Pharmacology and Therapeutics - Journal Articles

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Ethanolamine is a novel STAT-3 dependent cardioprotective agent
(Springer, 2010-10-12) Kelly-Laubscher, Roisin; Lamont, Kim T.; Somers, Sarin; Hacking, Damian; Lacerda, Lydia; Thomas, Paul; Opie, Lionel H.; Lecour, Sandrine; National Research Foundation; South African Medical Research Council; Claude Leon Foundation
Ethanolamine is a biogenic amine found naturally in the body as part of membrane lipids and as a metabolite of the cardioprotective substances, sphingosine-1-phosphate (S1P) and anandamide. In the brain, ethanolamine, formed from the breakdown of anandamide protects against ischaemic apoptosis. However, the effects of ethanolamine in the heart are unknown. Signal transducer and activator of transcription 3 (STAT-3) is a critical prosurvival factor in ischaemia/reperfusion (I/R) injury. Therefore, we investigated whether ethanolamine protects the heart via activation of STAT-3. Isolated hearts from wildtype or cardiomyocyte specific STAT-3 knockout (K/O) mice were pre-treated with ethanolamine (Etn) (0.3 mmol/L) before I/R insult. In vivo rat hearts were subjected to 30 min ischaemia/2 h reperfusion in the presence or absence of 5 mg/kg S1P and/or the FAAH inhibitor, URB597. Infarct size was measured at the end of each protocol by triphenyltetrazolium chloride staining. Pre-treatment with ethanolamine decreased infarct size in isolated mouse or rat hearts subjected to I/R but this infarct sparing effect was lost in cardiomyocyte specific STAT-3 deficient mice. Pre-treatment with ethanolamine increased nuclear phosphorylated STAT-3 [control 0.75 ± 0.08 vs. Etn 1.50 ± 0.09 arbitrary units; P < 0.05]. Our findings suggest a novel cardioprotective role for ethanolamine against I/R injury via activation of STAT-3.
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.
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.
A meta-analysis of thyroid-related traits reveals novel loci and gender-specific differences in the regulation of thyroid function
(Public Library of Science, 2013) Porcu, Eleonora; Medici, Marco; Pistis, Giorgio; Volpato, Claudia B.; Wilson, Scott G.; Cappola, Anne R.; Bos, Steffan D.; Deelen, Joris; den Heijer, Martin; Freathy, Rachel M.; Lahti, Jari; Liu, Chunyu; Lopez, Lorna M.; Nolte, Ilja M.; O'Connell, Jeffrey R.; Tanaka, Toshiko; Trompet, Stella; Arnold, Alice; Bandinelli, Stefania; Beekman, Marian; Bohringer, Stefan; Brown, Suzanne J.; Buckley, Brendan M.; Camaschella, Clara; de Craen, Anton J. M.; Davies, Gail; de Visser, Marieke C. H.; Ford, Ian; Forsen, Tom; Frayling, Timothy M.; Fugazzola, Laura; Goegele, Martin; Hattersley, Andrew T.; Hermus, Ad R.; Hofman, Albert; Houwing-Duistermaat, Jeanine J.; Jensen, Richard A.; Kajantie, Eero; Kloppenburg, Margreet; Lim, Ee M.; Masciullo, Corrado; Mariotti, Stefano; Minelli, Cosetta; Mitchell, Braxton D.; Nagaraja, Ramaiah; Netea-Maier, Romana T.; Palotie, Aarno; Persani, Luca; Piras, Maria G.; Psaty, Bruce M.; Räikkönen, Katri; Richards, J. Brent; Rivadeneira, Fernando; Sala, Cinzia; Sabra, Mona M.; Sattar, Naveed; Shields, Beverley M.; Soranzo, Nicole; Starr, John M.; Stott, David J.; Sweep, Fred C. G. J.; Usala, Gianluca; van der Klauw, Melanie M.; van Heemst, Diana; van Mullem, Alies; Vermeulen, Sita H.; Visser, W. Edward; Walsh, John P.; Westendorp, Rudi G. J.; Widen, Elisabeth; Zhai, Guangju; Cucca, Francesco; Deary, Ian J.; Eriksson, Johan; Ferrucci, Luigi; Fox, Caroline S.; Jukema, J. Wouter; Kiemeney, Lambertus A.; Pramstaller, Peter P.; Schlessinger, David; Shuldiner, Alan R.; Slagboom, P. Eline; Uitterlinden, Andre G.; Vaidya, Bijay; Visser, Theo J.; Wolffenbuttel, Bruce H. R.; Meulenbelt, Ingrid; Rotter, Jerome I.; Spector, Tim D.; Hicks, Andrew A.; Toniolo, Daniela; Sanna, Serena; Peeters, Robin P.; Naitza, Silvia
