Publications
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Alvarez-Fuente M, Moreno L, Mitchell JA, et al., 2019, Preventing bronchopulmonary dysplasia: new tools for an old challenge, PEDIATRIC RESEARCH, Vol: 85, Pages: 432-441, ISSN: 0031-3998
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- Citations: 28
Mitchell JA, Bishop-Bailey D, 2019, PPARβ/δ a potential target in pulmonary hypertension blighted by cancer risk, Pulmonary Circulation, Vol: 9, Pages: 1-2, ISSN: 2045-8940
Mitchell J, Bishop-Bailey D, 2018, PPARβ/δ a potential target in pulmonary hypertension blighted by cancer risk., Pulmonary Circulation, ISSN: 2045-8940
Dear Editor,Our group and others have used preclinical in vitro and in vivo models that highlight the potential therapeutic benefit of PPARβ/δ as a target in the treatment of pulmonary arterial hypertension. Selective agonists of PPARβ/δ inhibit fibroblast and pulmonary arterial vascular smooth muscle cell growth and prevent right heart hypertrophy in rat models of pulmonary arterial hypertension. Further work published in Pulmonary Circulation established the transcriptomic profile and pathways associated with activating PPARβ/δ in a model of pulmonary artery banding and right heart hypertrophy (1). These results and the fact that enhancing PPARβ/δ is linked to increased endurance exercise performance (2) supports the idea that drugs working on this pathway could be beneficial in pulmonary arterial hypertension. However, there is cause for concern regarding at least one drug that activates PPARβ/δ, GW501516, developed by GlaxoSmithKline plc (GSK) in the early 2000’s. Despite these concerns and although not confirmed in humans, following the publication of endurance exercise studies in rodents, a significant underground market has developed for unlicensed GW501516 (also referred to as Endurobol or Cardarine) in a bid to enhance human athletic performance. PPARβ/δ agonists, including GW501516 were developed for the treatment of hyperlipidemia and other cardiovascular diseases and a number of clinical trails have been registered on clinicaltrials.gov (Clinical trials id NCT00388180; NCT00318617; NCT00158899; NCT00841217). Whilst, long term clinical data are not available, GW501516 improved lipid profiles in short term studies in man (3-5). However safety concerns over GW501516 and potentially other drugs in the class have emerged. Of particular relevance are two abstracts from GSK showing that GW501516 causes cancer in rats (6) and mice (7) after 104 weeks of dosing. Although, neither of these stu
Kirkby NS, Akhmedov D, Berdeaux R, et al., 2018, Bioluminescent Imaging of Tissue From Creb Reporter Mice Reveals the Endothelium as the Principle Site of Vascular Prostacyclin Sensing, Publisher: LIPPINCOTT WILLIAMS & WILKINS, ISSN: 0009-7322
Kirkby NS, Akhmedov D, Shala F, et al., 2018, The Right Heart is Specifically Targeted by Intravenous Administration of Treprostinil: Implications for Our Understanding of How Prostacyclin Drugs Work to Treat Pulmonary Arterial Hypertension, Publisher: LIPPINCOTT WILLIAMS & WILKINS, ISSN: 0009-7322
Mitchell JA, Shala F, Elghazouli Y, et al., 2018, Renal or Vascular Deletion of COX-2 Increases Thrombotic Tone: Relevance to Cardiovascular Side Effects of Non-Steroidal Anti-Inflammatory Drugs, Publisher: LIPPINCOTT WILLIAMS & WILKINS, ISSN: 0009-7322
Mitchell JA, Shala F, Elghazouli Y, et al., 2018, Systemic Anti-Thrombotic Protection by a Non-Endothelial COX-1 / Prostacyclin Pathway, Publisher: LIPPINCOTT WILLIAMS & WILKINS, ISSN: 0009-7322
Kawai R, Ahmetaj-Shala B, Shih CC, et al., 2018, Development of a human autologous 3-cell cytokine release assay that models the vascular wall <i>in vitro</i>, 54th Congress of the European-Societies-of-Toxicology (EUROTOX) - Toxicology Out of the Box, Publisher: ELSEVIER IRELAND LTD, Pages: S114-S114, ISSN: 0378-4274
Ahmetaj-Shala B, Olanipekun M, Tesfai A, et al., 2018, Development of a novel UPLC-MS/MS-based platform to quantify amines, amino acids and methylarginines for applications in human disease phenotyping, Scientific Reports, Vol: 8, ISSN: 2045-2322
Amine quantification is an important strategy in patient stratification and personalised medicine. This is because amines, including amino acids and methylarginines impact on many homeostatic processes. One important pathway regulated by amine levels is nitric oxide synthase (NOS). NOS is regulated by levels of (i) the substrate, arginine, (ii) amino acids which cycle with arginine and (iii) methylarginine inhibitors of NOS. However, biomarker research in this area is hindered by the lack of a unified analytical platform. Thus, the development of a common metabolomics platform, where a wide range of amino acids and methylarginines can be measured constitutes an important unmet need. Here we report a novel high-throughput ultra-high performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS) platform where ≈40 amine analytes, including arginine and methylarginines can be detected and quantified on a molar basis, in a single sample of human plasma. To validate the platform and to generate biomarkers, human plasma from a well-defined cohort of patients before and after coronary artery bypass surgery, who developed systemic inflammatory response syndrome (SIRS), were analysed. Bypass surgery with SIRS significantly altered 26 amine analytes, including arginine and ADMA. Consequently, pathway analysis revealed significant changes in a range of pathways including those associated with NOS.
