ORCID Profile
0000-0003-2564-8068
Current Organisation
University of Leeds
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Publisher: Wiley
Date: 29-04-2011
Abstract: Hydroxycinnamic acids are abundant antioxidants in our diet. In humans, hydroxycinnamic acids are metabolized to form sulfates and glucuronides, with the majority recovered in urine. We assessed the potential roles of organic anion transporters (OATs) and ATP-binding cassette (ABC) transporters in the renal uptake and efflux of hydroxycinnamic acid conjugates. Uptake studies using OAT1 (SLC22A6)-, OAT2 (SLC22A7)-, and OAT3 (SLC22A8)-expressing 293H embryonic kidney cells showed that OAT1 and OAT3, but not OAT2, accepted hydroxycinnamic acid conjugates as substrates. OAT1 and OAT3 mediated the basolateral uptake of hydroxycinnamic acid sulfates and glucuronide conjugates, respectively. Hydroxycinnamic acid sulfates are substrates of OAT4 and were capable of trans-stimulating 5-carboxyfluorescein uptake mediated by OAT4. On the other hand, hydroxycinnamic acid conjugates are not substrates for the ABC transporters, multidrug resistance protein 2 (MRP2/ABCC2) or breast cancer resistance protein (BCRP/ABCG2), demonstrated by the inability to alter ATPase activity. Cis-inhibition studies with OATs and MRPs revealed that hydroxycinnamic acid conjugates have limited impact on the transport of model substrates significantly at physiological concentrations. Concerted action of OAT1, OAT3, and OAT4 is involved in the elimination of hydroxycinnamic acid conjugates into urine, whereas MRP2 and breast cancer resistance protein are not involved in the disposition of these conjugates.
Publisher: Elsevier BV
Date: 04-2011
DOI: 10.1016/J.BCP.2011.01.004
Abstract: Flavonoids are conjugated by phase II enzymes in humans to form glucuronidated and sulfated metabolites that are excreted in urine via the kidney. In this study, we examined the interaction between metabolites of quercetin and isoflavonoids found in vivo with human organic anion transporters 1 (OAT1) and 3 (OAT3) and their potential in attenuating OAT-induced cytotoxicity of adefovir. Accumulation of flavonoid conjugates was studied in human embryonic kidney 293H cells overexpressing OAT1 or OAT3. OAT1-overexpressing cells exhibited an increased uptake of the sulfated conjugates, genistein-4'-O-sulfate and quercetin-3'-O-sulfate. OAT3-overexpressing cells demonstrated enhanced uptake of glucuronide conjugates, such as daidzein-7-O-glucuronide, genistein-7-O-glucuronide, glycitein-7-O-glucuronide and quercetin-3'-O-glucuronide. Position of conjugation was important since quercetin-3-O-glucuronide and quercetin-7-O-glucuronide were poorly transported. Kinetic analysis revealed high affinity uptake of quercetin-3'-O-sulfate by OAT1 (K(m)=1.73μM V(max)=105 pmol/min/mg). OAT3 transported isoflavone glucuronides with lower affinity (K(m)=7.9-19.1 μM) but with higher V(max) (171-420 pmol/min/mg). Quercetin-3'-O-sulfate strongly inhibited OAT1-mediated p-aminohippuric acid uptake with an IC(50) of 1.22μM. Transport of 5-carboxyfluorescein by OAT3 was potently inhibited by quercetin-3-O-glucuronide, quercetin-3'-O-glucuronide and quercetin-3'-O-sulfate (IC(50)=0.43-1.31μM). In addition, quercetin-3'-O-sulfate was shown to effectively reduce OAT1-mediated cytotoxicity of adefovir, an antiviral drug, in a dose-dependent manner. These data suggest that OAT1 and OAT3 are responsible for basolateral uptake of flavonoid conjugates in kidney, and flavonoid conjugates inhibit OAT1 and OAT3 activity at physiologically relevant concentrations. Interaction with OATs limits systemic availability of flavonoids and may be a mechanism of food-drug interaction via inhibition of renal uptake.
Publisher: Springer Science and Business Media LLC
Date: 21-06-2022
DOI: 10.1038/S41467-022-31150-5
Abstract: Robotics and autonomous systems are reshaping the world, changing healthcare, food production and bio ersity management. While they will play a fundamental role in delivering the UN Sustainable Development Goals, associated opportunities and threats are yet to be considered systematically. We report on a horizon scan evaluating robotics and autonomous systems impact on all Sustainable Development Goals, involving 102 experts from around the world. Robotics and autonomous systems are likely to transform how the Sustainable Development Goals are achieved, through replacing and supporting human activities, fostering innovation, enhancing remote access and improving monitoring. Emerging threats relate to reinforcing inequalities, exacerbating environmental change, erting resources from tried-and-tested solutions and reducing freedom and privacy through inadequate governance. Although predicting future impacts of robotics and autonomous systems on the Sustainable Development Goals is difficult, thoroughly examining technological developments early is essential to prevent unintended detrimental consequences. Additionally, robotics and autonomous systems should be considered explicitly when developing future iterations of the Sustainable Development Goals to avoid reversing progress or exacerbating inequalities.