Thyroid hormone is essential for normal metabolism and development, and overt abnormalities in thyroid function lead to common endocrine disorders affecting approximately 10% of individuals over their life span. In addition, even mild alterations in thyroid function are associated with weight changes, atrial fibrillation, osteoporosis, and psychiatric disorders. To identify novel variants underlying thyroid function, we performed a large meta-analysis of genome-wide association studies for serum levels of the highly heritable thyroid function markers TSH and FT4, in up to 26,420 and 17,520 euthyroid subjects, respectively. Here we report 26 independent associations, including several novel loci for TSH (PDE10A, VEGFA, IGFBP5, NFIA, SOX9, PRDM11, FGF7, INSR, ABO, MIR1179, NRG1, MBIP, ITPK1, SASH1, GLIS3) and FT4 (LHX3, FOXE1, AADAT, NETO1/FBXO15, LPCAT2/CAPNS2). Notably, only limited overlap was detected between TSH and FT4 associated signals, in spite of the feedback regulation of their circulating levels by the hypothalamic-pituitary-thyroid axis. Five of the reported loci (PDE8B, PDE10A, MAF/LOC440389, NETO1/FBXO15, and LPCAT2/CAPNS2) show strong gender-specific differences, which offer clues for the known sexual dimorphism in thyroid function and related pathologies. Importantly, the TSH-associated loci contribute not only to variation within the normal range, but also to TSH values outside the reference range, suggesting that they may be involved in thyroid dysfunction. Overall, our findings explain, respectively, 5.64% and 2.30% of total TSH and FT4 trait variance, and they improve the current knowledge of the regulation of hypothalamic-pituitary-thyroid axis function and the consequences of genetic variation for hypo- or hyperthyroidism.
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.
Loss of p38δ mitogen-activated protein kinase expression promotes oesophageal squamous cell carcinoma proliferation, migration and anchorage-independent growth.
(Spandidos Publications, 2013-05-29) O'Callaghan, Carol; Fanning, Liam J.; Houston, Aileen M.; Barry, Orla P.; Health Research Board
Oesophageal cancer is an aggressive tumour which responds poorly to both chemotherapy and radiation therapy and has a poor prognosis. Thus, a greater understanding of the biology of oesophageal cancer is needed in order to identify novel therapeutic targets. Among these targets p38 MAPK isoforms are becoming increasingly important for a variety of cellular functions. The physiological functions of p38α and -β are now well documented in contrast to -γ and -δ which are comparatively under-studied and ill-defined. A major obstacle to deciphering the role(s) of the latter two p38 isoforms is the lack of specific chemical activators and inhibitors. In this study, we analysed p38 MAPK isoform expression in oesophageal cancer cell lines as well as human normal and tumour tissue. We observed specifically differential p38δ expression. The role(s) of p38δ and active (phosphorylated) p38δ (p-p38δ) in oesophageal squamous cell carcinoma (OESCC) was delineated using wild-type p38δ as well as active p-p38δ, generated by fusing p38δ to its upstream activator MKK6b(E) via a decapeptide (Gly-Glu)5 linker. OESCC cell lines which are p38δ-negative (KE-3 and -8) grew more quickly than cell lines (KE-6 and -10) which express endogenous p38δ. Re-introduction of p38δ resulted in a time-dependent decrease in OESCC cell proliferation which was exacerbated with p-p38δ. In addition, we observed that p38δ and p-p38δ negatively regulated OESCC cell migration in vitro. Finally both p38δ and p-p38δ altered OESCC anchorage-independent growth. Our results suggest that p38δ and p-p38δ have a role in the suppression of OESCC. Our research may provide a new potential target for the treatment of oesophageal cancer.