Mitchell JA, Knowles RB, Kirkby NS, et al., 2018, Letter by Mitchell et al Regarding Article, "Urinary Prostaglandin Metabolites: An Incomplete Reckoning and a Flush to Judgment"., Circulation Research, Vol: 122, Pages: e84-e85, ISSN: 0009-7330
Kirkby NS, Sampaio W, Etelvino G, et al., 2018, Cyclooxygenase-2 Selectively Controls Renal Blood Flow Through a Novel PPAR beta/delta-Dependent Vasodilator Pathway (vol 71, pg 297, 2018), HYPERTENSION, Vol: 71, Pages: e10-e10, ISSN: 0194-911X
Mitchell JA, Knowles RB, Kirkby NS, et al., 2018, Kidney transplantation in a patient lacking cytosolic phospholipase A2Proves renal origins of urinary PGI-M and TX-M, Circulation Research, Vol: 122, Pages: 555-559, ISSN: 0009-7330
RATIONALE: The balance between vascular prostacyclin, which is antithrombotic, and platelet thromboxane A2, which is prothrombotic, is fundamental to cardiovascular health. Prostacyclin and thromboxane A2are formed after the concerted actions of cPLA2α (cytosolic phospholipase A2) and COX (cyclooxygenase). Urinary 2,3-dinor-6-keto-PGF1α(PGI-M) and 11-dehydro-TXB2(TX-M) have been taken as biomarkers of prostacyclin and thromboxane A2formation within the circulation and used to explain COX biology and patient phenotypes, despite concerns that urinary PGI-M and TX-M originate in the kidney. OBJECTIVE: We report data from a remarkable patient carrying an extremely rare genetic mutation in cPLA2α, causing almost complete loss of prostacyclin and thromboxane A2, who was transplanted with a normal kidney resulting in an experimental scenario of whole-body cPLA2α knockout, kidney-specific knockin. By studying this patient, we can determine definitively the contribution of the kidney to the productions of PGI-M and TX-M and test their validity as markers of prostacyclin and thromboxane A2in the circulation. METHODS AND RESULTS: Metabolites were measured using liquid chromatography-tandem mass spectrometry. Endothelial cells were grown from blood progenitors. Before kidney transplantation, the patient's endothelial cells and platelets released negligible levels of prostacyclin (measured as 6-keto-prostaglandin F1α) and thromboxane A2(measured as TXB2), respectively. Likewise, the urinary levels of PGI-M and TX-M were very low. After transplantation and the establishment of normal renal function, the levels of PGI-M and TX-M in the patient's urine rose to within normal ranges, whereas endothelial production of prostacyclin and platelet production of thromboxane A2remained negligible. CONCLUSIONS: These data show that PGI-M and TX-M can be derived exclusively from the kidney without contribution from prostacyclin made by endothelial cells or thromb
Kirkby NS, Sampaio W, Etelvino G, et al., 2018, Cyclooxygenase-2 selectively controls renal blood flow through a novel PPARβ/δ-dependent renal vasodilator pathway, Hypertension, Vol: 71, Pages: 297-305, ISSN: 0194-911X
Cyclooxygenase-2 (COX-2) is an inducible enzyme expressed in inflammation and cancer targeted by nonsteroidal anti-inflammatory drugs. COX-2 is also expressed constitutively in discreet locations where its inhibition drives gastrointestinal and cardiovascular/renal side effects. Constitutive COX-2 expression in the kidney regulates renal function and blood flow; however, the global relevance of the kidney versus other tissues to COX-2–dependent blood flow regulation is not known. Here, we used a microsphere deposition technique and pharmacological COX-2 inhibition to map the contribution of COX-2 to regional blood flow in mice and compared this to COX-2 expression patterns using luciferase reporter mice. Across all tissues studied, COX-2 inhibition altered blood flow predominantly in the kidney, with some effects also seen in the spleen, adipose, and testes. Of these sites, only the kidney displayed appreciable local COX-2 expression. As the main site where COX-2 regulates blood flow, we next analyzed the pathways involved in kidney vascular