Pharmacology and Therapeutics - Journal Articles

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Acceptability of microneedle-patch vaccines: A qualitative analysis of the opinions of parents
(Elsevier Ltd., 2017-08-02) Marshall, Sarah; Fleming, Aoife; Moore, Anne C.; Sahm, Laura J.; Health Research Board
Vaccines incorporated into microneedle-based patch platforms offer advantages over conventional hypodermic injections. However, the success and clinical utility of these platforms will depend on its acceptance among stakeholders. Minimal focus has been placed on determining parents' acceptability of microneedle-patch vaccines intended for paediatric use. This qualitative study probes the perceived acceptability of microneedle technology for paediatric vaccination in a parent population. Focus groups (n=6) were convened through purposive sampling of Cork city primary schools. Discussions were audio-recorded, transcribed verbatim, anonymised, independently verified and analysed by thematic analysis, with constant comparison method applied throughout. The opinions of 32 parents were included. All participants declared that their children were fully vaccinated. Five core themes were identified and defined as: (i) concern, (ii) suitability for paediatric use, (iii) potential for parental administration, (iv) the role of the healthcare professional and (v) special populations. Drivers for acceptance include; concerns with current vaccines and vaccination programmes; attributes of microneedle-patch (reduced pain, bleeding, fear and increased convenience) and endorsement by a healthcare professional. Barriers to acceptance include; lack of familiarity, concerns regarding feasibility and suitability in paediatrics, allergic potential, inability to confirm delivery and potential reduction in vaccine coverage. This is the first study to explore parental acceptance of microneedle-patch vaccines. Capturing the opinions of parents, the ultimate decision makers in paediatric vaccination, is crucial in the understanding of the eventual uptake of microneedle technology and therefore adds to literature currently available. This study has revealed that even "vaccine-acceptors"; parents who agree with, or do not question vaccination, will question the safety and efficacy of this novel method. Participants in this study remained tentative. However, the study has also revealed that endorsement by healthcare professionals could reduce this tentativeness, thereby identifying the role of healthcare professionals in disseminating information and providing support to parents. An increased awareness of developments in microneedle technology is needed to permit informed decision-making by parents.
Activation of a TLR9 mediated innate immune response in preeclampsia
(Nature Publishing Group, 2019-04-11) Williamson, Rachel D.; McCarthy, Fergus P.; Kenny, Louise C.; McCarthy, Cathal M.; Science Foundation Ireland; Health Research Board
Preeclampsia is a multisystemic disorder leading to the development of a placental ischemic microenvironment with a resultant increase in oxidative stress. There is evidence that mitochondrial dysfunction and the innate immune system both play a role in the pathophysiology of this disease. Mitochondrial DAMPs such as mtDNA bind specific pattern recognition receptors such as Toll-like receptor 9 (TLR9) on the endosomal surface of immune cells, in particular neutrophils, subsequently activating them and triggering an innate response. We hypothesised that the exaggerated innate immune response seen in preeclampsia is provoked by dysfunctional mitochondria. Here we provide evidence that TLR9 activity is significantly increased at time of disease in women with preeclampsia. Furthermore, we show activation of neutrophil markers, Calprotectin, Myeloperoxidase (MPO), and IL-8 are significantly increased at time of disease compared to uncomplicated pregnancies. This research supports a potential role of TLR9 activation of an innate immune response evident in preeclampsia which may possibly be initially triggered by dysfunctional mitochondria.
Age-dependent differences in pulmonary host responses in ARDS: A prospective observational cohort study
(Springer Open, 2019-05-14) Schouten, Laura R.; van Kaam, Anton H.; Kohse, Franziska; Veltkamp, Floor; Bos, Lieuwe D.; de Beer, Friso M.; van Hooijdonk, Roosmarijn T.; Horn, Janneke; Straat, Marleen; Witteveen, Esther; Glas, Gerie J.; Wieske, Luuk; van Vught, Lonneke A.; Wiewel, Maryse A.; Ingelse, Sarah A.; Cortjens, Bart; van Woensel, Job B.; Bos, Albert P.; Walther, Thomas; Schultz, Marcus J.; Wösten-van Asperen, Roelie M.; Center for Translational Molecular Medicine
Background: Results from preclinical studies suggest that age-dependent differences in host defense and the pulmonary renin–angiotensin system (RAS) are responsible for observed differences in epidemiology of acute respiratory distress syndrome (ARDS) between children and adults. The present study compares biomarkers of host defense and RAS in bronchoalveolar lavage (BAL) fluid from neonates, children, adults, and older adults with ARDS. Methods: In this prospective observational study, we enrolled mechanical ventilated ARDS patients categorized into four age groups: 20 neonates (< 28 days corrected postnatal age), 29 children (28 days–18 years), 26 adults (18–65 years), and 17 older adults (> 65 years of age). All patients underwent a nondirected BAL within 72 h after intubation. Activities of the two main enzymes of RAS, angiotensin converting enzyme (ACE) and ACE2, and levels of biomarkers of inflammation, endothelial activation, and epithelial damage were determined in BAL fluid. Results: Levels of myeloperoxidase, interleukin (IL)-6, IL-10, and p-selectin were higher with increasing age, whereas intercellular adhesion molecule-1 was higher in neonates. No differences in activity of ACE and ACE2 were seen between the four age groups. Conclusions: Age-dependent differences in the levels of biomarkers in lungs of ARDS patients are present. Especially, higher levels of markers involved in the neutrophil response were found with increasing age. In contrast to preclinical studies, age is not associated with changes in the pulmonary RAS.
