlorosulphonic acid-pyridine technique, used for the sulfation modification of TG to improve their biological activity, and the infrared spectroscopic characteristics of TG and SMTG-d3 were investigated, and the effects of SMTG-d3 on immunocytes and cytokines relevant to tumor treatment were assessed. The MTT assay was used to assess the effect of TG and SMTG-d3 on the cytotoxicity and T-lymphocytic proliferation against mouse splenocytes. The LDH method was employed to evaluate NK activity induced by TG or SMTG-d3. The production levels of splenocytes-secreted IL-2 and IFN-γ and peritoneal macrophages-secreted TNF-α were determined using mouse ELISA kits.
    Results and discussion: It showed that the ideal conditions for the sulfation modification of TG: the volume ratio of chlorosulfonic acid to pyridine lower than 1:2.5; controlled amount of chlorosulfonic acid; and a yield of 51.5% SMTG-d3 (2 h, < 45°C). SMTG-d3 showed two characteristic absorption peaks at 1,230 cm-1 and 810 cm-1, indicating the formation of sulfuric acid esters and the presence of sulfuric acid groups. SMTG-d3 exhibited higher antitumor immunological activity than TG by promoting the proliferation of T lymphocytes and the production of IFN-γ and TNF-α, thus enhancing NK cell activity, and reducing cytotoxicity. The findings imply sulfated modification represents an effective method of enhancing the immunomodulatory activities of TG and could be used as the basis for developing new drug target compounds; SMTG-d3 can serve as an antitumor immunomodulator and can be considered an effective and prospective herbal formulation in clinical applications.
    Keywords:  antitumor; cytotoxicity; immunological activity; sulphation derivative; total ginsenosides (TG)
    DOI:  https://doi.org/10.3389/fvets.2023.1068315
  12. Cancers (Basel). 2023 Jan 24. pii: 715. [Epub ahead of print]15(3):
    Seaweed-Derived Sulfated Polysaccharides; The New Age Chemopreventives: A Comprehensive Review.
    Prajna Paramita Bhuyan, Rabindra Nayak, Srimanta Patra, Hadi Sajid Abdulabbas, Mrutyunjay Jena, Biswajita Pradhan.
      Seaweed-derived bioactive compounds are regularly employed to treat human diseases. Sulfated polysaccharides are potent chemotherapeutic or chemopreventive medications since it has been discovered. They have exhibited anti-cancer properties by enhancing immunity and driving apoptosis. Through dynamic modulation of critical intracellular signalling pathways, such as control of ROS generation and preservation of essential cell survival and death processes, sulfated polysaccharides' antioxidant and immunomodulatory potentials contribute to their disease-preventive effectiveness. Sulfated polysaccharides provide low cytotoxicity and good efficacy therapeutic outcomes via dynamic modulation of apoptosis in cancer. Understanding how sulfated polysaccharides affect human cancer cells and their molecular involvement in cell death pathways will showcase a new way of chemoprevention. In this review, the significance of apoptosis and autophagy-modulating sulfated polysaccharides has been emphasized, as well as the future direction of enhanced nano-formulation for greater clinical efficacy. Moreover, this review focuses on the recent findings about the possible mechanisms of chemotherapeutic use of sulfated polysaccharides, their potential as anti-cancer drugs, and proposed mechanisms of action to drive apoptosis in diverse malignancies. Because of their unique physicochemical and biological properties, sulfated polysaccharides are ideal for their bioactive ingredients, which can improve function and application in disease. However, there is a gap in the literature regarding the physicochemical properties and functionalities of sulfated polysaccharides and the use of sulfated polysaccharide-based delivery systems in functional cancer. Furthermore, the preclinical and clinical trials will reveal the drug's efficacy in cancer.
    Keywords:  apoptosis; cancer; chemoprevention; sulfated polysaccharides
    DOI:  https://doi.org/10.3390/cancers15030715
  13. Int J Mol Sci. 2023 Jan 27. pii: 2489. [Epub ahead of print]24(3):
    Semi-Targeted Profiling of Bile Acids by High-Resolution Mass Spectrometry in a Rat Model of Drug-Induced Liver Injury.
    Myriam Mireault, Vivaldy Prinville, Leanne Ohlund, Lekha Sleno.
      Using a semi-targeted approach, we have investigated the effect of acetaminophen on circulating bile acid profiles in rats, including many known bile acids and potential isomeric structures, as well as glucuronide and sulfate conjugates. The chromatographic separation was based on an optimized reverse-phase method exhibiting excellent resolution for a complex mix of bile acids using a solid-core C18 column, coupled to a high-resolution quadrupole time-of-flight system. The semi-targeted workflow consisted of first assigning all peaks detectable in samples from 46 known bile acids contained in a standard mix, as well as additional peaks for other bile acid isomers. The presence of glucuronide and sulfate conjugates was also examined based on their elemental formulae and detectable peaks with matching exact masses were added to the list of features for statistical analysis. In this study, rats were administered acetaminophen at four different doses, from 75 to 600 mg/kg, with the highest dose being a good model of drug-induced liver injury. Statistically significant changes were found by comparing bile acid profiles between dosing levels. Some tentatively assigned conjugates were further elucidated using in vitro metabolism incubations with rat liver fractions and standard bile acids. Overall, 13 identified bile acids, 23 tentatively assigned bile acid isomers, and 9 sulfate conjugates were found to increase significantly at the highest acetaminophen dose, and thus could be linked to drug-induced liver injury.
    Keywords:  acetaminophen; bile acids; drug-induced liver injury; hepatotoxicity; liquid chromatography–high resolution mass spectrometry; metabolomics; rat plasma
    DOI:  https://doi.org/10.3390/ijms24032489
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