responses using a novel technique of video imaging small arteries in living tissue slices. We found that the protective effect of COX-2 on renal vascular function was associated with prostacyclin signaling through PPARβ/δ (peroxisome proliferator-activated receptor-β/δ). These data demonstrate the kidney as the principle site in the body where local COX-2 controls blood flow and identifies a previously unreported PPARβ/δ-mediated renal vasodilator pathway as the mechanism. These findings have direct relevance to the renal and cardiovascular side effects of drugs that inhibit COX-2, as well as the potential of the COX-2/prostacyclin/PPARβ/δ axis as a therapeutic target in renal disease.
Kirkby NS, Morris AP, Lytton J, et al., 2017, Genome-Wide Association Study Links Variants With Occurrence of Cardiovascular Events in People Taking the COX-2 Inhibitor Celecoxib: Identification of NCKX2 as a Novel Protective Pathway in Renal Vessels, Scientific Sessions of the American-Heart-Association / Resuscitation Science Symposium, Publisher: LIPPINCOTT WILLIAMS & WILKINS, ISSN: 0009-7322
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Mitchell JA, Shala F, Ahmetaj-Shala B, et al., 2017, Novel Tissue-specific Cyclooxygenase-1 Knockout Mice Demonstrate a Dominant Role for Endothelial Cyclooxygenase-1 in Prostacyclin Production, Scientific Sessions of the American-Heart-Association / Resuscitation Science Symposium, Publisher: LIPPINCOTT WILLIAMS & WILKINS, ISSN: 0009-7322
Mitchell JA, Benson J, Shala F, et al., 2017, Vascular Prostanoids Paradoxically Amplify Vasoconstriction During Platelet Activation, Scientific Sessions of the American-Heart-Association / Resuscitation Science Symposium, Publisher: LIPPINCOTT WILLIAMS & WILKINS, ISSN: 0009-7322
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Kirkby NS, Jiao J, Herschman HR, et al., 2017, Production of High Levels of PGI-M in the Kidney and Bladder Explains the Renal Origin of Urinary Markers of Prostacyclin, Scientific Sessions of the American-Heart-Association / Resuscitation Science Symposium, Publisher: LIPPINCOTT WILLIAMS & WILKINS, ISSN: 0009-7322
Tesfai A, MacCallum N, Kirkby NS, et al., 2017, Metabolomic profiling of amines in sepsis predicts changes in NOS canonical pathways, PLoS ONE, Vol: 12, ISSN: 1932-6203
RationaleNitric oxide synthase (NOS) is a biomarker/target in sepsis. NOS activity is driven by amino acids, which cycle to regulate the substrate L-arginine in parallel with cycles which regulate the endogenous inhibitors ADMA and L-NMMA. The relationship between amines and the consequence of plasma changes on iNOS activity in early sepsis is not known.ObjectiveOur objective was to apply a metabolomics approach to determine the influence of sepsis on a full array of amines and what consequence these changes may have on predicted iNOS activity.Methods and measurements34 amino acids were measured using ultra purification mass spectrometry in the plasma of septic patients (n = 38) taken at the time of diagnosis and 24–72 hours post diagnosis and of healthy volunteers (n = 21). L-arginine and methylarginines were measured using liquid-chromatography mass spectrometry and ELISA. A top down approach was also taken to examine the most changed metabolic pathways by Ingenuity Pathway Analysis. The iNOS supporting capacity of plasma was determined using a mouse macrophage cell-based bioassay.Main resultsOf all the amines measured 22, including L-arginine and ADMA, displayed significant differences in samples from patients with sepsis. The functional consequence of increased ADMA and decreased L-arginine in context of all cumulative metabolic changes in plasma resulted in reduced iNOS supporting activity associated with sepsis.ConclusionsIn early sepsis profound changes in amine levels were defined by dominant changes in the iNOS canonical pathway resulting in functionally meaningful changes in the ability of plasma to regulate iNOS activity ex vivo.
