bims-supasi 2024-09-22 papers

bims-supasi

Biomed News

on Sulfation pathways and signalling

Issue of 2024‒09‒22
thirteen papers selected by
Jonathan Wolf Mueller, University of Birmingham

Sulfation pathways in the maintenance of functional beta-cell mass and implications for diabetes.
Evaluation of the protective effects of chondroitin sulfate oligosaccharide against osteoarthritis via inactivation of NLRP3 inflammasome by in vivo and in vitro studies.
Sulfated polysaccharide from Apostichopus japonicus viscera exhibits anti-inflammatory properties in vitro and in vivo.
Regioselective sulfation of alginate at 2-O-position of mannuronic acid unit with Py∙SO3 in DMSO.
Tyrosylprotein Sulfotransferase Positively Regulates Symbiotic Nodulation and Root Growth.
Improving the Determination of Carbon Isotope Ratios of Endogenous Steroids Found in Human Serum.
Sulfated glycosaminoglycans are host epithelial cell targets of the Candida albicans toxin candidalysin.
18β-Glycyrrhetinic acid synergizes with enzalutamide to counteract castration-resistant prostate cancer by inhibiting OATP2B1 uptake of dehydroepiandrosterone sulfate.
Chitosan-chondroitin sulfate-daidzein nanoconjugate ameliorates glucocorticoid induced osteoporosis in vivo.
Laser-responsive erastin-loaded chondroitin sulfate nanomedicine targeting CD44 and system xc- in liver cancer: A non-ferroptotic approach.
Human sulfotransferase SULT2B1 physiological role and the impact of genetic polymorphism on enzyme activity and pathological conditions.
Lead toxicity mitigation effect of a Lactiplantibacillus plantarum-chondroitin sulfate complex revealed by microbiome and metabolomic analyses.
Pharmacokinetics of Ethyl Glucuronide and Ethyl Sulfate and Pharmacodynamic Effects Following Intravenous and Oral Administration of Ethanol to Exercised Horses.

Essays Biochem. 2024 Sep 18. pii: EBC20240034. [Epub ahead of print]

Sulfation pathways in the maintenance of functional beta-cell mass and implications for diabetes.

Jonathan Wolf Mueller, Patricia Thomas, Louise Torp Dalgaard, Gabriela da Silva Xavier.

  Diabetes Type 1 and Type 2 are widely occurring diseases. In spite of a vast amount of biomedical literature about diabetic processes in general, links to certain biological processes are only becoming evident these days. One such area of biology is the sulfation of small molecules, such as steroid hormones or metabolites from the gastrointestinal tract, as well as larger biomolecules, such as proteins and proteoglycans. Thus, modulating the physicochemical propensities of the different sulfate acceptors, resulting in enhanced solubility, expedited circulatory transit, or enhanced macromolecular interaction. This review lists evidence for the involvement of sulfation pathways in the maintenance of functional pancreatic beta-cell mass and the implications for diabetes, grouped into various classes of sulfated biomolecule. Complex heparan sulfates might play a role in the development and maintenance of beta-cells. The sulfolipids sulfatide and sulfo-cholesterol might contribute to beta-cell health. In beta-cells, there are only very few proteins with confirmed sulfation on some tyrosine residues, with the IRS4 molecule being one of them. Sulfated steroid hormones, such as estradiol-sulfate and vitamin-D-sulfate, may facilitate downstream steroid signaling in beta-cells, following de-sulfation. Indoxyl sulfate is a metabolite from the intestine, that causes kidney damage, contributing to diabetic kidney disease. Finally, from a technological perspective, there is heparan sulfate, heparin, and chondroitin sulfate, that all might be involved in next-generation beta-cell transplantation. Sulfation pathways may play a role in pancreatic beta-cells through multiple mechanisms. A more coherent understanding of sulfation pathways in diabetes will facilitate discussion and guide future research.

