ORCID Profile
0000-0002-1838-5282
Current Organisations
MRC London Institute of Medical Sciences
,
University of Birmingham
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Publisher: Elsevier BV
Date: 05-2019
Publisher: Royal Society of Chemistry (RSC)
Date: 2017
DOI: 10.1039/C7AY00550D
Abstract: This study describes the application of Multi-platform Unbiased optimization of Spectrometry via Closed-Loop Experimentation (MUSCLE) software to automate the development of an LC-MS/MS method to measure multiple metabolites of vitamin D.
Publisher: Elsevier BV
Date: 06-2018
DOI: 10.1016/J.JCHROMB.2018.04.025
Abstract: In recent years, increased interest in the human health benefits of vitamin D has led to demand for improved analysis of patient vitamin D 'status'. Studies to date have focused primarily on a single vitamin D metabolite, 25-hydroxyvitamin D, despite the existence of a broad range of vitamin D metabolites, referred to as the vitamin D metabolome. This study reports on the development of a rapid UPSFC-MS/MS method for the analysis of nine vitamin D metabolites in human serum. Optimum separation was obtained with a Lux-Cellulose chiral column. We observed an orthogonal elution order when compared with ultra-high performance liquid chromatography (UHPLC). The order of elution was reversed based on hydroxyl- group number, however elution order did not differ between isomeric changes in hydroxyl- group position or epimers. Although UPSFC yielded superior resolution and selectivity over previously developed UHPLC-MS/MS methods, improvements in sensitivity could not be achieved owing to the lower injection volume required for UPSFC relative to UHPLC. Method validation was performed on the developed UPSFC-MS/MS method and found to be within acceptable limits. Applying the method to the analysis of human serum s les showed a significant correlation with serum concentrations of metabolites measured by UHPLC-MS/MS (25OHD3 r = 0.997, P=<0.001, and 3-epi-25OHD3 r = 0.996, P ≤0.001). These data indicate that UPSFC provides an efficient analytical platform for rapid analysis of multiple vitamin D metabolites from serum.
Publisher: American College of Physicians
Date: 03-2022
DOI: 10.7326/M21-1737
Publisher: Cold Spring Harbor Laboratory
Date: 03-2021
DOI: 10.1101/2021.03.01.431439
Abstract: Pregnancy 25-hydroxyvitamin D (25(OH)D) concentrations are associated with maternal and fetal health outcomes. Using physiological human placental perfusion and villous explants, we investigate the role of the placenta in regulating the relationships between maternal 25(OH)D and fetal physiology. We demonstrate active placental uptake of 25(OH)D3 by endocytosis, placental metabolism of 25(OH)D3 into 24,25-dihydroxyvitamin D3 and active 1,25-dihydroxyvitamin D [1,25(OH)2D3], with subsequent release of these metabolites into both the maternal and fetal circulations. Active placental transport of 25(OH)D3 and synthesis of 1,25(OH)2D3 demonstrate that fetal supply is dependent on placental function rather than simply the availability of maternal 25(OH)D3. We demonstrate that 25(OH)D3 exposure induces rapid effects on the placental transcriptome and proteome. These map to multiple pathways central to placental function and thereby fetal development, independent of vitamin D transfer. Our data suggest that the underlying epigenetic landscape helps dictate the transcriptional response to vitamin D treatment. This is the first quantitative study demonstrating vitamin D transfer and metabolism by the human placenta, with widespread effects on the placenta itself. These data demonstrate a complex interplay between vitamin D and the placenta and will inform future interventions using vitamin D to support fetal development and maternal adaptations to pregnancy.
Publisher: Cold Spring Harbor Laboratory
Date: 31-05-2019
DOI: 10.1101/648410
Abstract: Treatment options for idiopathic intracranial hypertension are limited. The enzyme 11β-hydroxysteroid dehydrogenase type 1 has been implicated in regulating cerebrospinal fluid secretion, and its activity is associated with alterations in intracranial pressure in idiopathic intracranial hypertension. We assessed therapeutic efficacy, safety and tolerability, and investigate indicators of in vivo efficacy of the 11β-hydroxysteroid dehydrogenase type 1 inhibitor AZD4017 compared to placebo in idiopathic intracranial hypertension. A multicenter, UK, 16-week phase II randomized, double-blind, placebo-controlled trial of 12-weeks treatment with AZD4017 or placebo was conducted. Women aged 18 to 55 years with active idiopathic intracranial hypertension ( cmH 2 O lumbar puncture opening pressure and active papilledema) were included. Participants received 400mg twice daily of oral AZD4017 compared to matching placebo over 12-weeks. The outcome measures were initial efficacy, safety and tolerability. The primary clinical outcome was lumbar puncture opening pressure at 12 weeks analysed by intention-to-treat. Secondary clinical outcomes were symptoms, visual function, papilledema, headache and anthropological measures. In vivo efficacy was evaluated in the central nervous system and systemically. 31 subjects (mean age 31.2 (SD=6.9) years and BMI 39.2 (SD=12.6) kg/m 2 ) were randomized to AZD4017 (n=17) or placebo (n=14). At 12 weeks, lumbar puncture pressure was lower in the AZD4017 group (29.7 cmH 2 O) compared with placebo (31.3 cmH 2 O), but the difference between groups was not statistically significant (mean difference: −2.8, 95% confidence interval: −7.1-1.5 p=0.2). An exploratory analysis assessing mean change in lumbar puncture pressure within each group found a significant decrease in the AZD4017 group (mean change: −4.3 cmH 2 O (SD=5.7) p =0.009) but not in the placebo group (mean change: −0.3 cmH 2 O (SD=5.9) p=0.8). AZD4017 was safe, with no withdrawals related to adverse effects. Nine transient drug-related adverse events were reported. One serious adverse event occurred in the placebo group (deterioration requiring shunt surgery). In vivo biomarkers of 11β-hydroxysteroid dehydrogenase type 1 activity (urinary glucocorticoid metabolites, hepatic prednisolone generation and CSF cortisone to cortisol ratios) demonstrated significant enzyme inhibition. This is the first phase 2 randomized controlled trial in idiopathic intracranial hypertension evaluating a novel therapeutic target. AZD4017 was safe, well-tolerated and inhibited 11β-hydroxysteroid dehydrogenase type 1 activity in vivo . Possible clinical benefits were noted in this small cohort. A longer, larger study would now be of interest.