Angiotensin receptors and β-catenin regulate brain endothelial integrity in malaria
(American Society for Clinical Investigation, 2016-09-19) Gallego-Delgado, Julio; Basu-Roy, Upal; Ty, Maureen; Alique, Matilde; Fernandez-Arias, Cristina; Movila, Alexandru; Gomes, Pollyanna; Weinstock, Ada; Xu, Wenyue; Edagha, Innocent; Wassmer, Samuel C.; Walther, Thomas; Ruiz-Ortega, Marta; Rodriguez, Ana
Cerebral malaria is characterized by cytoadhesion of Plasmodium falciparum–infected red blood cells (Pf-iRBCs) to endothelial cells in the brain, disruption of the blood-brain barrier, and cerebral microhemorrhages. No available antimalarial drugs specifically target the endothelial disruptions underlying this complication, which is responsible for the majority of malaria-associated deaths. Here, we have demonstrated that ruptured Pf-iRBCs induce activation of β-catenin, leading to disruption of inter–endothelial cell junctions in human brain microvascular endothelial cells (HBMECs). Inhibition of β-catenin–induced TCF/LEF transcription in the nucleus of HBMECs prevented the disruption of endothelial junctions, confirming that β-catenin is a key mediator of P. falciparum adverse effects on endothelial integrity. Blockade of the angiotensin II type 1 receptor (AT1) or stimulation of the type 2 receptor (AT2) abrogated Pf-iRBC–induced activation of β-catenin and prevented the disruption of HBMEC monolayers. In a mouse model of cerebral malaria, modulation of angiotensin II receptors produced similar effects, leading to protection against cerebral malaria, reduced cerebral hemorrhages, and increased survival. In contrast, AT2-deficient mice were more susceptible to cerebral malaria. The interrelation of the β-catenin and the angiotensin II signaling pathways opens immediate host-targeted therapeutic possibilities for cerebral malaria and other diseases in which brain endothelial integrity is compromised.
Angiotensin-(1-7) counteracts the transforming effects triggered by angiotensin II in breast cancer cells
(Impact Journals, 2017) Cambados, Nadia; Walther, Thomas; Nahmod, Karen; Tocci, Johanna M.; Rubinstein, Natalia; Boehme, Ilka; Simian, Marina; Sampayo, Rocio; Del Valle Suberbordes, Melisa; Kordon, Edith C.; Schere-Levy, Carolina; Deutsche Forschungsgemeinschaft; Ministerio de Ciencia, Tecnología e Innovación Productiva; National Cancer Institute; Consejo Nacional de Investigaciones Científicas y Técnicas; Agencia Nacional de Promoción Científica y Tecnológica
Angiotensin (Ang) II, the main effector peptide of the renin-angiotensin system, has been implicated in multiple aspects of cancer progression such as proliferation, migration, invasion, angiogenesis and metastasis. Ang-(1-7), is a biologically active heptapeptide, generated predominantly from AngII by the enzymatic activity of angiotensin converting enzyme 2. Previous studies have shown that Ang-(1-7) counterbalances AngII actions in different pathophysiological settings. In this study, we have analysed the impact of Ang( 1-7) on AngII-induced pro-tumorigenic features on normal murine mammary epithelial cells NMuMG and breast cancer cells MDA-MB-231. AngII stimulated the activation of the survival factor AKT in NMuMG cells mainly through the AT1 receptor. This PI3K/AKT pathway activation also promoted epithelial-mesenchymal transition (EMT). Concomitant treatment of NMuMG cells with AngII and Ang-(1-7) completely abolished EMT features induced by AngII. Furthermore, Ang-(1-7) abrogated AngII induced migration and invasion of the MDA-MB-231 cells as well as pro-angiogenic events such as the stimulation of MMP-9 activity and VEGF expression. Together, these results demonstrate for the first time that Ang-(1-7) counteracts tumor aggressive signals stimulated by AngII in breast cancer cells emerging the peptide as a potential therapy to prevent breast cancer progression.