Keywords:  beta-cells; diabetes; insulin; sulfate activation; sulfation pathways

DOI:  https://doi.org/10.1042/EBC20240034
Int Immunopharmacol. 2024 Sep 13. pii: S1567-5769(24)01669-2. [Epub ahead of print]142(Pt A): 113148

Evaluation of the protective effects of chondroitin sulfate oligosaccharide against osteoarthritis via inactivation of NLRP3 inflammasome by in vivo and in vitro studies.

Yu-Ting Chang, Kuo-Ching Huang, Rosita Pranata, Yen-Lin Chen, Ssu-Ning Chen, Yung-Hsuan Cheng, Rong-Jane Chen.

  Osteoarthritis (OA) is the most prevalent degenerative arthritis disease linked to aging, obesity, diet, and accumulation of octacalcium phosphate (OCP) crystals in joints. Current research has focused on inflammation and chondrocytes apoptosis as underlying OA mechanisms. Inflammatory cytokines like IL-1β activate matrix metalloproteinase-13 (MMP-13) and aggrecanase (the member of A Disintegrin and Metalloproteinase with Thrombospondin motifs family, ADAMTS), leading to cartilage matrix degradation. The NLRP3 inflammasome also contributes to OA pathogenesis by maturing IL-1β. Natural products like chondroitin sulfate oligosaccharides (oligo-CS) show promise in OA treatment by inhibiting inflammation. Our study evaluates the protective effects of oligo-CS against OA by targeting NLRP3 inflammation. Stimulating human SW1353 chondrocytes and human mononuclear macrophage THP-1 cells with OCP showed increased NLRP3 inflammation initiation, NF-κB pathway activation, and the production of inflammatory cytokines (IL-1β, IL-6) and the metabolic index (MMP-13, ADAMTS-5), leading to cartilage matrix degradation. However, oligo-CS treatment significantly reduced inflammation. In a 28-day in vivo study with C57BL/6 female mice, OCP was injected into their right knee and oligo-CS was orally administered. The OCP group exhibited significant joint space narrowing and chondrocyte loss, while the oligo-CS group maintained cartilage integrity. Oligo-CS groups also regulated gut microbiota composition to a healthier state. Taken together, our findings suggest that oligo-CS can be considered as a protective compound against OA.

Keywords:  Chondroitin sulfate oligosaccharides; Gut microbiota; NLRP3 inflammasome; Octacalcium phosphate; Osteoarthritis

DOI:  https://doi.org/10.1016/j.intimp.2024.113148
Int J Biol Macromol. 2024 Sep 12. pii: S0141-8130(24)06308-6. [Epub ahead of print]280(Pt 1): 135500

Sulfated polysaccharide from Apostichopus japonicus viscera exhibits anti-inflammatory properties in vitro and in vivo.

Jing Ye, Linjing Zheng, Weipeng Pan, Yayan Huang, Na Zhang, Dongda Yang, Yucheng Yang, Bingde Zheng, Xueqin Zhang, Meitian Xiao.

  Polysaccharides from sea cucumbers are known for their biological activities, but little is known about those from sea cucumber viscera. The present study isolated a sulfated polysaccharide (SCVP-2) from the viscera of Apostichopus japonicas, which had a molecular weight of 209.1 kDa. SCVP-2 comprised 66.3 % total sugars, 2.1 % uronic acid, 4.5 % proteins, and 25.5 % sulfate groups, containing glucosamine, galactosamine, glucose, galactose, and fucose. FT-IR and NMR analyses identified SCVP-2 as a fucoidan sulfate with sulfation patterns of the fucose branches as Fuc2S, Fuc4S, and Fuc0S. SEM and AFM analyses showed irregular clusters and linear conformations. SCVP-2 demonstrated strong anti-inflammatory properties both in vitro and in vivo. In lipopolysaccharide (LPS)-induced inflammation in macrophage RAW264.7 cells, SCVP-2 significantly reduced nitric oxide (NO) and cytokine secretion (IL-1β, IL-6, TNF-α). Additionally, it downregulated the expression of these cytokine genes. Furthermore, the anti-inflammatory mechanism of SCVP-2 was related to the inhibition of the MAPKs and NF-κB pathways. SCVP-2's anti-inflammatory capacity was confirmed in acute inflammation models, including xylene-induced ear swelling and acetic acid-induced peritoneal capillary permeability, and in high-fat diet-induced systemic low-grade chronic inflammation. In conclusion, SCVP-2 exhibits significant anti-inflammatory activity, suggesting its potential for development as a functional food ingredient or therapeutic agent for inflammation-related diseases.