Mohamed NA, Davies RP, Lickiss PD, et al., 2017, Chemical and biological assessment of metal organic frameworks (MOFs) in pulmonary cells and in an acute in vivo model: relevance to pulmonary arterial hypertension therapy, Pulmonary Circulation, Vol: 7, Pages: 1-11, ISSN: 2045-8940
Pulmonary arterial hypertension (PAH) is a progressive and debilitating condition. Despite promoting vasodilation, current drugs have a therapeutic window within which they are limited by systemic side effects. Nanomedicine uses nanoparticles to improve drug delivery and/or reduce side effects. We hypothesize that this approach could be used to deliver PAH drugs avoiding the systemic circulation. Here we report the use of iron metal organic framework (MOF) MIL-89 and PEGylated MIL-89 (MIL-89 PEG) as suitable carriers for PAH drugs. We assessed their effects on viability and inflammatory responses in a wide range of lung cells including endothelial cells grown from blood of donors with/without PAH. Both MOFs conformed to the predicted structures with MIL-89 PEG being more stable at room temperature. At concentrations up to 10 or 30 µg/mL, toxicity was only seen in pulmonary artery smooth muscle cells where both MOFs reduced cell viability and CXCL8 release. In endothelial cells from both control donors and PAH patients, both preparations inhibited the release of CXCL8 and endothelin-1 and in macrophages inhibited inducible nitric oxide synthase activity. Finally, MIL-89 was well-tolerated and accumulated in the rat lungs when given in vivo. Thus, the prototypes MIL-89 and MIL-89 PEG with core capacity suitable to accommodate PAH drugs are relatively non-toxic and may have the added advantage of being anti-inflammatory and reducing the release of endothelin-1. These data are consistent with the idea that these materials may not only be useful as drug carriers in PAH but also offer some therapeutic benefit in their own right.
Crescente M, Armstrong PC, Chan MV, et al., 2017, PLATELET COX-1 KNOCKOUT MOUSE AS A MODEL OF THE EFFECTS OF ASPIRIN IN THE CARDIOVASCULAR SYSTEM, Annual Conference of the British-Cardiovascular-Society (BCS), Publisher: BMJ PUBLISHING GROUP, Pages: A108-A109, ISSN: 1355-6037
Parzych K, Zetterqvist A, Wright WR, et al., 2017, Differential role of the pannexin-1/ATP/P2X7 axis in IL-1β release by human monocytes, The FASEB Journal, Vol: 31, Pages: 2439-2445, ISSN: 0892-6638
IL-1βrelease is integral to the innateimmune system. The release of mature IL-1β depends on two regulated events; (i) the denovoinduction of pro-IL-1β, generally via NFκB-dependenttransduction pathwaysand (ii) the assembly and activation of the NLRP3 inflammasome. This latter step is reliant on active capase-1, pannexin-1 and P2X7receptor activation. Pathogen associated molecular patterns in Gram-positive and Gram-negative bacteria activate IL-1β release from immune cells via TLR2 and TLR4 receptors respectively. Here,we show that pro-IL-1β and mature IL-1β release from human monocytes is stimulated by the TLR2 agonists,Pam3CSK4 or FSL-1,and the TLR4 agonist,LPS, in the absence of additional ATP. TLR2 agonists required pannexin-1 and P2X7receptor activationto stimulate IL-1βrelease. By contrast, IL-1β release stimulated by the TLR4 agonist,LPS,is independent of both pannexin-1 and P2X7activation. In the absence of exogenous ATP,P2X7activation requires endogenous ATP release, which occurs in some cells via pannexin-1. In line with this,we found that LPS-stimulated human monocytes released relatively low levels of ATP,whereas cells stimulated with TLR2 agonists released high levels of ATP. These findings suggest that,in human monocytes, TLR2 and TLR4 signalling bothinduce pro-IL-1β expression,but the mechanism by which they activate caspase-1 diverges at the level of the pannexin-1/ATP/P2X7axis.