Beneficial effects of magnesium treatment on heart rate variability and cardiac ventricular function in diabetic rats
(Sage, 2016-06-08) Amoni, Matthew; Kelly-Laubscher, Roisin; Blackhurst, Dee; Gwanyanya, Asfree; National Research Foundation; University of Capetown; ADInstruments, Australia
Background: Diabetes mellitus induces life-threatening cardiovascular complications such as cardiac autonomic neuropathy and ventricular dysfunction and is associated with hypomagnesemia. In this study, we investigated the short-term effects of magnesium (Mg2+) treatment on streptozotocin (STZ)-induced diabetic cardiac complications. Methods: Adult Wistar rats were treated once with STZ (50 mg/kg, intraperitoneally [ip]) or vehicle (citrate) and then daily for 7 days with MgSO4 (270 mg/kg, ip) or saline. On the eighth day, in vivo tail-pulse plethysmography was recorded for heart rate variability (HRV) analysis, and ex vivo Langendorff-based left ventricular (LV) pressure–volume parameters were measured using an intraventricular balloon. Measurements of plasma lipid and Mg2+ levels as well as blood glucose and cardiac tissue Mg2+ levels were also performed. Results: Treatment with Mg2+ prevented diabetes-induced alterations in the standard deviation of the averages of normal-to-normal (NN) intervals (SDANN), root mean square differences of successive NN intervals (RMSSD), heart rate, and low-frequency (LF) power–high-frequency (HF) power ratio. In addition, Mg2+ restored orthostatic stress-induced changes in SDANN, RMSSD, and LF–HF ratio in diabetic rats. In isolated hearts, Mg2+ reversed the diabetes-induced decrease in LV end-diastolic elastance and the right shift of end-diastolic equilibrium volume intercept, without altering LV-developed pressure or end-systolic elastance. However, Mg2+ did not prevent the elevation in blood glucose, total cholesterol, and triglycerides or the decrease in high-density lipoprotein cholesterol in diabetes. Plasma- or cardiac tissue Mg2+ was not different among the treatment groups. Conclusion: These results suggest that Mg2+ treatment may attenuate diabetes-induced reduction in HRV and improve LV diastolic distensibility, without preventing hyperglycemia and dyslipidemia. Thus, Mg2+ may have a modulatory role in the early stages of diabetic cardiovascular complications.
Bioaccessibility and bioavailability of a marine-derived multimineral, Aquamin-Magnesium
(MDPI AG, 2018) Felice, Valeria D.; O'Gorman, Denise M.; O'Brien, Nora M.; Hyland, Niall P.; Marigot Ltd; Irish Research Council; Science Foundation Ireland
Introduction: Magnesium is an essential mineral involved in a range of key biochemical pathways. Several magnesium supplements are present on the market and their degree of bioavailability differs depending on the form of magnesium salt used. Aquamin-Mg is a natural source of magnesium, containing 72 additional trace minerals derived from the clean waters off the Irish coast. However, the in vitro bioaccessibility and bioavailability of Aquamin-Mg in comparison with other supplement sources of magnesium has yet to be tested. Method: Aquamin-Mg, magnesium chloride (MgCl2) and magnesium oxide (MgO) were subjected to gastrointestinal digestion according to the harmonized INFOGEST in vitro digestion method and in vitro bioavailability tested using the Caco-2 cell model. Magnesium concentration was measured by atomic absorption spectrophotometry (AAS). Results: Magnesium recovery from both Aquamin-Mg and MgCl2 was greater than for MgO. Magnesium from all three sources was transported across the epithelial monolayer with Aquamin-Mg displaying a comparable profile to the more bioavailable MgCl2. Conclusions: Our data support that magnesium derived from a marine-derived multimineral product is bioavailable to a significantly greater degree than MgO and displays a similar profile to the more bioavailable MgCl2 and may offer additional health benefits given its multimineral profile.