Keywords:  Anti-inflammation; Apostichopus japonicus viscera; Chemical structure; MAPKs; NF-κB; Sulfated polysaccharide

DOI:  https://doi.org/10.1016/j.ijbiomac.2024.135500
Carbohydr Res. 2024 Sep 14. pii: S0008-6215(24)00255-6. [Epub ahead of print]545 109276

Regioselective sulfation of alginate at 2-O-position of mannuronic acid unit with Py∙SO3 in DMSO.

Karl Martin Ingerma, Indrek Reile, Rando Tuvikene.

  Alginates are brown algal polysaccharides consisting of β-D-mannuronic (M) and α-l-guluronic acid (G) residues linked with 1→4 glycosidic bonds. To functionalize these natural resources for biomedical use, alginates can be chemically modified, including by sulfation. Here regioselective sulfation of alginates at M-2 in DMSO with Py∙SO3 is described, by either sulfating alginates directly or through using alginates with added protecting groups (PG-s), including TBDMS-ether, Piv-, Bz-esters and intramolecular 3,6-lactone. Highest regioselectivity was found by sulfating TBDMS- and Piv-protected alginates, with over 65 % of M-residues being 2-O-sulfated. However significant reduction in molecular weight was found when alginates were sulfated in DMSO. Results from this work will allow a degree of control over substitution patterns in sulfated alginates. This will allow to more accurately determine structure-property relationships in biomedical research.

Keywords:  Alginate; Protecting groups; Regioselective sulfation; Sulfated alginate

DOI:  https://doi.org/10.1016/j.carres.2024.109276
Plant Cell Environ. 2024 Sep 17.

Tyrosylprotein Sulfotransferase Positively Regulates Symbiotic Nodulation and Root Growth.

Danping Zhang, Qi Di, Jinshan Gui, Qiong Li, Kirankumar S Mysore, Jiangqi Wen, Li Luo, Liangliang Yu.

  Posttranslational tyrosine sulfation of peptides and proteins is catalysed by tyrosylprotein sulfotransferases (TPSTs). In Arabidopsis, tyrosine sulfation is essential for the activities of peptide hormones, such as phytosulfokine (PSK) and root meristem growth factor (RGF). Here, we identified a TPST-encoding gene, MtTPST, from model legume Medicago truncatula. MtTPST expression was detected in all organs, with the highest level in root nodules. A promoter:GUS assay revealed that MtTPST was highly expressed in the root apical meristem, nodule primordium and nodule apical meristem. The loss-of-function mutant mttpst exhibited a stunted phenotype with short roots and reduced nodule number and size. Application of both of the sulfated peptides PSK and RGF3 partially restored the defective root length of mttpst. The reduction in symbiotic nodulation in mttpst was partially recovered by treatment with sulfated PSK peptide. MtTPST-PSK module functions downstream of the Nod factor signalling to promote nodule initiation via regulating accumulation and/or signalling of cytokinin and auxin. Additionally, the small-nodule phenotype of mttpst, which resulted from decreased apical meristematic activity, was partially complemented by sulfated RGF3 treatment. Together, these results demonstrate that MtTPST, through its substrates PSK, RGF3 and other sulfated peptide(s), positively regulates nodule development and root growth.

Keywords:  Medicago truncatula; PSK; RGF; root growth; symbiotic nodulation; tyrosylprotein sulfotransferase

DOI:  https://doi.org/10.1111/pce.15154
Drug Test Anal. 2024 Sep 16.

Improving the Determination of Carbon Isotope Ratios of Endogenous Steroids Found in Human Serum.

Thomas Piper, Mario Thevis.

