bims-supasi 2023-03-19 papers

bims-supasi

Biomed News

on Sulfation pathways and signalling

Issue of 2023–03–19
fiveteen papers selected by
Jonathan Wolf Mueller, University of Birmingham

A seminal perspective on the role of chondroitin sulfate in biomineralization.
Nanoparticle targeting of mechanically modulated glycocalyx.
Quantification of Glycosaminoglycans in Urine by Isotope-Dilution Liquid Chromatography-Electrospray Ionization Tandem Mass Spectrometry.
Chemical, Molecular, and Single-nucleus Analysis Reveal Chondroitin Sulfate Proteoglycan Aberrancy in Fibrolamellar Carcinoma.
Drosophila hedgehog signaling range and robustness depend on direct and sustained heparan sulfate interactions.
Inhibition of Astrocytic Carbohydrate Sulfotransferase 15 Promotes Nerve Repair After Spinal Cord Injury via Mitigation of CSPG Mediated Axonal Inhibition.
Potency Adjusted Blended Heparin of Bovine, Ovine, and Porcine Heparin Exhibit Comparable Biologic Effects to Referenced Single-Sourced Porcine Heparin.
Glycocalyx engineering with heparan sulfate mimetics attenuates Wnt activity during adipogenesis to promote glucose uptake and metabolism.
Chemical Synthesis of Glycopeptides containing l-Arabinosylated Hydroxyproline and Sulfated Tyrosine.
Impact of hyaluronan size on localization and solubility of the extracellular matrix in the mouse brain.
A liquid chromatography-tandem mass spectrometry method for the analysis of dehydroepiandrosterone sulphate (DHEAs) in serum and plasma with comparison to an immunoassay method in a neonatal population.
Discovery of a sulfated fucan-specific carbohydrate-binding module: The first member of a new carbohydrate-binding module family CBMxx.
Indoxyl Sulfate Promotes Metastatic Characteristics of Ovarian Cancer Cells via Aryl Hydrocarbon Receptor-Mediated Downregulation of the Mas Receptor.
Immunomodulatory effect of sulfated galactofucan from marine macroalga Turbinaria conoides.
Acetaminophen metabolites on presentation following an acute acetaminophen overdose (ATOM-7).

Carbohydr Polym. 2023 Jun 15. pii: S0144-8617(23)00202-3. [Epub ahead of print]310 120738

A seminal perspective on the role of chondroitin sulfate in biomineralization.

Jia-Xin Hao, Qian-Qian Wan, Zhao Mu, Jun-Ting Gu, Wei-Wei Yu, Wen Qin, Yu-Tao Li, Chen-Yu Wang, Yu-Xuan Ma, Kai Jiao, Franklin Tay, Lina Niu.

  Chondroitin sulfate (CS) is an important extracellular matrix component of mineralized tissues. It participates in biomineralization, osteoblast differentiation and promotes bone tissue repair in vitro. However, the mechanism in which CS functions is unclear. Accordingly, an in-depth investigation of how CS participates in mineralization was conducted in the present study. Chondroitin sulfate was found to directly induce intrafibrillar mineralization of the collagen matrix. The mineralization outcome was dependent on whether CS remained free in the extracellular matrix or bound to core proteins; mineralization only occurred when CS existed in a free state. The efficacy of mineralization appeared to increase with ascending CS concentration. This discovery spurred the authors to identify the cause of heterotopic ossification in the Achilles tendon. Chondroitin sulfate appeared to be a therapeutic target for the management of diseases associated with heterotopic calcification. A broader perspective was presented on the applications of CS in tissue engineering.

Keywords:  Amorphous calcium phosphate; Chondroitin sulfate; Heterotopic ossification; Intrafibrillar mineralization; Proteoglycans

DOI:  https://doi.org/10.1016/j.carbpol.2023.120738
bioRxiv. 2023 Feb 27. pii: 2023.02.27.529887. [Epub ahead of print]

Nanoparticle targeting of mechanically modulated glycocalyx.

Afia Ibnat Kohon, Kun Man, Katelyn Mathis, Jade Webb, Yong Yang, Brian Meckes.

