Combination of cyclic nucleotide modulators with P2Y12 receptor antagonists as anti-platelet therapy

"This is the peer reviewed version of the following article: Armstrong, PC, Ferreira, PM, Chan, MV, et al. Combination of cyclic nucleotide modulators with P2Y12 receptor antagonists as anti‐platelet therapy. J Thromb Haemost. 2020 https://doi.org/10.1111/jth.14826 which has been published in final form at   https://doi.org/10.1111/jth.14826BACKGROUND: Endothelium-derived prostacyclin and nitric oxide elevate platelet cyclic nucleotide levels and maintain quiescence. We previously demonstrated that a synergistic relationship exists between cyclic nucleotides and P2Y12 receptor inhibition. A number of clinically approved drug classes can modulate cyclic nucleotide tone in platelets including activators of NO-sensitive guanylyl cyclase (GC) and phosphodiesterase (PDE) inhibitors. However, the doses required to inhibit platelets produce numerous side effects including headache. OBJECTIVE: We investigated using GC-activators in combination with P2Y12 receptor antagonists as a way to selectively amplify the anti-thrombotic effect of both drugs. METHODS: In vitro light transmission aggregation and platelet adhesion under flow were performed on washed platelets and platelet rich plasma. Aggregation in whole blood and a ferric chloride-induced arterial thrombosis model were also performed. RESULTS: The GC-activator BAY-70 potentiated the action of the P2Y12 receptor inhibitor prasugrel active metabolite in aggregation and adhesion studies and was associated with raised intra-platelet cyclic nucleotide levels. Furthermore, mice administered sub-maximal doses of the GC activator cinaciguat together with the PDE inhibitor dipyridamole and prasugrel, showed significant inhibition of ex vivo platelet aggregation and significantly reduced in vivo arterial thrombosis in response to injury without alteration in basal carotid artery blood flow. CONCLUSIONS: Using in vitro, ex vivo, and in vivo functional studies, we show that low dose GC activators synergize with P2Y12 inhibition to produce powerful anti-platelet effects without altering blood flow. Therefore, modulation of intra-platelet cyclic nucleotide levels alongside P2Y12 inhibition can provide a strong, focused anti-thrombotic regimen while minimizing vasodilator side effects

3D N=6 Gauged Supergravity: Admissible Gauge Groups, Vacua and RG Flows

We study N=6 gauged supergravity in three dimensions with scalar manifolds $\frac{SU(4,k)}{S(U(4)\times U(k))}$ for $k=1,2,3,4$ in great details. We classify some admissible non-compact gauge groups which can be consistently gauged and preserve all supersymmetries. We give the explicit form of the embedding tensors for these gauge groups as well as study their scalar potentials on the full scalar manifold for each value of $k=1,2,3,4$ along with the corresponding vacua. Furthermore, the potentials for the compact gauge groups, $SO(p)\times SO(6-p)\times SU(k)\times U(1)$ for $p=3,4,5,6$, identified previously in the literature are partially studied on a submanifold of the full scalar manifold. This submanifold is invariant under a certain subgroup of the corresponding gauge group. We find a number of supersymmetric AdS vacua in the case of compact gauge groups. We then consider holographic RG flow solutions in the compact gauge groups $SO(6)\times SU(4)\times U(1)$ and $SO(4)\times SO(2)\times SU(4)\times U(1)$ for the k=4 case. The solutions involving one active scalar can be found analytically and describe operator flows driven by a relevant operator of dimension 3/2. For non-compact gauge groups, we find all types of vacua namely AdS, Minkowski and dS, but there is no possibility of RG flows in the AdS/CFT sense for all gauge groups considered here.Comment: 43 pages, no figures references added, typoes corrected and more information adde

Oral nitrate supplementation improves cardiovascular risk markers in COPD: ON-BC a randomised controlled trial