  The determination of serum concentrations of testosterone (T) and 4-androstenedione (A4) was implemented into the steroidal module of the Athlete Biological Passport in 2023. Monitoring T, A4, and the ratio of T/A4 in a longitudinal manner enables the detection of the misuse of low-dose T administrations especially in female athletes, whereas urinary markers of the steroid profile may not be influenced significantly. In contrast to the urinary steroid profile, knowledge on confounding factors regarding serum concentrations of T and A4 is yet comparably scarce, and corroborating exogenous sources of the target analytes by isotope ratio mass spectrometry (IRMS) is desirable. In a recent study, it was demonstrated that carbon isotope ratios (CIRs) of serum steroids can be determined if analyte concentrations permit. The therein-employed method utilized 2D-GC/IRMS, and only a limited number of potential endogenous reference compounds were available. The here-presented approach uses complementary analyte purification strategies, addressing previous limitations. A high-performance liquid chromatography cleanup was developed and fully validated for serum steroids in order to enable all doping control laboratories to potentially implement this method alongside existing protocols for urinary steroids. Besides the already-investigated endogenous steroids cholesterol, dehydroepiandrosterone sulfate, androsterone sulfate, and epiandrosterone sulfate, two additional steroids were included in the test menu, namely, pregnenolone sulfate and 5-androstene-3β,17β-diol sulfate. Serum steroid concentrations down to 25 ng/mL were found to allow robust CIR determinations, and a reference population encompassing 124 male and female athlete samples was investigated to enable the calculation of population-based thresholds for all relevant steroid combinations.

Keywords:  carbon isotope ratios; doping controls; endogenous steroids; human serum; isotope ratio mass spectrometry

DOI:  https://doi.org/10.1002/dta.3793
Nat Microbiol. 2024 Sep 16.

Sulfated glycosaminoglycans are host epithelial cell targets of the Candida albicans toxin candidalysin.

Jianfeng Lin, Jian Miao, Katherine G Schaefer, Charles M Russell, Robert J Pyron, Fuming Zhang, Quynh T Phan, Norma V Solis, Hong Liu, Masato Tashiro, Jonathan S Dordick, Robert J Linhardt, Michael R Yeaman, Gavin M King, Francisco N Barrera, Brian M Peters, Scott G Filler.

Candidalysin, a cytolytic peptide produced by the fungal pathogen Candida albicans, is a key virulence factor. However, its host cell targets remain elusive. Here we performed a genome-wide loss-of-function CRISPR screen in the TR146 human oral epithelial cell line and identified that disruption of genes (XYLT2, B3GALT6 and B3GAT3) in glycosaminoglycan (GAG) biosynthesis conferred resistance to damage induced by candidalysin and live C. albicans. Surface plasmon resonance and atomic force and electron microscopy indicated that candidalysin binds to sulfated GAGs, facilitating its enrichment on the host cell surface. Adding exogenous sulfated GAGs or the analogue dextran sulfate protected cells against candidalysin-induced damage. Dextran sulfate also inhibited C. albicans invasion and fungal-induced epithelial cell cytokine production. In mice with vulvovaginal candidiasis, topical dextran sulfate administration reduced intravaginal tissue damage and inflammation. Collectively, sulfated GAGs are epithelial cell targets of candidalysin and can be used therapeutically to protect cells from candidalysin-induced damage.

DOI: https://doi.org/10.1038/s41564-024-01794-8
Eur J Pharmacol. 2024 Sep 12. pii: S0014-2999(24)00685-X. [Epub ahead of print]983 176995

18β-Glycyrrhetinic acid synergizes with enzalutamide to counteract castration-resistant prostate cancer by inhibiting OATP2B1 uptake of dehydroepiandrosterone sulfate.

Ting Lu, Bin Liao, Ronghe Lin, Chao Meng, Ping Huang, Cheng Wang, Fanglan Liu, Chunhua Xia.