Effects of centrally acting ACE inhibitors on the rate of cognitive decline in dementia
(BMJ Publishing Group, 2013-07-22) Gao, Yang; O'Caoimh, Rónán; Healy, Liam; Kerins, David M.; Eustace, Joseph A.; Guyatt, Gordon; Sammon, David; Molloy, D. William; Atlantic Philanthropies; Health Service Executive, Ireland; Irish Hospice Foundation; Canadian Institutes of Health Research
Objectives: There is growing evidence that antihypertensive agents, particularly centrally acting ACE inhibitors (CACE-Is), which cross the blood–brain barrier, are associated with a reduced rate of cognitive decline. Given this, we compared the rates of cognitive decline in clinic patients with dementia receiving CACE-Is (CACE-I) with those not currently treated with CACE-Is (NoCACE-I), and with those who started CACE-Is, during their first 6 months of treatment (NewCACE-I). Design: Observational case–control study. Setting: 2 university hospital memory clinics. Participants: 817 patients diagnosed with Alzheimer's disease, vascular or mixed dementia. Of these, 361 with valid cognitive scores were included for analysis, 85 CACE-I and 276 NoCACE-I. Measurements: Patients were included if the baseline and end-point (standardised at 6 months apart) Standardised Mini-Mental State Examination (SMMSE) or Quick Mild Cognitive Impairment (Qmci) scores were available. Patients with comorbid depression or other dementia subtypes were excluded. The average 6-month rates of change in scores were compared between CACE-I, NoCACE-I and NewCACE-I patients. Results: When the rate of decline was compared between groups, there was a significant difference in the median, 6-month rate of decline in Qmci scores between CACE-I (1.8 points) and NoCACE-I (2.1 points) patients (p=0.049), with similar, non-significant changes in SMMSE. Median SMMSE scores improved by 1.2 points in the first 6 months of CACE treatment (NewCACE-I), compared to a 0.8 point decline for the CACE-I (p=0.003) group and a 1 point decline for the NoCACE-I (p=0.001) group over the same period. Multivariate analysis, controlling for baseline characteristics, showed significant differences in the rates of decline, in SMMSE, between the three groups, p=0.002. Conclusions: Cognitive scores may improve in the first 6 months after CACE-I treatment and use of CACE-Is is associated with a reduced rate of cognitive decline in patients with dementia.
Long-term effects of statin treatment in elderly people: extended follow-up of the PROspective Study of Pravastatin in the Elderly at Risk (PROSPER)
(Public Library of Science, 2013-09-02) Lloyd, Suzanne M.; Stott, David J.; de Craen, Anton J. M.; Kearney, Patricia M.; Sattar, Naveed; Perry, Ivan J.; Packard, Christopher J.; Briggs, Andrew; Marchbank, Laura; Comber, Harry; Jukema, J. Wouter; Westendorp, Rudi G. J.; Trompet, Stella; Buckley, Brendan M.; Ford, Ian; Wellcome Trust, United Kingdom; Chief Scientist Office, Scotland
Background The PROspective Study of Pravastatin in the Elderly at Risk (PROSPER), a placebo-controlled trial of pravastatin, demonstrated a 19% reduction in coronary outcomes (p = 0.006) after a mean of 3.2 years, with no impact on stroke outcomes or all-cause mortality. However, there was a suggestion of increased cancer risk. Our aim is to determine the long-term benefits and safety of pravastatin treatment in older people using post-trial follow-up of the PROSPER participants. Methods: 5,804 (2,520 Scottish) men and women aged 70–82 years with either pre-existing vascular disease or increased risk of such disease because of smoking, hypertension or diabetes, were randomised to 40 mg pravastatin or matching placebo. Using record linkage to routinely collected health records, all participants (full cohort) were linked to death and cancer registries, and the Scottish cohort additionally to hospital admissions, to provide composite fatal/non-fatal cardiovascular outcomes (total mean follow-up 8.6 years). Results: Pravastatin treatment for 3.2 years reduced CHD death in the full cohort, hazard ratio (HR) 0.80, 95% confidence interval (CI) 0.68–0.95, p = 0.0091 and fatal coronary events or coronary hospitalisations in the Scottish cohort (HR 0.81, 95% CI 0.69–0.95, p = 0.0081) over 8.6 years. There was no reduction in stroke or all-cause mortality. Cancer risk was not increased in the full cohort (HR 1.08, 95% CI 0.96–1.21, p = 0.22). Conclusions: Pravastatin treatment of elderly high-risk subjects for 3.2 years provided long-term protection against CHD events and CHD mortality. However, this was not associated with any increase in life expectancy, possibly due to competing mortality with deaths from other causes. There was no evidence of long-term increased risk of cancer.
