Papers by Saoirse O'Sullivan
Pharmaceuticals
Cachexia syndrome, leading to reduced skeletal muscle and fat mass, is highly prevalent in cancer... more Cachexia syndrome, leading to reduced skeletal muscle and fat mass, is highly prevalent in cancer patients, resulting in further negative implications for these patients. To date, there is no approved therapy for cachexia syndrome. The objective of this study was to establish an in vitro model of cancer cachexia in mature human skeletal muscle myotubes, with the intention of exploiting the cell model to assess potential cachexia therapeutics, specifically cannabinoid related drugs. Having cultured and differentiated primary human muscle myoblasts to mature myotubes, we successfully established two cancer cachexia models using conditioned media (CM) from human colon adenocarcinoma (SW480) and from non-small-cell lung carcinoma (H1299) cultured cells. The cancer-CM-induced extensive myotube degeneration, demonstrated by a significant reduction in mature myotube diameter, which progressed over the period studied. Myotube degeneration is a characteristic feature of cancer cachexia and w...
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Prostaglandins & Other Lipid Mediators
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Pharmacology & Therapeutics
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Cannabis and Cannabinoid Research
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Wellcome Open Research, 2021
Background: Animal models of stroke have been criticised as having poor predictive validity, lack... more Background: Animal models of stroke have been criticised as having poor predictive validity, lacking risk factors prevalent in an aging population. This pilot study examined the development of comorbidities in a combined aged and high-fat diet model, and then examined the feasibility of modelling stroke in such rats. Methods: Twelve-month old male Wistar-Han rats (n=15) were fed a 60% fat diet for 8 months during which monthly serial blood samples were taken to assess the development of metabolic syndrome and pro-inflammatory markers. Following this, to pilot the suitability of these rats for undergoing surgical models of stroke, they underwent 30min of middle cerebral artery occlusion (MCAO) alongside younger controls fed a standard diet (n=10). Survival, weight and functional outcome were monitored, and blood vessels and tissues collected for analysis. Results: A high fat diet in aged rats led to substantial obesity. These rats did not develop type 2 diabetes or hypertension. Ther...
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European Journal of Neurology, 2020
Background and purposeRemote ischaemic per‐conditioning (RIC) is neuroprotective in experimental ... more Background and purposeRemote ischaemic per‐conditioning (RIC) is neuroprotective in experimental ischaemic stroke. Several neurohumoral, vascular and inflammatory mediators are implicated. The effect of RIC on plasma biomarkers was assessed using clinical data from the REmote ischaemic Conditioning After Stroke Trial (RECAST‐1).MethodsRECAST‐1 was a pilot sham‐controlled blinded trial in 26 patients with ischaemic stroke, randomized to receive four 5‐min cycles of RIC within 24 h of ictus. Plasma taken pre‐intervention, immediately post‐intervention and on day 4 was analysed for nitric oxide (nitrate/nitrite) using chemiluminescence and all other biomarkers by multiplex analysis. Biomarkers were correlated with clinical outcome (day 90 National Institutes of Health Stroke Scale, modified Rankin Scale, Barthel index).ResultsRemote ischaemic per‐conditioning reduced serum amyloid protein (SAP) and tissue necrosis factor α (TNF‐α) levels from pre‐ to post‐intervention (n = 13, two‐way ...
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Cannabis and Cannabinoid Research, 2021
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Medical Cannabis and Cannabinoids, 2021
Introduction: Cannabidiol (CBD) can be isolated from Cannabis sativa L. or synthetically produced... more Introduction: Cannabidiol (CBD) can be isolated from Cannabis sativa L. or synthetically produced. The aim of this study was to compare the in vitro effects of purified natural and synthetic CBD to establish any pharmacological differences or superiority between sources. Methods: Six purified samples of CBD were obtained, 4 of these were natural and 2 synthetic. The anticancer effects of CBD were assessed in a human ovarian cancer cell line (SKOV-3 cells). The neuroprotective effects of CBD were assessed in human pericytes in a model of stroke (oxygen glucose deprivation [OGD]). The ability of CBD to restore inflammation-induced intestinal permeability was assessed in differentiated human Caco-2 cells (a model of enterocytes). Results: (1) In proliferating and confluent SKOV-3 cells, all CBD samples similarly reduced resazurin metabolism as a marker of cell viability in a concentration-dependent manner (p < 0.001). (2) In pericytes exposed to OGD, all CBD samples similarly reduce...