Ahmetaj-Shala B, Tesfai A, Constantinou C, et al., 2017, Pharmacological assessment of ibuprofen arginate on platelet aggregation and colon cancer cell killing, Biochemical and Biophysical Research Communications, Vol: 484, Pages: 762-766, ISSN: 1090-2104
Nonsteroidal anti-inflammatory drugs (NSAIDs), including ibuprofen, are amongst the most commonly used medications and produce their anti-inflammatory and analgesic benefits by blocking cyclooxygenase (COX)-2. These drugs also have the potential to prevent and treat cancer and some members of the class including ibuprofen can produce anti-platelet effects. Despite their utility, all NSAIDs are associated with increased risk of cardiovascular side effects which our recent work suggests could be mediated by increased levels of the endogenous NO synthase (NOS) inhibitor asymmetric dimethylarginine (ADMA) leading to reduced endothelial NOS activity and associated endothelial cell dysfunction. ADMA is a cardiotoxic hormone and biomarker of cardiovascular risk whose effects can be prevented by l-arginine. The ibuprofen salt, ibuprofen arginate (Spididol®) was created to increase drug solubility but we have previously established that it not only effectively blocks COX-2 but also provides an arginine source able to reverse the effects of ADMA in vitro and in vivo. Here we have gone on to explore whether the formulation of ibuprofen with arginine influences the potency and efficacy of the parent molecule using a range of simple in vitro assays designed to test the effects of NSAIDs on (i) platelet aggregation and (iii) colon cancer cell killing. Our findings demonstrate that ibuprofen arginate retains these key functional effects of NSAIDs with similar or increased potency compared to ibuprofen sodium, further illustrating the potential of ibuprofen arginate as an efficacious drug with the possibility of improved cardiovascular safety.
Duluc L, Ahmetaj-Shala B, Mitchell J, et al., 2017, Tipifarnib prevents development of hypoxia-induced pulmonary hypertension, Cardiovascular Research, Vol: 113, Pages: 276-287, ISSN: 1755-3245
Aims.RhoB plays a key role in the pathogenesis of hypoxia-induced pulmonary hypertension. Farnesylated RhoB promotes growth responses in cancer cells and we investigated whether inhibition of protein farnesylation will have a protective effect. Methods and Results.The analysis of lung tissues from rodent models and pulmonary hypertensive patientsshowed increased levels of protein farnesylation. Oral farnesyltransferase inhibitor tipifarnib prevented development of hypoxia-induced pulmonary hypertension in mice. Tipifarnib reduced hypoxia-induced vascular cell proliferation, increased endothelium-dependent vasodilatation and reduced vasoconstriction of intrapulmonary arteries without affecting cell viability. Protective effects of tipifarnib were associated with inhibition of Ras and RhoB, actin depolymerisation and increased eNOS expression in vitroand in vivo. Farnesylated-only RhoB (F-RhoB) increased proliferative responses in cultured pulmonary vascular cells, mimicking the effects of hypoxia, while both geranylgeranylated-only RhoB (GG-RhoB) and tipifarnib had an inhibitory effect. Label-free proteomics linked F-RhoB with cell survival, activation of cell cycle and mitochondrial biogenesis. Hypoxia increased and tipifarnib reduced the levels of F-RhoB-regulated proteins in the lung, reinforcing the importance of RhoB as a signalling mediator.Unlike simvastatin, tipifarnib did not increase the expression levels of Rho proteins.Conclusions.Our study demonstrates the importance of protein farnesylation in pulmonary vascular remodeling and provides a rationale for selective targeting of this pathway in pulmonary hypertension.