  Androgen dependence is a key feature of prostate cancer, and androgen deprivation is effective in treating prostate cancer. However, the disease often worsens and develops into castration-resistant prostate cancer after short-term control. The current study aimed to explore the mechanism of the synergistic action of 18β-glycyrrhetinic acid (18β-GA) and enzalutamide (ENZ) against prostate cancer. Our findings showed that 18β-GA significantly inhibited the expression of OATP2B1 and the transport of dehydroepiandrosterone sulfate (DHEAS) in LNCap and 22RV1 cells. It also downregulated the expression of androgen receptor (AR) to some extent. ENZ strongly inhibited AR expression, but it did not affect OATP2B1-mediated uptake of DHEAS. Compared to the effects of 18β-GA and ENZ alone, the combination of 18β-GA and ENZ significantly enhanced the inhibitory effects on AR, prostate-specific antigen (PSA) expression, tumor cell proliferation, and migration. The results obtained in castrated model mice matched the findings of in vitro experiments. 18β-GA significantly reduced the uptake of DHEAS mediated by OATP2B1 in mouse tumor tissues and cooperated with ENZ to further inhibit the expression of AR and PSA, combat the growth of tumor cells, and promote the apoptosis of tumor cells. In conclusion, 18β-GA considerably decreased the uptake of DHEAS and androgen production in cells by inhibiting the transport function of OATP2B1, while ENZ inhibited the nuclear translocation of AR and reduced the expression of AR. The combination of 18β-GA and ENZ can simultaneously inhibit androgen production and AR expression and exhibit a synergistic effect against castration and prostate cancer progression.

Keywords:  18β-glycyrrhetinic acid; Enzalutamide; OATP2B1; Prostate cancer; Synergistic action

DOI:  https://doi.org/10.1016/j.ejphar.2024.176995
Int J Biol Macromol. 2024 Sep 14. pii: S0141-8130(24)06470-5. [Epub ahead of print]280(Pt 1): 135662

Chitosan-chondroitin sulfate-daidzein nanoconjugate ameliorates glucocorticoid induced osteoporosis in vivo.

P Snega Priya, Rachitha Surisetti, Sanjay Gopi, Raman Pachaiappan, Mukesh Pasupuleti, Rajakrishnan Rajagopal, Ahmed Alfarhan, Ajay Guru, Jesu Arockiaraj.

  The use of nanotechnology and polymer-based carriers in osteoporosis treatment offers promising avenues for targeted drug delivery and enhanced therapeutic efficacy. In this study, we developed a novel nanoconjugate composed of Chitosan (CH), Chondroitin Sulfate (CS), and Daidzein (DZ) to treat glucocorticoid-induced osteoporosis in an in vivo zebrafish model. The CH-CS-DZ nanoconjugate were synthesized using the ionic gelation method, with a CH: CS ratio of 1:1 and a 3 % DZ concentration was identified as optimal for further analysis. The resulting nanoparticles exhibited a particle size of 401.2 ± 0.87 nm. The polydispersity index (PDI) and zeta potential of nanoconjugate were of 0.147 ± 0.04 and 43.55 ± 0.68 mV respectively. Drug release studies demonstrated that 79.66 ± 4.04 % of DZ was released under physiological conditions (pH 7.5) after 96 h, indicating a sustained release profile beneficial for prolonged therapeutic effects. In vivo, studies using zebrafish larvae revealed a significant reduction in oxidative stress and apoptosis in the CH-CS-DZ treated group compared to the glucorticoid dexamethasone (Dex) treated group. Specifically, reactive oxygen species (ROS) levels were reduced, and lipid peroxidation was markedly decreased (p < 0.001) in the CH-CS-DZ treated group. Additionally, the survival and hatching rates of CH-CS-DZ-treated larvae were 94 % and 95 %, respectively, significantly higher than those in the Dex-treated group. The CH-CS-DZ nanoconjugate also restored bone mineralization, as evidenced by a significant increase in calcium deposition (p < 0.001) and alkaline phosphatase (ALP) activity (122 ± 0.4 U/L), compared to the Dex group (84 ± 0.7 U/L). Gene expression analysis showed upregulation of OPG and ALP and downregulation of RANKL and RUNX2b, further indicating the anti-osteoporotic potential of the CH-CS-DZ nanoconjugates. These findings suggest that polymer-based nanoconjugates like CH-CS-DZ can effectively mitigate osteoporosis through targeted delivery and sustained release, offering a potent strategy for bone health restoration.