The mechanical properties and forces in the extracellular environment surrounding alveolar epithelial cells have the potential to modulate their behavior. Particularly, breathing applies 3-dimensional cyclic stretches to the cells, while the stiffness of the interstitium changes in disease states, such as fibrosis and cancer. A platform was developed that effectively imitates the active forces in the alveolus, while allowing one to control the interstitium matrix stiffnesses to mimic fibrotic lung tumor microenvironments. Alveolar epithelial cancer cells were cultured on these platforms and changes in the glycocalyx expression were evaluated. A complex combination of stiffness and dynamic forces altered heparan sulfate and chondroitin sulfate proteoglycan expressions. Consequently, we designed liposomal nanoparticles (LNPs) modified with peptides that can target heparan sulphate and chondroitin sulfates of cell surface glycocalyx. Cellular uptake of these modified nanoparticles increased in stiffer conditions depending on the stretch state. Namely, chondroitin sulfate A targeting improved uptake efficiency in cells experiencing dynamic stretches, while cells seeded on static stiff interstitium preferentially took up heparan sulfate targeting LNPs. These results demonstrate the critical role that mechanical stiffness and stretching play in the alveolus and the importance of including these properties in nanotherapeutic design for cancer treatment.

DOI: https://doi.org/10.1101/2023.02.27.529887
Curr Protoc. 2023 Mar;3(3): e701

Quantification of Glycosaminoglycans in Urine by Isotope-Dilution Liquid Chromatography-Electrospray Ionization Tandem Mass Spectrometry.

Haoyue Zhang, Sarah P Young, David S Millington.

  Mucopolysaccharidoses (MPSs) are complex lysosomal storage disorders that result in the accumulation of glycosaminoglycans (GAGs) in urine, blood, and tissues. Lysosomal enzymes responsible for GAG degradation are defective in MPSs. GAGs including chondroitin sulfate (CS), dermatan sulfate (DS), heparan sulfate (HS), and keratan sulfate (KS) are disease-specific biomarkers for MPSs. This article describes a stable isotope dilution-tandem mass spectrometric method for quantifying CS, DS, and HS in urine samples. The GAGs are methanolyzed to uronic or iduronic acid-N-acetylhexosamine or iduronic acid-N-sulfo-glucosamine dimers and mixed with internal standards derived from deuteriomethanolysis of GAG standards. Specific dimers derived from HS, DS, and CS are separated by ultra-performance liquid chromatography (UPLC) and analyzed by electrospray ionization tandem mass spectrometry (MS/MS) using selected reaction monitoring for each targeted GAG product and its corresponding internal standard. This UPLC-MS/MS GAG assay is useful for identifying patients with MPS types I, II, III, VI, and VII. © 2023 Wiley Periodicals LLC. Basic Protocol: Urinary GAG analysis by ESI-MS/MS Support Protocol 1: Prepare calibration samples Support Protocol 2: Preparation of stable isotope-labeled internal standards Support Protocol 3: Preparation of quality controls for GAG analysis in urine Support Protocol 4: Optimization of the methanolysis time Support Protocol 5: Measurement of the concentration of methanolic HCl.

Keywords:  LC-ESI-MS/MS; dermatan sulfate; glycosaminoglycans; heparan sulfate; isotope dilution; mucopolysaccharidosis

DOI:  https://doi.org/10.1002/cpz1.701
Cancer Res Commun. 2022 Jul;2(7): 663-678

Chemical, Molecular, and Single-nucleus Analysis Reveal Chondroitin Sulfate Proteoglycan Aberrancy in Fibrolamellar Carcinoma.

Adam B Francisco, Jine Li, Alaa R Farghli, Matt Kanke, Bo Shui, Paul R Munn, Jennifer K Grenier, Paul D Soloway, Zhangjie Wang, Lola M Reid, Jian Liu, Praveen Sethupathy.