Bone regenerative potential of the selective sphingosine 1-phosphate receptor modulator siponimod: In vitro characterisation using osteoblast and endothelial cells
(Elsevier B.V., 2020-06-10) Sartawi, Ziad; Ryan, Katie B.; Waeber, Christian
The repair of critical bone defects remains a significant therapeutic challenge. While the implantation of drug-eluting scaffolds is an option, a drug with the optimal pharmacological properties has not yet been identified. Agents acting at sphingosine 1-phosphate (S1P) receptors have been considered, but those investigated so far do not discriminate between the five known S1P receptors. This work was undertaken to investigate the potential of the specific S1P1/5 modulator siponimod as a bone regenerative agent, by testing in vitro its effect on cell types critical to the bone regeneration process. hFOB osteoblasts and HUVEC endothelial cells were treated with siponimod and other S1P receptor modulators and investigated for changes in intracellular cyclic AMP content, viability, proliferation, differentiation, attachment and cellular motility. Siponimod showed no effect on the viability and proliferation of osteoblasts and endothelial cells, but increased osteoblast differentiation (as shown by increased alkaline phosphatase activity). Furthermore, siponimod significantly increased endothelial cell motility in scratch and transwell migration assays. These effects on osteoblast differentiation and endothelial cell migration suggest that siponimod may be a potential agent for the stimulation of localised differentiation of osteoblasts in critical bone defects.
Building a supportive framework for brain research in Ireland: Inaugural position paper of the Irish Brain Council
(John Wiley & Sons, Inc., 2019-01-23) Rogers, Mags; Boland, Barry; Clarke, Sarah; Craven, Audrey; Fassbender, Catherine; Gill, Michael; Hardiman, Orla; Henshall, David C.; Lynch, Tim; Mitchell, Kevin; Pender, Niall; Rogan, Carol; Roche, Richard A. P.
Cardioprotective and anti-arrhythmic effects of magnesium pretreatment against ischaemia/reperfusion injury in isoprenaline-induced hypertrophic rat heart
(Springer, 2015-12-22) Amoni, Matthew; Kelly-Laubscher, Roisin; Petersen, Morea; Gwanyanya, Asfree; University of Cape Town; National Research Foundation
The effects of magnesium (Mg2+) on ischaemic complications of pathological cardiac hypertrophy are unclear. In this study, we investigated effects of Mg2+ pretreatment on ischaemia/reperfusion (I/R) injury in isoprenaline (ISO)-induced hypertrophic hearts. Wistar rats were treated for 7 days with different combinations of ISO (1.25 mg/kg) subcutaneously, MgSO4 (270 mg/kg) intraperitoneally, or vehicle (saline). On the eighth day, hearts were either subjected to regional I/R during Langendorff perfusion or histologically stained with haematoxylin and eosin and Masson’s trichrome. Haemodynamic and electrocardiographic parameters were recorded using the PowerLab data-acquisition system. Infarcts were identified by triphenyltetrazolium chloride staining. Plasma Mg2+ was measured using photometric assays. Mg2+ pretreatment significantly decreased I/R-induced infarct size (p = 0.001) and the overall arrhythmia score (p < 0.001) of I/R-induced ventricular ectopics, ventricular tachycardia, and ventricular fibrillation in hypertrophic hearts, but not non-hypertrophied hearts. Mg2+ also improved post-I/R left ventricular developed pressure in hypertrophic hearts. However, Mg2+ did not reverse the ISO-induced myocyte thickening and interstitial fibrosis or increases in heart weight. Plasma Mg2+ was not different among treatment groups. These results suggest that Mg2+ pretreatment may protect against I/R-induced injury and malignant arrhythmias in hypertrophic hearts, possibly via mechanisms unrelated to long-lasting changes in plasma Mg2+ or prevention of structural changes such as fibrosis.
Cardioprotective effect of fingolimod against calcium paradox-induced myocardial injury in the isolated rat heart
(Canadian Science Publishing, 2021-09-24) Alatrag, Fatma; Amoni, Matthew; Kelly-Laubscher, Roisin; Gwanyanya, Asfree; South African Medical Research Council; National Research Foundation
Fingolimod (FTY720) inhibits Ca2+-permeable, Mg2+-sensitive channels called transient receptor potential melastatin 7 (TRPM7), but its effects on Ca2+ paradox (CP)-induced myocardial damage have not been evaluated. We studied the effect of FTY720 on CP-induced myocardial damage, and used other TRPM7 channel inhibitors nordihydroguaiaretic acid (NDGA) and Mg2+ to test if any effect of FTY720 was via TRPM7 inhibition. Langendorff-perfused Wistar rat hearts were treated with FTY720 or NDGA and subjected to a CP protocol consisting of Ca2+ depletion followed by Ca2+ repletion. Hearts of rats pre-treated with MgSO4 were also subjected to CP. Hemodynamic parameters were measured using an intraventricular balloon, and myocardial infarct size was quantified using triphenyltetrazolium chloride stain. TRPM7 proteins in ventricular tissue were detected using immunoblot analysis. FTY720, but not NDGA, decreased CP-induced infarct size. Both FTY720 and NDGA minimized the CP-induced elevation of left ventricular end-diastolic pressure, but only FTY720 ultimately improved ventricular developed pressure. Mg2+ pre-treatment had effect neither on CP-induced infarct size, hemodynamic parameters during CP, nor the level TRPM7 protein expression in ventricular tissue. Overall, FTY720 attenuated CP-induced myocardial damage, with potential therapeutic implications on Ca2+-mediated cardiotoxicity. However, the cardioprotective mechanism of FTY720 seems to be unrelated to TRPM7 channel modulation.
