ORCID Profile
0000-0001-5794-748X
Current Organisations
Swansea University Department of Biosciences
,
Nottingham Trent University
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Publisher: American Society for Clinical Investigation
Date: 03-06-2013
DOI: 10.1172/JCI64162
Publisher: Springer Science and Business Media LLC
Date: 08-2019
Publisher: Elsevier BV
Date: 08-2017
Publisher: Wiley
Date: 18-10-2016
DOI: 10.1002/PATH.4806
Publisher: Elsevier BV
Date: 08-2019
Publisher: Wiley
Date: 22-11-2019
Publisher: The Endocrine Society
Date: 27-03-2017
DOI: 10.1210/EN.2016-1722
Abstract: Glucocorticoids (GCs) are potent regulators of energy metabolism. Chronic GC exposure suppresses brown adipose tissue (BAT) thermogenic capacity in mice, with evidence for a similar effect in humans. Intracellular GC levels are regulated by 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) activity, which can lify circulating GC concentrations. Therefore, 11β-HSD1 could modulate the impact of GCs on BAT function. This study investigated how 11β-HSD1 regulates the molecular architecture of BAT in the context of GC excess and aging. Circulating GC excess was induced in 11β-HSD1 knockout (KO) and wild-type mice by supplementing drinking water with 100 μg/mL corticosterone, and the effects on molecular markers of BAT function and mitochondrial activity were assessed. Brown adipocyte primary cultures were used to examine cell autonomous consequences of 11β-HSD1 deficiency. Molecular markers of BAT function were also examined in aged 11β-HSD1 KO mice to model lifetime GC exposure. BAT 11β-HSD1 expression and activity were elevated in response to GC excess and with aging. 11β-HSD1 KO BAT resisted the suppression of uncoupling protein 1 (UCP1) and mitochondrial respiratory chain subunit proteins normally imposed by GC excess. Furthermore, brown adipocytes from 11β-HSD1 KO mice had elevated basal mitochondrial function and were able to resist GC-mediated repression of activity. BAT from aged 11β-HSD1 KO mice showed elevated UCP1 protein and mitochondrial content, and a favorable profile of BAT function. These data reveal a novel mechanism in which increased 11β-HSD1 expression, in the context of GC excess and aging, impairs the molecular and metabolic function of BAT.
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: Elsevier BV
Date: 08-2018
Publisher: The Endocrine Society
Date: 15-05-2017
Publisher: Bioscientifica
Date: 10-01-2014
DOI: 10.1530/JOE-13-0494
Abstract: The activity of the enzyme 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1), which converts inactive cortisone (11-dehydrocorticosterone (11-DHC)) (in mice) into the active glucocorticoid (GC) cortisol (corticosterone in mice), can lify tissue GC exposure. Elevated TNFα is a common feature in a range of inflammatory disorders and is detrimental to muscle function in diseases such as rheumatoid arthritis and chronic obstructive pulmonary disease. We have previously demonstrated that 11β-HSD1 activity is increased in the mesenchymal stromal cells (MSCs) by TNFα treatment and suggested that this is an autoregulatory anti-inflammatory mechanism. This upregulation was mediated by the P2 promoter of the Hsd11b1 gene and was dependent on the NF-κB signalling pathway. In this study, we show that in contrast to MSCs, in differentiated C2C12 and primary murine myotubes, TNFα suppresses Hsd11b1 mRNA expression and activity through the utilization of the alternative P1 promoter. As with MSCs, in response to TNFα treatment, NF-κB p65 was translocated to the nucleus. However, ChIP analysis demonstrated that the direct binding was seen at position −218 to −245 bp of the Hsd11b1 gene's P1 promoter but not at the P2 promoter. These studies demonstrate the existence of differential regulation of 11β-HSD1 expression in muscle cells through TNFα 65 signalling and the P1 promoter, further enhancing our understanding of the role of 11β-HSD1 in the context of inflammatory disease.
Publisher: Wiley
Date: 26-12-2019
DOI: 10.1113/JP278752
Publisher: Cold Spring Harbor Laboratory
Date: 17-03-2021
DOI: 10.1101/2021.03.15.21253591
Abstract: Alveolar macrophage dysfunction may contribute to Acute Respiratory Distress Syndrome (ARDS) pathogenesis, however this has been little studied. Objective: To investigate the pathophysiological link between alveolar macrophage efferocytosis, alveolar neutrophil apoptosis and clinical outcomes in ARDS patients, and to determine whether efferocytosis can be restored. Ventilated sepsis patients with or without ARDS underwent broncho-alveolar lavage. Apoptosis of alveolar neutrophils was assessed using flow cytometry. Alveolar macrophages were isolated and used in flow cytometric efferocytosis assays with labelled apoptotic neutrophils. Alveolar macrophages were also isolated from the lung tissue of lobectomy patients, then treated with pooled ARDS BAL fluid prior to functional assessment. Rac1 gene expression was assessed using RT-qPCR. Patients with sepsis-related ARDS have decreased alveolar macrophage efferocytosis and increased alveolar neutrophil apoptosis compared to control ventilated sepsis patients. Across all ventilated sepsis patients, alveolar macrophage efferocytosis correlated negatively with alveolar cytokines (IL-8, IL-1ra), duration of ventilation and mortality. ARDS BAL treatment of alveolar macrophages decreased efferocytosis and Rac1 gene expression, however bacterial phagocytosis was preserved. Unexpectedly, alveolar macrophage efferocytosis receptor expression (MerTK, CD206) decreased and expression of the anti-efferocytosis receptor SIRPα increased following ARDS BAL treatment. Rho-associated kinase inhibition partially restored alveolar macrophage efferocytosis in an in vitro model of ARDS. Patients with sepsis-related ARDS have impaired AM efferocytosis, which potentially contributes to ARDS pathogenesis and negatively impacts clinical outcomes, including mortality. Strategies to upregulate AM efferocytosis may be of value for attenuating inflammation in ARDS.
Publisher: Springer Science and Business Media LLC
Date: 16-08-2019
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 Gareth Lavery.