Fibrolamellar carcinoma (FLC) is an aggressive liver cancer with no effective therapeutic options. The extracellular environment of FLC tumors is poorly characterized and may contribute to cancer growth and/or metastasis. To bridge this knowledge gap, we assessed pathways relevant to proteoglycans, a major component of the extracellular matrix. We first analyzed gene expression data from FLC and nonmalignant liver tissue (n = 27) to identify changes in glycosaminoglycan (GAG) biosynthesis pathways and found that genes associated with production of chondroitin sulfate, but not other GAGs, are significantly increased by 8-fold. We then implemented a novel LC/MS-MS based method to quantify the abundance of different types of GAGs in patient tumors (n = 16) and found that chondroitin sulfate is significantly more abundant in FLC tumors by 6-fold. Upon further analysis of GAG-associated proteins, we found that versican (VCAN) expression is significantly upregulated at the mRNA and protein levels, the latter of which was validated by IHC. Finally, we performed single-cell assay for transposase-accessible chromatin sequencing on FLC tumors (n = 3), which revealed for the first time the different cell types in FLC tumors and also showed that VCAN is likely produced not only from FLC tumor epithelial cells but also activated stellate cells. Our results reveal a pathologic aberrancy in chondroitin (but not heparan) sulfate proteoglycans in FLC and highlight a potential role for activated stellate cells.
Significance: This study leverages a multi-disciplinary approach, including state-of-the-art chemical analyses and cutting-edge single-cell genomic technologies, to identify for the first time a marked chondroitin sulfate aberrancy in FLC that could open novel therapeutic avenues in the future.

DOI: https://doi.org/10.1158/2767-9764.CRC-21-0177
Front Mol Biosci. 2023 ;10 1130064

Drosophila hedgehog signaling range and robustness depend on direct and sustained heparan sulfate interactions.

Dominique Manikowski, Georg Steffes, Jurij Froese, Sebastian Exner, Kristina Ehring, Fabian Gude, Daniele Di Iorio, Seraphine V Wegner, Kay Grobe.

  Morphogens determine cellular differentiation in many developing tissues in a concentration dependent manner. As a central model for gradient formation during animal development, Hedgehog (Hh) morphogens spread away from their source to direct growth and pattern formation in the Drosophila wing disc. Although heparan sulfate (HS) expression in the disc is essential for this process, it is not known whether HS regulates Hh signaling and spread in a direct or in an indirect manner. To answer this question, we systematically screened two composite Hh binding areas for HS in vitro and expressed mutated proteins in the Drosophila wing disc. We found that selectively impaired HS binding of the second site reduced Hh signaling close to the source and caused striking wing mispatterning phenotypes more distant from the source. These observations suggest that HS constrains Hh to the wing disc epithelium in a direct manner, and that interfering with this constriction converts Hh into freely diffusing forms with altered signaling ranges and impaired gradient robustness.

Keywords:  Drosophila; QCM-D; development; hedgehog; heparan sulfate; heparin; morphogen; wing disc

DOI:  https://doi.org/10.3389/fmolb.2023.1130064
Cell Mol Neurobiol. 2023 Mar 13.

Inhibition of Astrocytic Carbohydrate Sulfotransferase 15 Promotes Nerve Repair After Spinal Cord Injury via Mitigation of CSPG Mediated Axonal Inhibition.

Liming Li, Heping Zheng, Xuepei Ma, Jie Bai, Shumin Ma, Zhuoyue Li, Chong Qin.

  Nerve tissue regeneration is a significant problem. After neural diseases and damage such as spinal cord injury (SCI), the accumulation of chondroitin sulfate proteoglycans (CSPG) comprising axonal inhibitory glycosaminoglycan chains in the microenvironment is a major barrier that obstructs nerve repair. Interfering with the production of glycosaminoglycans, especially the critical inhibitory chains, could be a potential therapeutic strategy for SCI, which is, however, poorly defined. This study identifies Chst15, the chondroitin sulfotransferase controlling the generation of axonal inhibitory chondroitin sulfate-E, as a therapeutic target of SCI. Using a recently reported small molecular Chst15 inhibitor, this study investigates the effects of Chst15 inhibition on astrocyte behaviors and the associated consequences of in vivo disruption of the inhibitory microenvironment. Deposition of CSPGs in the extracellular matrix and migration of astrocytes are both significantly impaired by Chst15 inhibition. Administration of the inhibitor in transected spinal cord tissues of rats effectively promotes motor functional restoration and nerve tissue regeneration by a mechanism related to the attenuation of inhibitory CSPGs, glial scar formation and inflammatory responses. This study highlights the role of Chst15 in the CSPG-mediated inhibition of neural recovery after SCI and proposes an effective neuroregenerative therapeutic strategy that uses Chst15 as a potential target.

Keywords:  Astrocytes; Chondroitin sulfate proteoglycan; Chondroitin sulfotransferase; Regeneration; Spinal cord injury

DOI:  https://doi.org/10.1007/s10571-023-01333-9
Clin Appl Thromb Hemost. 2023 Jan-Dec;29:29 10760296231163251

Potency Adjusted Blended Heparin of Bovine, Ovine, and Porcine Heparin Exhibit Comparable Biologic Effects to Referenced Single-Sourced Porcine Heparin.