Publisher: Oxford University Press (OUP)
Date: 21-06-2023
DOI: 10.1093/JALM/JFAD030
Publisher: eLife Sciences Publications, Ltd
Date: 06-12-2021
Publisher: Wiley
Date: 22-07-2019
DOI: 10.1002/CBF.3421
Abstract: Current understanding of vitamin D tends to be focussed on the measurement of the major circulating form 25-hydroxyvitamin D3 (25OHD3) and its conversion to the active hormonal form, 1α,25-dihydroxyvitamin D3 (1α,25(OH)
Publisher: Elsevier BV
Date: 05-2018
DOI: 10.1016/J.JCHROMB.2018.03.033
Abstract: Liquid chromatography tandem mass spectrometry (LC-MS/MS) assays are considered the reference standard for serum steroid hormone analyses, while full urinary steroid profiles are only achievable by gas chromatography (GC-MS). Both LC-MS/MS and GC-MS have well documented strengths and limitations. Recently, commercial ultra-high performance supercritical fluid chromatography-tandem mass spectrometry (UHPSFC-MS/MS) systems have been developed. These systems combine the resolution of GC with the high-throughput capabilities of UHPLC. Uptake of this new technology into research and clinical labs has been slow, possibly due to the perceived increase in complexity. Here we therefore present fundamental principles of UHPSFC-MS/MS and the likely applications for this technology in the clinical research setting, while commenting on potential hurdles based on our experience to date.
Publisher: Elsevier BV
Date: 10-2018
Publisher: eLife Sciences Publications, Ltd
Date: 08-03-2022
DOI: 10.7554/ELIFE.71094
Abstract: Pregnancy 25-hydroxyvitamin D [25(OH)D] concentrations are associated with maternal and fetal health outcomes. Using physiological human placental perfusion and villous explants, we investigate the role of the placenta in regulating the relationships between maternal 25(OH)D and fetal physiology. We demonstrate active placental uptake of 25(OH)D 3 by endocytosis, placental metabolism of 25(OH)D 3 into 24,25-dihydroxyvitamin D 3 and active 1,25-dihydroxyvitamin D [1,25(OH) 2 D 3 ], with subsequent release of these metabolites into both the maternal and fetal circulations. Active placental transport of 25(OH)D 3 and synthesis of 1,25(OH) 2 D 3 demonstrate that fetal supply is dependent on placental function rather than simply the availability of maternal 25(OH)D 3 . We demonstrate that 25(OH)D 3 exposure induces rapid effects on the placental transcriptome and proteome. These map to multiple pathways central to placental function and thereby fetal development, independent of vitamin D transfer. Our data suggest that the underlying epigenetic landscape helps dictate the transcriptional response to vitamin D treatment. This is the first quantitative study demonstrating vitamin D transfer and metabolism by the human placenta, with widespread effects on the placenta itself. These data demonstrate a complex interplay between vitamin D and the placenta and will inform future interventions using vitamin D to support fetal development and maternal adaptations to pregnancy.
Publisher: The Endocrine Society
Date: 27-09-2021
Abstract: Vitamin D status is conventionally defined by measurement of unconjugated circulating 25-hydroxyvitamin D (25OHD), but it remains uncertain whether this isolated analysis gives sufficient weight to vitamin D’s erse metabolic pathways and bioactivity. Emerging evidence has shown that phase II endocrine metabolites are important excretory or storage forms however, the clinical significance of circulating phase II vitamin D metabolites remains uncertain. In this study we analyzed the contribution of sulfate and glucuronide vitamin D metabolites relative to unconjugated levels in human serum. An optimized enzyme hydrolysis method using recombinant arylsulfatase (Pseudomonas aeruginosa) and beta-glucuronidase (Escherichia coli) was combined with liquid chromatography mass spectrometry (LC-MS/MS) analysis to measure conjugated and unconjugated vitamin D metabolites 25OHD3, 25OHD2, 3-epi-25OHD3, and 24,25(OH)2D3. The method was applied to the analysis of 170 human serum s les from community-dwelling men aged over 70 years, categorized by vitamin D supplementation status, to evaluate the proportions of each conjugated and unconjugated fraction. As a proportion of total circulating vitamin D metabolites, sulfate conjugates (ranging between 18% and 53%) were a higher proportion than glucuronide conjugates (ranging between 2.7% and 11%). The proportion of conjugated 25OHD3 (48 ± 9%) was higher than 25OHD2 conjugates (29.1 ± 10%) across all supplementation groups. Conjugated metabolites correlated with their unconjugated forms for all 4 vitamin D metabolites (r = 0.85 to 0.97). Sulfated conjugates form a high proportion of circulating vitamin D metabolites, whereas glucuronide conjugates constitute a smaller fraction. Our findings principally in older men highlight the differences in abundance between metabolites and suggest a combination of both conjugated and unconjugated measurements may provide a more accurate assessment of vitamin D status.
Location: United Kingdom of Great Britain and Northern Ireland
Location: United Kingdom of Great Britain and Northern Ireland
Location: United Kingdom of Great Britain and Northern Ireland
No related grants have been discovered for Carl Jenkinson.