BACKGROUND: Short term studies suggest that dietary nitrate supplementation may improve cardiovascular risk profile, lowering blood pressure (BP) and enhancing endothelial function. It is not clear if these beneficial effects are sustained and whether they apply in people with COPD, who have a worse cardiovascular profile than those without COPD. Nitrate-rich beetroot juice BRJ (NR-BRJ) is a convenient dietary source of nitrate. METHODS: The ON-BC trial was a randomized, double-blind, placebo-controlled parallel group study in stable COPD patients with home systolic BP (SBP) measurement ≥130 mmHg. Participants were randomly allocated (1:1) using computer-generated, block randomization to either 70 mL of NR-BRJ (400 mg NO3 -) (n=40) or an otherwise identical nitrate-depleted placebo juice Pl-BRJ (0 mg NO3 -) (n=41), once daily for 12 weeks. The primary endpoint was between group change in home SBP measurement. Secondary outcomes included change in 6-minute walking distance (6MWD) and measures of endothelial function (reactive hyperaemia index (RHI) and augmentation index (AIx75)) using an EndoPAT device. Plasma nitrate and platelet function were also measured. RESULTS: Compared to placebo, active treatment lowered SBP (Hodges-Lemman treatment effect MD[95% CI]; -4.5[-3.0 to -5.9] improved 6MWD (+30.0 m [15.7 to 44.2], p<0.001), RHI +0.34 (0.03 to 0.63) p=0.03, and AIx75 -7.61% [-14.3 to -0.95], p=0.026. CONCLUSIONS: In people with COPD, prolonged dietary nitrate supplementation in the form of beetroot juice produces a sustained reduction in BP, associated with an improvement in endothelial function and exercise capacity

Traditional use of medicinal plants by the Jaintia tribes in North Cachar Hills district of Assam, northeast India

The study of ethnobotany relating to any tribe is in itself a very intricate or convoluted process. This paper documents the traditional knowledge of medicinal plants that are in use by the indigenous Jaintia tribes residing in few isolated pockets of northeast India. The present study was done through structured questionnaires in consultations with the tribal practitioners and has resulted in the documentation of 39 medicinal plant species belonging to 27 families and 35 genera. For curing diverse form of ailments, the use of aboveground plant parts was higher (76.59%) than the underground plant parts (23.41%). Of the aboveground plant parts, leaf was used in the majority of cases (23 species), followed by fruit (4). Different underground plant forms such as root, tuber, rhizome, bulb and pseudo-bulb were also found to be in use by the Jaintia tribe as a medicine. Altogether, 30 types of ailments have been reported to be cured by using these 39 medicinal plant species. The study thus underlines the potentials of the ethnobotanical research and the need for the documentation of traditional ecological knowledge pertaining to the medicinal plant utilization for the greater benefit of mankind

Developmental regulation of tau splicing is disrupted in stem cell-derived neurons from frontotemporal dementia patients with the 10 + 16 splice-site mutation in MAPT

The alternative splicing of the tau gene, MAPT, generates six protein isoforms in the adult human central nervous system (CNS). Tau splicing is developmentally regulated and dysregulated in disease. Mutations in MAPT that alter tau splicing cause frontotemporal dementia (FTD) with tau pathology, providing evidence for a causal link between altered tau splicing and disease. The use of induced pluripotent stem cell (iPSC)-derived neurons has revolutionized the way we model neurological disease in vitro. However, as most tau mutations are located within or around the alternatively spliced exon 10, it is important that iPSC-neurons splice tau appropriately in order to be used as disease models. To address this issue, we analyzed the expression and splicing of tau in iPSC-derived cortical neurons from control patients and FTD patients with the 10 + 16 intronic mutation in MAPT. We show that control neurons only express the fetal tau isoform (0N3R), even at extended time points of 100 days in vitro. Neurons from FTD patients with the 10 + 16 mutation in MAPT express both 0N3R and 0N4R tau isoforms, demonstrating that this mutation overrides the developmental regulation of exon 10 inclusion in our in vitro model. Further, at extended time points of 365 days in vitro, we observe a switch in tau splicing to include six tau isoforms as seen in the adult human CNS. Our results demonstrate the importance of neuronal maturity for use in in vitro modeling and provide a system that will be important for understanding the functional consequences of altered tau splicing