Guy Olson, Walter Jeske, Omer Iqbal, Emily Krupa, Amber Farooqui, Fakiha Siddiqui, Debra Hoppensteadt, Ahmed Kouta, Jawed Fareed.

  Introduction: Bovine and ovine mucosa represent alternate anticoagulants to porcine mucosa for production of unfractionated heparin (UFH). Standardized heparins from various sources can be blended and potency adjusted, blended heparins exhibit comparable effects as single-sourced porcine UFH. This study evaluated the pharmacologic profile of blended heparin and compared their activities to that of single sourced porcine, ovine, and bovine heparins. Methods: The anticoagulant effects of gravimetric and potency-adjusted heparins were evaluated with aPTT, TT, anti-Xa, anti-IIa, ACT, and TGA studies. Protamine sulfate studies were used for neutralization potential of each of the individual heparins. Results: The potency-adjusted heparins demonstrated comparable aPTT, TT, anti-Xa, anti-IIa, and ACT values at all concentrations (U/mL). However, in gravimetric studies, bovine heparin consistently showed lower values with the exception of thrombin generation inhibition studies. The protamine sulfate neutralization studies demonstrated complete neutralization at all concentrations for the potency-adjusted heparins. However, at gravimetric concentrations, minor differences were noted in the neutralization profile in each of these heparins. Conclusion: These studies support the hypothesis that blended heparin from bovine, ovine, and porcine tissue, when standardized in unit-equivalent proportions, exhibits a comparable anticoagulant profile to the single species derived heparins.

Keywords:  USP reference heparin; anticoagulant assays; blended heparins; gravimetric; heparin

DOI:  https://doi.org/10.1177/10760296231163251
J Biol Chem. 2023 Mar 15. pii: S0021-9258(23)00253-3. [Epub ahead of print] 104611

Glycocalyx engineering with heparan sulfate mimetics attenuates Wnt activity during adipogenesis to promote glucose uptake and metabolism.

Greg W Trieger, Ariane R Pessentheiner, Sean C Purcell, Courtney R Green, Natalie DeForest, Karl Willert, Amit R Majithia, Christian M Metallo, Kamil Godula, Philip L S M Gordts.

Adipose tissue (AT) plays a crucial role in maintaining metabolic homeostasis by storing lipids and glucose from circulation as intracellular fat. As peripheral tissues like AT become insulin resistant, decompensation of blood glucose levels occurs causing type 2 diabetes (T2D). Currently, modulating the glycocalyx, a layer of cell-surface glycans, is an underexplored pharmacological treatment strategy to improve glucose homeostasis in T2D patients. Here, we show a novel role for cell surface heparan sulfate (HS) in establishing glucose uptake capacity and metabolic utilization in differentiated adipocytes. Using a combination of chemical and genetic interventions, we identified that HS modulates this metabolic phenotype by attenuating levels of Wnt signaling during adipogenesis. By engineering the glycocalyx of preadipocytes with exogenous synthetic HS mimetics, we were able to enhance glucose clearance capacity after differentiation through modulation of Wnt ligand availability. These findings establish the cellular glycocalyx as a possible new target for therapeutic intervention in T2D patients by enhancing glucose clearance capacity independent of insulin secretion.

DOI: https://doi.org/10.1016/j.jbc.2023.104611
Org Lett. 2023 Mar 14.

Chemical Synthesis of Glycopeptides containing l-Arabinosylated Hydroxyproline and Sulfated Tyrosine.

Jasper W van de Sande, Bauke Albada.

Post-translationally modified peptides are important regulating molecules for living organisms. Here, we report the stereoselective total synthesis of β-1,2-linked l-arabinosylated Fmoc-protected hydroxyproline building blocks and their incorporation, together with sulfated tyrosine and hydroxyproline, into the plant peptide hormone PSY1. Clean glycopeptides were obtained by performing acetyl removal from the l-arabinose groups prior to deprotection of the neopentyl-protected sulfated tyrosine.

DOI: https://doi.org/10.1021/acs.orglett.3c00411
Glycobiology. 2023 Mar 16. pii: cwad022. [Epub ahead of print]

Impact of hyaluronan size on localization and solubility of the extracellular matrix in the mouse brain.