Protein quality and the protein to carbohydrate ratio within a high fat diet influences energy balance and the gut microbiota in C57BL/6J mice
(Public Library of Science, 2014) McAllan, Liam; Skuse, Peter; Cotter, Paul D.; O'Connor, Paula M.; Cryan, John F.; Ross, R. Paul; Fitzgerald, Gerald F.; Roche, Helen M.; Nilaweera, Kanishka N.; Teagasc; Science Foundation Ireland
Macronutrient quality and composition are important determinants of energy balance and the gut microbiota. Here, we investigated how changes to protein quality (casein versus whey protein isolate; WPI) and the protein to carbohydrate (P/C) ratio within a high fat diet (HFD) impacts on these parameters. Mice were fed a low fat diet (10% kJ) or a high fat diet (HFD; 45% kJ) for 21 weeks with either casein (20% kJ, HFD) or WPI at 20%, 30% or 40% kJ. In comparison to casein, WPI at a similar energy content normalised energy intake, increased lean mass and caused a trend towards a reduction in fat mass (P = 0.08), but the protein challenge did not alter oxygen consumption or locomotor activity. WPI reduced HFD-induced plasma leptin and liver triacylglycerol, and partially attenuated the reduction in adipose FASN mRNA in HFD-fed mice. High throughput sequence-based analysis of faecal microbial populations revealed microbiota in the HFD-20% WPI group clustering closely with HFD controls, although WPI specifically increased Lactobacillaceae/Lactobacillus and decreased Clostridiaceae/Clostridium in HFD-fed mice. There was no effect of increasing the P/C ratio on energy intake, but the highest ratio reduced HFD-induced weight gain, fat mass and plasma triacylglycerol, non-esterified fatty acids, glucose and leptin levels, while it increased lean mass and oxygen consumption. Similar effects were observed on adipose mRNA expression, where the highest ratio reduced HFD-associated expression of UCP-2, TNFα and CD68 and increased the diet-associated expression of β3-AR, LPL, IR, IRS-1 and GLUT4. The P/C ratio also impacted on gut microbiota, with populations in the 30/ 40% WPI groups clustering together and away from the 20% WPI group. Taken together, our data show that increasing the P/C ratio has a dramatic effect on energy balance and the composition of gut microbiota, which is distinct from that caused by changes to protein quality.
No evidence for genome-wide interactions on plasma fibrinogen by smoking, alcohol consumption and body mass index: results from meta-analyses of 80,607 subjects
(Public Library of Science, 2014) Baumert, Jens; Huang, Jie; McKnight, Barbara; Sabater-Lleal, Maria; Steri, Maristella; Chu, Audrey Y.; Trompet, Stella; Lopez, Lorna M.; Fornage, Myriam; Teumer, Alexander; Tang, Weihong; Rudnicka, Alicja R.; Maelarstig, Anders; Hottenga, Jouke-Jan; Kavousi, Maryam; Lahti, Jari; Tanaka, Toshiko; Hayward, Caroline; Huffman, Jennifer E.; Morange, Pierre-Emmanuel; Rose, Lynda M.; Basu, Saonli; Rumley, Ann; Stott, David J.; Buckley, Brendan M.; de Craen, Anton J. M.; Sanna, Serena; Masala, Marco; Biffar, Reiner; Homuth, Georg; Silveira, Angela; Sennblad, Bengt; Goel, Anuj; Watkins, Hugh; Mueller-Nurasyid, Martina; Rueckerl, Regina; Taylor, Kent; Chen, Ming-Huei; de Geus, Eco J. C.; Hofman, Albert; Witteman, Jacqueline C. M.; de Maat, Moniek P. M.; Palotie, Aarno; Davies, Gail; Siscovick, David S.; Kolcic, Ivana; Wild, Sarah H.; Song, Jaejoon; McArdle, Wendy L.; Ford, Ian; Sattar, Naveed; Schlessinger, David; Grotevendt, Anne; Franzosi, Maria Grazia; Illig, Thomas; Waldenberger, Melanie; Lumley, Thomas; Tofler, Geoffrey H.; Willemsen, Gonneke; Uitterlinden, Andre G.; Rivadeneira, Fernando; Räikkönen, Katri; Chasman, Daniel I.; Folsom, Aaron R.; Lowe, Gordon D.; Westendorp, Rudi G. J.; Slagboom, P. Eline; Cucca, Francesco; Wallaschofski, Henri; Strawbridge, Rona J.; Seedorf, Udo; Koenig, Wolfgang; Bis, Joshua C.; Mukamal, Kenneth J.; van Dongen, Jenny; Widen, Elisabeth; Franco, Oscar H.; Starr, John