Mitchell JA, Knowles R, Kirkby NS, et al., 2016, Kidney Transplantation in a Patient Lacking Cytosolic Phospholipase A<sub>2</sub> Leads to Urinary Prostacyclin and Thromboxane A<sub>2</sub> Metabolites Within Normal Ranges, Scientific Sessions of the American-Heart-Association / Resuscitation Science Symposium, Publisher: LIPPINCOTT WILLIAMS & WILKINS, ISSN: 0009-7322
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Rauzi F, Kirkby NS, Edin ML, et al., 2016, Aspirin inhibits the production of proangiogenic 15(S)-HETE by platelet cyclooxygenase-1, Faseb Journal, Vol: 30, Pages: 4256-4266, ISSN: 1530-6860
Regular consumption of low-dose aspirin reduces the occurrence of colorectal, esophageal, stomach, and gastrointestinal cancers. The underlying mechanism is unknown but may be linked to inhibition of angiogenesis. Because the effective doses of aspirin are consistent with the inhibition of cyclooxygenase-1 in platelets, we used liquid chromatography with tandem mass spectrometry analyses and immunoassays of human platelet releasates coupled with angiogenesis assays to search for the mediator(s) of these effects. Blood or platelet-rich plasma from healthy volunteers stimulated with platelet activators produced a broad range of eicosanoids. Notably, preincubation of platelets with aspirin, but not with a P2Y12 receptor antagonist, caused a marked reduction in the production of 11-hydroxyeicosatetraenoic acid (HETE) and 15(S)-HETE, in addition to prostanoids such as thromboxane A2 Releasates from activated platelets caused cell migration and tube formation in cultured human endothelial cells and stimulated the sprouting of rat aortic rings in culture. These proangiogenic effects were absent when platelets were treated with aspirin but returned by coincubation with exogenous 15(S)-HETE. These results reveal 15(S)-HETE as a major platelet cyclooxygenase-1 product with strong proangiogenic effects. Thus, 15(S)-HETE represents a potential target for the development of novel antiangiogenic therapeutics, and blockade of its production may provide a mechanism for the anticancer effects of aspirin.-Rauzi, F., Kirkby, N. S., Edin, M. L., Whiteford, J. Zeldin, D. C., Mitchell, J. A., Warner, T. D. Aspirin inhibits the production of proangiogenic 15(S)-HETE by platelet cyclooxygenase-1.
Grimaldi C, Finco D, Fort MM, et al., 2016, Cytokine release: A workshop proceedings on the state-of-the-science, current challenges and future directions, Cytokine, Vol: 85, Pages: 101-108, ISSN: 1096-0023
In October 2013, the International Life Sciences Institute - Health and Environmental Sciences Institute Immunotoxicology Technical Committee (ILSI-HESI ITC) held a one-day workshop entitled, “Workshop on Cytokine Release: State-of-the-Science, Current Challenges and Future Directions”. The workshop brought together scientists from pharmaceutical, academic, health authority, and contract research organizations to discuss novel approaches and current challenges for the use of in vitro cytokine release assays (CRAs) for the identification of cytokine release syndrome (CRS) potential of novel monoclonal antibody (mAb) therapeutics. Topics presented encompassed a regulatory perspective on cytokine release and assessment, case studies regarding the translatability of preclinical cytokine data to the clinic, and the latest state of the science of CRAs, including comparisons between mAb therapeutics within one platform and across several assay platforms, a novel physiological assay platform, and assay optimization approaches such as determination of FcR expression profiles and use of statistical tests. The data and approaches presented confirmed that multiple CRA platforms are in use for identification of CRS potential and that the choice of a particular CRA platform is highly dependent on the availability of resources for individual laboratories (e.g. positive and negative controls, number of human blood donors), the assay through-put required, and the mechanism-of-action of the therapeutic candidate to be tested. Workshop participants agreed that more data on the predictive performance of CRA platforms is needed, and current efforts to compare in vitro assay results with clinical cytokine assessments were discussed. In summary, many laboratories continue to focus research efforts on the improvement of the translatability of current CRA platforms as well explore novel approaches which may lead to more accurate, and potentially patient-specific, CRS prediction
Mohamed NA, Ahmetaj-Shala B, Duluc L, et al., 2016, A New NO-Releasing Nanoformulation for the Treatment of Pulmonary Arterial Hypertension., Journal of Cardiovascular Translational Research, Vol: 9, Pages: 162-164, ISSN: 1937-5395
Pulmonary arterial hypertension (PAH) is a chronic and progressive disease which continues to carry an unacceptably high mortality and morbidity. The nitric oxide (NO) pathway has been implicated in the pathophysiology and progression of the disease. Its extremely short half-life and systemic effects have hampered the clinical use of NO in PAH. In an attempt to circumvent these major limitations, we have developed a new NO-nanomedicine formulation. The formulation was based on hydrogel-like polymeric composite NO-releasing nanoparticles (NO-RP). The kinetics of NO release from the NO-RP showed a peak at about 120 min followed by a sustained release for over 8 h. The NO-RP did not affect the viability or inflammation responses of endothelial cells. The NO-RP produced concentration-dependent relaxations of pulmonary arteries in mice with PAH induced by hypoxia. In conclusion, NO-RP drugs could considerably enhance the therapeutic potential of NO therapy for PAH.