Diana Egorova, Yoshihiro Nomura, Shinji Miyata.

  Hyaluronan (HA) is a central component of the extracellular matrix (ECM) in the brain and plays a pivotal role in neural development and plasticity. Brain HA exists in two distinct forms of the ECM: the diffuse ECM, which is soluble in saline and detergents, and the condensed ECM, which forms aggregates, such as perineuronal nets. Although the physiological functions of HA significantly differ depending on its size, size differences in HA have not yet been examined in the two ECM types, which is partly due to the lack of methods to rapidly and accurately measure the molecular weight (MW) of HA. In this study, we established a simple method to simultaneously assess the MW of HA in multiple crude biological samples. HA was purified through single-step precipitation from tissue extracts using biotinylated HA-binding protein and streptavidin-coupled magnetic beads, followed by separation on gel electrophoresis. By applying this method to HA in the mouse brain, we revealed that the condensed ECM contained higher MW HA than the diffuse ECM. Higher MW HA and lower MW HA exhibited different spatial distributions: the former was confined to perineuronal nets, while the latter was widely present throughout the brain. Furthermore, the limited degradation of HA showed that only higher MW HA was required to form an insoluble HA-aggrecan complex. The present study demonstrated that the MW of HA in the brain strongly correlates with the localization and solubility of the ECM it forms.

Keywords:  Brain extracellular matrix; Chondroitin sulfate proteoglycans; Glycosaminoglycan; Hyaluronan; Perineuronal nets

DOI:  https://doi.org/10.1093/glycob/cwad022
J Chromatogr B Analyt Technol Biomed Life Sci. 2023 Jan 31. pii: S1570-0232(23)00025-9. [Epub ahead of print]1220 123615

A liquid chromatography-tandem mass spectrometry method for the analysis of dehydroepiandrosterone sulphate (DHEAs) in serum and plasma with comparison to an immunoassay method in a neonatal population.

Craig Livie, Louisa C Y Lee, Malika Alimussina, Carina Conceicao, Chui Ha Leung, Jane McNeilly, Syed Faisal Ahmed, Charlotte Syme, Karen Smith, Susan Johnston.

  The measurement of dehydroepiandrosterone-sulphate (DHEAs) is an important second-line test to aid in the diagnosis of premature adrenarche, peripubertal gynaecomastia in males and in identifying the source of elevated androgens in females. Historically, DHEAs has been measured by immunoassay platforms which are prone to poor sensitivity and more importantly poor specificity. The aim was to develop an LC-MSMS method for the measurement of DHEAs in human plasma and serum, develop an in-house paediatric (<6 year old) reference limit and compare the performance against the Abbott Alinity DHEAs immunoassay method. Following pre-treatment with an internal standard, samples were loaded onto EVOLUTE® EXPRESS ABN plate. Analytes were separated with reverse-phase chromatography using ACQUITY® UPLC® HSS T3 2.1 mm × 50 mm, 1.8 μm column. Mass spectrometry detection was performed using a Waters® Xevo TQ-XS in electrospray negative mode. For the paediatric reference range, samples were collected from an inpatient setting (age ≤ 6 years old) with no evidence of adrenal dysfunction or history of/current steroid use. The method comparison was performed using samples from this cohort aged between 0 and 52 weeks. The assay demonstrated linearity up to 15 µmol/L (r2 > 0.99) with a functional sensitivity of 0.1 µmol/L. Accuracy results revealed a mean bias of 0.7% (-14% to 15%) when compared against the NEQAS EQA LC-MSMS consensus mean (n = 48). The paediatric reference limit was calculated as ≤ 2.3 µmol/L (95% C.I. 1.4 to 3.8 µmol/L) for ≤ 6 year olds (n = 38). Comparison of neonatal (<52 weeks) DHEAs with the Abbott Alinity revealed that the immunoassay ran at a 166% positive bias (n = 24) which appeared to lessen with increasing age. Described is a robust LC-MSMS method for the measurement of plasma or serum DHEAs validated against internationally recognised protocols. Comparison of paediatric samples of <52 weeks against an immunoassay platform demonstrated that in the immediate new-born period results generated from the LC-MSMS method offer superior specificity than an immunoassay platform.