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British Journal of Pharmacology, 2020
Embase and PubMed were systematically searched for articles addressing the neuroprotective proper... more Embase and PubMed were systematically searched for articles addressing the neuroprotective properties of phytocannabinoids, apart from cannabidiol and Δ9‐tetrahydrocannabinol, including Δ9‐tetrahydrocannabinolic acid, Δ9‐tetrahydrocannabivarin, cannabidiolic acid, cannabidivarin, cannabichromene, cannabichromenic acid, cannabichromevarin, cannabigerol, cannabigerolic acid, cannabigerivarin, cannabigerovarinic acid, cannabichromevarinic acid, cannabidivarinic acid, and cannabinol. Out of 2,341 studies, 31 articles met inclusion criteria. Cannabigerol (range 5 to 20 mg·kg−1) and cannabidivarin (range 0.2 to 400 mg·kg−1) displayed efficacy in models of Huntington's disease and epilepsy. Cannabichromene (10–75 mg·kg−1), Δ9‐tetrahydrocannabinolic acid (20 mg·kg−1), and tetrahydrocannabivarin (range 0.025–2.5 mg·kg−1) showed promise in models of seizure and hypomobility, Huntington's and Parkinson's disease. Limited mechanistic data showed cannabigerol, its derivatives VCE.003...
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Neuro-Oncology, 2020
Paediatric brain tumours are the second most common cancer after haematological malignancies. Int... more Paediatric brain tumours are the second most common cancer after haematological malignancies. Intermittent dosing regimens are typical for chemotherapy drugs in order to avoid excessive damage to organs and avoid the onset of late effects. Cannabidiol (CBD) has been shown to have cytotoxic properties on paediatric brain tumour cell lines. Although CBD is far less toxic and damaging than the classical chemotherapy options which are currently available to children suffering with brain tumours, there are some possible side effects. Given that the half-life of the drug is 24 hours, it was important to establish the nature of the effect of cumulative dosing on top of the remaining drug in the system. The pHGG cell line, SF188 was cultured in different concentrations of CBD with either 1, 2 or 3 doses being given on consecutive days. 24 hours after the last dose the cells were analysed using the resazurin assay. It was observed that the amount of drug required for an EC50 to be obtained d...
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Neuro-Oncology, 2020
Brain tumours are the leading cause of cancer related death in children with limited treatment op... more Brain tumours are the leading cause of cancer related death in children with limited treatment options and high recurrence rates. Recent evidence suggests there may be anti-tumoral properties of cannabinoids, and of cannabidiol (CBD) in particular. We evaluated the effect of CBD on paediatric brain tumour cell lines in 2D and 3D spheroids; pHGG (SF188), ependymoma (BxD-1425EPN) and human astrocytes. At the CBD EC50 concentration, astrocytic cell death was insignificant. 3D spheroids decreased in size by approximately 20% when cultured in CBD compared to cells only after 5-day exposure. Cell death increased with time after a single dose of CBD. Western Blot showed an increase in Lc3b expression (autophagy) after 24 hours incubation (early cell death) with CBD in both BxD-1425EPN and SF188 with PARP expression (apoptosis) increased after 5 days incubation (late cell death). Cell cycle analysis showed a decrease of cells in G1 and no change in G2 indicating cell cycle arrest. In hypoxi...
