Pharmacology and Therapeutics - Journal Articles
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Item Human α‐synuclein overexpression upregulates SKOR1 in a rat model of simulated nigrostriatal ageing(Wiley, 2024-03-26) Morales‐Prieto, Noelia; Bevans, Rebekah; O'Mahony, Adam; Barron, Aaron ; Doran, Conor Giles ; McCarthy, Erin ; Concannon, Ruth M.; Goulding, Susan R.; McCarthy, Cathal M.; Collins, Louise M.; Sullivan, Aideen M.; O'Keeffe, Gerard W.; Science Foundation Ireland; Cure Parkinson's Trust; HORIZON EUROPE Marie Sklodowska-Curie ActionsParkinson's disease (PD) is characterised by progressive loss of dopaminergic (DA) neurons from the substantia nigra (SN) and α-synuclein (αSyn) accumulation. Age is the biggest risk factor for PD and may create a vulnerable pre-parkinsonian state, but the drivers of this association are unclear. It is known that ageing increases αSyn expression in DA neurons and that this may alter molecular processes that are central to maintaining nigrostriatal integrity. To model this, adult female Sprague–Dawley rats received a unilateral intranigral injection of adeno-associated viral (AAV) vector carrying wild-type human αSyn (AAV-αSyn) or control vector (AAV-Null). AAV-αSyn induced no detrimental effects on motor behaviour, but there was expression of human wild-type αSyn throughout the midbrain and ipsilateral striatum at 20 weeks post-surgery. Microarray analysis revealed that the gene most-upregulated in the ipsilateral SN of the AAV-αSyn group was the SKI Family Transcriptional Corepressor 1 (SKOR1). Bioenergetic state analysis of mitochondrial function found that SKOR1 overexpression reduced the maximum rate of cellular respiration in SH-SY5Y cells. Furthermore, experiments in SH-SY5Y cells revealed that SKOR1 overexpression impaired neurite growth to the same extent as αSyn, and inhibited BMP-SMAD-dependent transcription, a pathway that promotes DA neuronal survival and growth. Given the normal influence of ageing on DA neuron loss in human SN, the extent of αSyn-induced SKOR1 expression may influence whether an individual undergoes normal nigrostriatal ageing or reaches a threshold for prodromal PD. This provides new insight into mechanisms through which ageing-related increases in αSyn may influence molecular mechanisms important for the maintenance of neuronal integrity.Item An altered gut microbiome in pre-eclampsia: cause or consequence(Frontiers Media, 2024-05-07) Deady, Clara; McCarthy, Fergus P.; Barron, Aaron; McCarthy, Cathal M.; O'Keeffe, Gerard W.; O'Mahony, Siobhain M.; Irish Research CouncilHypertensive disorders of pregnancy, including pre-eclampsia, are a leading cause of serious and debilitating complications that affect both the mother and the fetus. Despite the occurrence and the health implications of these disorders there is still relatively limited evidence on the molecular underpinnings of the pathophysiology. An area that has come to the fore with regard to its influence on health and disease is the microbiome. While there are several microbiome niches on and within the body, the distal end of the gut harbors the largest of these impacting on many different systems of the body including the central nervous system, the immune system, and the reproductive system. While the role of the microbiome in hypertensive disorders, including pre-eclampsia, has not been fully elucidated some studies have indicated that several of the symptoms of these disorders are linked to an altered gut microbiome. In this review, we examine both pre-eclampsia and microbiome literature to summarize the current knowledge on whether the microbiome drives the symptoms of pre-eclampsia or if the aberrant microbiome is a consequence of this condition. Despite the paucity of studies, obvious gut microbiome changes have been noted in women with pre-eclampsia and the individual symptoms associated with the condition. Yet further research is required to fully elucidate the role of the microbiome and the significance it plays in the development of the symptoms. Regardless of this, the literature highlights the potential for a microbiome targeted intervention such as dietary changes or prebiotic and probiotics to reduce the impact of some aspects of these disorders.Item The impact of fingolimod on Treg function in brain ischaemia(John Wiley and Sons Inc, 2023) Malone, Kyle; Shearer, Jennifer A.; Waeber, Christian; Moore, Anne C.; Irish Research Council; Health Research Board; European Regional Development FundFingolimod has generally shown neuroprotective effects in stroke models. Here, we tested the hypothesis that fingolimod modulates T-cell cytokine production towards a regulatory phenotype. Second, we investigated how fingolimod altered the Treg suppressive function and the sensitivity of effector T cells to regulation. Mice that had underwent the permanent electrocoagulation of the left middle cerebral artery