Keywords:  Dehydroepiandrosterone-sulphate; Immunoassay; LC-MSMS; Paediatric; Reference limit

DOI:  https://doi.org/10.1016/j.jchromb.2023.123615
Int J Biol Macromol. 2023 Mar 14. pii: S0141-8130(23)00931-5. [Epub ahead of print] 124037

Discovery of a sulfated fucan-specific carbohydrate-binding module: The first member of a new carbohydrate-binding module family CBMxx.

Xuanwei Mei, Guanchen Liu, Jingjing Shen, Guangning Chen, Yuying Zhang, Changhu Xue, Yaoguang Chang.

  Sulfated fucan is an important functional polysaccharide with various physiological activities. Carbohydrate-binding module (CBM) is a representative class of carbohydrate-binding protein, which could be employed as a favorable tool for the investigations and applications of polysaccharides. Nevertheless, only one confirmed sulfated fucan-binding CBM has been hitherto reported. In the present study, an unknown domain with a predicted β-sandwich fold was discovered from a fucanase Fun174A, and further cloned and heterologously expressed in Escherichia coli. The expressed protein Fun174A-CBMxx displayed a specific binding capacity to sulfated fucan. The bio-layer interferometry assays showed that the protein could bind to the sulfated fucan tetrasaccharide with an affinity constant of 2.83 × 10-4 M. Fun174A-CBMxx shared no significant sequence similarity to any identified CBMs, indicating that it represents a new CBM family (CBMxx). The discovery of Fun174-CBMxx and the novel CBM family would beneficial to the investigations of sulfated fucan-binding proteins.

Keywords:  CBMxx family; Carbohydrate-binding module; Sulfated fucan

DOI:  https://doi.org/10.1016/j.ijbiomac.2023.124037
Lab Invest. 2023 Mar;pii: S0023-6837(22)00406-8. [Epub ahead of print]103(3): 100025

Indoxyl Sulfate Promotes Metastatic Characteristics of Ovarian Cancer Cells via Aryl Hydrocarbon Receptor-Mediated Downregulation of the Mas Receptor.

Shinichi Saito, Yoshihiro Koya, Hiroaki Kajiyama, Mamoru Yamashita, Akihiro Nawa.

  Although platinum-combination chemotherapy shows a high response rate at the primary site, epithelial ovarian cancer (EOC) treatment remains challenging because of tumor recurrence and metastasis. Recent studies have revealed that chemotherapy paradoxically promotes cancer cell survival, proliferation, and metastasis, although the reason for this remains unclear. The underlying molecular mechanisms that contribute to chemotherapy-induced metastasis need to be elucidated to establish effective therapeutic strategies. Acute kidney injury is a known side effect of cisplatin treatment, and kidney dysfunction results in the accumulation of uremic toxins in the serum. The present study aimed to investigate whether indoxyl sulfate (IS), a representative uremic toxin, affects the pathophysiology of EOC. In this study, IS reduced the expression of Mas receptor (MasR) in cultured human EOC cells. Both knockdown of the aryl hydrocarbon receptor (AhR), which is an intracellular IS receptor, and inhibition of AhR function suppressed IS-mediated downregulation of MasR in SK-OV-3 cells. IS induced the phosphorylation of signal transducer and activator of transcription 3 (STAT3) in an AhR-dependent manner. Inhibition of the STAT3 pathway or reactive oxygen species production suppressed the IS-mediated reduction of MasR. IS stimulated cell migration and invasion of SK-OV-3 cells in an AhR-dependent manner. Cisplatin-nephropathy model mice exhibited elevated levels of serum IS accompanied by elevated levels of blood urea nitrogen and serum creatinine. Furthermore, intraperitoneal administration of IS in mice promoted tumor growth and metastasis. Finally, we found that the MasR agonist Ang-(1-7) suppressed the IS-mediated effects on cell proliferation, migration, and invasion of SK-OV-3 cells. However, the knockdown of MasR expression by specific small interfering RNA in the absence of IS resulted in only minimal promotion of cell migration and invasion. These findings demonstrate that IS promotes malignancy in ovarian cancer via AhR-mediated downregulation of MasR function, whereas Ang-(1-7) attenuates this effect, thereby suggesting that Ang-(1-7) could provide a future treatment strategy for this cancer type.