Keywords:  Nanotechnology; Osteoprotegerin; Polymers; Targeted delivery; Zebrafish

DOI:  https://doi.org/10.1016/j.ijbiomac.2024.135662
J Control Release. 2024 Sep 16. pii: S0168-3659(24)00639-4. [Epub ahead of print]

Laser-responsive erastin-loaded chondroitin sulfate nanomedicine targeting CD44 and system xc- in liver cancer: A non-ferroptotic approach.

So-Yeol Yoo, Hyun Young Kim, Dong Hyun Kim, Wan Seob Shim, Sang Min Lee, Dong Hwan Lee, Jang Mo Koo, Ji Hoon Yoo, Seokjin Koh, Jong Chan Park, Jieun Yu, Jang Su Jeon, Min-Jun Baek, Dae-Duk Kim, Ji-Yoon Lee, Soo Jin Oh, Sang Kyum Kim, Jae-Young Lee, Keon Wook Kang.

  Erastin, a ferroptosis-inducing system xc- inhibitor, faces clinical challenges due to suboptimal physicochemical and pharmacokinetic properties, as well as relatively low potency and off-target toxicity. Addressing these, we developed ECINs, a novel laser-responsive erastin-loaded nanomedicine utilizing indocyanine green (ICG)-grafted chondroitin sulfate A (CSA) derivatives. Our aim was to improve erastin's tumor targeting via CSA-CD44 interactions and enhance its antitumor efficacy through ICG's photothermal and photodynamic effects in the laser-on state while minimizing off-target effects in the laser-off state. ECINs, with their nanoscale size of 186.7 ± 1.1 nm and high erastin encapsulation efficiency of 93.0 ± 0.8 %, showed excellent colloidal stability and sustained drug release up to 120 h. In vitro, ECINs demonstrated a mechanism of cancer cell inhibition via G1-phase cell cycle arrest, indicating a non-ferroptotic action. In vivo biodistribution studies in SK-HEP-1 xenograft mice revealed that ECINs significantly enhanced tumor distribution of erastin (1.9-fold greater than free erastin) while substantially reducing off-target accumulation in the lungs and spleen by 203-fold and 19.1-fold, respectively. Combined with laser irradiation, ECINs significantly decreased tumor size (2.6-fold, compared to free erastin; 2.4-fold, compared to ECINs without laser irradiation) with minimal systemic toxicity. This study highlights ECINs as a dual-modality approach for liver cancer treatment, demonstrating significant efficacy against tumors overexpressing CD44 and system xc-.

Keywords:  CD44–xCT axis; Cell cycle arrest; Chondroitin sulfate a nanomedicine; Erastin; Hepatocellular carcinoma; Photothermal and photodynamic therapy

DOI:  https://doi.org/10.1016/j.jconrel.2024.09.029
Front Genet. 2024 ;15 1464243

Human sulfotransferase SULT2B1 physiological role and the impact of genetic polymorphism on enzyme activity and pathological conditions.

Fatemah A Alherz.

  Human SULT2B1gene is responsible for expressing SULT2B1a and SULT2B1b enzymes, which are phase II metabolizing enzymes known as pregnenolone and cholesterol sulfotransferase (SULT), respectively. They are expressed in several tissues and contribute to steroids and hydroxysteroids homeostasis. Genetic variation of the SULT2B1 is reported to be associated with various pathological conditions, including autosomal recessive ichthyosis, cardiovascular disease, and different types of cancers. Understanding the pathological impact of SULT2B1 genetic polymorphisms in the human body is crucial to incorporating these findings in evaluating clinical conditions or improving therapeutic efficacy. Therefore, this paper summarized the most relevant reported studies concerning SULT2B1 expression, tissue distribution, substrates, and reported genetic polymorphisms and their mechanisms in enzyme activity and pathological conditions.

Keywords:  SULT2B1; autosomal recessive ichthyosis; cholesterol sulfotransferase; colon cancer; polymorphism; pregnenolone sulfotransferase

DOI:  https://doi.org/10.3389/fgene.2024.1464243
Food Funct. 2024 Sep 18.