Decarboxylation of Ang-(1–7) to Ala1-Ang-(1–7) leads to significant changes in pharmacodynamics
(Elsevier B.V., 2018-05-21) Tetzner, Anja; Naughton, Maura; Gebolys, Kinga; Eichhorst, Jenny; Sala, Esther; Villacañas, Óscar; Walther, Thomas; Deutsche Forschungsgemeinschaft
The heptapeptide angiotensin (Ang)–(1–7) is part of the beneficial arm of the renin-angiotensin system. Ang-(1–7) has cardiovascular protective effects, stimulates regeneration, and opposes the often detrimental effects of Ang II. We recently identified the G protein-coupled receptors Mas and MrgD as receptors for the heptapeptide. Ala1-Ang-(1–7) (Alamandine), a decarboxylated form of Ang-(1–7), has similar vasorelaxant effects, but has been described to only stimulate MrgD. Therefore, this study aimed to characterise the consequences of the lack of the carboxyl group in amino acid 1 on intracellular signalling and to identify the receptor fingerprint for Ala1-Ang-(1–7). In primary endothelial and mesangial cells, Ala1-Ang-(1–7) elevated cAMP concentration. Dose response curves generated with Ang-(1–7) and Ala1-Ang-(1–7) significantly differed from each other, with a much lower EC50 and a bell-shape curve for Ala1-Ang-(1–7). We provided pharmacological proof that both, Mas and MrgD, are functional receptors for Ala1-Ang-(1–7). Consequently, in primary mesangial cells with genetic deficiency in both receptors the heptapeptide failed to increase cAMP concentration. As we previously described for Ang-(1–7), the Ala1-Ang-(1–7)-mediated cAMP increase in Mas/MrgD-transfected HEK293 cells and primary cells were blocked by the AT2 receptor blocker, PD123319. The very distinct dose-response curves for both heptapeptides could be explained by in silico modelling, electrostatic potential calculations, and an involvement of Galpha i for higher concentrations of Ala1-Ang-(1–7). Our results identify Ala1-Ang-(1–7) as a peptide with specific pharmacodynamic properties and build the basis for the design of more potent and efficient Ang-(1–7) analogues for therapeutic interventions in a rapidly growing number of diseases.
Determination of parameters for successful spray coating of silicon microneedle arrays
(Elsevier, 2011-08-30) McGrath, Marie G.; Vrdoljak, Anto; O'Mahony, Conor; Oliveira, Jorge C.; Moore, Anne C.; Crean, Abina M.; Enterprise Ireland; Higher Education Authority; Science Foundation Ireland
Coated microneedle patches have demonstrated potential for effective, minimally invasive, drug and vaccine delivery. To facilitate cost-effective, industrial-scale production of coated microneedle patches, a continuous coating method which utilises conventional pharmaceutical processes is an attractive prospect. Here, the potential of spray-coating silicon microneedle patches using a conventional film-coating process was evaluated and the key process parameters which impact on coating coalescence and weight were identified by employing a fractional factorial design to coat flat silicon patches. Processing parameters analysed included concentration of coating material, liquid input rate, duration of spraying, atomisation air pressure, gun-to-surface distance and air cap setting. Two film-coating materials were investigated; hydroxypropylmethylcellulose (HPMC) and carboxymethylcellulose (CMC). HPMC readily formed a film-coat on silicon when suitable spray coating parameter settings were determined. CMC films required the inclusion of a surfactant (1%, w/w Tween 80) to facilitate coalescence of the sprayed droplets on the silicon surface. Spray coating parameters identified by experimental design, successfully coated 280 μm silicon microneedle arrays, producing an intact film-coat, which follows the contours of the microneedle array without occlusion of the microneedle shape. This study demonstrates a novel method of coating microneedle arrays with biocompatible polymers using a conventional film-coating process. It is the first study to indicate the thickness and roughness of coatings applied to microneedle arrays. The study also highlights the importance of identifying suitable processing parameters when film coating substrates of micron dimensions. The ability of a fractional factorial design to identify these critical parameters is also demonstrated. The polymer coatings applied in this study can potentially be drug loaded for intradermal drug and vaccine delivery.