Keywords:  Mas receptor; acute kidney injury; aryl hydrocarbon receptor; cisplatin; indoxyl sulfate; ovarian cancer

DOI:  https://doi.org/10.1016/j.labinv.2022.100025
Int J Biol Macromol. 2023 Mar 13. pii: S0141-8130(23)00915-7. [Epub ahead of print] 124021

Immunomodulatory effect of sulfated galactofucan from marine macroalga Turbinaria conoides.

Shubhajit Dhara, Kajal Chakraborty.

  Sulfated polysaccharides are effective immunostimulating agents by activating several intracellular signaling pathways. A sulfated (1 → 3)/(1 → 4)-linked galactofucan TCP-3 with promising immunomodulatory effects was purified from a marine macroalga Turbinaria conoides. The immune-enhancing potential of TCP-3 (100-400 mg/kg BW) was evaluated on cyclophosphamide-induced immunosuppressed animals by increasing bone marrow cellularity (10-13 cells/femur/mL x 106), α-esterase activity (1200-1700 number of positive cells/4000 BMC), interferon-γ (1.31-1.49 pg/mL), interleukin-2 (3.49-3.99 pg/mL) secretion, and WBC count (> 8000 cells/cu mm). The proliferation of lymphocytes for in vitro and in vivo conditions was enhanced by administering TCP-3 besides regulating the secretion of pro-inflammatory cytokines (interleukin-6/1β/12, tumor necrosis factor-α, transforming growth factor-β), and an inducible isoform of nitric oxide synthase. A promising reduction of viral copy formation was observed by administering TCP-3 (< 2 × 107 number) on SARS CoV-2 (delta variant) induced Vero cells in comparison with the infected group (> 5 × 107 number).

Keywords:  Anti-SARS-CoV-2 effect; Immunomodulation; Sulfated (1 → 3)/(1 → 4)-linked galactofucan

DOI:  https://doi.org/10.1016/j.ijbiomac.2023.124021
Clin Pharmacol Ther. 2023 Mar 15.

Acetaminophen metabolites on presentation following an acute acetaminophen overdose (ATOM-7).

Angela L Chiew, Geoffrey K Isbister, Paul Stathakis, Katherine Z Isoardi, Colin Page, Kirsty Ress, Betty Sh Chan, Nicholas A Buckley.

Acetaminophen is commonly taken in overdose and can cause acute liver injury via the toxic metabolite NAPQI formed by cytochrome (CYP) P450 pathway. We aimed to evaluate the concentrations of acetaminophen metabolites on presentation following an acute acetaminophen poisoning and whether these predicted the subsequent onset of hepatotoxicity (peak ALT >1000 U/L). The Australian Toxicology Monitoring (ATOM) study is a prospective observational study, recruiting via two PICs and four toxicology units. Patients following an acute acetaminophen ingestion presenting <24h post-ingestion were recruited. Initial samples were analysed for acetaminophen metabolites those measured were the nontoxic glucuronide (APAP-Glu) and sulfate (APAP-Sul) conjugates and NAPQI (toxic metabolite) conjugates APAP-cysteine (APAP-Cys) and APAP-mercapturate (APAP-Mer). The primary outcome was hepatotoxicity. In this study, 200 patients were included, with a median ingested dose of 20g, 191 received acetylcysteine at median time of 5.8h post-ingestion. 26 developed hepatotoxicity, one had hepatotoxicity on arrival (excluded from analysis). Those who developed hepatotoxicity had significantly higher total CYP metabolite concentrations: [36.8μmol/L(IQR: 27.8-51.7) vs 10.8μmol/L(IQR:6.9-19.5)] and these were a greater proportion of total metabolites [5.4%(IQR:3.8-7.7) vs 1.7%(IQR:1.3-2.6)(p<0.001)]. Furthermore, those who developed hepatotoxicity had lower APAP-Sul concentrations [49.1μmol/L(IQR:24.7-72.2) vs 78.7μmol/L (53.6-116.4)] and lower percentage of APAP-Sul [6.3%(IQR:4.6-10.9) vs 13.1%(9.1-20.8)(p<0.001)]. This study found that those who developed hepatotoxicity had higher acetaminophen metabolites derived from CYP pathway and lower sulfation metabolite on presentation. Acetaminophen metabolites may be utilised in the future to identify patients who could benefit from increased acetylcysteine or newer adjunct or research therapies.

DOI: https://doi.org/10.1002/cpt.2888