Lead toxicity mitigation effect of a Lactiplantibacillus plantarum-chondroitin sulfate complex revealed by microbiome and metabolomic analyses.

Feng Chen, Jiani Pan, Leilei Yu, Chuan Zhang, Jianxin Zhao, Fengwei Tian, Qixiao Zhai, Wei Chen.

Lead (Pb) is a highly toxic metal with no physiological function in humans, accumulates in the body through food intake, and causes gut microbiome disorders and other hazards. In the present study, we examined the efficacy of a combination of chondroitin sulfate and Lactiplantibacillus plantarum CCFM8661 (CCFM8661 + CS) on tissue Pb accumulation and pathological damage to the liver and kidneys, gut microbiota, and fecal metabolites in Pb-exposed mice. Oral administration of CCFM8661 + CS to Pb-exposed mice reduced Pb accumulation in the liver, kidney, and bone tissues (from 3.70, 14.11 and 121.20 mg g-1 wet tissue to 2.26, 8.72 and 65.57 mg g-1 wet tissue, respectively) and increased total antioxidant capacity, superoxide dismutase, and glutathione in the liver and kidneys. Additionally, gut microbiome analysis showed that CCFM8661 + CS intervention attenuated Pb-induced perturbation in gut microbiota, altering the abundance of bacteria such as Faecalibaculum, Ruminococcaceae UCG 014, Anaerostipes, and Enterorhabdus. Untargeted metabolomics analyses showed that CCFM8661 + CS significantly increased cinnamoylglycine, hippuric acid, and equol (to 31.24, 28.77 and 20.13 times the baseline, respectively) and decreased guanine and 4-coumaric acid (0.30 and 0.09 times the baseline, respectively) in the feces, affecting pathways such as purine and amino acid metabolism. Further analyses showed that promoting Pb excretion and restoring the Pb-impaired gut microbiome and its metabolism may be important contributors to CCFM8661 + CS alleviation of Pb toxicity.

DOI: https://doi.org/10.1039/d4fo02815e
Drug Test Anal. 2024 Sep 15.

Pharmacokinetics of Ethyl Glucuronide and Ethyl Sulfate and Pharmacodynamic Effects Following Intravenous and Oral Administration of Ethanol to Exercised Horses.

Heather K Knych, Jeff Blea, Mary Scollay, Philip H Kass, Daniel S McKemie.

  Ethanol, a central nervous system depressant and banned substance in horseracing, has reportedly been administered to horses prior to competition to "calm a horse's nerves." In this study, the pharmacokinetics of two metabolites of ethanol were studied to better understand the behavior of this compound in the horse and provide a scientific basis for regulation of its administration. Six horses received a single intravenous (30 mL; 1200 mg) and oral (90 mL; 3600 mg) administration of ethanol (vodka, 40% ABV) in a balanced cross-over design. Blood and urine samples were collected at various times post administration for up to 24 h. Concentrations of ethyl glucuronide and ethyl sulfate were determined using liquid chromatography-tandem mass spectrometry and pharmacokinetic analysis performed. Behavioral, locomotor activity and effects on heart rate were assessed. The maximum concentration (mean ± SD) of ethyl glucuronide was 71.5 ± 42.7 and 105.0 ± 47.5 ng/mL at 0.88 h following IV and oral administration, respectively. The maximum concentrations for the ethyl sulfate metabolite following IV and oral administration were 1.61 ± 0.60 and 3.46 ± 1.68 ng/mL, respectively. Urine concentrations of both metabolites were non-detectable by 24 h post ethyl alcohol administration. No observable behavioral responses were noted following IV or oral administration. Significant decreases in heart rate were noted at various times starting at 10 min until 4 h post administration in the oral dose group. Both ethyl glucuronide and ethyl sulfate could be useful markers for detection of illicit administration of ethanol to horses.

Keywords:  ethanol; ethyl glucuronide; ethyl sulfate; horsepharmacodynamicspharmacokinetics

DOI:  https://doi.org/10.1002/dta.3803