M.; Liu, Kiang; Ferrucci, Luigi; Polasek, Ozren; Wilson, James F.; Oudot-Mellakh, Tiphaine; Campbell, Harry; Navarro, Pau; Bandinelli, Stefania; Eriksson, Johan; Boomsma, Dorret I.; Dehghan, Abbas; Clarke, Robert; Hamsten, Anders; Boerwinkle, Eric; Jukema, J. Wouter; Naitza, Silvia; Ridker, Paul M.; Voezke, Henry; Deary, Ian J.; Reiner, Alexander P.; Tregoueet, David-Alexandre; O'Donnell, Christopher J.; Strachan, David P.; Peters, Annette; Smith, Nicholas L.; National Heart, Lung and Blood Institute; Affymetrix Inc.; Bristol-Myers Squibb; AXA Research Fund; Nestlé Nutrition; Metagenics Inc.; Siemens Healthcare; Federal State of Mecklenburg
Plasma fibrinogen is an acute phase protein playing an important role in the blood coagulation cascade having strong associations with smoking, alcohol consumption and body mass index (BMI). Genome-wide association studies (GWAS) have identified a variety of gene regions associated with elevated plasma fibrinogen concentrations. However, little is yet known about how associations between environmental factors and fibrinogen might be modified by genetic variation. Therefore, we conducted large-scale meta-analyses of genome-wide interaction studies to identify possible interactions of genetic variants and smoking status, alcohol consumption or BMI on fibrinogen concentration. The present study included 80,607 subjects of European ancestry from 22 studies. Genome-wide interaction analyses were performed separately in each study for about 2.6 million single nucleotide polymorphisms (SNPs) across the 22 autosomal chromosomes. For each SNP and risk factor, we performed a linear regression under an additive genetic model including an interaction term between SNP and risk factor. Interaction estimates were meta-analysed using a fixed-effects model. No genome-wide significant interaction with smoking status, alcohol consumption or BMI was observed in the meta-analyses. The most suggestive interaction was found for smoking and rs10519203, located in the LOC123688 region on chromosome 15, with a p value of 6.2x10(-8). This large genome-wide interaction study including 80,607 participants found no strong evidence of interaction between genetic variants and smoking status, alcohol consumption or BMI on fibrinogen concentrations. Further studies are needed to yield deeper insight in the interplay between environmental factors and gene variants on the regulation of fibrinogen concentrations.
Hypermethylation of MAPK13 promoter in oesophageal squamous cell carcinoma Is associated with loss of p38δ MAPK expression
(MDPI AG, 2015-10-23) O'Callaghan, Carol; Fanning, Liam J.; Barry, Orla P.; Health Research Board
The loss of tumour suppressor gene function is a hallmark of malignant transformation and can occur by a variety of genetic and/or epigenetic alterations. We have previously characterised p38δ mitogen-activated protein kinase (MAPK) as a tumour suppressor in oesophageal squamous cell carcinoma (OESCC) and outlined how loss of p38δ MAPK expression promotes increased proliferation and migration, as well as reduced chemosensitivity. Our aim was to investigate the underlying molecular causes of loss of p38δ MAPK expression in OESCC. Sequence analysis of DNA from p38δ MAPK positive and p38δ MAPK negative OESCC cell lines was used to investigate potential loss of function causing mutations. Epigenetic control of p38δ expression in OESCC was examined using methylation-specific PCR and sequencing of bisulfite-converted DNA. We did not identify any mutations in the MAPK13 sequence in OESCC cell lines which lack p38δ MAPK expression. However, we identified a differential pattern of methylation between p38δ MAPK positive and p38δ MAPK negative cell lines. We outline here for the first time differential MAPK13 promoter methylation in OESCC. Our results suggest that epigenetic alterations are responsible, in part, for the suppression of p38δ MAPK expression and promotion of tumourigenesis in OESCC.