Development of stabilized vaccines with needle-free devices for targeted skin immunization
(Russell Publishing Limited, 2010-12) Moore, Anne C.; Crean, Abina M.; O'Mahony, Conor; Difford, Helen
Vaccination represents the primary public health measure to combat infectious diseases. However, limitations of cold-chain storage, vaccine wastage, hazardous sharps-waste and the requirements for trained personnel add significant and unsustainable financial and logistic costs to immunisation programmes. Developments of needle-free methods should aim to overcome these logistics issues from the very start of the vaccine production process. Dermal vaccine administration using microneedle-based devices promises to be one such needle-free method that addresses all of these issues. Methods of stabilisation of vaccines onto or incorporated into microneedles should be developed to permit seamless transition and cost-effectiveness from vaccine bulk-up to final product. This review examines recent developments in microneedle technology and highlights the current challenges to translate this technology into practice.
Discovery of genetic variation on chromosome 5q22 associated with mortality in heart failure
(PLoS, 2016-05-05) Smith, J. Gustav; Felix, Janine F.; Morrison, Alanna C.; Kalogeropoulos, Andreas; Trompet, Stella; Wilk, Jemma B.; Gidlöf, Olof; Wang, Xinchen; Morley, Michael; Mendelson, Michael; Joehanes, Roby; Ligthart, Symen; Shan, Xiaoyin; Bis, Joshua C.; Wang, Ying A.; Sjögren, Marketa; Ngwa, Julius; Brandimarto, Jeffrey; Stott, David J.; Aguilar, David; Rice, Kenneth M.; Sesso, Howard D.; Demissie, Serkalem; Buckley, Brendan M.; Taylor, Kent D.; Ford, Ian; Yao, Chen; Liu, Chunyu; CHARGE-SCD consortium; EchoGen, consortium; QT-IGC consortium; CHARGE-QRS consortium; Sotoodehnia, Nona; van der Harst, Pim; Stricker, Bruno H. Ch; Kritchevsky, Stephen B.; Liu, Yongmei; Gaziano, J. Michael; Hofman, Albert; Moravec, Christine S.; Uitterlinden, André G.; Kellis, Manolis; van Meurs, Joyce B.; Margulies, Kenneth B.; Dehghan, Abbas; Levy, Daniel; Olde, Björn; Psaty, Bruce M.; Cupples, L. Adrienne; Jukema, J. Wouter; Djousse, Luc; Franco, Oscar H.; Boerwinkle, Eric; Boyer, Laurie A.; Newton-Cheh, Christopher; Butler, Javed; Vasan, Ramachandran S.; Cappola, Thomas P.; Smith, Nicholas L.; National Heart, Lung, and Blood Institute; National Human Genome Research Institute; National Institutes of Health; National Institute of Environmental Health Sciences; Bristol-Myers Squibb Foundation; National Institute on Aging; National Institute of Diabetes and Digestive and Kidney Diseases; Seventh Framework Programme; Hartstichting; Netherlands Genomics Initiative; Nederlandse Organisatie voor Wetenschappelijk Onderzoek; Research Institute for Diseases in the Elderly; Erasmus Medisch Centrum; Erasmus Universiteit Rotterdam; ZonMw; Ministerie van Onderwijs, Cultuur en Wetenschap; Ministerie van Volksgezondheid, Welzijn en Sport; European Commission; Municipality of Rotterdam; Fondation Nestlé; Metagenics Inc.; AXA Research Fund; Cancerfonden; Medicinska Forskningsrådet; Swedish Dairy Association; Direktör Albert Påhlssons Stiftelse; Gunnar Nilssons Cancerstiftelse; Malmö City Council; Public Health Agency of Sweden; Märta Winkler Foundation; Hjärt-Lungfonden; Swedish Society of Cardiology; Vetenskapsrådet; European Research Council; Skåne University Hospital; Crafoordska Stiftelsen; National Cancer Institute
Failure of the human heart to maintain sufficient output of blood for the demands of the body, heart failure, is a common condition with high mortality even with modern therapeutic alternatives. To identify molecular determinants of mortality in patients with new-onset heart failure, we performed a meta-analysis of genome-wide association studies and follow-up genotyping in independent populations. We identified and replicated an association for a genetic variant on chromosome 5q22 with 36% increased risk of death in subjects with heart failure (rs9885413, P = 2.7x10-9). We provide evidence from reporter gene assays, computational predictions and epigenomic marks that this polymorphism increases activity of an enhancer region active in multiple human tissues. The polymorphism was further reproducibly associated with a DNA methylation signature in whole blood (P = 4.5x10-40) that also associated with allergic sensitization and expression in blood of the cytokine TSLP (P = 1.1x10-4). Knockdown of the transcription factor predicted to bind the enhancer region (NHLH1) in a human cell line (HEK293) expressing NHLH1 resulted in lower TSLP expression. In addition, we observed evidence of recent positive selection acting on the risk allele in populations of African descent. Our findings provide novel genetic leads to factors that influence mortality in patients with heart failure.