received saline or fingolimod (0.5 mg/kg) daily for 10-days post-ischaemia. Fingolimod improved neurobehavioural recovery compared to saline control and increased Treg frequency in the periphery and brain. Tregs from fingolimod-treated animals had a higher expression of CCR8. Fingolimod increased the frequencies of CD4+ IL-10+ , CD4+ IFN-γ+ and CD4+ IL-10+ IFN-γ+ cells in spleen and blood, and CD4+ IL-17+ cells in the spleen, with only minor effects on CD8+ T-cell cytokine production. Treg from post-ischaemic mice had reduced suppressive function compared to Treg from non-ischaemic mice. Fingolimod treatment rescued this function against saline-treated but not fingolimod-treated CD4+ effector T cells. In conclusion, fingolimod seems to improve the suppressive function of Treg post-stroke while also increasing the resistance of CD4+ effector cells to this suppression. Fingolimod's capacity to increase both effector and regulatory functions may explain the lack of consistent improvement in functional recovery in experimental brain ischaemia.Item DNA vaccination via RALA nanoparticles in a microneedle delivery system induces a potent immune response against the endogenous prostate cancer stem cell antigen(Acta Materialia Inc, 2019) Cole, Grace; Ali, Ahlam A.; McErlean, Emma; Mulholland, Eoghan J.; Short, Amy; McCrudden, Cian M.; McCaffrey, Joanne; Robson, Tracy; Kett, Vicky L.; Coulter, Jonathan A.; Dunne, Nicholas J.; Donnelly, Ryan F.; McCarthy, Helen O.; Prostate Cancer UK, (S12-006)Castrate resistant prostate cancer (CRPC) remains a major challenge for healthcare professionals. Immunotherapeutic approaches, including DNA vaccination, hold the potential to harness the host's own immune system to mount a cell-mediated, anti-tumour response, capable of clearing disseminated tumour deposits. These anti-cancer vaccines represent a promising strategy for patients with advanced disease, however, to date DNA vaccines have demonstrated limited efficacy in clinical trials, owing to the lack of a suitable DNA delivery system. This study was designed to evaluate the efficacy of a two-tier delivery system incorporating cationic RALA/pDNA nanoparticles (NPs) into a dissolvable microneedle (MN) patch for the purposes of DNA vaccination against prostate cancer. Application of NP-loaded MN patches successfully resulted in endogenous production of the encoded Prostate Stem Cell Antigen (PSCA). Furthermore, immunisation with RALA/pPSCA loaded MNs elicited a tumour-specific immune response against TRAMP-C1 tumours ex vivo. Finally, vaccination with RALA/pPSCA loaded MNs demonstrated anti-tumour activity in both prophylactic and therapeutic prostate cancer models in vivo. This is further evidence that this two-tier MN delivery system is a robust platform for prostate cancer DNA vaccination. Statement of Significance: This research describes the development and utilisation of our unique microneedle (MN) DNA delivery system, which enables penetration through the stratum corneum and deposition of the DNA within the highly immunogenic skin layers via a dissolvable MN matrix, and facilitates cellular uptake via complexation of pDNA cargo into nanoparticles (NPs) with the RALA delivery peptide. We report for the first time on using the NP-MN platform to immunise mice with encoded Prostate Stem Cell Antigen (mPSCA) for prostate cancer DNA vaccination. Application of the NP-MN system resulted in local mPSCA expression in vivo. Furthermore, immunisation with the NP-MN system induced a tumour-specific cellular immune response, and inhibited the growth of TRAMP-C1 prostate tumours in both prophylactic and therapeutic challenge models in vivo. © 2019 Acta Materialia Inc.Item The future of pharmacology education: A global outlook(Taylor & Francis, 2024-01-29) Guilding, Clare; Kelly-Laubscher, Roisin; White, PaulPharmacology educators play a unique role in higher education, at the intersection of basic biological, and clinical sciences. They teach a on wide range of courses including undergraduate and postgraduate medicine, pharmacy, nursing, dentistry, physiotherapy, osteopathy, veterinary science and biomedical science. Note that this is far from an exhaustive list. Significant changes have taken place in pharmacology education in response to advances in pharmacology, developments in educational approaches and learning technologies, changes in healthcare education delivery, and the massification and internationalization of higher education. These challenge the educator, whose role is increasingly recognized as encompassing teaching, leadership and scholarly activity. The future of pharmacology education depends on our ability to navigate these changes. We argue that there are sets of interrelated knowledge, skill, and attribute competencies that pharmacology educators must master to ultimately enable their students to succeed, discussed in detail in the following sections.