Paul-Clark M, Elsheikh W, Kirkby N, et al., 2016, Profound Chemopreventative Effects of a Hydrogen Sulfide-Releasing NSAID in the APC(Min/+) Mouse Model of Intestinal Tumorigenesis, PLOS One, Vol: 11, ISSN: 1932-6203
Nonsteroidal anti-inflammatory drugs have been shown to reduce the incidence of gastrointestinalcancers, but the propensity of these drugs to cause ulcers and bleeding limits theiruse. H2S has been shown to be a powerful cytoprotective and anti-inflammatory substancein the digestive system. This study explored the possibility that a H2S-releasing nonsteroidalanti-inflammatory drug (ATB-346) would be effective in a murine model of hereditary intestinalcancer (APCMin+ mouse) and investigated potential mechanisms of action via transcriptomicsanalysis. Daily treatment with ATB-346 was significantly more effective at preventingintestinal polyp formation than naproxen. Significant beneficial effects were seen with atreatment period of only 3–7 days, and reversal of existing polyps was observed in thecolon. ATB-346, but not naproxen, significantly decreased expression of intestinal cancerassociatedsignaling molecules (cMyc, β-catenin). Transcriptomic analysis identified 20genes that were up-regulated in APCMin+ mice, 18 of which were reduced to wild-type levelsby one week of treatment with ATB-346. ATB-346 is a novel, gastrointestinal-sparing antiinflammatorydrug that potently and rapidly prevents and reverses the development of precancerouslesions in a mouse model of hereditary intestinal tumorigenesis. These effectsmay be related to the combined effects of suppression of cyclooxygenase and release ofH2S, and correction of most of the APCMin+-associated alterations in the transcriptome.ATB-346 may represent a promising agent for chemoprevention of tumorigenesis in the GItract and elsewhere.
Raouf J, Kirkby NS, Ahmetaj-Shala B, et al., 2016, mPGES-1 DELETION INCREASES PROSTACYCLIN AND EVADES THE ELEVATED SYSTEMIC ADMA ASSOCIATED WITH COX-2 INHIBITORS: RELEVANCE TO CARDIOVASCULAR SAFETY OF mPGES-1 INHIBITORS, 36th European Workshop for Rheumatology Research (EWRR), Publisher: BMJ PUBLISHING GROUP, Pages: A11-+, ISSN: 0003-4967
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Kirkby NS, Chan MV, Zaiss AK, et al., 2016, Systematic study of constitutive cyclo-oxygenase-2 expression: role of NFκB and NFAT transcriptional pathways, Proceedings of the National Academy of Sciences of the United States of America, Vol: 113, Pages: 434-439, ISSN: 1091-6490
Cyclooxygenase-2 (COX-2) is an inducible enzyme that drives inflammation and is the therapeutic target for widely used nonsteroidal antiinflammatory drugs (NSAIDs). However, COX-2 is also constitutively expressed, in the absence of overt inflammation, with a specific tissue distribution that includes the kidney, gastrointestinal tract, brain, and thymus. Constitutive COX-2 expression is therapeutically important because NSAIDs cause cardiovascular and renal side effects in otherwise healthy individuals. These side effects are now of major concern globally. However, the pathways driving constitutive COX-2 expression remain poorly understood. Here we show that in the kidney and other sites, constitutive COX-2 expression is a sterile response, independent of commensal microorganisms and not associated with activity of the inflammatory transcription factor NF-κB. Instead, COX-2 expression in the kidney but not other regions colocalized with nuclear factor of activated T cells (NFAT) transcription factor activity and was sensitive to inhibition of calcineurin-dependent NFAT activation. However, calcineurin/NFAT regulation did not contribute to constitutive expression elsewhere or to inflammatory COX-2 induction at any site. These data address the mechanisms driving constitutive COX-2 and suggest that by targeting transcription it may be possible to develop antiinflammatory therapies that spare the constitutive expression necessary for normal homeostatic functions, including those important to the cardiovascular-renal system.
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