Disodium cromoglycate reverses colonic visceral hypersensitivity and influences colonic ion transport in a stress-sensitive rat strain
(Public Library of Science, 2013) Carroll, Siobhan Y.; O'Mahony, Siobhain M.; Grenham, Susan; Cryan, John F.; Hyland, Niall P.; Science Foundation Ireland
The interface between psychiatry and stress-related gastrointestinal disorders (GI), such as irritable bowel syndrome (IBS), is well established, with anxiety and depression the most frequently occurring comorbid conditions. Moreover, stress-sensitive Wistar Kyoto (WKY) rats, which display anxiety-and depressive-like behaviors, exhibit GI disturbances akin to those observed in stress-related GI disorders. Additionally, there is mounting preclinical and clinical evidence implicating mast cells as significant contributors to the development of abdominal visceral pain in IBS. In this study we examined the effects of the rat connective tissue mast cell (CTMC) stabiliser, disodium cromoglycate (DSCG) on visceral hypersensitivity and colonic ion transport, and examined both colonic and peritoneal mast cells from stress-sensitive WKY rats. DSCG significantly decreased abdominal pain behaviors induced by colorectal distension in WKY animals independent of a reduction in colonic rat mast cell mediator release. We further demonstrated that mast cell-stimulated colonic ion transport was sensitive to inhibition by the mast cell stabiliser DSCG, an effect only observed in stress-sensitive rats. Moreover, CTMC-like mast cells were significantly increased in the colonic submucosa of WKY animals, and we observed a significant increase in the proportion of intermediate, or immature, peritoneal mast cells relative to control animals. Collectively our data further support a role for mast cells in the pathogenesis of stress-related GI disorders.
DNA vaccination for cervical cancer: Strategic optimisation of RALA mediated gene delivery from a biodegradable microneedle system
(Elsevier, 2018-03-03) Cole, Grace; Ali, Ahlam A.; McCrudden, Cian M.; McBride, John W.; McCaffrey, Joanne; Robson, Tracey; Kett, Vicky L.; Dunne, Nicholas J.; Donnelly, Ryan F.; McCarthy, Helen O.; Prostate Cancer UK
Dissolvable microneedles can be employed to deliver DNA to antigen presenting cells within the skin. However, this technology faces two main challenges: the poor transfection efficacy of pDNA following release from the microneedle matrix, and the limited loading capacity of the micron-scale devices. Two-tier delivery systems combining microneedle platforms and DNA delivery vectors have increased efficacy but the challenge of increasing the loading capacity remains. This study utilised lyophilisation to increase the loading of RALA/pDNA nanoparticles within dissolvable PVA microneedles. As a result, delivery was significantly enhanced in vivo into an appropriate range for DNA vaccination (∼50 μg per array). Furthermore, modifying the manufacturing process was not detrimental to the microneedle mechanical properties or cargo functionality. It was demonstrated that arrays retained mechanical and functional stability over short term storage, and were able to elicit gene expression in vitro and in vivo. Finally, treatment with this novel formulation significantly retarded the growth of established tumours, and proved superior to standard intramuscular injection in a preclinical model of cervical cancer.
Drug-gut microbiota interactions: implications for neuropharmacology
(John Wiley & Sons, Inc. on behalf of the British Pharmacological Society, 2018-05-21) Walsh, Jacinta; Griffin, Brendan T.; Clarke, Gerard; Hyland, Niall P.; Science Foundation Ireland
The fate and activity of drugs are frequently dictated not only by the host per se but also by the microorganisms present in the gastrointestinal tract. The gut microbiome is known to, both directly and indirectly, affect drug metabolism. More evidence now hints at the impact that drugs can have on the function and composition of the gut microbiome. Both microbiota-mediated alterations in drug metabolism and drug-mediated alterations in the gut microbiome can have beneficial or detrimental effects on the host. Greater insights into the mechanisms driving these reciprocal drug-gut microbiota interactions are needed, to guide the development of microbiome-targeted dietary or pharmacological interventions, with the potential to enhance drug efficacy or reduce drug side-effects. In this review, we explore the relationship between drugs and the gut microbiome, with a specific focus on potential mechanisms underpinning the drug-mediated alterations on the gut microbiome and the potential implications for psychoactive drugs.