Non-response to (statin) therapy: The importance of distinguishing non-responders from non-adherers in pharmacogenetic studies
(Springer Berlin Heidelberg, 2015-12-19) Trompet, S.; Postmus, I.; Slagboom, P. E.; Heijmans, B. T.; Smit, R. A. J.; Maier, A. B.; Buckley, Brendan M.; Sattar, N.; Stott, D. J.; Ford, I.; Westendorp, R. G. J.; de Craen, A. J. M.; Jukema, J. W.; Sixth Framework Programme
Purpose: In pharmacogenetic research, genetic variation in non-responders and high responders is compared with the aim to identify the genetic loci responsible for this variation in response. However, an important question is whether the non-responders are truly biologically non-responsive or actually non-adherent? Therefore, the aim of this study was to describe, within the PROspective Study of Pravastatin in the Elderly at Risk (PROSPER), characteristics of both non-responders and high responders of statin treatment in order to possibly discriminate non-responders from non-adherers. Methods: Baseline characteristics of non-responders to statin therapy (≤10 % LDL-C reduction) were compared with those of high responders (>40 % LDL-C reduction) through a linear regression analysis. In addition, pharmacogenetic candidate gene analysis was performed to show the effect of excluding non-responders from the analysis. Results: Non-responders to statin therapy were younger (p = 0.001), more often smoked (p < 0.001), had a higher alcohol consumption (p < 0.001), had lower LDL cholesterol levels (p < 0.001), had a lower prevalence of hypertension (p < 0.001), and had lower cognitive function (p = 0.035) compared to subjects who highly responded to pravastatin treatment. Moreover, excluding non-responders from pharmacogenetic studies yielded more robust results, as standard errors decreased. Conclusion: Our results suggest that non-responders to statin therapy are more likely to actually be non-adherers, since they have more characteristics that are viewed as indicators of high self-perceived health and low disease awareness, possibly making the subjects less adherent to study medication. We suggest that in pharmacogenetic research, extreme non-responders should be excluded to overcome the problem that non-adherence is investigated instead of non-responsiveness.
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.
Microneedle technology for immunisation: Perception, acceptability and suitability for paediatric use
(Elsevier Ltd., 2016-02-03) Marshall, Sarah; Sahm, Laura J.; Moore, Anne C.
Objective: To examine published research which explores the perception and acceptability of microneedle technology for immunisation and to investigate the suitability of this technology for paediatric use. Methods: A series of keywords and their synonyms were combined in various combinations and permutations using Boolean operators to sequentially search four databases (PubMed, Web of Science, Embase and CINAHL). Following removal of duplications and irrelevant results, 12 research articles were included in the final literature review. Results: The opinions of patients, parents, children and healthcare professionals (HCP) were collated. A positive perception and a high level of acceptability predominated. Conclusion: Microneedle technology research has been focussed on demonstrating efficacy with minimal focus on determining HCP/public perception and acceptability for paediatric use, exemplified by the paucity of studies presented in this review. Commercial viability will depend on HCP/public acceptability of microneedle technology. An effort must be made to identify the barriers to acceptance and to overcome them by increasing awareness and education in stakeholder groups pertaining to the paediatric population.
Induction of broad immunity by thermostabilised vaccines incorporated in dissolvable microneedles using novel fabrication methods
(Elsevier, 2016-03) Vrdoljak, Anto; Allen, Evin A.; Ferrara, Francesca; Temperton, Nigel J.; Crean, Abina M.; Moore, Anne C.; Science Foundation Ireland; Enterprise Ireland; University College Cork
Dissolvable microneedle (DMN) patches for immunization have multiple benefits, including vaccine stability and ease-of-use. However, conventional DMN fabrication methods have several drawbacks. Here we describe a novel, microfluidic, drop dispensing-based dissolvable microneedle production method that overcomes these issues. Uniquely, heterogeneous arrays, consisting of microneedles of diverse composition, can be easily produced on the same patch. Robustness of the process was demonstrated by incorporating and stabilizing adenovirus and MVA vaccines. Clinically-available trivalent inactivated influenza vaccine (TIV) in DMN patches is fully stable for greater than 6months at 40 degrees C. Immunization using low dose TIV-loaded DMN patches induced significantly higher antibody responses compared to intramuscular-based immunization in mice. TIV-loaded patches also induced a broader, heterosubtypic neutralizing antibody response. By addressing issues that will be faced in large-scale fill-finish DMN fabrication processes and demonstrating superior thermostable characteristics and immunogenicity, this study progresses the translation of this microneedle platform to eventual clinical deployment.