Publisher: Elsevier BV
Date: 08-2012
DOI: 10.1016/J.BCP.2012.05.011
Abstract: Flavonoids modulate cell signaling and inhibit oxidative enzymes. After oral consumption, they circulate in human plasma as hiphilic glucuronide or sulfate conjugates, but it is unknown how these physiological metabolites permeate into cells. We examined the mechanisms of uptake of these conjugates into hepatocellular carcinoma (HepG2) cells, and found that uptake of quercetin-3'-O-sulfate was saturable and temperature-dependent, indicating the involvement of carrier-mediated transport. Quercetin-3-O-glucuronide was taken up predominantly via passive diffusion in these cells. Quantitative real-time PCR analysis showed high expression of OATP4C1, followed by OAT2, OAT4 and low expression of OATP1B1 in HepG2 cells, and addition of inhibitors of OATs and OATPs resulted in a significant reduction in quercetin-3'-O-sulfate uptake. The accumulation of quercetin-3'-O-sulfate was further evaluated in HEK293 cells expressing OAT2, OAT4 and OATP4C1. Uptake of quercetin-3'-O-sulfate was 2.3- and 1.4-fold higher in cells expressing OAT4 and OATP4C1 at pH 6.0, respectively, than in control HEK293 cells. siRNA knockdown of OATP4C1 expression in HepG2 cells reduced uptake of quercetin-3'-O-sulfate by ∼40%. This study highlights a role for OATs and OATPs in the cellular uptake of biologically active flavonoid conjugates.
Publisher: MDPI AG
Date: 24-08-2021
DOI: 10.3390/NU13092917
Abstract: Context: Astaxanthin (ASX), a xanthophyll carotenoid derived from microalgae Haematococcus pluvialis, mitigating skin photoaging and age-related skin diseases by its antioxidant and anti-inflammatory effects in animal studies. Objective: The aim was to systematically evaluate if ASX applications have anti-ageing effects in humans. Methods: A comprehensive search of PubMed, Scopus and Web of Science found a total of eleven studies. Nine randomised, controlled human studies assessed oral ASX effects and two open-label, prospective studies evaluated topical, oral-topical ASX effects on skin ageing. GetData Graph Digitizer was used to extract mean values and standard deviations of baseline and endpoint, and Cochrane Collaboration’s tool assessed RoB for all included studies. Review Manager 5.4 was used to conduct meta-analysis of RCTs the results were reported as effect size ± 95% confidence interval. Results: Oral ASX supplementation significantly restored moisture content (SMD = 0.53 95% CI = 0.05, 1.01 I2 = 52% p = 0.03) and improved elasticity (SMD = 0.77 95% CI = 0.19, 1.35 I2 = 75% p = 0.009) but did not significantly decrease wrinkle depth (SMD = −0.26 95% CI = −0.58, 0.06 I2 = 0% p = 0.11) compared to placebo. Open-label, prospective studies suggested slightly protective effects of topical and oral-topical ASX applications on skin ageing. Conclusions: Ingestion and/or topical usages of ASX may be effective in reducing skin ageing and have promising cosmetical potential, as it improves moisture content and elasticity and reduces wrinkles.
Publisher: Oxford University Press (OUP)
Date: 23-02-2013
Abstract: Nearly all polysaccharides in plant cell walls are O-acetylated, including the various pectic polysaccharides and the hemicelluloses xylan, mannan, and xyloglucan. However, the enzymes involved in the polysaccharide acetylation have not been identified. While the role of polysaccharide acetylation in vivo is unclear, it is known to reduce biofuel yield from lignocellulosic biomass by the inhibition of microorganisms used for fermentation. We have analyzed four Arabidopsis (Arabidopsis thaliana) homologs of the protein Cas1p known to be involved in polysaccharide O-acetylation in Cryptococcus neoformans. Loss-of-function mutants in one of the genes, designated REDUCED WALL ACETYLATION2 (RWA2), had decreased levels of acetylated cell wall polymers. Cell wall material isolated from mutant leaves and treated with alkali released about 20% lower amounts of acetic acid when compared with the wild type. The same level of acetate deficiency was found in several pectic polymers and in xyloglucan. Thus, the rwa2 mutations affect different polymers to the same extent. There were no obvious morphological or growth differences observed between the wild type and rwa2 mutants. However, both alleles of rwa2 displayed increased tolerance toward the necrotrophic fungal pathogen Botrytis cinerea.
Location: United Kingdom of Great Britain and Northern Ireland
No related grants have been discovered for Caroline Orfila.