The effect of fingolimod on regulatory T cells in a mouse model of brain ischaemia
(BioMed Central Ltd, 2021) Malone, Kyle; Diaz Diaz, Andrea C.; Shearer, Jennifer A.; Moore, Anne C.; Waeber, Christian; Science Foundation Ireland; Irish Research Council; Health Research Board; European Commission
Background: The role of the immune system in stroke is well-recognised. Fingolimod, an immunomodulatory agent licensed for the management of relapsing-remitting multiple sclerosis, has been shown to provide benefit in rodent models of stroke. Its mechanism of action, however, remains unclear. We hypothesised fingolimod increases the number and/or function of regulatory T cells (Treg), a lymphocyte population which promotes stroke recovery. The primary aim of this study was to rigorously investigate the effect of fingolimod on Tregs in a mouse model of brain ischaemia. The effect of fingolimod in mice with common stroke-related comorbidities (ageing and hypercholesteremia) was also investigated. Methods: Young (15–17 weeks), aged C57BL/6 mice (72–73 weeks), and ApoE?/? mice fed a high-fat diet (20–21 weeks) underwent permanent electrocoagulation of the left middle cerebral artery. Mice received either saline or fingolimod (0.5 mg/kg or 1 mg/kg) at 2, 24, and 48 h post-ischaemia via intraperitoneal injection. Another cohort of young mice (8–9, 17–19 weeks) received short-term (5 days) or long-term (10 days) fingolimod (0.5 mg/kg) treatment. Flow cytometry was used to quantify Tregs in blood, spleen, and lymph nodes. Immunohistochemistry was used to quantify FoxP3+ cell infiltration into the ischaemic brain. Results: Fingolimod significantly increased the frequency of Tregs within the CD4+ T cell population in blood and spleen post-ischaemia in all three mouse cohorts compared to untreated ischemic mice. The highest splenic Treg frequency in fingolimod-treated mice was observed in ApoE?/? mice (9.32 ± 1.73% vs. 7.8 ± 3.01% in young, 6.09 ± 1.64% in aged mice). The highest circulating Treg frequency was also noted in ApoE?/? mice (8.39 ± 3.26% vs. 5.43 ± 2.74% in young, 4.56 ± 1.60% in aged mice). Fingolimod significantly increased the number of FoxP3+ cells in the infarct core of all mice. The most pronounced effects were seen when mice were treated for 10 days post-ischaemia. Conclusions: Fingolimod increases Treg frequency in spleen and blood post-ischaemia and enhances the number of FoxP3+ cells in the ischaemic brain. The effect of fingolimod on this regulatory cell population may underlie its neuroprotective activity and could be exploited as part of future stroke therapy.
The effect of sphingosine‐1‐phosphate on the endothelial glycocalyx during ischemia‐reperfusion injury in the isolated rat heart
(John Wiley & Sons, Inc., 2020-02-03) Araibi, Hala; van der Merwe, Elizabeth; Gwanyanya, Asfree; Kelly-Laubscher, Roisin; South African Medical Research Council; Ministry of Higher Education and Scientific Research; National Research Foundation of South Africa
Objective: Sphingosine‐1‐phosphate is a natural metabolite that is cardioprotective, but its effects on endothelial glycocalyx damage during ischemia‐reperfusion are unknown. Therefore, we investigated the effect of sphingosine‐1‐phosphate on the endothelial glycocalyx during ischemia‐reperfusion. Methods: Isolated hearts from Wistar rats were perfused on a Langendorff system with Krebs‐Henseleit buffer and pretreated with sphingosine‐1‐phosphate (10 nmol/L) before ischemia‐reperfusion. Infarct size was measured by triphenyl tetrazolium chloride staining (n ≥ 6 per group). Cardiac edema was assessed by calculating total water content (n = 7 per group) and histologically quantifying the interstitial compartment (n ≥ 3 per group). The post‐ischemic coronary release of syndecan‐1 was quantified using ELISA. Syndecan‐1 immunostaining intensity was assessed in perfusion‐fixed hearts (n ≥ 3 per group). Results: Pretreatment with sphingosine‐1‐phosphate decreased infarct size in isolated hearts subjected to ischemia‐reperfusion (P = .01 vs ischemia‐reperfusion). However, sphingosine‐1‐phosphate had no effect on syndecan‐1 levels in the coronary effluent or on the intensity of the syndecan‐1 immunostaining signal in cardiac tissue. Heart total water content was not significantly different between control and ischemic groups but was significantly decreased in hearts treated with sphingosine‐1‐phosphate alone. Conclusion: These results suggest that sphingosine‐1‐phosphate‐induced cardioprotection against ischemia‐reperfusion injury is not mediated by the maintenance of syndecan‐1 in the endothelial glycocalyx.

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