Pregnancy-specific glycoprotein expression in normal gastrointestinal tract and in tumors detected with novel monoclonal antibodies.
(Taylor & Francis, 2016-03-18) Houston, Aileen M.; Williams, John M.; Rovis, Tihana L.; Shanley, Daniel K.; O'Riordan, Ronan T.; Kiely, Patrick A.; Ball, Melanie; Barry, Orla P.; Kelly, Jacquie; Fanning, Aine; MacSharry, John; Mandelboim, Ofer; Singer, Bernhard B.; Jonjic, Stipan; Moore, Thomas F.; Science Foundation Ireland
Pregnancy-specific glycoproteins (PSGs) are immunoglobulin superfamily members related to the carcinoembryonic antigen-related cell adhesion molecule (CEACAM) family and are encoded by 10 genes in the human. They are secreted at high levels by placental syncytiotrophoblast into maternal blood during pregnancy, and are implicated in immunoregulation, thromboregulation, and angiogenesis. To determine whether PSGs are expressed in tumors, we characterized 16 novel monoclonal antibodies to human PSG1 and used 2 that do not cross-react with CEACAMs to study PSG expression in tumors and in the gastrointestinal (GI) tract using tissue arrays and immunohistochemistry. Staining was frequently observed in primary squamous cell carcinomas and colonic adenocarcinomas and was correlated with the degree of tumor differentiation, being largely absent from metastatic samples. Staining was also observed in normal oesophageal and colonic epithelium. PSG expression in the human and mouse GI tract was confirmed using quantitative RT-PCR. However, mRNA expression was several orders of magnitude lower in the GI tract compared to placenta. Our results identify a non-placental site of PSG expression in the gut and associated tumors, with implications for determining whether PSGs have a role in tumor progression, and utility as tumor biomarkers.
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.
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.
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.
Leptin modifies the prosecretory and prokinetic effects of the inflammatory cytokine interleukin-6 on colonic function in Sprague–Dawley rats
(Wiley, 2016-09-27) Buckley, Maria M.; O'Brien, Rebecca L.; Devlin, Michelle; Creed, Aisling A.; Rae, Mark G.; Hyland, Niall P.; Quigley, Eamonn M.; McKernan, Declan P.; O'Malley, Dervla; Physiological Society; University College Cork
Leptin ameliorates the prosecretory and prokinetic effects of the pro-inflammatory cytokine interleukin-6 on rat colon. Leptin also suppresses the neurostimulatory effects of irritable bowel syndrome plasma, which has elevated concentrations of interleukin-6, on enteric neurons. This may indicate a regulatory role for leptin in immune-mediated bowel dysfunction. In addition to its role in regulating energy homeostasis, the adipokine leptin modifies gastrointestinal (GI) function. Indeed, leptin-resistant obese humans and leptin-deficient obese mice exhibit altered GI motility. In the functional GI disorder irritable bowel syndrome (IBS), circulating leptin concentrations are reported to differ from those of healthy control subjects. Additionally, IBS patients display altered cytokine profiles, including elevated circulating concentrations of the pro-inflammatory cytokine interleukin-6 (IL-6), which bears structural homology and similarities in intracellular signalling to leptin. This study aimed to investigate interactions between leptin and IL-6 in colonic neurons and their possible contribution to IBS pathophysiology. The functional effects of leptin and IL-6 on colonic contractility and absorptosecretory function were assessed in organ baths and Ussing chambers in Sprague–Dawley rat colon. Calcium imaging and immunohistochemical techniques were used to investigate the neural regulation of GI function by these signalling molecules. Our findings provide a neuromodulatory role for leptin in submucosal neurons, where it inhibited the stimulatory effects of IL-6. Functionally, this translated to suppression of IL-6-evoked potentiation of veratridine-induced secretory currents. Leptin also attenuated IL-6-induced colonic contractions, although it had little direct effect on myenteric neurons. Calcium responses evoked by IBS plasma in both myenteric and submucosal neurons were also suppressed by leptin, possibly through interactions with IL-6, which is elevated in IBS plasma. As leptin has the capacity to ameliorate the neurostimulatory effects of soluble mediators in IBS plasma and modulated IL-6-evoked changes in bowel function, leptin may have a role in immune-mediated bowel dysfunction in IBS patients.

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