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Frontiers in Endocrinology, 2020
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Basic Science, 2019
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Journal of Cellular Physiology, 2019
Some human observational studies have suggested an anti‐inflammatory role of osteocalcin (OCN). A... more Some human observational studies have suggested an anti‐inflammatory role of osteocalcin (OCN). An inflammatory protocol using interferon‐γ and tumor necrosis factor‐α (10 ng/ml) was employed to examine the acute (24 hr) and chronic (144 hr) effects of uncarboxylated OCN (ucOCN) in commercial, primary, subcultured human aortic endothelial cells (HAEC), and human smooth muscle cells (HASMCs). The inflammatory protocol increased phosphorylation of intracellular signaling proteins (CREB, JNK, p38, ERK, AKT, STAT3, STAT5) and increased secretion of adhesion markers (vascular cell adhesion molecule‐1, intracellular adhesion molecule‐1, monocyte chemoattractant protein‐1) and proinflammatory cytokines (interleukin‐6 [IL‐6], IL‐8). After acute inflammation, there were no additive or reductive effects of ucOCN in either cell type. Following chronic inflammation, ucOCN did not affect cell responses, nor did it appear to have any pro‐ or anti‐inflammatory effects when administered acutely or ...
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PeerJ, 2019
Bone-derived factors that demonstrate extra-skeletal functions, also termed osteokines, are fast ... more Bone-derived factors that demonstrate extra-skeletal functions, also termed osteokines, are fast becoming a highly interesting and focused area of cross-disciplinary endocrine research. Osteocalcin (OCN), fibroblast growth factor-23 (FGF23) and lipocalin-2 (LCN-2), produced in bone, comprise an important endocrine system that is finely tuned with other organs to ensure homeostatic balance and health. This review aims to evaluatein vitroevidence of the direct involvement of these proteins in vascular cells and whether any causal roles in cardiovascular disease or inflammation can be supported. PubMed, Medline, Embase and Google Scholar were searched for relevant research articles investigating the exogenous addition of OCN, FGF23 or LCN-2 to vascular smooth muscle or endothelial cells. Overall, these osteokines are directly vasoactive across a range of human and animal vascular cells. Both OCN and FGF23 have anti-apoptotic properties and increase eNOS phosphorylation and nitric oxide...
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British Journal of Clinical Pharmacology, 2019
AimsCannabidiol (CBD) is a cannabis‐derived medicinal product with potential application in a wid... more AimsCannabidiol (CBD) is a cannabis‐derived medicinal product with potential application in a wide‐variety of contexts; however, its effective dose in different disease states remains unclear. This review aimed to investigate what doses have been applied in clinical populations, in order to understand the active range of CBD in a variety of medical contexts.MethodsPublications involving administration of CBD alone were collected by searching PubMed, EMBASE and ClinicalTrials.gov.ResultsA total of 1038 articles were retrieved, of which 35 studies met inclusion criteria covering 13 medical contexts. Twenty‐three studies reported a significant improvement in primary outcomes (e.g. psychotic symptoms, anxiety, seizures), with doses ranging between <1 and 50 mg/kg/d. Plasma concentrations were not provided in any publication. CBD was reported as well tolerated and epilepsy was the most frequently studied medical condition, with all 11 studies demonstrating positive effects of CBD on r...
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Frontiers in Cellular Neuroscience, 2019
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Journal of Cellular Physiology, 2019
The purpose of this study was to characterize the direct effects of uncarboxylated osteocalcin (u... more The purpose of this study was to characterize the direct effects of uncarboxylated osteocalcin (ucOCN) on vascular cell biology in vitro, to assess its potential function in pathophysiological conditions such as atherosclerosis. Human aortic endothelial cells (HAECs) and smooth muscle cells (HASMCs) were treated with ucOCN (0.1–50 ng/ml) and changes in phosphorylation of intracellular signaling proteins, angiogenesis, proliferation, migration, monolayer permeability, and protein secretion were measured. In HAECs, phosphorylated JNK and CREB were decreased with ucOCN (p < 0.05). In HASMCs, phosphorylated p70S6K and NF‐ΚB were increased by ucOCN (p < 0.05). Cell proliferation increased in both cell types dose dependently which was blocked by AKT and ERK pathway inhibitors. ucOCN did not affect cell permeability, angiogenesis, or migration. The direct activity of ucOCN on vascular cells is recognized, particularly its proliferative effects. However, at least in physiological sett...
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Inflammatory Bowel Diseases, 2019
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Papers by Saoirse O'Sullivan